Title:  Brain delivery of folic acid for the prevention of alzheimer's disease and stroke

United States Patent:  6,369,058

Assignee:  New Millennium Pharmaceutical Research Inc. (Lexington, KY)

Filed:  January 14, 2000

This invention provides a method of rapidly and reliably delivering folic acid, alone or in combination with other compounds, to the systemic circulation by administration via the nasal route to produce rapid onset of beneficial effects in the treatment or prevention of Alzheimer's Disease and stroke. The present invention further provides intranasal pharmaceutical compositions comprising folic acid, and/or pharmaceutically acceptable salts thereof in a variety of unique pharmaceutical dosage forms, with and without other anti-Alzheimer's or anti-stroke compounds.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Thus, the present inventors have discovered a novel method for the delivery of folic acid (N-[4-[[(2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methly] amino]benzoyl]-L-glutamic acid; pteroylglutamic acid), or derivatives thereof, to a patient in need of such treatment, comprising the intranasal administration of folic acid. This method offers significant clinical advantages over the prior art.

More specifically, the inventors sought to provide a rapid, reliable, safe, effective and convenient treatment for Alzheimer's disease or stroke comprising administering folio acid to a patient in need of such treatment, which comprises the administration of folio acid intranasally, thus providing rapid response compared to prior art methods of treatment of Alzheimer's disease or stroke while avoiding the side-effects associated with oral dosage forms. Specifically, smaller doses of folio acid can be administered through the nasal route, thus resulting in fewer side effects. By using the method of the present invention, which produces an rapid response, the drug will become more tolerable and more effective in treating patients suffering from Alzheimer's disease or stroke.

More particularly, the present invention concerns the intranasal administration of folic acid, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound. Preferred pharmaceutically acceptable salts of folio acid for use in the present invention include, but are not limited to, folic acid sulfate and folic acid phosphate. Such pharmaceutical compositions may be a medicament for the treatment of Alzheimer's disease or stroke in an animal, particularly a mammal, including a human. Alternatively, such pharmaceutical compositions may be a medicament for the prevention of Alzheimer's disease or stroke in an animal, particularly a mammal, including a human.

The present inventors have found that intranasal administration of folic acid effectively results in complete and very rapid absorption of these compounds into the central nervous system (CNS). Intranasal administration of folic acid is more effective than other routes of administration, because it permits absorption of folic acid directly into the central nervous system, bypassing the metabolic enzymes present in the circulation, the gastrointestinal tract, and liver. Moreover, intranasal formulations of folic acid may be conveniently and painlessly self-administered by the patient. Intranasal administration can be employed at far lower doses than oral administration, thereby allowing a decreased incidence of side effects.

According to the present invention, folic acid may be administered either as a free base, or in the form of a pharmaceutically acceptable salt thereof.

A still further aspect of this invention is a pharmaceutical composition of matter that comprises folic acid, or derivatives thereof, as described above, and/or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers therefor.

For therapeutic use in the prevention of treatment of Alzheimer's disease or stroke, folic acid or salts thereof, can be conveniently administered in the form of a pharmaceutical composition containing folic acid, or its salt, and a pharmaceutically acceptable carrier therefor. Typically, the carrier may be a liquid, solution, gel, or combinations thereof. In a preferred embodiment, the carrier is a pharmaceutically acceptable aqueous solution. Such compositions may require the use of one or more solubilizing agents to both effect dissolution of the drug(s) and/or keep them in aqueous solution. Suitable applications of solubilizing agents are exemplified below. Compositions according to the present invention may be prepared in accordance with accepted pharmaceutical practice, for example, as described in Remington's Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Penn., Eighteenth edition (1990), which is hereby incorporated by reference.

Folic acid or its salt may be formulated together with the carrier into any desired unit dosage form. Unit dosage forms such as solutions, suspensions, and water-miscible semisolids are particularly preferred.

Each carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient. The carrier must be biologically acceptable and inert. In most cases, suitable buffers are included in the carriers to maintain the pH within the limits required to keep the drugs in solution. For example, for drugs containing a basic center, the solutions are buffered in the acidic pH range (approximately 2 to 6), and for drugs containing an acidic center, the solutions are buffered in the pH range (approximately 6 to 8). To prepare formulations suitable for intranasal administration, solutions and suspensions are sterilized and are preferably isotonic to blood.

In formulating a composition according to the present invention for the treatment of Alzheimer's disease, other drugs used in the treatment of AD, or agents useful in treating dementia (i.e., improving cognitive function), may be included. Preferred agents for use in combination with the folic acid according to the present invention for treating Alzheimer's disease include acetylcholine precursors (e.g., choline chloride and phosphatidyl choline (lecithin)); cholinergic agonists (e.g., acetylcholine, acetyl-L-carnitine, anatoxine a, arecoline, bethanecol, carbachol, decamethonium, 1,1-dimethyl-4-phenyl-piperazinium, cis-Dioxolane, epibatidine, epiboxidine, methacholine, methylcarbamylcholine, methylfurtrethonium, metoclopramide, muscarine, nicotine, oxotremorine, pilocarpine, and pharmaceutically acceptable salts thereof); cholinesterase inhibitors (e.g., ambenonium, adrophonium, methylphysostigmine, neostigmine, pyridostigmine, and pharmaceutically acceptable salts thereof) and acetylcholinesterase inhibitors (e.g., physostigmine, tacrine (1,2,3,4-tetrahydro-9-aminoacridine), galanthamine, and pharmaceutically acceptable salts thereof).

In formulating a composition according to the present invention for the treatment of stroke, other drugs used in the treatment of stroke may also be included. Such additional drugs include, but are not limited to, anticoagulants, antiplatelet agents, calcium channel antagonists, and glutamate receptor antagonists. Preferred anticoagulants for use in the present invention include, but are not limited to, heparin, warfarin, and pharmaceutically acceptable salts thereof. Preferred antiplatelet agents for use in the present invention include, but are not limited to, aspirin, dipyridamole, and ticlopidine, and pharmaceutically acceptable salts thereof. Preferred calcium channel antagonists for use in the present invention include, but are not limited to, bepridil; calciseptine; cyproheptadine; diltiazem; flunarizine; fluspirilen; HA-1077; loperamide; nicardipine; nifedipine; niguldipine; nimodipine; nitrendipine; pimozide; ryanodine; verapamil; and pharmaceutically acceptable salts thereof. Preferred glutamate receptor antagonists (specifically the NMDA subtype) for use in the present invention include, but are not limited to: AP3, (.+-.)-; AP4, (.+-.)-; AP5, (.+-.)-; AP5, D(-)-; AP7, (.+-.)-; AP7, D(-)-; CGS 19755; 7-chlorokynurenic acid; CPP, (.+-.)-; CPP,D-; dextromethorphan; dextrorphan; 5,7-dichlorokynurenic acid; 6,7-dichlorquinoxaline-2,3-dione (DCQX); 5,5-dimethyl-1-pyrroline-N-oxide; 5-fluroindole-2-carboxylic acid; HA-966, (.+-.)-; HA-966, R(+)-; HA-966, S(-)-; ketamine; kynurenic acid; MDL 105,519; memantine; MK-801; 1-napthyl-acetyl spermine; pentamidine isethionate; and pharmaceutically acceptable salts thereof.

According to the present invention, the term "patient" will encompass any mammal requiring treatment with folio acid, or derivatives thereof, particularly a human patient suffering from an Alzheimer's disease, or at risk for Alzheimer's disease or stroke.

The dosage of folio acid or pharmaceutically acceptable salts thereof in the compositions of the invention will vary depending on several factors, including, but not limited to, the age, weight, and species of the patient, the general health of the patient, the severity of the symptoms, whether the composition is being administered alone or in combination with other agents, the incidence of side effects and the like. The desired dose may be administered as needed, and may be administered repeatedly over a period of months or years. Higher and lower doses may also be administered. A major advantage of the present invention is the extremely rapid onset of response, which enables the physician to adjust the dose to produce only the desired effects and nothing more, thereby optimizing drug use and minimizing side-effects.

The daily dose may be adjusted taking into account, for example, the above-identified variety of parameters. Typically, folio acid may be administered in an amount of up to about 60 mg/dose. Preferably, the amount of folic acid administered will not exceed 30 mg/dose. However, other amounts may also be administered, in particular, much smaller amounts of folio acid will be required when administered intranasally, in accordance with the present invention.

While it is possible for the active ingredient to be administered alone, as noted above, it is preferably present as a pharmaceutical formulation. The formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.

The method of the present invention may be practiced by administration of folic acid by itself or in a combination with other active ingredients in a pharmaceutical composition. Other therapeutic agents suitable for use herein are any compatible drugs that are effective by the same or other mechanisms for the intended purpose, or drugs that are complementary to those of folic acid. Such additional drugs include, but are not limited to, those drugs mentioned above in conjunction with treatment of Alzheimer's Disease or stroke.

The compounds utilized in combination therapy may be administered simultaneously, in either separate or combined formulations, or at different times than the folic acid, e.g., sequentially, such that a combined effect is achieved. The amounts and regime of administration will be adjusted by the practitioner, by preferably initially lowering their standard doses and then titrating the results obtained. The therapeutic method of the invention may be used in conjunction with other therapies as determined by the practitioner.

Claim 1 of 6 Claims

What is claimed is:

1. A method for treating Alzheimer's Disease in a patient in need of such treatment comprising intranasally administering an effective amount of a pharmaceutical composition consisting essentially of folic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.

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