Sublingual or buccal administration of melatonin and/or valerian

Abstract

A pharmaceutical composition for sublingual or buccal administration of melatonin and valerian is complexed with a beta cyclodextrin or another complexation agent. It is then encased in a liposome. The molecules encased in the liposome are then dehydrated and compounded into any of a number of dosage forms such as a dissolvable strip of material, a gum, lozenge, mint, tablet, or powder.

Claims

1. A compound for use in inducing sleep, comprising: melatonin in a cyclodextrin compound; valerian extract in a cyclodextrine compound; a liposomal construct encapsulating the cyclodextrine complexes through use of a hydrated phospholipid; an absorption enhancer; a solvent for said absorption enhancer.

2. The compound of claim 1, wherein a weight of said melatonin is between 0.05 milligrams and 5 milligrams, inclusive.

3. The compound of claim 2, wherein a weight of said valerian is between 0.5 milligrams and 25 milligrams, inclusive.

4. The compound of claim 3, wherein said compound is produced into a water soluble strip.

5. The compound of claim 1, wherein said absorption enhancer comprises piperin.

6. The compound of claim 5, wherein said solvent comprises olive oil as a solvent for said piperin.

7. The compound of claim 6, wherein said compound further comprises a plasticizer.

8. The compound of claim 1 further comprising at least two of myrcene, linalool, betacaryophyllene, gamma amino butyric acid.

9. The compound of claim 1, further comprising at least two of tryptophan or a derivative thereof, magnesium salts, chelates, and a sedative.

10. The compound of claim 8, wherein said compound is designed to be placed sub-lingually or buccally.

11. The compound of claim 10, wherein said compound is in a dissolvable rectangular strip of material.

12. The compound of claim 1, wherein said compound is in a gum, lozenge, mint, tablet, or powder form.

Description

DETAILED DESCRIPTION OF EMBODIMENTS OF THE DISCLOSED TECHNOLOGY

(1) The present technology provides a pharmaceutical composition for sublingual or buccal administration of a hormone, namely on or both of melatonin and valerian. The hormones have relatively low to poor solubility in water or other aqueous solutions. The composition comprises the hormones which are, in a first step (in some embodiments), complexed with a beta cyclodextrin or another complexation agent and in second step (in some embodiments), encased in a liposome. In a third step (in some embodiments), the molecules encased in the liposome are then dehydrated. In a fourth step, the liposomal complex is then compounded into any of a number of dosage forms either a dissolvable strip of material, a gum (malleable solid which is designed to be chewed and at least partially dissolve during chewing), lozenge (hard and non-malleable solid which is designed to be chewed or sucked and dissolve), mint (hard and flavored with menthol), tablet (hard and unflavored; designed dissolve in the mouth), or powder forms for subingual, buccal, rectal, vaginal or even nasal application.

(2) Uniquely and unexpectedly discovered during testing, the composition described above elicits a first effect denoting a preliminary Tmax (first peak of metabolic effect or maximum concentration) at around 5 to 10 minutes (where around is defined as within one minute thereof) with a pronounced secondary effect within one hour denoting a secondary uptake at the level of the small intestine and a secondary and pronounced Tmax (second peak of metabolic effect or maximum concentration).

(3) For purposes of the subject invention, it should be understood that the term melatonin is a specific hormone having low to poor water solubility. Melatonin is used as the active ingredient in compositions of the invention. It would also be understood that use of the term melatonin refers to other hormone active ingredients having low to poor water solubility, such as estrogens, progesterone, testosterone, and dihydrotestosterone. Accordingly, embodiments of the subject invention include compositions wherein an estrogen, progesterone, testosterone, or dihydrotestosterone, or combinations thereof, are substituted for or used with melatonin. It would also be understood that these hormones may be in their respective derivative form. Therefore, reference to melatonin, estrogens, progesterone, testosterone, or dihydrotestosterone includes any salt, prodrug, metabolite, isomer, or derivative thereof having low to poor water or aqueous solubility. Low to poor water or aqueous solubility is defined as having a solubility of greater than 10, 30, or 100 mass parts of water required to dissolve 1 mase part of the solute.

(4) For purposes of the invention the term valerian extract refers to either an aqueous or ethanolic extract of the plant valeriana officinialis quantified to a specific quantity of valerenic acid. In accordance with certain embodiments of the present invention, the composition comprises a mixture of both melatonin and valerian extract complexed with beta cyclodextrin and subsequently encased in the core of a liposome. In certain embodiments, the liposomal complex can be administered as a powder, a tablet, a gum, a lozenge, a strip, a mint, a vaginal suppository, or an anal suppository.

(5) The concentration of active ingredients, such as melatonin and/or valerian (alone or in combination), in the delivery form is, in some embodiments, in a range of about 2.5% to about 40%, and in some more specific embodiments, between about 10% to 20% (where about is defined as within/less than 1% thereof).

(6) The pharmaceutical composition of the subject invention may further comprise other active molecules such as terpenes having as their main effect either a soporific or relaxant effect upon the central nervous system of the patient. Such terpenes for example can be, but are not limited to, myrcene or alpha linalool. These terpenes can also be complexed with beta cyclodextrin for enhanced solubility and bioavailability of the respective terpenes. Furthermore these complexed terpenes can be further encased into the liposomal complex protecting their stability and allowing for both enhanced sublingual absorption and enhanced absorption of the complex in the small intestine.

(7) In embodiments of the disclosed technology, the composition of the subject invention is provided in a unit dose form such as dosed in a compressed tablet, strip, or gum for buccal or sublingual administration porviding rapid administration of the API upon sublingual or buccal administration of the composition.

(8) The composition of the subject invention advantageously provides the active ingredient, e.g., a hormone such as melatonin having relatively low to poor solubility in aqueous solvents, in a liposomal complexed form. Being in a highly water soluble form, the melatonin can be directly absorbed into the bloodstream through the oral mucosa having been dissolved by the aqueous environment provided by saliva in the mouth or in the gastrointestinal tract. A further advantage of the drug delivery system of the subject invention includes enhanced and rapid oral mucosal absorption of the active provided in the composition. Accordingly, this drug delivery system provides for rapid onset of drug action with higher and more consistent bioavailability both with the initial onset between 5 and 10 minutes and the secondary absorption at the small intestine providing enhanced intestinal absorption and prolonged effect. The technology described herein can be used to treat insomnia, jet lag, and/or sleep related disorders.

(9) The melatonin/valerian extract sublingual forms, in embodiments of the disclosed technology, range from approximately 0.1 mg (milligrams) to 100 mg total weight depending on the dosage form. In vitro dissolution from these rapid release formulations is substantially complete within 5 minutes and the form disintegrates under the tongue typically within a few minutes, such as less than 5 minutes, and in some cases, within one to three minutes, and in some cases, even within 30 seconds to about two minutes.

(10) A secondary absorption of some of the complexed forms occurs at the level of the small intestine prolonging the effect of the formulation beyond that absorbed at the primary mucosal surface, thus prolonging the effect on duration of sleep and sleep intensity.

(11) A single dose of active ingredient, e.g., melatonin, in some embodiments of the disclosed technology is between 0.01 mg to 3 mg and, in some more specific embodiments, between 0.2 and 2.0 mg. Valerian extract in such embodiments can be between 0.5 mg and 15 mg or more specifically between 1 mg and 10 mgs. When used in such low doses, compositions in accordance with the administration have a metabolic effect of at lest one hour and are effective in treatment of insomnia, or in causing extreme drowsiness or sleep in humans. Thus, the present invention can advantageously provide consistent and sufficiently high peak melatonin and valerenic acid blood plasma concentration (Cmax.). Consistently effective melatonin and valerenic acid blood plasma concentrations are thus achieved even when using lower melatonin and valerian extract doses than administered in currently available products.

(12) The composition can also include various other compounds of lesser concentration, preferably from 0.01 to 0.1 mg per dose, such as linalool or myrcene by way of example.

(13) While the disclosed technology has been taught with specific reference to the above embodiments, a person having ordinary skill in the art will recognize that changes can be made in form and detail without departing from the spirit and the scope of the disclosed technology. The described embodiments are to be considered in all respects only as illustrative and not restrictive. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope. Combinations of any of the methods, systems, and devices described herein-above are also contemplated and within the scope of the disclosed technology.