AU2008100919B4 - Method for and Composition of Excipient Suitable for Use in Herbal Formulations and Formulations Derived Therefrom - Google Patents

Description

P0/00=2 Regulabon 3.28 AUSTRALIA Patents Act 1990 ORIGINAL COMPLETE SPECIFICATION INNOVATION PATENT Application No. Lodged: 19 September 2008 Innovation Title: METHOD FOR AND COMPOSITION OF EXCIPIENT SUITABLE FOR USE IN HERBAL FORMULATIONS AND FORMULATIONS DERIVED THEREFROM The following statement is a full description of this innovation, including the best method of performing it known to the Applicant, GreenTaste Pty Ltd: 2 METHOD FOR AND COMPOSITION OF EXCIPIENT SUITABLE FOR USE IN HERBAL FORMULATIONS AND FORMULATIONS DERIVED THEREFROM FIELD OF INVENTION The present invention relates to the field of human and animal health, 5 nutrition and wellbeing. In one form, the present invention relates to liquid formulations comprising excipients suitable for application in the ingestion of substances. It will be convenient to hereinafter describe the invention in relation to foods, beverages, supplements, active ingredients, excipients, natural or synthetic, in their application to therapy, prevention, treatment, nutrition and 10 diagnosis, however it should be appreciated that the present invention is not limited to that use, only. BACKGROUND ART Throughout this specification the use of the word "inventor" in singular form may be taken as reference to one (singular) inventor or more than one (plural) 15 inventor of the present invention. Consumers have embraced the benefits of herbal medicine and nutritional supplements to the extent that the current widespread use is based on a combination of "mass market" acceptance, advice from complementary medicine practitioners and nutritionists, and an increasing endorsement from conventional 20 medicine practitioners. Such acceptance is now driving practitioner and consumer/client expectations for more effective, better tasting and/or more efficacious forms of preventative healthcare and self-medication. Accordingly, herbal medicine is considered a major contributor to consumer health in Australia and the benefits are marketed through professional practitioner, retail and direct 25 marketing channels. Traditional liquid herbal formulations have an established market base through complementary health practitioners and a small market base in retail and direct marketing channels. In each of these marketing channels consumer acceptance is limited due to presence of alcohol, usually ethanol and/or glycerol, 30 and taste characteristics that limit acceptance and compliance. Furthermore, the presence of alcohol in such formulations is contraindicated in a significant proportion of consumers with gastrointestinal or liver disease; who are pregnant; who have certain religious beliefs; who have a predisposed genetic susceptibility 3 to alcohol; who are taking certain other drugs; who have a history of alcoholism; who are operating machinery, transport vehicles or aircraft under strict blood alcohol regulations; who are convalescing from medical intervention, or who are children. 5 Some compositions of liquid herbal medicines have attempted to reduce or overcome the issue of alcohol content in the formulations by substituting alcohol in the form of ethanol with another alcohol, glycerol. In these cases glycerol has been used as a preservative and also as a taste modifier due to its artificial sweet taste. Nonetheless, glycerol is also an alcohol, presents a glycaemic load, and 10 for some has an unpleasant "mouth feel" and artificial taste. The perceptions and effects of ingesting excipients of natural and non animal origin are of importance to consumers. Furthermore, in many existing products the source of glycerol is usually not disclosed to consumers and while glycerol from vegetable sources can be obtained, it is expensive and often mixed 15 or substituted by glycerol produced as a by-product of biodiesel production or as a by-product from saponification of animal fat in soap making. It is considered that the advantages of substituting glycerol for ethanol are that it has allowed removal of ethanol and provided for a degree of taste substitution in the formulations. However, there are significant disadvantages of 20 using glycerol, in particular, the expense and often uncertain origin. Moreover, glycerols, being a form of alcohol do not mean the resultant formulations are entirely free from alcohol. Glycerols also have an artificial taste. Furthermore, medicines based on botanical and fungal extracts are complex mixtures of chemical components, many of which are subject to oxidation and other chemical 25 instabilities. Neither alcohols nor glycerol provide the required antioxidant and molecular stabilising properties. In contrast, components specifically conferring anti-oxidant properties enhance the stability of botanical and fungal extracts. Other compositions of liquid herbal medicines have retained either an alcohol such as ethanol or, have used glycerol for their preservative function and 30 added flavours (natural or synthetic) and/or fruit juice concentrates to address the unpleasant taste profile/s. The formulations which have added fruit concentrates and/or flavours have achieved a greater degree of taste modification, however, fruit concentrates, extracts, pulps, balms and flavours are very sensitive to 4 oxidation and this sensitivity has an impact on the reliability of their taste properties. Also there may be a necessity for adding a benzoate for the preservation function, which is considered a significant disadvantage. Benzoates are found 5 naturally in certain fruits and spices but are considered to have potential health implications that may be contrary to the fundamental benefits of health promoting herbal formulation(s). Honey has occasionally been attempted as an alternative to alcohol or glycerol, or in combination with reduced concentrations of alcohol and/or glycerol, 10 but suffers from major drawbacks. At too low a concentration the sugar in honey can support fermentation by contaminating yeasts. At levels providing antimicrobial activity honey presents a high glycaemic load that is contraindicated in consumers with metabolic disorders, and limits flexibility with taste modification of herbal characteristics due to its dominating taste at such concentrations. 15 Generally, it can be stated therefore that three great disadvantages of current liquid herbal medicines exist; firstly, the presence of alcohol (including glycerol) in formulations which results in both health contra-indications and unpleasant taste contributing in turn to poor consumer compliance, secondly, the lack of acceptable alternative compositions to replace benzoate preservatives 20 when required, and thirdly, the lack of specific antioxidants to stabilise actives as well as flavour-modifying juice extracts, concentrates, pulps, balms, sera and flavours. It was previously known that licorice, stevia or other strong or sweet tasting herbs could be included as a taste modifier. If licorice or other naturally strong 25 tasting herbs are added for taste modification effects, then either alcohol or benzoates are commonly added for preservative function. However, licorice for example is a valued active ingredient for specific indications and should not be used as a general excipient. Thus, due to its active constituents, licorice presents taste and compliance issues and importantly compromises regulatory status by 30 using the "active" licorice as an "excipient", per se. Generally, while the liquid herbal product category is currently a relatively small niche, growth has been limited due to lack of innovation and the disadvantages of current offerings based 5 on formulations containing alcohol, honey, glycerol and/or licorice, or benzoates as taste-masking and/or preservative excipients. The discussion throughout this specification comes about due to the realisation of the inventor and/or the identification of certain related art problems 5 by the inventor and, moreover, any discussion of documents, devices, acts or knowledge in this specification is included to explain the context of the invention. It should not be taken as an admission that any of the material forms a part of the prior art base or the common general knowledge in the relevant art in Australia or elsewhere on or before the priority date of the disclosure and claims herein. 10 SUMMARY OF INVENTION It is an object of the embodiments described herein to overcome or alleviate at least one of the above noted drawbacks of the related art or to at least provide a useful alternative to related art. In a first aspect of embodiments described herein there is provided a 15 composition of matter comprising an excipient for use in formulating ingestible substances wherein the excipient comprises one or a combination of: a herbal stabiliser; a herbal antimicrobial agent; an antifungal agent 20 In one preferred form, the composition of matter comprises an excipient for a liquid formulation wherein the excipient comprises a combination of: herbal extract as a botanical stabiliser; hops beta acids as antimicrobial agent; and sorbate as an antifungal agent in an acid environment of less than pH 6.5; 25 wherein the liquid formulation comprises no added ethanol or glycerol or benzoates. It will be appreciated by the person skilled in the art that the term 'no added ethanol or glycerol or benzoates' means that these substances are not includes as a per se component of the excipient. 30 The herbal stabiliser preferably comprises a botanical extract having anti oxidant properties. The herbal stabiliser may be present in a concentration ranging from about 1:1 extract ratios to about 2 parts per million.

6 The herbal antimicrobial agent is preferably present in a. concentration ranging from about 1:1 extract ratios to about 2 parts per million The antifungal agent may be of botanical origin and is preferably present in a concentration ranging from about 1:1 extract ratios to about 10 parts per million. 5 In a second aspect the present embodiments provide a liquid herbal formulation comprising an excipient wherein the excipient comprises one or a combination of: a botanical stabiliser, and; a hops extract. In a third aspect of embodiments, there is provided a liquid herbal formulation comprising an excipient wherein the excipient comprises one or a 10 combination of: a botanical stabiliser selected from one of rosemary extract, sage, thyme, vitamin E and witchhazel; an antimicrobial agent selected from one of a hops extract, alpha acids, beta acids, and benzoate, and; 15 an antifungal agent selected from one of apple, cinnamon, cranberry, ginger, peppermint, sorbic acid, tea tree, and sorbate in an acid environment of less than about 6.5pH; The botanical stabiliser is preferably rosmarinic acid that may be provided as a standardised rosemary extract. In preferred forms, a botanical stabiliser is 20 provided by rosemary extract standardised to not less than about 4.5% rosmarinic acid and may be water soluble and/or deodorized. The hops extract may comprise beta acids, which may be purified from hops. Preferably, the beta acids are present in a concentration of about 10% and, in preferred forms the beta acids may comprise lupulone, colupulone, and 25 adlupulone. A liquid herbal formulation in accordance with preferred embodiments may further comprise sorbate wherein the sorbate is preferably present in a concentration of about 0.01% to about 1%. In an alternate form, one embodiment provides a liquid herbal formulation 30 as noted above in which the beta acids may be substituted, in whole or in part, with antimicrobially active benzoate.

7 In another aspect of embodiments described herein there is provided a method of manufacturing a liquid herbal formulation, the method comprising the steps of: mixing an excipient composition comprising one or a combination of an 5 organoleptic modifier of botanical origin; a herbal stabiliser, a herbal antimicrobial agent and an antifungal agent of botanical origin in an aqueous solution; mixing at least one therapeutically active substance in an aqueous solution; combining the mixed excipient composition and the at least one mixed 10 therapeutically active substance to a predetermined volumetric concentration in an aqueous solution. The method preferably further comprises the steps of: separately weighing a predetermined required quantity of all ingredients, which may be listed as Parts A, B C ,D and E and storing these in suitable containers. In this example, Part A 15 constitutes the active herbal ingredients (vitamin, pharmaceutical etc), Part B constitutes the antifungal agent, which preferably further comprises a pre determined amount of purified water at a pH of not more than about 6.5. Part C constitutes the organoleptic modifier(s), Part D constitutes the botanical stabiliser components. Part E may preferably constitute the antimicrobial agent and a pre 20 determined amount of water at a pH of not less than about 7. Preferably, the following blending steps are utilised: For Part B as described in the example above, the method may further comprise the step of heating the purified water to a temperature equal to or greater than about 250C then add the antifungal agent and mix until dissolved. 25 Check that the pH at no time exceeds about 6.5. The method may further comprise the steps of: mixing Part E (the antimicrobial) with a pre-determined amount of purified water; mixing Part D (the herbal stabiliser) with a pre-determined amount of 30 purified water; mixing components of Part C together. blending each of these Parts B, D and E in tum with Part C, the organoleptic components.

8 i.e. with mixing commenced, add Parts B, D and E to Part C and mix until blended evenly. Slowly add Part A to mixture until all constituents are evenly dissolved. Bring volume up to specified volume with additional purified water, all the 5 time ensuring that the pH is less than approximately 6.5. For formulations involving actives in Part A that are particularly "tarry" or hydrophobic e.g Hypericum perforatum, mixer speeds need to be high enough to ensure a homogenous mixture. Preferably, the method steps are performed at ambient temperature in the 10 range of about 4 0 C - about 30 0 C. In yet a further aspect of embodiments described herein there is provided a method of manufacturing an excipient composition for use in the formulation of ingestible substances, the method comprising the steps of segregating the above noted excipients into Parts B and C and processing each excipient in accordance 15 with the above noted blending steps individually in isolation. Other aspects and preferred forms are disclosed in the specification and/or defined in the appended claims, forming a part of the description of the invention. In essence, embodiments of the present invention stem from the realization that natural extracts and/or compounds that are used in the sugar, 20 food and beverage industries primarily for their taste modifying and preservative properties and being acceptable to regulatory authorities, practitioners and consumers can provide, in newly devised combinations, a substitute for alcohol or other active excipients in herbal formulations. Advantages provided by the present invention comprise the following: 25 * Formulations in accordance with embodiments of the invention have a base of natural excipients, standardised concentrates or extracts thereof, or purified compounds of natural origin to preserve the active constituents in the absence of alcohol. Preferred formulations contain no added alcohol or glycerol, no sucrose, glucose or artificial sweeteners, no colours, no 30 artificial flavours and no gluten. Accordingly, the relevant active constituents are fully active and the efficacy of traditional extracts is retained in the presence of the organoleptic modifiers; 9 e Preferred formulations contain specific components that are capable of slowing or preventing oxidation of other components in the formulation that are part of the active and organoleptic modifier function. Such components may comprise excipients with chemical properties exhibited 5 by polyphenols, tannins, vitamins and thiols, all being examples of compound classes that inhibit oxidative reactions by being oxidized themselves. * Preferred formulations may use stabilisers, antimicrobial and antifungal excipients in a form containing the most effective natural constituents in a 10 concentrated or purified form, thereby minimising unwanted components or interference with the active constituents; e The formulations of preferred embodiments are designed to be naturally pleasant tasting and palatable without undue masking of the taste of the herbal constituents or compromising gastrointestinal tract response to 15 bitter principles and other active constituents; e The components in the formulations of preferred embodiments are naturally occurring; e Health contra-indications associated with alcohol, glycerol and honey are eliminated due to their absence, improving practitioner recommendation 20 and consumer compliance, and increasing market penetration of the liquid herbal formulation market; e Sweetening agents are not required due to elimination of alcohol and effective taste modification from the organoleptic taste modifiers; e No licorice or other strong or sweet tasting herbs are used as a taste 25 masking and compromising excipient; e Simplified manufacturing process provides high margins due to low costs of blending/mixing and packaging of herbal preparations; * Elimination of the use of alcohol and other common additives in liquid therapeutic formulations and therefore also the contraindications and 30 disadvantages associated with these. e Taste profiles of formulations are significantly improved by using natural excipients - all of botanical origin.

10 * Preservatives derived from plant origins are used for product stability. Further scope of applicability of embodiments of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while 5 indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure herein will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS 10 Further disclosure, objects, advantages and aspects of preferred and other embodiments of the present application may be better understood by those skilled in the relevant art by reference to the following description of embodiments taken in conjunction with the accompanying drawings, which are given by way of illustration only, and thus are not limitative of the disclosure herein, and in which: 15 Figures Ia and lb are a graphical illustration of a High Pressure Liquid Chromatograpy (HPLC) elution profile for components in a dry extract of Siberian Ginseng and corresponding components detected in liquid compositions according to a preferred embodiment of the invention; Figure 2a and 2b are a graphical illustration of a High Pressure Liquid 20 Chromatograpy (HPLC) elution profile for components in a dry extract of Panax Ginseng and corresponding components detected in liquid compositions according to a preferred embodiment of the invention; Figure 3a and 3b are a graphical illustration of a High Pressure Liquid Chromatograpy (HPLC) elution profile for components in a dry extract of St John's 25 Wort and corresponding components detected in liquid compositions according to a preferred embodiment of the invention; Figures 3c and 3d are graphical representations of a mass spectrogram of components in a dry extract of St John's Wort and corresponding components detected in liquid compositions according to a preferred embodiment of the 30 invention; Figure 3e is a graphical representation of a High Pressure Liquid Chromatograpy (HPLC) elution profile for components in a dry extract of St John's 11 Wort and corresponding components detected at 520 nm in liquid compositions according to a preferred embodiment of the invention. DETAILED DESCRIPTION For the purposes of this description, it is to be noted that, although it may 5 be common in the art for usage of the term "herbal" to refer to herbal formulations and herbal medicines that predominantly include herbs, it is to be taken herein that such compositions, in accordance with the present embodiments, may be derived not only from herbs per se but also from other botanical or fungal components. Accordingly, compositions of the present embodiments may be 10 derived from ingredients that may comprise herbs, spices, fruits, vegetables, fungi such as mushrooms and yeast. Accordingly, use of the term "herbal" in the appended claims is not limiting the claims to a particular botanical element or plant. Further, the term "herb" as used herein and in the appended claims may be taken as giving the same meaning as "herbal extract" or "active herbal 15 constituent". "Complementary medicine" as used herein may also be taken as reference to "herbal medicine" and /or "nutritional medicine". In preferred aspects of the present invention, the inventor has provided commercially useful solutions for the herbal medicine and associated pharmaceutical industry which offer liquid herbal formulations that are a) free from 20 alcohol, b) stable using novel plant based preservatives and c) selectively taste modified. Furthermore, the use of glycerol in formulations has been addressed where the inventor has recognised that the taste aspect of glycerol is a question of degree. For instance, it may be better than alcohol and may also be influenced by the herbal constituents being used in formulations. 25 Preferred formulations in accordance with embodiments of the present invention desirably use herbal antimicrobial agents to replace the addition of benzoate/s which may confer unwanted health and/or consumer acceptance consequences. Although certain embodiments described herein may also include benzoate(s) as a preferred antimicrobial preservative.

12 A further preferred aspect of formulations according to embodiments of the invention is the use of herbal or vitamin stabilizers to preserve properties of the formulation. It is highly preferable not to use excipient botanical extracts, such as 5 licorice, stevia, marshmallow and others as part of the therapeutic claims of the formulation or to have such excipients at a level where they are conferring unwanted therapeutic or other side-effects. In a preferred embodiment, botanical extracts with a known preservative property as exemplified in Appendix 1 are specifically identified and where 10 possible concentrates are used that retain the active preservative constituents but reduce or eliminate other interfering constituents. For example, rosemary (Rosmarinus officinalis) is a known stabilising preservative. One of its constituents, rosmarinic acid is a highly effective natural antioxidant for the food, beverage and cosmetic industry. While crude herb extract can be used, it has a 15 strong characteristic odour and the content of the specific components has not been optimized, In the case of using rosemary as a stabilizer, preferred embodiments use water soluble, deodorized rosemary extract standardised to not less than about 4.5% rosmarinic acid. It is considered that this has not been used before for liquid herbal formulations. For the purposes of this description, a 20 stabilizer comprising rosemary is to be taken as reference to substances comprising rosemary extract derived from the plant source and standardised to contain rosmarinic acid. Another example is provided by the antimicrobial action of hops (Humulus lupulus). Hops have been widely used in the brewing industry for their 25 characteristic taste properties. More recently, the antibacterial activity of concentrated hops extracts has been used in the food, beverage and sugar industries. One of the constituents in hops, beta acids (comprising lupulone, colupulone and adlupulone), has properties similar to sodium benzoate and has been suggested as a substitute for this preservative in the food and beverage 30 industries. While crude hops extracts can be used as an antimicrobial, they have a very bitter taste and other constituents that confer pharmacological activities. In the case of using hops as an antimicrobial excipient a preferred embodiment uses beta acids extracted from hops and standardized to about 10% w/w. At the 13 concentrations used in the preferred embodiments any bitterness or aroma is negligible. It is considered that this has not been used before for liquid herbal formulations. For the purposes of this description, a hops extract is to be taken as reference to substances comprising one or a combination of the following: a 5 base of hops, in particular beta fraction; hop extracts as may be known in the art, in particular THIAA (tetrahydro-iso-alpha acid), RHO (dihydro-iso-alpha acid), isomerised hop extract (IHE), isomerised hop boiler extract, hop emulsion, beta emulsion One preferred embodiment is based on a unique approach to addressing 10 five component areas when developing formulations for liquid medicines. Preferred formulations are based on specific consideration of the following five component areas: 1. Herbal or pharmaceutical active(s) - The choice of botanical, fungal, nutritional, that is herbal in this context or pharmaceutical actives depends on the 15 therapeutic indication and label claims being sought. All dose levels and herb, nutritional supplement or drug specifications are chosen for the purpose of therapeutic claims and whenever possible, standardised extracts and components are preferred. It is also to be taken that herbal or pharmaceutical actives, in this context, may comprise nutritional supplements as may be known 20 by the person skilled in the art. 2. Taste and organoleptic modifiers - Taste and organoleptic modifiers of botanical, fungal or nutritional origin are chosen to achieve the desired level of taste modification or masking as well as modifying mouth feel. The type and amount of modifier depends on the herb, drug or their combinations to be 25 included in the formulation and the quantity of the herbal extract or drug. Aligning the taste properties of the herbal extract(s) or drug(s) and modifiers is an important aspect of achieving formulations acceptable to both practitioners and consumers. Whenever possible standardised taste and organoleptic modifiers are preferred. 30 3. Stabiliser(s) - Potential changes in formulation stability due to oxidation and changes in degree of polymerisation are minimised through the addition of specific botanical or nutritional extracts having anti-oxidant activity. Whenever possible standardised stabilisers are preferred and antioxidant activity 14 is due to the presence of, but not limited to, phenolic acid, carnosolic acid, rosmarinic acid, camosic acid, caffeic acid, ursolic acid, betulinic acid, rosmaridiphenol and rosmanol An example of standardisation is to use rosmarinic acid as a reference in the botanical stabiliser extract. 5 4. Antimicrobial(s) - Potential endogenous or exogenous microbial contamination is managed through the addition of botanical extracts with strong anti-microbial action. Whenever possible standardised and concentrated antimicrobials are preferred. 5. Food grade antifungal - The spectrum of antimicrobial preservative 10 activity is increased through specifically addressing the challenge potentially presented by yeast and fungal contamination through the addition of a food grade antifungal agent of natural origin. Each of the above five components may be included in a preferred herbal formulation. When combined, these components may then be used to develop 15 formulations containing single or multiple herbal, nutritional or pharmaceutical active ingredients. An aim of preferred embodiments is to eliminate entirely the need for alcohol in the formulations (including its occasional substitute glycerol). The elimination of alcohol from liquid herbal formulations means they can 20 be prescribed and consumed by consumers who currently fall into the main contraindicated groups for whom alcohol is inappropriate including infants and children, the elderly, those with disturbed gastrointestinal tract function and/or liver damage, those convalescing from surgery, those requiring "zero" blood alcohol levels for equipment and vehicle operation, alcoholics, and those who are 25 opposed to alcohol consumption. A significant issue for many consumers and their subsequent compliance with treatment or therapy is the unacceptable taste of liquid herbal medicines in their current formulations. This poor taste arises from excipients such as alcohol, and excessive licorice, and the therapeutic herbal extracts themselves. A major 30 challenge in the formulation of liquid herbal medicines has been the removal of alcohol, which exacerbates the unpleasant taste of liquid formulations and heightens the need for powerful excipients to mask alkaloids, tannins and other potentially unpleasant tasting compounds in herbal extracts.

15 According to preferred embodiments, compliance may be enhanced through effective taste-modification with natural botanical extracts, juices, concentrates, pulps, sera as exemplified in Appendix 1 rather than the clumsy and suboptimal taste masking attempted through use of glycerol, licorice extract 5 or honey. While a minority of consumers accept that the characteristic tastes of herbal extracts and alcohol are a part of treatment with complementary medicines, the majority of consumers find the taste unacceptable with the consequence that the compliance required for effective treatment with herbal medicines is significantly compromised. 10 Preservatives are necessary in all forms of liquid herbal extracts, without which the shelf-life of the medicines is compromised. Formulations according to preferred embodiments contain natural preservatives of botanical origin that ensure antimicrobial activity and allow development of formulations having an appropriate and acceptable shelf-life. The preferred excipients are highly 15 effective preservatives conferring stabilisation and antimicrobial activities to the formulation. The preferred preservatives used are recognised safe preservatives used in the food and beverage industry. Such preferred formulations contain rosmarinic acid, beta acids and sorbate as preservatives. 20 It is advantageous to identify key parameters and quantities of specific classes of excipients that can be used to create a successful formulation. Once a particular herb extract(s), vitamin (s) or drug(s) and/or herbal or pharmaceutical active is determined to form the basis for a formulation, the following is used to define the precise excipients and their quantities. 25 1. Stabiliser excipient(s) - Typically, the stabilising component is based on a botanical extract with strong anti-oxidant properties such as rosemary extract, grape seed extract and other anti-oxidant extracts. Preferred stabilisers are listed in Appendix 1. The concentration of stabiliser used in a formulation depends on a) its impact on taste and organoleptic feel, b) any potential 30 therapeutic effect or side effect conferred on the formulation, and c) the requirements for stabilisation related to specific herbal extracts and excipients. Depending on the type and amount of active herb, vitamin or drug, the stabiliser would be added in concentrations ranging from 1:1 extract ratios to quantities as 16 low as 2 parts per million. The stabilising properties are ideally conferred by, but not limited to, the presence of phenolic acid, camosolic acid, rosmarinic acid, carnosic acid, caffeic acid, ursolic acid, betulinic acid, rosmaridiphenol and rosmanol. 5 2. Antimicrobial excipients(s) - Typically, the antimicrobial component is based on a botanical extract with strong antimicrobial properties such as hops extract, ginger extract and other antimicrobial herbal extracts that are not part of the therapeutic claims. Typical sources of antimicrobials are listed in Appendix 2. The concentration of antimicrobial used depends on a) the requirement for 10 antimicrobial action, b) estimated microbial load (qualitative and quantitative), c) any potential therapeutic effect or side effect conferred on the formulation and d) the impact on taste modification. Depending on the type and amount of active herb, vitamin or drug the antimicrobial would be added in concentrations ranging from 1:1 extract ratios to 2 parts per million. The antimicrobial activity can be 15 conferred by a variety of components in botanical extracts described in Appendix 3 and can be specifically exemplified by beta acids from hops. In an alternative form, one preferred embodiment provides for benzoates to be included as an antimicrobial in the presence of a preferred antifungal as a substitute for ethanol in liquid botanical formulations. 20 3. Antifungal excipient(s) - Formulations may also include addition of a specific antifungal excipient to provide additional protection from potential growth of yeast and fungal spores. Typical sources of antifungals are listed in Appendix 3. The concentration of antifungal used depends on the anticipated fungal load and is up to that concentration permitted by regulatory authorities. The preferred 25 antifungal excipient is sorbic acid and its salts and preferably, the sorbate is present in an acidic environment of less than about pH 6.5. In one preferred form, hops beta acids standardised to 10% may be provided in a concentration range of about 0.01% to about 1 % and are combined with sorbates in a concentration range of about 0.01% to about 1%. In 30 accordance with this embodiment a synergistic effect is observed between the beta acids and sorbate enabling antifungal activity of the sorbates at the lower noted concentrations.

17 Many different single and multiple herb formulations have been created as exemplified in Examples 1, 2, 3, 6, 7, 8, and Appendix 4. All formulations can be achieved using excipients of natural origin or derivation. The inventor has worked with all the major herbal extracts used in 5 consumer and practitioner products in Australia and has not observed drawbacks to the use of the preferred embodiments with respect to the major herbal extracts. Manufacturing requires a simple three stage process, preferably at ambient temperature; - a) mixing of each of four groups of excipients in water, b) mixing of actives together, where more than one are present and c) combining excipients 10 and actives to volume with water. As an exemplary production method, manufacturing at approximately the 200 litre batch scale has been used to produce products in their final presentation form. Standard stock batch size is considered to be at least 2,000 litres. Unlike other products, each formulation produced in accordance with 15 preferred embodiments comprises a distinct fruit flavour profile that best suits the active constituents and also where possible reflects the functionality of the actives. It should be noted that there are two distinct markets for such formulations and these are diametrically opposed in terms of purpose for formulation. The retail market formulations need to reflect distinct functionality 20 and concomitant flavour profiles in order to distinguish purpose. For the practitioner market the reverse is true. Each single (one active herbal constituent only) herbal formulation for the practitioner market needs to be as uniform as possible within the group of formulations to enable inter-mixing by the practitioner for individualised prescription. The taste profile should remain as consistent as 25 possible; a microcosm of a broader formulation which is made up at the point of sale for the consumer. Retail products by contrast need to be well differentiated from each other in both active constituents and flavour profile. Wherever possible the flavour profile should reflect functionality of formulation. Examples of formulations: 30 Example 1: Formulation for energy Each L of formulation contains extracts equivalent to the following: Eleutherococcus senticosus (Siberian ginseng) dry root 99.9g Schisandra chinensis (wu wei zi 99.9g 18 Glycyrrhiza glabra (licorice) dry rhizome 33.3 Panax ginseng (Korean ginseng) dry root 79.92g Withania somnifera (Winter Cherry) dry root 99.9g Apple juice concentrate 600g 5 Lime juice concentrate 1 00g Lime flavour 1.25g West Indian Lime Oil (distilled) 1g Potassium sorbate 2.5g Hops extract standardised to 10% beta acids 0.1g 10 Rosemary extract standardised to NLT 4.5% rosmarinic acid 0.1g where "NLT" means "not less than". Water to make 1 L Example 2: Formulation for mood Hypericum perforatum (St John's Wort) dry herb 133.2g 15 Withania somnifera (winter cherry) dry root 66.6g Matricaria recutita (chamomile) dry flower 133.2g Passiflora incarnate (passionflower) dry herb 9 9.9g Zingiber officinale (ginger) dry root 13.26g Apple juice concentrate 450g 20 Passionfruit pulp 200g Lemon serum 25g Passionfruit flavour 0.5g Lemon oil distilled 2g Potassium sorbate 2.5g 25 Hops extract standardised to 10% beta acids 0.1g Rosemary extract standardised to NLT 4.5% rosmarinic acid 0.1g where "NLT" means "not less than" Water to make 1L Example 3: Formulation for female function 30 Black cohosh formulation Cimicifuga racemosa (black cohosh) dried rhizome/root 74.07g Apple juice concentrate 150g Pear juice concentrate I 00g 19 Lemon serum 50g Lemon oil 1.5g Potassium sorbate 2.5g Hops extract standardised to 10% beta acids 0.1g 5 Rosemary extract standardised to NLT 4.5% rosmarinic acid 0.1g where "NLT" means "not less than". Purified water to make 1 L Detailed analyses of both specific actives in formulations of preferred embodiments of the invention have been undertaken by the Centre for 10 Phytochemistry and Pharmacology at Southern Cross University (Lismore, NSW). This research shows that products formulated using the preferred embodiments retain the identified actives and that the formulations did not modify or eliminate the presence of the key compounds. This preservation of the active herbal compounds after exposure to the taste and organoleptic modifiers is an important 15 functional advantage for preferred embodiments of the invention. Analyses using High Performance Liquid Chromatography and Mass Spectrometry (LC-MS) demonstrate that the active compounds in botanical extracts are unaltered by the preferred formulations and show quantitative equivalence after formulation. This is considered an important observation with 20 respect to bioavailability. The analytical evidence from the Centre for Phytochemistry, Southern Cross University has established molecular integrity of specific active chemical components. For example, key entities in Echinacea are quantitatively present and detectable after formulation in accordance with preferred embodiments. 25 Successful accelerated stability tests examining microbiological contamination, appearance and flavour/aroma preservation have been undertaken for several formulations containing from one up to nine herbal extracts. Example 4: Siberian Ginseng 30 Figures la and lb illustrate the similarity in High Pressure Liquid Chromatograpy (HPLC) profile for components in a dry extract of Siberian Ginseng and components detected in liquid compositions according to preferred embodiments described herein.

20 LC (HPLC) data was obtained on an Agilent I 100SL LC-MSD. The LC was fitted with an Aqua C18, 125A, 5u, 150 x 4.6 mm if column (Phenomenex) at a column temperature of 40*C. The mobile phases consisted of A: 0.005% TFA in MilliQ water; B: 0.005% TFA in acetonitrile. The photodiode array detector was 5 set to detection at 210 nm and 280 nm and scan (190 - 600 nm) spectral data with peakwidth at >0.1 min. The system data was controlled by Agilent Chemstation software. Figure Ia shows a strong quantitative and qualitative similarity between elution profiles of the dry herbal extract active ingredient and its components 10 recovered from the liquid formulation the subject of this preferred embodiment. The main difference is seen in the specifically added preservatives the subject of this invention that elute at approximately 5.5 and approximately 10 minutes. Figure 1b presents a Total Ion Chromatograph (TIC) showing strong similarity between profiles of drug actives and components recovered from the 15 liquid formulation for Siberian Ginseng extract. Example 5: Panax Ginseng Figures 2a and 2b illustrate the similarity in HPLC for components in a dry extract of Panax Ginseng and components detected in liquid compositions according to preferred embodiments described herein. 20 LC data were obtained on an Agilent 1100SL LC-MSD. The LC was fitted with an Aqua C18, 125A, 5u, 150 x 4.6 mm if column (Phenomenex) at a column temperature of 40C. The mobile phases consisted of A: 0.005% TFA in MilliQ water; B: 0.005% TFA in acetonitrile. The photodiode array detector was set to detection at 210 nm and 280 nm and scan (190 - 600 nm) spectral data with 25 peakwidth at >0.1 min. The system data was controlled by Agilent Chemstation software. Figures 2a and 2b show the strong similarity between elution profiles of the dry herbal extract and components recovered from the liquid formulation embodied in this embodiment. Critical to the quality of ginseng is the ginsengosides that elute between about 10.5 and about 16 minutes and these 30 are all substantially unaffected by the liquid formulation. The additional component eluting in the liquid formulation at about 10 min is the introduced preservative. Example 6: St John's Wort 21 Figures 3a to 3e illustrate the similarity in HPLC and MS profile for components in a dry extract of St John's Wort and components detected in liquid compositions described herein. LC-Mass Spectrometer (MS) data was obtained on an Agilent 11 OOSL LC 5 MSD. The LC was fitted with an Aqua C18, 125A, 5u, 150 x 4.6 mm if column (Phenomenex) at a column temperature of 40C. The mobile phases consisted of A: 0.005% TFA in MilliQ water; B: 0.005% TFA in acetonitrile. The photodiode array detector was set to detection at 210 nm and 280 nm and scan (190 - 600 nm) spectral data with peakwidth at >0.1 min. The SL1100 Series Mass 10 Spectrometer Detector was in scan mode (100 - 1350 amu) using chemical ionisation as follows: ionisation voltage: 150 V (+ve mode) and 175 V (-ve mode); capillary voltage: 2000V; corona current: 8uA (both modes); drying gas flow: 3,0 L/min; drying gas temperature: 300C; vaporiser temperature: 320C; nebuliser pressure: 20 psig. The system data was controlled by Agilent Chemstation 15 software. Figures 3a and 3b illustrate the qualitative and quantitative recovery of components in St John's Wort detected at 280 nm and with respect to Total Ion Content (TIC). This recovery is also reflected in the Mass Spectrograms presented jn Figures 3c and 3d showing the recovery of the hypericin 20 components (MW around 520) and the quercetin glycosides (MW around 303).. Figure 3e illustrates the recovery of the important hypericin components eluting after approximately 26, 28 and 31 minutes as detected at 520 nm and having a molecular weight of 522, 520 and 520 respectively. The suite of quercetin glycosides and aglycones eluting between about 7 and about 11 minutes as seen 25 in Figure 3e was similar for the dry herbal extract (lower trace) and the components recovered from the liquid formulation (upper trace). These data illustrate the continued chemical integrity of key components of herbal actives after formulation according to this embodiment. Example 7: 30 Accelerated stability tests at 30*C including aerobic plate count, yeast and mould, preservative efficacy revealed the following composition containing five different active herbal extracts to be stable for more than 12 months. This

Claims (5)

1. A liquid excipient formulation suitable for addition to an active, the liquid excipient formulation comprising a combination of: 5 herbal extract as a botanical stabiliser at a concentration of no more than a 1:1 aqueous extract ratio of dry herb, corresponding to 10,000 ppm ; hops beta acids as antimicrobial agent at a concentration of no more than a 1:1 aqueous extract ratio of dry hops, corresponding to 50,000 ppm; and sorbate as an antifungal agent at a concentration of no more than 1 wt% in 10 an acid environment of less than pH 6.5; wherein the liquid excipient formulation comprises no added ethanol or glycerol or benzoates, and wherein the liquid excipient formulation in the absence of the aforesaid active, has no therapeutic effect when administered to a human or animal subject. 15

2. A liquid excipient formulation according to claim 1 wherein the herbal extract added as a botanical stabiliser results in a final rosmarinic acid concentration in the formulation of not less than 2 ppm, the hops beta acids are present in the final formulation at a concentration of not less than 5 ppm, and the 20 sorbate is present in the combination at a concentration of not less than 0,01 wt%.

3. A liquid excipient formulation according to claim 1 wherein the herbal extract added as a botanical stabiliser results in a final rosmarinic acid 25 concentration in the formulation of not less than 4 ppm, the hops beta acids are present in the final formulation at a concentration of not less than 7.5 ppm, and the sorbate is present in the combination at a concentration of not less than 0.01%. 30

4. A method of manufacturing a liquid excipient formulation according to claim 1, the method comprising the steps of: combining the herbal extract, hops beta acids and sorbate in an aqueous solution having a pH of less than 6.5, 32 without the addition of ethanol or glycerol or benzoates, the combination comprising herbal extract at a concentration of no more than a 1:1 extract ratio, hops beta acids standardised to 10% at a concentration of no more than 1 wt%; and sorbate at a concentration of no more than 1 wt%. 5

5. A liquid preparation according to claim 1 and substantially as herein described with reference to Examples 1, 2, 3, 7 and 8.