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WO2012030314A1 - Compositions comprenant de la 5-(3-éthyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tétrahydropyrimidine, et procédés d'administration desdites compositions - Google Patents

Compositions comprenant de la 5-(3-éthyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tétrahydropyrimidine, et procédés d'administration desdites compositions Download PDF

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Publication number
WO2012030314A1
WO2012030314A1 PCT/US2010/002411 US2010002411W WO2012030314A1 WO 2012030314 A1 WO2012030314 A1 WO 2012030314A1 US 2010002411 W US2010002411 W US 2010002411W WO 2012030314 A1 WO2012030314 A1 WO 2012030314A1
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Prior art keywords
compound
pharmaceutical composition
dosage form
serum
animal
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PCT/US2010/002411
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English (en)
Inventor
Trevor M. Twose
Melinda L. Verdone
Richard C. Copp
James G. Farnham
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MITHRIDION Inc
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MITHRIDION Inc
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Priority to PCT/US2010/002411 priority Critical patent/WO2012030314A1/fr
Publication of WO2012030314A1 publication Critical patent/WO2012030314A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • compositions Comprising 5-(3-Ethyl-l,2,4-Oxadiazol-5-yl)-l, 4,5,6- Tetrahydropyrimidine, and Methods of Administering Same
  • compositions for enhancing cognitive function in animals such as humans the compositions comprising 5 -(3 -ethyl- 1,2,4- oxadiazol-5-yl)-l ,4,5,6-tetrahydropyrimidine or a pharmaceutically suitable form thereof.
  • This disclosure also relates in part to methods of treating animals such as humans by administering such compositions.
  • muscarinic receptor agonists for treating cognitive defects, however, may be hindered by the undesirable cholinergic side effects produced by their administration, including diaphoresis (excessive sweating), hypersalivation (excessive salivation), flushing (reddening of the skin, especially in the cheeks and neck), gastro-intestinal tract upsets, such as increased stomach acid, nausea, vomiting and diarrhea, breathing difficulties, tachycardia (slow heart beat), dizziness, syncope (fainting), headache, convulsions, and somnolence (sleepiness).
  • diaphoresis excessive sweating
  • hypersalivation excessive salivation
  • flushing reddening of the skin, especially in the cheeks and neck
  • gastro-intestinal tract upsets such as increased stomach acid, nausea, vomiting and diarrhea, breathing difficulties, tachycardia (slow heart beat), dizziness, syncope (fainting), headache, convulsions, and somnolence
  • Compound I the muscarinic agonist 5-(3-ethyl- l ,2,4-oxadiazol-5-yl)-l ,4,5,6-tetrahydropyrimidine
  • Compound I can cause severe cholinergic side effects in humans when administered in low dosages.
  • Compound I has a very short half-life, i.e., on the order of about 1.44 hours, when administered to humans who are able to metabolize the drug.
  • compositions comprising Compound I that can be administered to an animal, particularly a mammalian subject or patient such as a human, and which will limit the maximum circulating concentration of Compound I (e.g., in serum, plasma or cerebrospinal fluid) so as to avoid undesired levels of cholinergic side effects that can result from its administration.
  • compositions and/or dosage forms e.g., iontophoretic patches
  • Compound I may be administered in a number of pharmaceutically acceptable forms, such as the free base (“Compound II”) or in a salt form such as a hydrochloride salt (the hydrochloride salt is referred to herein as "Compound III").
  • Compound I will thus be used herein to designate 5-(3-ethyl-l ,2,4-oxadiazol-5-yl)-l ,4,5,6-tetrahydropyrimidine, and all pharmaceutically acceptable forms thereof such as Compound II and Compound III, including active forms of the drug (such as the protonated form of Compound I) existing in an animal, e.g., in the stomach or bloodstream of a human patient.
  • Embodiments of this disclosure thus provide cognition enhancing pharmaceutical compositions for administration to an animal and especially to a human. Included within such embodiments are compositions comprising an amount of Compound I sufficient to achieve a cognition enhancing effect in said animal, wherein the composition provides in the animal a serum or plasma Cmax of Compound I of about 25 ng/ml or less, and wherein the serum or plasma concentration of Compound I in the animal decreases by less than the elimination constant of in the two hours following Tmax.
  • Ti ⁇ for Compound I is about 1.44 hours for persons who are able to metabolize the drug and thus for such persons the serum or plasma concentration of Compound I decreases by less than 48.125% in two hours following administration.
  • compositions of Compound I are expressed in terms of weight of the free base (Compound II)/ml.). Such compositions are useful for treating neurological disorders such as Alzheimer's disease. Yet other embodiments of this disclosure provide cognition enhancing pharmaceutical compositions wherein the Tmax is greater than 2.0 hours. Embodiments of such compositions include compositions where Tmax is greater than 2.5, 3.0, 4.0, 5.0, and 6.0 hours.
  • the pharmaceutical compositions provided herein will cause substantially no noticeable cholinergic side effects, or at most only mild or moderate cholinergic side effects, in the animal or in a majority (i.e., >50%) of animals of the same species.
  • Embodiments described herein include combination pharmaceutical compositions comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein the combination pharmaceutical composition provides in the animal a serum or plasma Cmax of Compound I of about 25 ng/ml or less, and wherein for animals that are able to metabolize Compound I, the serum or plasma concentration of Compound I in the animal decreases by less than 0.693/Ti /2 or 48.125% in the two hours following Tmax.
  • the first composition provides a sustained release of Compound I and the second pharmaceutical composition comprising a substantially immediate release formulation of Compound I.
  • the combination composition thus provides the patient with the benefit of a relatively quick concentration of Compound I, as well as the benefit of a sustained delivery of Compound I at or below 25 ng/ml.
  • compositions described herein provide for pharmaceutical dosage forms comprising Compound I for administration to an animal, which dosage forms cause substantially no noticeable cholinergic side effects, or at most only mild or moderate cholinergic side effects in the animal, or in a majority of the species of said animal.
  • dosage forms include patches that comprise an amount of Compound I sufficient to achieve a cognition enhancing effect, wherein the patches provide in the animal a serum or plasma Cmax of Compound I of about 25 ng/ml or less, and wherein the serum or plasma concentration of Compound I in animals that are able to metabolize Compound I decreases by less than or 48.125% in the two hours following Tmax.
  • Embodiments include iontophoretic patches.
  • Yet other embodiments provide multiparticulate dosage forms of compositions of Compound I that can be provided in capsule form or added to food or drink for administration. Yet other embodiments provide dosage forms that are of a size that provides extended retention of the dosage form within the stomach or are designed to swell in the stomach so as to provide extended retention of the dosage form within the stomach where the Compound I is released over time to provide a serum or plasma Cmax of Compound I of about 25 ng/ml or less, and a serum or plasma concentration of Compound I that decreases in animals that are able to metabolize Compound I by less than 0.693/Ti ⁇ or 48.125% in the two hours following Tmax.
  • Yet other embodiments provide dosage forms that are designed to provide such sustained release of the Compound I both in the stomach and following passage through the stomach, i.e., in the small intestine and/or colon. Yet other embodiments provide dosage forms that are designed to provide such sustained release of the Compound I primarily following passage through the stomach, i.e., in the small intestine and/or colon.
  • Yet other embodiments described herein provide methods of enhancing the cognition in an animal, methods of treating a cognitive disorder in an animal, methods for maintaining cognition in an animal, and methods for slowing, preventing and or reversing the decrease of cognition in an animal, which methods comprise administering to the animal the compositions and dosage forms of Compound I described herein.
  • Figure 1 shows the Cmax and diaphoresis results for two cohorts of patients described in Example 1 who were given 1 mg and 5 mg of immediate release formulations of Compound III.
  • Figure 2 is a plan view of a representative iontophoretic patch in accordance with this disclosure.
  • Figure 3 is a chart illustrating the serum pharmacokinetic profile of humans who received controlled release formulations of Compound III (as described in Example 5) and humans who received immediate release formulations of MCD-386 (as described in Example 1).
  • Figure 4 is a chart illustrating the Cmax results for individual subjects after one, four and seven days of dosing with controlled release formulations of Compound III, with indications of those individuals who experienced sweating or salivation.
  • Embodiments of the present disclosure provides compositions and dosage forms for administration of Compound I to provide concentrations in the blood, organs or tissues that produce substantially no noticeable cholinergic side effects, or at most only mild or moderate unwanted cholinergic side effects in an animal that receive the composition, while providing therapeutic levels of Compound I sufficient to provide cognitive enhancement.
  • Advantageous embodiments described herein include sustained/controlled release delivery compositions and dosage forms for Compound I.
  • Embodiments of the sustained release pharmaceutical compositions for Compound I can offer significant advantages over immediate release formulations to both clinicians and their patients.
  • Embodiments of the sustained release dosage forms generally control the rate of Compound I release so as to avoid the development of excessive concentrations of drug in the subject, thus avoiding undesirable sympathomimetic and parasympathomimetic side effects that can be associated with its administration.
  • embodiments of the sustained release formulations of Compound I maintain an effective concentration of the drug, thereby providing the recipient with a therapeutic effect over an extended duration of time.
  • Embodiments of the sustained release dosage forms of Compound I are thus advantageously administered to recipients in fewer doses than their immediate release counterparts and thus achieve improved therapeutic effect in the fewer doses. This can provide a significant benefit for patients whose cognition is sufficiently impaired such that compliance with self-administration schedules can present a real problem. Moreover, because Compound I has a short half-life in humans, conventional immediate release compositions may have to be administered to a patient multiple times within a 24 hour window in order to maintain adequate bioavailability of the drug to achieve therapeutic effect.
  • compositions can yield a series of sub-optimal serum or plasma concentration profiles characterized by rapid increases of Compound I, followed by fairly rapid decreases. Such rapid increases and decreases can provide a patient with a short window of appropriate blood concentration of the medicament for optimum therapy. Such profiles can be even worse if the patient or caregiver forgets to promptly administer a subsequent dosage.
  • Embodiments of a sustained release dosage form of Compound I may only have to be administered to a patient one to four times at most in a 24 hour period in order to achieve the target organ concentration of Compound I in a desired therapeutic range for a prolonged period of time.
  • the compositions and dosage forms described herein will provide sustained release such that the serum or plasma concentration of Compound I in an animal (e.g., human) that is able to metabolize Compound I decreases by less than or 48.125% in a time period in hours selected from the group consisting of at least 3, at least 4, at least 6, at least 8, at least 10, at least 12, at least 16 and at least 24.
  • Tmax as compared to the Tmax achieved using an immediate release formulation.
  • the Tmax is greater than 2.0 hours, greater than 2.5, greater than 3.0, greater than 3.5, greater than 4.0, greater than 5.0 and greater than 6.0 hours.
  • Yet other embodiments will provide both the delayed Tmax and the sustained release described above.
  • compositions and dosage forms described herein thus will provide sustained release such that, when compared to an equivalent amount of Compound I administered to an animal in an immediate release dosage form, the composition or dosage form provides a serum or plasma Cmax that is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or greater.
  • Such compositions and dosage forms when administered to animals capable of metabolizing Compound I, also provide a serum or plasma concentration that decreases in the 1.44 hours following Cmax by less than 50%, by less than 40%, by less than 35%, by less than 30%), by less than 25%), by less than 20%), by less than 15%, and by less than 10%.
  • such compositions and dosage forms also provide a serum or plasma concentration that decreases in the 4 hours following Cmax by less than 50%, by less than 40%, by less than 35%, by less than 30%, by less than 25% or by less than 20%
  • Embodiments of the sustained release formulations of Compound I that limit the Cmax also permit administration of therapeutic amounts of the drug while substantially avoiding undesirable cholinergic side effects observed with administration of even low dosages of Compound I in a form that provides substantially immediate release.
  • undesirable cholinergic side effects can include diaphoresis (excessive sweating), hypersalivation (excessive salivation), flushing (reddening of the skin, especially in the cheeks and neck), gastro-intestinal tract upsets, such as increased stomach acid, nausea, vomiting and diarrhea, breathing difficulties, tachycardia (slow heart beat), dizziness, syncope (fainting), headache, convulsions, and somnolence (sleepiness).
  • sustained release dosage forms of Compound I can reduce or eliminate the side effects that otherwise occur even at low dosages of Compound I.
  • sustained release dosage forms of Compound I will generally result in better patient compliance and clinical outcomes due to the lower frequency of dosing (patients are less likely to miss doses), lower quantity of dosage units to be consumed, and the reduced undesired side-effects. As also mentioned above, this is particularly important in patients with cognitive deficiencies such as Alzheimer's disease who may have trouble remembering to take their medication.
  • Embodiments of sustained or controlled release compositions and dosage forms for the delivery of Compound I may be divided broadly into categories based on their routes of administration, e.g., oral dosage forms (including inhalable forms), parenteral/implantable dosage forms, and transdermal (including transmucosal) dosage forms.
  • compositions or dosage form may be suitable for delivery by more than one route of administration (e.g. , some dosage forms that deliver drugs by osmotic means can be used orally or subcutaneously).
  • routes of administration e.g. , some dosage forms that deliver drugs by osmotic means can be used orally or subcutaneously.
  • a variety of treatises address the delivery of pharmaceuticals including sustained release formulations and methods of their use including: Sustained and Controlled Release Drug Delivery Systems, Robinson, J.R., Ed. 1978, Marcel Dekker Inc, NY and Modified Release Drug Delivery Technology, by Michael J. Rathbone, Jonathan Hadgraft (Editor), Michael S. Roberts (Editor), Majella E. Lane (Editor), Published by Taylor & Francis, Inc.
  • the pharmaceutical composition is a dosage form selected from the group consisting of a tablet, liquid for oral administration, oral spray, intranasal spray, inhalable formulation, pill, gel, solid, capsule, multiparticulate, transdermal patch, implantable dosage, and injectable solution including intravenous drip (including in lyophilized and re-constituted form). Included within such embodiments are dosage forms that swell or unfold to a size such that the dosage form is retained in the stomach or the upper portion of the small intestine for at period of least 1 hour, at least 2 hours, at least three hours, at least 4 hours, at least 5 hours, at least 6 hours or for a period of longer than 6 hours.
  • sustained release and “controlled release” are used interchangeably in this disclosure and are defined for purposes of this disclosure as the release of Compound I from the dosage form at such a rate that blood (e.g., plasma or serum) concentrations are maintained within the desired therapeutic range longer than would be observed for the same dose of drug given by the same route of administration in a formulation that provides substantially immediate release. It will be apparent that different time periods will be relevant for different routes and means of administration. In some embodiments the period over which extended release is observed is about one or two hours. In other embodiments, the period over which the extended release is observed is for about three, four, five, or six hours. In still other embodiments, the extended release is observed for about eight, ten, twelve, sixteen twenty or twenty four hours.
  • sustained or controlled release may be extended from hours to once daily, or longer on the order of days, or even weeks to months, depending upon the device employed and its ability to be replenished and/or replaced with a supply of the drug for administration.
  • the term "pulsed release” is defined as a series of releases of a drug (e.g., Compound I) from a dosage form that acts to provide a sustained or controlled release.
  • a drug e.g., Compound I
  • Embodiments of the compositions and dosage forms described herein can provide pulsed release.
  • immediate release is defined as a release of compound from a dosage form in a relatively brief period of time.
  • the purpose of the excipients is to bind together the drug in a stable, mechanically robust dosage form, such as a tablet, that rapidly disintegrates on ingestion, providing little or no restraint on the release of the drug.
  • the dosage form will not generally contain excipients intended to slow down the release of the compound.
  • Highly soluble compounds in rapidly disintegrating immediate release dosage forms might release the compound in only seconds to minutes after making contact with the fluid in the stomach, although it may take longer (e.g., up to 60 minutes) with other compounds/formulations.
  • cogntive enhancement refers to an enhancement of one or more of an individuals' characteristics selected from the group consisting of: improved memory of places; improved memory " of people; improved memory of information; improved memory of facts; improved memory of how to operate and use tools; improved ability to analyze information; improved ability to deduce or reason; improved ability to synthesize conclusions; improved ability to think strategically; improved ability to make plans and decisions; improved ability to execute on plans and decisions; improved ability to perform activities of daily living; improved ability to be employed; enhanced activity of neuronal mechanisms responsible for effective memory and cognition (including muscarinic functions); reduced pathogenetic mechanisms leading to loss of memory and cognitive function; reduced loss of neurons or neuronal activity that lead to loss of cognitive and memory function; improved scores on neuropsychological tests such as ADAS-Cog or MMSE and others, improved scores on clinical assessments of the activities of daily living such as ADCS-ADL; increased ⁇ x- secretase activity as compared to similarly situated animals (e.g., humans with Alzheimer'sis, etc.
  • Oral dosage forms suitable for sustained delivery of Compound I include without limitation, forms such as tablets, multi-particulates, sprays, inhalable dosages, beads, granules, aggregates, powders, gels, solids, semi-solids, foodstuffs, liquids, and capsules (including those containing any of the aforementioned forms).
  • forms such as tablets, multi-particulates, sprays, inhalable dosages, beads, granules, aggregates, powders, gels, solids, semi-solids, foodstuffs, liquids, and capsules (including those containing any of the aforementioned forms).
  • Other forms of orally administered compositions may be readily apparent to skilled artisans and are included within the scope of the term "oral dosage.”
  • Embodiments of the oral dosages described herein can provide an increase in Ti/ 2 (1.44 hours) for persons able to metabolize the drug, wherein the increase is selected from the group consisting of at least 20%; at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, at least 500% and at least 600%.
  • the oral dosage form will be in the form of a tablet that provides a sustained release of Compound I.
  • Compound I may be combined with a variety of agents that will form a composition from which the drug is released with sustained release kinetics.
  • agents including, by way of non-limiting example, hydrophilic polymers (including polymers that form hydrogels upon hydration), and hydrophobic polymers.
  • compositions may be employed for the sustained release delivery of Compound I from tablets, including for example tablets having a monolithic core composed of a single pharmaceutical composition.
  • examples of such compositions include but are not limited to, those found in U.S. Pat. Nos. 5,292,534 and 5,415,871 , which teach sustained release formulations employing xanthum gum, U.S. Pat. No. 4,795,327, which discloses a method for preparing a composition comprising a medicament and a mixture of one or more nonionic cellulose ethers (methyl cellulose or hydroxypropylmethyl-cellulose) and an anionic surfactant, U.S. Pat. No.
  • the oral dosage form will be in the form of a tablet for oral administration having a first layer and a second layer; where the first layer comprises a first composition comprising Compound I and a second layer comprises a second composition comprising Compound I.
  • the first and second compositions may release Compound I at different rates when administered to an animal.
  • the first layer is a sustained release layer and the second layer is an immediate release layer.
  • Such embodiments advantageously provide a relatively rapidly-achieved concentration of Compound I (which may or may not be the Tmax for the combination composition), followed by a prolonged delivery of Compound I.
  • both layers are sustained release layers which release Compound I at different rates.
  • tablets comprise a first layer and a second layer
  • the two layers may be compressed against one another so that a portion of each layer is exposed on at least one face of the tablet (e.g. , as either the top or bottom of the tablet).
  • the tablet may comprise the first layer within a coating of the second layer.
  • the second layer may be formulated to be the immediate release layer so that the sustained release layer (or core) is coated by the immediate release layer which coats the sustained release layer.
  • oral dosage form is a tablet comprising a first, second and third layers; where the each layer comprises a different Compound I pharmaceutical composition that releases Compound I at a different rate when administered to an animal.
  • the three layers may be compressed against one another so that a portion of each layer is exposed on at least one face of the tablet.
  • the layers of the tablet may be arrange as approximately concentric layers, so that the first layer is within the second layer and the second layer is within the third layer.
  • the bi-layer and tri-layered tablets may be manufactured according to any method known to those of skill in the art.
  • Formulations having multiple layers that may be adapted for the sustained release delivery of Compound I are described for example in U.S. Pat. Nos. 6,372,252, 6,039,974, 5,462,747, 5,407,687, 5,200, 193, 4,844,907, 3,184,386, and U.S. Pat. Nos. 6,899,896 and 5,543, 155, which describe coated bi-layer controlled release tablets.
  • Other multiple-layer tablet formulations may be readily apparent to skilled artisans and are included within the scope of this disclosure of multi-layer tablet formulations.
  • the oral dosage form will be in the form of a tablet having one or more coatings that control the release of the pharmaceutical composition contained therein.
  • the tablet may take a variety of forms and have a variety of characteristics.
  • coated tablets may have a monolithic core comprised of a single pharmaceutical composition of Compound I or the coated tablets may comprise a core of layered pharmaceutical compositions comprising Compound I.
  • the tablets comprise at least one coating applied over an amount of Compound I or an amount of a compositions comprising Compound I. Multiple layers and multiple coatings obviously may be employed.
  • sustained release tablets or matrices may be coated externally to control the rate at which Compound I is released, it is not required that a controlled release coating form the external coating of the tablet.
  • the controlled release layer which overlies a coated amount of an Compound I-containing composition may be coated with an immediate release layer or another controlled release layer.
  • Such compositions include pigmented coatings and the like.
  • the outermost layer is an immediate release layer, it may be coated with a layer that does not significantly interfere with the immediate release of Compound I. Compound I thus may be administered in any suitable sustained release coated tablet form.
  • coated pharmaceutical compositions in the form of tablets that can be adapted for the sustained release delivery of Compound I include, but are not limited to, those described in the following patents:
  • U.S. Pat. No. 5,543,155 provides a diffusion-osmotic controlled drug-release pharmaceutical composition comprising a monolithic or bi-layer core and a polymeric film-coat.
  • the film coating is comprised of an ammonium methacrylate copolymer.
  • U.S. Pat. No. 5,849,330 provides a rapid release core of active coated with slow releasing coating containing active. As such composition increase the rate of delivery of active as the drug in the rapid release core becomes available, such compositions may raise the circulating concentration of drug late in the delivery profile.
  • U.S. Pat. No. 6,1 10,500 provides coated tablet providing a release of active agent with zero-order release kinetics.
  • U.S. Pat. No. 6,156,343 discloses a tablet comprising a mixture of a drug and a water- soluble polymer coated with a material consisting of a water-insoluble polymer and a water-soluble polymer and/or an enteric polymer.
  • U.S. Pat. No. 6,264,985 provides a tablet having an erodible core containing at least one active substance, and a substantially erosion-resistant shell consisting of a dry-coated layer, where the shell has at least one opening.
  • Pat. No. 6,365,185 describes a modified release drug delivery system, consisting of a solid core comprising an active agent together with a hydrogel, with the solid core being coated with a semi-permeable, self-destructing membrane which is optionally drilled to provide a release orifice, and optionally further coated with the same or different active agent material.
  • U.S. Pat. No. 6,649, 187 provides a coated composition comprising a combination of an amine drug with a polyalkylamine polymer, which can be a hydrogel, the combination of which is coated with a film-forming polymer having apertures in the coat.
  • U.S. Pat. No. 7,125,563 describes tablets comprising a core of active combined with an extended release agent (e.g.
  • a hydrophobic polymer such as ethyl cellulose
  • the core is coated with an extended release coating of a hydrophobic polymer (e.g. a polymer comprising ethyl cellulose).
  • a hydrophobic polymer e.g. a polymer comprising ethyl cellulose
  • coated pharmaceutical compositions in the form of tablets for sustained delivery may be readily apparent to skilled artisans and are included within the scope of this disclosure of such tablets.
  • the oral dosage form will be in the form of a capsule that provides a sustained release dosage of Compound I.
  • capsules may contain any number of Compound I compositions, including beads, granules, aggregates, powders, gels, solids, semi-solids, liquids, and particles, to name a few.
  • One such embodiment is a capsule comprising a plurality of particles that are prepared so that different groups of the particles release Compound I with different kinetics. The release of Compound I by different groups of particles with different kinetics can be achieved by changing the composition of the particle, applying different coatings to different groups of particles, or both.
  • Particles can be of any size and shape, provided they can be loaded into a capsule suitable for oral administration.
  • the particles can be spheroids, which are spherical granule having a diameter of approximately 0.5 to 2mm.
  • microparticles can include particles having a diameter of about 100 microns, although smaller or larger diameter particles are possible. Ranges of particulate diameters can include, for example, less than 50 microns, 50-100 microns, 50-150 microns, 100- 150 microns, 100-200 microns, 150-250 microns, and larger than 250 microns.
  • particulates can be included within the same capsule to effect different release rates for the Compound I compositions in the particulates
  • Such particulates can be prepared using fluidized bed coating processes and devices (e.g., Wurster coating) as employed in the Glatt Pharmaceutical Systems GCPG-3.
  • Possible commercial providers of microparticle compositions include Aptuit, Patheon Inc. and Eurand.
  • Microparticles may be incorporated into quick-dissolving films or other dosage forms designed to melt in the mouth and then be swallowed with the saliva or with a drink.
  • microparticles may be packaged in unit doses in two-part capsules or in sachets, which may be opened, to enable administration by sprinkling on food, such as apple sauce.
  • Such microparticles may be coated to mask the taste of the drug, since they directly contact the taste buds. In each case these dosage forms may improve compliance and be more convenient for patients, particularly the elderly or those who have difficulty with swallowing tablets.
  • embodiments of capsule dosage forms for pharmaceutical compositions of Compound I may comprise more than one group of particles where each group of particles is coated with a coating that provides a different rate of Compound I release from the particle.
  • Exemplary coatings for particles include those suitable for the preparation of coated tablets described above.
  • the capsule itself may be coated to control its degradation.
  • capsules may contain particles having a single composition that provide for sustained release of Compound I.
  • the pharmaceutical compositions described herein are sustained release pharmaceutical compositions in the form a capsule containing film coated spheroids having a matrix comprising Compound I in admixture with non-water- swellable microcrystalline cellulose, where the film coat comprises ethylcellulose optionally combined with hydroxypropyl methylcellulose.
  • the capsule of the composition may be comprised of any suitable polymeric material, such as gelatin.
  • Suitable microcrystalline cellulose can be, for example, Avicel-PH-101 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa, U.S.A.).
  • Suitable forms of ethylcellulose can have a viscosity in the range of 5 to 100 cps at 20° C. (U.S. National Formulary XIII) (content of ethoxy groups 44 to 51% by weight), and more particularly a viscosity of 50 cps at 20° C. (content of ethoxy groups 48 to 49% by weight).
  • One suitable form of hydroxypropyl methylcellulose is that having a viscosity in the range 3 to 100 cps at 20 C. (U.S. National Formulary XIII), and more particularly a viscosity of 6 cps at 20° C.
  • the film coat may comprise, for example, 80 to 100% by weight of ethylcellulose and 0 to 35% or more by weight of hydroxypropyl methylcellulose, with 25% by weight of hydroxypropyl methylcellulose providing acceptable results, and combinations of 90% by weight of ethylcellulose and 10% by weight of hydroxypropyl methylcellulose also being acceptible.
  • the film coat may optionally contain up to 20% by weight of a plasticizer, for example a vegetable oil, for example castor oil, or glycerol, or a glyceryl ester of a fatty acid, for example glyceryl triacetate or glyceryl monoricinoleate.
  • the film coat may comprise 5 to 15% by weight of the coated spheroids, and preferably 9 to 10% by weight thereof. The thickness of the coating may be adjusted as desired.
  • compositions in the form of a capsule that contains particles comprised of an active drug substance that may be adapted for the delivery of Compound I include, but are not limited to the compositions described in U.S. Pat. Nos. 5,670,172, 5,565,295, 4,867,985, 4,844,910, 4,309,406, and 4,138,475.
  • the pharmaceutical compositions described herein are sustained release pharmaceutical compositions in the form of capsules containing a composition comprising Compound I and a polymer that provides sustained release such as a hydrogel.
  • the capsule may contain a tablet and smaller particles or granules wherein both the tablet and the particles and granules each contain Compound I.
  • compositions in the form of a capsule that can be adapted to provide for the sustained release of Compound I include, but are not limited to, those described below.
  • U.S. Pat. No. 7,022,342 describes a pharmaceutical composition in the form of a capsule comprising a plurality of particles (pellets).
  • the particles have a core of active in combination with microcrystalline cellulose and ethylcellulose and are coated with a mixture comprising ethylcellulose, hydroxypropyl methylcellulose, acetyl tributyl citrate and talc.
  • U.S. Pat. Nos. 4,140,755, 4,167,558 and 4,424,235 disclose sustained release pharmaceutical formulations that freely float in the gastric fluid for an extended period of time during which substantially all of the active substance is released therefrom.
  • 4,126,672 discloses uncoated sustained release pharmaceutical capsules comprising a mixture of one or several active substances and at least one hydrophilic colloidal substance, which in contact with water forms gel, where hydroxypropyl- methylcellulose is preferably used as a hydrocolloid substance.
  • U.S. Pat. No. 5,198,229 discloses floating capsules having a part containing the active substance, a part containing air or some other gas, providing buoyancy, and two separate parts containing inert material which swells upon contact with fluid. The capsule floats in the stomach and is retained there as it dispenses drug.
  • Other pharmaceutical compositions in the form of a capsule that can be adapted to provide for the sustained release of Compound I may be readily apparent to skilled artisans and are included within the scope of this disclosure of such capsules.
  • Capsules are well known in the art and may be formed from any suitable material.
  • capsules may be prepared from polymer-based materials including, but not limited to, such as, for example, hydroxypropyl methylcellulose, gelatin and starch.
  • embodiments of this disclosure are directed to sustained release dosage forms comprising a water swellable composition.
  • the entire core of a pharmaceutical composition formed as a tablet will be comprise of a pharmaceutical composition comprising Compound I that swells upon hydration.
  • only a portion of a tablet's core will comprise a composition that swells upon hydration.
  • Such tablets hydrate and expand in the stomach providing a controlled release of the drug contained in the pharmaceutical composition.
  • Tablets comprising components that swell upon hydrating can advantageously be coated or covered with a membrane that acts to control the release of Compound I, e.g., being of either limited permeability to Compound I or being impermeable for some time to Compound I. Coatings may also be applied to regulate the rate at which the contents of the tablet are hydrated.
  • Exemplary formulations that may be adapted for the delivery of Compound I include, but are not limited to, those found in the following disclosures.
  • U.S. Pat. No. 6,733,784 describes an expanding tablet that can be adapted to deliver Compound I.
  • the tablet comprises a drug release controlling membrane material over a pharmaceutical composition that swells upon hydration.
  • U.S. Pat. No. 4,252,786 provides a rupturable relatively water-insoluble water-permeable film which is formed of a combination of hydrophobic and hydrophilic polymers over an insoluble swelling type delayed release matrix or core containing the medicament which core includes a blend of polyvinyl pyrrolidone and a carboxyvinyl hydrophilic polymer.
  • gastric-retained formulations include concertina- folded films containing drug that are contained in a gelatin capsule then released as the capsule dissolves in the stomach, and swell and unfold to a size that is retained in the stomach until it breaks down into smaller pieces.
  • the hydrated form may or may not be retained in the stomach or upper intestine for an extended period of time.
  • Another aspect of this disclosure is directed to a cognition-enhancing pharmaceutical composition for administration of Compound I to an animal in an oral dosage form that is retained in the upper gastrointestinal tract (e.g., the stomach or the stomach and upper part of the small intestine).
  • the upper gastrointestinal tract e.g., the stomach or the stomach and upper part of the small intestine.
  • compositions that are retained in the upper gastrointestinal tract are a pharmaceutical composition prepared in a dosage form that swells or unfolds to a size such that the dosage form is retained in the stomach for at least 1 hour, at least 2 hours, at least three hours, at least 4 hours, at least 5 hours, at least 6 hours or for a period of longer than 6 hours.
  • compositions that are retained in the upper gastrointestinal tract are in the form of a tablet comprising a pharmaceutical composition that expands or changes shape upon hydration so as to prevent its passage out of the stomach.
  • Such compositions which are adapted for retention in the stomach and are useful for the prolonged delivery of an active agent, typically comprise a polymer matrix that swells upon hydration when contacted with the fluids of the stomach resulting in a form that will not easily pass out of the stomach.
  • embodiments of these pharmaceutical compositions provide a sustained release of Compound I at levels that cause substantially no noticeable cholinergic side effects, or at most only mild or moderate cholinergic side effects in an animal or in a majority of animals of the same species.
  • composition for delivering Compound I is a controlled-release oral drug dosage form for releasing a drug into at least a portion of a region defined by the stomach and the upper gastrointestinal tract, where the dosage form is a solid monolithic matrix containing Compound I.
  • the matrix is non-circular in shape and has first and second orthogonal axes of unequal length, the matrix being one that swells in an unrestricted manner along both such axes upon exposure to water, the longer such axis having a maximum length of 3.0 cm when said matrix is unswollen, and the shorter such axis achieving a minimum length of 1.2 cm within one hour of immersion of said dosage form in water and wherein the matrix has a shape which when projected onto a plane, is either an oval or a parallelogram
  • the pharmaceutical compositions of the present disclosure comprises a multiple granular composition, each granular composition comprises at least one pharmaceutically acceptable, water swellable polymer or hydrogel.
  • the controlled release dosage form comprises a bi-granular composition comprising a first granulation and a second granulation wherein the first granulation comprises at least one polymer and a drug (Compound I) and the second granulation comprises at least one polymer which may be the same polymer as the polymer of the first granulation, or a different polymer than the polymer of the first granulation.
  • the second granulation contains a drug which may be the same drug or a different drug than the Compound I of the first granulation.
  • the first granulation has a faster dissolution rate than the dissolution rate of the second granulation, and the release rate of the drug from the dosage form can be modified by adjusting the ratio of two types of granulations.
  • Such formulations are described for example in U.S. Pat. No.: 7,476,403.
  • compositions that undergo a shape change upon hydration
  • a variety of other pharmaceutical compositions recognized in the art may be adapted for the sustained release delivery of Compound I with substantially no noticeable cholinergic side effects, or at most only mild or moderate cholinergic side effects.
  • Such compositions include: the prolonged release dosage form adapted for gastric retention employing a swellable/erodible polymer, such as poly(ethylene oxide) described in U.S. Pat. No.: 6,120,803, which may additionally include liposomes, nanoparticles or enteric-coated drug particles; the layered formulations comprising at least one layer that can swell described in U.S. Pat No.: 5,780,057; the tablets described in U.S.
  • sustained release compositions that may be employed to provide sustained release of Compound I.
  • Exemplary patents and applications that describe sustained release compositions include U.S. Pat. No. 7,438,927 Methods of treatment using a gastric retained gabapentin dosage, U.S. Pat. No. 7,413,751 Methods of treatment using a gastric retained losartan dosage, U.S. Pat. No. 7,405,238 Pharmacological inducement of the fed mode for enhanced drug administration to the stomach, U.S. Pat. No. 6,723,340 Optimal polymer mixtures for gastric retentive tablets, U.S. Pat. No.
  • polymers meeting this description include, without limitation: cellulose polymers and their derivatives including, but not limited to, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, and microcrystalline cellulose polysaccharides and their derivatives polyalkylene oxides polyethylene glycols chitosan poly(vinyl alcohol) xanthan gum maleic anhydride copolymers poly(vinyl pyrrolidone) starch and starch- based polymers maltodextrins poly (2-ethyl-2-oxazoline) poly(ethyleneimine) polyurethane hydrogels crosslinked polyacrylic acids and their derivatives.
  • cellulose polymers and their derivatives including, but not limited to, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, and microcrystalline cellulose polysaccharides and their derivatives polyalkylene oxides
  • copolymers of the polymers listed above including block copolymers and graft polymers.
  • specific examples of copolymers are PLURONIC ® and TECTONICS ® , which are polyethylene oxide-polypropylene oxide block copolymers available from BASF Corporation, Chemicals Div., Wyandotte, Mich., USA.
  • Further examples are hydrolyzed starch polyacrylonitrile graft copolymers, commonly known as "Super Slurper,” which are available from Illinois Corn Growers Association, Bloomington, 111., USA.
  • cellulose is used herein to denote a linear polymer of anhydroglucose.
  • cellulosic polymers are alkyl-substituted cellulosic polymers that ultimately dissolve in the GI tract in a predictably delayed manner.
  • Types of alkyl-substituted cellulose derivatives include those substituted with alkyl groups of 1 to 3 carbon atoms each.
  • one class of alkyl-substituted celluloses includes those whose viscosities are within the range of about 3 to about 1 10,000 centipoise as a 2% aqueous solution at 25°C.
  • alkyl-substituted celluloses include hydroxyethyl cellulose and hydroxypropyl methylcellulose.
  • hydroxyethyl celluloses include NATRASOL ® 250HX and 250HHX NF (National Formulary), available from Aqualon Company, Wilmington, Del., USA, the hydroxypropylmethylcelluloses comprising the "Methocel” range from Dow Chemical Company (http://www.dow.com/dowexcipients/products/index.htm), including the Methocel K range, and the Eudragit series of poly(meth)acrylates from Degussa.
  • polyalkylene oxides that can be used in the dosage forms disclosed herein include poly(ethylene oxide) and poly(propylene oxide).
  • Poly(ethylene oxide) is a linear polymer of unsubstituted ethylene oxide.
  • Poly(ethylene oxide) polymers having viscosity-average molecular weights of about 200,000 and higher can be used.
  • poly(ethylene oxide)s examples include: POLYOX ® NF, grade WSR Coagulant, molecular weight 5 million POLYOX ® grade WSR 301, molecular weight 4 million POLYOX ® grade WSR 303, molecular weight 7 million POLYOX ® grade WSR N-60K, molecular weight 2 million; each of which are products of Union Carbide Chemicals and Plastics Company Inc. of Danbury, Conn., USA.
  • coatings may be selected from those known in the art. Coatings that are permeable to Compound I, partly (semi-permeable) to Compound I, or impermeable to Compound I may be employed. Such coatings may be complete coatings or coatings provided with openings (drilled). Coatings may also be selected on properties other than their permeability to Compound I, including their solubility in various environments and their permeability to water.
  • Examples of coatings insoluble in an acidic medium, such as stomach acid include without limitation, polymers such as cellulose acetate phthalate, cellulose acetate mellitate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose ether, polyvinylacetate phthalate, polyester of styrene and maleic acid copolymer, polyester of vinylether and maleic acid copolymer, vinylacetate and crotonic acid copolymer, copolymers of methacrylic acid and ethylacrylate, copolymer of methacrylic acid and methacrylate, e.g. , EUDRAGRIT® LlOO, EUDRAGRIT® L100-55, EUDRAGRIT® L30D-55, EUDRAGRIT® SI 00, or their combinations.
  • polymers such as cellulose acetate phthalate, cellulose acetate mellitate, cellulose acetate succinate, hydroxyprop
  • Examples of coatings which are insoluble (insoluble polymers), irrespective of pH, include without limitation, coatings that may comprise ethylcellulose, copolymers of methacrylate/trimethyl-amonioethylmethacrylate (e.g. , EUDRAGRIT® RL PO, EUDRAGRIT® RL 100, EUDRAGRIT® RL30D, EUDRAGRIT® RS PO, EUDRAGRIT® RS 100, EUDRAGRIT® RS30D or their combinations), neutral polymer of methacrylate (e.g., EUDRAGRIT® NE 30 D, EUDRAGRIT® NE 40 D) or their combinations.
  • EUDRAGRIT® NE 30 D EUDRAGRIT® NE 40 D
  • Examples of coatings that have limited solubility include coatings formed from combinations of the above-listed insoluble polymers with soluble polymers such as, for example, combinations of ethylcellulose and hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose or polyvinylpyrrolidone, a combination of methacrylate/ trimethylammonio ethylmethacrylate copolymers (e.g., EUDRAGRIT® RL PO, EUDRAGRIT® RL 100, EUDRAGRIT® RL30D, EUDRAGRIT® RS PO, EUDRAGRIT® RS 100, EUDRAGRIT® RS30D or their combinations) and hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose or methylcellulose, a combination of neutral methacrylate polymer (e.g., EUDRAGRIT® NE 30 D, EUDRAGRIT® NE 40 D) and hydroxy
  • Coatings may optionally comprise other excipients conventionally used in coatings, including, but not limited to, fillers, e.g., talc, lactose, polysaccharides and others, plasticizers, e.g. , dibutyl sebacate, triethyl citrate, polyethylene glycol, adipic acid, coconut oil, oleic acid and the like, colorants, e.g. , titanium dioxide, lakes, pigments and the like, antioxidants and other excipients.
  • the release rates may be modified by including additional polymers ("modifiers"). These may also strengthen the tablet to reduce the rate of erosion. They may also prevent unwanted initial release of drug in a "burst" when the tablet first hydrates.
  • Formulation #2 below in Example 4 contains Ethocel as a modifier
  • formulation #3 in Example 4 contains partially pre- gelatinized starch as a modifier.
  • the starch may actively interact with the Methocel to improve the properties of the tablets.
  • Numerous modifier polymers are known to those skilled in the art and may replace a proportion of the filler.
  • various fillers and/or binders may be used.
  • formulation #1 in Example 4 below contains finely milled microcrystalline cellulose (MCC), which has excellent properties for dry compression.
  • MCC microcrystalline cellulose
  • Formulations #2 and #4 in Example 4 below also contain lactose, which is soluble, and leaches out of the tablet along with drug and may help water penetrate into the tablet, but may cause drug to be release more quickly than desired.
  • lactose which is soluble
  • insoluble fillers such as calcium phosphate dehydrate or calcium sulfate. Insoluble fillers will generally slow down release of drug.
  • the oral dosage forms described herein can find utility when administered to subjects who are either in the fed mode or the fasting mode.
  • the fed more is also referred to as post-prandial.
  • particulate matter is retained in the stomach longer, as a result of the different modes of contractions in the stomach.
  • the narrowing of the pyloric opening that occurs in the fed mode serves as a further means of promoting gastric retention by retaining a broader range of smaller dosage form sizes.
  • the fed mode is normally induced by food ingestion, but can also be induced pharmacologically by the administration of pharmacological agents that have an effect that is the same or similar to that of a meal.
  • These fed-mode inducing agents may be administered separately or they may be included in the dosage form as an ingredient dispersed in the dosage form or in an outer immediate release coating or as a separate dosage form. Examples of pharmacological fed-mode inducing agents are disclosed in U.S. Pat. No. 7,405,238, entitled "Pharmacological Inducement of the Fed Mode for Enhanced Drug Administration to the Stomach," mentioned above.
  • Compound I is metabolized in human patients and thus the transdermal or transmucosal route for delivery of drugs may provide an advantageous ability to provide Compound I to a human patient in a sustained release fashion. Indeed, as shown in Example II, it was found that in rats, approximately 1/3 of the oral dosage could be delivered via iontophoretic patch and achieve approximately the same blood level of Compound I.
  • a variety of dosage forms are suitable to provide transdermal deliver of Compound I in a sustained release fashion, including but not limited to lotions, creams, salves, transdermal patches and iontophoretic transdermal patches.
  • the dosage form is intended to deliver Compound I via a transmucosal route (e.g., nasal, oral, rectal vaginal etc.) the dosage form may be lotion, gel, cream, salve, suppository, pessary, or a mist for nasal administration.
  • transmucosal route e.g., nasal, oral, rectal vaginal etc.
  • the dosage form may be lotion, gel, cream, salve, suppository, pessary, or a mist for nasal administration.
  • transdermal or transmucosal systems for delivery of drugs that may be adaptable to the delivery of Compound I are described, for example, in U.S. Patent Nos.
  • Lotions, gels, salves, and creams suitable for the delivery of Compound I may be formulated from a variety of components. Examples of lotions and gels providing sustained release may be found in US Pat. Nos. 5,939,427; 5,670,547; and 5,721 ,275. U.S. Pat. No.: 7,404,965 describes cream, lotion, spray, ointment, gel, aerosol, tablet, suppository or patch device for transdermal or transmucosal administration of medicaments.
  • the lotion or gel is water based the composition providing sustained release of Compound I, it will typically comprise a gelling agent and water, the compositions may optionally contain polyols (such as glycerin or propylene glycol), chelating or sequestering agent such as EDTA, antioxidants, preservatives, surfactants and proteinaceous materials.
  • polyols such as glycerin or propylene glycol
  • chelating or sequestering agent such as EDTA
  • antioxidants such as glycerin or propylene glycol
  • preservatives such as sodium metabisulfite
  • surfactants and proteinaceous materials.
  • Suitable water soluble gelling/viscosity enhancing agents include, without limitation, acidic carboxy polymers such as polyacrylate polymers.
  • the polyacrylate polymers are CARBOPOL ® polymers such as CARBOPOL ® 940 CARBOPOL ® 934 and CARBOPOL ® 941 (available from B.F. Goodrich Chemical Co., Cleveland, Ohio).
  • Gelling agents such as CARBOPOL ® 940 are typically employed in an amount of about 0.2 to 0.5 weight percent of the formulation or vehicle, although other percentages may be suitable.
  • Polyols may be incorporated into the compositions to provide a variety of desirable properties. Polyols can stabilize the formulation, and act as a humectant so as to avoid irritation of the skin, especially where repeated applications of the composition may be necessary.
  • Suitable antioxidants include BHT and related compounds.
  • Preservatives to retard the growth of microorganisms suitable for use in the compositions and dosage forms described herein include, for example, sorbic acid and imidazolidinyl urea, although numerous others are available.
  • Suitable surfactants can be selected from pharmaceutically acceptable non- ionic, anionic and cationic compounds.
  • Suitable surfactants include, without limitation, octoxynol-9 (polyethylene glycol mono[p-(l ,l ,3,3-tetramethylbutyl)phenyl]ether), lecithin; sorbitan monoesters, such as sorbitan monoleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate; polysorbates, such as those prepared from lauric, palmitic, stearic and oleic acids; polysorbate 20, mononylphenyl ethers of polyethylene glycols, such as the monoxynols; polyoxyethylene monoesters, such as polyoxeethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene monoleate; dioctyl sodium sulfosuccinate; sodium lauryl sulfate.
  • suitable proteins may include collagen, elastin and the like.
  • transdermal patch designs provide a suitable means for the sustained delivery of Compound I.
  • the first design is the reservoir type where the drug is contained within a reservoir having a basal surface that is permeable to the drug, and a matrix type, where the drug is dispersed in a polymer layer affixed to the skin. Both designs typically include a backing layer and an inner release liner layer that is removed prior to use.
  • Transdermal patches that may be adapted for the delivery of Compound I include but are not limited to those described in previous patents and patent applications.
  • Such transdermal patches include, without limitation: patches with reservoir layer comprising water-swellable matrixes described in U.S. Pat. No. 4,668,232; transdermal patches comprised of water-insoluble material that contains particles of medicament in a water-soluble/swellable polymer and an underlayer that controls the amount of water vapor passing from the skin to the matrix described in U.S. Pat. No. 5,230,898; transdermal patches comprising two-phase drug-containing matrix for sustained release of medicament described in U.S. Pat. No.
  • transdermal patches that may be adapted for the delivery of Compound I include: the three layer patches employing a pressure-sensitive adhesive which controls release of the active agent described in WO 9825592; and the acrylate polymer/ polysiloxane patches that act as solubility based drug delivery systems described in U.S. Patent No. 5,958,446.
  • Transdermal patches typically employ one or more skin-penetration enhancers to assist medicaments , in passing through the skin.
  • skin penetration enhancers have been described in the field. See e.g., U.S. Pat. Nos.: 7,425,340, 5,41 1 ,740; 5,500,222; 5,614,21 1 ; 5,736,577; 5,834,010; 6,555, 129; 5,747,065.
  • skin-penetration enhancers include, but are not limited to, polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol which may enhance drug solubility; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate which enhance drug diffusibility; urea and urea derivatives such as allantoin which affect the ability of keratin to retain moisture; polar solvents such as dimethyldecylphosphoxide, methyloctyl-sulfoxide, dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethyl- acetonide, dimethylsulfoxide, decylmethyl-sulfoxide, and dimethylformamide which affect keratin permeability; salicylic acid which softens the keratin; amino acids which are penetration assistant
  • agents include oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate
  • transdermal delivery formulations may be applied in conjunction with he use of an apparatus that generates hydrophilic micro-channels in skin of a subject using the patch or composition. See, e.g., U.S. Pat. Nos. : 7,415,306 and 6, 148,232. Where such an apparatus is employed, the transdermal patch and other formulations may avoid or limit the need to use skin penetration enhancing agents.
  • apparatuses that generate hydrophilic micro-channels in skin are compatible with the use of iontophoretic patches that are described below. See, e.g., U.S. Pat. No. 7,415,306.
  • Iontophoresis also referred to as electrotransport, in drug delivery is well known.
  • Iontophoresis is the process of delivering an ionized substance (such as a drug) through intact skin by the application of an electrical field to generate an electrical current.
  • the iontophoretic drug delivery device described herein comprises a power source for generation of an electrical current and two electrode compartments that when in contact with the skin or adhering to the skin of a subject will pass a generated electrical current through the skin. In the presence of the electrical current, drug passage through the skin is enhanced.
  • the rate of transdermal delivery can be controlled by selection of the patch design, including the selection of the contents of the electrode compartments, the surface area of the patch, and by the strength of the generated electrical current.
  • the rate of delivery of drug is proportional to the current and therefore the quantity of drug delivered will be determined by the current and duration of current, thereby enabling convenient control of drug delivery by adjustment of the current.
  • Controlled and/or continuous delivery at constant rates is thus a useful method of delivering the compounds and compositions described herein.
  • iontophoretic devices also can be desirable since the subject may have cognitive impairmaent and so there may be a real risk that the subject may forget to take other forms of medication discussed above such as pills, or may take too much or too little of his/her medication.
  • Ionophoretic delivery can ensure relatively constant plasma concentrations and, more importantly, proper control of pharmacologic and toxic effects.
  • the control of delivery through iontophoresis allows for the ability to modify the cholinergic side effects discussed herein, whether by controlled delivery of the muscarinic agonist and/or controlled co-delivery of a muscarinic antagonist that can reduce or eliminate the cholinergic side effects that otherwise would be experienced in the absence of the antagonist.
  • Iontophoretic devices are described in numerous U.S. patents, including for example, the following U.S. Patent Nos.
  • At least two electrodes are used in an iontophoretic device. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the subject.
  • One electrode called the active or donor electrode, is the electrode from which a drug, drug precursor or other substance is delivered into the body of the subject by iontophoresis and/or by bulk flow of drug solution induced by the current.
  • the active electrode is the anode and for a negative ionic form, the cathode.
  • the other electrode called the counter or return or indifferent electrode, serves to close the electrical circuit through the subject's body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, for example, a battery.
  • Electrodes may be constructed of any of a large variety of electrically conductive materials, including both inert and sacrificial materials.
  • Inert conductive materials are those electrically conductive materials which, when employed in the iontophoretic devices, do not themselves undergo or participate in electrochemical reactions. Thus, ' an inert material distributes without being eroded or depleted due to the distribution of current, and conducts current through the generating hydronium or hydroxyl ions by, respectively, either reduction or oxidation of water. Inert conductive materials typically include, for example, stainless steel, platinum, gold, and carbon or graphite.
  • the electrode may comprise a sacrificial conductive material.
  • a material may be considered sacrificial if, when employed as an electrode in an iontophoretic device described herein, material is eroded or depleted due to its oxidation or reduction. Such erosion or depletion occurs when the materials and formulations used in the iontophoretic device enable a specific electrochemical reaction, such as when a silver electrode is used with a formulation containing chloride ions. In this situation, the current distributing member would not cause electrolysis of water, but would itself be oxidized or reduced.
  • a sacrificial material would include an oxidizable metal such as silver, zinc, copper, etc.
  • the ions electrochemically generated via a sacrificial material would include metal cations resulting from oxidation of the metal.
  • Metal/metal salt anodes may also be employed. In such cases, the metal would oxidize to metal ions, which would then be precipitated as an insoluble salt.
  • the current distributing member may be constructed from any electrically conductive material provided an appropriate electrolyte formulation is provided.
  • the cathodic current distributing member may be constructed from a metal/metal salt material.
  • a preferred cathodic material is a silver/silver halide material.
  • a metal halide salt is preferably employed as the electrolyte.
  • the device would electrochemically generate halide ions from the electrode as the metal is reduced. Also, accompanying silver ions in a formulation would be reduced to silver metal and would deposit (plate) onto the electrode.
  • the cathode material may be an intercalation material, an amalgam, or other material which can take electrolyte cations such as sodium out of solution, below the reduction potential of water.
  • other materials may be used which permit the plating out of a metal from the appropriate electrolyte solution.
  • metals such as silver, copper, zinc, and nickel, and other materials, such as carbon, may be employed when an appropriate metal salt such as silver nitrate or zinc sulfate is in solution in the electrolyte reservoir. While such materials may develop increased resistivity as a metal plates out during use, they are not eroded or depleted during use as cathodic current distributing members. They are therefore not strictly "sacrificial" in this context.
  • sacrificial encompasses such materials and is intended to include materials that undergo physical and/or chemical changes during iontophoresis.
  • the current distributing member may take any form known in the art, such as the form of a plate, foil layer, screen, wire, or dispersion of conductive particles embedded in a conductive matrix.
  • Iontophoresis device includes a drug or agent reservoir or source to be iontophoretically delivered or introduced into the subject. Such drug reservoir is electrically connected to the anode or the cathode of the iontophoretic device to provide a fixed or renewable source of one or more drugs. In the case of Compound I, a high proportion of which is positively charged at physiological pH, the drug reservoir will be connected to the anode.
  • iontophoretic patch designs can be employed to deliver the compositions described herein.
  • iontophoretic delivery devices have been developed in which the donor and counter electrode assemblies have a multi-laminate construction. In these devices, the donor and counter electrode assemblies are each formed by multiple layers of usually polymeric matrices.
  • U.S. Patent No. 4,731 ,049 discloses a donor electrode assembly having a hydrophilic polymer based electrolyte reservoir and drug reservoir layers, a skin-contacting hydrogel layer, and optionally one or more semipermeable membrane layers.
  • U.S. Patent No 7,031,768 discloses a planar disposable transdermal iontophoretic delivery system with a galvanic battery, serving as the sole source of power and control for the system, and in which the galvanic battery is provided with a lot-tested coulombic capacity rating to predict dosage.
  • the drug and electrolyte reservoir layers of the iontophoretic delivery device may be, for example, formed of hydrophilic polymers, as described, for example, in U.S. Patent Nos. 4,474,570, 4,383,529 and 4,764,164. Hydrophilic polymers may be desired since water is the preferred solvent for ionizing many drug salts, and hydrophilic polymer components of the drug reservoir in the donor electrode and the electrolyte reservoir in the counter electrode can be hydrated in situ while attached to the body by absorbing water from the skin through transepidermal water loss or sweat or from a mucosal membrane by absorbing saliva in the case of oral mucosal membranes. Once hydrated, the device begins to deliver ionized agent to the body. This enables the drug reservoir to be manufactured in a dry state, giving the device a longer shelf life.
  • Hydrogels have been used as the drug reservoir matrix and electrolyte reservoir matrix in iontophoretic delivery devices, in part due to their high equilibrium water content and their ability to quickly absorb water. In addition, hydrogels tend to have good
  • An electrolyte reservoir can be arranged in electrical communication with a current distributing member.
  • electrical communication requires that electrons from the current distributing member are exchanged with ions in the electrolyte reservoir upon the application of electrical current.
  • Such electrical communication is preferably not impeded to any excessive degree by any intervening material(s) used in the construction of the iontophoretic device.
  • the resistivity of the interface is preferably low.
  • the electrolyte reservoir comprises at least one electrolyte, i.e., an ionic or ionizable component which can act to conduct current toward or away from the current distributing member.
  • the electrolyte comprises one or more mobile ions, the selection of which is dependent upon the desired application.
  • electrolytes examples include aqueous solutions of salts.
  • One electrolyte is an aqueous solution of NaCl, having a concentration of less than 1 mole/liter ( ⁇ 1 M) or at about physiological concentration.
  • Other electrolytes include salts of physiological ions including, but not limited to, potassium, chloride, and phosphate. The salt and its concentration may be selected as desired for particular applications.
  • Other chemical species may be selected by the skilled artisan for inclusion in the electrolyte reservoir.
  • Such other reservoir species include, without limitation, chelation agents (e.g., citrate ions, EDTA) surfactants (e.g., non-ionic, cationic, or anionic), buffers, ionic excipients, osmolarity adjusters (e.g., polyethylene glycols, sugars), ionic antibiotics, penetration enhancers (e.g., alkanols), stabilizers, enzyme inhibitors, preservatives, thickening agents (e.g. , acrylic acids, cellulosic resins, clays), and the like.
  • chelation agents e.g., citrate ions, EDTA
  • surfactants e.g., non-ionic, cationic, or anionic
  • buffers e.g., ionic excipients
  • osmolarity adjusters e.g., polyethylene glycols, sugar
  • the iontophoretic patch may contain chemical substances to prevent the build up of hydrogen ions and hydroxyl ions produced by the electrolysis of water, which may interfere with drug delivery, cause breakdown of drugs, or cause skin irritation.
  • U.S. Patent No 4,973,303 discloses an iontophoretic electrode containing a non-mobile, insoluble ion-exchange resin to buffer pH.
  • the electrolyte may have a material which is itself relatively immobile in the absence of an electric field, but which acts to deliver mobile ions in the presence of an electric field. In the latter case, the electrolyte may more properly be termed an ion source. Examples of ion sources can include polyelectrolytes, ion exchange membranes and resins, non-ionic buffers which become ionic upon pH change, and other known ion sources.
  • the electrolyte reservoir may contain counter-ions that form a soluble salt with an electrochemically generated ion.
  • a suitable counter-ion might be acetate or nitrate.
  • Such counter-ions can be used when other means are provided for sequestering electrochemically generated ions.
  • the electrolyte reservoir can provide at least one ion of the same charge as the electrochemically generated ion, to permit current to be conducted, and at least one oppositely charged ion.
  • the flux profile of a composition described herein that is being delivered by iontophoresis can be controlled by adding to or having other ions present in the reservoir containing the drug. These ions which would compete with the drug ions for current (competing ions). To achieve various flux profiles for the drug being iontophoretically delivered, constant current can be applied but with varying concentrations of the competing ions.
  • Embodiments of the iontophoretic apparatus described herein can include a suitable backing film positioned on top of the electrolyte reservoir.
  • the backing film provides protection against contamination and damage to the current distributing member, if present, and the electrolyte reservoir of the apparatus.
  • Embodiments of the iontophoretic devices described herein can include a release liner which may be fixed to the underside of the ionized substance reservoir by an adhesive.
  • the release liner protects the surface of the ionized substance reservoir which contacts the epithelial surface from contamination and damage when the device is not in use.
  • the release liner may be peeled off to expose the epithelial contacting surface of the ionized substance reservoir for application of the device to a subject.
  • patches and iontophoretic devices are also advantages.
  • the active ingredient is passed through the skin instead of through the patient's digestive tract, and thus the active ingredient(s) avoid "first-pass metabolism” that can cause a loss or degradation of the active ingredient(s).
  • the agonist and antagonist may be in a mixture in one device or patch, may be provided separately within the same device or patch, or may be provided in two separate devices and/or patches that would both be applied to the patient.
  • Infusion pumps may be electro/mechanical infusion pumps that may be external (not implanted) or implantable. Infusion pumps may also be osmotic pumps that can be implanted rather than electro/mechanical pumps.
  • One advantage of employing an electro/mechanical or osmotic pump to infuse Compound I is that the compound may be administered in a more local fashion, that is achievable by oral delivery (e.g. , the drug may be delivered to cerebrospinal environment).
  • compositions containing Compound I that the infusion pump administers may be controlled by limiting the quantity (volume) of the pharmaceutical composition containing Compound I that the infusion pump administers, the concentration of Compound I present in the infused pharmaceutical composition, the rate of infusion, or any combination thereof.
  • the infusion pump is an electro/mechanical pumping systems it may contain a programmable pumping mechanism (and any necessary memory or computer implemented functions) that permit controlled delivery of Compound I pharmaceutical compositions.
  • programmable pumps permit both the duration and rate of pump action to be regulated and provide any desired delivery profile for Compound I.
  • Implantable pumps some of which are refillable with out being removed, are described for example in U.S. Patent Nos. 7,351,239, 7,347,854, 7,341,577, 7,044,932, 7,043,295, 4,013,074, and 4,692,147.
  • Implantable delivery devices that are controlled by an external control device such as the system described in U.S. Pat. No. 6,873,268 may also be employed.
  • External pumps are described for example in U.S. Patent Nos. 7,347,836 and 6,475,180.
  • Implantable osmotic delivery devices referred to as “osmotic pumps” or “osmotic infusion pumps” may also be employed for the delivery of Compound I.
  • osmotic pumps or “osmotic infusion pumps” may also be employed for the delivery of Compound I.
  • osmotic pumps or “osmotic infusion pumps” may also be employed for the delivery of Compound I.
  • such devices typically include a reservoir, an expandable osmotic material, a drug formulation which in this case comprises a Compound I containing composition, and at least one delivery orifice.
  • the expandable osmotic material and the drug formulation are formed of separate materials, the expandable osmotic material and the drug formulation may be separated by a member, such as a piston, which is movable within the reservoir.
  • At least a portion of the reservoir included in an osmotic pump is generally semipermeable, allowing water to be taken into the system while preventing or minimizing the undesired escape of materials forming the expandable osmotic material or the drug formulation from the reservoir.
  • the osmotic material draws water from the environment into the osmotic pump through the semipermeable portion of the reservoir which expands as it imbibes water and the pharmaceutical composition comprising Compound I is discharged through the delivery orifice of the osmotic pump.
  • Implantable osmotic delivery devices that may be adapted for the sustained release delivery of Compound I and include, but are not limited to, those described in: U.S. Pat. Nos.: 5,234,693, 5,279,608, 5,336,057, 5,728,396, 5,985,305, 5,997,527, 5,997,902, 6, 1 13,938, 6,132,420, 6,217,906, 6,261,584, 6,270,787, 6,287,295
  • the implantable delivery devices operate by diffusion and may also operate osmotically.
  • Such devices employ one or more semipermeable membranes surrounding or separating a composition comprising Compound I (that may have additional coatings or layers internal or external to one or more semipermeable membrane(s)) from the surrounding environment into which the Compound I is to be released.
  • Implantable diffusional delivery devices that may be adapted for the sustained release delivery of Compound I at levels that enhance cognitive function and substantially eliminate or limit the undesirable side effects include, but are not limited to, those described in U.S. Pat. Nos. 6,375,978 and 6,004582.
  • Implantable delivery devices may be implanted in a variety of locations, but are generally implanted subcutaneously. Such devices, particularly osmotic pumps and devices that operate by diffusion devices, may be adapted for use as rectal suppositories, vaginal pessaries for delivery of Compound I. (See e.g., U.S. Pat. No. 4,576,604.) Such devices may be implanted in other environments. For example U.S. Pat.
  • No.: 6,004,582 describes the use of a device in environments including "oral, ocular, nasal, vaginal, glands, gastrointestinal tract, rectum, cervical, intrauterine, arterial, venous, otic, sublingual, dermal, epidermal, subdermal, implant, buccal, bioadhesive, mucosal and other similar environments.”
  • U.S. Pat. No. 4,576,604 describes the use of osmotic delivery devices orally and also as vaginal pessaries and ano-rectal suppositories.
  • U.S. Pat. No. 6,740,333 describes controlled release suppositories.
  • Compound I is incorporated into implantable biodegradable or resorbable compositions and matrices adaptable for the delivery of the Compound I. Included in such compositions are the biodegradable polymer compositions described in U.S. Patent No. 6,455,526, the resorbable matrices described in U.S. Pat. No. 6,497,901 , the injectable biodegradable matrices described in U.S. Pat. No. 5,384,333, the poly(phosphoesters) compositions described in U.S. Pat. No. 5, 194,193, and the Calcium sulfate controlled release matrices described in U.S. Pat. No. 6,030,636.
  • acids for the formation of pharmaceutically acceptable acid addition salts are hydrochloric, sulfuric, phosphoric, acetic, trifluoro acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methane and ethanesulfonic, hydroxymethane and hydroxyethanesulfonic acids and the like. Further particulars can be had by reference to the Journal of Pharmaceutical Science, 66 (1 ) 1 -19 (1977).
  • the amount of Compound I present in sustained release oral pharmaceutical compositions may vary from about 0.1 to 99% of the dosage by weight depending on the dosage form.
  • Compound I may comprise from 0.01 to 5%, from 5% to 10%, from 10% to 15%, from 15% to 25%, from 25% to 50%, from 50% to 75%, and in some embodiments greater than 75%.
  • some embodiments of a tablet comprising Compound I can contain 0.01 to 20 mg of Compound I in 750-1000 mg of excipients.
  • compositions according to this disclosure may be used to prepare compositions according to this disclosure.
  • excipients and carriers are described, for example, in “Remington's Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) and other related such texts.
  • compositions and dosage forms are useful for providing cognitive enhancement to animals, and especially humans.
  • the Cmax of the Compound I generally should not exceed 25 ng/ml so as to avoid the severe cholinergic side effects that can occur at higher Cmax concentrations.
  • concentrations of Compound I discussed herein are expressed in terms of weight of the free base (Compound II)/ml. Due to patient-to- patient variability observed with Compound I, which as discussed below may be due at least in part to the effect of the patient's ability to metabolize the drug, in practice it may be advantageous to initially test a patient to determine his/her response to the drug.
  • the patient may be given an initial dose of Compound I and then tested at a pre-determined time interval following administration to determine his/her serum or plasma concentration of Compound I.
  • the patient may observe or be observed for the onset of substantially no, mild, moderate or severe cholinergic side effects to determine the patient's response to the drug and tolerance to the side effects, if any. In this way, a more accurate determination of the appropriate dose to prescribe can be made.
  • embodiments of the disclosure herein provide testing a patient to determine the concentration of Compound I in his/her serum or plasma at a pre-determined time following administration of a pre-determined dose of Compound I and or testing a patient to determine the amount of cholinergic side effects, if any, following administration of a pre-determined dose of Compound I. Either or both of these tests may be conducted prior to prescribing the dosage for a patient in order to prescribe the appropriate dosage for the patient. Alternatively, or in addition, patients may be tested again over time to determine whether their concentration of Compound I following administration has changed, thereby warranting a change in their prescription.
  • Embodiments of the compositions and dosage forms described herein may be used to providing a Cmax of Compound I within a ng/ml range selected from the group consisting of 0.01 to 1.0, 1.0 to 5.0, 5.0 to 10.0, 10.0 to 15.0, 15.0 to 20.0 and 20.0 to 25.0.
  • embodiments of the compositions and dosage forms described herein may be used to providing a Cmax of Compound I within a ng/ml range selected from the group consisting of 0.01 to 0.05, 0.05 to 0.1 , 0.1 to 0.5, 0.5 to 1 , 1 to 2, 2 to 3, 3 to 5, 5 to 7, 7 to 10, 10 to 12, 12 to 15, 15 to 20 and 20 to 25.
  • compositions and dosage forms described herein may be used to providing a Cmax of Compound I within a ng/ml range selected from the group consisting of 0.01 to 0.025, 0.025 to 0.05, 0.05 to 0.075, 0.075 to 0.1 , 0.1 to 0.15, 0.15 to 0.2, 0.2 to 0.25, 0.25 to 0.5, 0.5 to 0.75, 0.75 to 1.0, 1.0 to 1.5, 1.5 to 2.0, 2.0 to 2.5, 2.5 to 3.0, 3.0 to 4.0, 4.0 to 5.0, 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, 9.0 to 10.0, 10.0 to 1 1.0, 1 1.0 to 12.0, 12.0 to 13.0, 13.0 to 14.0, 14.0 to 15.0, 15.0 to 16.0, 16.0 to 17.0, 17.0 to 18.0, 18.0 to 19.0, 19.0 to 20.0, 20.0 to 21.0, 21.0 to 22.0, 22.0 to 23.0
  • Embodiments of the compositions and dosage forms described herein may be used to providing a Cmax of Compound I within a ng/ml range formed by any two, three or four adjacent ranges in the foregoing sets of adjacent ranges in this paragraph.
  • the desired Cmax chosen may depend on several factors and will be within the purview of the physician. For example, some patients may be more sensitive to the cholinergic side effects of Compound I and for those patients compositions providing lower Cmax values may be preferred. Generally speaking, at Cmax values below about 10 ng/ml, most subjects will be free of cholinergic side effects and those with side effects will likely experience at most mild cholinergic side effects.
  • Cmax values greater than 25 ng/ml also may be possible depending on the reaction of the patient to-Compound I. That is, for some patients, values greater than 25 ng/ml may not produce more than moderate levels of cholinergic side effects that are acceptable to the patient.
  • Compound I compositions and dosage forms described herein may be administered periodically to provide a sporadic or occasional effect, or consistently to provide a relatively constant effect.
  • Cognition enhancing effects that may be achieved from administration of Compound I include but are not limited to improved memory of places; improved memory of people; improved memory of information; improved memory of facts; improved memory of how to operate and use tools; improved ability to analyze information; improved ability to deduce or reason; improved ability to synthesize conclusions; improved ability to think strategically; improved ability to make plans and decisions; improved ability to execute on plans and decisions; improved ability to perform activities of daily living; improved ability to be employed; enhanced activity of neuronal mechanisms responsible for effective memory and cognition (including muscarinic functions); reduced pathogenetic mechanisms leading to loss of memory and cognitive function; reduced the loss of neurons or neuronal activity that lead to loss of cognitive and memory function; improved scores on neuropsychological tests such as ADAS-Cog or MMSE; and improved scores on clinical assessments of the activities of daily living such as ADCS-ADL.
  • the Compound I compositions and dosage forms described herein may be administered to treat normal cognitive impairment that accompanies aging, or to treat disorders such as Alzheimer's disease, dementia, ADHD, autism and schizophrenia, or to treat cognitive impairment due to injury, e.g., due to concussions or other brain trauma.
  • the Compound I compositions and dosage forms described herein may be administered to enhance cognition, to help maintain cognition, or to slow, prevent and/or reverse a decrease of cognition due to aging, trauma or a disorder such as Alzheimer's disease.
  • cognition enhancement i.e., cognitive enhancement, treating cognitive impairment, maintaining cognition and slowing, preventing or reversing a decrease in cognition
  • cognitive enhancement may result from treatment of symptoms related to natural aging or a medical condition such as Alzheimer's Disease.
  • the effects may result from disease modification caused by the administration of the Compound I, for example, reduced neuron loss as compared to similarly situated animals, i.e., animals having the same cognitive disorder such as Alzheimer's Disease, that are not administered the Compound I, increased a-secretase activity as compared to similarly situated animals that are not administered the Compound I, reduced ⁇ production as compared to similarly situated animals that are not administered the Compound I, increased sAPPa production as compared to similarly situated animals that are not administered the Compound I, and/or reduced Tau pathology and/or apoptosis as compared to similarly situated animals that are not administered the Compound I.
  • reduced neuron loss as compared to similarly situated animals, i.e., animals having the same cognitive disorder such as Alzheimer's Disease, that are not administered the Compound I
  • increased a-secretase activity as compared to similarly situated animals that are not administered the Compound I
  • reduced ⁇ production as compared to similarly situated animals that are not administered the Compound I
  • Compound I may be co-administered with other compounds useful for treating Alzheimer's Disease or symptoms associated therewith. Such compounds include but are not limited to Memantine, cholinesterase inhibitors such as donepizel, galantamine and rivastigmine, and therapeutic antibody treatments.
  • the amount of Compound I and co-administered compound may be administered in the same amounts as if administered singularly, or the Compound I and/or other compound may be administered or reduced dosage.
  • the main metabolite of Compound I which is 5-(3-((l-hydroxyethyl)-l,2,4-oxadiazol-5-yl)-l,4,5,6-tetrahydropyrimidine ("Compound IV")
  • Compound IV can be screened for directly by preparing a test to detect the presence and quantity of the metabolite following administration of the drug.
  • a test can be accomplished any number of ways. For example, following a predetermined time after administration, a blood sample can be taken and used to determine the concentration of Compound I in the patient's bloodstream. That concentration then can be compared against known values (as determined from patients who are able to metabolize the drug) to determine the patient's ability to metabolize the drug.
  • the blood can be tested to determine the presence and quantity of the metabolite, which is then compared to known values.
  • Any number of methods for determining the presence and quantity of the Compound I or its metabolite can be employed.
  • an antibody to Compound I or its metabolite can be generated using known methods of immunization and selection, and used to detect and quantify the metabolite, e.g., in a antibody-antigen binding reaction. Other quantification tests such as HPLC can be used.
  • the enzymes (or variant alleles of the respective genes) responsible for metabolism can be identified and the patient then could be screened for the presence of the enzyme or gene variant.
  • the test for determining the patient's ability to metabolize Compound I may be performed instead of or in addition to either or both of the tests described above, i.e., to determine the patient's concentration of Compound I or observed cholinergic side effects, following administration of Compound I.
  • embodiments of the disclosure herein provide testing patients to determine their ability to metabolize Compound I. This test may be conducted prior to prescribing the dosage for a patient in order to prescribe the appropriate dosage for the patient. Alternatively, or in addition, patients may be tested over time to determine whether their ability to metabolize the drug has changed, thereby warranting a change in their prescription.
  • Compound III was formulated with the following excipients and loaded into #3 hard gelatin capsules (5mg dose) or #2 hard gelatin capsules (0.2mg dose).
  • a single 5 mg capsule or 5x 0.2 mg capsules (1 mg total dose) were administered orally to healthy male volunteer human subjects with 125 ml of water. Six such subjects receiving the 5 mg dose, and a different 6 subjects received the 1 mg dose.
  • Subjects were monitored, among other things, for typical signs of muscarinic cholinergic action, such as increased salivation, lachrimation and diaphoresis.
  • Venous blood samples were drawn at various intervals after dosing from each subject into standard tubes for bioanalytical and pharmacokinetic analysis. The blood was allowed to clot, and the serum separated, using common clinical laboratory techniques. Serum samples were stored at -20 deg C until used for analysis.
  • Compound III (which exists in serum principally as the protonated form of Compound I) was assayed in clinical serum samples as follows. 200 ⁇ L aliquots of serum samples were spiked with 50.0 of diluent for subject samples and QC samples and 50 of the appropriate intermediate standard solution for standards. Twenty five microliters (25.0 ⁇ ,) of working internal standard stock solution and 40.0 ⁇ , of 10 N sodium hydroxide was then added and the samples were vortex mixed. Three milliliters (3.00 mL) of ethyl acetate was added followed by 5 minutes of vigorous vortexing and centrifugation.
  • the top organic layer was transferred to a clean tube, evaporated to dryness, and the sample was reconstituted with 100 xL of diluent (0.1% formic acid).
  • a 10 ⁇ , aliquot of this reconstituted sample was injected into Phenomenex Synergy 4 ⁇ POLAR-RP, 75 x 2.0 mm (P/N 00C-4336-B0) on a Waters Acuity UPLC LC system, and eluted using a gradient of from 12% to 90% acetonitrile containing 0.1 % formic acid /0.1% formic acid in water.
  • the eluant flow of the LC was injected by Turbo Ion Spray (positive ion) into a Sciex API 4000 (Applied Biosystems).
  • the MS/MS transitions monitored were 181.1 m/z to 1 1 1.0 m/z for Compound III and 186.1 m/z to 1 1 1.1 m/z for the internal standard, D5-Compound III.
  • the calibration curve was linear between 0.100 ng/mL and 50.0 ng/mL for Compound III.
  • the lower limit of quantitation (LLOQ) was 0.100 ng Compound III per mL of serum.
  • Compound III concentrations are expressed as free base (Compound II).
  • the bioanalytical method for the extraction of metabolites from serum samples entailed adding 450 uL of a 90% acetonitrile + 0.1 % formic acid solution to 50 uL of the serum samples.
  • the samples were vortexed and centrifuged at 16,000 x g at 4°C for 10 minutes.
  • the supernatants were transferred to 3K molecular weight cut-off (MWCO) spin filters (Pall, Nanosep, #82031-346). Samples were filtered by centrifugation at 13,000 x g at 4°C for 20 minutes.
  • the filtrates were transferred to a 96- well plate and sealed for LC/MS/MS analysis.
  • the system used for this analysis was a Shimadzu Prominence HPLC system.
  • Sample separation and desalting was achieved with a HILIC column (Phenomenex Luna, 3 um, 150 x 2.0 mm) maintained at 35°C, using a gradient of 100% to 50% of 90% acetonitrile + 30 mM ammonium formate, pH 3.5/H20 + 30 mM ammonium formate, pH 3.5 at a flowrate of 0.3 mL/min.
  • the autosampler was maintained at 4°C. Injection volumes for all samples and standards were 40 uL. MRM methods for two possible metabolites were made.
  • the pharmacokinetic analysis showed that Compound II was rapidly released from the formulation and rapidly absorbed.
  • the Tmax was between 1 and 1.5 hours.
  • the serum Cmax in the 6 subjects receiving 1 mg of Compound III did not exceed 8 ng/ml.
  • the serum Cmax in the 6 subjects receiving 5 mg of Compound III ranged from 7.9 ng/ml to 25.2 ng/ml, demonstrating a degree of subject-to-subject variability.
  • the two subjects with moderate diaphoresis had higher Cmax than the subjects with mild diaphoresis.
  • the subject experiencing mild hypersalivation had the highest Cmax.
  • the side effects appeared to be related to the serum concentration of Compound I. However the Cmax in two subjects experiencing no side effects was within the range of the four subjects that experienced side effects, demonstrating that there is person-to-person variability in the relationship between side effects and serum concentration.
  • the pharmacokinetic analysis also revealed a short half-life of Compound I.
  • the half-life was 1.44+/-0.28 (SD) hours.
  • the half-life was 1.71+/-0.62 (SD) hours.
  • the half-life in one subject was longer than any of the other 5 subjects, and was 2.93 hours.
  • the mean half-life for the other 5 subjects in the 5 mg cohort was 1.44+/-0.19 hours.
  • the mean half-life in a third cohort of 6 subjects receiving 0.2mg of Compound III was 1.2+/-0.28 (SD) hours.
  • the transdermal delivery method described herein should provide an advantageous approach to not only reduce the deleterious effects of metabolism by avoiding first-pass metabolism by bypassing the intestinal walls and liver, thereby improving bioavailability, but also means to control blood levels of the drug, thereby avoiding side effects, maintaining therapeutic effects, and reducing the dosage frequency.
  • transdermal delivery method described in this application provides a practical way to not only reduce metabolism (since transdermal delivery the drug avoids first-pass metabolism by bypassing the intestinal walls and liver), improving bioavailability, but also to provide a means to control blood levels of the drug, thereby avoiding side effects.
  • Two patches were made up, consisting (in order from the outer layer to the skin contacting surface, respectively): adhesive tape (Transpore, 27mm wide, 3M), circular stainless steel electrodes (22 mm dia) with a central hole for a stainless steel machine screw to which the electrode wire was attached, and 2 layers of 3MM CHR filter paper (Cat #3030-861 , Whatman International, Ltd).
  • ⁇ of a solution of Compound III (10 mg/ml) was applied to the filter paper pad of one electrode patch assembly, to become the anode, and 100 ⁇ of 0.9% saline was applied to the filter paper pad of another electrode patch assembly, to become the cathode.
  • the electrode patch assemblies were place one on each side of the spine in the mid-dorsal region, previously prepared as above.
  • the electrodes were connected with the indicated polarity to a simple electrical circuit comprising a 9 volt alkaline battery, a variable resistance potentiometer (10k ohms) and a digital multimeter. The current was manually adjusted to and maintained at 380 microamps, using the potentiometer.
  • a second similar catheterized rat was dosed orally by gavage with Compound III (10 mg/kg).
  • Blood 400 ⁇ was withdrawn from the catheters in each rat every 30 minutes, transferred to 1.5 ml centrifuge tubes containing heparin ( 15 units/tube), and the plasma was separated by centrifugation from the cellular components. The plasma samples were maintained at 4 deg C until analyzed.
  • Proteins were precipitated from plasma samples with two volumes of ice- cold 2% formic acid and clarified by centrifugation. The supernatants were ultra-filtered by centrifugation through a 3K MWCO spin column (Pall Life Sciences), following the manufacturer's instructions.
  • the ultra- filtrates were subjected to reverse-phase liquid chromatography using a 150 x 2.1 mm Agilent C8 reverse-phase column on a Shimadzu Prominence LC, eluting the Compound I with an isocratic flow of 2% acetonitrile + 0.1% formic acid.
  • the concentration of Compound I in the column effluent was measured using an Applied Biosystems API-3200 triple quadrupole mass spectrometer equipped with a Turbo V source (electrospray sample injection) system.
  • the experiment demonstrates that Compound I may be delivered efficiently by iontophoresis.
  • the plasma concentration of Compound I reached almost 850 nM 30 minutes after turning on the current.
  • the plasma concentration at 30 minutes of a rat administered 3.1 mg/kg by iontophoresis was almost identical to that of the rat administered Compound I by oral gavage (Table 2), suggesting that the bioavailability by transdermal delivery is up to three times higher than by oral administration.
  • the results indicate that transdermal delivery may avoid first-pass metabolism of Compound I in the intestinal wall and/or liver, as appears to occur with oral dosing of Compound I.
  • the patch delivered drug at a rate sufficiently high to exceed the threshold plasma concentration to cause increased salivation.
  • Skilled artisans will appreciate that the current may be adjusted to deliver drug at a lower rate to maintain a steady plasma concentration above the therapeutic level and below the level at which side effects such as diaphoresis or salivation are triggered.
  • an iontophoresis patch designed for human use may have several additional features, e.g., to assure the safety and comfort of patients, the quality, cost and reproducibility of manufacture, the shelf- life, and to improve the convenience to patients and the like.
  • the adhesive tape would be medical grade, so as not to irritate the skin.
  • the patch may be distributed preassembled in an impermeable pouch, such as a peel-apart foil pouch, and may have the appropriate amount of drug already loaded, and may be pre-wetted, so that the patient need only open the packaging and apply the patch to the skin.
  • the drug-containing anodic compartment and the cathodic compartment may be part of a unitary device, with the optimum spacing, to simplify the accurate placement of the electrodes on the skin.
  • the electrode compartments may contain immobilized buffers to absorb the ions produced by electrolysis of the water, thereby stabilizing the pH and preventing skin irritation or chemical burns.
  • the electrodes may be any inert, electrically conducting material (such as carbon), and may be fabricated economically by many different processes such as deposition by spraying or printing. Alternatively, the electrodes may be consumed (even provide the current by acting as a battery), providing a means to control the amount of electrical power provided by controlling the amount of electrode material.
  • the electronic circuit preferably contains current controlling components, since current determines the rate of delivery of the drug, and most preferably will provide constant current against varying electrical resistance.
  • the electronic circuit may usefully provide indicators that the unit is functional, that it is within specifications, that it has been activated, and may also provide safety interlocks and warnings for patient safety.
  • Example 3 Prophetic example of delivery of Compound I to humans using an iontophoresis patch
  • the drug is delivered from a reservoir compartment, in intimate contact with the skin, containing an anodic electrode.
  • Both compartments contain absorbent layers which contain dissolved buffers and electrolytes wetted with an aqueous solution providing electrical contact between the electrodes and the skin.
  • the reservoir compartment additionally contains a measured amount of drug dissolved in the aqueous phase.
  • the electrodes are connected with the appropriate polarity to a direct current source with a means to control the current.
  • the drug Since the drug is positively charged at the pH of the drug solution and at the pH of the epidermis and dermis, it is transported out of the reservoir, through the epidermis and dermis, taken up by the microvasculature, and distributed around the vascular system.
  • the rate of delivery of drug is proportional to the current, so the dosing rate may be controlled by controlling the current by varying the voltage, preferably using a constant current control device.
  • DuPel BLUE electrodes (EMPI, St Paul, MN) are used for iontophoretic delivery of Compound I. These ready-made devices contain (in order of distance from the skin) an adhesive patch, carbon electrodes with a snap connector for electrical connection, a layer of pH buffering resin, a foam drug reservoir, and wicking paper layer that contacts the skin. Depending on the dose required, small (cat #199332 -1.5 ml capacity), medium (cat #199335 - 2.5 ml capacity) or large (Cat#199336 - 4.0 ml capacity) patches are used.
  • a solution of Compound III (3.1 mg/ml) in sterile water for injection USP is applied to the device that is to be the anode (in the small sized device, assuming three times a day dosing in an average patient), and a few drops of sterile water for injection USP is applied to the part of the device that is to be the cathode, following the manufacturer's instructions contained in the product insert.
  • the amount of Compound III applied to the device may be tailored for each patient, either by adjusting the concentration of Compound I, or using the medium or large devices.
  • the devices are pressed onto the skin, following the instructions in the product insert, and are attached by the adhesive on the outer circumference of the patch.
  • the positive (red) wire of a constant current DC power source (EMPI DuPel device) is applied to the drug containing (anodic) device and the black wire is attached to the non-drug containing (cathodic) device.
  • the current is tailored for each patient, starting at 250 microamps, using increasing current until the appearance of diaphoresis signals the maximum tolerated dose has been reached.
  • the current is then reduced until no diaphoresis occurs, and maintained until a maximum current dose of 80 mA*min has been administered.
  • the current may be set using the serum concentration of Compound I.
  • Example 4 Prophetic examples of gastric retained tablet formulations of Compound III
  • Drug, polymer(s) and filler(s) are provided in fine particulate form, about 90% passing through a 100-mesh screen.
  • CR grades and direct compression grades of polymer(s) and fillers are used. All excipients are produced under GMP for Finished Pharmaceuticals and meet the compendial requirements of the United States and Europe.
  • a pre-selected amount of Compound III is added to the blender to provide a dose of 5.0 mg (expressed as Compound II) per finished tablet - in this case approximately 5.0 grams for each 750 grams of formulation mix to make about 1,000 tablets, without allowance for waste.
  • Drug, polymer and filler are blended for 10 minutes in a V-blender.
  • Powder flow aid and lubricant are added and blending is continued for a further 5 minutes.
  • drug release is principally controlled by the rapid formation of a dense gel layer on the outside layers of the tablet when it contacts fluid in the stomach of the patient.
  • the gel is formed by rapid hydration of the Methocel polymer.
  • the Methocel polymer is in fine particle form to ensure rapid hydration and uniform dense gel formation.
  • the drug release rate is controlled by the concentration of polymer and its viscosity. For faster release, the lower viscosity Methocel K4M grade is used. For slower release, the higher viscosity K15M or K100M grades are used. These may be mixed to achieve intermediate levels of viscosity, and the properties of the mixes may be predicted using the Furchgott equation.
  • Formulation mix #4 contains a high molecular weight polyoxyethylene diffusion control polymer (Polyox WSR-303 NF from Dow Chemical Company). Other suppliers provide hydrophilic gel matrices with similar properties and these may be substituted for Methocel by one skilled in the art.
  • the Eudragit RS and RL grades of (meth)acrylate polymers from Degussa/Evonik are two examples of suitable polymers.
  • Tablet erosion is also controlled by the polymer concentration and viscosity, higher concentrations and higher viscosity reducing the disintegration rate of the tablets.
  • the release rates may be modified by including additional polymers ("modifiers"). These may also strengthen the tablet to reduce the rate of erosion. They may also prevent unwanted initial release of drug in a "burst" when the tablet first hydrates.
  • Formulation #2 contains Ethocel as a modifier
  • formulation #3 contains partially pre-gelatinized starch as a modifier. The starch may actively interact with the Methocel to improve the properties of the tablets.
  • Numerous modifier polymers are known to those skilled in the art and may replace a proportion of the filler.
  • formulation #1 contains finely milled microcrystalline cellulose (MCC), which has excellent properties for dry compression - the compressibility indexes of selected grades of MCC are quite similar to that of Methocel K4M.
  • Formulation #2 and #4 contain lactose, which is soluble, and leaches out of the tablet along with drug and may help water penetrate into the tablet, but may cause drug to be release more quickly than desired.
  • insoluble fillers such as calcium phosphate dehydrate or calcium sulfate. Insoluble fillers will generally slow down release of drug.
  • wet granulation techniques well know in the art are used to provide uniform distribution of the relatively low dose of drug and thereby achieve adequate dose reproducibility.
  • the drug, polymer and filler are mixed and wetted with water using a cone spray nozzle, wet milled, dried in a 1 10 deg F oven, dry milled, blended with lubricant for 1 minute in a suitably-sized V-blender, and then compressed into tablets.
  • the blended mix is compressed into tablets using a tablet press (e.g. Manesty F3 single station press, or fully instrumented Piccolla rotary 10-station) using 12.8 mm concave tooling.
  • the compression force and rate is controlled to provide well- compressed non-friable tablets without layering flaws and with suitable hardness.
  • the tablets made with formulation mix #2 are also coated with ethylcellulose to further modify the release rate, using an aqueous suspension of ethylcellulose (Surelease, Colorcon) and methods that are well-known in the art.
  • the tablets are tumbled in a coating machine, Surelease is sprayed onto the tablets at a suitable rate and they are quickly and continuously air-dried.
  • Coating is complete when the weight has increased by about 4%.
  • the coating machine may be the pan type (O'Hara Lab Coat-I) or may use a fluidized bed process (Glatt).
  • the coatings may contain plasticizers to avoid crazing and cracking, and glidants such as talc or silica may be added, to improve processability and handling.
  • Coating substances are available from many manufacturers that may be substituted for ethylcellulose by a person skilled in the art, such as the Eudragit NE or NM grades of (meth)acrylate polymers from Degussa/Evonik (Rohm GMBH & Co KG, Germany)
  • any of the tablets manufactured using any these formulation mixes may be additionally coated with an active layer such as ethyl cellulose, or a coating to make it easier to swallow the tablets, or simply for esthetics.
  • an active layer such as ethyl cellulose
  • Such coating substances and methods are well-known in the art. .
  • Tablets are tested for physical properties (e.g. hardness - Key International Hardness Tester, Model HT500), dissolution (standard USP protocols, using a USP Type 2 apparatus (Distek Model 2100) with a paddle speed of 50rpm and artificial gastric fluid, and disintegration. It will be appreciated that the compositions exemplified in this example may be modified to achieve the desired release rate and duration of release.
  • Aerosil 200 (colloidal
  • the coating material was made by dissolving an appropriate amount of Pharmacoat 606 in water for injection USP, then adding an appropriate amount of Surelease E-7- 19040, and mixing for 30 minutes.
  • Atomising air pressure 0.5 bar
  • Controlled release tablets were placed in a standard USP dissolution apparatus and 0.9L of simulated gastric fluid (0.1N hydrochloric acid in water) was added. The agitation paddles were rotated at a rate of 100 revolutions per minute. Samples were removed at appropriate times. The concentration of Compound I (protonated form) was determined using a validated LC-UV bioanalytical assay. The amount of Compound I release from the tablet was calculated by reference to the total amount of Compound I in the tablet. The latter was measured by treating dry tablets with methanol, then crushing the tablets, treating them with ultrasound produced using an ultrasound transducer to disrupt their structure, and then quantitatively extracting Compound I into simulated gastric fluid. The amount of Compound I released as a function of time into the simulated gastric fluid in the dissolution apparatus was 17.5% in 30 minutes, 73% in 240 minutes and 100% in 720 minutes.
  • Controlled release tablets containing 5mg of Compound III were administered by mouth to three different cohorts of human volunteers. Following administration of the drug, venous blood was withdrawn at appropriate intervals, serum was prepared, and the concentration of Compound I (protonated form) was determined using the validated sample preparation procedures and an LC-MS-MS assay, essentially as described in Example 1. The results are described below.
  • the highest individual Cmax was 12.1 ng/ml, and this individual experienced no parasympathetic adverse events.
  • Tmax Two hours after mean Tmax (i.e. at 5 hours) the mean serum concentration of Compound II (expressed as free base) was 4.02 ng/ml. This was 68% of the mean Cmax.
  • the mean Tmax was later than with the. immediate release capsule (3 hours compared to 1.5 hours).
  • the mean Cmax with the CR tablets was lower than the mean Cmax with the immediate release capsules (5.92 ng/ml compared to 17.76 ng/ml).
  • the Cmax with the CR tablet was reduced by a factor of approximately 3 fold, or was reduced by 66.7%.
  • the mean Cmax with the CR tablets was lower than the mean Cmax with the immediate release capsules (6.44 ng/ml compared to 17.76 ng/ml).
  • the Cmax with the CR tablet was reduced by a factor of approximately 2.7 fold, or was reduced by 63.7%.
  • Cohort 3 A Cohort of six elderly male and 4 elderly female female subjects in a 7-day, twice-a-day dosing, multi-dose study received doses of the Batch 1 CR tablets. Each tablet contained 5 mg of Compound III. On the morning of Day 1, the mean Tmax was at 5 hours, at which time the mean serum Cmax was 5.37 ng/ml of Compound I (expressed as free base). The highest individual Cmax was 14.6 ng/ml, and this individual experienced no parasympathetic adverse events on this day. Two hours after mean Tmax (i.e. at 7 hours) the mean serum concentration of Compound I (expressed as free base) was 3.36 ng/ml. This was 63% of the mean Cmax.
  • the mean Tmax was later than with the immediate release capsule (5 hours compared to 1.5 hours).
  • the mean Cmax with the CR tablets was lower than the mean Cmax with the immediate release capsules (5.37 ng/ml compared to 17.76 ng/ml).
  • the Cmax with the CR tablet was reduced by a factor of approximately 3.3 fold, or was reduced by 68.7%.
  • a dose of 5 mg twice-a-day (bid) should be well tolerated by most or all subjects. Most individuals in which the serum concentration of Compound III are maintained below 12 ng/ml should not experience sweating or salivation. A proportion of patients may be more comfortable on a lower dose, such as 2.5 mg bid, and the dose might usefully be titrated down to 2.5 mg if such a patient experiences occasional sweating or salivary hypersecretion. Additionally, those patients who tolerate the tablets well, without experiencing sweating or salivary hypersecretion, might benefit from a higher dose, for example they might benefit from a greater disease-modifying action of the drug.
  • the dose might usefully be titrated upwards to a dose just below that which causes sweating or salivary hypersecretion, or to a dose producing a serum concentration of drug up to about 12 ng/ml. While the well-tolerated side effects of sweating and salivary hypersecretion provide low-cost and convenient parameters to optimize dosing, the serum concentration of drug or metabolite (Compound IV) may also be used for this purpose.
  • patients may be phenotyped or genotyped for the drug metabolizing enzyme.
  • Tablets were manufactured as in Example 5 with a core containing drug, hydrogel polymer, release modifiers and inactive excipients, with the composition shown in Table 7. Cores were coated with an ethyl cellulose/ hydroxypropylmethyl cellulose coating. Tablets with a coating containing different ratios of ethylcellulose and hydroxypropylmethyl cellulose or different amounts of coating, as measured by weight gain, release Compound I at different rates in the dissolution apparatus as described above. The dissolution results are shown in Table 8.
  • Tablet cores are manufactured and coated with ethylcellulose/hydroxypropylmethyl cellulose coatings, as in Examples 5 and 6, with the concentrations of hydroxypropylmethylcellulose in the cores or of ethylcellulose/hydroxypropylmethyl cellulose optionally being varied to obtain the desired dissolution results.
  • concentrations of hydroxypropylmethylcellulose in the cores or of ethylcellulose/hydroxypropylmethyl cellulose optionally being varied to obtain the desired dissolution results.
  • an undercoat of hydroxypropylmethyl cellulose can be applied using a suitable formulation such as Pharmacoat 606 or Opadry (Colorcon).
  • the coated tablets optionally may then be maintained at normal ambient temperatures rather than being chilled.
  • a different formulation of ethylcellulose/hydroxyl- propylmethyl cellulose which lacks ammonia and has a neutral to acid pH may be used for the outer coating, in which case the undercoating is not required, and the tablets may be maintained at ambient temperatures.
  • a suitable formulation is Aquacoat ECD (FMC BioColloids) to which Pharmacoat 606 or another form of hydroxypropylmethyl cellulose has been added.
  • Such a water-based formulation may be used instead of an organic solvent formulation of ethylcellulose/hydroxypropylmethyl cellulose, in particular a flammable solvent formulation. If the release profile of the tablets changes as a result of these variations in composition or manufacture, the optimal dose might need to be adjusted.
  • the optimal dose is likely to increase to above that described in Example 5.
  • the "normal" dose or starting dose might be greater than 5 mg, for example in the range of 5 mg to 10 mg bid, or most probably in the range 6 mg to 8 mg bid.
  • Silver and silver chloride electrodes (circular, 22 mm diameter x 0.1 , 0.25 and 0.5mm thick) were prepared by known methods. Circular hydrogel pads (22mm diameter x 2 mm thick) were prepared as described below. The silver electrode was connected to the positive terminal of a constant-current DC source, driven by a 9 volt battery, and was placed in contact with the upper side of a hydrogel pad containing Compound III. The silver chloride electrode was connected to the negative terminal of the constant current DC source and placed in contact with the upper side of a hydrogel pad that contained no Compound 1.
  • the lower side of the hydrogel pads were placed on the dorsal shaved skin of a Long Evans Hooded rat, on either sides of the spine, with about 20 mm between the closest parts of the pads.
  • An occlusive water-impermeable covering of silicon rubber sheet was placed over the electrode/gel assemblies and held in place with adhesive tape. The voltage was turned on and set such that a current of 300 to 500 microamperes flowed through the circuit.
  • the rats were anesthetized with 2% isoflurane, placed slightly head down, and the amount of saliva produced in successive 5 minute period was captured on pre- weighed filter papers, and quantitated by weighing the saliva produced.
  • Compound I causes salivation when it is circulated with blood through the salivary glands. Salivation increases when the plasma concentration of Compound I exceeds a threshold value of approximately 200 nM in the plasma, and further increases with the increasing plasma concentration of Compound I. Salivation is an indication that Compound III has been absorbed and is circulating in the blood. It is also a convenient indirect measure of the concentration of circulating Compound I.
  • Polyvinyl alcohol (Sigma Aldrich cat no PI 763) was mixed with water and heated at 92-98 °C until dissolved. Successively, glycerol, cholestyramine resin (Sigma Aldrich cat no C4650), Amberlite resins IRP64 Polyacrilin and IRP88 Polyacrilex (Rohm & Haas) and a solution of Compound III in water were added and mixed well. Other compounds, if added, were dissolved in water and replaced part or all of the citrate buffered saline. Water was added to replace any loss through evaporation, using a graduation mark on the vessel. The hot liquid was dispensed into molds.
  • Molds were made using a suitable thickness silicon rubber sheet sandwiched between two vertical glass plates and clamped together.
  • the silicon rubber sheet contained circular cut-outs and inlet holes at the top through which the mix described above could be introduced.
  • the molds containing the mix were twice frozen at -80 °C and thawed to room temperature, to produce stiff cryogels.
  • the cryogels were removed from the molds and trimmed into circular discs by removing the gel that set in the inlet holes.
  • Cryogels were stored in individual Ziploc polyethylene bags at -80 °C until used, then thawed and allowed to come to room temperature immediately before use.
  • the concentration of Compound I in the plasma of rats administered Compound III by iontophoresis was measured directly.
  • the plasma concentrations of Compound I were measured as follows. Blood was taken from the rat by cardiac puncture, placed in a heparin-containing collection tube and centrifuged to separate the plasma, which was transferred to new tubes for storage. 450 uL of 0.1% formic acid was added to 50 uL of the serum samples. The samples were vortexed and centrifuged at 16,000 x g at 4°C for 10 minutes. The supematants were transferred to 3K molecular weight cut-off (MWCO) spin filters (Pall, Nanosep, #82031-346).
  • MWCO molecular weight cut-off

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Abstract

La présente invention concerne des compositions pharmaceutiques améliorant la cognition et les formes galéniques comprenant une quantité de 5-(3-éthyl-1,2,4-oxadiazol-5- yl)-1,4,5,6-tétrahydropyrimidine, ou une forme pharmaceutiquement acceptable de celle-ci, qui ne provoque au plus que des effets secondaires cholinergiques modérés chez un animal recevant la composition.
PCT/US2010/002411 2010-09-01 2010-09-01 Compositions comprenant de la 5-(3-éthyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tétrahydropyrimidine, et procédés d'administration desdites compositions Ceased WO2012030314A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9403806B1 (en) 2010-09-08 2016-08-02 Neurosolis, Inc. Cognition enhancing compounds and compositions, methods of making, and methods of treating
CN106456622A (zh) * 2014-07-09 2017-02-22 皮埃尔法布雷医药公司 用贝非拉醇治疗运动障碍的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MESSER ET AL.: "The Utility of Muscarinic Agonists in the Treatment of Alzheimer's Disease.", JOURNAL OF MOLECULAR NEUROSCIENCE, vol. 19, 2002, pages 187 - 193 *
SIEGAL ET AL.: "A Unique lontophoretic Patch for Optimal Transdermal Delivery of Sumatriptan.", PHARMACUETICAL RESEARCH, vol. 24, 2007, pages 1919 - 1926 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9403806B1 (en) 2010-09-08 2016-08-02 Neurosolis, Inc. Cognition enhancing compounds and compositions, methods of making, and methods of treating
US9738633B2 (en) 2010-09-08 2017-08-22 Neurosolis, Inc. Cognition enhancing compounds and compositions, methods of making, and methods of treating
CN106456622A (zh) * 2014-07-09 2017-02-22 皮埃尔法布雷医药公司 用贝非拉醇治疗运动障碍的方法
US10548885B2 (en) 2014-07-09 2020-02-04 Pierre Fabre Medicament Method for treating movement disorders with befiradol
CN106456622B (zh) * 2014-07-09 2020-05-19 皮埃尔法布雷医药公司 用贝非拉醇治疗运动障碍的方法
US11090298B2 (en) 2014-07-09 2021-08-17 Pierre Fabre Medicament Method for treating movement disorders with befiradol
US12472169B2 (en) 2014-07-09 2025-11-18 Pierre Fabre Medicament Method for treating movement disorders with befiradol

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