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Title:  Protection against traumatic brain injury

United States Patent:  6,255,280

Inventors:  Scheff; Stephen William (Lexington, KY)

Assignee:  University of Kentucky Research Foundation (Lexington, KY)

Appl. No.:  288515

Filed:  April 8, 1999


The present invention relates to therapeutic uses of cyclosporin A to reduce adverse effects of neural injury.


The present invention provides a method of treating a mammal, including humans, suffering from traumatic brain injury, which method comprises administering a therapeutically effective amount of cyclosporin A.

Cyclosporin A is known and has been proposed for use for various therapeutic methods. For example, U.S. Pat. Nos. 4,117,118 and 5,766,629, which are incorporated herein in their entirety by reference thereto, describe this compound, methods for preparing this compound, and methods for formulating this compound into pharmaceutical compositions.

The compounds for use in the present invention can be administered as a pharmaceutical composition. The pharmaceutical compositions used in the methods of this invention for administration to animals and humans comprise an active agent in combination with a pharmaceutical carrier or excipient acceptable for delivery of the compounds to the brain.

The pharmaceutical compositions can be in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.

"Pharmaceutical composition" means physically discrete coherent portions suitable for medical administration. "Pharmaceutical composition in dosage unit form" means physically discrete coherent units suitable for medical administration, each containing a daily dose or a multiple (up to four times) or a sub-multiple (down to a fortieth) of a daily dose of the active compound of the invention in association with a carrier and/or enclosed within an envelope. Whether the composition contains a daily dose, or for example, a half, a third or a quarter of a daily dose will depend on whether the pharmaceutical composition is to be administered once or, for example, twice, three times or four times a day, respectively.

Advantageously, the compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage forms according to the invention. It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be consistent with the dosage form employed in single or multiple unit doses. The exact individual dosages, as well as daily dosages, are determined according to standard medical principles under the direction of a physician or veterinarian.

The active agents can also be administered as suspensions, solutions and emulsions of the active compound in aqueous or non-aqueous diluents, syrups, granulates or powders. Diluents that can be used in pharmaceutical compositions (e.g., granulates) containing the active compound adapted to be formed into tablets, dragees, capsules and pills include the following: (a) fillers and extenders, e.g., starch, sugars, mannitol and silicic acid; (b) binding agents, e.g., carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g., glycerol; (d) disintegrating agents, e.g., agar--agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution, e.g., paraffin; (f) resorption accelerators, e.g., quaternary ammonium compounds; (g) surface active agents, e.g., cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g., kaolin and bentonite; (i) lubricants, e.g., talc, calcium and magnesium stearate and solid polyethylene glycols.

The tablets, dragees, capsules and pills comprising the active agent can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, from polymeric substances or waxes.

The active ingredient can also be made up in microencapsulated form together, with one or several of the above-mentioned diluents.

The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g., cocoa oil and high esters, (e.g., C14 -alcohol with C16 -fatty acid]) or mixtures of these diluents.

The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200, in the presence of a surface-active agent), such as diluents, dissolving agents and emulsifiers. Specific non-limiting examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (for example, ground nut oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.

For parenteral administration, solutions and suspensions should be sterile, e.g., water or arachis oil contained in ampoules and, if appropriate, blood-isotonic.

The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g., water, ethyl alcohol, propylene glycol, surface active agents (e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitols and sorbitan esters), polycrystalline cellulose, aluminum methahydroxide, agar--agar and tragacanth, or mixtures thereof.

The pharmaceutical compositions can also contain bulking agents and preservatives, as well as perfumes and flavoring additions (e.g., peppermint oil and eucalyptus oil, and sweetening agents, (e.g., saccharin and aspartame).

The pharmaceutical compositions will generally contain from about 0.0001 to 90 wt. %, preferably about 0.01 to 10 wt. % of the active ingredient by weight of the total composition. In addition to the active agent, the pharmaceutical compositions and medicaments can also contain other pharmaceutically active compounds.

Any diluent in the pharmaceutical compositions of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions. Such compositions may include solvents of molecular weight less than 200 as the sole diluent.

The active compound is administered perorally, parenterally (for example, intramuscularly, intraperitoneally, subcutaneously, transdermally or intravenously), rectally or locally, preferably orally or parenterally, especially perlingually, or intravenously.

The dosage rate, e.g., about 0.0001 to about 200 mg/kg of body weight, such as from about 10 mg/kg to about 150 mg/kg, preferably from about 20 mg/kg to about 40 mg/kg, will be a function of the nature and body weight of the human or animal subject to be treated, the individual reaction of this subject to the treatment, type of formulation in which the active ingredient is administered, the mode in which the administration is carried out and the point in the progress of the disease or interval at which it is to be administered. Thus, it may in some case suffice to use less than a minimum dosage rate, while other cases an upper limit must be exceeded to achieve the desired results. Where larger amounts are administered, it may be advisable to divide these into several individual administrations over the course of the day.

It is presently preferred to administer cyclosporin A parenterally, such as intravenously, in a bolus, so as to obtain the most rapid delivery of the active agent to the brain. A suitable dosage for obtaining attenuation of the effects of traumatic brain injury is from about 1 to about 1000 mg/kg body weight, such as from about 10 to about 100 mg/kg body weight, although the optimum dosage of cyclosporin A will be determined by the physician taking into account the age, weight and general health of the subject. In other embodiments of the present invention, the cyclosporin A may be administered directly to the brain, e.g. intraventricularly, intracerebrally or intracisternally. The dosage may be administered in one or more treatments following traumatic brain injury such as by way of a single or multiple doses or from sustained release compositions over a period of time, such as immediately after the TBI to about 1 or more day after the TBI. Preferably, the initial dosage is administered less than about 6 hours after TBI, such as from about 15 minutes to about 1 hour after injury. However, one or more doses may be administered after 6 hours such as from about 6 hours to about 24-48 hours after injury.

Cyclosporin A may also be administered in association with other therapeutic agents including, for example, antibiotics or antiviral agents.

Claim 1 of 10 Claims

What is claimed is:

1. A method for treating a mammal suffering from traumatic brain injury caused by an external mechanical force on the cerebral cortex, which method comprises:

administering a therapeutically effective amount of cyclosporin A in a dose from about 1 to about 1000 mg/kg to a mammal in need thereof within about 48 hours after the injury to reduce or ameliorate brain tissue damage by reducing lesion volume size by more than about 5%.

If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.



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