WO2017125924A1

WO2017125924A1 - Anxiolytic compositions

Info

Publication number: WO2017125924A1
Application number: PCT/IL2017/050070
Authority: WO
Inventors: Yoram Sela; Mor ZEILKHA; Itschak Lamensdorf
Original assignee: My Nutra Ltd.
Priority date: 2016-01-18
Filing date: 2017-01-18
Publication date: 2017-07-27

Abstract

The present invention is primarily directed to a therapeutic composition comprising caffeine, valerenic acid and 5-hydroxytryptophan (5-HTP). Additional herbal material and other natural products may also be present in the composition. The invention also encompasses the use of this composition in the treatment and/or prevention of anxiety. The composition is preferably formulated for delivery by the sublingual route, the oral route or a combination of these routes.

Description

ANXIOLYTIC COMPOSITIONS

Field of the invention

The present invention relates to therapeutic compositions having significant anxiolytic activity. More specifically, the presently-disclosed and claimed compositions comprise synergistic combinations of caffeine and valerenic acid. The compositions of the present invention may optionally further comprise one or more additional active ingredients that synergistically enhance the anxiolytic activity.

Background of the invention

Anxiety is a commonly experienced state characterized by an abnormal and overwhelming sense of apprehension and fear in response to a real or perceived (but imaginary or non- tangible) threat. The emotional components of anxiety are often accompanied by certain characteristic physiological changes, including increased perspiration, increased muscular tension, and elevated pulse rate. Various different psychiatric disorders include anxiety as at least one of their elements, and taken as a whole, anxiety and anxiety-related conditions are highly prevalent in most countries, and it has been estimated that approximately 20 million adults in the USA are affected thereby.

Examples of commonly-used anxiolytics include benzodiazepines (such as diazepam, clonazepam, lorazepam), carbamates and barbiturates. Other drug classes used to manage anxiety include those which are not primarily intended for this use, but which may have anxiolytic effects in addition to their other activities. Commonly used examples of such agents include beta blockers and antidepressants of various kinds.

In addition to the abovementioned prescription-only medicines, several different OTC drugs and supplements have been used for the management of anxiety, including chlorpheniramine, melatonin and inositol. Similarly, various plant-derived materials (e.g. from coriander, chamomile, lemon balm, passiflora, valerian). In many cases, the efficacy of certain herbal remedies and food supplements as anxiolytic agents has been brought into question. On the other hand, the long-term use of many of the powerful pharmaceutical agents used as anxiolytics is associated with undesirable effects, sometimes of such a severe nature that treatment has to be discontinued, either permanently or temporarily.

Caffeine is well known for its central nervous system (CNS) stimulatory effects, and is one of the most widely-consumed psychoactive substances, primarily in the form of tea, coffee and various other beverages. One of the negative effects that is sometimes encountered with regular caffeine consumption is anxiety. Thus, caffeine ingestion - especially at high does, such as greater than 300 mg - may either cause anxiety or worsen pre-existing anxiety. In some cases, discontinuing caffeine intake may reduce or eliminate the anxiety.

As mentioned above, valerian (derived from Valeriana species such as V. officinalis) has been found to possess a certain degree of anxiolytic activity. This effect has been the subject of several studies, some of which support the clinical use of valerian, while others conclude that while generally safe, valerian is of low efficacy in the treatment of anxiety and other psychological conditions such as insomnia.

One of the aims of the present invention is to provide novel anxiolytic compositions that have an efficacy that is at least as good or greater than many prior art anxiolytic drugs, but which exhibit no side effects, or greatly reduced side effects, when compared with said drugs. Other aims and objectives will become apparent as the description proceeds.

Summary of the invention

Although caffeine is generally considered to possess anxiogenic effects, the present inventors have unexpectedly found that at certain doses, and particularly in combination with certain other natural products, caffeine may be anxiolytic.

The present invention is thus primarily directed to a therapeutic composition that is suitable for use in the treatment or prevention of anxiety, wherein said composition comprises caffeine and valerenic acid. Preferably, the caffeine and valerenic acid (and any additional active components, as disclosed hereinbelow) are present in a synergistic combination.

The term "synergistic combination" is used to indicate that when used together, the individual components (such as caffeine and valerenic acid) cause an anxiety-reducing effect that is greater than the sum of the anxiety-reducing effect caused by each of said components when used alone. In other words, the combination of components causes a greater than additive effect.

In some preferred embodiments of the invention, the therapeutic composition may also comprise (as well as caffeine and valerenic acid) one or more additional components selected from the group consisting of 5-hydroxytryptophan (5-HTP; e.g. obtained from Griffonia simplicifolia), extracts of passiflora (e.g. Passiflora incarnata), carnosic acid, melatonin, Gingko biloba, phenylethylamine, Bacopa monnieri, Kava - Kava, St. John's wort, ginseng, hops, guarana [Paullinia cupana, also known as P. crysan or P. sorbilis) and combinations thereof.

In one particularly preferred embodiment of the invention, the therapeutic composition comprises caffeine, valerenic acid and 5-HTP.

In another particularly preferred embodiment, the therapeutic composition comprises caffeine, valerenic acid, 5-HTP and carnosic acid.

In a further preferred embodiment, the therapeutic composition comprises caffeine, valerenic acid, 5-HTP and guarana.

In another aspect, the present invention is directed to a method for treating or preventing anxiety in a mammalian subject, wherein said method comprises the administration of a dosage form containing a combination of caffeine and valerenic acid. In one preferred embodiment, said combination of caffeine and valerenic acid further comprises 5-HTP. In another preferred embodiment, said combination of caffeine and valerenic acid further comprises both 5-HTP and carnosic acid.

In one preferred embodiment, the mammalian subject is a human. The present invention is also directed to the use of the above-disclosed composition in the preparation of a medicament for treating or preventing anxiety in a mammalian (preferably human) subject.

The present invention also encompasses the use of compositions disclosed herein for the treatment of inflammatory disorders. In another embodiment, the invention is directed to compositions of the present invention for use in the treatment and/or prevention of anxiety in mammalian (preferably human) subjects.

Brief description of the drawing

Fig. 1 graphically presents results of an animal study, demonstrating the anxiolytic effect of a composition of the present invention.

Detailed description of preferred embodiments of the invention

As disclosed hereinabove, the present invention is primarily directed to a therapeutic composition that is suitable for use in the treatment or prevention of anxiety, wherein said composition comprises a combination of caffeine and valerenic acid.

The caffeine used in the compositions of the present invention may be obtained from any suitable and convenient source including, but not limited to, coffee beans, black tea, green tea and guarana (Paullinia cupana, also known as P. crysan or P. sorbilis).

Valerenic acid, as used herein, may be of any suitable and convenient source, including (but not limited to) an extract of Valeriana officinalis or a related species. The valerenic acid may be added to the composition as a crude extract of a Valeriana species, as a partially- purified extract, a highly pure extract. Alternatively, the valerenic acid may be chemically synthesized. In one preferred embodiment, the composition of the present invention comprises caffeine and valerenic acid.

In another preferred embodiment, the composition of the present invention comprises caffeine, valerenic acid and 5-HTP. In this embodiment, the active components of the composition are preferably present in a dosage form (such as a tablet or capsule), said components being present in the following preferred amounts:

Caffeine: l-200mg/dosage form

Valerenic acid: 0.2-100 mg/dosage form

5-HTP: 1-150 mg/dosage form.

More preferably, the amounts of each of the components in each dosage form are as follows:

Caffeine: 10-lOOmg/dosage form

Valerenic acid: 0.2-18 mg/dosage form

5-HTP: 5-100 mg/dosage form.

In one particularly preferred embodiment, the amounts of each of the components in each dosage form are as follows:

Caffeine: 20 mg/dosage form

Valerenic acid: 4 mg/dosage form

5-HTP: 35 mg/dosage form

In a still further preferred embodiment, the composition of the present invention comprises caffeine, valerenic acid, 5-HTP and carnosic acid.

In one particularly preferred embodiment, the compositions and dosage forms of the present invention comprise a minimum of 2 mg valerenic acid. In one typical (but non-limiting) preferred embodiment, a dosage form containing the composition of the present invention may comprise the following components, at the amounts shown:

Caffeine: 20 mg/tablet

Valerenic acid: 4 mg/tablet

5-HTP: 35 mg/tablet

Carnosic acid: 3 mg/tablet

Vitamin E-TPGS: 10 mg/tablet

In one preferred embodiment, the ratio between the amount (expressed in moles) of each of the key active components of the composition of the present invention is in the range of:

Caffeine: Valerenic acid: 5-HTP 1-10: 0.1 - 5: 5-50

In a further preferred embodiment, the ratio between the amount (expressed in moles) of each of the key active components of the composition of the present invention is:

Caffeine: Valerenic acid: 5-HTP

6: 1: 9

Preferably, dosage forms (such as tablets, capsules and caplets) containing the composition of the present invention comprise at least 2 mg valerenic acid per unit dosage form.

The compositions of the present invention may be administered by any convenient route. Most preferably, the compositions are administered by the oral and/or sublingual route. When prepared for use by these routes, the composition may be formulated such that it provides immediate release (I ) of the active ingredients or controlled release (CR; for example, delayed release and sustained release), or a combination of I R and CR within a single dosage form. In other embodiments of the present invention, the composition may be administered by an injectable route, such as intravenously or intramuscularly.

Generally, each dosage form unit for either oral or sublingual use will contain about 10-150 mg of caffeine and 10-900 mg of valerian. The total concentration of valerenic acid and its major derivatives, hydroxyvalerenic acid and acetoxyvalerenic acid within the valerian extract is generally in the range of 0.1 -10%. When used, 5-HTP is present at a dose of 5- 100 mg in each dosage unit.

In one preferred embodiment, the composition of the present invention is formulated such that a single dosage form comprises 20 mg of caffeine and 4 mg of valerenic acid.

In another preferred embodiment of the invention, the composition of the present invention is formulated such that a single dosage form comprises 20 mg of caffeine, 4 mg of valerenic acid and 35 mg of 5-HTP.

In a further preferred embodiment, the composition comprises 20 mg of caffeine and 35 mg of 5-HTP.

In yet another preferred embodiment, the therapeutic composition comprises a synergistic combination of one or more stimulants selected from the group consisting of caffeine, guarana and ginseng, and one or more anxiolytic-sedative agents selected from the group consisting of valerenic acid, hops, Kava-Kava and passiflora.

The above-disclosed dosage forms may be formulated for sublingual administration, as is well known in the art. Up to two doses of each of these formulations may be administered at any one time.

In one preferred embodiment, the sublingual tablet can be prepared as a double layer tablet where one part of the tablet dissolves and absorbed sublingually, while ER components are swallowed and released continuously in the Gl tract during the subsequent 1-12 hours. In some preferred embodiments, the sublingual tablet can be prepared as a presscoat tablet, wherein one or more of the active ingredients is contained in the external layer in immediate release (I R) form, while the internal core contains one or more said ingredients in controlled release (CR) form.

The controlled release components of the dosage form may be prepared in accordance with any of the methods known to the skilled artisan in this field. Generally, in CR dosage forms the active pharmaceutical (or nutraceutical) ingredient is embedded within an insoluble matrix. The matrix is generally porous, and the active ingredient exits the matrix via the pores. In other types of CR formulation, the active ingredient is dissolved within a polymeric matrix which swells, thereby forming a gel through which said active ingredient needs to exit. In another approach, micro-encapsulation is used, whereby an inert core is coated with the active ingredient and then surrounded by one or more layers of insoluble envelope materials, the number, type and thickness of which may be selected in order to obtain the desired release characteristics. Many different types of controlled release polymer may be used to manufacture these various types of CR formulations, including (but not limited to): hydroxypropylmethyl cellulose, microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose, ethyl cellulose, and other cellulose derivatives, polymethacrylic copolymers, poloxamers, polyoxyethylene stearate, polyvinylpyrrolidone, polyvinylpyrrolidone- polyvinylacetate copolymers, polyvinyl alcohol, polyethylene oxide, and gums (e.g., xanthan gum or guar gum).

In one preferred embodiment of the present invention, the controlled release components of the dosage form are matrix minitabs, coated minitabs or coated microcapsules prepared by multistage layering or extrusion and spheronization followed by functional coating.

In addition to the active ingredients, the dosage forms of the present invention may further comprise one or pharmaceutical excipients, including (but not limited to) binding agents, bulking agents, fillers, diluents, additional release-control polymers, polymeric matrices, disintegrants, flavors, coating agents, penetration enhancers, and so on. In one preferred embodiment, the dosage form further comprises one or more penetration enhancers. Examples of two suitable penetration enhancers are menthol and vitamin E- TPGS.

It is to be noted that the plant-derived material used in the manufacture of the compositions of the present invention (e.g. valerian and caffeine-containing plant material such as green tea or guarana) is obtained in any of the various forms well known to the skilled artisan in this field, including: dried plant material obtained from roots, leaves, shoots, flowers and whole plants; aqueous and non-aqueous extracts; teas or tisanes; decoctions and tinctures; oils.

As disclosed hereinabove, the compositions of the present invention may also be administered by the oral route instead of, or in addition to, sublingual delivery.

As disclosed hereinabove, in another aspect, the present invention is also directed to a method for treating or preventing anxiety in a mammalian (preferably human) subject, wherein said method comprises the administration of a dosage form containing a combination of caffeine and valerenic acid.

In one preferred embodiment of this aspect of the invention, said dosage form further comprises 5-HTP. In another preferred embodiment, said dosage form further comprises both 5-HTP and carnosic acid.

In the embodiments of the method disclosed immediately hereinabove, the amount of each of the three main active components administered to a human subject (per day) are preferably as follows:

Caffeine: 15-50 mg/day

Valerenic acid: 2-8 mg/day

5-HTP: 20-50 mg/day Preferably, the dosage form is a sublingual tablet as disclosed and described hereinabove, and preferably, the administration of the dosage form is performed sublingually. In other preferred embodiments, the administration is performed by the oral route or by a combination of the oral and sublingual routes. In still further preferred embodiments, the synergistic combination may be administered by a parenteral route such as intramuscular or intravenous injection.

In any of the methods of treatment defined above, the dosage form used may further comprise one or more further active ingredients such as plant-derived material, vitamins, minerals, 5-HTP, tryptophan and other amino acids, as described hereinabove.

Example

In the following non-limiting example, the valerian extract (containing 2% valerenic acid) was purchased from Indo World Trading Corp., Badarpur, India, while the caffeine was obtained from BASF and the 5-HTP was obtained from Jiaherb. Other standard reagents and materials were purchased from various different laboratory and pharmaceutical suppliers.

Example 1

Synergistic interaction between caffeine, valerenic acid and 5HTP: anxiolytic effect

Method:

The Elevated Plus Maze (EPM) test was used to assess anxiety-related behavior in rodent models of CNS disorders. The EPM apparatus consists of a "+"-shaped maze elevated above the floor with two oppositely positioned closed arms, two oppositely positioned open arms, and a center area. This test can be used to screen for putative anxiolytic compounds. In this test a rat is placed in the center area of the maze with its head directed toward a closed arm. The number of entries (an entry is defined as the center of mass of the rat enters the arm) into each arm and the time spent in the open arms are recorded and these measurements serve as an index of anxiety-like behavior. Rats are allowed to move freely about the maze for 5 min. Rats were tested on Elevated Plus Maze 30 min after administration of test items. The time spent in the open arm ("open arm latency"; expressed as a percentage of the time spent in the maze) is one of the indexes used for evaluating anxiety-like behavior, with non-anxious (or less anxious) animals spending more time in the open arm.

The following treatment agents (separately, and in some cases in binary and ternary combination) were compared using this experimental model:

Results:

The results of this study are presented graphically in Fig. 1, and summarized in the following table:

Baseline Treatment With Caffeine

(no

caffeine)

Vehicle 8% 7% 17%

Valerian 10% 15%

5HTP 15% 30% 38%

5HTP+Valerian 15% 25% 70%

Diazepam 5% 20% It may be seen from these results (as shown in the above table and in Fig. 1) that binary combinations of valerenic acid with 5HTP, and 5HTP with caffeine appeared to have less anxiolytic activity than would have been predicted from the sum of the activities of each member of the binary pair (i.e. less than additive effect).

However, the ternary combination: valerenic acid, 5HTP and caffeine caused a much larger than expected (i.e. greater than additive) anxiolytic effect, indicating that there is a synergistic interaction between these components when all three are present in combination.

It is also to be noted that the total anxiolytic effect achieved with the ternary combination (70%) was significantly greater than the anxiolytic effect obtained with the diazepam positive control (20%).

Claims

1. A therapeutic composition comprising caffeine, valerenic acid and 5-hydroxytryptophan (5-HTP).

2. The therapeutic composition according to claim 1, when said composition further comprises guarana.

3. The therapeutic composition according to claim 1, wherein said composition further comprises one or more additional components selected from the group consisting of carnosic acid, melatonin, phenylethylamine, extracts of passiflora, Gingko biloba, Bacopa monnieri, Kava - Kava, St. John's wort, ginseng and hops.

4. The therapeutic composition according to claim 1, wherein the caffeine is obtained from green tea.

5. The therapeutic composition according to claim 1, wherein said composition is formulated as a dosage unit containing 10-100 mg caffeine, 0.2-18 mg valerenic acid and 5- 100 mg 5-HTP.

6. The therapeutic composition according to claim 5, where each dosage unit comprises 20 mg caffeine, 4 mg valerenic acid and 35 mg 5-HTP.

7. The therapeutic composition according to claim 1, wherein said composition is formulated for sublingual administration.

8. The therapeutic composition according to claim 1, wherein said composition is formulated for oral administration.

9. A method for treating or preventing anxiety in a mammalian subject, wherein said method comprises the administration of a dosage form comprising caffeine, valerenic acid and 5-HTP.

10. The method according to claim 9, wherein the dosage form is administered by the sublingual route, the oral route or a combination of the sublingual and oral routes.

11. The method according to claim 9, wherein the dosage form further comprises one or more additional components selected from the group consisting of carnosic acid, phenylethylamine melatonin, extracts of passiflora, Gingko biloba, Bacopa monnieri, Kava - Kava, St. John's wort, ginseng and hops.