TOPICAL COMPOSITION CONTAINING HYALURONIC ACID AND NSAIDS

Abstract: A pharmaceutical composition comprising a plurality of effective non-toxic dosage amounts of a composition for topical administration to the site of pathology and/or trauma of skin and/or exposed tissue of a human patient in need of treatment suffering from a disease or condition, each such dosage amount comprising a therapeutically effective non-toxic (to the patient) dosage amount of a drug for the treatment of the disease and/or condition of the skin and/or exposed tissue at the site of the pathology and/or trauma and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to transport (to facilitate or cause the transport of) the drug to the site of the pathology and/or trauma of the disease or condition.

Description: ... TOPICAL COMPOSITION CONTAINING HYALURONIC ACID AND NSAIDS F ELP OF INVENTION This invention relates to the treatment of diseas and conditions of the skin and exposed tissue. In som embodiments this invention finds application to the treatmen of a disease or condition of the skin and exposed tissu including basal cell carcinoma, squamous cell tumours metastatic cancer of the breast to the skin, primary an metastatic melanoma in the skin, malignancies and tumours i the skin, genital warts (condyloma acuminata) , cervica cancer, HPV (Human Papilloma Virus) including HPV (Huma Papilloma Virus) on the cervix, psoriasis (both plaque-typ psoriasis and nail bed psoriasis), corns on the feet, actini keratoses lesions, "liver" spots, fungal' lesions, and othe such types of lesions, and hair loss on the head of pregnant women. This invention also relates to compositions an formulations suitable for use in such treatments, the use o such formulations in such treatments, methods of suc treatment, and the delivery of drugs for such treatments. BACKGROΠNΠ OF THE INVENTION Basal cell carcinoma is presently treated b surgery. Each lesion, together with all surrounding an underlying tissue (dermis, epidermis, and subdermis) , is cu out. In -some instances, surgery, while necessary for- th patient's welfare, puts the patient at risk in some othe respect (for example, the removal of a lesion on a patient' temple (resection) may jeopardize the patient's health) Squamous cell tumours are also treated the same way as a • other forms of cancer in the skin and exposed tissu Furthermore, other conditions and diseases of the skin a exposed tissue are treated in the same way or in ways th cause discomfort to the patient, for example melanoma, genit warts, cervical cancer, HPV (Human Papilloma Virus) . Actinic keratoses lesion is dealt with similarl Liquid nitrogen is also used to remove the lesion. These diseases and conditions are usually found the epidermis (at least for the most part, extending into t dermis and upwards through the Stratum Corneum) . Hyaluronic acid is a naturally occurring glycosaminoglycan. Its molecular weight may vary from 50,000 daltons upwards, and it forms highly viscous solutions. As regards the actual molecular weight of hyaluronic acid in natural biological contexts, this is still a matter of much uncertainty; when the molecular weight of hyaluronic acid is to be determined, different values are obtained depending on the assay method employed, and on the source, the isolation method etc. The acid occurs in animal tissue, e.g. spinal fluid, ocular fluid, synovial fluid, cockscombs, skin, and also in some streptococci. Various grades of hyaluronic acid have been obtained. A preparation with an allegedly high degree of purity and alleged to be entirely free from side effects, is a non-inflammatory form described in U.S. Patent No.4, 141, 973; this preparation is said to have a molecular weight exceeding 750,000 dalton, preferably exceeding 1,200,000 dalton and is suggested for therapeutic use in various articular conditions . Applicants believe that hyaluronic acid claimed in this patent is sold under the trade mark Healon. United States Patent 4,801,619 relates to hyaluronic acid,having a molecular weight of about 3 X 10 6 dalton or more, administered intra-articularly which is prone to decrease the proteoglycan content of synovial fluid to almost normal levels. According to this patent, this indicates a positive effect on the proteoglycan metabolism of a joint. According to the patent, this is applicable both to inflammatory conditions and to degeneration caused by treatment with symptomatics, such as corticosteroid preparations. It is thus clear that a sufficiently high molecular weight of the hyaluronic acid is alleged to counteract side effects that might be caused by corticosteroids or other symptomatics producing similar effects. When corticosteroids are applied, the amount of hyaluronic acid in the synovial cavity will, according to the patent, increase substantially and, according to the inventors, their hyaluronic acid preparations have a very positive effect on such clinical symptoms as pain, swelling, and lameness . The patent states that the objectives of the invention are attained by intra-articular administration (injection) of an effective amount of hyaluronic acid with a mean molecular weight exceeding 3 X 10 6 dalton, preferably exceeding 4 X 10 6 dalton; usually the molecular weight will not exceed 7 X 10 6 dalton. The dosage of hyaluronic acid administered is stated to be preferably within the range of 5mg-80mg. The amount of solution given at each administration is generally less than 60 ml, e.g. less than 20 ml. of an aqueous solution of the acid or its salt . It is convenient to administer the acid dissolved in water (<2% w/w, buffered to physiological pH) , for instance in the form of a water-soluble sodium salt. The exact amount will depend on the particular joint to be treated. The Merck Index Specifies that Hyaluronic Acid has a Molecular Weight within the range pf 50,000 to 8 X 10 6 depen ding on source, methods of preparation, and methods of determination. The Merck Publication teaches hyaluronic acid as a surgical aid (ophthalmological) . United States Patent 4,808,576 purports to teach that hyaluronic acid, an agent well known for reducing the sequelae of trauma in mammalian joint tissue when injected directly into the traumatized joint tissue, will be carried to such traumatized tissue by the mammal's natural processes if applied at a site remote from the traumatized tissue. Thu-s, hyaluronic acid in any therapeutically acceptable form can, according to the Patent, be administered by the typical remote routes including intravenous, intramuscular, subcutaneous, and topical. This, the patent alleges, makes the utilization of hyaluronic acid much more convenient and attractive. For instance, the treatment of arthritis in horse or human joints with hyaluronic acid, according to the patent, no longe requires more difficult intra-articular injections. United States Patent 4,725,585 relates to a metho of enhancing or regulating the host defence of a mammal b administering to a mammal a therapeutically effective amoun of hyaluronic acid. At column 1, lines 43 - 46, the patent provides that the invention was based on the unexpected discovery that administration of hyaluronic acid to mammals results in a considerable increase in the defence. The hyaluronic acid employed in the patent was Healon (t.m) provided by Pharmacia AB, Uppsala, Sweden (Pharmacia AB is also entitled to the benefit of United States Patent 4,141,973) . The patent provides at column 4, line 19 that because a patient's infections had been hard to treat, instead of just hyaluronic acid being administered to the patient to increase the patient's defence, the patient was given hyaluronic acid and an antibiotic. While one reading the patent may conclude that the antibiotic was given in combination with hyaluronic acid, in fact because the hyaluronic acid was administered subcutaneously and because the patient was a heart patient, one skilled in the art would understand that any antibiotic administered, while possibly administered simultaneously with the administration of the hyaluronic acid, was definitely administered separately intravenously (probably) or intramuscularly (less probably) . Thus, the hyaluronic acid administered, according to the teachings of this patent, was administered in order to prevent possible development of infections (increase the host's defence) and not for any other reason. United States Patent 4,636,524 discloses cross- linke gels of hyaluronic acid, alone and mixed with other hydrophilic polymers and containing various substances or covalently bonded low molecular weight substances and processes for preparing them. These products are alleged to be useful in numerous applications including cosmetic formulations and as drug delivery systems . The patent further states that as hyaluronic acid is known to be a biologically tolerable polymer in the sense that it does not cause any immune or other kind of response when introduced into a human body, the cross-linked hyaluronic acid gels can be used for various medical applications. The cross- linked gels modified with other polymers or low molecular weight substances, it is alleged, can be used as drug delivery devices. For example, the inventors are alleged to have found that heparin introduced in a cross-linked hyaluroni acid gel retained its antithrombogenic activity. The inventors also allege that they have also foun that cross-linked gels of hyaluronic acid can slow down th release of a low molecular weight substance dispersed therei but not covalently attached to the gel macromolecular matrix. Unites States Patent 4,736,024 purports to teach ne medicaments for topical use containing: (i) an active pharmacological substance or a mixtur of pharmacological substances, either active o suitable for topical administration and (ii) a topical vehicle which comprises hyaluroni acid or a molecular fraction of hyaluronic acid or a salt o the same with an alkaline metal, an alkaline earth metal, magnesium, aluminium, ammonium, or a pharmacological substanc optionally together with additional conventional excipient for pharmaceutical preparations for topical use. Applicants are also aware of published Japanes Patent Document 61000017, dated 86/01/06, whose Englis abstract of disclosure states that the Japanese Paten Document relates to the use of hyaluronic acid or cross-linke hyaluronic acid or their salts as the active ingredient fo inhibiting carcinoma metastasis. According to the purported abstract of the patent more that 1.0% of hyaluronic acid is dissolved in alkaline aq soln. and pref. more than 50% of H 2 0 sol. org. solvent, eq alcohol, acetone, dioxane, against total- soln. is added Preferably the pH is 12-14. Then a multifunctional epoxy cpd is added and reacted at 10-60 deg. C, pref. at 20^-40- deg. for ' 24 hrs . ■ Cross-linking ratio of crosslinked hyaluroni acid or its salt is regulated by changing mol ratio o hyaluronic acid or its salt and multifunctional epoxy cpd. Pref. hyaluronic acid used has intrinsic viscosity 0.2-30,m.w 4000-2000000. The hyaluronic acid is allegedly used in severa dosage forms . The clinical dose for an adult is alleged to b normally, as hyaluronic acid or cross-linked hyaluronic acid 25mg-5 g/day (p.o.) and 10 mg-2.5 g/1 dose (inj) . Th abstract alleges that the advantage is that the hyaluroni acid has no side effects as may other anti-cancer drugs and has an analgesic and a tissue restoration effect. - European Patent Application 0295092 purports to teach a vehicle together with fragments of hyaluronic acid for delivering of the fragments of hyaluronic acid into the skin to reach the dermal layer of the skin to increase the development of blood vessels for stimulating hair growth or regrowth. The preferred fragments of hyaluronic acid are polysaccharides containing from 7 to 25 monosaccharide units. The patent provides that it is apparent that the larger the fragments of hyaluronic acid, the greater the difficulty there is in delivering the fragments to the dermal layer of the skin, unless there is also present in the composition a means for enhancing the activity of said fragments . The combination may thus include a means for enhancing the activity of the fragments of hyaluronic acid, especially to improve their penetration through the skin following topical application. Some activity enhancers, it is alleged, also function as. vehicles for the fragments of the hyaluronic acid. Some activity enhancers are also alleged to possess the ability to stimulate or increase hair growth. Minoxidil is asserted among others to be such an activity enhancer. Thus both the fragments of hyaluronic acid and minoxidil are alleged to stimulate hair growth both delivered by a vehicle.' European Patent Application 0179442 asserts that where free radicals are formed in considerable quantities, hyaluronic acid is broken down or degraded before the hyaluronic acid has given the desired effect. Canadian Letters Patent 1,240,929 -teaches the combination of chondroit ' in sulfate compound and a hyaluronate to protect both human and animal cell layers and tissue subject to exposure to trauma. European Patent Application 0208623 purports to teach hyaluronic acid as "une augmentation de I'activite de certaines proteases". It also purports to teach the use of hyaluronic acid for treating connective tissue diseases, including malignant tumours and cardiovascular disorders. European Patent Application 270317 purports to teac the combination of an antiviral agent lacking inhibitor action and a compound [for example, hyaluronic acid] possessing cell fusion inhibitory activity and/or virus adsorption inhibitory activity for treating disease carried b a virus . United States Patent 4,840,941 purports to teach th use of an effective amount of hyaluronic acid as the activ agent for the treatment of retroviruses in association with pharmaceutically acceptable carrier, diluent, or excipient. United States Patent 4,851,521 and European Paten Application.0265116 both describe hyaluronic acid fractions, the making thereof and cross-linked esters of hyaluronic. United States Patent 4,851,521 describes esters of hyaluroni acid incorporated into pharmaceutical preparations as th active ingredient and as vehicles for ophthamologica medicines for topical use (See column 11, lines 35 to 42; an column 12, lines 62 to column 13, line 3) and in suppositorie for a systemic effect due to the effect of transcutaneou absorption, such as in suppositories. The patent provides ' at column 13, lines 5 to 31: "The vehicling action of the hyaluronic esters also applies to associated medicaments of the type mentioned above in which the active substance acts not only topically or by nasal or rectal absorption, for example by nasal sprays or preparations for inhalation for the oral cavity or the pharynx, but also by oral or parenteral route, for example by intramuscular, subcutaneous or intravenous route, as it favors absorption of the drug into the application site. The new medicaments can therefore be applied, apart from i the fields already mentioned, in practically all sectors of medicine, such as internal medicine, for example in pathologies of the cardiovascular system, in infections of the respiratory system, the digestive system, the renal system, in diseases of an endocrinological nature, in oncology, in psychiatry etc., and may also be classified therefore from the point of view of their specific action, being perhaps anesthetics, analgesics, anti-inflammatories, wound healers, antimicrobics , adrenergic agonists and antagonists, cytostatics, antirheumatics, antihypertensives, diuretics, sexual hormones, immunostimulants and immunosuppressants, for example, one of the drugs having the activity already described for the therapeutically active alcohols to be used as esterifying component according to the present invention, or for the therapeutically active bases used for the salification of the free carboxylic groups. " There have been extensive studies to determine the defect in immune function that allows a tumour cell to develop. It was postulated initially by Jerne, and subsequently by Burnett, that the immune system's major role was that of immunological surveillance to destroy abnormal cells. The concept of surveillance, while somewhat simplistic, remains an accepted concept for the elaborate mechanism of immune recognition and function that is present in the higher species - mammals. It has then been postulated that tumours develop because of local or generalized immune suppression. However, as pointed out by Moller, if general immune suppression occurs, it is only certain types of neoplastic disorders that develop, mainly those of the lympho-reticular system. This observation is generally correct and represents a major challenge to the immune surveillance theory unless a specific reason can be shown as to why the individual cancer cell can develop plus individually evade the immune system. It was demonstrated experimentally in 1974 that defects of macrophage function may exist in neoplastic disease. The initial experiments found suppressor cells to be part of the immune system; these were either of the T-cell type of the macrophage cell system. There was presence demonstrated in neoplasia, chronic bacterial infection, recovery from massive injury and chronic fungal infection. There has been repeated demonstration i experimental animals that the macrophage cell function i altered in neoplastic disease. The macrophages in th animal's systems appeared "blocked" in their function Generally when removed from the in vivo situation, washed i saline and cultured, they perform normally. This block ha been shown to be related to the excessive production o prostaglandin by neoplastic tissue or by the macrophag itself. Similarly, the N.K. cells (which are said to b primitive or immature macrophages and which may be involved i cancer defence) are also blocked. In the basic research efforts in the latter '70s an the early '80's, there existed considerable confusion as t what role immunotherapy should take in cancer. Activation o "hyping" of macrophages was thought to be important. However in an examination by Romans and Falk of peritoneal macrophage obtained from patients with neoplastic disease, there wa definite evidence that these macrophages were alread activated yet were co-existing with cancer cells and no causing their destruction. It has recently been shown by several independen investigators that the malfunction of macrophages or th putitive block is due to excessive prostaglandin and that thi can be altered in tissue culture by corticosteroids, ASA, an the non-steroidal anti-inflammatory drugs, i.e. indomethaci and naproxen (Naprosyn™) . Again, it was repeatedl demonstrated that in animal tumours these substances coul alter the response to neoplastic cells' and that variou combinations of these substances employed with immun enhancing agents could produce very credible success i eliminating experimental tumours. Lala and co-worker combined Indomethacin therapy with Interleukin 2 and showe that this could effect a cure with experiment neoplasm. There were continued problems with the use of any o these agents in the actual human in vivo experience. All o the non-steroidal anti-inflammatory agents (NSAID) produce major toxicity in terms of gastro-intestinal, neurological and other areas. Thus, the basis of the present approach is that, under general circumstances, with the use of these agents in human disease in sufficient amounts, the drug will penetrate to any pathological tissue to alter therapeutically local prostaglandin production. While intravenous preparations of Indomethacin (and now of other agents) exist, using these drugs alone produces prohibitive side effects in human subjects. Therefore, only insufficient amounts can be brought into the body to effect more than occasional responses in neoplasm. However, the majority of the evidence is present to indicate and therefore, it can be postulated that the basis for neoplastic development and how the initial cell "sneaks by" the immune surveillance mechanism relates to its production of prostaglandin. One need postulate only one mutation to alter the amount of prostaglandin synthesis produced by cells when they become "malignant" to establish a mechanism of blocking out the initial cell in any immune reaction, i.e. the macrophage. It therefore became essential to develop a combination of NSAIDs for clinical use to produce a major improvement .in response in neoplastic disease and other conditions where excessive prostaglandin synthesis represents the basis of the pathogenesis of this disease state, i.e. arthritis and various others of the so-called connective tissue inflammatory disorders and/or auto- aggressive diseases . See also: 1. Modulation of Immunity in Cancer Patients by Prostaglandin Antagonists, Immunity to Cancer II r Alan R. Liss, Inc.; and 2 . Goodwin, J. S . , (1981) Prostaglandin E and Cancer Growth Potential for Immunotherapy with Prostaglandin Synthesis Inhibitors , Au mentive Agents in Cancer Therapy r Raven Press, New York . United States Patent 4 , 711 , 780 teaches a pharmaceutical composition comprising Vitamin C, a zinc salt, and a sulfur amino acid for treating surface epithelium for epithelium regeneration . Hyaluronic acid may be added for applications in the reproductive tract to block the passage o toxins into the blood system. U.S. Patent 4,937,254 (Ethicon) teaches combination of hyaluronic acid and salts thereof with NSAIDS for th prevention of adhesions after surgery. Because of the side effects of the use of non steroidal anti-inflammatory drugs (major toxicity in terms o gastro-intestinal, neurological, and other areas),use thereo should also be restricted (if possible) to the area of us without delivery to other areas which are not in need o treatment. Thus, if useful amounts of the non-steroidal anti inflammatory drugs or for that matter any drugs could b delivered to a site in need thereof without carriage o substantial amounts away from the site to.be treated, thereb accumulating an amount of the drug at the site to be treate for a prolonged period of time, then the use of the drug fo example a non-steroidal anti-inflammatory drug at a site ma have many other useful applications . SUMMARY OF THE INVENTION Applicants have now developed compositions, (combinations and formulations) which are topically applied t the skin and/or exposed tissue of a human and which ar quickly transported in dosage amounts percutaneousl (intracutaneously) at a site in need of treatment, (site o pathology and/or trauma) best targeting the epidermis an subsequently remaining (accumulating) at the site for prolonged period of time. The. compositions subsequently clea through the lymphatics thereby bringing dosage amounts of th compositions to the lymphatics for the treatment of diseas and conditions in the lymphatics. These compositions, (combinations and formulations employ, combine, or incorporate (as the case may be) plurality of effective non-toxic dosage amounts, each dosag amount comprising an effective non-toxic dosage amount of drug for example a drug which inhibits prostaglandin synthesi for example an NSAID and an effective non-toxic dosage amoun of a form of hyaluronic acid (preferably hyaluronic acid o salt thereof) for the transport of the drug to the site of th pathology and/or trauma. Suitable dosage amounts of th composition may be removed from a container (for example a tube or jar) and administered (for example, applied) . Thus according to one aspect of the invention these pharmaceutical compositions (combinations and formulations) comprise a plurality of effective non-toxic dosage amounts for administration to the skin and/or exposed tissue of a human in need of treatment, each such dosage amount comprising a therapeutically effective non-toxic (to the patient) dosage amount of a drug to treat a disease and/or condition for example a drug which inhibits prostaglandin synthesis, preferably being a non-steroidal anti-inflammatory drug (NSAID) , for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) and an effective non-toxic dosage amount (for example in excess of 5 mg per cm 2 (square centimeter) of skin or exposed tissue to which the dosage amount of the composition is to be applied) of hyaluronic acid and/or salts thereof (for example the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid (preferably hyaluronic acid and/or salts thereof) to transport (to faciliate or cause the transport of) the drug to the site of the pathology and/or trauma of the disease or condition. These compositions may be applied topically to treat diseases and conditions of the skin and/or exposed tissue at the site of the trauma and/or pathology, (for example, basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots and like lesions (found for the most part in the epidermis) , squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, malignancies and/or tumours in the skin, genital warts (condyloma acuminata) , cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis) , corns on the feet and hair loss on the head of pregnant women) . The results of the treatment with suitable dosage amounts taken from these compositions (combinations and formulations) have been in some instances quite dramatic - difficult situations have been successfully treated and resolved. Furthermore, application of the dosage amounts of the compositions, combinations and formulations are, systemic independent (there is a lack of a blood level of the drug for example NSAID) , are quick to penetrate into the skin to the site of the trauma and/or pathology because the effective dosage amount of the form of hyaluronic acid transports (facilitates or causes the transport of) the drug (for example NSAID) particularly to the epidermis where the composition, combination or formulation accumulates and remains for prolonged periods. The compositions subsequently clear through the lymphatics and are available for the treatment of disease and conditions of the lymphatics. In this regard effective amounts of the form of hyaluronic acid exceeds in the order of about 5 mg per square cm. (cm 2 ) of the area of for example the skin and/or exposed tissue to which the dosage amounts of the composition is to be applied. Thus, according to another aspect of the invention, Applicants have provided topically applicable percutaneous (intracutaneous) penetrating (best targeting the epidermis) systemic independent acting (not acting essentially throug the blood) pharmaceutical compositions (combinations an formulations) comprising a plurality of dosage amounts eac comprising, together with pharmaceutical excipients suitable for topical application, a therapeutically effective (to treat and to assist to resolve diseases and conditions of the ski and exposed tissue (for example basal cell carcinoma, th precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots and like lesions (found for th most part in the epidermis) , squamous cell tumours, metastati cancer of the breast to the skin, malignancies and/or tumour in the skin primary and metastatic melanoma in the skin, genital warts (condyloma acuminata) , cervical cancer, and HP (Human Papilloma Virus) including HPV of the cervix, psoriasi (both plaque-type psoriasis and nail bed psoriasis) , corns o the feet and hair loss on the head of pregnant women) , non toxic (to the patient) dosage amount of a drug for exampl which inhibits prostaglandin synthesis, preferably a non steroidal anti-inflammatory drug (NSAID) , for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) and an effective non-toxic amount of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) to transport (facilitate or cause the transport of) the drug (for example NSAID's) rapidly to the site in the skin (for example epidermis) and/or exposed tissue of the disease or condition into the tissue to remain there for a prolonged period of time to assist to treat and assist to resolve the disease or condition for example by blocking prostaglandin synthesis. Effective dosage amounts of the form of hyaluronic acid to facilitate or cause the transport of the drug into the skin and/or exposed tissue by the form of hyaluronic acid exceeds about 5 mg. - 10 mg. in the dosage amount administered (applied and rubbed in) for each 1 cm 2 of skin and/or exposed tissue area of the disease or condition (for example basal cell carcinoma) to which the dosage amount is applied. The dosage amount applicable will depend upon the surface area of the skin and/or exposed tissue in which the condition or disease exists . Thus if the disease or condition occupies about .5 cm 2 , in excess of about 2 1 / 2 mg of the . form of hyaluronic acid would be used (applied and rubbed in) . In the same way if the area is 2 cm 2 , the amount of the form of hyaluronic acid preferably exceeds about 10-20 mg of the dosage amount of the formulation or composition applied. Preferred forms of the hyaluronic acid (for example hyaluronic acid and the sodium salt thereof) have molecular weights less than about 750,000 daltons (for example about 150,000 to about 225,000 daltons) to transport the medicine in the skin and/or exposed tissue. While higher molecular weights of the hyaluronic acid and forms thereof may be used to penetrate the skin and/or exposed tissue and transport the medicines or drugs, where the molecular weight of the hyaluronic acid chosen for use is very large, it is preferred that the form of hyaluronic acid is autoclaved, to break down the hyaluronic acid to fragments of lesser molecular weight or if feasible diluted to permit administration and ensure no coagulation o or in the skin. Where the molecular weight of the form o hyaluronic acid being employed is large, the concentration o the form of the hyaluronic acid in the composition may fo example be reduced (for example to less than about 3%) dependent on the molecular weight. The blockage of prostaglandin synthesis by th transported drug (for example NSAIDS) then unblocks th macrophages and permits the macrophages of the patien proximate the lesion (for example, the basal cell carcinoma) to destroy the lesion or condition. Treatment by dosag amounts of the composition (formulation and/or combination) eliminates the condition without recurrence, even where th lesion has recurred a number of times after unsuccessfu treatments according to the prior art . Other non-steroidal anti-inflammatory drugs (NSAIDS) may be used such -as other propionic acid derivatives, Ibuprofen, acetylsalicylic acid, piroxicam and flunixin.. When dosage amounts of such compositions, combinations and formulations are applied to the site of th disease or condition for ■ example the basal cell carcinoma o the patient suffering from the basal cell carcinoma, over period of time (for example, for a period of 2-4 weeks 3 time daily) the basal cell carcinoma " is completely resolved an disappears. Thus according to another aspect of the inventio there is provided a pharmaceutical composition from whic dosage amounts may be taken for application to the skin and/o exposed tissue, the pharmaceutical composition comprising in form for application to a human a plurality of dosage amount of medicine and/or therapeutic agent to treat a disease o condition in a human and a plurality of dosage amounts o hyaluronic acid and/or salts and/or homologues, analogues derivatives, complexes, esters, fragments, and/or sub-units o hyaluronic acid such that when dosage amounts of th pharmaceutical composition are taken from the composition, th amount of the medicine and/or therapeutic agent comprises a effective non-toxic dosage amount of the medicine to treat th disease or condition in the skin and/or exposed tissue in • human and the amount of the form of hyaluronic acid in the dosage amount is present in an effective amount to transport (facilitate or cause the transport of) the medicine and/or therapeutic agent intradermally (percutaneously, intercutaneously, intracutaneously) into the skin (preferably to the epidermis and dermis) and/or exposed tissue of a human to the site of a pathology and/or trauma. The effective amount of the form of hyaluronic acid has a molecular weight and concentration to transport the medicine (drug) and/or therapeutic agent to the site of trauma and/or pathology in the skin and/or exposed tissue. In this regard the preferred amount of the form of hyaluronic acid in each dosage amount exceeds 5 mg./cm 2 and preferably the molecular weight is less than about 750,000 daltons, (in one embodiment about 150,000 to about 225,000 daltons) in some embodiments with a concentration of between about 1 and 3%, preferably concentrations of between about 2 to about 3% by weight. Where forms of hyaluronic acid are used having greater molecular weights, they are preferably cleaved and/or diluted to smaller concentrations, to facilitate or cause the transport, of the medicine and/or therapeutic agent. According to another aspect of the invention there is provided a pharmaceutical composition (for example a gel or cream) from which dosage amounts may be taken and applied to the skin to treat a disease or condition in humans, for example as discussed above, the pharmaceutical composition comprising: (1) a medicinal and/or therapeutic agent suitable for treating a disease or condition in the skin and/or exposed tissue in humans, for example a drug which inhibits prostaglandin synthesis (for example an NSAID) ; and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, in a form suitable for administration to the skin and/or exposed tissue in humans; characterized in that an effective non-toxic dosage amount comprising components (1) and (2) taken and administered from said composition (i) is available in the skin and/or exposed tissue upon administration to treat said disease or condition in humans by penetration at the site to be treated to the site of trauma and/or pathology, and (ii) comprises an effective non-toxic dosage amount of component (2) effective to transport (facilitate or cause the transport of) component (1) immediately upon administration percutaneously into the skin (preferably the epidermis) to the site to be treated for example the site of trauma and/or pathology where it remains for a prolonged time, accumulating there and from which it is discharged via the lymphatic system. Therefore according to another aspect of the invention a pharmaceutical composition is provided comprising: (1) a medicinal and/or therapeutic agent which for example inhibits prostaglandin synthesis in a therapeutically effective amount to treat a disease or condition of the skin and/or exposed tissue; and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, characterized in that said composition (a) is in a dosage form (for example a gel or cream) which is suitable for administration to the skin and/or exposed tissue; and (b) is in such an amount and in such form that (i) component (1) is in ' an effective dosage amount to treat said disease or condition by penetration at the site of the skin and/or exposed tissue to be treated for example the basal cell carinoma and other lesions; and (ii) component (2) is immediately available to transport (facilitate or cause the transport of) component (1) to the site of trauma and/o pathology to be treated, percutaneously into the s-kin (o exposed tissue) where the composition resides and accumulates for a prolonged period, and which component (2) is in a effective non-toxic dosage amount to transport (facilitate o cause the transport of) component (1) upon administration, percutaneously into the skin or exposed tissue to the site o the trauma and/or pathology. Preferably the form of hyaluroni acid in the composition comprises hyaluronic acid and/or salt thereof. An effective amount of the form of hyaluronic aci exceeds about 5-10 mg per square centimeter (cm 2 ) of skin and/or exposed tissue to which it is to be applied. According to another aspect of the invention there is provided the use of: (1) a medicinal and/or therapeutic agent for example which inhibits prostaglandin synthesis, and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, in the manufacture of a pharmaceutical composition for treating a disease or a condition (for example those discussed above) of the skin and/or exposed tissue in a therapy wherein dosage amounts taken from the composition each comprise: (1) a therapeutically effective amount of said medicinal and/or therapeutic agent and (2) a therapeutically effective amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub- units of hyaluronic acid, the pharmaceutical composition being characterized in that for each dosage amount taken from the pharmaceutical composition, the amount of component (2) is immediately available to transport component (1) percutaneously to the site of " trauma and/or pathology for example into the epidermis where the composition accumulates and remains for a prolonged period, at the site of the skin or exposed tissue to be treated, and component (2) is in an effective non-toxic amount to transport (facilitate or cause the transport of) component (1) into the skin ^ or exposed tissue (for- example into the epidermis) . Preferably component (2) is hyaluronic acid and/or salts thereof and preferably the dosage amount of component (2) in the amount of the composition taken from the composition (to be taken from the composition) and applied to the skin or exposed tissue is a dose amount greater than about 5-10 mg per cm 2 of skin and/or exposed tissue to which the dosage amount is to be applied. The pharmaceutical composition will normally include pharmaceutically compatible excipients to provide a form for ease of administration to the skin and/or exposed tissue for transport into the epidermis . For example a suitable dosag amount of a gel may be squeezed from a tube as a ribbon of ge "X" cm long (which dosage amount (in the form of the ribbo "X" cm long) contains the effective non-toxic dosage amount of the drug and form of hyaluronic acid. Or a dosage amount o cream packaged in a jar may be scooped from the jar by measuring device or by "two fingers" in a suitable amount (fo example in a spoon containing a premeasured volume or a amount about half the "length of the fingers") . Each of th dosage amounts selected comprises the effective amounts o drug (for example NSAID) and effective amount of the form o hyaluronic acid (for example hyaluronic acid and/or salt thereof) . In this way the patient may "squeeze" or "scoop" o "what have you" the appropriate dosage amount and apply (ru in) the dosage amount onto the skin and/or exposed tissue fo transport into the epidermis. Thus, according to another aspect of the invention a method of treating a disease and/or condition of the skin o exposed tissue, for example basal cell carcinoma, th precancerous, often recurrent, actinic keratoses lesions fungal lesions, "liver" spots and like lesions (found for th most part in the epidermis), squamous cell tumours, metastati cancer of the breast to the skin, primary and metastati melanoma in the skin, malignancies and/or tumours in the skin genital warts (condyloma acuminata) , cervical cancer, HP (Human Papilloma Virus) including HPV of the cervix, psoriasi (both plaque-type psoriasis and nail bed psoriasis) , corns o the feet and hair loss on the head of pregnant women, in human is provided comprising administering topically to huma skin and/or exposed tissue an effective non-toxic dosag amount of a composition comprising, together wit pharmaceutical excipients suitable for topical application t the skin and/or exposed tissue, for example in the form of gel or cream (to give the composition definition and form s that specific dosage amounts are easily selected or taken fo administration (for example squeezed from a tube or scoope from a jar and rubbed into the skin or exposed tissue) , therapeutically effective (to treat and to assist to resolv the disease or condition for example basal cell carcinoma o other lesion) , non-toxic (to the patient) dosage amount of a drug for example which inhibits prostaglandin synthesis, for example a non-steroidal anti-in lammatory drug (NSAID) , for example, diclofenac, indomethacin, naproxen, and (+/-) tro ethamine salt of ketorolac (sold under the trademark Toradol™) and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) to transport (facilitate or. cause the transport of) the drug (for example NSAID) into the skin or exposed tissue to the site of the disease or condition to be treated percutaneously, (to the site of trauma and/or pathology) , for example into the epidermis, where the form of hyaluronic acid and medicine accumulates and remains for a prolonged period of time thereby for example blocking prostaglandin synthesis in the skin or exposed tissue. The form of hyaluronic acid is then cleared through the lymphatics (lymphatics system) . Thus, according to another aspect of the invention, the treatment may . employ - the use of the composition, formulation or combination for the treatment of the diseases and conditions aforesaid as for example by applying dosage amounts of the composition, formulation or combination a number of times daily (for example, 3 times daily) for a period of time, for example, 2-4 weeks to clear the disease, lesion or condition. Each dosage amount applied will depend upon the size of the lesion or condition on the skin or exposed tissue. For example, a suitable dosage amount may include 5-10 mg. of the form of hyaluronic acid per 1 cm 2 skin area or exposed tissue area. One such formulation may comprise 3% (by weight) diclofenac in a 2-/ 2 % (by weight), hyaluronic acid (sodium hyaluronate - molecular weight 661,600) gel formulation, with the excipients being glycerine (5%) , benzyl alcohol (3%) (acting in part as a solubilizer and preservative) , and sterile water (the balance) in a 50 gm. tube of the composition (a plurality of dosage amounts) whose tube O.D. (outer diameter) of the opening through which the gel formulation is discharged from the tube is 8 mm and whose I.D. (inner diameter) of the opening is 4 mm. Therefore a ribbon 2-3 cm in length, squeezed from a tube gives about 5 mg-7 1 / 2 mg of hyaluronic acid for application to a skin or exposed tissue surface area of l-l 1 2 cm 2 with an effective dosage amount of diclofenac. While greater amounts squeezed from the tube, may be applied, the application of substantial excessive dosage amounts to the skin and/or exposed tissue may saturate the skin or exposed tissue and thus the epidermis. (There is therefore no more room for the composition to pass between the cells and therefore further applications at that time will not provide additional benefit) . Where pain relief is also required additional dosage amounts, for example in excess of about 10 mg. of the hyaluronic acid taken from the same pharmaceutical composition applied per/cm 2 of surface area of the skin or exposed tissue may be required to be applied. Another formulation may comprise 3% (by weight) diclofenac in a 2 1 / 2 % (by weight) hyaluronic acid (sodiu hyaluronate - molecular weight 679,000) gel formulation (als in a tube) with excipients being benzyl alcohol (1%) ( preservative), methoxypolyethylene glycol 350 (20% by weight) (a solubilizer) , and sterile water (the balance) . While the above compositions, . combinations an formulations are proposed, provided there is sufficien amounts of the form of the hyaluronic acid (for example, sodium hyaluronate) in the dosage amounts applied to the ski and/or exposed tissue to facilitate or cause the percutaneou (intracutaneous) transport of the drug for example whic inhibits prostaglandin synthesis, preferably an NSAID (fo example, diclofenac) to block prostaglandin synthesis, the the formulations may be of any suitable form, for example, 1% lotion of hyaluronic acid with NSAID, or a cream or gel o any other suitable form. Therefore according to another aspect of th invention, there is provided containers (for example tubes an jars) containing compositions comprising a plurality of dosag amounts of the drug and form of hyaluronic acid, each dosag amount comprising an effective non-toxic dosage amount of th drug and an effective non-toxic dosage amount of the form o hyaluronic acid (preferably sodium hyaluronate having molecular weight less than about 750,000 daltons) to transport the drug into the skin and/or exposed tissue. In some embodiments, means are provided to assist the removal from the container of an effective dosage amount of the composition in the container for use to apply to the skin or exposed tissue at the site of trauma and/or pathology to treat the disease and/or condition (for example mouth opening of a tube to control the amount discharged from the tube) . Furthermore, because there is little concern with respect to the toxicity or adverse effects of the use of, for example, the NSAIDs with the hyaluronic acid in the compositions of this invention the NSAID may be combined as needed (after solubilizing (if required) of the NSAID in a suitable solubilizer) with the form of the hyaluronic acid. Therefore according to another aspect of the invention, percutaneous (intercutanous) delivery of a therapeutically effective dosage amount of a drug (in a composition, combination or formulation) ' and which drug for example inhibits prostaglandin synthesis, preferably being a non-steroidal drug (NSAID) is provided. In this regard the drug is transported to the site of, on, or in the skin and/or exposed tissue of trauma and/or pathology to treat the disease or condition for example the basal cell carcinoma or actinic keratoses lesion in a mammal (human) . The delivery may comprise topically administering (to the skin or exposed tissue site of for example the basal cell carcinoma or other lesion) a therapeutically effective non-toxic (to the patient) dosage amount of a composition comprising a drug for example which inhibits prostaglandin synthesis, preferably an NSAID (non-steroidal anti-inflammatory drug) , for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) , and an effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, preferably hyaluronic acid and salts thereof, sufficient to transport, (facilitate or cause the transport of) , the drug for example NSAID percutaneously (to for example the epidermis) to the site of the trauma and/or pathology in fo example the epidermis, for example the basal cell carcinom (or other lesion) , to be treated for example to block th synthesis of prostaglandins . Delivery may be also accomplished by the same amoun of the form of hyaluronic acid, of other drugs percutaneousl (intercutaneously) to the skin and exposed tissue b application and rubbing in of an effective non-toxic dosag amount of the formulation or composition comprising a effective non-toxic dosage amount of the drug and an effectiv non-toxic dosage amount of the form of hyaluronic acid for th transport of the drug percutaneously into the skin or expose tissue to the epidermis where the dosage amount of th composition is accumulated and remains for a prolonged perio of time before the form of hyaluronic acid is cleared throug the lymphatics. In this regard the drug may be novantrone (a anti-cancer drug) for administration to a tumour or malignanc in the skin. The novantrone may comprise 10 mg in the .dosag amount of the composition and the form of hyaluronic acid ma be in excess of about 5 mg of sodium hyaluronic per cm 2 of th skin or exposed tissue (about 2.5% of the composition) for th percutaneous transport of the novantrone. Thus, according to another aspect of the invention use of a composition, combination or formulation is provide to treat a disease or condition for example basal cel carcinoma (or other lesion) , by the application of th composition, combination or .formulation, the amount of th composition, .combination and formulation administere comprising together with pharmaceutical excipients suitabl for topical application, a therapeutically effective (to trea and assist to resolve a disease or condition for example basal cell carcinoma) , non-toxic (to the patient) amount of drug for example which inhibits prostaglandin synthesi preferably a non-steroidal anti-inflammatory drug. (NSAID) , fo example, diclofenac, indomethacin, naproxen, and (+/- tromethamine salt of ketorolac (sold under the trademar Toradol™) administered together with, or carried in, effective dosage amount of hyaluronic acid and/or salt thereof (for example, the sodium salt) and/or homologues analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) effective to transport the drug for example the NSAID (to facilitate or cause the transport of the drug for example NSAID) percutaneously into the skin especially the epidermis at the site of the disease or condition for example basal cell carcinoma (or other lesion) to be treated, thereby, if an NSAID, blocking prostaglandin synthesis to enable the macrophages (and N.K. cells) to resolve the disease or condition for example basal cell carcinoma or other lesion. Applicants postulate that the hyaluronic acid and/or salts thereof and/or the homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid facilitate or cause the transport of -the drug for example which blocks prostaglandin synthesis (preferably an NSAID) to the site of prostaglandin synthesis to block prostaglandin synthesis. Applicants' compositions and dosage amounts of their compositions and the use of their compositions and dosage amounts of their compositions, at the same time, abate pain that the patient is experiencing at the paccinian nerve bundles (superficial nerve bundles) at the site of the trauma and/or pathology on/in the exposed tissue and/or skin. Thus, according to another aspect of the invention, a method of abating pain in the skin and/or exposed tissue for example suffering a disease or condition (for example those discussed above) , and a composition from which dosage amounts may be taken and- applied (rubbed in) which is useful for abating such pain are provided, the method comprising administering (rubbing on) an effective dosage amount of the composition to the skin and/or exposed tissue, and the composition comprises a plurality of dosage amounts, each comprising an effective non-toxic dosage amount of an NSAID and an effective non-toxic dosage amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or subunits of hyaluronic acid (preferably hyaluronic acid and salts thereof) , for example amounts exceeding 10-20 mg. per square cm (cm 2 ) of skin or exposed tissue to which it is applied, for percutaneous transport of the NSAID by the form of hyaluronic acid into the epidermis proximate the paccinian nerve bundles (superficial nerve bundles at the end of the nerves) to abate pain. Thus, according to another aspect of the invention, compositions are provided for use to relieve pain from which dosage amounts of the composition comprising dosage amounts of the NSAID and form of hyaluronic acid are taken. By way of example and to illustrate the facilitation of the delivery or transport of a chemical to a site in a human, when ethyl alcohol is injected directly into a tumour and sonographic (ultrasound) assessment is made, it is not dispersed throughout the tumour. When the ethyl alcohol to be administered into a tumour is carried by hyaluronic acid and/or salts thereof, sonographic assessment of the tumour demonstrates the dispersion of the ethyl alcohol throughout the tumour. While Applicants postulate that the hyaluronic acid facilitate or causes the transport and delivery, Applicants' invention may be used as described irrespective of the actual method of operation of the hyaluronic acid and/or salts thereof and/or the homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid. The combination of hyaluronic acid and salts thereof and other forms with drugs for example that inhibit prostaglandin synthesis, for example NSAIDs, alters their distribution and performance in the skin and/or exposed tissue particularly the epidermis (the combinations and formulations being systemic independent) , and produces an unusual targetin for underperfused skin and/or pathological tissue in the ski (site of trauma and/or pathology) . The application may b made as required with the amount depending upon the conditio of the skin or exposed tissue. As a major amount of soluble indomethacin may b incorporated into the formulation, or composition, th indomethacin may be solubilized using n-methyl glucamine at dilution of 5mg/ml of n-methyl glucamine (NMG) . Thi substance is then passed through a 22 micron Milipore filte to produce sterility. This material is non-toxic at 16 fol the therapeutic dose in animals (with hyaluronic acid) and fo this reason was considered appropriate to be used in human conditions. Thus, Indocid™ solubilized in NMG may be administered with hyaluronic acid topically for percutaneous penetration at, for example, varying doses. The solution of indomethacin and NMG may be mixed with, for example, "LifeCore™" hyaluronic acid in dosage amounts discussed above. This produces an appropriate mixture and can be administered safely. When the NSAID, for example indomethacin (dissolved in n-methyl glucamine) or other NSAID, is applied topically in an effective dosage amount from a composition or formulation also including the effective dosage amount of the form of hyaluronic acid, no major toxic side effects occur, such as gastro-intestinal distress, neurological abnormalities, depression, etc., even at elevated amounts of indomethacin (if necessary) . (This may be in part because of the clearing of the hyaluronic acid through the lymphatic system from the site) . In addition, the responses that have been observed are dramatic when the drug for example NSAID (for example diclofenac) is combined with hyaluronic acid, demonstrating clearly that the combination is now "targeting" to the site of pathology or trauma, or pathological tissue. Furthermore, patients using the formulations and combinations of drug (for example NSAID) - hyaluronic acid (sodium hyaluronate) (for example, diclofenac or indomethacin and hyaluronic acid) , experience dramatic relief of pain immediately. Thus, Applicants believe that the use of the NSAID, for example with hyaluronic acid (sodium hyaluronate), deblocks the macrophages (and N.K. cells (Natural Killer Cells) thought to be immature macrophages) by preventing enzymatic production of prostaglandin which blocks macrophage (and N.K. cell) functioning. The hyaluronic acid (and salt and other forms) not only enhances the activity of the drug (NSAID) but also reduces any side effects and toxicity that is associated with the use of the prostaglandin synthesis inhibitors. When effective dosage amounts of compositions, formulations and combinations containing effective dosage amounts of the drugs for example, (NSAIDs (for example, diclofenac) ) and effective dosage amounts of, for example, hyaluronic acid or the sodium salt thereof, are applied to fo example the tumour lesion (for example basal cell carcinoma) or other condition (for example, actinic keratoses lesion) fo a period of time (for example, 3 times daily for 2-4 weeks) , the carcinoma and lesions, as the case may be, disappear. Applicants also postulate that when the combinatio or formulation is applied to the disease or condition (fo example, basal cell carcinoma or actinic keratoses) , th hyaluronic acid passes between the cells (in the stratu corneum and epidermis to the dermis depending on amounts) t the areas of trauma and/or pathology deficient in hyaluroni acid (or forms thereof) , transporting, taking, drawing, carrying or pulling the NSAID with it to the sites o prostaglandin synthesis, penetrating to inhibit prostaglandi synthesis until the space between the cells is saturated. Th NSAID now being proximate the Paccinian nerve bundl (superficial nerve bundles at the end of the nerves) give pain .relief. The macrophages (which had been previousl blocked) are unblocked and act to destroy the disease o condition for example basal cell carcinoma, actinic keratose lesion, or other disease or lesion. Furthermore, th effective non-toxic dosage amount of the composition, combination or formulation, comprising the effective dosag amount of the form of hyaluronic acid and the effective dosag amount of NSAID passing through the stratum corneum to th epidermis and to the dermis (if a sufficient amount of th form of hyaluronic acid is present) , passes into the skin, accumulating and staying longer in the skin at the site of th trauma and/or pathology. Therefore, after having had a immediate effect at the site of trauma and/or pathology (fo example, relieving pain and acting on the basal cel carcinoma, actinic keratoses and other disease, condition o lesion) , the NSAID-hyaluronic acid combination continues t accumulate at the site in need of treatment and thereafte clears through the lymphatic system. Thus according to another aspect of Applicant' invention, Applicants' compositions, formulations an combinations quickly penetrate on application through th stratum corneum into the epidermis (to the dermis) by the for of hyaluronic acid transporting the NSAID, to the site of trauma and/or pathology where the amounts applied accumulate and remain for a prolonged time for treatment. Fifteen (15) minutes after application of one of Applicants' formulations, about three times the amount of Applicants' formulation has penetrated into the skin (particularly the epidermis) than formulations and combinations not containing hyaluronic acid or effective dosage amounts of hyaluronic acid, but containing the same drug. Furthermore, the drug and hyaluronic acid accumulate and remain at the site in need of treatment for a longer period of time. Thus according to another aspect of the invention, non-toxic effective dosage amounts of forms of hyaluronic acid (preferably sodium hyaluronate) and effective non-toxic dosage amounts of a drug may be administered in compositions to sites of trauma or pathology, on/in the skin and/or exposed tissue (for example the epidermis) by the application . of the effective non-toxic dosage amount of the composition comprising an effective non-toxic dosage amount of a drug (for example an NSAID) and an effective non-toxic dosage amount of a form of hyaluronic acid (for example sodium hyaluronate) to the skin or exposed tissue whereby the forms hyaluronic acid transport the drug percutaneously to the site of trauma and/or pathology where the composition accumulates and remains for a prolonged period of time thereby retaining the drug at the site of trauma and/or pathology (for example the epidermis) for the treatment of the condition or disease and the reduction of pain. Thus according to another aspect of the invention, Applicants have provided compositions (formulations and combinations) (including pharmaceutical excipients suitable for topical application) from which effective non-toxic (to the patient) dosage amounts of a drug (for example an NSAID) to treat and to assist to resolve diseases and conditions of the skin and/or exposed tissue (for example basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots and like lesions (found for the most part in the epidermis) , squamous cell tumours, metastatic cancer of the breast to the skin primary and metastatic melanoma in the skin, malignancie and/or tumours of the skin, gential warts, cervical cancer and HPV (Human Papilloma Virus) including HPV of the cervix psoriasis (both plaque-type psoriasis and nail bed psoriasis) corns on the feet and hair loss on the head of pregnan women) , and effective non-toxic dosage amounts of hyaluroni acid and/or salts thereof (for example, the sodium salt and/or homologues, analogues, derivatives, complexes, esters fragments, and/or sub-units of hyaluronic acid (preferabl hyaluronic acid and salts thereof) sufficient to transport (t facilitate or cause the transport of) the drug, for exampl NSAID, are taken for application, to a site in the skin (fo example epidermis) or exposed tissue having a disease o condition for percutaneous transport into the skin and/o exposed tissue to accumulate and remain there for a prolonge period of time to for example block prostaglandin synthesis Thus an effective dosage amount of the composition o formulation or combination penetrates quickly into the skin for example by the hyaluronic acid transporting the NSAID o causing the NSAID to be transported for example to th epidermis of the skin, accumulates there and remains there fo a prolonged period of time, thereby accumulating the drug an forms of hyaluronic acid in the skin (particularly th epidermis) . Thus according to another aspect of the invention, method of accumulating a drug, and a form of hyaluronic acid i skin and/or exposed tissue is provided comprising topicall administering a therapeutically effective non-toxic dosag amount of a composition comprising pharmaceutical excipient suitable for topical applications, an effective non-toxic (t the patient) dosage amount of a drug for example whic inhibits prostaglandin synthesis, preferably a non-steroida anti-inflammatory drug (NSAID) , for example, diclofenac indomethacin, naproxen, and (+/-) tromethamine salt o ketorolac (sold under the trademark Toradol™) (to treat and assist to resolve the disease and conditions of the skin an exposed tissue (for example basal cell carcinoma, th precancerous, often recurrent, actinic keratoses lesions fungal lesions, "liver" spots and like lesions (found for the most part in the epidermis) , squamous cell tumours, metastatic cancer of the breast to the skin, malignancies and/or tumours of the skin, primary and metastatic melanoma in the skin, genital warts cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis) , corns on the feet and hair loss on the head of pregnant women) , and an effective non- toxic dosage amount of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) effective to transport (to facilitate or cause the transport of) the drug (for example NSAID) percutaneously to the site in the skin (for example epidermis) or exposed tissue of the disease or condition to accumulate and remain there for a prolonged period of time for example to block prostaglandin synthesis. According to another aspect of the invention, a method of quickly delivering a drug to the skin or exposed tissue, particularly the epidermis, and maintaining the drug therein for a prolonged period of time is provided, the method comprising topically administering (for example rubbing in) an effective non-toxic dosage amount of a composition comprising pharmaceutical excipients suitable for topical application, a therapeutically effective (to treat and assist to resolve the disease and/or condition of the skin and exposed tissue (for example basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots and like lesions (found for the most part in the epidermis) , squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, malignancies and/or tumours of the skin, genital warts, cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque- type psoriasis and nail bed psoriasis) , corns on the feet and hair loss on the head of pregnant women) ) , non-toxic (to the patient) dosage amount of a drug for example which inhibits prostaglandin synthesis, preferably a non-steroidal anti- inflammatory drug (NSAID) , for example, diclofenac indomethacin, naproxen, and (+/-) tromethamine salt o ketorolac (sold under the trademark Toradol™) and an effecti non-toxic dosage amount of hyaluronic acid and/or salt thereof (for example, the sodium salt) and/or homologues analogues, derivatives, complexes, esters, fragments, and/o sub-units of hyaluronic acid (preferably hyaluronic acid an salts thereof) sufficient to transport (to facilitate or caus the transport of) the drug for example the NSAI percutaneously to the site of the trauma and/or pathology i the skin (for example epidermis) or exposed tissue, fo remaining there for a prolonged period of time (for example i the epidermis and dermis) to for example block prostaglandi synthesis. Suitable amounts of the form of hyaluronic acid ma comprise in excess of 5 mg. per cm 2 in a form which transport the drug (for example molecular weights of the form o hyaluronic acid being less than about 750,000 Daltons or i at substantially greater molecular weights, diluted (t reduce) the concentration or autoclaved or cleaved if require to reduce the size of the molecules . According to another aspect of the invention, method of controlling the unloading of a drug from the skin o exposed tissue into the lymphatic system comprises deliverin (transporting) an amount of drug into the ' skin or expose tissue by an effective non-toxic dosage amount of a form o hyaluronic acid and/or salts thereof and/or homologues analogues, derivatives, complexes, esters, fragments, and/o sub-units of hyaluronic acid to the skin (epidermis) o exposed tissue to control the unloading of the drug into, th lymphatic system (for example by the application of greate than 5 mg./cm 2 ) of the form of hyaluronic acid. Thus according to another aspect of the invention composition is provided which when administered to a human b preferably administration to the skin and/or exposed tissue o a human, unloads its contents into the lymphatic system, th composition comprising an effective non-toxic dosage amount o a drug (for example an NSAID or an anti-can ' cer dru (Novantrone) and an effective non-toxic amount of hyaluroni acid and/or salts thereof and/or homologues, analogues derivatives, complexes, esters, fragments and/or sub-units of hyaluronic acid (for example at least about 5-10 mg/cm 2 of skin or exposed tissue) . Thus the composition is made up of a plurality of such dosage forms (for example a cream or lotion or gel) . Thus according to another aspect of the invention, a new composition for treating diseases via the lymphatic system is provided comprising a plurality of effective non-toxic dosage amounts of the composition, each dosage amount comprising hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and/or sub-units of hyaluronic acid for passing into the lymphatic system and a therapeutic effective amount of medicine for treatment of a disease (which disease may be in the lymphatic system) . According to another aspect of the invention, the composition may be for application to the skin or exposed tissue. According to another aspect " of the invention, a composition is provided from which effective dosage amounts may be taken and administered, each effective dosage amount of the composition comprising an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and/or sub-units for transporting a therapeutically effective non-toxic dosage amount of a medicine and/or therapeutic agent (for example an NSAID) in the composition into the skin and/or exposed tissue when applied thereto to an area of pathology and/or trauma then into the lymphatic system, the dosage amount being essentially systemic independent such that substantial amounts do not enter the blood system prior to clearing (passing) into the lymphatic system. Preferably the amount of the form of hyaluronic acid in each dosage amount administered is greater than about 5-10 mg./cm 2 and the molecular weight is less than about 750,000 daltons. We have compared the penetration and retention of one of our combinations (formulations) with a control and Voltarol Emulgel in the skin as follows : (A) OUR FORMULATION 1% DTCLOFF.NAC IN 3.0% HA GEL 50σ/tube EPDICLOl LOT XPB 044 Quantity 1500ml Mol. Wt. 661,600 PROCEDURE Set up stirring apparatus using a 3 liter stainless stee beaker Add Water, Glycerin, Benzyl Alcohol and Liquid Wax DICDD stir and mix for 10 minutes Add Diclofenac Sodium and stir for 30 minutes to dissolv Add Sodium Hyaluronate and stir for 90 minutes ZI LE . In a 50 ml aluminum collapsible tube, inside of tube lacquered with a phanolic resin, outside of tube white regular enamel coating; 9 mm white polypropylene screw on cap with pierce tip Gels Batch No. s (B) Voltarol Emulgel 060400 10 93 (C) 1% Diclofenac Gel XPB049 (Control. (C) CONTROL 1% DICLOFENAC IN CARAPOL GEL. 50a Jar LOT XPB 049 Quantity 100ml PROCEDURE - Set up stirring apparatus using a 400ml stainless steel beaker - Add Water, Glycerin, Benzyl Alcohol, Liquid Wax DICDD, and stir to mix thoroughly for 10 minutes Add Diclofenac Sodium and stir for 20 minutes to dissolve Very slowly add Carbopol 934, avoid getting lumps Samples Cell A B C D E F * - Our Formulation Skin ypfi One piece of skin (Female, 37 years, smoker, breas skin) was used for one sample from each batch. A second piec of skin (no further details available) was used for the secon sample from each batch. The skin was stored deep frozen (< 20°C) until thawed for thii. experiment. Full thickness ski was used for this experiment . Experimental Conditions Skin permeation cells were prepared containing a exposed skin surface- area of- 9.6 cm 2 and a constantly stirre receptor fluid beneath the skin consisting of 135 ml o ethanol:phosphate buffered saline (25:75 v/v) . Each cell was allowed to equilibrate for 1 hour a 37°C after which the gel was spread evenly over the ski surface at a concentration of 20 mg/cm 2 ) . See table above. The cell was then maintained ■ at 37°C with an air temperatur above the skin of 35°C. 24 hours after application of the gel the experimen was stopped and a portion of the receptor fluid removed. Th skin was removed from the cell and any gel remaining on th surface carefully wiped off with dry paper towel followed b paper towel, moistened with water. The skin was cut with scalpel to obtain thin top and thicker lower sections of skin This was done in order to obtain layers of ski which approximated the epidermal and dermal layers . Each ski section was weighed and the residual diclofenac extracted wit 10ml of fresh receptor fluid using an ultra turra homogeniser. The homogenates were centrifuged and a portion of the resultant supernatant solutions removed. The receptor fluid and skin extracts from each cell were assayed for diclofenac content by using a validated reverse phase high performance liquid chromatography (HPLC) method. Results D i stribut i on of Diclofenac 24 hours after appl i cat ion of Diclofenac Gel Sample Receptor Top Skin portion Bottom SJtin portion μg Skin μg μg/ g Skin μg μg/g Weight Weight ( g ) (Voltarol Emugel) 060400 10 93 447 0.1363 101 742 1.2449 217 174 060400 10 93 764 0.2445 141 577 1.2351 202 164 He an 606 660 169 ( Our Formulation) EPDICLOl 247 0.1535 133 867 1.4663 148 101 EPDICLOl 29,2 0.1647 145 879 1.0022 86 86 Mean 269 873 93 (Control) XPB049 184 0.1275 35 272 1.1324 58 51 XPB049 147 0.2068 82 396 1.0893 - 68 63 Mean 165 334 57 Thus having regard to the above and Figures 1 ' , 2 ' and 3 ' , it is clear that the sodium hyaluronate takes the diclofenac into the skin to the epidermis level (See Figure 1') more rapidly than the Voltarol E ugel or non-hyaluronic acid diclofenac containing control formulation, accumulates it there and retains it there longer. The other formulations permit the NSAID, diclofenac, to pass through the bottom skin portion (dermis) quicker, thereby clearing it from the epidermis and dermis, quicker. Furthermore, more of Applicants ' formulation is in the epidermis and in the dermis even after 12 hours. With respect to Figure 1 ' , the top of the graph should have the following heading "DICLOFENAC TOP SKIN PORTION" , the left side of the graph should have the following side heading "DICLOFENAC (MICROGRAMS) (THOUSANDS)" and the bottom of the graph should have the following bottom heading "ELAPSED TIME (HOURS) π 0604001093 + EPDICLOl 0 XP8049". With respect to Figure 2', the top of the graph should have the following heading "DICLOFENAC BOTTOM SKIN PORTION" , the left side of the graph should have the following side heading "DICLOFENAC (MICROGRAMS) " and the bottom of the graph should have the following bottom heading "ELAPSED TIME (HOURS) □ 0604001093 + EPDICLOl 0 XP8049" .. With resp.ect to Figure 3 ' , the top of the graph should have the following heading "DICLOFENAC RECEPTOR SOLUTION", the left side of the graph should have the following side heading "DICLOFENAC (MICROGRAMS) " and the bottom of the graph should have the following bottom heading "ELAPSED TIME (HOURS) 0 0604001093 + EPDICLOl 0 XP8049" . It is also clear that Applicants ' formulations clear into the lymphatic system not through the blood- system. Yet the prior art topical formulations have always tried "to drive" the formulations through the skin into the blood for treatment of the disease or condition in the area (i.e. systemic action) . Thus, our composition, formulation and combination, (and dosage amounts thereof) penetrate quickly and rapidly at the site of treatment through the upper skin into the epidermis, where the paccinian bundles are located and the NSAID and the form of hyaluronic acid are accumulated and are retained longer, where needed (for example for the treatment of basal cell carcinoma) . Further, the NSAIDs are retained in the area to be treated with the form of hyaluronic acid. In doing so, they preclude prostaglandin synthesis , in effect, deactivating the synthesis or inhibiting the synthesis, of prostaglandins, permitting the macrophages ' scavenger cell activity to eliminate the tumour and lesion. Additionally, a rapid onset of pain relief (analgesic effect) is provided (depending on the amount of NSAID and form of hyaluronic acid) usually where in excess of about 10 mg of the form of hyaluronic acid (preferably hyaluronic acid and salts thereof) is administered per cm 2 of surface area comprises the dosage amount administered. However, there are no blood levels of the NSAID in the immediate area of treatment. The forms of hyaluronic acid are thus cleared via the lymphatic system. Then the lymphatics pass the forms of hyaluronic acid, Applicants believe, to the blood system. Thus, the NSAIDs and forms of hyaluronic acid stay at the site to be treated for well in excess of 12 - 24 hours, a protracted stay. Thus, over the period of treatment (for example, applications of effective non-toxic dosage amounts of compositions containing for example effective non-toxic dosage amounts of the NSAIDS and effective non-toxic dosage amounts of the sodium hyaluronate, 3 times a day for 2-4 weeks, transport the NSAIDS to to the epidermis to inhibit prostaglandin synthesis to enable the macrophages to "scavenge" the tumour cells and eliminate them. The end result is the successful treatment of the disease or condition at the site of trauma and/or pathology of the skin or exposed tissue, for example, the resolution of, the basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots and like lesions (found for the most part in the epidermis) , squamous cell tumours, metastatic cancer of the breast to the skin, malignancies and/or tumours in the skin, primary and metastatic melanoma in the skin, genital warts cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis) , corns on the feet and hair loss on the head of pregnant women, with complete disappearance of the disease or condition as the case may be, by topical therapy without resorting to surgery. One of the formulations which ' we have employed successfully is a gel formulation comprising 3% diclofenac in 2.5% sodium hyaluronate formulated as follows: Formulation 1 (3000 ml.) Formula Supplier [LOT) Amount Percent Glycerine Life 1043 150 g (119 ml) 5 Benzyl Alcohol Caledon 02517 90 g (86 ml) 3 Diclofenac Sodium Prosintex 9113003 90 grams 3 Sodium Hyaluronate Skymark HG1003 75 grams 2.5 (M 661,660) Sterile water Baxter AW4455 2795 ml. balance Procedure - set up stirring apparatus using a 4 litre stainless steel beaker add water, Glycerine, and Benzyl Alcohol; stir to mix add Diclofenac Sodium and stir for 30 minutes then add the Sodium Hyaluronate and stir for 90 minutes - initially, stir at a high torque but avoid splashing; .as the gel thickens, stir at a lower torque. The gel is then packaged in a tube or jar or other suitable container for use. Identification of suitable dosage amounts and how they are taken from the container may be provided with the container - for example squeeze "X" cm. of ribbon from the tube; fill spoon or spatula accompanying jar; (the spoon or spatula containing a predetermined dosage amount) then apply and rub into site of trauma and/or pathology (the dosage amount indicated will be such amount of the composition which comprises in excess of about 5 mg. of sodium hyaluronate per cm 2 (square centimeter) of skin or exposed tissue to which the dosage amount is to be applied. The amount of Diclofenac Sodium was determined in the same manner (having regard to the dosage amount required) . Another such formulation is : Formulation 2 Formula Supplier ( LOT) Amount Percent Methoxypolyethylene Sigma 34F-0266 300 g. 20 Glycol 350 Benzyl Alcohol BDH 23797 15 g. 1 Diclofenac Sodium Prosintex 9123012 45 g. 3 Sodium Hyaluronate Skymart HG 1004 37.5 g. 2.5 (MW 679,000) Sterile Water Baxter AW45R6 1200 ml. balance Procedure - set up stirring apparatus using a 3 litre stainless steel beaker add water, Methoxypolyethylene Glycol 350, and Benzyl Alcohol and stir for 20 minutes to mix - add Diclofenac Sodium and stir for 30 minutes to dissolve add Hyaluronate Sodium slowly and stir initially at a high speed, but avoid splashing after addition, stir at a slower speed for 90 minutes; the slower speed reduces the formation of air bubbles - the result is a clear, transparent, viscous gel which is put into a container. Once again instructions are given for administration and if applicable measuring devices (to provide a premeasured dosage amount) accompany the container. Still other formulations are: SUBSTITUTE SHEE ' Formulation 3 3% Diclofenac in 2.5% HA Gel Formula Supplier Sterile Water Baxter Methoxypolyethylene Sigma Glycol 350 Benzyl Alcohol BDH Diclofenac Sodium Prosintex Sodium Hyaluronate Skymart MW 679,000 Procedure Set up stirring apparatus using a 2 liter stainless steel beaker, Add water, Methoxypolyethylene Glycol 350, and Benzyl Alcohol and stir for 20 minutes to mix, Add Diclofenoc Sodium and stir for 30 minutes to disolve, Add Hyularonate Sodium slowly and stir initially at a high speed, but avoid splashing, After addition, stir at a slower speed for 90 minutes,the slower speed reduces the formation of air bubbles, The result is a clear transparent, viscous gel which is poured into jars and tubes. Once again instructions accompany the container and where applicable appropriate devices for providing a premeasured amount of the composition accompany the container. Formulation 4 5% IBUPROFEN TN 3.0% HA GEL. 50 ml JAR Formula Supplier ΩI Amoun Percent 5% 1% 1% 3% PROCEDURE - Set up stirring apparatus using a 300 ml stainless steel beaker, - Add Sterile Water and Meglumine, and stir for 10 minutes, - Add Ibuprofen and stir for 15 minutes, - Add Benzyl Alcohol, followed by Glycerin and stir for 15 minutes, - Finally, add Hyaluronate Sodium slowly and stir initially at a high torque to mix, but avoid splashing, - As the gel thickens, stir at a slow speed for 90 minutes. Set up stirring apparatus using a 300 ml stainless steel beaker, Add 200 ml of sterile water, Add 8 grams of Meglumine and dissolve, Very slowly add 4 grams of Piroxicam and stir for 20 minutes, Slowly add 5 grams of Hyaluronate Sodium and stir at high speed, Stir for 90 minutes at a slower speed COMMENTS - A clear yellowish transparent gel Formulation 6 5% IBUPROFEN CREAM. 50 ml JAR OILY PHASE A - Add all the ingredients of the oily phase A into a 4 liter stainless steel beaker, melt at 55°c, finally heat to 75% when Aqueous Phase B is ready B - Into a 3 liter stainless steel beaker , add 1950 ml water, set up, the stirring apparatus, add the Meglumine, stir to dissolve for 10 minutes, - Slowly add Ibuprofen, stir to dissolve for 20 minutes, - Very slowly add Sodium Hyaluronate and stir for one hour to dissolve all the Sodium Hyaluronate, - Finally, heat to 75°C,with stirring for a total time of 30 minutes. POUR B INTO A r both at a temperature of 75°C, slowly - Remove the heat source and stir with a strong vortex for one hour, - When the temperature has cooled down to 45°C add preservative Suttocide A, - Continue stirring at a slower speed until the temperature is 35°C, - At 35°C remove the propeller, pour into 50 ml jars . Formulation 7 1 % DICLOFENAC IN 3 % HA Gel . 50 ml j ar Quantity 3000ml Formula Supplier Sterile Water Baxter Glycerin BDH Benzyl Alcohol BDH Liquid wax DICDD Brooks Diclofenac Sodium Prosintex Hyaluronate Sodium Skymout MW 679,000 PROCEDURE - Set up stirring apparatus using a 4 liter stainless steel beaker. - Add water, Glycerin, Benzyl Alcohol and Liquid wax DICDD and stir to mix thoroughly for 10 minutes Add Diclofenac Sodium and stir for 30 minutes to dissolve. - Slowly add Hyaluronate Sodium, stirring at a high torque initially during addition. - After addition stir at a slower speed for 90 minutes . A white opaque viscous gel is formed. Formulation 8 1 % DICLOFENAC IN 3 . 0 % HA Gel . 50 ml tube Quantity 1500 ml Formula Supplier LOT Amount Percent Sterile Water Baxter Glycerin Life Benzyl Alcohol Caledon Liquid wax DICDD Brooks Diclofenac Sodium Prosintex Sodium Hyaluronate Skymart Mol. Wt. 661,600 PROCEDURE - Set up stirring apparatus using a 3 liter stainless steel beaker. - Add water, Glycerin, Benzyl Alcohol and Liquiwax. DICDD, stir to mix for 10 minutes. - Add Diclofenac Sodium and stir for 30 minutes to dissolve. - Add Sodium Hyaluronate and stir for 90 minutes. Formulat ion 9 HYANALGESE CREAM - L) 50 ml tube Quantity 3000 ml FORMULA A . Oi 1 y Pha se SUPPLIER LOT AMOUNT PERCENT Liquid Wax DICDD Brooks/Amisol Brookswax D Brooks/Amisol Glycerine Amisol B. Aqueous Phase AW4YA8 POl PROCEDURE A. - Add all the ingredients of the oily phase into a 4 liter stainless steel beaker, melt at 55°C, finally heat to 75°C when aqueous phase is ready (at 75°C) to pour. in. B. - Into another 4 liter stainless steel beaker, add 1950 ml water. - Set up the stirring apparatus and add the Meglumine Stir to dissolve with high torque, then slowly add Ibuprofen - When the Ibuprofen is dissolved, slowly add Sodium Hyaluronate - Stir cold for one hour to dissolve all the ingredients - Finally heat to 75°C and stir thoroughly throughout a 30 minute period MIX B INTO A - Slowly pour B into A (both at 75°C) with stirring Immediately remove the hot plate (heat) and stir - Stir with a strong vortex for one hour When the temperature is 45°C, add the preservative Suttocide A Stir for about an hour to cool to 35°C At 35°C remove the propeller and pour into 50 ml tubes Pour 50 grams of the cream into each tube 1% BANAMINE IN 2 . 5% HA GEL (L) XPB 041 Quantity 3000 ml FORMULA SUPPLIER LOT AMOUNT PERCENT Sterile Water Boxter Sodium Hyaluronite Skymart MW 661, 600 *Banamine, 100 ml vial Scheing Banamine. 100 ml vial Scheing 3000 ml (50 mg/ml) 600 = 30,000mg = 30 grams Flunixin in 600 ml *Banamine contains Flunixin Meglumine (50 mg Flunixin per ml) or 83 mg Flunixin Meglumine PROCEDURE - Set up stirring apparatus using a 4 liter stainless steel beaker - Add water, stir with a strong vortex, ' then add sodium Hyoluronate slowly - Then immediately add the Banamine, stir the mixture for 4 hours . One form of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, preferably hyaluronic acid and salts and thereof, suitable for use with Applicant's invention is a fraction supplied by Hyal Pharmaceuticals Limited. One such fraction is a 15 ml vial of Sodium hyaluronate 20mg/ml (300mg/vial - Lot 2F3) . The sodium hyaluronate fraction is a 2% solution with a mean average molecular weight of about 225,000. The fraction also contains water q.s. which is triple distilled and sterile in accordance with the U.S.P. for injection formulations. The vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial. The fraction of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, preferably hyaluronic acid and salts thereof, may comprise hyaluronic acid and/or salts thereof having the following characteristics: a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from the group (and preferably all characteristics) consisting of the following: i) a molecular weight within the range of 150,000-225,000; ii) less than about 1.25% sulphated mucopoly- saccharides on a total weight basis; iii) less than about 0.6% protein on a total weight basis; iv) less than about 150 ppm iron on a total weight basis; v) less than about 15 ppm lead on a total weight basis; vi) less than 0.0025% glucosamine; vii) less than 0.025% glucuronic acid; viii) less than 0.025% N-acetylglucosamine; ix) less than 0.0025% amino acids; x) a UV extinction coefficient at 257 nm o less than about 0.275; xi) a UV extinction coefficient at 280 nm o less than about 0.25; arid xii) a pH within the range of 7.3-7.9. Preferably, the hyaluronic acid is mixed with water and th fraction of hyaluronic acid has a mean average molecula weight within the range of 150,000-225,000. More preferably, the fraction of hyaluronic acid comprises at least on characteristic selected from the group (and preferably al characteristics) consisting of the following characteristics: i) less than about 1% sulphated mucopolysaccharides on a total weight basis; ii) less than about 0.4% protein on a total weight basis; iii) less than about 100 ppm iron on a total weight basis; iv) less than about 10 ppm lead on a total weight basis; -v) less than 0.00166% glucosamine; vi) less than 0.0166% glucuronic acid; vii) less than 0.0166% N-acetylglucosamine; viii) less than 0.00166% amino acids; x) a UV extinction coefficient at 257 nm of less than about 0.23; xi) a UV extinction coefficient at 280 nm of less than 0.19; -and xii) a pH within the range -.of 7.5-7.7 Applicants also propose to use sodium hyaluronate produced and supplied by LifeCore™ Biomedical, Inc., having the following specifications: Characteristics Specification Appearance White to cream colored particles Odor No perceptible odor Viscosity Average < 750,000 Daltons Molecular Weight UV/Vis Scan, 190-820nm Matches reference scan OD, 260nm < 0.25 OD units Hyaluronidase Sensitivity Positive response IR Scan Matches reference pH, lOmg/g solution 6.2 - 7.8 Water 8% maximum Protein < 0.3 mcg/mg NaHy Acetate < 10.0 mcg/mg NaHy Heavy Metals, maximum ppm As Cd Cr Co Cu Fe Pb Hg Ni 2.0 5.0 5.0 10.0 10.0 25.0 10.0 10.0 5.0 Microbial Bioburden None observed Endotoxin < 0.07EU/mg NaHy Biological Safety Testing Passes Rabbit Ocular Toxicity Test Another form of sodium hyaluronate is sold under the name Hyaluronan HA-M5070 by Skymart Enterprises, Inc. having the following specifications: Specifications' Test Results Lot No. HG1004 pH 6.12 Condroitin Sulfate not detected Protein 0.05% Heavy Metals Not more than 20 ppm Arsenic Not more than 2 ppm Loss on Drying 2.07% Residue on Ignition 16.69% Intrinsic Viscosity 12.75 dl/s (XW: 679,000) Nitrogen 3.14% Assay 104.1% Microbiological Counts 80/g E. coli Negative Mold and Yeast Not more than 50/g Other forms of hyaluronic acid and/or its salts, and homologues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for example those described in prior art documents provided the form of hyaluronic acid chosen is suitable for transport of the medicine. The following references teach hyaluronic acid, sources thereof, and processes for the manufacture and recovery thereof which may be suitable. United States Patent 4,141,973 teaches hyaluronic acid fractions (including sodium salts) having: " (a) an average molecular weight greater than about 750,000, preferably greater than about 1,200,000 - that is, a limiting viscosity number greater than about 1400 cm 3 /g., and preferably greater than about 2000 cm 3 /g.; (b) a protein content of less than 0.5% by weight; (c) ultraviolet light absorbance of a 1% solution of sodium hyaluronate of less than 3.0 at 257 nanometers wavelength and less than 2.0 at 280 nanometers wavelength; (d) a kinematic viscosity of a 1% solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes; (e) a molar optical rotation of a 0.1 - 0.2% sodium hyaluronate solution in physiological buffer of less than -11 X 10 3 degree - cm 2 /mole (of disaccharide) measured at 220.nanometers; (f) no significant cellular infiltration of the vitreous and anterior chamber, no flare in the aqueous humour, no haze or flare in the vitreous, and no pathological changes to the cornea, lens, iris, retina, and choroid of the owl monkey eye when one milliliter of a 1% solution of sodium hyaluronate dissolved in physiological buffer is implanted in the vitreous replacing approximately one-half the existing liquid vitreous, said HUA being (g) sterile and pyrogen free and (h) non-antigenic. ιr Canadian Letters Patent 1,205,031 (which refers to United States Patent 4,141,973 as prior art) refers to hyaluronic acid fractions having average molecular weights of from 50,000 to 100,000; 250,000 to 350,000; and 500,000 to 730,000 and discusses processes of their manufacture. In order to determine the blood levels in patients using formulations made according to embodiments of the invention, a study of the pharmacokinetic profiles of two topical diclofenac formulations after repeat dosing were undertaken. One such product was the product Voltarol Emulgel marketed in the United Kingdom by Geigy. The other was a Diclofenac preparation in Hyaluronic Acid. This was an open, repeat dose, crossover comparison using a randomized balanced block in six healthy volunteers. The study consisted of administration with one, two week period in between periods, each period lasting fourteen days. The test articles applied were for the first six days of each period and the seventh day was study day during which the final application is made and blood samples taken. The approximate duration of the study including pre and post study screening was six weeks . Doses Diclofenac (3.0%) with Hyaluronic Acid (2.5%) Dose: Approximately 2 g, three times daily Route: Topical (Wl)Voltarol Emulgel, Diclofenac diethylammonium salt l.l6g aqueous gel (Geigy) Dose : Approximately 2 g, three times daily Route: Topical (Wl) ADMINISTRATION: to suitable patients Subjects applied one ' of the designated test articles topically to the calves and massaged into the skin, in a dose of approximately 2 g per application three times a day for six consecutive days . The size of a 2g dose was prepared by comparison with a silicone example given to each subject. On the seventh day, the cream was applied once, in the same manner as before, under the supervision of the staff of the Clinical Investigation Unit. After a washout period of one week the procedure was repeated with the alternate test article. The following were the results of the tests: (H = hyaluronic acid formulation) (V = Voltarol Emulgel) PERIOD 1 All concentrations ng ml - - ■ SUBJECT TIME POINT (hours ) ND = NONE DETECTED (>5 . 0 ng ml -1 ) PERIOD II All concentrations ng ml -1 SUBJECT TIME POINT (hours ) 0 0 - 7-5 0 . 5 l 2 2_ 4 5_ 0 12 V-1 ND ND ND ND ND ND ND ND ND ND ND ND V-2 ND ND ND ND ND ND ND ND ND ND ND ND H-3 ND ND ND ND ND ND ND ND ND ND ND ND V-4 ND ND ND ND ND ND ND ND ND ND ND ND H-5 ND ND ND ND ND ND ND ND ND ND ND ND H-5 _ND_ _ND_ ND ND Jffi- ND ND ND ND ND ND ND ND = NONE DETECTED (>5.0 ng ml -1 ) Other tests were undertaken to determine blood levels comparing Proflex (a formulation containing Ibuprofen) and the following formulation containing hyaluronic acid and Ibuprofen. HYANALGESE CREAM (L) X PB 022 - 50 ml tube Quantity 3000 ml The following were the results (B) HYALURONIC ACID AND IBUPROFEN ND None detected <0.05 μg/ml The above clearly indicates that the blood levels are much less using hyaluronic acid to administer the NSAID. PRELIMINARY REPORT A trial was conducted using a gel composition (Number 109) comprising 3% Diclofenac in 2.5% Hylauronic Acid as previously described and a composition containing Diclofenac sodium salt 3% but not including any form of hyaluronic acid. (Number 112) The trial was conducted with 60 patients who were randomly assigned to test preparations number 109 or 112. The trial has not been completed as yet but so far 31 patients have finished the protocol. Patients were diagnosed: 4 Rheumatoid arthritis of the knee 8 Myofascial trigger points in the M.trapezius area 12 Periarthropathies of knee without effusion 7 Periarthropathies with effusion in the knee joint The 31 patients were aged 22-7'5 years (27 females, 4 males) . All patients were hospitalized. Patients entering the trial were thoroughly examined and type of extraarticular or articular rheumatism assessed. On day 1 baseline pain was assessed on the 10 cm visual analogue scale (VAS) and pain measurement of the quantititative pain sensitivity using a pressure tolerance meter (PTM) were performed. Then test gel - approximately 2.g - was massaged on to the skin of maximum pain. Gels were applied 3 times daily. 0.5, 1, 1.5, and 2 hours after morning application measurements of pain sensitivity were carried out and values recorded. This procedure was countinued on day 2, 3 and 4; measurements (VAS and PTM) of pain severity were done on day 1, 2 and 4. Prior of the beginning of the study and at the end on day 4, physician's global assessment, assessment of swelling, tenderness and limitation of movement were recorded. As the study is ongoing statistical evaluation is not yet available. For further details see Table 1. TABLE 1 ' -- Composition Composition Reaction 109, n = 16 112, n - 15 Good Alleviation 13 8 of pain Moderate Alleviation 2 2 of pain No Alleviation 1 5 of pain From the data recorded we have concluded that the patients to whom composition 109 was administered did better in terms of earlier and longer lasting analgesic effect (up to 4 hours) than the 112 composition especially in patients with myofascial trigger points and with periarthropathies of the knee joints without effusions. Neither composition 109 nor composition 112 treated patients showed any effect on swelling if any swelling exist at all. Systemic side effects have not been observed; one patient to whom composition 112 was administered showed reddening of the skin on the site of application. Any intake of system NSAIDS,corticosteroids and other analgesics was not allowed one week before and during the trial. EXAMPLES The following examples are offered to illustrate uses of Applicants' invention. Example 1 A male patient had a number of lesions (basal cell carcinoma) , including one on his forehead which was a combination of major "horny epithelium" and some degree of ulceration. After continuous treatment with Formulation 1 (several times per day for several weeks of dosage amounts squeezed from tubes as ribbons of composition) , the lesions showed epithelialization, no he orrhagic areas, and no initiated areas (as they were in the past without our treatment) . The "horny epithelium" and ulceration of the forehead lesion were also gone . The patient had a complete. successful response with the formulation. All basal cell carcinoma lesions had been resolved and disappeared. There has been no recurrence. Example 2 . 60 year old male tennis player had sore elbow and basal cell carcinoma on forearm proximate sore elbow. Patient tried Formulation 1 to abate pain in tennis elbow. (Dr. Falk was not treating this patient for anything at the time, did not know of the basal cell proximate the elbow and merely offered the formulation for pain relief of the elbow instucting the patient to squeeze a ribbon of the composition and apply and rub into the sore elbow) . However, the formulation "spilled" over onto the Patient's basal cell carcinoma. Patient was planning to have basal cell carcinoma removed surgically by another doctor, but when the patient returned to see the doctor, the basal cell carcinoma was disappearing (because of spill-over of Formulation 1) . Dr. Falk was then advised and treatment was now undertaken by Dr. Falk with direct application of Formulation 1 to the lesion 3 times a day for two additional weeks. After two weeks, the basal cell carcinoma disappeared. There has been no recurrence. Example 3 Male, mid to late 40 's had severe basal cell carcinoma on left temple. Doctors recommended its removal by surgery. However, the surgery would have been risky because of the lesion's proximity to facial nerves . Patient saw Dr. Falk who gave him Formulation 2 to be applied in dosage amounts 3 times daily. After 14 days, 75% of the lesion " was gone. Surgery was postponed and the treatment was continued. Application of dosage amounts of Formulation 2 was continued for an additional two weeks . At the end of the 2- week period, the lesion was completely resolved and disappeared without any surgery being required. There has been no recurrence. Example 4 Male, early 40 's, had recurrent actinic keratoses lesion on his right temple. Early attempts at removal by third parties involved the application of liquid nitrogen (twice) without final resolution. The lesion kept recurring. The patient was sent to Dr. Falk who treated the lesion with Formulation 1 with applications of dosage amounts 3 times daily for 7 days. After 7 days, the lesion was completely resolved with no subsequent recurrence. Example 5 A male patient suffering from kyphosis suffered from constant back pain. Taking analgesics orally and rubbing back preparations onto his back did little to alleviate the back pain. When NSAIDs in hyaluronic acid (sodium hyaluronate) were applied directly to the back, the back pain eased and disappeared. With indomethacin (dissolved in N-methyl glucamine) and naproxen both dissolved in hyaluronic acid, the patient experienced some side effects. However, with Toradol™ (the [+/-] form tromethamine salt of ketorolac - a prostaglandin biosynthesis inhibitor and analgesic and anti-inflammatory, the back pain eased and disappeared for some time and there were no side effects . The compositions were applied generously onto the sites of back pain. Example 6 A male patient with basal cell carcinoma was first treated by an oncologist who attempted to surgically excise the lesion (without success) and then irradiated the lesion again without success. The patient then attended before Dr. Falk who applied Applicant's formulation (diclofenac with sodium hyaluronate and excipients) . Application was made three times daily for .about a month and the lesion disappeared. Some excoriation anterior and slightly superior developed over the last two weeks but was cleared by the application of hyaluronic acid by itself. This resolution clearly indicates- that even with prior applications of unsuccessful therapies (surgery and irradiation) , Applicant's formulations can be used successfully. Example 7 In another patient, a drug (methotrexate) was carried in hyaluronic acid and applied topically to a patient . with psoriasis . The formulation was absorbed and the psoriasis cleared. Example 8 A patient with dermal (skin) metastases in a fibratic scar form and metastatic cancer in the form of musculoskeletal involvement in her thorax. On topical application of our formulation comprising diclofenac (Voltaren) in hyaluronic acid (sodium hyaluronate), her pain decreased dramatically and her skin and boney involvements steadily improved. TOPICAL DICLOFENAC ACID 3% IN HYALURONIC ACID GEL (2.5%) BASE A practitioner reviewed the effectiveness of topical Diclofenac Acid 3% in hyaluronic acid gel (2.5%) base in acute traumatic injuries of no longer than 3 days duration. The cases were all in the spectrum of ages between 18 and 65. Normal exclusion criteria were followed regarding exclusion of pregnancy, aspirin or N.S.A.I.D., allergies or active peptic ulceration. As an overall, the following impressions were gained from 30 cases: 1. The topical H.D. (composition comprising sodium hyaluronate and diclofenac) had an obvious analgesic action with onset occurring rapidly within one hour; this is a phenomenon not obviously seen with other non-steroidals that we have used. 2. There was a very definite patient acceptance of the gel as a form of treatment, being logical, easy to apply, without local or systemic side effects,- rapid absorption with no staining of clothing. 3. The anti-inflammatory action was equivalent on a "guestimate" based on experience of similar . injuries to oral N.S.A.I.D.s, without the threat or risk of side effects. ' In summary, compared with other topical N.S.A.I.D.s the analgesic effect is distinct, the anti-inflammatory is equal to oral N.S.A.I.D.s and the patients' acceptance is far superior to any other diclofenac or piroxicam topical that the practitioner evaluated. Following the practitioner's basic preamble regarding the parallelism of topical N.S.A.I.D.s and topical steroids,the practitioner has used the former in contact dermatitis, insect bites and U.V. erothema, all with very positive effects, again pointing direction to trials of a double blind nature in these fields . CHRONIC CONDITIONS - EVALUATIONS CHRONIC CONDITIONS - EVALUATIONS CHRONIC CONDITIONS - EVALUATIONS CHRONIC COND ITIONS - EVALUATIONS HYALURONIC ACID WITH 3 * D ICLOFENAC ACID _ιsn∑ Positive (P) Patients Date Negative (N) Initials Cf File Unable to ■ M. or ( F ) Birth No. Diagnosi s Comments on Outcome Comment fU) JL (M) 10-12.45 Chronic Pain has failed to respond N rryositis to many aggressive treat¬ secondary to ments. query facet syndrome RMC (F) 13.06.57 Neuronitis It is a difficult case with following considerable overlay, she facet obtained some relief with rhizotomy H.D., would estimate 30-40% with result¬ Interestingly hyper- ing pain in anaesthesia was decreased. her back RM (F) 20.08.52 Chronic Using H.D. significant capsulitis improvement in pain while used, on stopping treatment recurrence of pain, needed intra-articular cortisone- GM (F) Sub-acute Rapid resolution of pain tendonitis within one day and positive right ankle return of function. PM (F) 20.09.46 Acute on Rapid analgesic response chronic with rapid settlement. osteo- arthritis of first: eta- tarsal phalyngeal joints DN (F) 10-03-44 Chronic Excellent response to appli¬ fasciaitis cation of H-D. with occlu¬ cf feet sion. Had failed to respond to oral N.S.A.I.D.s and physiotherapy. Query posi¬ tive result due to short application target distance in a vascular tissue. CHRONIC CONDITIONS - EVALUATIONS CHRONIC CONDITIONS - EVALUATIONS CHRONIC CONDITIONS - EVALUATIONS CHRONIC CONDITIONS - EVALUATIONS CHRONIC CONDITIONS EVALUATIONS * Two types of pain-response in only one 1. Interestingly in the whole series, there was not one case of local side effects and as expected from past studies, no general or systemic. Since this report was prepared we have had one case of mild folliculitis which responded to discontinuation of treatment, will rechallenge. 2. A number of patients commented that they felt the gel improved the texture and softness of their skin, and commented that it was messy or stained their clothes. 3. In one ' case of topical thrombophlebitis where the inflamed vein crossed the area of treatment, the vein in the area of treatment improved while that outside at a distance did not. Again, similar to using oral N.S.A.I.D.s. ***. Photographs were taken of patients with basal cell carcinoma Figures 1-6 photographs, and of mice with tumors induced in the skin of the hind legs (Figure 7 photographs) . The patients were treated by using combinations of NSAIDS , (non-steroidal anti-inflammatory drugs) and hyaluronic acid (including sodium hyaluronate) according to the invention (3% diclofenac in 2.5% sodium hyaluronate gel base) . Each of the six sets of Figures made up of photographs of the different persons should include a legend describing or explaining each picture as follows: Legend for Figures 1A and IB should read: Patient .D., male, 82 years Diagnosis Basal cell carcinoma Treatment NSAIDS plus HA gel. 3 times per day Figure 1A June, 1991 Figure IB December, 1-991 Legend for Figures 2A and 2B should read': Patient M.F., male, 45 years Diagnosis Basal cell carcinoma Treatment NSAIDS plus HA gel. 3 times per day Figure 2 January, 1992 Figure 2B April, 1992 - Legend for Figures 3A, 3B, 3C and 3D should read: Patient H.A. , male, 82 years Diagnosis Basal cell carcinoma Treatment NSAIDS plus HA gel. 3 times per day Figure 3A January 26, 1992 Figure 3B March 16, 1992 Figure 3C January 26, 1992 Figure 3D March 16,1992 Legend for Figures 4A, 4B, 4C and 4D should read: Patient R.F., male, 64 years Diagnosis Basal cell carcinoma Treatment NSAIDS plus HA gel. 3 times per day Figure 4A January 26, 1992 Figure 4B March 16, 1992 Figure 4C January 26, 1992 Figure 4D March 16, 1992 SUBSTITUTE SHEET Legend for Figures 5A, 5B, 5C and 5D should read: Patient R. . , male, 86 years Diagnosis Basal cell carcinoma Treatment NSAIDS plus HA gel. 3 times per day Figure 5A January 26, 1992 Figure 5B March 16, 1992 Figure 5C January 26, 1992 untreated Figure 5D March 16, 1992 untreated Legend for Figures 6A, 6B and 6C should read: 0 Patient E.D. , female, 70 years Diagnosis Basal cell carcinoma Treatment NSAIDS plus HA gel. 3 times per day Figure 6A April 20, 1992 Figure 6B May 13, 1992 5 Figure 6C July 7, 1992 The Legend for Figure 7 (Figures 7A and 7B) relate to: Mouse Strain: DBA2 Tumour: p815 Figure 7A: control, 19 days 0 Figure 7B: Novantrone plus HA gel 19 days The mice shown in' Figures 7A and 7B had tumours induced in the skin of their hind legs and dosage amounts (2ml) of Novatrone (10 mg. per dosage amount) (MITOXANTRONE (t.m.) and 2.5% sodium hyaluronate were applied (rubbed onto) 25 the skin at the site of the pathology. The tumours reduced in size (See Figure 7B) clearly illustrating the percutaneous delivery of the medicine by the hyaluronic acid. (See Figure 7) . The following additional comments are made with 30 respect to the patients. With respect to R.W. and Figure 5, the reader will note in Figures 5a and 5c the patient suffered from basal cell carcinoma on his back (Figure 5c) and his temple (Figure 5a) . Because of the age of the individual (86) the basal cell 35. carcinoma on his back could not be reached by him for application of the medication. Thus the basal cell carcinoma in 5c remained untreated and grew (see Figure 5d) . However, the portion indicated in 5a on his temple could be reached and after application of the basal cell carcinoma formulation to SUBSTITUTE SHEET the temple and forehead the results are as in 5b; the basal cell carcinoma is disappearing. Thus, the gentlemen's own method of treatment acted as a control. With respect to R.F. and Figures 4, two areas of basal cell carcinoma in need of treatment are shown by the arrows in Figures 4a and 4c and the results are shown in Figures 4b and 4d as indicated by the arrows after treatment with Applicant's invention. With respect to H.A. , male, and Figures 3, Figures 3 indicates two areas of basal cell carcinoma by the arrows, close-ups of which are shown in Figures 3a and 3c. After treatment with the NSAIDS and HA gel three times a day for the period between January 26, 1992 and March 16, 1992 the basal cell carcinoma is clearing as per Figures 3b and 3d. The same is true with respect to male M.F. and Figures 2 which appears clear in the photographs (see Figure 2a and the response shown in Figure 2b) . With respect to male, W.D. and Figures 1, the upper lesion in Figure la (indicated by the upper arrow) is gone after treatment with Applicant's invention (See Figure lb) and the two lower lesions in Figure la are well on their way to disappearing (See Figure lb) . With respect to female D and Figure.6, the lesion was left untreated for a long period and gradually encompassed her eye. Surgery could not be undertaken without jeopardizing the eye. By applying Applicant's invention (dosage amounts) over a prolonged period, the basal cell carcinoma has constantly decreased in size. With respect to Figure 7, (7a) shows mice having tumors in the skin induced in their hind legs. After continuous applications to the shaved hind legs having the tumors in the skin by rubbing in dosage amounts by Applicant's invention, the tumors have decreased in size. (See Figure 7b) SUBSTITUTE SHEET The effect of Hyaluronic acid as a drug carrier of anti-cancer agent (5-FU) 5-Fluoracil was also studied. (Intratumour injection study) B. EXPERIMENTAL MODEL ( 2 ) 1. Method and Material a. Animal : Fisher 344 rat, male 200-250g b. Tumor model Fisher Bladder Carcinoma Tumor (2mm viable tumor fragment) was transplanted subcutaneously on the right frank by trocar c. Treatment was started when tumor size is about 1.5 cm. (2 weeks after implantation. ) 1. These drugs were administrated by intratumor injection. (right frank) At the same time, injection into normal skin (left frank) was carried out similarly. Group A : H-5-FU 5mg/kg + saline /0.3ml (i.t.) B : H-5-FU 5mg/kg + HA 15 mg/kg /0.3ml (s.c.) 3H-FU without or with HA was injected as a single dose (0.3ml) into the center of the tumor (on the right frank) with a 30 gause needle. At the same time, injection into normal skin (on the left frank) was carried out similarly. The tumor and skin was then removed at different times (lh,6hr) for counting radioactivity of the remaining content in the tissue. SUBSTITUTE SHEET 2 . Result All the results were expressed as Mean + S.E. under the following headings: TUMOR TISSUE NORMAL SKIN (left hand portion (Right hand portion of the graph) of the graph) (See Figure 4' of Page 4/12) 3. Conclusion 1. In 5-FU HA group radioactivity was accumulated and retained in the tumor tissue for a long period, whereas rapid clearance was demonstrated in normal tissue. (skin) 2. In 5-FU group, radioactivity immediately disappeared from the tumor or the normal tissue by diffusion, primarily into blood capillaries. 5FU can traverse freely between the interstitial space and blood capillary. The Effect of Hyaluronic Acid as a__ Drug Carrier in Target Cancer Chemotherapy A. EXPERIMENTAL MODEL (1) Intravenous Injection) 1. Method and Material a. Animal : Fisher 344 rat, male 200-250g b. Tumor model Fisher Bladder Carcinoma Tumor (2mm viable tumor fragment) was transplanted subcutaneously on the right frank by trocar SUBSTITUTE SHEET c. Treatment was started when tumor size is about 1.5 cm. (2 weeks after implantation. ) ....tumor weight:1.0 ± 0.3g The drug was administered Intravenouslv (through the penile vein) Group A : 5-FU 20mg/kg (3H-5-FU30μCi) + saline B : 5-FU 20mg/kg (3H-5-FU30μCi) + HA 15mg/kg C : 5-FU 20mg/kg (3H-5-FU30μCi) + HA 15mg/kg + (3H-HA30μCi) 2. Sample Collection a. accumulation of ADR, 5-FU in tumor tissue and liver (1) . Tumor was surgically removed (and blood was collected) at *predeterminated time after drug administration. Tumor weight was measured (and blood was centrifuged to obtain a plasma sample.) * 15min, 60 min, 3hr, 4hrs, .... after drug administration Liver was removed for radioactivity counting at the same time. (2) . Radioactivity level in tumor tissue was counted, using a liquid scintillation counter. SUBSTITUTE SHEET 3 . Conclusion Radioactivity in Tumor Tissue and Liver Tumor Liver 15min 3H-5FU (n=6) 2810+165 18680+625 3H-5FU+HA (n=6 ) 352±190 235S3±I460 3H-5FU+3H-HA (n=4 ) 4087±681 32060+2145 HA : 15 mg/kg (30μCi/kg) 5-FU : 20mg/kg (30μCi/kg) See Figure 5' of Page 5/12 'of the Figures which comprises a graph entitled "RADIOACTIVITY IN TUMOR TISSUE" comparing CPM on the vertical with time in Minutes on the horizontal (for example 100, 200, 300) . 1. Radioactivity in tumor tissue in 5-FU + HA group is higher than that in 5-FU group. There is significant difference (p>0.05, ANOVA) between with and without HA at 3hrs after infection. The high intra umor concentration was retained for a prolonged time in 5-FU+HA group. (This retention was confirmed by the intratumor injection s udy.) 2. These results teach that HA can enhance 5-FU uptake in tumor tissue. This phenomenon results from HA distribution (in tumor tissue HA may be lost from the extracellular matrix) and the vascular uniqueness of tumor tissue (hyperpermiability of tumor vessels to macromolecular drug, HA) . As many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense. SUBSTITUTE SHEET

Claims: THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE AS FOLLOWS: 1. A pharmaceutical composition comprising a plurality of effective non-toxic dosage amounts of a composition for topical administration to the site of pathology and/or trauma of skin and/or exposed tissue of a human patient in need of treatment suffering from a disease or condition, each such dosage amount comprising a therapeutically effective non-toxic (to the patient) dosage amount of a drug for the treatment of the disease and/or condition of the skin and/or exposed tissue at the site of the pathology and/or trauma and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to transport (to facilitate or cause the transport of) the drug to the site of the pathology and/or trauma of the disease or condition. 2. The pharmaceutical composition of Claim 1, wherein each of the plurality of effective non-toxic dosage amounts of the composition making up the pharmaceutical composition comprises at least about 5-10mg of the form of hyaluronic acid per cm 2 of the skin and/or exposed tissue to which the composition is to be applied. 3. The pharmaceutical composition of Claim 1 or 2 wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes,, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof. SUBSTITUTE SHEET 4. The pharmaceutical composition of Claim 1, 2 or 3 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons. 5. The pharmaceutical composition of Claim 1, 2, 3 or 4 wherein the disease and/or condition of the skin and/or exposed tissue at the site of the trauma and/or pathology is selected from at least one of basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots, squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, malignancies and/or tumours in the skin, genital warts (condyloma acuminata) , cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis) , corns on the feet and hair loss on the head of pregnant women. 6. The pharmaceutical composition of Claim 1, 2, 3, 4 or 5 wherein the drug comprises an effective non-toxic dosage amount which inhibits prostaglandin synthesis. 7. The pharmaceutical composition of Claim 6 wherein the drug is a non-steroidal anti-inflammatory drug (NSAID) . 8. The pharmaceutical composition of Claim 1, 2, 3, 4 or 5 wherein the drug is an anti-cancer drug. 9. The pharmaceutical composition of Claim 8 wherein the anti-cancer drug is selected from novantrone. 10. The pharmaceutical composition of Claim 7 wherein the NSAID is selected from diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac. 11. The pharmaceutical composition of Claim 7 wherein the NSAID is selected from IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin. EET 12. A topically applicable percutaneous (intracutaneous) penetrating (best targeting the epidermis) systemic independent acting (not acting essentially through the blood) pharmaceutical composition comprising a plurality of dosage amounts, each dosage amount comprising, pharmaceutical excipients suitable for topical application, a therapeutically effective (to treat and to assist to resolve a disease and/or condition of the skin and exposed tissue, selected from at least one of basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots, squamous cell tumours, metastatic cancer of the breast to the skin, malignancies and/or tumours in the skin primary and metastatic melanoma in the skin, genital warts (condyloma acuminata) , cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis) , corns on the feet and hair loss on the head of pregnant women, non-toxic (to the patient) dosage amount of a non-steroidal anti-inflammatory drug (NSAID) selected from diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac and an effective non- toxic amount of hyaluronic acid and/or salts thereof to facilitate or cause the NSAID's rapid transport by the form of the hyaluronic acid to the site in the skin including the epidermis or exposed tissue of the disease or condition into the tissue to remain there for a prolonged period of time to assist to treat and assist to resolve the disease or condition by blocking prostaglandin synthesis. 13. The pharmaceutical composition of Claim 12 wherein the effective non-toxic dosage amount of the hyaluronic acid and/or salts thereof to transport the drug into the skin and/or exposed tissue exceeds about 5 mg. - 10 mg. for each 1 cm 2 of skin or exposed tissue area of the disease or condition to which the dosage amount is to be applied. 14. The pharmaceutical composition of Claim 13 wherein the molecular weight of the hyaluronic acid and/or salts is less than about 750,000 daltons. SUB 15. A pharmaceutical composition from which dosage amounts may be taken and applied to the skin to treat a disease or condition in humans, the pharmaceutical composition comprising: (1) a medicinal and/or therapeutic agent suitable for treating a disease or condition in the skin and/or exposed tissue in humans, and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, in a form suitable for administration to the skin and/or exposed tissue in humans; characterized in that an effective dosage amount comprising effective non-toxic dosage amounts of components (1) and (2) taken and administered from said . composition (i) is available in the skin and/or exposed tissue upon administration to treat said disease or condition in humans by penetration at the site to be treated to the site of trauma and/or pathology, and (ii) comprises an effective non-toxic dosage amount of component (2) to transport (facilitate or cause the transport of) component (1) immediately upon administration percutaneously into the skin including the epidermis, to the site to be treated where it remains a prolonged time, accumulating there and from which it is discharged via the lymphatic system. 16. The pharmaceutical composition of Claim 15 wherein the effective non-toxic dosage amount of component (2) comprises an effective non-toxic dosage amount of at least about 5-10mg/cm 2 of the skin and/or exposed tissue to which the dosage amounts taken from the pharmaceutical composition is to be applied. 17. The pharmaceutical composition of Claim 15 or 16, wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof. SUBSTITUTE SHEET 18. The pharmaceutical composition of Claim 15, 16 or 17, wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons. 19. The pharmaceutical composition of Claim 15, 16, 17 or 18 wherein the medicinal and/or therapeutic agent is a non- steroidal anti-inflammatory drug (NSAID) . 20. A pharmaceutical composition comprising: (1) a medicinal and/or therapeutic agent in a therapeutically effective amount to treat disease or condition of the skin and/or exposed tissue; and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, characterized in that said composition (a) is in a dosage form which is suitable for administration to skin and/or exposed tissue; and (b) is in such an amount and in such form that (i) component (1) is in an effective dosage amount to treat said disease or condition by penetration at the site of the skin or exposed tissue to be treated, and (ii) component (2) is immediately available to transport (facilitate or cause the transport of) component (1) to the site of trauma and/or pathology of the disease or condition to be treated, percutaneously into the skin or exposed tissue where the composition resides and accumulates for a prolonged period, and which component (2) is in an effective non-toxic dosage amount to transport (facilitate or cause the ' transport of) component (1) upon administration, percutaneously into the skin or exposed tissue to the site of the trauma and/or pathology. 21. ■ The composition of Claim 20 wherein the form of hyaluronic acid in the composition comprises hyaluronic acid and/or salts thereof. 22. The composition of Claim 20 or 21 wherein the effective amount of the form of hyaluronic acid in the SUBSTITUTE SHEET composition exceeds about 5-10 mg per square centimeter (cm 2 ) of skin or exposed tissue to which it is to be applied. 23. The composition of Claim 20, 21 or 22 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons. 24. The composition of Claim 20, 21, 22 or 23 wherein the drug is a non-steroidal anti-inflammatory (NSAID) . 25. The composition of Claim 20, 21, 22 or 23 wherein the drug is an anti-cancer agent. 26. The use of: ■ (1) a medicinal and/or therapeutic agent, and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, in the manufacture of a pharmaceutical composition for treating a disease or a condition of the skin and/or exposed tissue in a therapy wherein dosage amounts taken from the composition each comprise: (1) a therapeutically effective amount of said medicinal and/or therapeutic agent and (2) a therapeutically effective amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes., esters, fragments, and sub¬ units of hyaluronic acid, the pharmaceutical composition being characterized in " that for each dosage amount taken from the pharmaceutical composition, the amount of component (2) is immediately available to transport component (1) percutaneously to the site of trauma and/or pathology caused by a disease and/or condition of the skin and/or exposed tissue into the epidermis of the skin and/or exposed .tissue to be treated, and component (2) is in an effective non-toxic amount to transport (facilitate or cause the transport of) component (1) into the skin or exposed tissue (for example into the epidermis) to the site of trauma and/or pathology. 27. The use of Claim 26 wherein component (2) is hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons. 28. The use of Claim 26 or 27 wherein the dosage amount of component (2) in the amount of the composition taken from the composition (to be taken from the composition) and applied to the skin and/or exposed tissue is present in a dose amount greater than about 5-10 mg per cm 2 of skin or exposed tissue to which the dosage amount is to be applied. 29. The use of Claim 26, 27 or 28 wherein component (1) is a non-steroidal anti-inflammatory drug (NSAID) . 30. The use of: (1) a medicinal and/or therapeutic agent which inhibits prostaglandin synthesis, and (2) hyaluronic acid and/or salts thereof, in the manufacture of a pharmaceutical composition for treating disease or condition at the site of trauma and/or pathology of the skin and exposed tissue in a therapy wherein a dosage amount comprises a therapeutically effective amount of said medicinal and/or therapeutic agent and a therapeutically effective amount of the hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons, the use being characterized in that the amount of component (2) is immediately available to transport component (1) percutaneously into the epidermis at the site of the skin or exposed tissue to be treated and component (2) is an effective non-toxic amount to transport (facilitate the transport) of component (1) into the skin or exposed tissue. 31. The use of Claim 30 wherein the dosage amount of component (2) is present in a dose greater than 5-10 mg per cm 2 of skin or exposed tissue to which the composition is to be applied. 32. The pharmaceutical composition of Claim 20, 21, 22, 23, 24, or 25 include pharmaceutically compatible excipients to provide a form for ease of administration to the skin or exposed tissue for transport into the epidermis. 33. The pharmaceutical composition of Claim 32 comprising a gel squeezed from a tube as a ribbon of gel and which dosage amount is in the form of the ribbon of gel "X" cm long containing the effective non-toxic amounts of the drug and form of hyaluronic acid. 34. The pharmaceutical composition of Claim 32 comprising a cream taken from a jar to be scooped from the jar in a dosage amount comprising the effective amount of drug and effective amount of the form of hyaluronic acid. 35. The pharmaceutical composition of Claim 32 comprising a form selected from a gel, lotion or cream. 36. A method of treating a disease or condition of- the skin or exposed tissue comprising administering topically a non-toxic dosage amount of a composition comprising pharmaceutical excipients suitable for topical application, a therapeutically effective (to treat and to assist to resolve the disease or condition) non-toxic dosage amount of a drug which inhibits prostaglandin synthesis, and . an effective non- toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to transport (facilitate the transport of) the drug into the skin or exposed tissue at the site of the disease or condition to be treated percutaneously into epidermis and rubbing the composition into the skin and/or exposed tissue. 37. The method of Claim 36 wherein the form of hyaluronic acid is hyaluronic acid and salts thereof. 38. The method of Claim 36 or 37 wherein the amount of the hyaluronic acid exceeds about 5mg./cm 2 of the skin or exposed tissue to which the dosage amount of the composition is applied. 39. The method of Claim 36, 37 or 38 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons. 40. The method of Claim 36, 37, 38 or 39 wherein the treatment is applied daily for a number of weeks. 41. The method of Claim 36, 37, 38, 39 or 40 wherein the drug is a non-steroidal anti-inflammatory drug (NSAID) . 42. The method of Claim 41 wherein the NSAID is selected from diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac. 43. The method of Claim 41 wherein the NSAID is selected from IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin. 44. The method of treatment of Claim 41, 42 or 43 wherein the treatment comprises applying effective dosage amounts of the composition, a number of times daily for a period of weeks to clear the trauma or pathology. 45. A container containing compositions for topical application to the skin and/or exposed tissue of a human comprising a plurality of dosage amounts of each of (a) a drug and (b) hyaluronic acid and/or sodium hyaluronate, each dosage amount comprising an effective non-toxic dosage amount of the drug to treat a disease and/or condition of the skin and an effective non-toxic dosage amount of hyaluronic acid and/or sodium hyaluronate to transport the drug into the skin and/or exposed tissue to the site of the pathology and/or trauma. 46. The container of Claim 45 wherein the hyaluronic acid and/or sodium hyaluronate has a molecular weight less than about 750,000 daltons to transport the drug into the skin and/or exposed tissue. 47. The container of Claim 45 wherein the effective dosage amount of the hyaluronic acid and/or sodium hyaluronate is in a dosage amount exceeding 5mg/cm 2 of the hyaluronic acid and/or sodium hyaluronate in the dosage amount discharged. 48. The container of Claim 45, 46 or 47 wherein means are provided to assist the removal from the container of an effective dosage amount of the composition in the container for use to apply to the skin or exposed tissue at the site of trauma and/or pathology to treat the disease and/or condition. 49. The container of Claim 48 wherein the container is a tube and said means comprises a mouth opening of the tube to assist in the discharge of an effective dosage amount for discharge from the tube. 50. Percutaneous (intercutanous) delivery of a therapeutically effective dosage amount of a drug and which inhibits prostaglandin synthesis in a pharmaceutical composition the drug being transported to the site of, on, or in the skin and/or exposed tissue of a human of trauma and/or pathology to treat a disease or condition of the skin and/or exposed tissue, the delivery comprising topically administering to the skin and/or exposed tissue site of the trauma and/or pathology, the therapeutically effective, non- toxic (to the patient) dosage • amount of the drug which inhibits prostaglandin synthesis, in a composition which comprises an effective non-toxic amount of hyaluronic acid and/or salts thereof sufficient to transport, (facilitate or cause the transport of) , the drug to the epidermis to the site of the trauma and/or pathology to block the synthesis of prostaglandins. 51. The percutaneous delivery of Claim 50 wherein the amount of hyaluronic acid and/or salts thereof exceeds at least about 5mg/cm 2 of the skin and/or exposed tissue to which the composition is to be applied. 52. The percutaneous delivery of Claim 50 or 51 wherein the molecular weight of the hyaluronic acid and/or salts is less than about 750,000 daltons. 53. The percutaneous delivery of Claim 50, 51 or 52 wherein the drug comprises an anti-cancer drug for administration to a tumour or malignancy in the skin and/or exposed tissue. 54. The percutaneous delivery of Claim 53 wherein the drug is 10 mg of novantrone in the dosage amount of the composition and the hyaluronic acid and/or salts thereof is in excess of about 5 mg of sodium hyaluronic per cm 2 of the skin or exposed tissue, about 2.5% of the composition, for the percutaneous transport of the novantrone. 55. Use of a pharmaceutical composition to treat a disease or condition by the application of the composition to the skin and/or exposed tissue of a human, the amount of the composition, administered comprising together with pharmaceutical excipients suitable for topical application, a therapeutically effective non-toxic (to a human) amount of a drug which inhibits prostaglandin synthesis and an effective non-toxic dosage amount of at least about 5mg/cm 2 of skin and/or exposed tissue of hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons effective to transport the drug • (to facilitate or cause the transport of the drug) percutaneously into the skin especially the epidermis at the site of the disease or condition to be • treated, thereby blocking prostaglandin synthesis - to enable the macrophages (and N.K. cells) to resolve the disease or condition. 56. A method of abating pain in skin and exposed tissue of a human suffering from a disease or condition comprising administering a composition comprising an effective non-toxic dosage amount of a drug which relieves pain and an effective non-toxic dosage amount of the hyaluronic acid and/or salts thereof and/or homoloσues. analogues, derivatives, complexes. esters, fragments, and/or subunits of hyaluronic acid in an amount exceeding 10-20 mg. per square cm (cm 2 ) of the skin or exposed tissue to which it is applied for percutaneous transport of the drug by the form of hyaluronic acid into the epidermis proximate the paccinian nerve bundles to give pain relief. 57. The method of abating pain of Claim 56 wherein the form of hyaluronic acid is hyaluronic acid and/or salts thereof. 58. The method of abating pain of Claim 56 or 57 wherein the drug is an NSAID. 59. The method of Claim 56, 57 or 58 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons. 60. A composition from which dosage amounts may be taken and applied to human skin and/or exposed tissue suffering pain for abating the pain, the composition comprising a plurality of dosage amounts which may be taken and applied, each dosage -amount comprising an effective non- toxic dosage amount of an NSAID and an effective non-toxic dosage amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or subunits of hyaluronic acid exceeding 10-20 mg. per square cm (cm 2 ) of skin and/or exposed tissue to which it is applied, for percutaneous transport of the NSAID by the form of hyaluronic acid into the epidermis • proximate the paccinian nerve bundles (superficial nerve bundles at the end of the nerves) to abate the pain. 61. The composition of ciaim 60 wherein the form of hyaluronic acid is hyaluronic acid is hyaluronic acid and/or salts thereof. 62 . The composition of Claim 60 or 61 wherein the molecular weight of the form of hyaluronic acid is less than about 750 , 000 daltons . 63 . The composition of Claim 60 , 61 , or 62 in a container including means for assisting the discharge of an effective dosage amount from the container . 64. The composition of Claim 63 wherein the container is a tube and said means comprises a mouth opening of predetermined diameter through which the ef fective dosage amount of the composition is discharged .

Inventors: ASCULAI SAMUEL SIMON, FALK RUDOLF EDGAR, ASCULAI, SAMUEL, SIMON, FALK, RUDOLF, EDGAR
Applicants: NORPHARMCO INC, NORPHARMCO INC.
Application year: 1993
Main classification: A61K47
IPC codes: A61K9, A61K31, A61K45, A61K47, A61P17, A61P35