AU2018101231A4 - Methods to create a double nanoemulsion for transdermal delivery of hydrophilic and hydrophobic phytochemical active ingredients. - Google Patents

Abstract

The present invention relates to topical compositions comprising plant extracts thereof in the form of double nanoemulsions. The composition comprises active ingredients which are either hydrophilic, hydrophobic or combinations thereof which are solubilised to nanoparticle size with at least one surface surfactant and one co-surfactant absorbed onto the surface of the nanoparticle. The invention provides a method of generating a double emulsion.

Description

PRIOR ART

Plant based medicated products have drawn considerable awareness from research bases and industries in recent years at the national and international levels'.

Plant-based medicine or phytotherapy, refers to the medical utilization of phytochemical plant components (leaves, stems, roots, flowers, fruits and seeds) for their curative properties. Generally, herbal products contain a variety of bioactive phytochemicals, including alkaloids, steroids, terpenoids, saponins, phenolics, flavonoids, etc.

Numerous epidemiological studies show an inverse correlation between dietary phytochemical consumption and chronic degenerative diseases, such as cardiovascular diseases, diabetes, osteoporosis, neurodegenerative diseases and cancers23.

Phytochemicals have been shown to act as free radical scavengers, anti-oxidants, superoxide anions, UV absorbers, and lipid peroxy radicals. Phytochemicals compounds are also known to be effective in strengthening collagen structures and reducing elastase activity and have regularly been utilised in cosmetic compounds. Furthermore, phytochemicals have been shown to exhibit anti-mutagenic, anti-inflammatory and anti-viral effects by influencing numerous biological pathways in humans.

However, the observed limited bioavailability, and consequently low plasma concentrations of dietary phytochemicals, raise questions about the mechanisms by which they attain affective intracellular concentrations in the target tissues. Considering also that phytochemicals are either, strongly hydrophilic (having low logP values) or strongly hydrophobic (having high logP values), have relatively short pharmacokinetic half-lives and are subject to first pass metabolism by the liver; suggests that large quantities of phytochemicals must be orally ingested on a regular basis to provide any therapeutic effect.

At present, purified phytochemical oral administration is the most commonly utilised route of administration, which includes incorporation into fortified food products or capsules/gelcaps. However, the variability in solubility in aqueous solutions will affect the capacity of these agents to be absorbed from the gut. The solubility of families of phytochemicals from the same plant species can vary significantly. For example, ginsenosides isolated from the roots of Panax ginseng show significant variation in aqueous solubility; Ginsenoside Rbl is relatively water soluble whilst Ginsenoside Rh2 is practically insoluble in water. Thus, there is a need for methods for enhancing the solubility and bioavailability of these phytochemicals compounds by utilizing acceptable ingredients and methods4,5.

The oral administration route is indeed unsatisfactory, due to the high potential for phytochemical to small proportion of molecules administered orally are absorbed, because of insufficient gastric residence time, low permeability and/or low solubility. Phytochemical instability during food processing, distribution or storage, or in the gastrointestinal tract (pH, 1 (Kumar S, Madaan R, Bansal G, Jamwal A, Sharma A. Plants and plant products with potential anticonvulsant activity-A review. Pharma Comm. 2012; (1)2: 3-84)

2 Williamson G, Manach C. Bioavailability and bioefficacy of polyphenols in humans. 11. Review of 93 intervention studies. Am J Clin Nutr 2005; 81 (1):243S-55S 3 Kishimoto Y, Tani M, Kondo K. Pleiotropic preventive effects of dietary polyphenols in cardiovascular diseases. Eur J Clin Nutr 2013; 67 (5):532-5 4Flavonoids, Coumarins, and Cinnamic Acids as Antioxidants in a Micellar System. Structure—Activity Relationship. Mario Foti. Mario Piattelli. Maria Tiziana Baratta. and Giuseppe Ruberto. J. Agric. Food Chem., 1996, 44 (2), pp 497-501. 5 Flavonoid Bioavailability and Attempts for Bioavailability Enhancement. Suranei H. Thilakarathna and Η. P. Vasantha Rupasinehe: Nutrients 2013, 5(9), 3367-3387 enzymes, presence of other nutrients), limits the activity and the potential health benefits of phytochemicals. Additionally, the conjugation of phytochemicals into inactive compounds by either intestinal epithelium or the liver limits their effects in-vivo. Large doses of phytochemicals, when taken orally, may have adverse effects, including diarrhoea or intestinal irritation6.

Therefore, the administration of phytochemical compounds requires the formulation of a finished protecting product able to maintain the structural integrity of the active agent until the administration, increase its solubility and bioavailability, and convey it precisely towards a physiological target.

The skin is the largest organ in the body and serves important functions that are necessary to life. The skin acts as a barrier to the invasion of various pathogens and toxic substances. Skin is composed of the two layers: the epidermis is the first layer; and the dermis is the layer below the epidermis7.

However, because it must serve as a barrier to the ingress of pathogens and toxic materials, and the egress of physiologic fluids, the skin is highly impermeable. It must be impermeable to preserve its own integrity while at the same time maintaining the delicate dynamic electrolyte balance of the body. The skin must serve a containment function; it must also function as a microbial, chemical, radiation and thermal barrier. A good deal of this impermeability of the skin results from the nature of one very thin layer created by normal developmental and physiological changes in the skin. After cells are formed in the basal layer, they begin to migrate toward the skin surface, until they are eventually sloughed off. As they undergo this migration, they become progressively more dehydrated and keratinized. When they reach the surface, just prior to being discarded, they form a thin layer of dense, metabolically inactive cells approximately ten microns (10-15 cells) thick. This layer is called the stratum comeum or the “comified layer”. As a result of the high degree of keratinization of the cells which comprise the stratum comeum, a formidable barrier is created. Therefore, penetration via the nonpolar route, i.e., across the membrane of these cells, remains most difficult.

Accordingly, in an effort to take advantage of this route of administration and overcome the obstacles the skin and nails naturally provide, the art has turned to the use of specifically selected vehicles and carriers into which the pharmaceutical active is incorporated so that the vehicle or carrier aids in, or at a minimum does not adversely affect, the penetration of the selected active agent. The art recognizes that to a vast degree the rate of percutaneous delivery of a pharmaceutical active can be significantly decreased by the selection of an improper vehicle.

Because of the ease of access, dynamics of application, large surface area, vast exposure to the circulatory and lymphatic networks, and non-invasive nature of the treatment, the delivery of pharmaceutically-active agents through the skin has long been a promising 6 First-Pass Metabolism via UDP-Glucuronosyltransjerase: a Barrier to Oral Bioavailability of Phenolics BaoiianWu, KaustubhKulkarni, SumitBasu, ShuxingZhang, MingHu, Journal of Pharmaceutical Sciences 100 (9) 2011, 3655-368

Interaction of inorganic nanoparticles with the skin barrier: current status and critical review; Hagar I.Labouta Marc Schneider; Nanomedicine: Nanotechnology, Biology and Medicine 9(1), 2013, 39-54 concept. This is true whether the bioavailability desired is systemic or dermal, regional or local8.

The advantages of this form of delivery include, but are not limited to: avoidance of the risks associated with parenteral treatment; elimination of the inconveniences of parenteral treatment; avoidance of the variable rates of absorption and metabolism inherent in oral treatment; increasing the continuity of drug administration by permitting delivery of agents with short biological half-lives; and elimination of gastrointestinal irritation resulting from exposing the gastrointestinal tract to pharmaceutical actives, preservatives, tableting agents, and the like. Most importantly, topical delivery possesses the potential for effectively treating conditions which are local in nature (or which exhibit local manifestations), systemically as well as locally with the same treatment regimen. Thus, effective compositions to deliver pharmaceutical agents are highly sought after.

The topical use of natural phytochemical is also delicate because of their important sensitivity to environmental factors, including physical, chemical, and biological conditions. Unfortunately, they oxidize very quickly, leading to the progressive appearance of a brown colour and/or unwanted odours with a considerable loss in activity.

Vectors (e.g., nanoliposome, microemulsion, and nanoemulsion) improve the stability of the functional ingredients and the biological activity of drugs, and current studies are focusing on creating them9. Aditya et al prepared a double emulsion to embed curcumin and catechin, and the results showed a remarkable enhancement of the stability and bioavailability of curcumin and catechin in a simulated gastrointestinal tract environment10. Wu et al studied the influence of pH and NaCl concentration on oil emulsion stability11.

Therefore, it would be highly advantageous to provide a novel formulation for phytochemical compounds which can be delivered by said route of administration and able to provide a continuous and constant release over time, without undesired effects on these active agents. It would be even more advantageous to provide a formulation compatible with the physiological pH values of the skin in whose microenvironment phytochemicals are stable.

Methods of Forming Nanoparticles US Patent Application US 2010 0047297 to Petersen discloses nanocrystals of compounds such as apigenin for use in topical cosmetic formulations. U.S. Pat. No. 5,145,684 to Liversidge et al discloses methods to form nanocrystals of drugs by mechanical means producing shear, impact, cavitation and attrition forces. U.S. Pat. No. 5,510,118 to Bosch et al similarly discloses methods to form nanocrystals of drugs by mechanical means producing shear, impact, cavitation and attrition forces. 8 A transdermal review on permeation of drug formulations, modifier compounds and delivery methods; V.Rai’ I.Ghosh S.Bose’ S. M.C. Silva P. Chandra B.Michniak-Kohn, Journal of Drug Delivery Science and Technology, 20, 2, 2010, 75-88 9 Yang, X.; Tian, H.; Ho, C. T; Huang, Q. Inhibition of Citral Degradation by Oil-In-Water Nanoemulsions Combined with Antioxidants. Journal of Agricultural and Food Chemistry 2011, 59, 6113-6119 10 Aditya, N. P.; Macedo, A. S.; Doktorovov, S.; Souto, E. B.; Kim, S.; Chang, P.-S.; Ko, S. Development and Evaluation of Lipid Nanocarriers for Quercetin Delivery: A Comparative Study of Solid Lipid Nanoparticles (SLN), Nanostructured Lipid Carriers (NLC), and Lipid Nanoemulsions (LNE). LWT-Food Sci Technol 2014, 59, 115-121 11 Wu, Q.; Uluata, S.; Cui, L.; Wang, C.; Li, I).; McClements, J.; Decker, E. A. Physical and Oxidation Stability of Self-Emulsifying Krill Oil-In-Water Emulsions. Food & Function 2016, 7, 3590-3598 U.S. Pat. No. 5,510,118 to Muller et al discloses high pressure homogenization methods for the formation of nano particulate suspensions. U.S. Pat. No. 4,826,689 describes a process for the preparation of amorphous particles of a solid by infusing an aqueous precipitating liquid into a solution of the solid in an organic liquid under controlled conditions of temperature and infusion rate, thereby controlling the particle size.

Aqueous suspensions of a solid material can be prepared by mechanical fragmentation, for example by milling. U.S. Pat. No. 5,145,684 describes wet milling of a suspension of a sparingly soluble compound in an aqueous medium.

Crystalline dispersions obtained directly by precipitation are known in the art to be influenced by agitation of the solutions. Various methods of agitation are known in the art, for example mechanical mixing, vibration, microwave treatment and sonication (see e.g. WO 01/92293). Agitation is achieved using a number of techniques including ultrasonic agitation. The resulting crystals generally have a mass median diameter of 1 to 6 microns. U.S. Pat. No. 5,314,506 describes a crystallization process in which a jet of a solution containing a substance is impinged with a second jet containing an anti-solvent for the substance. The rapid mixing produced by the impinging jets results in a reduction of the crystals so formed compared to conventional slow crystallization processes. The smallest crystals disclosed are about 3 microns and the majorities are in the range of from 3 to 20 microns. EP 275 607 describes a process wherein ultrasound energy is applied to a suspension of crystals in a liquid phase, the ultrasound being used to fragment the pre-formed crystals. Generally, the volume mean diameter of the resulting crystals was 10 to 40 microns. WO 03/059319 describes the formation of small particles by adding a solution of a drug dissolved in a water immiscible organic solvent to a template oil-in-water emulsion after which the water immiscible organic solvent is evaporated off. Water is then removed, e.g. using a spray-drying process to obtain a powder. U.S. Pat. No. 6,197,349 describes a process for the formation of amorphous particles by melting a crystalline compound and mixing the compound with a stabilizing agent, e.g. a phospholipid, and dispersing this mixture in water at elevated temperature using high pressure homogenization, after which the temperature is lowered. PCT/US2006/020905 to Doseff discloses methods of treating inflammation with apigenin or its derivatives. US Patent application US 2008/0227829 to Hammerstone discloses methods of treating subjects with a neurogenic compound including apigenin. U.S. Patent application US 2007/0154540 to Park et al discloses the use of apigenin as a chondroregenerative agent for the treatment of osteoarthritis. U.S. Patent application US 2007/0189680 to Bing-Hua et al discloses the use of apigenin for chemoprevention and chemotherapy combined with therapeutic reagents. U.S. Patent application US 2006/0067905 to Lintnera et al discloses the use of apigenin as a vasodilatory agent for treating baldness.

Surfactants

Polysorbates and sorbitan fatty acid esters (commercially also known as Tweens and Spans) are non-ionic surfactants and emulsifiers derived from polyethoxylated sorbitan and fatty acids. They are often used in foods and in cosmetics to solubilize essential oils into water-based products. The surfactants are viscous, water-soluble (tweens) or water-insoluble (spans) liquids, respectively. Surfactants help to form emulsions by reducing the surface tension of the substances to be emulsified. Polysorbates have been recognized for their ability to help ingredients to dissolve in a solvent in which they would not normally dissolve.

Tweens function to disperse oil in water as opposed Spans which disperse water in oil. U.S. Pat. No. 7,329,797 to Gupta discloses antiaging cosmetic delivery systems which includes the use of flavonoids including apigenin as an anti-inflammatory agent and polysorbate surfactants as emulsifying agents, U.S. Patent Application 2006/0229262 to Higuchi et al disclose pharmaceutical compositions for the treatment of infections for treatment of infections with a drug resistant bacterium including flavonoids such as apigenin as an active ingredient and polysorbates as emulsifying agents.

In view of the foregoing, it is most desirable to incorporate phytochemicals as part of topical formulations to aid in the prevention and/or treatment of skin damage, skin aging or skin cancer resulting from the effects of sun exposure and also to provide a skin treatment composition useful in the treatment of a variety of dermatological conditions. Additionally, the topical nano formulation can be utilised to deliver phytochemical compounds systemically without subjecting them to biological degradation and/or inactivation that is commonly seen after oral administered.

SUMMARY OF THE INVENTION

It has now been found that a pharmaceutical composition suitable for the transdermal administration can be obtained by solubilizing hydrophobic and hydrophilic phytochemical mixtures, in a particular nanoemulsion, which overcomes the drawbacks of the known technique.

Nanoemulsions (submicron emulsions) are novel drug delivery forms. They are single-phase and thermodynamically stable isotropic systems that consist of emulsified oil, and water and amphiphilic molecules. The diameter of the emulsion globule (droplet) reaches approximately 20-500 nm, although usually this diameter is from 100 to 500 nm. A nanoemulsion, which is categorized as a multiphase colloidal dispersion, is generally characterized by its stability and clarity.

Double emulsions are very attractive systems for many reasons; the most important of these are their capacity to encapsulate hydrophilic and lipophilic molecules simultaneously in a single particle and their potentiality to protect fragile hydrophilic molecules from the continuous phase. Double emulsions are prepared by emulsifying an existing emulsion in a continuous phase. Double emulsions can represent an ‘oil-in-water-in-oiT (O/W/O) type or the reverse (W/O/W). Double emulsions on a nanoemulsions scale can be effectively utilised to simultaneously deliver hydrophilic and lipophilic compounds across membrane barriers.

Therefore, the object of the present invention is a pharmaceutical composition comprising hydrophobic and hydrophilic phytochemical mixtures, suitable for the transdermal administration, characterized in that the carrier for phytochemicals is in the form of nano-size double emulsion.

The characteristics and the advantages of the hydrophobic and hydrophilic phytochemical mixtures composition according to the present invention and of the related preparation process will be shown in detail in the following disclosure.

DETAILED DISCLOSURE OF I II I INVENTION

The process for the preparation of the nanoemulsions of the present invention comprises the following steps: • a) preparing an aqueous mixture containing one or more surfactants, and optionally, one or more co-surfactants; • b) preparing a mixture containing at least one oil, at least one surfactant, one or more co-surfactants; • c) adding phytochemicals to the aqueous mixture and stirring the mixture, • d) adding phytochemicals to the oily mixture and stirring the mixture; • e) removing any undissolved phytochemicals in either the aqueous and/or oil phases by sedimentation or centrifugation; • e) emulsifying the oily mixture with the aqueous mixture in specified proportions, under high energy processing means, familiar to those knowledgeable in the art to produce a Primary emulsion; • f) optionally adding a viscosizing agent and an absorption promoter to the nanoemulsion obtained in steps c and/or d); • g) emulsifying the Primary emulsion with the either an aqueous or oily similar to those prepared in steps a or b, mixing in specified proportions, under either low or high energy processing means, familiar to those knowledgeable in the art to produce a Double emulsion;

The pH of the aqueous mixture and of the double nanoemulsion typically ranges between 5.4 and 6.2 and is preferably in the range 5.6 - 6.0.

When phytochemicals are added to the aqueous mixture a), the pH of the nanoemulsion is adjusted, if necessary, to said range of values by addition of a diluted HC1 aqueous solution, in appropriate amount.

When phytochemicals are added to the oily mixture b), the pH of the nanoemulsion is adjusted, if necessary, to said values by addition of a diluted NaOH solution.

It has also been found that said pH range is optimal for stabilizing the ion-pair between the phytochemical and the medium aliphatic chain carboxylic acid, one of the utilized cosurfactant, and thus to increase the lipophilicity of the whole molecule. High lipophilicity, in turn is an important requirement for transdermal therapy as it gives rise to an increment of the amount and the rate of the drug delivered.

Phytochemical mixtures can be used as active ingredient for the formulations of the invention, advantageously in concentration between 0.5 and 10%, preferably between 1.0 and 5.0% based on the total weight of the formulation.

Advantageously, the double nanoemulsions of the invention could be in the form of w/o/w or o/w/o emulsions, wherein the active phytochemical ingredients are dissolved in the both the aqueous and oily phase.

The double emulsion contains nanodroplets of the dispersed phase having a diameter ranging from 60 to 500 nm, preferably from 70 to 90 nm, and a polydispersity index ranging from 0.10 to 0.35. In the double emulsions of the invention the phytochemicals can be present in combination with other active ingredients also useful for the treatment of Parkinson's disease,

Alzheimer’s disease, frontotemporal dementia and in particular with other agents useful for reducing the skin irritation effects, for example anti-inflammatory steroids such as dexamethasone.

The oil phase used in the preparation of the nanoemulsions of the invention is selected from the group consisting of vegetal oils, aliphatic alcohols, esters of aliphatic alcohols, glycerol esters and mixtures thereof.

According to a preferred embodiment of the present invention, the oil is selected from mean chain aliphatic alcohols and esters thereof, in particular decanol, dodecanol, isopropyl myristate and mixtures thereof.

The surfactants used for the preparation of the nanoemulsions of the invention are selected from polyoxyethylene sorbitans, such as Tween 20, Tween 40, Tween 60, Tween 80, polyethoxylated sorbitans, such as Span 20, Span 40, Span 60, Span 80, soy lecithin, purified egg lecithin, phospholipids and mixtures thereof.

The cosurfactants and the other adjuvants used for the preparation of the nanoemulsions of the invention are selected from alcohols and glycols, such as butanol, hexanol, benzyl alcohol, cyclohexanol, phenyl ethyl alcohol, propylene glycol, hexanediol, bile salts such as taurocholic and glycocolic, medium aliphatic chain carboxylic acids (C4-C12) such as butyric, hexanoic, octanoic acid or salts thereof, monoalkyl phosphates such as octyl phosphate and hexadecyl phosphate. In a preferred embodiment of the invention, the cosurfactant is selected from the group of hexanoic acid, octanoic acid, sodium taurocholate, sodium glycocholate or mixtures thereof. The antioxidant agents used for preserving the present nanoemulsions can be of lipophilic nature, for example Vitamin E, ascorbyl palmitate, and/or of hydrophilic nature, for example ascorbic acid.

Antioxidants may be added to either the aqueous and/or oily preparations. These antioxidants may include Vitamin C, Vitamin E, butylated hydroxy toluene, ascorbyl palmitate, uric acid, glutathione, beta-carotene or retinol.

The optional viscosity-increasing agent, added to increase the nanoemulsion viscosity, is selected from a polymeric viscosity enhancer for example Carbomer Carbopol 941 or Xanthan Gum.

Preferred primary nanoemulsions according to the present invention have the following composition:

Aqueous Preparation 1 % by weight

Phytochemical Agent(s) 1.0-5.0

Tween 80 1.0-5.0

Ethanol 5.0-15.0

Water q.s. to obtain 100 parts by weight of nanoemulsion

Oily Preparation 1 % by weight

Phytochemical Agent(s) 1.0-5.0

Mono-diglyceride of medium 1 * Λ 1 1 · J J. V »U“^U · V/ chain tatty acids

Span 80 1.0-5.0

Propylene glycol 5.0-10.0 ^ater q.s. to obtain 100 parts by weight of nanoemulsion

The continuous phase for the preparation of the double emulsion is selected from either Aqueous Preparation 1 or Oily Preparation 1 and is dependent on the relevant concentration of compounds utilised for preparation of the primary emulsion.

The formulation can be a topical composition in the form of a spray, lotion, soap, cream, paste, ointment, emulsion (e.g., water-in-oil emulsion, oil-in-water emulsion, microemulsion, emulsion of nanoparticles), colloid, suspension (e.g., suspension of nanoparticles), powder, gel, foam, anhydrous composition, and so forth, as well as combinations comprising at least one of the foregoing forms.

The pharmaceutical compositions of the invention are useful in all the treatments wherein the administration of apomorphine is required, in particular in the treatment of neurological diseases (Alzheimer’s, Parkinson’s etc).

The present invention is illustrated in more detail in the following preparation examples. Example 1 A W/O/W double nanoemulsion according to the invention is prepared by the following procedure:

The Primary Emulsion is produced by: • the aqueous phase is consisting of mixing 5% of phytochemical extract in water (75gm) added with 5 gm of Tween 80, ethanol (15gm) are mixed, undissolved extract is removed by sedimentation or centrifugation • b) the oily mixture consisting of mixing 5% of phytochemical extract in 75 gm of triolein added with 5 gm of Span 80, propylene glycol (15gm) are mixed, undissolved extract is removed by sedimentation or centrifugation; • c) the primary emulsion is produced by adding the aqueous mixture (20gm) from step a) to the oil mixture (80gm) from step b) and mixing under high energy mixing, to obtain a clear system.

All the steps are carried out at room temperature.

The Double Emulsion is produced: • by adding 25gm of the Primary Emulsion produced above to 75gm of the aqueous phase produced in Step a above. The solution is mixed by gentle stirring to produce an emulsion.

The pH value of the nanoemulsion is measured and adjusted to 5.8 by addition of a diluted NaOH or HC1 solution.

Claims (21)

1. A double nanoemulsion containing lipophilic and hydrophilic phytochemical or compounds thereof, suitable for transdermal administration.

2. A double nanoemulsion as claimed in claim 1, consisting of primary emulsion comprising: a) an aqueous mixture containing one or more surfactants, optionally one or more cosurfactants and phytochemical compounds; b) an aqueous mixture containing one or more surfactants, optionally one or more cosurfactants and phytochemical compounds; c) optionally, viscosity-increasing agents and absorption enhancers And a double emulsion formed by emulsifying the primary emulsion in either: e) an aqueous mixture containing one or more surfactants, optionally one or more cosurfactants and phytochemical compounds; f) an aqueous mixture containing one or more surfactants, optionally one or more cosurfactants and phytochemical compounds;

3. A nanoemulsion as claimed in the above claims, wherein pH ranges from 5.4 to 6.2.

4. A nanoemulsion as claimed in the above claims, wherein pH is in the range 5.6 - 6.0.

5. A nanoemulsion as claimed in the above claims, wherein the nanodrops of the dispersed phase have diameter ranging from 60 to 500 nm.

6. A nanoemulsion as claimed in the above claims, wherein the nanodrops of the dispersed phase have diameter ranging from 70 to 90 nm.

7. A nanoemulsion as claimed in the above claims, wherein the nanodrops have polydispersity index ranging from 0.10 to 0.35.

8. A nanoemulsion as claimed in the above claims, wherein the oil is selected from the group consisting of vegetal oils, aliphatic alcohols, esters of aliphatic alcohols, glycerol esters and mixtures thereof.

9. A nanoemulsion as claimed in claim 8, wherein the oil is selected from mean chain aliphatic alcohols and esters thereof, in particular decanol, dodecanol, isopropyl myristate and mixtures thereof.

10. A nanoemulsion as claimed in the above claims, wherein the aqueous liquid is selected from the group consisting of polar groups including water, methanol, ethanol, isopropanol and mixtures thereof

11. A nanoemulsion as claimed in the above claims, wherein the surfactants are selected from polyoxyethylene sorbitans, polyethoxylated sorbitans, polyoxyethylene castor oil derivatives, soy lecithin, purified egg lecithin, phospholipids and mixtures thereof.

12. A nanoemulsion as claimed in claim 10, wherein the surfactants are selected from Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Cremophor EL.

13. A nanoemulsion as claimed in the above claims, wherein the cosurfactants are selected from alcohols and glycols, such as butanol, hexanol, benzyl alcohol, cyclohexanol, phenylethyl alcohol, propylene glycol, hexanediol, bile salts such as taurocholic and glycocolic, carboxylic acids such as butyric, hexanoic, octanoic acids or salts thereof, monoalkyl phosphates such as octyl phosphate and hexadecyl phosphate.

14. A nanoemulsion as claimed in claim 12, wherein cosurfactants are selected from butanol, hexanol, benzyl alcohol, cyclohexanol, phenylethyl alcohol, propylene glycol, hexanediol.

15. A nanoemulsion as claimed in the above claims, wherein the antioxidants agents are of lipophilic and/or hydrophilic nature.

16. A nanoemulsion as claimed in claim 15, wherein the antioxidants agents are Vitamin C, Vitamin E, butylated hydroxy toluene, uric acid, ascorbyl palmitate, glutathione, beta-carotene or retinol.

17. A nanoemulsion as claimed in the above claims, wherein lipophilic antioxidant agents are added in concentrations ranging from 0.2 to 2.0 % by weight, and hydrophilic antioxidants are added in concentrations ranging from 0.2 to 0.8% by weight.

18. A nanoemulsion as claimed in the above claims, wherein the viscosity-increasing agent is selected from a Carbomer such as Carbopol 941, silicon dioxide or Xanthan gum.

19. The preparation of a double emulsion by mixing a primary emulsion with either an oily mixture as claimed in claim 8 or an aqueous mixture as claimed in claim 10.

20. The use of a double emulsion as claimed in the above claims, for the preparation of a medicament for use in all the treatments wherein the administration of phtyochemicals is required.

21. The use as claimed in claim 20 for the treatment of neurological diseases including Dementia, Alzheimer’s diseases, Fronto-temporal dementia, vascular dementia, Parkinson's disease.