This invention relates to pharmaceutical compositions and to transdermal delivery devices.

Sutherlandia frutescens, subspecies microphylla has been used in South Africa for centuries as a medicinal plant in traditional healing. The plant is known variously as cancerbush, unwele and insiswa. Some of the constituents of Sutherlandia frutescens which are believed to be active include L-canavanine, GABA, and D-pinitol. The plant has been used internally for the treatment of cancer, gastric ailments, gynaecological problems, backache, rheumatism, edema and fevers and also as a bitter tonic or blood purifier. Externally it has been used for the treatment of eye infections and wounds, as a douche for prolapse of the uterus for improving the quality of life in cancer patients HIV/AIDS patients and TB patients for stress reduction, for the enhancement of well- being, for chronic fatigue syndrome/ ME, for heartburn, gastritis and reflux oesophagitis. The precise mechanism of action remains the subject of speculation. In the immune system, Sutherlandia stimulates the proliferation of functional cells

CD8(-)LEU8(+) (T cells inductors/suppressors) more than CD4(-) cells, regulating the synthesis of antibodies and the proliferation of lymphocytes. Apparently, this effect is because canavanine produces an increase of the intra-lymphocyte level of calcium (Ca ²⁺ i). As an antioxidant, L-canavinine in Sutherlandia induces the synthesis of heat shock proteins that correspond to the antioxidative systems and cellular protectors that contribute to counteract the deleterious effects that stress impacts (physical, chemical, biological or emotional) may cause in the organism and increases the capacity of cellular recovery. A number of clinical trials have been conducted with Sutherlandia. These include trials reported by Fernandes AC, Cromarty AD, Albrecht C, van Rensburg CE, The antioxidant potential of Sutherlandia frutescens J Ethnopharmacol. 2004 Nov; 95(1 ) 1 -5; Tai J, Cheung S, Chan E, Hasman, D. In vitro culture studies of Sutherlandia frutescens on human tumor cell lines, J Ethnopharmacol. 2004; 93(1 ) 9-19, Mombereau C, Kaupmann K, Froestl W, Sansig G, van der Putten H, Cryan JF. Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety and antidepressant-like behaviour, Neuropsychopharmacol. 2004; 29(6) :1050-1062, Bell, E.A. et al. (1978), The systematic significance of canavanine in the Papilionoideae, Biochemical Systematics and Ecology 6: 201 -212, and Harnett SM, Oosthuizen V, van de Venter M, Anti-HIV activities of organic and aqueous extracts of Sutherlandia frutescens and Lobostemon trigonus, Department of Biochemistry and Microbiology, University of Port Elizabeth, South Africa. Echinacea, the purple coneflower, is the best known and most researched herb for stimulating the immune system. This native American herb has an impressive record of laboratory and clinical research. Many doctors currently use Echinacea for treating infectious diseases. Echinacea contains several compounds that play a role in its therapeutic effects. These primarily include polysaccharides, glycoproteins, alkyl amides, volatile oils, flavonoids and cichoric acid. Polysaccharides contribute to the herb's immune empowering effects and increase T-cell production and other natural killer cell activity.

Several laboratory and animal studies suggest that Echinacea contains active substances that enhance the activity of the immune system, relieve pain, reduce inflammation, and have hormonal, antiviral, and antioxidant effects. For this reason, some professional herbalists recommend Echinacea to treat urinary tract infections, vaginal yeast (Candida) infections, ear infections (also known as otitis media), athlete's foot, sinusitis, hay fever (also called allergic rhinitis) as well as slow-healing wounds. One study suggested that Echinacea extract exerted an antiviral action on the development of recurrent HSVI when supplied prior to infection.

In the immune system the alkyl amides of Echinacea are found to bind with type-2 cannabinoid receptors (CB2) and modulate the immune system by strongly affecting the regulation of Tumour Necrosis Factor (TNF) which is a key substance in cellular immune system. Cichoric acid, polysaccharides and alkyl amides at certain concentrations are found effective in stimulating non-specific immune response such as increased release of cytokines. In the case of inflammation, the mechanism of the antiinflammatory activity of Echinacea comes mainly via inhibited oedema, anti- hyaluronidase activity, COX-I and COX-II enzymes inhibition, cytokine antibody stimulation, inhibition of rhinovirus induced secretion of IL-6 (interleukin-6) and IL-8 (chemokine CXCL-8), PGE(2), inhibition with a synergistic manner, cyclooxygenase-2 (COX-2) enzyme inhibition, inflammatory response mediators (such as nitric oxide (NO), tumour necrosis factor-alpha (TNF-alpha), and interleukin-1 beta) inhibition.

As a free radical scavenger, Echinacea acts by directly scavenging various free radicals such as superoxide anion and hydroxyl radicals, and secondary radicals such as C-, N-, or S-centered radicals. As an antioxidant, Echinacea acts by scavenging hydroxyl radical (including 1 ,1 -diphenyl-2-picrylhydrazyl radical and ABTS radical, DPPH radical solution), human low-density lipoprotein oxidation suppression. As a HIV- 1 integrase inhibitor, some related studies propose that l-chicoric acid (l-CA) enters cells poorly but is a potent inhibitor of IN in vitro and likely interacts with amino acids other than those which bind substrate. Inhibition of IN diminished, demonstrating that l-CA was reversibly bound to the protein. These data demonstrate that l-CA is a noncompetitive but reversible inhibitor of IN in vitro and of HIV integration in vivo. By way of background, human immunodeficiency virus (HIV) integrase (IN) must covalently join the viral cDNA into a host chromosome for productive HIV infection. A number of clinical trials have also been conducted with Echinacea. These include trials reported by Geol V, Chang C, Slama JV, et al, Dose related effects of Echinacea on macrophage stimulation in lungs and in spleens of normal rats, Vomel V, Influence of a non-specific immune stimulant on phagocytosis of erythrocytes and ink by the reticuloendothelial system of isolated perfused rat livers of different ages, Arzneim Forsch 1984; 34, 691 -5, Echinacea increases arginase activity and has antiinflammatory properties in RAW 264.7 macrophage cells, indicative of alternative macrophage activation, Zhai Z, Solco A, Wu L, Wurtele ES, Kohut ML, Murphy PA, Cunnick JE, Pellati F, Benvenuti S, Magro L, Melegari M, Soragni F, Analysis of phenolic compounds and radical scavenging activity of Echinacea spp. J Pharm Biomed Anal. 2004 Apr 16; 35(2), 289-301 , Mishima S, Saito K, Maruyama H, Inoue M, Yamashita T, Ishida T, Gu Y, Antioxidant and immuno-enhancing effects of Echinacea purpurea, Biol Pharm Bull. 2004 Jul;27(7):1004-9, See D, Berman S, Justis J, Broumand N, Chou S, Chang J, Tilles J, "A Phase I Study on the Safety of Echinacea angustifolia and its Effect on Viral Load in HIV Infected Individuals, JANA 1998; 1 (1 ), 14-17.

Echinacea can be dosed orally. For example, 6-9ml of the expressed juice can be administered per day or an equivalent amount of dried expressed juice, divided into two or four doses. It can also be used cutaneously. For example 10-20g/100g of expressed juice or an equivalent amount of dried expressed juice can be applied as an ointment on an affected area 2-3 times a day. The German Commission E recommends the following for chronic conditions. E. purpurea fresh pressed juice, total of 6-9 ml/ day, (3cc BID-TID corresponding to 300 mg BID-TID), E. angustifolia root, total of 2-6ml of 1 :2 fluid extract or 5-15ml of a 1 :5 tincture, E. purpurea root, 1 :2 fluid extract, 3-9 ml/day or 7.5-22.5ml of a 1 :5 tincture.

Dimethylsulfoxide (DMSO) is a hydroxyl radical scavenger and antioxidant. In theory it has the potential to protect cells from hydroxyl radical mediated radiation damage (Dod 1968). Neutralizing the hydroxyl radical reduces inflammation and may be the primary mechanism of action allowing DMSO to work in immune disorders. DMSO reacts with the hydroxyl radical (OH) to form a methyl radical (CH3) which is much less reactive than the hydroxyl radical.

DMSO may also be used as a carrier of drugs and other compounds through the skin. Low molecular weight compounds when dissolved in DMSO and applied to the skin are readily carried into the systemic circulation. In various trials, DMSO has been used as a carrier for antibiotics, corticosteroids, anti-inflammatory agents and essential fatty acids. The key side effect of DMSO treatment is the characteristic garlic-like smell of the breath. DMSO is metabolized to dimethylsulphone (DMSO ₂ ) (which is also referred to as methylsulphonylmethane or MSM or dimethylsulphodioxide) and DMS (dimethylsulphide) in the body. The kidney excretes DMSO ₂ in the urine. The lungs excrete DMS, which gives breath a characteristic garlic-smell that can last for up to 72 hours. Other side effects involve erythema, itching, and urticaria. Concern has also been expressed over the potential for DMSO to cause cataracts.

The pharmacologic actions of dimethylsulphoxide (DMSO) have stimulated much research. When the theoretical basis of DMSO action is described, a large number of primary pharmacologic actions can be listed. These include membrane penetration, membrane transport, effects on connective tissue, anti-inflammatory effects, nerve blockade (analgesia), bacteriostasis, dieresis enhancement or reduction of effectiveness of other drugs, cholinesterase inhibition, nonspecific enhancement of resistance of infection, vasodilation, muscle relaxation, enhancement of cell differentiation and function, antagonism to platelet aggregation and influence on serum cholesterol in experimental hypercholesterolemia.

With regard to membrane penetration, DMSO readily crosses most tissue membranes of lower animals and man. Employing ³⁵ S DMSO Kolb et al (Kolb, K.H., Janicke, G., Kramer, M., Schulze, P.E., and Raspe, G. Absorption, distribution and elimination of labeled dimethyl sulfoxide in man and animals) evaluated the absorption and distribution of DMSO in lower animals and man. Ten minutes after cutaneous application in the rat, radioactivity was measured in the blood. In man radioactivity appeared in the blood 5 minutes after cutaneous application. One hour after application of DMSO to the skin, radioactivity could be detected in the bones. Denko et al (Denko Ann. N. Y. Acad. Sci. 141 : 85095 (196 Denko, C.W., Goodman, R.M., Miller, R., and Donovan, T. Distribution of dimethyl sulfoxide- ³⁵ S in the rat. Ann. N. Y. Acad. Sci. 141 : 77084 (1967)) applied ³⁵ S-labeled DMSO to the skin of rats. Within two hours a wide range of radioactivity was distributed in all organs studied. The highest values occurred in decreasing order in the following soft tissues; spleen, stomach, lung, vitreous humor, thymus, brain, kidney, sclera, colon, heart, skeletal muscle, skin, liver, aorta, adrenal, lens of eye, and cartilage. Rammier et al (Rammier, D.H., and Zaffaroni, A. Biological implications of DMSO based on a review of its chemical properties. Ann. N. Y. Acad. Sci. 141 : 13-23 (1967)) reviewed the chemical properties of DMSO and suggested that the rapid movement of this molecule through the skin, a protein barrier, depends on a reversible configurational change of the protein occurring when DMSO substitutes for water. Other studies of DMSO include Basch, H., and Gadebusch, H.H. In vitro antimicrobial activity of dimethyl sulfoxide. Appl. Microbiol. 16: 1953-1954 (1968), Gries, G., Bublitz, G., and Lindner. J. The effect of dimethylsulfoxide on the components of connective tissue (Clinical and experimental investigations). Ann. N. Y. Acad. Sci. 141 : 630-637 (1967) and Haigler, H.J. Comparison of the analgesic effects of dimethyl sulfoxide and morphine. Ann. N. Y. Acad. Sci. 41 1 : 19-27 (1983).

The term penetration enhancer is applied to materials that have a direct effect on the permeability of the skin barrier. Some materials may act by a direct chemical insult on the skin while others may not have a specific barrier effect. The latter may affect the solubility and/or dispersibility of the medicament and/or its delivery system (the vehicle). A variety of organic solvents are known to enhance the percutaneous absorption of medicaments, but few have been studied as extensively as dimethylsulphoxide (DMSO). Soon after the publication of its synthesis and physical properties, particularly the ease with which it traversed biological membranes, its potential as a penetration enhancer was and is still being investigated.

The superiority of DMSO to other solvents both in enhancing penetration and in favoring dermal retention was demonstrated in a study of the passage of 14C-labelled griseofulvin, dissolved in DMSO, dimethylacetaroide, dimethylformarnide, alcohol or benzene, through human skin in vitro. The ratios of penetration of griseofulvin in the various solvents was 60, 40, 7, 3, and 1 respectively. Even when a 50% solution of DMSO in water was used, the rate of penetration of 14C hydrocortisone was markedly enhanced. The retention of griseofulvin and hydrocortisone in the excised skin roughly parallels their rate of penetration.

In other in vitro and in vivo experiments, DMSO has been shown to enhance the percutaneous penetration of many drugs. DMSO has also been shown to enhance the rate of penetration of water through the skin when the epidermis was treated for 30 minutes with 60%, 80% and 90% aqueous solutions of DMSO.

Many theories concerning the mechanism of action of penetrants have appeared in the literature. One attributes the penetrant effects of DMSO, dimethylformarnide, and dimethylacetamide to their hygroscopic properties which increase the water content of the stratum corneum, thereby greatly increasing its permeability. Another attributes the effectiveness of penetration enhancers to their ability to lower the barrier properties of the stratum corneum by modifying its natural structure. Organic solvents like benzene, alcohol, and ether, which have been shown to enhance the penetration rate of both water-soluble and lipid-soluble substances, may act by removing the lipids from the stratum corneum. The mechanism involved is probably hole formation. However, the action of hydrogen-bonding solvents like DMSO, dimethylformamide, and dimethylacetamide is attributed to membrane expansion and uniform increase in media diffusivity.

Several other factors may influence the percutaneous absorption of medicaments: the site of application, the length of time such application remains in contact with the skin, the amount used in applying the medicated application, and skin temperature. Drugs which penetrate the stratum corneum do so most readily where the outer keratic layer is thin.

Although the information above refers largely to high strengths of DMSO to enhance penetration, it has been found that concentrations as low as 2% topical DMSO will significantly improve penetration. Very high grades of DMSO are virtually odor free.

Methylsulphonylmethane (MSM) or dimethylsulphone is a water soluble compound which is also soluble in methanol, ethanol, and acetone and less soluble in toluene and chloroform. The material is a white crystalline compound. MSM is one of the safest and most effective compounds in the support and maintenance of good health and vitality. It is an essential nutrient and has been called "a nutritional mineral" similar to metals such as sodium or sulphur, which are required for life processes. It has been said to help fortify the body's natural barriers against allergens, strengthen the lungs, aid in healthy carbohydrate metabolism, enhance tissue pliability and encourage repair of damaged skin, promote good digestion and absorption of nutrients and is critical in the formation of collagen and glucosamine.

Approximately half of the total body sulfur is concentrated in the muscles, skin and bones. One of the most significant uses of MSM as a supplement is its demonstrated ability to relieve pain and inflammation. When rigid fibrous tissue cells swell and become inflamed, pressure and pain result. Since MSM can restore flexibility and permeability to cell walls, fluids can pass through the tissues more easily. This helps equalize pressure and reduce or eliminate the cause of pain. Harmful substances such as lactic acid and toxins are allowed to flow out, while nutrients are permitted to flow in. This prevents the pressure buildup in cells that causes inflammation.

MSM has shown a remarkable ability to reduce or eliminate muscle soreness and cramps both in geriatric patients and in athletes. It has even been given to race horses before a race to prevent muscle soreness, and afterward to reduce the risk of cramping. People with arthritis report substantial and long-lasting relief with MSM supplements. Taken along with glucosamine, a key substance in the process of rebuilding cartilage, MSM can relieve pain and help repair worn or damaged cartilage in joints, ligaments and tendons with healthy, flexible new cells.

The body uses MSM along with Vitamin C to create new, healthy cells, and MSM provides the flexible bond between the cells. Without proper levels of MSM, the body is unable to build good healthy cells, and this leads to problems such as lost flexibility, scar tissue, wrinkles, varicose veins, hardened arteries, damaged lung tissues, dry cracking skin, digestive disorders, joint problems, and inability to defend against allergic reactions to food, animals and plants.

MSM is an anti-oxidant that helps to clean the blood stream and to flush toxins trapped in the cells. It is also a foreign protein and free radical scavenger. In order to maintain good health, a diet supplemented with MSM enables the body to heal itself. The body uses what it needs and after 12 hours will flush out any excess amounts.

Sulphur is also a component of insulin, the hormone that regulates carbohydrate metabolism and insufficient sulfur may result in decreased insulin production. It is also possible that a lack of bio-available sulfur would make the cells so rigid and impermeable that they become unable to absorb sugar from the blood efficiently, leaving blood sugar levels elevated. Studies indicate that regular MSM supplements which cause the cell to become permeable, could help balance blood sugar and allow the overworked pancreas to return to normal.

When skin cells are soft and permeable, many toxins can be eliminated through the sweat glands, which takes some of the load off the liver and kidneys. While MSM is not a cure for allergies, supplementation may reduce symptoms by allowing allergens to be removed from the body more quickly. Even reactions to insect bites, poison ivy and poison oak are less severe when the diet is supplemented with MSM.

The Applicant is aware of patents and patent applications dealing with the use of Sutherlandia and Echinacea such as WO 2009/001362, WO 2008/065473, WO 2007/059441 , US 2010/0143398, US 2009/0955377, US 2008/0261916, US 2008/0160042, US 2008/01 18582, US 2008/0063658, US 2009/0156982, US 7,682,671 , US 7,622,287, US 7,625,587, US 7,604,823 and US 7,553,501 . However none of these discloses the present invention. The Applicant has found that a combination of Sutherlandia and Echinacea used with a pharmaceutically active carrier increases the efficacy of the combination particularly in a patch formulation. In the context of this specification the words Sutherlandia, Echinacea Sutherlandia frutescens and Echinacea purpurea refer, according to the context, either to a plant genus or plant species or to a product or material obtained from a plant of the genus or species. The material may be a part of the plant or the whole plant which has been comminuted or finely ground, the liquid produced by crushing the whole plant or a part of the plant or an extract, for example an ethanol or water extract, prepared from the whole plant or a part of the plant or a combination thereof. The extract may, for example, be a powdered or spray-dried extract of the plant. For example the dried plant material can be ground to a powder and extracted and the extract subjected to a spray-drying process to produce a spray-dried extract.

The invention provides a transdermal delivery device, in the form of a transdermal patch, which includes a pharmaceutical composition comprising a first component produced from plants of the genus Echinacea, a second component produced from plants of the genus Sutherlandia and a third component selected from dimethylsulphoxide, dimethylformamide, dimethylsulphone and mixtures thereof.

The first component may be produced from plants of the species Echinacea purpurea and the second component may be produced from plants of the species Sutherlandia frutescens.

The components may be spray dried plant extracts or ground plant material. The first and second components may be commercially available materials. For example Sutherlandia frutescens can be obtained as a fine, light green powder from the aerial parts, stems and leaves of the plant (Warren Chem Specialties (Pty) Ltd, Cape Town, South Africa). Echinacea purpurea can be obtained as a brown-yellow powder from a 4:1 plant extract ratio (water/ethanol) of the whole plant (Blue California, USA), as a brown yellow powder from a 4:1 plant extract ratio (water/ethanol) of the root of the plant (SHAANXI Jinge Phytochem Co. Ltd. China) as a powder from the root of the plant (Alfred Galke GmbH) as a light green to grey green powder from the aerial parts of the plant (Warren Chem Specialties (Pty) Ltd). Where the material is an extract such as a spray-dried extract of the plant or a part of the plant, the material can be characterised by the extract ratio which varies from 1 :1 to 4:1 to 25:1 and is the ratio between the mass of the solvent used in the extraction (usually ethanol and water) and the mass of the plant material used. In an embodiment of the invention water extracts are prepared in an open-type extractor. The extractor is a cylindrical vessel made from type 316 stainless steel and has a diameter (D) greater than the height (H), i.e. the H/D ratio is approximately 0.5. The bottom of the vessel is welded to the dished end and is provided with an inside false bottom with a filter cloth. The outside vessel has a steam jacket and a discharge valve at the bottom. One part powdered plant material and sixteen parts demineralized water are fed into an open-type extractor. Heating is done by injecting steam into the jacket. The material is allowed to boil until the volume of water is reduced to one-fourth its original volume. By this time the medicinal ingredients present in the plant material have been fully extracted.

The extract so obtained is separated from the marc (exhausted plant material) by allowing it to trickle into a holding tank through the bottom of the extractor, which is covered with a filter cloth. The marc is retained at the bottom, and the extract is received in a holding tank. From the holding tank, the extract is pumped into a sparkler filter to remove fine or colloidal particles from the extract.

The filtered extract is subjected to spray drying with a high pressure pump at a controlled feed rate and temperature, to get dry powder. The desired particle size of the product is obtained by controlling the inside temperature of the chamber and by varying the pressure of the pump. The dry powder is mixed with suitable diluents or excipients and blended in a mixer to obtain a homogeneous powder that can be used for preparing the pharmaceutical composition of the invention. The composition may contain between 95% and 0,5% of the Echinacea and between 95% and 0,5% of the Sutherlandia. Preferably, the composition may contain between 70% and 30% of the Echinacea and the between 70% and 30% of the Sutherlandia. The Echinacea and the Sutherlandia may be the material obtained from a 1 :4 extract although material obtained from 1 :1 or 1 :25 extract can also be used.

The ratio (mass/mass) of the Echinacea to the Sutherlandia may be between about 10:1 and 1 :10. Preferably it will be between about 5:1 and 1 :5 and more preferably between about 2:1 and 1 :2, more preferably between about 2:8 and 3:7 and most preferably between about 1 :5 and 1 :2,3. In a preferred embodiment of the invention, the transdermal delivery device may include about 200-300mg of the first component and about 700-800mg of the second component. For example in an embodiment of the invention the composition may contain 800mg of Sutherlandia and 300 mg of Echinacea. The composition may contain about 1 and 97% of the third component. Preferably, the composition contains about 20 and 60% of the third component and more preferably about 40-50%.

The first, second and third components may be combined with a gelling agent. The gelling agent may, for example, be a polymer, such as Carbopol® ETD 2020 NF. It may, instead, be silica gel. In the gel, the first and second components may each comprise about 0,3% - 40% of the gel and the third component may comprise about 60-95% of the gel. Preferably it will comprise about 40-70% of the gel. The composition may also include ascorbic acid.

The delivery device may include a backing layer, a reservoir and an adhesive layer. The device may include a rate-controlling membrane between the reservoir and the adhesive layer. It may, in addition, include a protective peel-off strip covering the adhesive layer. Transdermal patches are described in Membrane Technology and Applications by R W Baker (2004 John Wiley & Sons, Ltd) which is incorporated herein by reference.

The patches may be circular, rectangular or square with a surface area of about 64cm ² . However the patches may be smaller (for example about 16-36cm ² ). The backing layer may be in the form of a translucent, smooth layer of high density polyethylene and the rate-controlling membrane may be in the form of a porous Teflon® membrane (0.2μ). The membrane may, instead, be a solid non-porous silicone membrane with a thickness of about 0.10-to 0.90mm.

In different embodiments of the invention, the delivery device is in the form of a transdermal patch comprising a gel which contains about 30-90%, preferably about 70- 80%, of Sutherlandia frutescens, microphylla, about 10-90% of an extract of Echinacia purpurea, about 1 -3% of Carbopol® pharmaceutical grade gelling agent polymer (for example ETD 2020 NF), about 100% pure ethanol as a preservative, de-ionised or de- mineralised water and about 5-95%, preferably about 20-80%, of pharmaceutical grade DMSO (99,9% pure) as an active ingredient and penetration enhancer to increase the efficacy of the herbal extracts due to fast absorption. In another embodiment of the invention, the composition is part of a transdermal delivery system which contains 700mg of Sutherlandia frutescens 300mg of Echinacia purpurea, 20% of a penetration enhancer in the form of DMSO (99,9%) in distilled water, 1 % of Carbopol® gel which is applied to the thigh for eight hours once a week. The active ingredients are readily absorbed through the skin at a constant rate and peak plasma levels are reached within 3,0 to 3,5 hours after application.

In another embodiment, each transdermal patch contains 10g of a formulation comprising an organic extract of Sutherlandia frutescens, microphylla 10-90% preferably 60-80% and most preferably 70%, combined with an organic extract of Echinacia purpurea 10-90%, preferably 20-40% and most preferably 70%, a preservative for example pure ethanol, a polymer gelling agent for example pharmaceutical grade Carbopol® (ETD 2020 NF), a solvent for example distilled, de- ionized or de-mineralized water. This embodiment also includes a skin moisturising agent, for example Vitamin E or glycerin, preferably glycerin, a pH Balancer for example triethanolamine (TEA) 85% purity, bioflavanoids/plasmolytic agents for example vanilla and or lemon verbona {Citris aurantium) or Aloysia citrodora, DMSO pharmaceutical grade (99.97% min purity). For dropper application the formulation will contain less gelling agent (about 1 %) for mixing with water or juice, taking 4-10 drops in half a glass of liquid 2- 3 times daily.

In a variation of this embodiment of the invention the gelling agent is pharmaceutical grade silicon dioxide (1 -3%). The patch is thus a reservoir type transdermal patch but the invention is not limited to such patches. Other patches which can be used include the matrix type, membrane matrix hybrid, micro reservoir type, drug in adhesive type membrane and the like. The active ingredients of the patch of the invention readily absorb through the skin at a constant rate via the membrane of the delivery system.

By combining the Sutherlandia frutescens and Echinacia purpurea in the ratios described above, an effective enhanced immune modulator, free radical scavenger and highly effective anti-inflammatory is produced, which is more effective when applied via a transdermal skin patch, or as a topical/dermal cream containing at least one skin penetration enhancer such as DMSO or DMF. The DMSO and DMF not act only as penetration enhancers but provide beneficial effects in their own right. Similarly, the MSM also provides beneficial effects and the combination of Sutherlandia, Echinacea and the DMSO, DMF and/or MSM have a synergistic effect in that the effects of these combinations are greater than the sum of the effects of the separate components. The invention further provides a novel pharmaceutical phyto-formulation for use as drops alone or in combination with DMSO or DMF for greater enhanced immune modulatory and anti-inflammatory effect.

The invention extends to a pharmaceutical composition comprising a first component produced from plants of the genus Echinacea, a second component produced from plants of the genus Sutherlandia and a third component selected from dimethylsulphoxide, dimethylformamide, dimethylsulphone or mixtures thereof. The composition may be as hereinbefore described. The composition may be incorporated in or be in the form of a cream, gel, spray, capsule, tablet, suppository, drops or an inhalant. Where the composition is in the form of a gel or cream or is incorporated in a patch, the composition may contain about 3-6ppm of triethanolamine to control the pH such as the 85% product marketed by Siyeza Fine Chem. Where the composition contains DMSO it may in addition include about 1 -2% of a flavourant or fragrance such the citrus extract marketed by Siyeza Fine Chem as Citrus Aurantium Extract Powder. Because of the additional agents (such as gelling agents) in the cream and the gel, the first and second components may make up a lower percentage of the composition in the cream and gel (between about 0,3% and 10%) than in the spray, capsule, tablet, suppository, drops or inhalant in which the concentrations of the first and second components are higher.

The invention extends to a dosage form containing a pharmaceutical composition as hereinbefore described. The dosage form may be a transdermal patch or in a topical form such as an aerosol, cream or gel in the case of Sutherlandia frutescens, Echinacea purpurea and DMSO. It may be in the form of a transdermal patch, a topical form such an aerosol, cream or gel or an oral form such as a sublingual drops in the case of Sutherlandia frutescens, Echinacea purpurea and DMF or MSM.

The specific amounts of the Echinacea, Sutherlandia and the third component will depend on the dosage form of the composition. For example, the amount of DMSO, DMF and/or MSM will be higher in the cream and gel (up to 70-90% or more) but will be much lower in the sublingual drops and tablets (about 5-20%). In an embodiment of the invention the tablet form contains Echinacea, Sutherlandia and MSM as the only active ingredients in which the MSM comprises about 20-85% of the composition. For example, 10ml of the cream may contain 800mg of organic Sutherlandia frutescens, 200ml of organic Echinacea purpurea and a penetration enhancer such as DMSO. This cream is useful in the management of inflammatory conditions, joint pains and sports injuries. The invention extends, further, to the use of a first component produced from plants of the genus Echinacea, a second component produced from plants of the genus Sutherlandia and a third component selected from dimethylsulphoxide, dimethylformamide, dimethylsulphone (MSM) or mixtures thereof in the manufacture of a medicament.

The first component, the second component and the third components may be as hereinbefore described. The masses and mass ratios (mass/mass) of the first component to the second component may be as hereinbefore described. The amount of the third component may be as hereinbefore described.

The invention thus provides a combination of the three components in a preselected ratio which is a highly effective immune modulator, which can be applied transdermal^ together with a skin penetration enhancer such as DMSO or DMF or in the form of a cream, gel, drops, tablets or the like.

The invention extends to a transdermal delivery kit, comprising at least one transdermal transfer device which is securable to the skin of a user, and a pharmaceutical composition as hereinbefore described for application to the transfer device prior to securing the device to the skin of the user.

The transdermal delivery device may be a skin patch. The kit will preferably include a number of patches and the composition may be provided in a tube or other container so that it can be applied to the patch prior to use.

The kit may include a single patch and a tube or other container containing a gel for single application or multiple patches and multiple tubes or other containers for multiple applications. The packages may also include alcohol swabs and adhesive bandage or tape to secure the patch to the skin. In use about 30-35% of the pharmaceutical formulation is absorbed by the skin over an eight hour period.

The invention extends to a method of treating a person in need of treatment the method including the step of administering to the person a pharmaceutical composition as herein described. The administration may be cutaneous, topical, sublingual or oral.

The invention extends to the use of Sutherlandia or Echinacea separately together with the third component.

The invention is now illustrated, by way of example, with reference to the following examples and the figures in which

Figure 1 is a schematic diagram of a skin patch in accordance with the invention. Referring to Figure 1 , reference numeral 10 schematically indicates a skin patch in accordance with the invention. The skin patch 10 is shown secured to the arm 12 of a person (not shown). The skin patch 10 has a backing layer 14, a drug reservoir 16, a rate controlling membrane 18, a contact adhesive 20 and a protective peel-off strip 22 which is removed before the patch 10 is secured to the arm 12. The backing layer 14 is made of high-density polyethylene. The drug reservoir 16 comprises a mixture of Echinacea purpurea (300mg), Sutherlandia frutescens (700mg), DMSO (20mg in distilled water) and Carbopol® ETD 2020 NF (1 mg). The rate controlling membrane 18 is a 0,2μ Teflon™ membrane. EXAMPLE 1

Preparation of gel

Method 1

Sutherlandia extract (20g) and Echinacea (3g) were added to water (100ml) and heated under reflux for 60 minutes and allowed to cool. The mixture was filtered and diluted to 100ml with water to produce a solution. The solution (5ml) was combined with ethanol (5ml) and DMSO (38ml) and stirred and Carbomer 940 (1 ,0g) was added with stirring. Sufficient DMSO was then added to produce a gel with a total mass of 50g containing about 1 g of Sutherlandia and about 0,3g of Echinanea.

In a variation on this embodiment the amount of Sutherlandia extract was 10g, the amount of Echinanea was 1 ,5g and water (5ml) was added. In other embodiments, the amount of DMSO was reduced to 15 ml and to 5ml. In other embodiments of the invention, the DMSO was combined with DMF or with MSM or both or was replaced with DMF, MSM or a combination of DMS and MSM in similar amounts. Method 2

Sutherlandia extract (7g), Echinacea (3g) and water (100ml) were heated under reflux for 60min. The mixture was centrifuged and the supernatant was diluted to 100ml to produce a solution. The solution (10ml) was diluted with 100% ethanol (10ml) and added to DMSO (75ml) with stirring. Carbomer® (0,25g) was added with stirring to produce a gel containing about 0,7g of Sutherlandia and about 0,3g of Echinanea.

In variations of this embodiment the DMSO was reduced to 15ml and 5ml respectively EXAMPLE 2

Capsules

(1 ) Capsules with cellulose vegetarian shells were prepared containing 700mg Sutherlandia Frutescence leaf extract (4:1 ), 150mg Echinachia purpurea leaf extract (4:1 ), 37.5mg Echinachia purpurea root extract (4:1 ) and 15mg buffered vitamin C as active ingredients and the inactive components vegetable magnesium striate (anti- caking agent) and microcrystaline cellulose as(bulking agent). The total capsule weight was 900mg. (2) Capsules with cellulose vegetarian shells were prepared containing 500mg

MSM crystalline powder; 200mg Sutherlandia frutescence leaf extract (4:1 ), 50mg Echinachia purpurea leaf extract (4:1 ), 12.5mg Echinachia purpurea root extract (4:1 ), and 15mg buffered vitamin C as active ingredients and the inactive components vegetable magnesium striate (anti-caking agent) and microcrystaline cellulose (bulking agent).

Total capsule weight 900mg Tablets

(1 ) Tablets were prepared from 700mg Sutherlandia frutescence leaf extract (1 :1 ), 150mg Echinachia purpurea leaf extract (1 :1 ), 37.5mg Echinachia purpurea root extract (1 :1 ) and 15mg buffered vitamin C as active ingredients and the inactive components microcrystaline cellulose (bulking agent) or other excipient. The total mass of the tablet was 10OOmg.

(2) Tablets were prepared from 500mg MSM crystalline powder, 200mg Sutherlandia frutescence leaf extract (4:1 ), 50mg Echinachia purpurea leaf extract (4:1 ), 12.5mg Echinachia purpurea root extract (4:1 ) and 15mg buffered vitamin C as active ingredients and microcrystaline cellulose (bulking agent) or other excipient as inactive components. Total tablet weight 1000mg.

Spray/ Vaporiser

(1 ) Spray vaporisers were made from 30% MSM crystalline powder dissolved in demineralised water (100ml), 200mg Sutherlandia frutescence leaf extract (4:1 ), 50mg Echinachia purpurea leaf extract (4:1 ) and 12.5mg Echinachia purpurea root extract (4:1 ). Triethanolamine was included for pH control.

(2) Spray vaporisers were made from 70% DMSO (100ml), 200mg Sutherlandia frutescence leaf extract (4:1 ), 50mg Echinachia purpurea leaf extract (4:1 ) and 12.5mg Echinachia purpurea root extract (4:1 ) as actives with triethanolamine for control of the pH to 3-5ppm and Lemon Verbona 1 -2% as a fragrance.

Concentrated Drops

Drops will be taken 3 times daily 1 drop per kg body weight in glass of juice or water.

1 ) Drops were made from 70% DMSO (200ml), 100mg Sutherlandia

frutescence leaf extract (10:1 ), 25mg Echinachia purpurea leaf extract(10:1 ), 6.35mg Echinachia and Purpurea root extract (10:1 ), as actives and triethanolamine for pH 3- 5ppm, lemon Verbona 1 -2% and demineralised water to 200ml.

2) Drops were made from7 0% DFM (200ml), 100mg Sutherlandia frutescence leaf extract(10:1 ), 25mg Echinachia purpurea leaf extract(10:1 ), 6.35mg Echinachia purpurea root extract (10:1 ) as actives and triethanolamine for pH 3-5ppm, lemon Verbona 1 -2% and demineralised water to 200ml.

EXAMPLE 3

A study was undertaken to show that a combination of Echinacea and Sutherlandia together with DMSO or DMF administered transdermally or Echinacea and Sutherlandia administered orally is an effective immune system enhancer/modulator. Fifteen subjects were selected.

The first cohort included subjects S1 , S2 and S3 who were treated transdermally with Sutherlandia and DMSO. The second cohort included subjects E1 , E2 and E3 who were treated transdermally with Echinacea and DMSO. The third cohort included subjects ESDMF1 , ESDMF2 and ESDMF3 who were treated transdermally with Sutherlandia and Echinacea and DMF. The fourth cohort included subjects T1 , T2 and T3 who were treated with Sutherlandia and Echinacea capsules. The fifth cohort included subjects ESDMSO1 , ESDMSO2 and ESDMSO3 who were treated transdermally with Sutherlandia and Echinacea and DMSO.

The dosage form was transdermal in cohorts 1 , 2, 3 and 5 and the treatment frequency was one transdermal patch weekly for 6 weeks. Each patch contained 700mg of Sutherlandia frutescens and 300 mg of Echinacea purpurea and 80% DMSO or DMF. The dosage form was oral for cohort 4. Each capsule contained 300mg of Sutherlandia and 700mg of Echinacea and the treatment frequency was two capsules once per day normally in the morning. The treatment duration was daily for 30 days.

Efficacy measurements (CD4 count) were made on day 0 (pre-dose) and day 16. The CD4 cells were the immune markers in the study.

The patches were placed on the skin for 8 hours once a week on days 1 , 8, 15, 22, 29 and 36 for 6 weeks. Base Line CD4 counts were measured pre-dose on day 0. CD4 counts were measured on days 7, 14, 21 , 28, 35 and 42. The results are set out in Tables 1 to 5 below.

Table 1

Cohort 1 CD4 count cells/m

Table 2

Cohort 2 CD4 count cells/m

Table 3

Cohort 3 CD4 count cells/m

Subject Base Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Average number line

SEDMF1 710 743 790 900 987 1005 1 150 929.166

SEDMF2 883 929 890 1 120 1331 1392.5 1451 1332.75

SEDMF3 699 650 712 845 829 991 1 123 974.8 Table 4

Cohort 4 CD4 count cells/m

Table 5

Cohort 5 CD4 count cells/m

It can be seen from the results of the CD4 counts that when Sutherlandia, Echinacea and DMF were introduced transdermal^, the average increase in CD4 count was 314.9. This is higher than Sutherlandia and DMSO or Echinacea and DMSO separately at 128 and 120 respectively. However, in the cohort in which Echinacea, Sutherlandia and DMSO were introduced transdermal^, the average increase in CD4 count was 282. In cohort 4 there was a significant increase in the CD4 count (average 158) after daily oral doses for 30 days. These results clearly show that Sutherlandia and Echinacea synergistically combined are more efficacious than Sutherlandia or Echinacea separately. The addition of DMSO or DMF to Sutherlandia and Echinacea in a transdermal formulation demonstrated an even larger increase in CD4 count. The composition of the invention acts as an adaptogenic cellular energy tonic, an immune system booster, for immunomodulatory response enhancement (EMRE), a free radical scavenger, an antioxidant and anti-Inflammatory agent and is useful in the treatment of most autoimmune diseased states.