CZ288292B6 - Compound therapeutic preparations intended for treatment of diseases or states of tissues comprising insufficiently perfused tissues and pathological tissues of human being - Google Patents

Abstract

New drug combinations or formulations comprise a drug and a hyaluronic acid cpd. (I) selected from hyaluronic acid and its salts, homologues, analogues, derivs., complexes, esters, fragments and subunits.

Description

Technical field

The invention relates to combination therapeutic agents for treating diseases or conditions of tissues including poorly perfused tissues and pathological tissues of a human. In particular, the invention relates to the use of hyalurated acid compounds for the manufacture of such compositions.

BACKGROUND OF THE INVENTION

In an article entitled "Solid Tumors Unavailable for the Best Drugs" published by Sandra Blakeslee on July 8, 1989 in Globe and Mail, Toronto, Ontario, the author notes that a growing number of researchers believe that a fundamental misunderstanding of solid tumor structure has led researchers to designing cytostatics condemned to fail in many patients.

The author states that Dr. Herberman, director of the Pittsburgh Cancer Center, claims that cancer researchers have simply developed drugs for decades, injected them into the blood stream, and expected to be delivered to the tumor, almost disregarding how even the drug was distributed after reaching the tumor.

The article also states that, according to Dr. Judah Folkman, senior researcher of blood growth factors at Harward Medical School, doctors have long argued that tumors outgrow their blood supply. According to that article, that assertion is not true. Tumors compress their blood supply. This compression makes drug administration more difficult.

The article further states that it is common for a tumor to be a mere cluster of cancer cells. Dr. Jain, another researcher, on the other hand, reports that the tumor contains only 50% of the cells. The other half are the blood vessels and the interstitial space. In his opinion, the interstitial space in the tumor can be compared to the space between the beads placed in the box.

The article also states that it does not matter how the biologically active substances are mixed and administered, but that they must penetrate the walls of the blood vessels and interstitium to reach the targeted cancer cells. The article goes on to say that each tumor is different and that there are different areas in each. In addition, tumors change daily as they grow, and parts of the tumors regroup. Most blood vessels within tumors are highly disordered, zigzag alternating and intergrowing insertions to adjacent vessels.

Generally, according to Dr. Jaina, as the tumor grows, its outer part is supplemented with new blood vessels from the surrounding normal tissue. The tumor also forms various abnormal intrinsic vessels. If the tumor grows in confined space, many of these twisted blood vessels are squeezed near the center. Conversely, tumor cells near them appear dead although, when transplanted to other animals, they grow into active carcinoma. In these necrotic areas, high pressures are generated. Both blood vessels and liquid plasma are crushed in the interstitial space. This pressure therefore prevents access to the central parts of the tumor by molecules contained in the blood, including oxygen.

Dr. Jain states that there is no uniform pressure in normal tissue, so that large molecules such as antibodies can reach targeted sites by convection induced by pressure differentiation.

At the center of the tumor, however, the pressure is uniformly high, preventing convection.

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Molecules can also migrate by diffusion, which can be compared to the way a drop of ink disperses in water, says Dr. Jain.

At the same time, however, he reported that when measuring the course of diffusion in tumors, he found that it may take days, weeks, or months for these large molecules to reach a uniform concentration in the tumor by diffusion. In the meantime, it may be too late to be beneficial.

Lastly, it states that the fluid that spends in the interstitium slowly flows out of the tumor and thus elutes molecules that attempt to reach the center of the tumor.

In Canadian Patent Application No. 568512 we disclose a novel composition suitable for the cure of cancer (when used in conjunction with at least thermotherapy (hyperthermia) and, if desired with other methods (such as chemotherapy or radiation)), wherein the composition comprises (e.g. suitable carrier):

(a) a glucose-inhibiting (non-toxic) amount of a substance that blocks glucose-transporting glucose (active membrane transport) of a cell that converts glucose into another cell; and

(b) an effective (non - toxic) quantity of substance ⁷ which:

i) enhances penetration and transport of a) tissues surrounding various cellular elements, generally referred to as scar tissue or connective tissue around a cancerous tumor, and ii) alters the penetration characteristics of the tissue surrounding the tumor to allow transport of a) to the tumor center.

Also disclosed are combinations and formulations suitable for use in the treatment of cancer, the combination comprising:

(a) a glucose-inhibiting (non-toxic) amount of a substance that blocks protein-transporting glucose (the active transport of a molecule in the membrane) of a cell that converts glucose into another cell; and

(b) an effective (non - toxic) quantity of a substance which:

i) enhances penetration and transport of a) tissues surrounding various cellular elements, generally referred to as scar tissue or connective tissue around a cancerous tumor, and ii) alters the penetration characteristics of the tissue surrounding the tumor to allow transport of a) to the tumor center.

After administration of a composition or combination comprising a) and b) to a patient that affects the metabolism of tumor cancer cells, the tumor and tumor-forming cancer cells are stressed at least by thermotherapy (hyperthermia). In this case, when substance a) is delivered to tumor cells whose cells are in a stress state, the amount of glucose available to the tumor cells is insufficient to continue their metabolism. This impairs the tumor cells with energy and dies. The application further provides a method for treating cancer, the method comprising administering (e.g., in a pharmaceutically acceptable carrier):

a) a glucose-inhibiting (non-toxic) amount of a substance that blocks glucose-transporting glucose (the active transport of a molecule in the membrane) of a cell that converts glucose to another cell; and

(b) an effective (non - toxic) amount of a substance which:

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(i) enhances penetration and transport of (a) tissues surrounding various cellular elements, commonly referred to as scar tissue or connective tissue around a cancerous tumor, and (ii) alters the penetration characteristics of the tissue surrounding the tumor to allow transport of (a) to the tumor center; and subjecting the cancer cells to hyperthermal treatment (thermotherapeutic). Other modalities (e.g., chemotherapy and / or radiation therapy) may also be used in some cases.

A glucose-inhibiting (nontoxic) amount of a substance that blocks the glucose-transporting protein of a cell that converts glucose to another cell (appears more in cancer cells than normal cells) may include:

phlorizine

phloretin

or analogs thereof including phlorizine glucoronide, 4-deoxyphloretine-2-D-glucoside and the like.

Effective (non-toxic) amount of the substance which:

(i) enhances penetration and transport of the substance (a) tissues surrounding various cellular elements, commonly referred to as scar tissue or connective tissue around a cancerous tumor, and (ii) alters the penetration characteristics of the tissue surrounding the tumor to allow transport of the substance (a) (DMSO), methylsulfonylmethane (MSM), also called methylsulfonomethane), or other transport type carrier molecules having properties that

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i) enhance penetration and transport of a) tissues surrounding various cellular elements, commonly referred to as scar tissue or connective tissue around a cancerous tumor, and ii) alter the penetration characteristics of the tissue surrounding the tumor to allow transport of a) to the tumor center.

In Ontario Medicine, Vol. 8, No. 16, August 21, 1989, the article "Toxic drug tamed but still potent" reported the use of an experimental liposomal drug delivery system used to encapsulate both a highly toxic but also a highly effective fungicidal agent to represent how harmful drugs can be converted to non-toxic substances without compromising clinical efficacy.

The article ends as follows:

“Originally, it was hoped that liposomes would provide significant capabilities as a delivery system for nearly most pharmaceuticals. However, research into this drug delivery system over the past two decades has shown that cell-size artificial spheres are formed spontaneously with only a small proportion of drugs available today, and their use is limited. ”

Hoffer studied the effects of ascorbic acid (vitamin C) in relation to the health of patients. In his article he discusses the effects of vitamin C in relation to cancer treatment. It also discusses the findings of Cameron and Pauling in using 10 gram doses of ascorbic acid for the treatment of cancer patients, where this administration of ascorbic acid increased the survival time of cancer patients. It also discusses the harmlessness of the use of ascorbic acid and the harmlessness of very high doses. On page 11 of his study, he states that ascorbic acid, both dissolved and free-flowing, has no LD-50 value. Hoffer states that:

If the vitamin cannot be completely absorbed from the gastrointestinal system, water will begin to accumulate in the intestines, leading to diarrhea that are watery but not dangerous unless they cause dehydration; this quickly causes patients to reduce their doses. Millions of people have taken these doses and are taking them. As I know, patients took 30 grams a day for 30 years. It's safer than ordinary table salt, gram per gram. It does not cause kidney stones, it does not cause pemicious anemia, it does not cause infertility of women, it does not cause cancer. ”

US Patent No. 4,801,619 relates to hyaluronic acid administered to an intra-articular having a molecular weight of about 3 ^× 10 ⁶ daltons or greater, having an effect on reducing the proteoglycan content of the synovial fluid to near normal levels. The process of said patent has a beneficial effect on the proteoglycan metabolism of the joints. The method of the patent is applicable to both inflammatory conditions and degenerative conditions caused by the treatment of symptomatics such as corticosteroid preparations. Accordingly, hyaluronic acid of sufficiently high molecular weight counteracts side effects that could be caused by corticosteroids or other symptomatics giving similar effects. When corticosteroids are administered, the amount of hyaluronic acid in the synovial cavity begins to increase substantially, and according to the inventors, their hyaluronic acid formulations have a very positive effect on such clinical symptoms as pain, swelling and paralysis.

The patent teaches that the objectives of the invention are achieved by intra-articular administration by administering an effective amount of hyaluronic acid having an average molecular weight in excess of 3. 10 ⁶ daltons, preferably exceeding ^{4 10 6} daltons, the molecular weight usually does not exceed 7. 9 ⁶ dalton. The preferred dosage of hyaluronic acid administered is in the range of 5 mg to 80 mg. The amount of solution administered per administration is generally less than 60 ml, for example less than 20 ml, in the form of an aqueous solution of the acid or a salt thereof. It is preferred to administer the acid dissolved in water (<2% w / w, buffered to physiological pH), for example in the form of a water-soluble sodium salt. The exact amount will depend on the joint to be treated.

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US Patent No. 4,808,573 discloses that hyaluronic acid, a substance well known for reducing the consequences of tissue injury in mammalian joints when directly applied to the injured tissue, is also delivered to the injured tissue by natural processes occurring in mammals even when applied to a site remote from the injured tissue. Thus, according to said patent, hyaluronic acid in any therapeutically suitable form can be administered by conventional non-local routes of administration, including intravenous, intramuscular, subcutaneous atopic.

This makes the use of hyaluronic acid much more attractive and advantageous. For example, the treatment of arthritis of equine or human joints with hyaluronic acid according to said patent no longer requires more difficult intra-articular injections.

U.S. Patent No. 4,725,585 relates to a method of enhancing or regulating host-mammalian immunity, said method comprising administering to the mammal a therapeutically effective amount of hyaluronic acid.

Column 1, lines 43-46, states that the invention was based on the unexpected discovery that administration of hyaluronic acid to mammals results in a significant increase in their defenses.

The hyaluronic acid used in the process of the above patent was of Pharmacia AB, Uppsala, Sweden, of the brand Healon (T.M.) (Pharmacia AB is also entitled to use U.S. Patent No. 4141973). The patent in column 4, line 19, states that since the patient's infections were difficult to treat, instead of administering hyaluronic acid alone to enhance its defenses, the patient was administered hyaluronic acid and an antibiotic. While the patent states that the antibiotic was administered in combination with hyaluronic acid, in fact, since hyaluronic acid was administered subcutaneously and the patient had heart problems, it would be obvious to the skilled person that administration of the antibiotic, when co-administered, was certainly given separately intravenously (presumably) or intramuscularly (less likely). Accordingly, it is most likely that hyaluronic acid, as reported in that patent, was administered to prevent the possible development of infections (increase host defense) and not for any other reason.

U.S. Patent No. 4,636,524 discloses cross-linked hyaluronic acid gels, alone or mixed with other hydrophilic polymers, including various substances or covalently bonded low molecular weight substances, and processes for their preparation. These products are reported to be suitable for a variety of applications including cosmetics and drug delivery systems.

The patent further teaches that hyaluronic acid is known to be a biocompatibility polymer in the sense that it does not cause any immunological or other response when introduced into the human body and that cross-linked hyaluronic acid gels can be used for various medical applications. Crosslinked gels modified with other polymers or low molecular weight substances are reported to be suitable drug delivery systems. For example, the inventors report that they have found that heparin introduced into the cross-linked hyaluronic acid gel maintains its anticoagulant activity.

The inventors also report that they have found that cross-linked hyaluronic acid gels can retard the release of low molecular weight substances dispersed in the gel, but not covalently bound to macromolecules! gel matrix.

US Patent No. 4736024 discloses novel drugs for topical use, comprising:

(i) an active pharmacological agent or a mixture of pharmacological agents either active or suitable for topical administration; and (ii) a topical vehicle containing hyaluronic acid or an alkali metal, alkaline earth metal, magnesium, aluminum, ammonia or pharmacological agent optionally containing other conventional ingredients for use in topical pharmaceutical formulations.

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Applicants are also aware of the newly published Japanese Patent Publication No. 61000017 dated 86/01/06, the English abstract of which states in the appendix that this Japanese patent relates to the use of hyaluronic acid or cross-linked hyaluronic acid or its salts as an active agent for inhibiting cancer metastases.

According to said abstract of this patent, more than 1% of hyaluronic acid is dissolved in an alkaline aqueous solution preferably containing more than 50% of water and the remainder being an organic solvent, an alcohol, acetone, dioxane. A preferred pH is 12-14. The polyfunctional epoxy compound is then added, reacted for 24 hours at 10-60 ° C, preferably 20-40 ° C. The degree of cross-linking of the cross-linked hyaluronic acid or salt thereof can be controlled by varying the molar ratio of the hyaluronic acid or salt thereof to the poly functional epoxy compound. Preferably, hyaluronic acid having an intrinsic viscosity of 0.2 to 30, a molecular weight of 4,000 to 2,000,000, is used. Adult clinical doses are common as hyaluronic acid or cross-linked hyaluronic acid, 25 mg to 5 g / day (per os) and 10 mg to 2.5 g / l dose (by injection). The abstract states that the advantage of using hyaluronic acid is that it has no side effects like other cytostatics and has analgesic and healing effects on tissues.

European Patent Application No. 0295092 discloses a vehicle comprising hyaluronic acid fragments for delivery of hyaluronic acid fragments to the skin which upon reaching the dermal layer of the skin increases blood vessel development to stimulate hair growth or regrowth. Preferred hyaluronic acid fragments are polysaccharides containing from 7 to 25 monosaccharide units. The patent states that it is clear that the larger the fragments of hyaluronic acid, the more difficult these fragments are to enter the dermal layer of the skin unless there are also means in the composition to enhance the activity of said fragments.

Thus, the combination may comprise means for enhancing the activity of the hyaluronic acid fragments, in particular to improve their penetration through the skin after topical application. Some activity enhancers have also been reported as vehicles of hyaluronic acid fragments.

Some activity enhancers also report their own ability to stimulate or increase hair growth. Among other means for increasing activity, minoxidil has this property. Both the hyaluronic acid fragments and the minoxidil are reported as hair growth stimulating agents in a vehicle.

European Patent Application No. 0179442 discloses that in an environment where a significant amount of free radicals is produced, hyaluronic acid is cleaved or degraded before the targeted effect occurs.

Canadian Patent No. 1240929 discloses a combination of chondroitin sulfate and hyaluronate to protect both human and animal cell layers and tissues exposed to traumatic exposure.

European Patent Application No. 0208623 discloses hyaluronic acid as a potentiating agent for certain proteases. It also discloses the use of hyaluronic acid for the treatment of connective tissue diseases including malignant tumors and cardiovascular problems.

European Patent Application No. 270317 discloses a concentration of antiviral agent without inhibitory effect and a compound (e.g. hyaluronic acid) having cell inhibitory activity and / or virus absorbing inhibitory activity for the treatment of viral diseases.

US Patent No. 4,840,941 discloses the use of an effective amount of hyaluronic acid as an active ingredient for the treatment of retroviruses in association with a pharmaceutically acceptable carrier, diluent or excipient.

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US Patent No. 4851521 and European Patent Application No. 0265116 both disclose hyaluronic acid fractions, their production and crosslinking with hyaluronic acid esters. US Patent No. 4851521 discloses hyaluronic acid esters incorporated into pharmaceutical compositions as an active ingredient and as a vehicle for ophthalmic preparations for topical use (see column 11, lines 35-42; column 12, lines 62- column 13, lines 3) and for suppositories for the systemic effect induced by transcutaneous absorption from the suppositories.

The patent states in columns 13 rows 5 to 31:

"The function of hyaluronic acid esters as a vehicle can be applied to a class of drugs of the above type wherein the active agent acts not only topically or nasally or rectally, e.g. in the form of nasal sprays or inhalants into the oral or pharynx cavity, but also by oral or prenteral routes, e.g. intramuscularly, subcutaneously or intravenously, if this promotes drug uptake at the administration site. Therefore, these new drugs can be applied irrespective of the fields of application already mentioned, in virtually all fields of medicine such as internal medicine, for example pathological conditions of the cardiovascular system, respiratory infections, digestive system, renal system in endocrinological diseases, oncology, psychiatry etc., and can also be characterized in terms of their specific effect as anesthetics, analgesics, anti-inflammatory drugs, healing drugs, antimicrobials, adrenergic agonists and antagonists, cytostatics, antirheumatics, antihypertensives, diuretics, sex hormones, immunostimulants and immunosimulants one of the drugs having the previously described activity as a therapeutically active alcohol is used as an esterification component according to the invention or as a therapeutically active base used for the salification of free carboxyl groups. '

Furosemide inhibits sodium reabsorption in the ascending arm of the Henley loop in both the proximal and distal tubules. The effect of the drug is independent of the inhibitory effects of carbon anhydrase or aldosterone. Furosemide is known to promote diuresis in cases where resistance to other diuretics has previously been established. It has no significant pharmacological effects other than on renal function. It is absorbed from the gastrointestinal tract in the human body. After intravenous administration, diuresis generally occurs within 30 minutes and the duration of action is about 2 hours.

However, in many circumstances, the patient may become relatively resistant to the effects of Lasix. This may be for a variety of reasons, but it is evident in those cases where there are significant peripheral edema or third spacing fluid that may confirm poor nutritional status and / or developed cancer. In the latter case, the level of albumin is significantly reduced and probably increased permeability and exudate formation by discharge from the vascular system. Therefore, these patients become relatively resistant to any of the diuretics, including high doses of Lasix administered intravenously.

Extensive studies have been conducted to determine a disorder of immunofunction that allows tumor development. Originally, it was assumed by Jem and then Bumett that the main role of the immune system is the immunological supervision of the destruction of abnormal cells. The concept of surveillance, although somewhat simplistic, remains as an accepted concept for elaborating the mechanism of recognition and immune function in higher mammals.

Thereafter, tumors were thought to develop as a result of local or generalized immunosuppression. However, as Moller has pointed out, only certain types of malignant neoplasms, especially neoplasms of the lymphoreticular system, develop in the presence of generalized immunosuppression. This observation is correct and represents the main importance of the theory of immune surveillance until a specific reason for a separate cancer cell to develop outside the immune system is demonstrated.

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In 1974 it was experimentally demonstrated that malignant neoplasms can be observed to impair macrophage function.

In the first experiments, the suppressor cells were found to be part of the immunosystem and are not T-type cells of the macrophage cell system. Their presence has been proven in neoplasia, chronic bacterial infection, in the treatment of large wounds and in chronic fungal disease.

It has been repeatedly shown that - in experimental animals - macrophage cell function is altered in malignant neoplasms. Macrophage function appears to be "blocked" in animal systems. In general, however, when removed from the environment in vivo, washed with brine and cultured, they may function normally. Blocking their function has been shown to be related to overproduction of prostaglandin by neoplastic tissue or macrophages themselves.

In basic research in the late 1970s and early 1980s, there was basically confusion about the role of immunotherapy in cancer. Activation or hyping of macrophages was considered important. However, in the experiments of Romans and Falk on peritoneal macrophages obtained from patients with malignant neoplasms, it was completely confirmed that these macrophages were already activated during coexistence with cancer cells and did not cause their destruction.

Earlier this year, several independent researchers have shown that macrophage malfunction or predicted block of function is due to excessive levels of prostaglandin that can be altered in tissue cultures by corticosteroids, ASA, non-steroidal anti-inflammatory drugs, ie, indomethacin and naproxen (Naprosyn ™). Animal tumors have been repeatedly shown that these agents can alter the response of neoplastic cells and that various combinations of these agents with immune-enhancing agents have a credible success in eliminating experimental tumors. Lala and co-workers have combined indomethacin therapy with interleukin-2 therapy and have proven to be a treatment for experimental neoplasms.

The use of these agents has continued in human medicine validation in vivo. All of the non-steroidal anti-inflammatory drugs (NSAIDs) are toxic in particular in the gastrointestinal, neurological and other areas. Thus, the basis of the current approach is that, under the general conditions of use of said drugs in the treatment of human diseases, in sufficient amounts to penetrate any pathological tissue in sufficient amounts therapeutically alter the local production of prostaglandin. Although intravenous formulations of indomethacin and other agents are known, however, to date, the data so far are not authoritative as these drugs used alone have prohibited adverse reactions in human subjects. Therefore, only insufficient amounts of these drugs enter the body to produce a more than occasional neoplasm response.

However, most of the conclusions are outlined, and it can therefore be assumed that the bases for neoplasm development and the way the parent cell “gets out” of immune surveillance are related to prostaglandin production itself. It should be assumed that only one mutation alters prostaglandin synthesis by cells before they become "malignant" to determine the mechanism of knockout of the original cell from any immunoreaction, ie, macrophages. Therefore, it has become necessary to develop a combination of NSAIDS for clinical use and to obtain substantial improvements in use in the treatment of neoplasms and other conditions where over-synthesis of prostaglandins is the basis for the pathogenesis of this stage of the disease, ie arthritis and various other so-called inflammatory connective tissue diseases and / or autoagressive diseases .

See also:

1. Modulation of immunity in cancer patients with prostaglandin antagonists, Immunity to Cancer II, Alan R. Liss, Inc., And

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2. Goodwin J. S. (1981) Prostaglandin E and Cancer Growth Potential for Immunotherapy with Prostaglandin Synthesis Inhibitors, Augmentive Agents in Cancer Therapy, Raven Press, New York.

US Patent No. 4,711,718 discloses pharmaceutical compositions comprising vitamin C, a zinc salt, and a thioamino acid for treating the epithelial surface to regenerate it. Hyaluronic acid may be added for reduction in the reproductive tract.

Japanese Patent Application No. 63/045223 relates to the treatment of diseases caused by retroviruses. Hyaluronic acid is said to be useful in preventing or treating leukemia or AIDS by suppressing viral replication.

In an article entitled "Inactivation of Herpes Simlex Viruses by Nonionic Surfactants," where one of the authors of this invention (Dr. Samuel Asculai) inter alia (published in Agents and Chemotherapy, April 1978, pp. 686-690) discloses nonionic surfactants, for example, nonoxynol-9, in said Delfen ™, "having an ester or amide bond between the hydrophilic and hydrophobic portion of the molecule and a rapidly inactivating infectivity of herpex simplex viruses. This activity is based on the ability of nonionic surfactants to dissolve lipid-containing membranes. This was confirmed by observing the destruction of the plasma membranes of mammalian cells and Herpex simplex viruses surrounded by a surfactant. Also, vaginal contraceptives containing nonionic surfactants inactivate the infectivity of herpex simplex virus. This observation suggests that nonionic surfactants in a suitable environment could effectively prevent the transmission of herpex simplex virus. ”

SUMMARY OF THE INVENTION

The present invention provides the use of hyaluronic acid compounds selected from hyaluronic acid and / or its salts and / or hyaluronic acid homologues for the manufacture of a combination therapeutic agent for treating diseases or conditions of tissues including poorly perfused tissues and pathological tissues of a human.

The term 'insufficiently perfused tissue' is an alternative description of the condition, which is called 'ischemia'. Thus, it is a condition in which blood flow to the affected body tissue is reduced, leading to an impaired oxygen supply, which in turn results in the development of a clinical disease.

Hyaluronic acid is a glycosaminoglucan found in nature. Its molecular weight can vary from 50,000 daltons upwards and form highly viscous solutions. There is still much uncertainty about the actual molecular weight of hyaluronic acid in the natural biological context: when determining the molecular weight of hyaluronic acid, different values are obtained depending on the assay method used, the source, the method of isolation, etc. This acid occurs in animal tissue , such as spinal fluid, eye fluid, synovial fluid, rooster combs, skin, and also some streptococci. Different quality hyaluronic acids were obtained. A composition with an allegedly high degree of purity and allegedly devoid of side effects and anti-inflammatory effects is disclosed in U.S. Patent No. 4141973, which is said to have a molecular weight in excess of 750,000 daltons, preferably in excess of 1,200,000 daltons, for therapeutic use in treatment of various joint problems.

The Gauges Index states that hyaluronic acid has a molecular weight in the range of 50,000 to 8. 10 ⁶ depending on the source, method of preparation and method of determination. This publication discloses that hyaluronic acid is an auxiliary surgical drug (ophthalmological).

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The inventors have now discovered that combinations and formulations (e.g., injectable preparations) can be prepared for administration to mammals for the treatment of diseases or conditions, wherein the combinations or preparations use or incorporate, for example, therapeutically effective non-toxic amounts of medicinal and / or therapeutic agent to treat the disease. or a condition (e.g. free radical scavengers such as ascorbic acid (vitamin C)), vitamin C (for the treatment of mononucleosis), an anticarcenogen, a chemotherapeutic, an antiviral such as a nonionic surfactant such as nonoxynol-9 (nonylphenoxypolyethoxyethanol) contained in the contraceptive DELFEN ™ cream, and an antionogenic surfactant (e.g. cetylpyrimidinium chloride) and a cationic surfactant (e.g. benzalkonium chloride), non-steroidal anti-inflammatory agents (NSAIDs) such as indomethacin, naproxen, and (+/-) tromethanine ketorola (marketed under the trademark Toradol ™) and steroidal anti-inflammatory agents, antifungal agents, detoxifying agents (e.g., for rectal administration by enema), analgesics. bronchodilators, antimicrobials, antibiotics, drugs for treating vascular ischemia (e.g., diabetes or Berger's disease), monoclonal antibodies, minoxidil for topical administration for hair growth, diuretics (e.g., furosemide (sold under the trademark Lassix ™)), immunosuppressive agents (e.g. cyclosporins), lymphokines (such as interleukin-2 and the like), alpha and beta-interferon and the like, administered together with or introduced into a carrier of hyaluronic acid and / or a salt thereof (e.g. sodium salt) and / or homologues, analogs, derivatives , esters, fragments, and / or subunits of hyaluronic acid (preferably hyaluronic acid and salts thereof) in an amount sufficient to allow tissue (including scar tissue) to penetrate the target for treatment through cell membranes into individual cells to be treated. Administration of said combinations and formulations to patients suffering from a disease or condition unexpectedly improves said disease or condition.

The composition may be administered, inter alia, intravenously, intraarterially, intraperitoneally, intrapleurally, transdermally, on the skin (topically), rectally, orally, or by direct injection (e.g., into a tumor, abscess, or a similar focus of disease), or patient. The hyaluronic acid and / or salts thereof and the medicament for the treatment of diseases or conditions may be administered separately, but in sufficient amounts and in an immediate time sequence or interval (preferably concurrently and even more preferably simultaneously), preferably to the same site (e.g. "Piggy bached").

Accordingly, it is one aspect of the present invention to provide a combination suitable for treating a condition or disease, wherein the combination suitable for treating a condition or disease, wherein the combination comprises a therapeutically effective non-toxic amount.

(a) medicinal and / or therapeutic agents for the treatment of a disease or condition (eg free radical scavenger (eg ascorbic acid (vitamin C)), vitamin C (for the treatment of mononucleosis)), anticarcenogen, chemotherapeutic, antiviral, eg non-ionic surfactant , for example, nonoxynol-9 (nonylphenoxypolyethoxyethanol) contained in Delfen ™ contraceptive cream and an anionic surfactant (eg cetylpyridinium chloride) and a cationic surfactant (eg benzalkonium chloride), non-steroidal anti-inflammatory agents (NSAIDs) such as indroxhacin (+/-), ) tromethamine salt of ketorolac (sold under the tradename Toradol ™) and steroid anti-inflammatory agents, antifungal agents, detoxifying agents (e.g., for rectal administration by enema), analgesics, bronchodilators, antimicrobials, antibiotics, drugs for treating vascular ischemia ie (e.g., diabetes or Berger's disease), monoclonal antibodies, minoxidil for topical administration for hair growth, diuretics (e.g., furosemide (sold as Lassix ™)), immunosuppressive agents (e.g., cyclosporine), lymphokines (such as interleukin-2 and the like), alpha and beta-interferon and the like) and

(b) a sufficient amount of hyaluronic acid and / or its salts (e.g. sodium salt) and / or homologues, analogs, derivatives, esters, fragments and / or subunits thereof, preferably hyaluronic acid and its salts, in an amount sufficient to permit penetration of the substance

The tissue (including scar tissue) to the site to be treated across cell membranes into the individual cells to be treated.

The combination may be administered separately or in a mixed solution. When administered separately, simultaneous administration to the same site is preferred.

Another aspect of the invention is to provide a composition suitable for treating a condition or disease, wherein the composition comprises a therapeutically effective non-toxic amount of a medical and / or therapeutic agent for treating the disease or condition (e.g., free radical scavenger (e.g. ascorbic acid) , vitamin C (for the treatment of mononucleosis), an anticancer agent, a chemotherapeutic, an antiviral agent such as a nonionic surfactant such as nonoxynol-9 (nonylphenoxypolvethoxx ethanol) contained in the Delfen ™ contraceptive cream and an anionic surfactant (e.g. cetylpyridinium chloride) a substance (e.g., benzalkonium chloride), non-steroidal anti-inflammatory agents (NSAIDs) such as indomethacin, naproxen, and (+/-) - tromethamine salt of ketorolac (sold under the trade name Toradol ™) and steroidal anti-inflammatory agents, antifungal agents, detoxifying agents (e.g., for rectal administration by enema), analgesics, bronchodilators, antimicrobials, antibiotics, drugs for treating vascular ischemia (e.g., diabetes or Berger's disease), monoclonal antibodies, minoxidil for topical administration for hair growth, diuretics (e.g., furosemide (administered as Lassix ™), immunosuppressive agents (e.g. cyclosporins), lymphokines (such as interleukin-2 and the like), alpha and beta-interferon, and the like) and

b) a sufficient amount of hyaluronic acid and / or its salts (e.g. sodium salt) and / or its homologues, analogs, derivatives, esters, fragments and / or subunits of hyaluronic acid, preferably hyaluronic acid and its salts, in an amount sufficient to allow tissue penetration (including scar tissue) to a site to be treated across cell membranes into individual cells to be treated.

The simultaneous administration of a) and b) to the same site is preferred, for example one substance intravenously and the other "pigs shag".

Another aspect of the present invention is to provide a method of treating a disease or condition comprising administering to a mammal a therapeutically effective non-toxic amount of a composition comprising a therapeutically effective amount of a medicinal and / or therapeutic agent for treating the disease or condition (e.g. ascorbic acid (vitamin C)), vitamin C ( mononucleosis), an anticancer agent, a chemotherapeutic agent, an antiviral agent such as a nonionic surfactant such as nonoxynol-9 (nonylphenoxypolyethoxyethanol) contained in the DELFEN ™ contraceptive cream, and an anionic surfactant (e.g. cetylpyrimidinium chloride) and a cation. benzalkonium chloride), non-steroidal anti-inflammatory agents (NSAIDs), such as indomethacin, naproxen, and (+/-) tromethanine salt of ketorolac (sold under the trademark Toradol ™), and steroidal anti-inflammatory agents, antifungal agents, detoxifying agents (e.g., for rectal administration by enema), analgesics, bronchodilators, antimicrobials, antibiotics, drugs for treating vascular ischemia (e.g., diabetes or Berger's disease), monoclonal antibodies, minoxidil for topical administration for hair growth, diuretics (e.g., furosemide (sold under Lassix ™), immunosuppressive agents (e.g. cyclosporins), lymphokines (such as interleukin-2 and the like), alpha and beta-interferon and the like, and a sufficient amount of hyaluronic acid and / or a salt thereof (e.g. sodium salt) and / or its homologues, analogs, derivatives, ester fragments and / or subunits of hyaluronic acid (preferably hyaluronic acid and its salts), to allow tissue to pass through the cell membranes into the individual cells to be treated.

The inventors contemplate that hyaluronic acid and / or its salts and / or homologues, analogs, derivatives, complexes, esters, fragments and / or subunits of hyaluronic acid,

They facilitate the transport of a drug to the site to be treated and the penetration of tissues (including scar tissue) across all membranes into individual cells to be treated.

An example to illustrate facilitating the delivery or transport of a chemical to a designated site in a mammal is a comparison of direct injection of ethanol into the tumor, where sonographic evaluation reveals that ethanol is not dispersed in the tumor. However, when ethanol is applied to a tumor in a carrier of hyaluronic acid and / or a salt thereof, sonographic evaluation has shown that ethanol is dispersed in the tumor.

Although the present inventors assume that hyaluronic acid facilitates transport and delivery, the inventors of the present invention may be used as described regardless of the actual course of action of hyaluronic acid and / or its salts and / or homologues, analogs, derivatives, complexes, esters, fragments and subunits of hyaluronic acid.

The combination of hyaluronic acid and its salts and other forms with various chemicals and drugs (vitamin C, anticancer drugs, etc.) alters their distribution and efficacy in the human body and provides unusual targeting for poorly washed and / or pathological tissue. In this regard, the use of ascorbic acid (vitamin C) as a free radical scavenger (50 g per day - doses 1000 times the daily dose in vitamin therapy) administered intravenously with 300 to 500 mg hyaluronic acid (sodium hyaluronate) immediately relieves bone and muscle pain, and reduces inflammation in cancer patients. Hyaluronic acid increases the antitumor activity and action of ascorbic acid. It is believed that such increased efficacy results in the elimination of free radicals by causing the substance to reduce free radicals. In any case, patients feel better. This phenomenon has also been demonstrated with furosemide and hyaluronic acid, where the efficacy of furosemide increased only minimally when co-administered with hyaluronic acid to “normal” patients, but increased significantly when administered to patients suffering from poor flow or renal malfunction due to insufficient intravascular volume.

A similar situation exists with NSAIDS. Since more soluble indomethacin is required, the chemical product was solubilized using n-methylglucamine at a dilution of 5 mg / ml n-methylglucamine (NMG). This solution was then filtered through a 22 micron Milipore filter to make it sterile. This substance is non-toxic at a 10-fold therapeutic dose in experimental animals and has therefore been accepted for human use. Thus, solubilized Indocid ™ in NMG was administered to patients in the tumor either intraperitoneally, intrapleurally or intravascularly at doses up to 10mg / kg, each dose combined with 200-1000 mg of hyaluronic acid (for example, hyaluronic acid "LifeCore ™" / sodium hyaluronate / ) by diluting the original solution of indomethacin and NMG with hyaluronic acid such as "LifeCore ™". This results in suitable compositions which can be administered safely by any means. (Similar clinical studies have been performed with hyaluronic acid prepared by other procedures, eg extraction. The extracted substance is reliable for intratumoral, intraperitoneal or intrapleural administration.)

Thus, according to another aspect of the invention, when administering NSAIDs such as indomethacin (dissolved in n-methylglucamine) or other NSAIDs simultaneously with more than 200 mg hyaluronic acid at a dose of NSAIDs (e.g. indomethacin and NMG) of 1 to 2 mg / kg body weight , there are no toxic side effects such as gastrointestinal problems, neurological abnormalities, depression, etc., even at increased doses (if necessary). If the amount of hyaluronic acid decreases below this level, common side effects may start to occur. In addition, when NSAIDs (such as Indocide ™) were combined with hyaluronic acid, excellent responses were observed, demonstrating clearly that the combination is now "targeted" to pathological tissue, even with systemic intravenous administration. It has also been observed that patients suffering from malignant neoplasms when administered, among other medicines (such as ascorbic acid / vitamin C), phloretin and anti-cancer drugs, 50 to 200 mg NSAID-hyaluronic acid (sodium hyaluronate), experience a marked immediate relief of pain. This is followed by a disruption and resorption of neoplastic lesions during a short period of time

-28EN 288292 B6 in improving lung and liver function when these organs are affected by the tumor. Dead tumor tissues, their residues and tumor toxins appear to be better eliminated by the organism by the action of macrophages whose activity is enhanced by the action of NSAIDs (or steroidal anti-inflammatory drugs) administered with hyaluronic acid (or a salt thereof, or another form thereof). The authors believe that the addition of an NSAID with, for example, hyaluronic acid (sodium hyaluronate) unblocks macrophages by preventing the enzymatic production of prostaglandin synthetase, which blocks macrophage function. In this way, hyaluronic acid (and its salts and other forms) not only increases the effectiveness of the NSAID, but also reduces any side effects and toxicity associated with the use of inhibitors of prostaglandin synthesis.

Examples of substances suitable for chemotherapeutic use are novantrone (Mitoxantrone), methotrexate, 5-FU (5-fluoro-uracil), carboplatin, methyl CCNU administered orally and Mitomycin C.

In one case, methotrexate with hyaluronic acid has been demonstrated over the entire area of tumor tissue (i.e., the thoracic wall) for 5 to 7 consecutive days. The patient's hematologic endpoints were reduced at least compared to methotrexate alone administered at the same doses either intravenously or orally.

Further, in the disruption of a cancerous tumor (after the treatment described above) in many cases, the liver cannot cope with the tumor toxins and the pissing of tissues damaging the patient. Therefore, not only use of hyaluronic acid with an NSAID, but also use of agents utilizing hyaluronic acid (sodium hyaluronate) and a detoxifying agent administered to the colon is suitable.

Hyaluronic acid and its salts can be taken at various dosages - 10 to 1,000 mg / 70kg person with optimal dosages ranging from 50 to 350 mg / 70 kg individual. Because it is not toxic, hyaluronic acid can be administered at higher doses (e.g., 3000 mg / 70 kg individual) without any side effects.

The inventors have combined hyaluronic acid and / or salts thereof with chemotherapeutic cytostatics, for example either by the immediate administration of hyaluronic acid after drug administration (if the two substances could not be premixed) or by mixing the two substances, i.e., hyaluronic acid and drugs before administration. For example, the authors used adriamycin where adriamycin was administered prior to administration of hyaluronic acid and methotrexate, both of which were mixed together, mitomicyn C, bleomycin, 5-fluorouracil, novantrone, carbo cistoplatin, in which all the drugs were mixed directly with hyaluronic acid. dose of 10 mg / ml hyaluronic acid with increasing the total dose up to 100 mg with the standard dose of the drug.

Previously, the inventors used phloridzine, phloretine, and phloridzine 5-deoxyfluoruride with dimethylsulfoxide as agents for competitively blocking glucose transport in tumor cells. They may also be combined with hyaluronic acid at similar dosages to those described above for chemotherapeutic agents where phloretin is solubilized, for example, with N-methylglucamine.

Thus, medical reports of various neoplasm diseases may include administration of ascorbic acid and Oncostatin IV, a combination of phloretin solubilized in N-methylglucamine in admixture with hyaluronic acid or a salt thereof, using 2 to 4 grams of phloretin solubilized as above with 30 mg to 1000 mg or more (in excess of dose) of hyaluronic acid or its sodium salt. This allows for substantially increased drug penetration into tumor cells, and the treatment has a much better outcome than disrupting the supply of glucose to the tumor with a consequent burden of either hyperthermia, chemotherapy and / or radiation. Similarly, the chemotherapeutic cytostatics mentioned above have been combined with comparable doses of hyaluronic acid and / or its salts and administered either intravenously, intraarterially, intraperitoneally

-13GB 288292 B6 or intrapleurally or directly by injection into the tumor using a needle inserted under sonographic or CT follow-up.

Intradermal administration of other drugs can also be improved with hyaluronic acid and / or salts thereof: for example, administration of insulin in diabetic women, estrogen in post-menopausal women, fertility management progestagens, and anti-metabolites to prevent topical infections such as Corynebacterium acnes infections. These drugs can also be administered using hyaluronic acid.

Also, intravenous administration of bronchodilators (e.g., aminophylline or theophylline) can be improved with hyaluronic acid and / or salts thereof.

Administration with hyaluronic acid resulted in an increase in bronchodilation. Oral administration with hyaluronic acid and / or a salt thereof may also be appropriate.

Another aspect of the invention is to provide a combination of a nonionic surfactant such as nonoxynol-9 (nonylphenoxypolyethoxyethanol contained in the Delfen ™ contraceptive cream) and hyaluronic acid and / or its salts and other forms for treatment

(a) herpes simplex type I and type II,

b) herpes zoster (shingles), with unexpected improvement in symptoms and subsequent disappearance of lesions.

These nonionic surfactants preferably comprise an ether or amide linkage between the hydrophilic moiety of the molecule, which is more effective than the ester or ether-ester linkages in terms of activity.

The following nonionic surfactants with other agents are suitable for use:

Surfactant: connection: none (control virus) 5% nonoxynol-9 (nonylphenoxy-polyethoxyethanol) ether 1% Triton X-100 (p-diisobutylphenoxy-polyethoxyethanol) ether 1% Brij-97 (polyoxyethylene (10) -oleylether) ether 1% Span-20 (sorbitan moncklamate) ester 1% Span-80 (sorbitan monooleate) ester 1% Tween-20 (polysorbate 20) ether-ester 1% Tween-80 (polysorbate 80) ether-ester 1% Onyxol 345 (nonyl phenoxypolyethoxyethanol) amid

If foreign objects (such as a drainage tube) need to be implanted in the human body and kept in it, it is necessary to prevent infection of the tissue surrounding the implant, since once the tissue is infected the infection usually does not subside regardless of antibiotic doses and the implant must be removed. The present inventors have now found that when the infected tissue surrounding the implant is treated with an antibiotic in a carrier of hyaluronic acid (sodium hyaluronate), the infection disappears rapidly and the implant does not need to be removed.

The inventors have also found in the treatment of vascular ischemia (for example in cancer patients where tumor tissue prevents perfusion, in patients suffering from diabetes and Berger's disease) that administration of drugs in hyaluronic acid (sodium hyaluronate) increases the patient's drug response.

Edema must be reduced in patients suffering from brain tumors. Administration of dimethylsulfoxide (DMSO) in doses less than 100 mg per day in a 10% solution in hyaluronic acid (sodium hyaluronate) - 300 to 500 mg reduces acute cerebral and spinal edema.

-14GB 288292 B6

For the treatment of mononucleosis, the inventors have successfully administered vitamin C and hyaluronic acid to a patient suffering from a particularly severe form of the disease for some time, and the patient has recovered rapidly.

One form of hyaluronic acid and / or its salts (e.g. sodium salt) and homologues, analogs, derivatives, esters, fragments and subunits of hyaluronic acid, preferably hyaluronic acid and its salts, suitable for use in the present invention is the fraction supplied by Sterivet Laboratories Limited. This fraction is supplied in a 15 ml vial containing 20 mg / ml sodium hyaluronate (300 mg / vial - lot 2F3). This fraction consists of a 2% solution of sodium hyaluronate with an average molecular weight of 225,000. The fraction also contains water q.s., three times distilled and sterile as required by U.S.P. for injectable preparations. Vials for hyaluronic acid and / or salts thereof may be made of type 1 borosilicate glass, the vials being closed with a butyl stopper that does not react with the contents of the vial.

The fraction of hyaluronic acid and / or its salt (e.g. sodium salt) and homologues, analogs, derivatives, complexes, esters, fragments and subunits of hyaluronic acid, preferably hyaluronic acid and its salts, may contain hyaluronic acid and / or its salts with the following characteristics: Purified, substantially pyrogen-free, fraction of hyaluronic acid obtained from natural sources, having at least one of the following characteristics:

(i) a molecular weight in the range of 150,000 to 225,000; (ii) less than about 1.25% sulphated mucopolysaccharides based on the total weight; (iii) less than about 0.6% protein based on the total weight; (iv) less than about 150 ppm iron based on total weight,

(v) less than about 15 ppm lead based on total weight; (vi) less than about 0.0025% glucosamines; (vii) less than 0.025% N-acetylglucosamine; (ix) less than 0.0025% amino acids;

x) a UV extinction coefficient at 257 nm of less than about 0.275; xi) a UV extinction coefficient at 280 nm of less than about 0.25; and xii) a pH in the range of from 7.3 to 7.9.

Preferably, the hyaluronic acid is mixed with water and the hyaluronic acid fraction has an average molecular weight in the range of 150,000 to 225,000. Even more preferably, the hyaluronic acid fraction has at least one property selected from the following:

i) less than about 1% sulphated mucopolysaccharides based on total weight, ii) less than about 0.4% protein based on total weight, iii) less than about 100 ppm iron based on total weight, iv) less than about 10 ppm lead based on the total weight,

(v) less than 0,00166% glucosamine; (vi) less than 0,0166% glucoronic acid; (vii) less than 0,00166% N-acetylglucosamine; (viii) less than 0,00166% amino acids;

x) UV extinction coefficient at 257 nm less than about 0.23; xi) UV extinction coefficient at 280 nm less than 0.19; and xii) pH in the range from 7.5 to 7.7.

Other forms of hyaluronic acid and / or its salts and homologues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid may be selected from other suppliers, for example, referred to in the prior art. In addition, the inventors have successfully used sodium hyaluronate, manufactured and supplied by Biomedical Inc, as LifeCore ™ having the following parameters:

-15GB 288292 B6

Properties appearance odor viscosity average molecular weight UV / vid. recording, 190-820 nm optical density, 260 nm hyaluronidase sensitivity

IR record pH, 10 mg / g solution water protein acetate heavy metals, maximum ppm

As Cd Cr Co

2,0 5,0 5,0 10,0 microbial contamination endotoxin biological harmlessness test white to cream colored particles no noticeable odor <750 000 daltons corresponding to reference record <0,25 positive reaction units corresponding to reference record 6,2-7, 8% max.

<0.3 mcg / mg NaHy <10.0 mcg / mg NaHy

Cu Fe Pb Hg Ni

10.0 25.0 10.0 10.0 5.0 not observed <0.07 EU / mgNaHy complies with eye test in rabbits

The following references relate to hyaluronic acid, its sources, methods of processing and recovery.

US Patent No. 4141973 discloses hyaluronic acid fractions (including sodium salts) having:

a) an average molecular weight of greater than about 750,000, preferably greater than about 750,000, preferably greater than about 1,200,000, i.e., a viscosity limit number greater than about 1,400 cm ³ (g) and preferably greater than about 2,000 cm ³ () G,

(b) a protein content of less than 0,5% by weight;

(c) ultraviolet absorbance for a 1% sodium hyaluronate solution less than 3,0 at 257 nm less than 2,0 at 280 nm;

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 0,1 to 0,2% sodium hyaluronate in physiological buffer less than -11 χ 10 ³ degrees - cm ² / mol (disaccharide) measured at 220 nm,

(f) no significant cellular infiltration of the vitreous humor and anterior chamber, no redness of the aqueous humor, no redness or turbidity of the vitreous humor and no pathological changes of redness or vitreous humor and no pathological changes of the cornea, lens, iris, retina and no pathological changes of the cornea, lens, iris , retina and choroid in the eye of an experimental owl monkey when one milliliter of a 1% solution of sodium hyaluronate in physiological buffer is introduced into the vitreous body, replacing one half of the present vitreous with said fluid, wherein said HUA is

g) sterile and pyrogen-free,

(h) non-antigenic.

Canadian Patent 1205031 (which is incorporated herein by reference in US Patent 4141973) discloses hyaluronic acid fractions having an average molecular weight of from 50,000 to 100,000, 250,000 to 350,000, and 500,000 to 730,000, and methods of making the same.

When using high molecular weight hyaluronic acid (or salts or other forms thereof), it is more necessary to dilute to allow administration to prevent intramuscular coagulation.

One ascorbic acid (vitamin C) injection product is manufactured by Steris Laboratories, Inc., Phoenix, Arizona, 85043 USA and contains 22 mg / ml (equivalent to 250 mg / ml sodium 10 ascorbate) in 30 ml, 50 ml or 100 ml containers. wherein a size of 30 ml is preferred.

The inventors have combined hyaluronic acid (and sodium hyaluronate and / or other forms) with medical and / or therapeutic results:

For example, a condition / disease also for disease treatment and an unexpectedly good condition

1. Cancer, increased activity of macrophages

IA. Reduction of brain swelling in patients with brain trauma

2. Hair growth

3. Herpes, herpetic inflammation of the oral cavity, shingles

4. Renal failure, cardiac insufficiency, hypertension, edema

5. Infections, acne, mononucleosis

6. Transplants

7. Inflammation, elimination of tumor disruption products (toxins, tissue debris), suppression of side effects, pain relief (eg back pain)

8. Detoxification of chemicals and drugs free radical scavengers, superoxidase dismutase, ascorbic acid (vitamin C), anticancer drugs, NSAIDs, chemotherapeutics, detoxifying agents (eg cholestyramine) dimethylsulfoxide (DMSO) minoxidil - combination - promotes non-ionic hair growth in topical application surfactants such as nonoxynol-9 and anionic (eg cetylpyridinium chloride) and cationic (eg benzalkonium chloride) surfactants diuretics - furosemide antibiotics, antibacterial and antimicrobial agents etc., ascorbic acid and hyaluronic acid cyclosporins non-steroidal anti-steroids, NSAIDs diclofenac, indomethacin, piroxicam, ibuprofen, tromethamine salt of Ketorolac, naproxen enema, detoxifying agent, peritoneal dialysis

-17GB 288292 B6

9. Bronchodilation

10. Vascular ischemia

11. HIV (AIDS)

12. Diabetes

13. Post-menopause

14. Prevention of topical infections

15. Reduction of swelling

16. Hypertension, cardiac insufficiency

17. Inhibition of prostaglandin synthase

18. Increase tissue oxidation by perfusion by soaking tissue (for transplantation purposes) bronchodilators, eg beclomethasone dipropionate (cromogycate sodium, although not a specific bronchodilator), theophylline treating limbs for diabetes, Berger's disease, etc. with a suitable agent eg Trental

DMSO, vitamin C, NSAIDs (eg indomethacin, naproxen, ketorolac tromethamine), interferon, Vibramycin ™ (doxycycline), tetracycline insulin estrogen replacement antimetabolites (eg sulfonamides)

DMSO calcium channel blockers (eg Nifedipine β-blockers eg atenolol, propanolol acetylsalicylic acid perfusion agent

Especially with regard to cancer treatment, the present inventors have now provided a method and combination of chemicals and drugs that appear to increase patient survival and quality of life (even in those patients who do not respond to conventional treatments). The inventors have successfully treated patients according to the invention, increasing the rate of tumor destruction, improving macrophage function, allowing the body to eliminate tumor cells, dead tumor debris, tissue debris, and toxins.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention. Essentially, all cases, not just cancer, were cases where the patient did not respond to conventional treatment. Other forms are also contemplated by the hyaluronic acid herein - for example, sodium hyaluronate.

Case 1

A 501-year-old patient suffering from epidermoid (scaled tumor type) was treated in the acute stage with a combination of surgery and radiation treatment, but a few years later liver metastases developed. The two main tumors were 12 cm and 6 cm in diameter. Treatment was performed with combination therapy, including systemic chemotherapy with addition of DMSO to increase penetration, where phloretin solubilized with N-methylglucanamine was added with addition of DMSO to increase penetration, and direct administration of adriamycin, carboplatin and methotrexate to the tumor by systematic and intratumoral injection. addition of hyaluronic acid for various drugs at a dose of 10 to 60 mg. This treatment was without side effects and after four weeks the patient was re-examined. At this time the smaller tumor disappeared completely. A larger tumor was apparent only as a necrotic lesion measuring 5 cm in diameter, but

Examination and needle biopsy revealed no apparent surviving tumor. This case illustrates the excellent effect of hyaluronic acid on drug penetration, allowing better tumor destruction.

Tracking

Subsequently, the patient was administered indomethacin 300 mg and 300 mg hyaluronic acid daily, the patient was in remission, but later died of infection.

Case II

A 42-year-old patient with developed malignant melanoma with tumors in the upper left thigh and in the inguinal nodes, in the abdominal cavity, liver, lungs and skull, affecting the involvement of various cranial nerves. After excision of the primary tumor, the patient developed a relapsing disease, which was considered incurable as no known cytotoxic or cytostatic chemotherapy would have significant effects on the tumor if it spreads as seen in the patient. The patient was treated with a combination of phloretin solubilized in N-methylglucamine with the addition of hyaluronic acid at a dose of 10 to 50 mg / 2-4 grams administered intravenously for five days at 4 to 24 hours / day. The patient was also treated with hyperthermia in various areas of tumor spread and concomitant systemic carboplatin therapy with hyaluronic acid added to a dose of 250 mg carboplatin plus methyl-CCNU at a total dose of 120 mg for 5 days orally with systemic hyaluronic acid. Hyaluronic acid-mixed methotrexate was injected directly into a tumor that was palpable on the left thigh or inguinal area at 37.5 mg with 60 mg of added hyaluronic acid, divided into two equal injections over two days. The patient responded over the next 10 to 20 days with a remarkable and overall regression of upper thigh and groin tumors, surprisingly finding improvements in liver function, with liver tumors becoming cystic (which is considered a symptom of tumor disintegration) and lung tumors disappeared. Tumor of the lower part of the brain subsided, which resulted in improvement of cranial nerve functions by the relief of headache and pain. In this patient and at her stage of disease development, where most of the drugs did not affect tumors, the same drugs elicited a considerable response using hyaluronic acid as a penetration agent.

Following:

The patient received subsequent treatment with phloretin, indomethacin (NSAID) and hyaluronic acid. This patient is now completely in remission.

Case III

The one-year-old patient suffered from gall bladder cancer, occupying the entire right liver lobe. This patient was treated with a combination of thermal therapy, systemic chemotherapy with DMSO addition, phloretin with DMSO addition and direct injection of cytotoxic drugs with DMSO addition in previous treatments. In early May 1989, it was treated with comparable drugs with the addition of hyaluronic acid as a carrier or dispersant, administered both systemically and by direct injection into the tumor. Tumor, which had previously decreased by about 20%, was significantly reduced by more than 50% after this treatment, and its size reduction continued. This tumor is believed not to respond to the above-mentioned drugs alone administered in a conventional manner.

Following:

Unfortunately, the patient had recurrence of the disease, depression and died.

-19GB 288292 B6

Case IV

5-year-old colon cancer patient with liver metastases, where the major large tumor 5 occupied the entire right lobe of the liver and the central part of the left lobe with the protuberances to the left lobe, where these liver tumors were considered inoperable two months ago. and direct injection of chemotherapeutics into the tumor together with phloretin solubilized with N-methylglucamine with hyaluronic acid and hyperthermia. The patient underwent a three-day therapy, in which case an injection of the cytostatic and hyaluronic acid 10 was injected directly into the tumor and re-examined after three weeks. Sonographic examination revealed that the tumor had completely liquefied, leaving only small margins of apparently living tissue; 500 ml of dark colored fluid with necrotic tumor tissue was aspirated from this cystic lesion. It was an unusual and successful response in adenocarcinoma, which generally responds extremely slowly to treatment. Less than 30% of patients diagnosed with this diagnosis are thought to achieve significant regression of the disease using standard or cytostatic chemotherapy. The increased tumor destruction observed after three weeks is attributed to the use of a carrier penetration agent, hyaluronic acid.

Following:

The examination revealed overall tumor necrosis. Unfortunately, the patient later died of liver failure and pulmonary embolism.

Case V

A 53-year-old patient with transient bladder cancer at a very advanced stage of the disease with metastases throughout the left pelvis, extending to the periaortal, parapancreatic and supraclavicular lymph nodes, relapsing after previous surgery and not responding to standard chemotherapy was treated with phloretin solubilized in N-methylglu by adding hyaluronic acid with direct injection of carboplatin and methotrexate into the tumor tissue. Hyperthermia was also applied to the tumor area. The patient received a successful response as well as a feverish reaction as the tumor disintegrated and bacteria were released. This reaction was handled by antibiotics and appropriate hydration, and a significant reduction in size was observed almost daily in the observation of the patient at this stage, with more than a 50% reduction in tumor size seven days after the therapy. It is a remarkable and successful tumor response that is considered non-responsive to overall therapy, and this is attributed to the use of a glucose blocking drug used as a carrier and penetration agent, i.e. hyaluronic acid, and chemotherapy applied directly to the tumor. tumor together with the above.

Following:

The result was total tumor necrosis. Unfortunately, the patient later died of an infection.

Case VI

The patient suffered from a diagnosis of a right upper lobe lesion that was confirmed by biopsy and assessed as non-operable. According to the documentation, this tumor had no response to chemotherapy and radiation therapy. He was therefore treated with systemic chemotherapy with hyaluronic acid as follows:

-20GB 288292 B6

Date (month / day) drug dose 05/10 vinblastine 3 mg 05/10 mitomycin 3 mg 05/10 calcium leukovorin 40 mg 05/10 5-fluorouracil 250 mg 05/10 5-fluorouracil 250 mg 05/10 Oncostatin IV hyaluronic acid III 3 mg 10 mg 05/11 carboplatin 250 mg 05/11 vinblastine 5 mg 05/11 mitomycin 4 mg 05/11 calcium leukovorin 40 mg 05/11 5-fluorouracil 250 mg 05/11 5-fluorouracil 250 mg 05/12 carboplatin 100 mg 05/12 vinblastine 2 mg 05/12 5-fluorouracil 250 mg 05/12 5-fluorouracil 250 mg 05/12 calcium leukovorin 40 mg 05/12 Oncostatin IV hyaluronic acid 2 mg 20 mg 06/12 mitomycin hyaluronic acid 5 mg 10 mg 06/19 vinblastine hyaluronic acid IV 5 mg 10 mg 06/09 5-Fluorouracil hyaluronic acid IV 250 mg 10 mg 06/09 5-Fluorouracil hyaluronic acid IV 250 mg 10 mg 06/09 calcium leukovorin 40 mg 06/09 Oncostatin IV hyaluronic acid 3 mg 50 mg 06/20 5-Fluorouracil hyaluronic acid IV 250 mg 10 mg 06/20 5-Fluorouracil hyaluronic acid IV 250 mg 10 mg 06/20 calcium leukovorin 40 mg 06/20 mitomycin hyaluronic acid IV 5 mg 10 mg 06/20 vinblastine hyaluronic acid 5 mg 10 mg 06/20 Oncostatin IV hyaluronic acid TV 3 mg 50 mg 06/21 carboplatin hyaluronic acid IV 20 mg 10 mg 06/21 methotrexate 12.5 mg 06/21 carboplatin hyaluronic acid IV Oncostatin IV hyaluronic acid IV 150 mg 50 mg 3 mg 50 mg 06/22 carboplatin hyaluronic acid IV 100 mg 10 mm 06/22 Oncostatin IV hyaluronic acid IV 3g 50 mg 06/23 Oncostatin IV 3g

-21EN 288292 B6

hyaluronic acid IV 50 mg 08/16 calcium leukovorin 40 mg 08/16 5-fluorouracil 500 mg hyaluronic acid IV 50 mg 08/16 carboplatin 250 mg hyaluronic acid IV 100 mg Oncostatin IV 3g hyaluronic acid IV 100 mg 08/17 carboplatin 200 mg hyaluronic acid IV 150 mg 08/17 carboplatin 30 mg hyaluronic acid IV 50 mg 08/17 adriamycin 2.5 mg hyaluronic acid 10 mg Oncostatin 3g hyaluronic acid 100 mg 08/18 5-fluorouracil 500 mg hyaluronic acid 100 mg 08/18 calcium leukovorin 40 mg Oncostatin IV ² g hyaluronic acid 200 mg

The patient was also treated with phloretin in hyaluronic acid. The following hyaluronic acid chemotherapeutic agents were injected into the patient's tumor:

Date (month / day) drug dose 05/11 methotrexate 12.5 mg hyaluronic acid 50 mg adriamycin 1 mg 06/21 methotrexate 12.5 mg carboplatin 20 mg hyaluronic acid 10 mg 08/18 carboplatin 30 mg hyaluronic acid 50 mg 08/18 adriamycin 25.5 mg hyaluronic acid 10 mg

The patient had a 50% reduction in disease in a situation that was otherwise considered incurable. This case documents that non-responsive tumors may respond to chemotherapy when the chemotherapy is administered in hyaluronic acid and / or its salts.

Case VII

A 58 year old patient suffered from massive breast cancer with palpable supraclavicular and axillary lymph nodes. She was treated with a combination of systemic therapy and hyperthermia, but the condition did not improve significantly. She was further treated with radiation therapy from December 1988 to January 1989. Then she was examined again by dr. Falka on May 17, 1989 and no response to this therapy was found. The patient developed multiple effusions. Further she was treated by dr. Falka combinations of chemotherapeutic agents as follows:

(hyaluronic acid may also mean sodium hyaluronate)

-22EN 288292 B6

Date (month / days) drug dose 05/16 methotrexate hyaluronic acid IV 25 mg 10 mg 05/16 methotrexate hyaluronic acid axilla IT 25 mg 10 mg 05/16 methotrexate hyaluronic acid SC nodeIT 25 mg 10 mg 05/16 Oncostatin IV hyaluronic acid 3g 20 mg 05/17 5-fluorouracil 250 mg 05/17 5-fluorouracil 250 mg 05/17 vinblastine 5 mg 05/17 mitomycin 5 mg 05/17 Onocostatin IV hyaluronic acid 3 mg 30 mg 06/02 methotrexate hyaluronic acid IT 25 mg 30 mg 06/02 vinblastine hyaluronic acid IV 5 mg 10 mg 06/02 Oncostatin IV hyaluronic acid 3 mg 30 mg 06/05 5-Fluorouracil hyaluronic acid IV 250 mg 10 mg 06/05 5-Fluorouracil hyaluronic acid IV 250 mg 10 mg 06/05 calcium leukovorin 35 mg 06/05 vinblastine hyaluronic acid IV 5 mg 10 mg 06/05 Oncostatin IV hyaluronic acid 3g 30 mg 06/21 carboplatin hyaluronic acid IT 20 mg 10 mg 06/21 methotrexate 12.5 mg 06/21 vinblastine hyaluronic acid IV 5 mg 10 mg 06/21 mitomycin hyaluronic acid IV 5 mg 10 mg 06/21 Oncostatin IV hyaluronic acid 3 mg 50 mg 07/10 carboplatin hyaluronic acid IT 25 mg 20 mg 07/10 methotrexate hyaluronic acid IT 12.5 mg 20 mg 07/10 Oncostatin IV hyaluronic acid 3 mg 50 mg 07/12 Oncostatin IV hyaluronic acid 2g 50 mg 08/14 vinblastine hyaluronic acid IV 5 mg 50 mg 08/14 5-Fluorouracil hyaluronic acid IV 50 mg 50 mg 08/14 calcium leukovorin 30 mg

-23EN 288292 B6

Date (month / day) drug dose

08/14 Oncostatin IV3 g hyaluronic acid100 g

08/16 Oncostatin IV3g hyaluronic acid 100 mg

The patient was also subjected to a chest puncture followed by introduction of 5-fluorouracil, mitomycin C and hyaluronic acid into the thoracic cavity. Her pleural effusion dissipated. Breast lesions subsided and supraclavicular and axillary lymphatic adenopathy subsided completely.

In this patient, a response was observed at relatively low doses of hyaluronic acid or its salts added to conventional chemotherapy drugs administered systemically by injection into the tumor and introduction into the intrapleural cavity. This response was further enhanced by the use of phloretin in synacid Τ. M. (hyaluronic acid and / or salts thereof) at the same time.

Following:

The patient has been in remission for a long time and is feeling very good.

Case VIII

This 62 year old patient was previously treated with systemic chemotherapy using two different combinations of drugs without any response. She also received treatment including hyperthermia and direct injection chemotherapy to which she responded in early September.

From April to May she observed a tumor enlargement in the upper right lung. It was small cell anaplastic carcinoma. The tumor was treated by injecting into the lesion using bleomycin with hyaluronic acid and indomethacin with hyaluronic acid. The patient also received systemically indomethacin 300 mg daily with 300 mg hyaluronic acid. Radiation treatment followed, and the condition improved significantly over the next 2-4 weeks. Recent images have shown that left hemithorax is clear. There were no signs of pleural reaction on the right side. Here the volume of the protruding upper right lobe decreased with the elevation of the right hilo. The lighted area in the right tip may indicate the area of the cavities in the collapsed lobe or the elevation of the upper segment of the right lower lobe. Comparison with previous records showed that the size of the tumor mass was significantly reduced and could not be clearly identified during the examination.

The inventors believe that this patient response results from the use of a carrier - hyaluronic acid - injected with a chemotherapeutic agent and a non-steroidal anti-inflammatory drug contributing to the destruction of a necrotic tumor.

Case IX

This patient was diagnosed with gastric cancer in July 1988 and considered unoperable. Bypass-type gastroenteroscopy was performed. The patient was examined at the beginning of August and treatment was started in September 1988. He was treated thermally, phloretine and low-dose chemotherapy were administered using 5-FU with other immunological additives.

Since May, these drugs have been administered to a patient in hyaluronic acid, but the initial doses of hyaluronic acid were small, amounting to 10 to 30 mg per dose of the drug being administered, i.e. phloretine or chemotherapeutic. Some initial improvement in his condition was observed, but in the middle of August he developed a condition where increased stomach problems as well as biliary duct obstruction

-24GB 288292 B6 jaundice and increased bilirubin levels. Then dr. Falk increased the treatment doses of hyaluronic acid up to a total dose of 500 to 600 mg of hyaluronic acid divided between drugs. The patient was further treated with the same doses of the above drugs.

Before the May treatment in February 1989 dr. DMSO was used as carrier / penetration reagent together with MNS. Increased amounts of chemotherapeutic agents including 5FU, leucovorin, mitomycin C and methotrexate were used and treatment continued in July and August, when novantron was also used for tumor progression.

While the patient's condition initially deteriorated, a gastrointestinal examination conducted on September 7 showed that the patient's gastric bypass was completely clear, while previously the patient had reversed all oral intake. His condition improved evenly.

Because the patient was previously given the same drugs, the improvement in his condition must be attributed to higher doses of the carrier, allowing better penetration of the drug by scar tissue and fibrotic tumors at this stage generally fatal.

Following:

Unfortunately, the patient later died as a result of tumor necrosis and scar tissue, not cancer.

Case X

The patient was diagnosed with hepatoma over two years old. In the last 18 months, the tumor has been stable, possibly with minimal growth. After low-dose chemotherapy, the patient developed a complete response. Its alkaline phosphatase value was 150 international units and also the remaining liver tests were essentially normal. Ultrasound examination revealed no distinct tumors anywhere in the liver. The patient is now treated with dr. Falkem every 2 to 3 months.

Following:

The patient still feels good.

Case XI

The patient underwent infusion chemotherapy on 15 June 1989 with the addition of hyaluronic acid. Hyperthermia was then applied. Multiple hepatic metastases from breast cancer non-responsive to tamoxifen, an estrogen blocking agent, have previously been identified.

After a single infusion after only 8 hours, the patient showed a complete response. Ultrasound examination showed no tumors in the liver, and the patient's liver function tests were normal.

At present, there is no need to continue treatment with tamoxifen to block estrogen receptors.

Following:

The patient experienced relapses after vaginal estrogen cream (tamofiphene) was administered by another doctor for vaginal irritation. To suppress, the patient was administered 300 mg of indomethacin in 300 mg of hyaluronic acid per day. Now the patient is in remission.

-25GB 288292 B6

Case ΧΙΑ

This patient had massive uterine leomyosarcoma removed on March 26, 1989. Residual tumor debris was detected in the patient by CAT examination. Dr. Falk treated the patient with a combination of hyperthermia and very low doses of methotrexate administered intraperitoneally with the carrier / penetration agent - hyaluronic acid, using a glucose transport protein blocking agent - phloretine, also with hyaluronic acid and alpha II interferon administered intraperitoneally in combination with hyaluronic acid.

Sequential CT examination showed a significant improvement in patient size in terms of tumor size. Since soft sarcoma tissues are very resistant to all forms of therapy, this case can be described as having an unusual response and in all likelihood this effect is associated with the use of a carrier / penetration agent - hyaluronic acid. Dr. Falk now treats the patient approximately every 6 to 8 weeks for two days with the hope that tumor regression will continue. If this happens, it may be considered to close her colostomy in about 6 months.

Following:

Tumor increased somewhat. The patient was treated with vitamin C (50 mg daily), indomethacin (300 mg daily) in 300 mg hyaluronic acid. The patient feels much better.

Case XIB

The patient initially received relatively low doses of methyl CCNU and carboplatin with methotrexate, injected into inguinal relapsing melanoma. All of these were administered in a carrier / penetration agent - hyaluronic acid. In addition, the patient received a glucose transport blocking agent developed by dr. Falkem. This substance is called phloretin and has been used for many years. Phloretin was solubilized in a special solution and also administered with hyaluronic acid to increase the penetration of this substance into the tumor. Dr. Flak then treated the patient with hyperthermia using both capacitive and inductive radiofrequency hyperthermia and microwave hyperthermia. In addition, the patient received immunostimulants, of which dr. Falk assumes that they are beneficial, but only in conjunction with other drugs.

In the last two treatments, the patient received only carboplatin with hyaluronic acid, phloretin with hyaluronic acid, and methotrexate now administered intraperitoneally at a low dose of 25 to 35 mg, again in hyaluronic acid.

After a tour of dr. The patient was treated with gals for 2 days. Clinically in excellent condition. She has only painful problems on her right back. Examination gave the impression that pain could be caused by the right kidney. Ultrasound examination of the kidneys indicated adipose mass in the right kidney, which was interpreted as either mamartoma or even angiomyolipoma.

Due to the very successful reaction of the patient dr. Falk considered it important to do CAT abdominal recording. There were still small cystic lesions in the right liver lobe, but the liver functions of the patient are already normal.

Following:

This patient is now completely in remission.

-26GB 288292 B6

Case XII

At the time of the initial abdominal surgery, the patient had an arterial and subcutaneous entry. After a visit to dr. Permanent redness and swelling around the subcutaneous entry were noted. The patient had feverish conditions and elevated leukocyte levels.

A 14G plastic cannula was introduced into this area and 75 ml of pus, which after cultivation gave E. coli and Pseudomonas aeruginosa, was aspirated. Dr. Falk treated the patient by rinsing the site with a combination of hyaluronic acid with ampicillin, hyaluronic acid with flagyl, and hyaluronic acid with ceflosporin. Thus, the wound was washed daily with 1 g ampicillin with 50 mg hyaluronic acid, 500 mg flagyl with 50 mg hyaluronic acid and 1 g Ancef with hyaluronic acid. During the first 2 to 3 days of rinsing treatment, it was still possible to continue aspirating the digested fluid from the subcutaneous sites. After five days, the fluid was not festered and no residual infection was detected at the end of the week. The introduced inputs were kept in office for a further three months.

This example shows how different bacterial agents with added hyaluronic acid penetrate better at the site of infection and it can also be assumed that the penetration of these substances into the actual bacteria has improved.

Case XIII

The patient was operated on June 1, 1989 and resection of a part of the rectum, sigmoid colon and small intestine was performed. On the seventh day after the operation, swelling and swelling were observed in the surgical site and surged fluid was aspirated from two sites. Thereafter, the patient was treated with topical washings using 1 ampicillin together with 50 mg hyaluronic acid and 500 mg flagyl together with hyaluronic acid. Both areas were cleared of bacterial contamination within 4 days. The usual time required for treatment was of the order of many weeks.

Case XIV

A breast cancer patient had an infected Hickman entry. This is a plastic catheter inserted into the subclavian vein for a long time. This infection was subcutaneous, with festering fluid emerging from the plastic cannula entry site. In this case, dr. Falk injected 1 g of ampicillin and 50 mg of hyaluronic acid just next to the plastic catheter. The infection subsided and the catheter was left in place for 4 days.

Case XV

This patient developed an abscess in the upper right abdominal quadrant, the anterior abdominal wall. Drainage was performed in the hospital but treatment was problematic. Dr. Falk cleaned the abscess and started washing daily with 500 mg ampicillin and 200 mg hyaluronic acid. Since the abscess was drained, it could be assumed that it was cured, but over a longer period of time.

Staphylococcus aureus and E. coli were found in the abscess.

After two days of rinsing with ampicillin and hyaluronic acid as described, the cavity was cleaned, cleared of infection and started to granulate. Dr. Falk continued the treatment for a week and the healing was satisfactory.

-27GB 288292 B6

In other patients suffering from acute oral herpes inflammation, alpha 2-interferon combined with hyaluronic acid was administered and herpes inflammation subsided rapidly.

In another psoriasis patient, methotrexate was topically administered in a carrier of hyaluronic acid. The medicine was absorbed and the psoriasis subsided.

An additional 10 patients with herpes simplex types I and II received an effective amount of nonoxynol-9 (nonylphenoxypolyethoxyethanol) (Delfen ™) combined with hyaluronic acid and / or its salts 2 to 3 times a day to provide immediate disappearance. symptoms (pain) and disappearance of lesions.

In at least two patients suffering from herpes zoster (shingles), an effective amount of nonoxynol-9 combined with hyaluronic acid and / or its salts was administered. This treatment was successful for herpes zoster.

Case XVI

A dentist aged 51 years suffering from melanoma developed acute herpes zoster in the 9th thoracic dermital in the left half of the body. He had unbearable pain that did not subside after classical treatment. Dr. Falk ordained oral administration of cyclofur as an antiviral, but the patient did not immediately take it. However, dr. Falk also ordered the administration of "Delfen ™" and hyaluronic acid "LifeCore ™", mixed in equal proportions and administered topically. The patient did this and the immediate pain relief came within 5 minutes. The pain was not present for another 4 days. In addition, herpes zoster lesions began to disappear immediately within the first 24 hours and are now not apparent after 5 days. This is a successful reaction which results in a marked antiviral effect of this combination with hyaluronic acid, which apparently increases penetration.

Case XVII

This man had developed gastric cancer metastasizing to the liver. He was treated for seven months with low doses of chemotherapeutic agents (5 FU), low doses of mitomycin and novantrone with varying amounts of hyaluronic acid and vitamin C (50 g per day). Tumors were then not detected. Now the patient is in remission and all tumors are calcified.

Case XVIII

This patient had a serious car accident and shortly afterwards he developed colon cancer that was operated but had multiple liver metastases. The patient came to Dr. Falk in June 1989. He was treated with chemotherapy (phloretin with hyaluronic acid) and thermal therapy. His condition was stable for about one year and then his alkaline phosphatase values began to rise. Then dr. Falk treated the patient with vitamin C (50 g daily for three days), hyaluronic acid (up to 300 mg daily), indomethacin in N-methylglucamine (300 mg daily in 300 mg hyaluronic acid) and Toradol ™ (60 mg) once or twice daily together with hyaluronic acid (50 mg). Since then, his condition has improved. Alkaline phosphatase values have decreased and therefore its liver functions are better.

Case XIX

This 46-year-old man has been diagnosed with difficult-to-treat bronchial alveolar lung cancer in the last three months. Despite the use of chemotherapy and larger doses

Certain indications of skeletal attack were evident in two areas, one side of the chest and one side of the chest.

The patient then visited the Cardiopulmonary Transplant Center in London, where they considered that the transplant might be appropriate, but the waiting period was about one year.

Then the patient visited the clinic of Dr. Frederick Douwe in Germany, where he has undergone many treatments, which essentially include: a) immunologically elevating T-cell levels, and b) free radical removal and detoxification.

With this treatment, his condition improved somewhat as treatment was initiated when the patient was breathless and such a condition was 24 hours prior to initiation of treatment.

The examination showed a significant restriction of air access on both sides of the entrance with bilateral murmurs and supraclavicular adenopathy was not found, neither skeletal pain at these sites nor liver enlargement was found.

Then the patient visited dr. Falka, who started to treat him with vitamin C (50 g), a non-steroidal indomethacin (NSAID) (100 mg - a dose reduced from the original 300 mg for heartburn) dissolved in hyaluronic acid (300 mg). After the first 5 days of treatment, his condition improved significantly with respect to lung capacity and radiographic results.

Dr. Falk then prescribed daily injections of hyaluronic acid (300 mg) with Toradol ™ (60 mg), to be given at home (meaning outside Canada).

Comparison with previous examinations was performed. In contrast to previous examinations, there were signs that the lungs were now clearer than they were before. However, increased interstitial signs in both lung lobes are still evident.

Case XX

A 74 year old female patient was diagnosed with colon cancer and resected. Unfortunately, the cancer metastasized to the liver (right lobe). During the month, the patient was treated twice with methotrexate (25 mg) in hyaluronic acid (400 mg) intraperitoneally, five times with oncostatin (2 g) in hyaluronic acid (300-500 mg), vitamin C (50 g) in hyaluronic acid (300 mg) and indomethacin (NSAID), 100 mg indomethacin in 300 mg hyaluronic acid and 250 mg indomethacin in 500 mg hyaluronic acid were administered twice.

The patient is now in very good condition, feels better and the liver tumor has resolved (shrunk).

Case XXI

This 51-year-old female patient was diagnosed with uterine cancer that spread to the lungs (leicomyosarcoma). Dr. Falk treated the patient with various doses of oncostatin (from low doses of 0.5 g to 3 g) with hyaluronic acid (300-500 mg), vitamin C (50 g) in hyaluronic acid (300 mg) and indomethacin in hyaluronic acid (intraperitoneally and intravenously) filed).

The pelvic mass has receded and the lungs are stable.

-29GB 288292 B6

Case XXII

A man aged 52 years suffering from Crohn's disease and chronic intestinal infection due to the disease eventually developed a peritoneal tumor (adenocarcinoma). The patient was treated with doses of 2 g and 3 g of Oncostatin ™ (phloretin), each dose in hyaluronic acid (500 mg) and DMSO (total 2,000). Patients were also dosed with indomethacin ranging from 75 to 450 mg in 200 to 700 mg hyaluronic acid. The patient was also treated with vitamin C (50 g) in hyaluronic acid (300 mg) and naproxon (1 g) in hyaluronic acid (400 mg). This treatment was performed in several different ways, interaperitoneally, intravenously, rectally (for detoxification) (catheter insertion and rectal administration). The pain now subsided.

The patient was subjected to abdominal and pelvic CT scans. Mild hepatic steatosis was evident with no evidence of metastasis. The spleen, pancreas, adrenal gland and right kidney were normal. Left tubular nephrotomy was found without evidence of residual hydronephrosis. A large necrotic tumor was detected, occupying most of the space of the small pelvis with anterior bladder displacement, probably affecting the prostate. No sacral destruction was detected although the rectal tumor closely touches the anterior surface.

The examination shows a large necrotic tumor in the pelvis without signs of sacral destruction, para-aortic lymphadenopathy or distal visceral metastases. The left percutaneous transrenal ureteral stent is suitable.

The patient was examined on August 1, 1990 at the clinic and feels very comfortable. Its condition is exceptionally good, and the size of the tumor necrosis mass is slowly reduced.

Case XXIII

A patient aged 47 years was diagnosed in January 1990. Gastric resection and esophageal intestinal replacement (for nutrient uptake) were performed. The patient also developed an intraperitoneal tumor. She went through chemotherapy and lost her hair (Dr. Falk gave her minoxidil and hyaluronic acid, which he applied to bare skin and hair started to grow again). Dr. Falk examined the patient on June 6, 1990, treating her with low doses of phloretin along with hyaluronic acid and heat, indomethacin in hyaluronic acid and vitamin C in hyaluronic acid.

The patient showed a significant improvement since this treatment. She gained weight and no longer feels pain. The carcinoembryotic antigen has values below 26 nanograms / ml and keeps decreasing.

Case XXIV

The patient (age 45 years) was first examined by dr. By March 1, 1988, a pancreatic cancer diagnosis was made. It was treated with DMSO and heat along with low doses of chemotherapeutic agents. Dr. Falk injected DMSO and other drugs directly into the tumor. More than one year later, the patient underwent vitamin C and other hyaluronic acid medications. The patient is now completely in remission. He has not been treated for more than six months.

Case XXV

Dr. Falk examined this patient at the age of 62 in August 1989. The woman was diagnosed with pancreatic cancer, treated with low-dose chemotherapeutic agents (5-FU and mitomycin) along with 300 mg of hyaluronic acid and heat. The patient had problems with the bile ducts. It was therefore operated but the tumor was not detected and bile duct by-pass was performed. The patient was then

-30EN 288292 B6 treated with indomethacin and vitamin C in hyaluronic acid, and thermal treatment was discontinued. Since this treatment, weight gain has been reported and there is no symptom of developing tumor.

Case XXVI

A 18 year old patient was treated for infectious mononucleosis. After three months, the patient showed positive heterophilic antibody tests. The patient is without energy. The patient was given 50 g of vitamin C and 300 mg of hyaluronic acid. Within sixteen hours after treatment, her energy increased significantly and after two weeks her tests for heterophilic antibodies were negative.

Case XXVn

The case of this 65-year-old patient is characterized by several points. Her previous chemotherapy did not recognize that most of the tumor had already been destroyed. Prior to that, she received chemotherapy. As he now assessed the situation dr. Falk, as the tumor was disrupted, had water and fluid retention in the tumor area (the patient was to be examined by ultrasound). After a tour of dr. Falka was started with heat, phloretin, vitamin C, indomethacin and partly 5-FU, in all cases the drugs were hyaluronic acid. (According to previous doctors, the patient had an enlarged tumor after administration of 5-FU. Therefore, chemotherapy was discontinued). The patient now looks good, feels better and has no swelling.

Case XXVIII

This patient had ovarian cancer intermittent to complete intestinal obstruction while surrounding the intestines with a tumor and a significant amount of pleural fluid. The most notable case of the effects of Lasix (furosemide) occurred in the following circumstances. On April 28 and 29, 1990, the patient's total excretion volume was 2 x 450 ml of urine in 48 hours despite receiving a solution of 0.33% sodium chloride supplemented with 40 meq / l of potassium administered at a dose of 100 to 125 ml per hour. The patient's total weight was 40 kg. During this time, the patient received 120 to 200 mg of Lasix administered intravenously.

On April 30, the patient received 40 mg of Lasix supplemented with 350 mg of hyaluronic acid, which was administered within half an hour. Over the next 5 hours, diurea appeared with 2,500 ml of urine. During the evening without further administration of Lasix, diurea decreased significantly and the patient excreted only 460 ml of urine from 7.00 in the evening from 30 April to 7.00 in the morning on 1 May. At 7.30 am she received 40 mg of Lasix in 300 mg of hyaluronic acid, which was administered intravenously. Over the next 8 hours, the patient excreted 2,600 ml of urine. This case demonstrates that even the relative insensitivity to furosemide (Lasix) can be overcome by the addition of hyaluronic acid to increase drug penetration into the site.

A similar phenomenon was observed by the inventors in patients who had the so-called "hepatorenal syndrome" and where renal function and urinary excretion were stopped due to the respective liver function failure. Under these circumstances, urinary excretion may be zero. This can be significantly influenced by furosemide (Lasix ™) administered intravenously in hyaluronic acid, even if furosemide (Lasix ™) administered alone does not produce any effect.

Case XXIX

In normal healthy subjects, the addition of hyaluronic acid to furosemide (Lasix ™) with 20 mg intravenous administration with 300 mg hyaluronic acid was observed to increase urinary excretion 3 to 5 times compared to administration of furosemide alone (Lasix ™). Case

-28GB 288292 B6 is reported as evidence that hyaluronic acid increases drug penetration / permeation and thus affects their function.

Case XXX

A patient with baldness was given minoxidil (Rogain) topically on his baldness. There was minimal or little hair growth. Thereafter, minoxidil was co-administered with hyaluronic acid continuously every 2 to 3 days. The result was more complete and faster hair growth.

Case XXXI

A 32-year-old female patient was diagnosed with epithelioid sarcoma based on a set of Mayo clinics.

A history of her illness should return to December 1978, when she developed a knotted swelling of the left ring finger, which was removed. She had recurrent conditions of this type and left fourth finger amputation. Her condition has been extensively investigated since it was found that a nodular swelling of the same type of disease has a patient on the upper arm and a biopsy of the left axillary lymph nodes performed in March 1990 was positive for epithelioid sarcoma.

At Mayo Clinic, the patient underwent three chemotherapeutic treatments using mitomycin C, adriamycin, cisplatin at high doses, without any response. Amputation of the arm and forearm due to sarcoma has been suggested.

The patient was first examined by dr. Falko on June 25, 1990 and was treated for three days with heat, phloretin - hyaluronic acid, vitamin C - hyaluronic acid, methotrexate - hyaluronic acid, and was also given sol-medrol. At this time, there was no visible response to this treatment and the lesions remained the same.

The patient returned on July 23 and was treated for the next three days with doses of phloretin, the same doses of vitamin C - hyaluronic acid, and also received naproxen and indomethacin with hyaluronic acid, administered both subcutaneously and intravenously. Upon returning home, she was given Toredol ™ (Syntex - a non-steroidal anti-inflammatory drug) intramuscularly, daily, at a dose of 30 to 120 mg, administered once or twice daily with Kyal Pharmaceutical hyaluronic acid at a dose of 100 mg.

Patient status was re-evaluated on August 20 and a significant reduction in all measurable signs of the disease by more than 50% was found. In fact, a biopsy would only show at this stage if any viable tumors are present. The treatment plan suggested continuing administration of Toredol ™ and hyaluronic acid.

While the patient had minimal response to thermal therapy, phloretine treatment, conventional chemotherapy with the addition of hyaluronic acid to these drugs, the patient had an excellent response to non-steroidal anti-inflammatory drugs of all three types, Indocide ™, naproxen and Toredol ™ when combined with hyaluronic acid as carrier. / a penetration vehicle allowing pathological tissue to be obtained. The patient had one or more of the standard side effects that occur with non-steroidal anti-inflammatory drugs.

-32GB 288292 B6

Case XXXII

The patient was diagnosed with gastric cancer in 1988. The tumor was spread to one third of the esophagus of the gastroesophageal junction. The Celestine tube was inserted by intraoperative abdominal procedure and sewn to a lesser stomach curvature.

The patient was then treated from January 1990 for 3 months (until June 1990). Repeated CAT images showed no changes in condition, but symptomatically his condition was quite good. The last CAT record was made on June 26, 1990. There were questions about certain areas of the liver, but sonographic examination showed that the liver was in fact homogeneous.

On July 4, the patient ingested several hot dogs at a picnic. He woke up during the night with acute pain in the upper left quadrant that was not associated with nausea or vomiting. After this incident, he suffered pain every time he ate any food. The pain was always the same, felt in the back and front of the abdomen, with a tendency to penetrate both abdominal sides. It was not associated with any direct peritoneal pain, vomiting, diarrhea or fever and freezing. The examinations included a previous CAT record made just eight days before the onset of pain and a subsequent series of GI examinations. Therefore, further CAT examination could not be performed because the patient had many barium.

Importantly, significant doses of Demerol alleviated the patient's pain only slightly. Further examinations indicated nothing. No abdominal, thoracic, or lymph nodes were found to indicate disease spread.

Dr. Falk assessed the radiographs together with a professor at the Radiology Department, Toronto, General Hospital, University of Toronto. He concluded that the upper part of the GI tract was a classic image of the "clamping" of the small intestine. He stated that this could be either due to fibrous adhesions or neoplasms or, in fact, a combination of both as is very common in gastric adenocarcinoma. However, the necessary signs of neoplasms were minimal as shown in previous CAT records.

Dr. Falk treated the patient with a combination of non-steroidal anti-inflammatory drugs administered intravenously with hyaluronic acid, in conjunction with hyperthermia and oncostatin, a combination of phloretin and hyaluronic acid, and managed to achieve an almost immediate relief of pain. The patient can now eat without the symptoms mentioned above (he has lobster soup in one of the local restaurants).

Dr. Falk also prescribed probanthin for the patient as the type of pain associated with these types of adhesions usually disappears when cholinergic drugs are administered. Dr. Falk also suggested further therapy after returning home, consisting of a combination of 10 mg b.i.d. and, for example, 500 mg directly administered as a suppository once daily and zantacu 150 mg twice daily.

In addition, Dr. Falk vibamycin (doxycycline) 200 mg daily for one day and 100 mg daily for a fortnight. This substance has antibacterial effects and also blocks intracellular and anerobic glycolysis.

Following:

At the same time a biopsy showed chronic inflammation of the lower one third of the esophagus (the esophagus tube was removed), but no signs of malignancy were found.

-33GB 288292 B6

Case XXXIII

In this patient, the main tumor was disrupted, which was manifested after discontinuation of chemotherapy from the treatment cure. Initially, he was much more aggravated, to a lesser extent, reflected in values such as liver tests. His alkaline phosphatase values began to increase. He suffered from nausea, weakness, excessive fatigue and anorexia. Correction treatment was performed by intensive administration of indomethacin in hyaluronic acid and detoxification treatment.

At the next inspection his condition was much better. Ultrasound revealed that the tumor did not completely necrotize. An increased presence of normal liver tissue was detected.

Case XXXIV

This patient had a chronic abscess in the pelvic cavity with bowel obstruction, which necessarily led to an operation performed on January 5, 1990. The pelvic cavity was washed and aspirated through the perineum. The postoperative course was without complications and the patient was discharged from the hospital on January 18, 1990.

However, fever subsequently developed and due to the presence of a large cavern in the pelvis, suction was managed through a large anterior portion of his abdominal immission. This occurred two weeks prior to the patient's current visit.

Dr. Falk inspected the patient. He searched for a large cavern and determined that it could close after 4 to 6 weeks. Dr. Falk determined daily washes during the five-day working week with ampicillin, flagyl and hyaluronic acid using 500 mg ampicillin and 500 mg flagyl. It was a very benign form of treatment compared to the one that dr. Falk usually uses open areas for rinsing and closing.

At a later inspection, the abscess cavity was closed. The patient reported that the nurse who was treating him during the weekends had trouble inserting the catheter into the cavity on Saturday and Sunday and in fact failed to insert the catheter. Dr. Falk noted that the cavity had granulated from the "opposite side" and that it had happened much more quickly than expected. Given that it was a chronic cavity in a patient with chronic and continuing pelvic disease, this is a clear and unexpected result with a much faster and better examination of the cavity condition of the chronic abscess than expected.

Dr. Falk instructed the patient to inform him when the temperature came. The patient suffered from a mild itching of the skin, of which dr. Falk believes that this is due to the cold reaction, to which he prescribed ointment for daily application.

Case XXXV

The patient had lesions of the 9th and 12th nerves that were located laterally in the skull. It was also believed that it may have metastasis in the area of tooth formation and was therefore subjected to MRI examinations to verify this assumption. There have been some abnormalities in this area. CT recording of this area did not help resolve the case.

The patient then came to The Ontario Cancer Treatment and Research Foundation, where a highly developed malignant melanoma was detected and was discharged from the hospital with a hopeless prognosis.

Much later, Ontario Cancer Treatment and Research Foundation staff were surprised and pleased to find that the patient responded incredibly well both mentally and to

-34EN 288292 B6 treatment dr. Falka. This included hyperthermia and chemotherapy in hyaluronic acid. Dr. Falk took the usual doses of Carboplastin and low doses of methotrexate in hyaluronic acid.

Her chest seemed clean, but she had some persistent changes in her kidneys and liver, but they could easily be controlled. During the summer, the state of the language improved, which was no longer deflected to the side. Unfortunately, her condition has worsened over the last three or four weeks.

At the current examination, the neurological examination was completely normal, except for an incomplete septum on the left side of the pharynx, problems with fasciculation and atrophy of the left side of the tongue.

The patient is in remarkably good condition.

Following:

The patient was now given hyaluronic acid (300 mg daily), NSAIDs and vitamin C (50 g daily).

The patient appears to be free of tumors.

Case XXXVI

The patient underwent mesothelioma with subsequent surgical removal and assistive treatment. Seven years have passed since the initial diagnosis. This spring, while in Florida, a relapse occurred. Although dr. Falk performed a biopsy three times, and failed once to obtain cells to confirm that it was a malignancy. However, clinically, the situation was clear from CAT examinations, liver tests and ultrasound examinations.

This patient was treated with phloretin in hyaluronic acid and thermal surface treatment. Initially, there was no great response. However, in the latter case, chemotherapy was omitted and the patient received only phloretin in hyaluronic acid, while the dose of hyaluronic acid was high. There was a strong response and fluid storage became the main problem. Dr. Falk assumed that the secondary tumor had disintegrated. Tumor disintegration was clearly evident on sonographic examination, real tumor fluidization was apparent.

At present, the patient was treated for one day with hyperthermia and also received phloridzine in hyaluronic acid. However, his condition required vitamin C in hyaluronic acid for the next two days, which contributes to detoxification. He also received the diuretic Lasix ™ (furosemide) with hyaluronic acid.

Creatinine levels decreased from 400 mmol / l to 155 mmol / l (renal function test - decreased from high to near normal). Dr. Falk instructed the patient to proceed. Dr. Falk did not assume that the patient's condition required more therapy as he believed that most of the tumor had already been disrupted by its own immune response and hyaluronic acid by allowing antibodies and soluble mediators to enter the tumor.

In July 1990, there was a slight dropout (fluid in the body). The patient received furosemide (Lasix ™) and hyaluronic acid, indomethacin and hyaluronic acid. The patient's urine excretion increased and his condition was resolved.

Case XXXVII

The 37-year-old patient had cervical cancer that was classified as Class IIIB at the time of diagnosis. She was treated with radiation at the Cross Cancer Center but unsuccessfully since about 1 to 2 months after

Further tumor growth was detected by radiotherapy. The patient was then examined by dr. Waldem of Sauld Ste. Marie. The patient was treated with epirubicin and cisplatin at high doses that induced tumor regression as determined by intravaginal examination and biopsy, but there were new and worse pains associated with partial ureteral obstruction as shown by a CT scan of the abdomen and pelvis on June 28, 1990.

In laparotomy, a large tumor was found to be largely necrotized but expanding and involving the left common hip artery and vein and causing vein obstruction, and the tumor was assessed to be surgically inoperable due to its lateral extent and adherence to the pelvic wall. The condition was assessed by a urologist and two oncologists.

For these reasons and due to imminent rectal obstruction, a colostomy was performed. In addition, the urologist conducted ileal guidance.

The patient suffered unbearable pain several weeks before and after surgery. Therefore, it was necessary to administer intravenously high doses of morphine with only limited pain.

On June 8, a feverish reaction was detected and CAT examination on the same day showed an abscess in the left pelvis. It was drained under the localization of CAT and the patient was systematically under antibiotics, with her symptoms of infection showing only a slight improvement.

The patient was brought by dr. Falka on Wednesday 11 July. The patient received 1 g of ampicillin through a drainage catheter in abscess together with 500 mg of hyaluronic acid. In addition, she received 1 mg ampicillin intravenously and ancef and flagyl systemically in 500 mg of hyaluronic acid "LifeCore ™". Within 12 hours the pain subsided significantly, all symptoms of the infection were eliminated and drainage drainage from the abscess cavity almost ceased. Her massively enlarged left leg, as a result of venous and lymphatic obstruction, improved to an almost normal size within about 12 hours.

The patient underwent another treatment of the same type for the next three days, resulting in overall pain relief and continued improvement of her condition, leading to hospital discharge on July 18 without antibiotic therapy. Systemic analgesia with morphine-type substances has also been abandoned. The patient has not received hyperthermia or cell chemotherapy and / or Oncostatin (phloretin) therapy. Antioxidant therapy with hyaluronic acid was continuously applied with indomethacin in hyaluronic acid. The case of this patient demonstrates a very successful improvement of the condition and emphasizes that the use of indomethacin - hyaluronic acid is targeted specifically to pathological tissue in improving macrophage function in this tissue and allows the body's immunosystem to perform appropriate tumor destruction.

Case XXXVIII

A patient suffering from HIV (AIDS) has been treated with indomethacin (NSAID), vitamin C, interferon and DMSO and / or hyaluronic acid, and the patient's condition is unexpectedly improving steadily.

Case XXXIX

The patient suffered from cyposis and the resulting back pain. Oral administration and use of back lubricants caused little pain relief. The use of NSAIDs in hyaluronic acid (sodium hyaluronate) applied directly to the back caused the relief of pain in the back.

Indomethacin (dissolved in N-methylglucamine) and naproxen, both dissolved in hyaluronic acid, experienced adverse reactions in the patient. Using Toradol ™ (+/- forms of ketorolac tromethamine salt) - an inhibitor of prostaglandin synthesis,

However, the analgesics and anti-inflammatory agents have subsided and the pain has subsided and disappeared for some time without side effects.

Case XL

This patient has been diagnosed with HTV (AIDS) and, as a possible consequence of this disease, unspecified neoplasms in the lungs. Prior to treatment, the patient was almost fatal, with a white blood cell count of 1.4 χ 10 ⁹ / liter. The patient was treated intravenously with indomethacin (300 mg), vitamin C (50 g daily) and hyaluronic acid (sodium hyaluronate) (300 mg). After treatment, the platelet count increased to 65 χ 10 ⁹ / liter and the white blood cell count increased to 8.2 χ 10 ⁹ / liter.

The number of lymphocytes doubled.

Other animal tests

Further tests were performed on animals (rats) with the following conclusions.

Increased effectiveness of antibiotics with hyaluronic acid. A chronic abscess model in rats was used. Sprague Dawley rats were used. Pellets of 20 bacteria were introduced into each rat tummy and treated as indicated. In this arrangement, the therapeutic efficacy of gentamycin was compared to gentamycin in hyaluronic acid and the experiment showed a significant improvement in the combination to the antibiotic alone. In this respect, lower doses of the antibiotic were possible in cases where the antibiotic did not work due to the administration of the antibiotic with hayluronic acid.

Comparison of abscess size (gm) (day 7)

N »9 σ, 4 »» 10 r, 3 X »« 9 Q _t 2 N-10

1.

3 · 4 ·

1. Gentamycin + HA (Cido)

2. Gentamycin (Cido)

3. HA

4. Control x _P 0.05, vs. Cido and HA (LSDMRT, Dunken)

-37GB 288292 B6

Gentamycin (Cido) and / or HA were injected IM, BID 5 days after surgery

Cido: 2 mg / kg / day (3 mg / kg / day for humans)

HA: 4 mg / kg / day (equivalent to 280 mg / day for a 70 kg human)

In other animal tests, rats of the ACI strain (black) set against Lewis strain (white) rats were found to have an increased survival time using a combination of immunosuppressors and hyaluronic acid administered to Lewis strain rats. The survival of the grafts depends largely on the ability to suppress rejection by immunosuppressive agents, and the optimal concentration of these agents is rarely achieved because their effective concentration at the graft site is not achieved, the combination of the agent with hyaluronic acid overcomes this difficulty. The combination of a specific agent with hyaluronic acid achieves an optimal immunosuppressive / graft survival relationship. A standard rat graft rejection model was used. Ciclosporin was used as an immunosuppressive agent. The results show that hyaluronic acid significantly increases cyclosporine-induced graft survival.

Graft survival in various treatments (July 12, 1990)

CYA + HA # days CyA # days 1 20 May 7 20 May 2 19 Dec 8 20 May 3 19 Dec 9 20 May 4 20 May 10 19 Dec 5 19 Dec 11 19 Dec 6 20 May 12 20 May 13 21 20 May 19 Dec 14 19 Dec 21 17 15 Dec 18 22nd 14 16 20 May 23 14 17 20 May 24 14 18 20 May 25 19 Dec 19 Dec 20 May diameter 19,615 17,917 SE 0.213 0.725

CyA + HA vs. CyA = P value, one-way ANOVA = <0.05 (= 0.0287) LSDMRT = <0.05

CyA = cyclosporin HA = hyaluronic acid.

Since many changes can be made in the present invention without departing from the scope of the invention, all examples herein are intended to be illustrative and not limiting.

PATENT CLAIMS

Claims (124)

Use of hyaluronic acid compounds selected from hyaluronic acid and / or its salts and / or hyaluronic acid homologues for the manufacture of a combination therapeutic agent for the treatment of diseases or conditions of tissues including poorly perfused tissues and pathological tissues of a human. -38GB 288292 B6 Use according to claim 1, wherein the hyaluronic acid compound is used in combination with at least one medical and / or therapeutic agent selected from the group consisting of free radical scavengers, ascorbic acid, vitamin C, anticancer agents, chemotherapeutic agents, antiviral agents, non-steroidal agents anti-inflammatory drugs, steroidal anti-inflammatory drugs, antifungal agents, detoxifying agents, analgesics, bronchodilators, antibacterial agents, antibiotics, medicines for the treatment of vascular ischemia, monoclonal antibodies, diuretics, immunosuppressants, lymphokines, α- and β-beta-progesterone antimetabolites, calcium channel blockers and drugs for the treatment of psoriasis. Use according to claim 1 or 2, wherein the disease or tissue condition to be treated is selected from the group consisting of abscesses, acne, AIDS, arthritis, auto-aggressive disease, Berger's disease, brain injuries such as edema, conditions and diseases requiring bronchodilation, cancer, cancer. malignant melanomas, acute herpetic gingivitis and oral mucosa, carcinomas, cancer metastasis, chronic bacterial infections, chronic fungal infections, connective tissue diseases, Crohn's disease, tissue degeneration, conditions and diseases requiring detoxification, diabetes, viral diseases, edema, epitheloid sarcomas, hair loss, herpes simplex, herpes zoster, hypertension, implantation-related conditions, infection, inflammatory conditions, insufficient perfusion and / or poor kidney function, kyphosis, lameness, leomyosarcomas, leukemia, poor nutrition consequences, massive damage, mesotheliomas, metastatic liver disease, mononucleosis, neop lastic disorders, neoplasia, pain, post-menopause, prostaglandin synthesis, psoriasis, kidney failure, respiratory problems, retroviral diseases, swelling, conditions associated with organ and tissue transplantation, tumors and vascular ischemia in man. Use according to any one of the preceding claims wherein the hyaluronic acid compound is hyaluronic acid and / or a salt thereof. Use according to any one of the preceding claims wherein the hyaluronic acid compound is sodium hyaluronate. Use according to any one of the preceding claims, wherein the medicament consists of a hyaluronic acid compound and a medicinal and / or therapeutic agent. Use according to any one of the preceding claims, wherein the combination therapeutic composition is in the form of a dosage form for intravenous or intramuscular administration. Use according to any one of claims 1 to 6, wherein the combination therapeutic composition is in the form of a dosage form for topical administration. Use according to any one of the preceding claims, wherein the hyaluronic acid compound is present in an amount of 10, preferably 50 to 1000 mg, based on the unit dosage form. Use according to any one of the preceding claims, wherein the hyalumic acid compound is present in an amount ranging from 50 to 1000 mg, based on the unit dosage form. Use according to any one of the preceding claims, wherein the hyaluronic acid compound is present in an amount above 200 mg, based on the unit dosage form. Use according to any one of the preceding claims, wherein the medical and / or therapeutic agent comprises an agent selected from the group consisting of free radical scavengers, ascorbic acid, vitamin C, anti-cancer agents, chemotherapeutic agents, antiviral agents, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, antifungal agents, detoxifying agents, analgesics, antibacterial agents, antibiotics, drugs for treating vascular ischemia, diuretics, immunosuppressants, drugs for psoriasis, and combinations thereof. -39GB 288292 B6 Use according to any one of the preceding claims, wherein the medical and / or therapeutic agent comprises a non-steroidal anti-inflammatory drug. Use according to any one of the preceding claims, wherein the medical and / or therapeutic agent comprises an agent selected from the group consisting of ascorbic acid, anti-cancer agents, non-steroidal anti-inflammatory drugs, antibiotics, diuretics and combinations thereof. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of psoriasis, a therapeutically effective amount of methotrexate. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for administration to a human, a cytotoxic chemotherapeutic agent selected from adriamycin, methotrexate. , mitomycin C, bleomycin, 5-fluorouracil, novantrone, carbo- and cis-platinum and combinations thereof. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for administration to a human, an agent selected from the group consisting of phloridzine, phloretin and 5. phloridzine deoxyglucuronide and combinations thereof for competitively blocking glucose transport to neoplastic cells and an agent selected from the group consisting of vitamin C, non-steroidal anti-inflammatory drugs and combinations thereof, wherein when the agent selected is phloretin, it is solubilized by a solubilizing agent. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising a bronchodilator in a form suitable for administration to a human. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for administration to a human, α- or βinterferon. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for administration to a human, a therapeutically effective amount of a diuretic. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for administration to a human, a therapeutically effective amount of a medicinal and / or therapeutic agent selected. from the group consisting of antibiotics and antibacterial agents. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for treating mononucleosis in a human, a therapeutically effective amount of ascorbic acid, i. vitamin C for the treatment of mononucleosis. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for administration to a human, a therapeutically effective amount of an immunosuppressant. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for internal administration to a human, a therapeutically effective amount of a nonsteroidal anti-inflammatory drug. Use according to claim 24, wherein the hyaluronic acid compound is present in an amount above 50 mg, based on the unit dosage form. -40GB 288292 B6 The use of claim 24, wherein the hyaluronic acid compound is present in an amount ranging from 50 to 1000 mg based on the unit dosage form. The use of claim 24, wherein the hyaluronic acid compound is present in an amount above 200 mg, based on the unit dosage form. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for external administration to a human, a therapeutically effective amount of a nonsteroidal anti-inflammatory drug. Use according to claim 24, wherein the hyaluronic acid compound is present in an amount above 10 mg, based on the unit dosage form. The use of claim 24, wherein the hyaluronic acid compound is present in an amount ranging from 10 to 1000 mg, based on the unit dosage form. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for internal administration to a human, a therapeutically effective amount of an antiviral agent. The use of claim 31, wherein the antiviral agent is a nonionic surfactant. The use of claim 31, wherein the antiviral agent is nonoxynol-9. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of diabetes, a therapeutically effective amount of insulin. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for treating postmenopausal women, a therapeutically effective amount of estrogen. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for fertility control, a therapeutically effective amount of progestegen. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a medicament which contains an anti-cancer agent as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic agent comprising as an anti-viral agent as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as an medicinal and / or therapeutic agent an antifungal agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition which contains an analgesic as a medicinal and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising a bronchodilator as a medical and / or therapeutic agent. -41GB 288292 B6 Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic agent comprising as an medicinal and / or therapeutic agent an antibacterial agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic agent comprising an antibiotic as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as an medicinal and / or therapeutic agent an anti-inflammatory agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising a monoclonal antibody as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising an immunosuppressant as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising lymphokine as a medical and / or therapeutic agent. The use of claim 47 for the manufacture of a combination therapeutic composition comprising interleukin-2 as a lymphokine. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic agent comprising interferon as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising ascorbic acid, i.e. vitamin C, as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic agent comprising a free radical scavenger as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as a medical and / or therapeutic agent a chemotherapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as a medical and / or therapeutic agent a nonionic surfactant. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, as a medical and / or therapeutic agent, a non-steroidal anti-inflammatory drug selected from indomethacin, naproxen, diclofenac, (+/-) - tromethamine salt of ketorolac and combinations thereof. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as a medical and / or therapeutic agent a steroidal anti-inflammatory agent. -42EN 288292 B6 Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising a detoxifying agent as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as a medical and / or therapeutic agent a medicament for the treatment of vascular ischemia. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as a medical and / or therapeutic agent minoxidil for topical application to stimulate hair growth . Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising a diuretic as a medical and / or therapeutic agent. The use of claim 53 for the manufacture of a combination therapeutic composition comprising nonoxynol-9 as a nonionic surfactant. The use of claim 53 for the manufacture of a combination therapeutic composition comprising, as a nonionic surfactant, a nonionic surfactant in which the hydrophobic portion of the molecule is linked by a hydrophilic portion of the molecule via an ether or amide bond. The use of claim 54 for the manufacture of a combination therapeutic composition, wherein the non-steroidal anti-inflammatory drug is selected from indomethacin, naproxen, diclofenac, (+/-) - tromethamine ketorolac salt, and combinations thereof. The use of claim 59 for the manufacture of a combination therapeutic agent wherein the diuretic is furosemide. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising insulin as a medicinal and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising estrogen as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as a medical and / or therapeutic agent progestegen. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic agent comprising as an medicinal and / or therapeutic agent an antimetabolite. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising a calcium channel blocker as a medical and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as a medical and / or therapeutic agent a medicament for the treatment of psoriasis. -43GB 288292 B6 Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising indomethacin as a medicinal and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising diclofenac as a medicinal and / or therapeutic agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising as a medical and / or therapeutic agent a (+/-) tromethamine salt of ketorolac. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for treating cancer or AIDS in humans, a therapeutically effective amount of a medicinal and / or or a therapeutic agent selected from the group consisting of ascorbic acid, i.e., vitamin C, non-steroidal anti-inflammatory drugs, and combinations thereof. Use according to claim 73, for the manufacture of a combination therapeutic composition which also comprises interferon. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of cancer, a therapeutically effective amount of a medicinal and / or therapeutic agent selected from the group consisting of ascorbic acid, non-steroidal anti-inflammatory drugs, anti-cancer drugs, chemotherapeutic agents, deotoxifying drugs and combinations thereof. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for treating diseases, a therapeutically effective amount of a medicinal and / or therapeutic agent selected from the group comprising ascorbic acid, non-steroidal anti-inflammatory drugs and at least one agent selected from the group consisting of anticancer drugs, chemotherapeutic agents, and detoxifying drugs. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition which, in a form suitable for the treatment of herpes, gangrene or ulcer disease, in particular the mouth and / or herpes zoster comprises a therapeutically effective amount of a medicinal and / or therapeutic agent consisting of a nonionic surfactant. The use of claim 77 for the manufacture of a combination therapeutic composition comprising, as a nonionic surfactant, a nonionic surfactant in which the hydrophobic moiety of the molecule is linked by a hydrophobic moiety through an ether or amide bond. The use of claim 77, wherein the combination therapeutic agent comprises nonoxynol-9 as a nonionic surfactant. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of renal failure, cardiac insufficiency, hypertension and / or edema an effective amount of a diuretic. The use of claim 80 for the manufacture of a combination therapeutic composition wherein the diuretic is furosemide. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition which, in a form suitable for the treatment of an infection, comprises therapeutically An effective amount of a medical and / or therapeutic agent selected from the group consisting of antibiotics, antibacterial agents, antimicrobial agents, and combinations thereof, optionally in admixture with ascorbic acid. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of acne, a therapeutically effective amount of a medicinal and / or therapeutic agent selected from the group consisting of antibiotics, antibacterials, antimicrobials and combinations thereof, optionally in admixture with ascorbic acid. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition which, in a form suitable for use in organ and tissue transplantation, to reduce the likelihood of rejection, it comprises a therapeutically effective amount of an immunosuppressant and a hyaluronic acid compound in an amount permitting transport of the medical and / or therapeutic agent to the tissues, including scar tissue through cell membranes, into individual cells at the site to be treated. Use according to claim 84, for the manufacture of a combination therapeutic composition comprising cyclosporin as an immunosuppressant. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for treating inflammation, a therapeutically effective amount of a non-steroidal anti-inflammatory drug. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition which is in a form suitable for facilitating the elimination of tumor degradation agents including toxins, residues and debris. from a human body comprises a therapeutically effective amount of a non-steroidal anti-inflammatory drug. The use of claim 87, wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of indomethacin, naproxen, diclofenac and (+/-) - tromethamine salt of ketorolac. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for detoxifying a human, a therapeutically suitable amount of a detoxifying agent. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising a therapeutically effective amount of a bronchodilator in a form suitable for treating respiratory problems in a human. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition which, in a form suitable for use in the treatment of infections surrounding implants in humans, comprises a therapeutic amount of treating the infected tissue surrounding the implant. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of human cancer, a therapeutically effective amount of an agent selected from the group consisting of non-steroidal anti-inflammatory agents, anti-cancer agents, and combinations thereof. 93. The use of claim 92, wherein the combination therapeutic composition further comprises a therapeutically effective amount of ascorbic acid, i.e., vitamin C. -45GB 288292 B6 Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of herpes simplex type I and / or II, a therapeutically effective amount nonionic surfactants. 5 95. The use of claim 94, wherein the combined therapeutic agent as a nonionic surfactant comprises a nonionic surfactant in which the hydrophobic portion of the molecule is coupled to the hydrophilic portion of the molecule via an ether or amide bond. The use of claim 94, wherein the combination therapeutic agent comprises nonoxynol-9 as a nonionic surfactant. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition which in a form suitable for the treatment of herpes, herpes simplex type I and II and / or herpes The zoster comprises a therapeutically effective amount of a surfactant selected from 15 is selected from the group consisting of anionic surfactants, cationic surfactants and combinations thereof. The use of claim 97, wherein the combination therapeutic agent comprises cetylpyridinium chloride as the anionic surfactant and cationic surfactant as the anionic surfactant. The substance contains benzalkonium chloride. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for treating a human disease, a therapeutically effective amount of a nonsteroidal anti-inflammatory agent and a therapeutically effectively 25 amount of chemotherapeutic agent. The use of claim 98, wherein the combination therapeutic composition further comprises a therapeutically effective amount of ascorbic acid, ie, vitamin C. 30 Use according to claim 99 or 100, wherein the non-steroidal anti-inflammatory drug is selected from indomethacin, naproxen, diclofenac and (+/-) - tromethamine salt of ketorolac. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination 35 therapeutic composition which, in a form suitable for the treatment of gangrenous or ulcerative disorders, especially the mouth, contains therapeutically effective the amount of α- or β-interferon. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of pain, a therapeutically effective 40 amounts of a non-steroidal anti-inflammatory drug. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for providing an increase in antineoplastic activity, a therapeutically effective amount of ascorbic acid. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for enhancing antineoplastic activity, a therapeutically effective amount of a nonsteroidal anti-inflammatory drug. 50 The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising an effective amount of a non-steroidal anti-inflammatory agent and to reduce its side effects of 200% hyaluronic acid compound. mg per unit dosage form. -46GB 288292 B6 The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for preventing topical infection, a therapeutically effective amount of an antimetabolite. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for treating bone and muscle pain and / or treating inflammation, effective amount of ascorbic acid, ie vitamin C. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for enhancing inhibition of prostaglandin synthesis, a therapeutically effective amount of a nonsteroidal anti-inflammatory drug. 110. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising a therapeutically effective amount of a non-steroidal anti-inflammatory drug in a form suitable for treating human cancer. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of diseases or conditions, a therapeutically effective amount of a nonsteroidal anti-inflammatory drug. vitamin C. 112. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising an effective amount of a medicinal or therapeutic agent and reducing the side effects of the hyaluronic acid compound in an amount. 200 mg, based on the unit dosage form. 113. The use of claim 111, wherein the combination therapeutic agent as a medical or therapeutic agent comprises a non-steroidal anti-inflammatory drug. 114. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 for the manufacture of a combination therapeutic composition comprising a therapeutically effective amount of liquid perfusate in a form suitable for enhancing tissue oxygenation with a tissue perfusate. and a hyaluronic acid compound in an amount permitting liquid perfusate to transport tissues, including scar tissue through cell membranes, to individual cells at the site to be treated. 115. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 for the manufacture of a combination therapeutic composition comprising a therapeutically effective amount of a non-steroidal anti-inflammatory drug in a form suitable for treating pain. Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or II for the manufacture of a combination therapeutic composition which in a form suitable for the treatment of pain, including bone and muscle pain and / or treatment inflammation contains an effective amount of ascorbic acid, ie vitamin C. 117. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of human disease, a therapeutically effective amount of a nonsteroidal anti-inflammatory drug. 118. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for treating diseases or conditions, a therapeutically effective amount of indomethacin and vitamin C. . Use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for the treatment of diseases or conditions, a therapeutically effective amount of a medicinal and / or a therapeutic agent selected from the group consisting of ascorbic acid, i.e., vitamin C and non-steroidal anti-inflammatory drugs, and combinations thereof. -47GB 288292 B6 The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 for the manufacture of a combination therapeutic composition comprising, in a form suitable for treating diseases or conditions, a therapeutically effective amount of a nonsteroidal anti-inflammatory drug. vitamin C. Use according to any one of the preceding claims, wherein the hyaluronic acid compound comprises hyaluronic acid or its salts with a molecular weight ranging from 150,000 to 225,000 Da. 122. The use of any one of the preceding claims, wherein the hyaluronic acid compound comprises hyaluronic acid or salts thereof with a molecular weight of less than 750,000 Da. Use according to any one of the preceding claims for the manufacture of a combination therapeutic composition in the form of at least one dosage amount. 124. The use according to any one of the preceding claims for the manufacture of a combination therapeutic composition in the form of a plurality of dosage amounts.