AP175A - Combination and formulations and the administration thereof to a mammal for the treatment of conditions and disease. - Google Patents

Combination and formulations and the administration thereof to a mammal for the treatment of conditions and disease. Download PDF

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Publication number
AP175A
AP175A APAP/P/1990/000206A AP9000206A AP175A AP 175 A AP175 A AP 175A AP 9000206 A AP9000206 A AP 9000206A AP 175 A AP175 A AP 175A
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AP
ARIPO
Prior art keywords
hyaluronic acid
salts
agent
treated
combination
Prior art date
Application number
APAP/P/1990/000206A
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AP9000206A0 (en
Inventor
Falk Rudolf E Dr
Asculai Samuel S Dr
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Norpharmco Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
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    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
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    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Diabetes (AREA)
  • Inorganic Chemistry (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Communicable Diseases (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicinal Preparation (AREA)

Abstract

A combination for

Description

The invention relates to, formulations suitable for use to treat conditions and disease, (for example cancer), the use of such formulations to treat conditions and disease, methods of treating conditions and disease, and the delivery of medicinal and therapeutic agents for the treatment of disease and conditions .
BACKGROUND OF THE INVENTION
It is therefore an object of this invention to provide formulations suitable for use to treat disease and conditions, the use of such formulations to treat disease and conditions, methods of treating disease and conditions and the delivery of medicinal and therapeutic agents for the treatment of disease (for example, cancer) and conditions.
Further and other objects of the invention will be realized by those skilled in the art from the following disclosure and in which Applicants refer to literature uncovered after the date of their invention.
Hyaluronic acid is a naturally occurring glycosaminoglucan. Its molecular weight may vary from 50,300 dalton upwards, and it forms highly viscous solutions. As regards the actual molecular weight of hyaluronic acid in natural biological contexts, this is still a matter of much uncertainty: When the molecular weight of hyaluronic acid is to be determined, different values are obtained depending on the assay method employed, and on the source, the isolation method etc. The acid occurs in animal tissue, e.g. spinal fluid, ocular fluid, synovial fluid, cockscombs, skin, and also in seme streptococci. Various grades of hyaluronic acid have been obtained. A preparation with an allegedly high degree of purity and alleged to be entirely free from side effects, is a teninflammatory form described in U.S. Patent No .4 , 14 1 , 973; this preparation is said to have a molecular weight exceeding 750,000 dalton, preferably exceeding 1,200,000 dalton and is suggested for therapeutic use in various articular conditions.
The Merck Index Specifies that Hyaluronic Acid has a Molecular Weight within the range pf 50,000 to 8 X 106 depending on source, methods of preparation and methods of determinate ion
AP 0 0 0 1 7 5 bad original
The Merck Publication teaches hyaluronic acid as a surgical aid (ophtnaimoiogicai).
SUMMARY QF THE INVENTION
Applicants have now discovered that combinations and formulations (for example an injectable formulation) can be provided for administration to a mammal for the treatment of a disease or condition, which combinations or formulations employ or incorporate as the case may be a therapeutically effective non-toxic amount of a medicinal and/or therapeutic agent to treat the disease or condition (for example a free radical scavenger (for example ascorbic acid (Vitamin C)), Vitamin C (for the treatment of mononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynoi-9 [nonyIphenoxy poiyetnoxy ethanol] found in Delfen™ contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and ( + /-) tromethamine salt of ketorolac (sold under the trademark Toradol™) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodiiator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark Lasix™)), immunosuppressants (for example cyclosporins), iymp’nokynes (such as interleukin - 2 and the like), aipha-and-S-interferon and the like) administered with, or carried in, an amount of hyaluronic acid and/or salts thereof (for example the sodium salt) and/or homoiogues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid (preferably hyaluronic acid and salts thereof) sufficient to facilitate the agent's penetration through the tissue (including scar tissue), at the site to be treated through the cell membranes into the individual cells to be treated. When such combinations and formulations are administered to patients suffering from the disease or condition, the disease or condition is unexpectedly improved.
The formulation can be administered among other ___—--BADORiGifSt methods, intravenously, intra arterially, intraperitoneally, intrapleurally, transderma 11y, on the skin (topically), rectally, orally or by direct injection (for example into a tumor, into an abscess or similar disease focus) or put on a patch to be secured to the skin of the patient. The hyaluronic acid and/or salts thereof and the agent can be administered separately but are administered in sufficient amounts and in an immediate time sequence or interval (preferably concurrently and more preferably simultaneously), preferably at the identical site (e.g. one given intravenously and the other piggy backed), to treat the disease or condition.
Thus according to an aspect of the invention, a combination is provided suitable for use to treat a condition or disease, the combination comprising therapeutically effective non toxic amounts of (a) a medicinal and/or therapeutic agent to treat a disease or condition (for example a free radical scavenger (for example ascorbic acid (Vitamin C)), Vitamin C (for the treatment of mononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in Delfen™ contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradoi™) and steroidal anti-inflammatory drugs for example *), anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, brcnchodiiator, anti-bacteria1 agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark Lasix™)), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), aipha-and-3interferon and the like) and
AP 0 0 0 1 7 5 (b) a sufficient amount of hyaluronic acid and/or salts thereof (for example sodium salt) and/or homoiogues, analogues, derivatives, complexes, esters, fragments, and/or subunits of hyaluronic acid, preferably hyaluronic acid . and λ salts thereof, sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated through the cell membranes into the individual cells to be treated.
The combination can be administered separately or as a mixture or solution. If administered separately the components are preferably administered simultaneously and at the identical site.
According to another aspect of the invention, a formulation is provided suitable for use to treat a condition or disease, the formulation comprising a therapeutically effective non-toxic amount of a medicinal and/or therapeutic agent to treat a disease or condition (for examole a free radical scavenger (for example a free radical scavenger ( ascorbic acid (Vitamin C) ) , Vitamin C (for the treatment of mononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynoi-9 [nonyiphenoxy polyethoxy ethanol] found in Telfen™ contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indcmethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, (for examole irosemide (sold under examDxe uretics trademark Lasix™)), immunosuppressants (for example cyclosporins), iymphmokyr.es (such as interleukin - 2 and the like), alpha-and-3-interferon and the like), in an amount of hyaluronic acid and/or salts thereof (for example the sodium salt) and/or homologues, anaiogues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid, preferably hyaluronic acid and salts thereof, sufficient to facilitate the agent at the site to be treated, to penetrate through the tissue (including scar tissue) through cell membranes into the individual cells to be treated.
.40
According to another aspect of the invention a method of treating a condition or a disease in a mammal is provided comprising administering to the mammal, a combination of a therapeutically effective non-toxic amount of (a) a medicinal and/or therapeutic agent to treat a disease or condition (for example a free radical scavenger (for example ascorbic acid (Vitamin C)) , Vitamin C (for the treatment of mononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol·] found in Deifen™ contraceptive cream, and anionic surfactants (e.g. cetyl· pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (N5A13) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark Lasix™)), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), alpha-and-fl-interferon and the like) and (b) a sufficient amount of hyaluronic acid and/or salts thereof (for example sodium salt) and/or hcmologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid, preferably hyaluronic acid and salts thereof sufficient to facilitate the agent at the site to be treated to penetrate through the tissue (including scar tissue), through the cell membranes into the individual ceils to be t reated.
Preferably (a) and (b) are administered simultaneously at the identical site, for example, one intravenously and the other piggy backed.
According to another aspect of the invention a method of treating disease or a condition is provided comprising administering to a mammal a therapeutically effective non toxic amount of a formulation comprising a therapeutically effective
AP 0 0 0 1 7 5
amount of a medicinal and/or therapeutic agent to treat a disease or condition (for example a vitamin (for example a free radical scavenger (for example ascorbic acid .'Vitamin C) ) , Vitamin C (for the treatment of mononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol-9 [nonyIphenoxy polyethoxy ethanol] found in Delfen™ contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal antiinflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark. Toradol™) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, cronchodiiator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark Lasix™)), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), alpha-and-S-interferon and the like) in an amount of hyaluronic acid and/or salts thereof (for example the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid, preferably hyaluronic acid and salts thereof, sufficient to facilitate the agent at the site to be treated to penetrate through the tissue (including scar tissue) through cell membranes into the individual ceils to be treated.
According to another aspect of the invention, delivery of a therapeutically effective amount of a medioinsl and. or therapeutic agent to treat a disease or condition in a mammal is provided, the delivery comprising administering a therapeutically effective non toxic amount of a medicinal and/or therapeutic agent (fcr example a free radical scavenger (for example ascorbic acid (Vitamin C)), Vitamin C (for the treatment of mononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in Delfen™ contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium
BAD ORIGINAL
Ί chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradoi™) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diusetics (for example furosemide (sold under the trademark Lasix™)), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), aipha-and-fl-interferon and the like) with a sufficient amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub units of hyaluronic acid, preferably hyaluronic acid and salts thereof, sufficient to transport or facilitate the transport of, the agent to the site to be treated through the cell membranes into the individual ceils to be treated.
Thus according to another aspect of the invention, use of a combination or formulation is provided to treat a disease or condition, the combination and formulation comprising a therapeutically effective non-toxic amount of a medicinal and/or therapeutic agent to treat a disease or condition (for example a vitamin (for example a free radical scavenger (for example ascorbic acid (Vitamin C)), Vitamin C (for the treatment of mononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol-9 ιnonyiphenoxy polyethoxy ethanol] found in Deifen™ contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradoi™) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretic^, s L 1· 0 0 0 dV
BAD ORIGINAL (for example furosemide (sold under ode trademark Lasix™)), immunosuppressants (for example cyclosporins), lympnokynes (sued as interleukin - 2 and the like), alpha-and-3-interferon and the like) and a sufficient amount of hyaluronic acid and/or salts thereof (for example sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid, preferably hyaluronic acid and salts thereof to facilitate agent transported to the site to be treated, to penetrate through the cell membranes into the individual cells to be treated.
Applicants postulate that the hyaluronic acid and/or salts thereof and/or the homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid facilitate the transport of the agent to the site to be treated and to penetrate the tissue (including scar tissue) through all membranes in the individual cells to be treated.
By way of example and to illustrate the facilitation of the delivery or transport of a chemical to a site in a mammal, when ethyl alcohol is injected directly into a tumor, and sonographic (ultrasound) assessment is made, if is not dispersed throughout the tumor. When the ethyl alcohol to be administered into a tumor is carried by hyaluronic acid and/or salts thereof, sonographic assessment of the tumor, demonstrates the dispersion of the ethyl alcohol throughout the tumor.
While Applicants postulate that the hyaluronic acid facilitates the transport and delivery, Applicants' invention may be used as described irrespective of the actual method of operation of the hyaluronic acid and/or salts thereof and or the homologues, analogues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid.
The combination of hyaluronic acid and salts thereof and other forms with different chemicals and drugs (Vitamin C, anti-cancer drugs, etc.) alters their distribution and performance in the human body and produces an unusual targeting for underperfused tissue and/or pathological tissue. In this regard the use of ascorbic acid (Vitamin C) as a free radical scavenger (50 gm daily - 1000 times the daily dose in therapeutic purposes as a Vitamin) administered intravenously with 300 - 500mg of hyaluronic acid (sodium hyalurcnate) immediately relieves bone pain and muscle pain and reduces tlGINAL inflammation in cancer patients. The hyaluronic acid enhances the anti-neoplastic activity and effect of the ascorbic acid.
It is thought that this enhanced activity eliminates the free radicals by acting as a free radical scavenger. In any event the patients feel better. This is also demonstrated with furosemide and hyaluronic acid where the activity of furosemide is enhanced only minimally when administered with hyaluronic acid to a normal subject but the activity is enhanced significantly when administered to a patient whose kidney is underperfused or malfunctioning due to insufficient intravascular volume.
A similar situation occurs with the NSAIDS. As a major amount of soluble indomethacin is required, the chemical product was solubilized using n-methyl glucamine at a dilution 15 of 5mg/ml of n-methyl glucamine (NMG) . This substance is then passed through a 22 micron Milipore filter to produce sterility. This material is non-toxic at 16 fold the therapeutic dose in animals and for this reason was considered appropriate to be used in human conditions. Thus, Indocid™ solubilized in NMG is 20 administered to human patients either into the tumor intraperitoneaily, intrapleurally, or intravascularly at a varying dose up to 10 mg/kg where each dose of indomethacin is combined with 200 - lOOOmg of hyaluronic acid (for example LifeCore™ hyaluronic acid [sodium hyaluronate]) diluted in 25 the original solution of indomethacin and NMG with for example the LifeCore™ hyaluronic acid. This produces an appropriate mixture and can be administered safely by any of the routes. [Similar clinical studies have been done with hyaluronic acid prepared by other methods, i.e. extraction. The extracted 30 material is satisfactory to use for intratumor, intraceritoneal or intrapleural use with this substance.]
Thus and according to another aspect of the invention when an NSAID for example indomethacin (dissolved in n-methyl glucamine) or other NSAID is administered with greater than 35 200mg hyaluronic acid for 1-2 mg/kg body weight of the NSAID (in one instance indomethacin and NMG), no major toxic side effects occur such as gastro-intestinal distress, neurological abnormalities, depression, etc., even at elevated amounts of indomethacin (if necessary). If the amount of hyaluronic acid is decreased below that amount, the usual side effects may begin .
bad original to reoccur. In addition, the responses that have been observed are superior when the NSAID (for example Indocia™) is combined with hyaluronic acid demonstrating clearly that the combination is now targeting to the pathological tissue even when administered by the systemic intravenous route. Thus, it has been observed that patients with neoplastic diseases when receiving in addition to other chemicals (for example ascorbic acid [Vitamin C], phloretin and anti-cancer drugs), 50 - 200 mg NSAID - hyaluronic acid (sodium hyaluronate) (for example indomethacin and hyaluronic acid) experience dramatic relief of pain immediately. This is followed within a short period of time by a resolution and resorbtion of neoplastic lesions with an improvement of pulmonary, and liver function if there is tumor present in these organs. Thus the dead tumor material and the debris and tumor toxins appear to be better eliminated by the body through the action of the macrophages whose activity is enhanced by the addition of the NSAID (or a steroidal antiinflammatory drug) administered with hyaluronic acid (or salt or other form thereof) . Thus Applicants believe that the addition of the NSAID for example with hyaluronic acid (sodium hyaluronate) deblocks the macrophages by preventing enzymatic production of prostaglandin synthetase which blocks macrophage functioning. Thus the hyaluronic acid (and salt and other forms) not only enhance the activity of the NSAID but also reduce any side effects and toxicity that is associated with the use of the prostaglandin synthesis inhibitors.
Examples of agents suitable for use as chemotherapeutic agents are novantrone ( Mitoxantrone ) , Methotrexate, 5-FU (5-Fiuouracii) , ca rbcp iat i.num, methyl CCNU administered orally and Mitomycin C.
In one instance methotrexate has been administered with hyaluronic acid over an area of tumor tissue, (e.g. the chest wall) for a period of 5-7 consecutive days. The patient's hemoto log ical indices were lowered at least comparable to methotrexate being given at the same doses either intravenously or orally.
Further when the cancerous tumor breaks up (after treatment as previously described) in many instances the liver cannot cope with the tumor toxins and debris and residue, killing the patient. Not only is the use of hyaluronic acid
IIGINAL with an NSAID appropriate, so is the use of enemas employing hyaluronic acid (sodium hyaluronate) and a detoxifying agent administered into the large bowel.
The hyaluronic acid and salts thereof may be utilized at varying doses - 10 to 1000 mg/70 kg person with the optimal doses tending to range between 50 and 350 mg/70 kg individual. As there is no toxicity, the hyaluronic acid can obviously be administered in a dose excess (for example 3000 mg/70 kg individual) without any adverse effects.
Thus, we have combined hyaluronic acid and/or salts thereof with cytotoxic chemotherapeutic agent, for example either administering hyaluronic acid immediately after the agent (if the two cannot be mixed beforehand) or having mixed the two, that is hyaluronic acid and the drug, before administration. We have utilized for example, adriamycin administering adriamycin prior to hyaluronic acid, methotrexate where the two agents are mixed together, mitomycin C, bleomycin, 5-Pluorouracil, novantrone, carbo- and cis-platinum, and in all of these latter instances the drug has been mixed directly with hyaluronic acid at a dose of 10 mg/per ml of the hyaluronic acid increasing the total dose up to 100 mg with the standard dose of the drug in question being utilized.
Previously, we have utilized phloridzin, phloretin, and 5-deoxyglucuronide of phloridzin as agents with dimethyl sulfoxide to competitively block glucose transport in neoplastic cells. These agents can also be combined with hyaluronic acid at similar doses to those already mentioned for chemotherapeutic drugs where phloretin is solubilized for example by the agent N - methyl glucamine.
Thus, a treatment protocol in various different neoplastic situations may consist of the administration of Ascorbic Acid and Cncostatin IV, a combination of phloretin, solubilized in N methyl glucamine, with a mixture of hyaluronic acid or salt thereof using a dose of 2 to 4 grams of phloretin solubilized as described with 30 mg to 1000 mgs or more (dose excess) of hyaluronic acid or sodium salt. This has allowed substantially enhanced penetration of the drug into tumor cells and has effected a much better result when these tumors are deprived of glucose and then subsequently stressed either by hyperthermia chemotherapy and/or radiation. Similarly,^
------------------- *BAD0mW^
AP 0 0 0 1 7 5 cytotoxic chemotherapeutic agents already mentioned have been combined with comparable doses of hyaluronic acid and and/or salts thereof administered either intravenously, intraarterially, intraperitoneally or intrapleural!’/ or directly into the tumor by injection through a needle placed under sonographic or CT guidance.
Intradermal delivery of other drugs may also be accomplished with hyaluronic acid and/or salts thereof: for example insulin in diabetes, estrogen in post - menopausal women, progestegens in control of fertility and anti-metabolites for the prevention of topical infection such as those caused by coryne bacterium acnes. They may also be applied using hyaluronic acid.
Intravenous administration of bronchodilators may also (for example aminophylline and theophylline) may also be accomplished with hyaluronic acid and/or salts thereof.
Enhancement of the effect of the bronchodilators by administration with hyaluronic acid has teen the result. Oral administration with hyaluronic acid and/or salt may also be suitable .
According to another aspect of the invention, the combination of a non-ionic surfactant for example nonoxynol-9 [nonylphenoxy polyethoxy ethanol] [found in Delfen (t.m.) contraceptive cream] and hyaluronic acid and/or salts thereof and other forms is provided for treating:
(a) herpes simplex type I and type II (b) herpes zoster (shingles ) and unexpectedly provide immediate relief cf symptoms and subsequent disappearance of lesions.
The ncn-ionic surfactant preferably comprises an ether or an amide linkage between the hydrophilic and hydrophobic portions of the molecule, being mere active than; the surfactants having an ester - or an ether- ester linkage.
The following nonionic surfactants and identified linkages are offered for consideration.
Surfactant 11ηλ&σ£
None (control virus)
5% Nonoxynol-9 (nonylphenoxy-polyethoxy ethanol) Ether 1% Triton X-100 (p-diisobutylphenoxy-polyethoxy -ethanol) -—am Ether p %.π oniQiN,
1¾ Brij-97 (polyoxyethylene (10) oleyl ether) 1¾ Span-20 (sorbitran monciamate)
1% Span-80 (sorbitan moncoleate)
1¾ Tween-20 (polysorbate 20)
1¾ Tween-80 (polysorbate 80)
1¾ Onyxol 345
For the successfully particularly bad case
Ether Ester
Ester
Ether-ester Ether-ester Amide
Where foreign objects (for example drainage tubes) must be implanted into a human body and be left for use, it is imperative that the tissue surrounding the implant not become infected because once the tissue becomes infected, usually no matter how much antibiotic is administered the infection does not clear and the implant must be removed. Applicants have found however that where the infected tissue surrounding the implant is treated with the antibiotic carried in hyaluronic acid (sodium hyaluronate), the infection rapidly clears and the implant need not be removed.
Applicants have also found that in respect of treating vascular ischemia (for example in cancer patients where the tumor tissue is under perfused, in patients suffering from diabetes and Berger's disease), the administration of the medicines in hyaluronic acid (sodium hyaluronate) enhances the patient's response to the drug.
In patients suffering from brain tumors, the swelling must be reduced. Administration of dimethyl sulfoxide (DMSO) in amounts of less than 100 gm daily in a 10% solution in hyaluronic acid (sodium hyaluronate) -300 - 500 mg reduces acute brain and spinal edema.
reatment of mononucleosis, Applicants have a patient suffering frcm a some time, Vitamin C and hyaluronic acid and the patient rapidly recovered.
One form of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub units of hyaluronic acid, preferably hyaluronic acid and salts and thereof suitable for use with Applicant's invention is a fraction supplied by Sterivet Laboratories Limited. One such fraction is a 15 ml vial of Sodium hyaluronate 20mg/ml (300mg/vial - Lot 2F3). The sodium hyaluronate fraction is a 2%' solution with a mean average molecular weight of about 225,000. The fraction also contains,
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BAD ORIGINAL water q.s. which is triple distilled and sterile in accordance with the U.S.?. for injection formulations. The vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial.
The fraction of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub units of hyaluronic acid, preferably hyaluronic acid and salts thereof may comprise hyaluronic acid and/or salts thereof having the following characteristics:
a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from the group consisting cf the following:
i) a molecular weight within the range of 150,000-225,000;
ii) less than about 1.25% sulphated mucopolysaccharides on a total weight basis;
20 iii) less than about 0.6% protein on a total
weight basis;
iv) less than about 150 ppm iron on a total
we ight basis;
v) less than about 15 ppm lead on a total
25 we ight basis;
vi) less than 0.0025% glucosamine;
vi i ) less than 0.025% glucuronic acid;
viii) 1$ 3 5 than 0.025% N-aoetyIglucosamin e;
ix ) less than 0.0025% amino acids;
-ι Λ c u x ) a TV ext i notion coefficient a^ 2 ς γ ω m of
less than about 0.275;
xi) a UV extinction cce f f i clent at 2 3 0 n m o f
less than about 0.25; and
xi i ) a pH within the range of 7.3-7 . 9 .
35 Preferably the hya lu ronic acid is mixed with water and the
fraction of hyaluronic acid fraction has a mean average molecular weight within the range of 150,000-225,000. More preferably the fraction of hyaluronic acid comprises at least one characteristic selected from the group consisting of the following characteristics:
i) less than about sulphate
mucopolysaccharides on a total weight basis;
ii) less than about 0.4¾ protein on a total
weight basis;
iii) less than about 100 ppm iron on a total
weight basis;
iv) less than about 10 ppm lead on a total
weight basis;
v) less than 0.00166% glucosamine; *
Vi) less than 0.0166% glucuronic acid;
vii) less than 0.0166% N-acetylglucosamine;
viii) less than 0.00166% amino acids;
x) a UV extinction coefficient at 257 nm of
less than about 0.23;
xi) a UV extinction coefficient at 280 nm of less than 0.19; and xii) a pH within the range of 7.5-7.7 Other forms cf hyaluronic acid and/or its salts, and homologues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for example those described in the prior art documents previously referred to. In addition Applicants have successfully employed sodium hyaluronate produced and supplied by LifeCore™ Biomedical, Inc. having the following specifications
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Characteristics
Appearance
Specification
White to cream colored cart ides
Odo:
No oercectible odor
Viscosity Average Molecular Weight < 750,000 Daltons
UV/Vis Scan, 190-820nm
OD, 260nm
Hyaluronidase Sensitivity
Matches reference scan < 0.25 OD units
Positive response
IR Scan
Matches referent pH, ICmg/g solution
6.2 - ^.3
Water
8¾ maximum
Protein < 0.3 mcg/mg NaHy
Acetate < 10.0 mcg/mg NaHy
Heavy Metals, maximum ppm As Cd Cr Co Cu
Pb
2.0 5.0 5.0 10.0 10.0 25.0
Hg N:
10.0 5
Microbial Bioburden
None observed ? ς
Endotoxin < 0.07EU/mg NaHy
Biological Safety Testing
Passes Rabbit Ocular Toxicity Test
The following references teach hyaluronic acid, sources thereof and processes of the manufacture and recovery thereof .
United States Patent 4,141,973 teaches hyaluronic acid fractions (including sodium salts) having:
(a) an average molecular weight greater about 50,000, preferably greater than 1,200,000 - that is, a limiting viscosity n greater than about 1400 cm-Cg., and greater than about 2000 cm’/g.;
(b) a protein content of less than 0.51 by we ight;
(c) ultraviolet light absorbance of a 1% solution of sodium hyaluronate of less than 3.0 at 257 nanometers wavelength and less than 2.0 at 230 nanometers wavelength;
(d) a kinematic viscosity of a 11 solution of sodium hyaluronate in physiological buffer, greater
than about 1000 centistokes, preferably greater than 10,000 centistokes;
(e) a molar optical rotation of a 0.1 - 0.2¾ sodium hyaluronate solution in physiological buffer of less than -11 X 103 degree - cm2 /'mole (of disaccharide) measured at 220 nanometers;
(f) no significant cellular infiltration of the vitreous and anterior chamber, no flare in the aqueous humor, no haze or flare in the vitrequs and no pathological changes to the cornea, lens, iris, retina, and choroid of the owl monkey eye when one milliliter of a 1¾ solution of sodium hyaluronate dissolved in physiological buffer is implanted in the vitreous replacing approximately one-half the existing liquid vitreous, said HUA being (g) sterile and pyrogen free and (h) non-antigenic.
Canadian Letters Patent 1,205,031 (which refers to United States Patent 4,141,973 as prior art) refers to hyaluronic acid fractions having average molecular weights of from 50,000 to 100,000; 250,000 to 350,000; and 500,000 to
730,000 and discusses processes of their manufacture.
Where high molecular weight hyaluronic acid (or salts or other forms thereof) is used, it must be diluted to permit administration and ensure no intramuscular coagulation.
One formulation of Ascorbic Acid (Vitamin C) injection CSP is manufactured by Steris Laboratories, Inc., Phoenix, Arizona, 35043 U.S.A. and comprises 22 mg/mi (equivalent to sodium ascorbate 250 mg/mi) in 30ml, 50ml, or lOCmi individual containers, 30mi size being preferred.
Thus Applicant has combined hyaluronic acid (and sodium hyaluronate and/or other forms) with medicinal and/or therapeutic agents for the treatment of conditions and diseases with totally unexpected results :
For Example
Condition/Disease Chemicals & Drugs
1. Cancer, increasing activity free radical scavenger, of macrophages superoxide dismutase, ascorbic
AP 0 0 0 1 7 5 bad ORIGINAL
IA. Reduction of swelling in brain of person suffering brain trauma
2. Hair growth
Herpes, canker sore, shinales
4. Renal failure, cardiac insufficiency, hypertension, edema
5. Infection, acne, mononucleosis
6. Transplants
7. Inflammation, elimination of tumor break down material (toxins and debris), decreasing side effects, relief of pain (e.g.
back pain)
3. Detoxification
9. Bronchcdilation
10. Vascular ischemia acid(Vitamin C) anti-cancer drugs, NSAID, Chemotherapeutic Agents, detoxifying Agents (e.g. cholestyramine)
Dimethyl Sulfoxide (DMSO) minoxidil - combination grow more hair when applied topically nonionic surfactants, e.g., nonoxynol-9 and anionic, (e.g. cetyl pyridiniom chloride) and cationic (e.g. benzalkonium choride), surfactants diuretics - furosemide antibiotics, antibacterials, antimicrobials, etc., ascorbic acid and hyaluronic acid cyclosporins non-steroidai anti-inflammatories, NSAID e.g. diclofenac, indomethacin, piroxicam, ibuprofen, tromethamine salt of Ketorolac, naproxen enema, detoxifying agent, peritoneal dialysis bronchodilators, e.g. ceciomethasone diproprionate (sodium cromoglycate although not specifically a bronchodialator), theophylline treat limbs in respect of diabetes, Serger's disease, etc. with suitable medicine
BAD ORIGINAL
11. HIV (AIDS) . Diabetes
13. Post-menopause . Prevention of topical infection
15. Reduction of swelling
16. Hypertension, cardiac insufficiency
e.g. Trental
DM50, Vitamin C, NSAID (e.g. indomethacin, naproxen, ketorolac tromethamine), interferon, Vibramycin™, (doxcycline) , tetracycline insulin estrogens replacement antimetabolites (e.g.
sulfonamides)
DMSO
Calcium channel blockers e.g. Nifedipine β-Blockers e.g. atenolol, propranolol acetylsalicylic acid
17. Prostaglandin Synthesis inhibition
18. Enhance oxygenation of perfusate tissue by perfusion fluid bathing the tissue (for transplantation purposes
In respect of the treatment of cancer particularly, Applicants have now provided a method of treatment and combinations of chemicals and drugs which appear to enhance a patient's life expectancy and quality of life patients not responding to the usual treatments), have successfully treated patients with their increasing the rate of tumor destruction, improving for example macrophage function, to enable the body to eliminate the tumor cells, dead tumor waste, debris, and toxins.
EXAMPLES
The following examples are offered to illustrate Applicants' invention. In substantially all, if not all cancer cases, the patient had been unresponsive to conventional treatment. The hyaluronic acid referred to herein also includes other forms - for example sodium hyaluronate.
(even those Applicants invent ion,
CASE I :
A 59 year old male with a laryngeal epidermoid (squamous type tumor) treated in its primary state with a combination of surgery and radiation developed metastatic bad ORIGINAL disease in the liver some seven years Later. Two major tumors were noted at a size of 12 cm and 6 cm diameter. These were treated with combination therapy using systemic chemotherapy with added DMSO to enhance penetration, phioretin solubilized by N methyl glucamine with added DMSO to enhance penetration and the direct administration of adriamycin, carboplatinum and methotrexate into the tumor by systemic and intratumor injection therapy but in this case but with added hyaluronic acid at a dose of 10 to 60 mgs for the different drugs. This was achieved without any adverse effects and the patient was reassessed four weeks later. At that point in time the smaller tumor had disappeared entirely. The larger tumor was apparent only as a necrotic focus measuring now 5 cm in diameter but no aooarent surviving tumor could be detected by examination and needle biopsy. This case illustrates the superior effect of hyaluronic acid on penetration of drug thus allowing better tumor destruction .
FoIIow-Tp
Subsequently patient was given treatment of
Indomethacin 300mg and 300mg Hyaluronic Acid daily; patient was in remission, however patient died of infection at a later date.
CASE 11 :
A 42 year old female developed malignant melanoma with tumor present in the left upper thigh and inguinal nodes, the abdominal cavity and liver, lungs, and the base of the brain affecting involvement of various cranial nerves. Her primary tumor had been excised and she had developed recurrent disease which was deemed untreatabie as there is no cytotoxic or cytostatic chemctherapy that has major effects on this turner when it is as widespread as observed in this patient. The patient was treated with a combination of phioretin solubilized in N methyl glucamine with added hyaluronic acid at a dose of 10 to 50 mg/2 to 4 grams administered intravenously and this agent was given for five days over 4-24 hours/day. She also received hyperthermia to the various areas of the tumor and concomitant systemic therapy with carboplatinum with added hyaluronic acid at a dose of 250 mg carbop iat inum total plus methyl CCNU administered at a total dose of 120 mg over 5 days orally while the patient received hyaluronic acid systemicaliy. Methotrexate
IJGINAL mixed with hyaluronic acid was injected into the tumor which could be palpated in the left thigh or inguinal region at a dose of 37.5mg with 60 mg of hyaluronic being added, the doses being divided equally at two different days by injection. The patient responded over the next 10 to 20 days with dramatic and total regression of the upper thigh and inguinal tumors, dramatic improvement in liver function with the tumors in the liver becoming cystic (generally regarded as a sign of tumor break down) and disappearance of the lung tumors. The tumor at the base of the brain regressed as manifested by improvement of her cranial nerve function and a decrease of pain and headaches. In this patient a tumor which is unresponsive to the majority of agents at this phase of development was made markedly responsive when the same agents were used with hyaluronic acid as a penetrating agent.
Follow-Up
The patient was subsequently given treatments of phloretin, indomethacin (NSAID) and hyaluronic acid. This patient is now in complete remission.
CASE III:
A 55 year old female patient with cancer of the gallbladder occupying the entire right lobe of the liver. This patient had been treated on three previous occasions with a combination of heat, systemic chemotherapy with added DMSC, phloretin with added DMSC and direct injection of cytotoxic drugs with added DMSO. Beginning May 1989 she was treated with the comparable drugs with added hyaluronic acid as a carrier or dispersing molecule administered both systemically and by direct injection into the tumor. The tumor which had shrunk marginally by approximately 20% prior to this now reduced in size dramatically by over 50% and continues to diminish in size. This tumor is judged unresponsive to these drugs alone when administered by the normal routes.
Follow-Up
Unfortunately the patient relapsed, became depressed and died.
s L I 0 0 0 dV
BADORIGINAl.
CASE IV:
A 55 year old female with cancer of the c
the liver with one major large tumor mass oc
right lobe of the liver and medial segment
extending into the 1 lef t lobe and j udged
of the left lobe ;astat ic hepatic surgeon two months earlier was treated with systemic chemotherapy and injection of chemotherapeutic agents directly into the tumor plus phioretin solubilized with N methyl glucamine with hyaluronic acid and hyperthermia. The patient had a three day course of therapy and was injected on one occasion directly into the tumor with cytotoxic drugs and hyaluronic acid and reassessed three weeks later. Sonographic examination showed total liquefaction of the tumor leaving only small rim aocarentiv viable tissue; 500 :cs amoe r colored fluid with necrotic tumor tissue present was drained from the now cystic lesion. This is an unusual and dramatic response for an adenocarcinoma which generally responds extremely slowly. It is judged that less than 30% of these patients achieved any significant disease regression utilizing standard cytotoxic or cytostatic chemotherapy. The enhanced destruction here occurring over three weeks and is judged as due to the use of the carrier penetrating molecule, hyaluronic acid.
Follow-Up
From the examinations, there was total tumor necrosis. The patient however died some time later of liver failure and pulmonary embolism.
CASE V:
A 53 year old man with transitional cell cancer of the bladder in a very advanced state of his disease with metastases involving the entire left pelvis, extending to the periaortic and parapancreatic and supraclavicular nodes having recurred after previous surgical excision, radiation and having not responded by major regression to standard chemotherapy was treated using phioretin solubilized in N-methyl glucamine with added hyaluronic acid with a direct injection of carboplatinum and methotrexate into the tumor tissue. Hyperthermia to the areas of the tumor was also applied. The patient developed a dramatic response and developed a febrile reaction due to tumor break down and release of bacteria. This reaction was controlled by antibiotics and appropriate hydration and as the patient was observed through this phase a dramatic decrease in the size of the tumor was observed on an almost daily basis with an over 50¾ reduction in tumor size having occurred by 7 days after therapy. This is a remarkable and dramatic response of a tumor which at this phase had been judged as unresponsive to all therapy and it is thought to be due to the use of the drug which blocks glucose transport employed here with a carrier and penetrating molecule, hyaluronic acid and chemotherapy administered directly into the tumor with the same agent.
Fo1low-To
There was, as a result, total tumor necrosis. However at a later date, the patient died of an infection.
CASE VI:
This patient had a right upper lobe lesion diagnosed, confirmed by biopsy and deemed not surgically resectable. This tumor, according to documentation utilizing chemotherapy or radiotherapy has a zero response rate. He was treated with systemic chemotherapy in hyaluronic acid as follows:
AP 0 0 0 1 7 5
Sg.OG DOSE
05/10 vinblastine 3 mg
05/10 mitomycin 3 mcr
05/10 calcium ieukovorin 40 mg
0 5 / 10 5 fluorouracil 250 mg
-Λ -
'J 3 ' x. U orxuorcuraci J. £ 3 v mg
0 5 / 10 Cncostatin IV mg
Hyaluronic Acid III 10 mg
0 5/11 carboplat in 250 mg
0 5/11 vinblast ine 5 mg
05/11 mitomycin 4 mg
05/11 calcium ieukovorin 40 mg
05/11 5fiuorouracil 250 mg
05/11 5fiuorouracil 250 mg
05/12 carboplat in 100 mg
05/12 vinblastine 2 mg
'BADORIGINAL
4
05/12 5fluorcuracil 2 50 mg
05/12 5 t 1'jorouraci 1 2 50 mg
05/12 calcium leukovorin 4 0 mg
05/12 Oncostatin IV 2 mg
5 Hyaluronic Acid 20 mg
06/19 mitomycin 5 mg
Hyaluronic Acid 10 mg ·-
06/19 vinblastine 5 mg
Hyaluronic Acid IV 10 mg 2
10 0 6/19 5fluorouracil 250 mg
Hyaluronic Acid IV 10 mg
06/19 5fluorouracil 250 mg
Hyaluronic Acid IV 10 mg
06/19 calcium leukovorin 40 mg
15 06/19 Oncostatin IV 3 mg
Hyaluronic Acid 50 mg
06/20 5fluorouracil 250 mg
Hyaluronic Acid IV 10 mg
06/20 5fluorouracil 250 mg
20 Hyaluronic Acid IV 10 mg
06/20 calcium leukovorin 40 mg
06/20 mitomycin 5 mg
Hyaluronic Acid IV 10 mg
06/20 vinblastine 5 mg
25 Hyaluronic Acid IV 10 mg
06/20 Oncostatin IV 3 m
Hyaluronic Acid IV ς n mg
06/21 Carboplatin 20 mg
Hyaluronic Acid IT IQ mg i
0 6/21 met het re xate 12.5 mg -
0 6/21 carboplat in - - Λ· mg
Hyaluronic Acid IV 50 mg
Oncostatin IV 3 mg
Hyaluronic Acid IV 50 mg
35 06/22 carboplatin 100 mg
Hyaluronic Acid IV 10 mg
06/22 Oncostatin IV 3 g
Hyaluronic Acid IV 50 mg
06/23 Oncostatin IV 3 g
40 Hyaluronic Acid IV 50 ma
0 8/16 calcium leukovorin 40 mg
08/16 5fluorouracii 500 mg
Hyaluronic Acid IV 50 nig
08/16 carboplatin 250 mg
Hyaluronic Acid IV 100 mg
Oncostatin IV 3 9
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
Oncostat in 3 9
Hyaluronic Acid 100 mg
08/18 5fluorouracii 500 mg
Hyaluronic Acid 100 mg
08/18 calcium leukovorin 40 mg
Oncostatin IV 2 9
Hyaluronic Acid 200 mg
He was also treated with phloretin in hyal uronic a
His tumor was injected with the following chemotherape·
agents in hyaluronic acid:
DATE DRUG
0 5/11 methotrexate 12.5 mg
hyaluronic acid 50
adriamycin 1 mg
0 6/21 methotrexate 12.5 mg
carboplatin 20 rr.g
hyaluronic acid 10 mg
08/18 carboplatin 30 mg
hyaluronic acid 50 , mg
08/18 adriamycin 25.5 mg
hyaluronic acid 10 mg
BAD ORIGINAL
AP 0 0 0 1 7 5
He has had regression of his disease by 30 per cent m a situation that is otherwise not treatable. This therefore documents that unresponsive tumors can respond to chemotherapy when administered in hyaluronic acid and/or salts thereof.
CASE VII:
Female patient, aged 58, had a massive cancer of the breast with supraclavicular and auxiliary lymph nodes palpable.
This has been confirmed by a combination systemic therapy improve significantly. She December, 1988 to January, again by Dr. Falk on May 17 biopsy. She was treated with and hyperthermia and did not then received radiation from
1989. She was subsequently seen 1939 and had not had a resconse tc iheraDv to date. She then develoced a dural effus:
ahe was treated by Dr. Falk by a combination of chemotherapeutic agents as follows:
(Hyaluronic Acid may be Sodium Hyaluronate)
PLUG DQ3S
05/16 methotrexate 25 mg
Hyaluronic Acid IT 10 mg
05/16 methotrexate 25 mg
Hyaluronic Acid
axilla IT 10 mg
05/16 methotrexate 25 mg
Hyaluronic Acid
SC node IT 10 mg
05/16 Oncostatin IV g
Hyaluronic Acid 20 mu
35/17 5flucrouracil J. * o' ~u
05/17 5flucrouracil 250 mg
0 5 / 17 vinblastine 5 mg
0 5 /'17 mitomycin 5 mg
05/17 Oncostatin IV 3 mg
Hyaluronic Acid 30 mg
06/02 methotrexate 25 mg
Hyaluronic Acid IT 30 mg
06/02 vinblastine 5 mg
Hyaluronic Acid IV 10 mg
06/02 Oncostatin IV
Hyaluronic Acid 30 mg
0 6/05 5fluorouracil 250 mg
Hyaluronic Acid IV 10 mg
06/05 5fluorouracil 250 mg
5 Hyaluronic Acid IV 10 mg
06/05 calcium leukovorin 35 mg
06/05 vinblastine 5 mg
Hyaluronic Acid IV 10 mg
06/05 Qncostatin IV 3 g
10 Hyaluronic Acid 30 mg
06/21 carboplatin 20 mg
Hyaluronic Acid IT 10 mg
0 6/21 methotrexate 12 . 5 mg
06/21 vinblastine 5 mg
15 Hyaluronic Acid IV 10 mg
06/21 mitomycin 5 mg
Hyaluronic Acid IV 10 mg
06/21 Qncostatin IV 3 mg
Hyaluronic Acid 50 mg
20 07/10 carboplatin 25 mg
Hyaluronic Acid IT 20 mg
07/10 methot rexate 12.5 mg
Hyaluronic Acid IT 20 mg
07/10 Qncostatin IV 3 g
25 Hyaluronic Acid 50 mg
07/12 Qncostatin IV 2 g
Hyaluronic Acid 50 mg
08/14 vinblastine 5 mg
Hyaluronic Acid IV 50 mg
3C 0 8 / 14 5 fluorouracil 50 mg
Hyaluronic Acid 17 - z u mq
03/14 calcium leukovorin 30 mq
03/14 Qncostatin IV 3 g
Hyaluronic Acid 100 mg
35 08/16 Oncostatin IV 3 g
Hyaluronic Acid 100 mg
ς L 10 0 0 dV
She had also had a thoracentesis with subsequent instillation of 5fluorouracil, mitomycin C and hyaluronic acid into the chest cavity. Her pleural effusion is totally
BAD ORIGINAL’ resolved. The lesions in her breast continue to recede and her supraclavicular and axillary lymph adenopathy is totally gone.
This patient represents a response with relatively low doses of hyaluronic acid and/or salts thereof added to conventional chemotherapy used systemically by injection into the tumor and by intra-pleural cavity instillation. The response has been further enhanced by the use of phloretin in synacid T.M. (hyaluronic acid and/or salts thereof) at the same time.
EgllQWrUg
At a much later date this patient is in remission and doing very well.
CASE VIII:
This is a 62 year old female treated previously with systemic chemotherapy, two different drug combinations without any response. She was referred for treatment including hyperthermia, and direct chemotherapy injections to which she responded initially, beginning September.
She was noted in April-May, to have an increase in the tumour in the right upper lobe of her lung. This tumour was an anaplastic small cell carcinoma. The tumour was treated by injecting into the lesion bleomycin with hyaluronic acid and indomethacin with hyaluronic acid. She also received systemically indomethacin 300 mg daily with 300 mg hyaluronic acid. The patient was followed radiological!;/ and improved very dramatically over the next 2 to 4 weeks. The last film report shows that the left hemi-thorax is clear. On the right sice there is no evidence of o.'eural reaction. Ther?
r ight
-nV, .cere is a pre mi.cent upper lobe volume loss with elevation of the right hilum.
increased lucency in the right apex may represent a :be oi e area o.
f cavitation within the collacsed region elevation or Comparison with the superior segment of the right lower lobe, previous films shows that the mass has decreased significantly in size and cannot now be distinctly identified on this examinat ion .
The applicants believe that this response is a direct result of the carrier molecule - hyaluronic acid - injected with a chemotherapeutic agent and with a non-steriodal anti-
bad original inflammatory drug to assist in clearance of the necrotic tumour.
CASE IX:
This patient was diagnosed as having a gastric cancer July, 1988 and it was deemed unresectable. A gastroenterostomytype of bypass was performed. Saw the patient initially in August and treatment was initiated in September, 1988. At that time he was heated and received phloretin with very low dose chemotherapy employing 5-FU plus immune augmenting agents.
This therapy essentially was continued until February, 1989 when Dr. Falk began to use DMSO as a carrier/penetrating agent in addition to MSN. He did receive increasing amounts of chemotherapy employing 5FU leukovorin, mitomycin C and methotrexate and subsequently in July and early August, as there was tumor progression, he also received novantrone.
As of May he began to receive these drugs in hyaluronic acid but the initial amounts of hyaluronic acid were small, employing 10-30 mg per average dose with the original drug i.e. phloretin, or the chemotherapeutic agent. There was some initial improvement in his status but then in mid August he progressed to a situation where there was increasing evidence of gastric obstruction, and also obstruction of the biliary tree with jaundice and elevation of the bilirubin. Dr. Falk then treated with higher doses of hyaluronic acid to a total dose of 500-600 mg cf hyaluronic acid divided among the different drugs. The patient continued to receive the same types of drugs.
While his condition initially deteriorated, an upper gastro-intestinal series performed on September the 7th shows his gastric bypass to be totally open whereas prior to this the patient had been vomiting all ora) intake. His status has new steadily improved.
On the basis that the patient received identical drugs earlier, the improvement must be attributed to the higher doses of the carrier molecule, allowing for better penetration of drug into what is always a scarred, fibrotic tumor and generally fatal at this stage.
AP 0 0 0 1 7 5
Follow-Up
Unfortunately at a subsequent date, patient died as a consequence of tumor necrosis and scar tissue developing - qot __________BADORIGINAL from cancer.
CASE X:
Patient was diagnosed as having a hepatoma now over 2 years age. The tumor had been stable or with minimal growth over the past 18 months. Since treatment with low dose chemotherapy and the carrier/penetrating molecule, hyaluronic acid, she appears to have had a complete response. Her alkaline phosphatase is now at 150 international units and the remainder of her liver function tests are essentially normal. Her ultrasound show no distinct tumors anymore in the liver. Dr. Falk is now treating her once every 2-3 months.
Fa.Llgw-ug
This patient is still doing well.
CASE XI:
This patient was infused on June 15, 1 989 with chemotherapy with added hyaluronic acid on one occasion. She then received hyperthermia. Previously with multiple hepatic metastases from cancer of the breast she had been stable on tamoxifen, the estrogen-blocking substance.
After one course of infusion of only 8 hours she has had what would appear to be a complete response. Her ultrasound
now shows no tumor present in the liver and her liver function
tests are all normal. For the present no furt her treatment necessary are
following her ar.d cont inu ing her on tamoxifen to block the
estrogen receptor.
Fallow-jp.
This patient relapsed after another doctor gave vaginal estrogen cream (tamoxifen) to her for vaginal irritation. In response, patient was given treatments of 30Cmg of indomethacin in 300mg of hyaluronic acid daily. She is now in remission.
BAD ORIGINAL
CASE XIA:
This patient had a massive leomyosarcoma of the uterus resected on March 26, 1989. There was residual tumor present as
demonstrated by a CAT scan. Dr. Falk has treated her with a combination of hyperthermia, very low dcse methotrex.ate using this intraperitonealy with a carrier/penetrating molecule hyaluronic acid and then using the agent that blocks glucose transport protein - phloretin, also with hyaluronic acid and alpha II interferon intraperitonealy again combined with hyaluronic acid.
On sequential CT scan this patient shows significant improvement in size of the residual mass. As soft tissue sarcomas are so very resistant to all forms of therapy this could be described as an unusual response and is in ail likelihood related to the use of the carrier/penetrating molecule - hyaluronic acid. Dr. Falk is now treating this patient approximately every 6-3 weeks for 2 days and hopefully her regression of tumor will continue. If that is the case, than one could consider closing her colostomy in about 6 month's time .
Follow-Up
Some tumor grew back. Patient was given treatments of
Vitamin C (50mg daily), indomethacin (300mg daily) in 300mg of hyaluronic acid. This patient is feeling much better.
CASE XIB:
AP 0 0 0 1 7 5
This patient has received relatively low doses initially of methyl CCNU and carbcplatin with methotrexate injected into the inguinal recurrent melanoma. All of these molecules were given in the carrier/penetrating agent hyaluronic acid. In addition she received the agent that blocks glucose transport which Dr. Falk has developed. This is a molecule called phloretin which was used many years ago. It has been solubilized in a special solution and is also given with hyaluronic acid as it will also enhance the penetration of this molecule into the tumor. Dr. Falk then treated her with hyperthermia using both capacitive and inductive radio frequency hyperthermia and microwave hyperthermia. In addition she has received immune stimulating agents which Dr. Falk believes will produce benefit but only in conjunction with other agents.
In the last 2 courses of treatment she has received Only carboplatin with added hyaluronic acid, phloretin with
BAD ORIGINAL added hyaluronic acid and methotrexate administered new by intra-peritoneai route at a low dose - 25-35 mg in hyaluronic acid again.
Dr. Falk saw her this week and he will treat her for 2 days. She is clinically in excellent condition. She has the one complaint of right-sided back pain. On examination one dees have the impression that this could be tenderness over the right kidney. The ultrasounds of her kidneys have suggested a solid mass in the right kidney which was interpreted as being either a τ
hamartoma or even an angiomyolipoma.
In view of the patient's rather dramatic response Dr. Falk thinks it would be worth while to get a CAT scan done of the abdomen. There is still the question of a small cystic lesion in the right lobe of the liver but her liver function in new normal.
Eq11qw-Ub
This patient is now in complete remission.
CASE XII:
The patient had an arterial line and subcutaneous port installed at the time of the original abdominal surgery. He came to see Dr. Falk and it was noted that there was redness, in duration and swelling around the subcutaneous port. The patient had a febrile response and elevation of his leukocytes.
A £ 14 gauge plastic cannula was inserted into the area and 75 cc of purulent material was drained and cultured growing E.coli and Pseudomonas aeruginosa. Dr. Falk treated him by irrigating the site with a combination of hyaluronic acid with ampicillin, hyaluronic acid with fiagyl., and hyaluronic acid with kefiosporin. Thus the wound was irrigated on a daily basis with 1 gram of ampicillin with 50 mgs. cf hyaluronic acid, 500 mgs. fiagyl with 50 mgs. of hyaluronic acid and 1 gram of Ancef with hyaluronic acid. During the first 2-3 days irrigation it was possible to continue to aspirate purulent material from the subcutaneous site. Within 5 days there was no purulent material remaining and there was just fluid present and by the end of the week there was no residual infection present. The port-a-cath continued to function over the next three months of the patient life.
_
BADQRlGlN AL
This is cited as an example of anti-bacteria1 agents with added hyaluronic acid producing better penetration cf the various different anti-bacterial drugs into the site of infection and one would have to postulate that there was improved penetration into the bacteria themselves.
CASE XIII:
This patient was operated on June 1st, 1989 and a resection was performed of a portion rectum and sigmoid colon, 10 and the small intestine. Post-operatively on day 7 he was noted to have swelling and induration in the wound tissue and two sites of purulent material were drained. He was treated subsequently with local irrigation with ampiciilin 1 gram combined with 50 mgs. hyaluronic acid and 500 mgs.
combined with hyaluronic acid. These two areas of cleared of any bacterial contamination within 4 days, time required would be in the order of a number of weeks.
cr f ragyi infect ion
The usual
CASE XIV:
This patient with cancer of the breast has an infected
Hickman Line. This is an indwelling plastic catheter in the subclavian vein. This infection was present subcutaneously with purulent material coming from the site of the entry of the plastic cannula. In this situation Dr. Falk injected ampiciilin
1 gram and 50 mgs. of hyaluronic acid directly adjacent to the plastic catheter. In addition the patient received flagyl intravenously with added hyaluronic acid. The infection cleared and the catheter was presented in a matter of 4 days.
CASE XV:
This man developed an abscess cn the right upper quadrant of his abdomen, in the anterior abdominal wall. This was drained in hospital but continued to be a problem. Dr. Falk has now discharged him and begun to irrigate this with ampiciilin 500 mg daily and 200 mg of hyaluronic acid. While this abscess was drained and therefore should have recovered eventually, it had taken a longer period of time than one would have anticipated. The abscess grew both staphlyococcus aureus and e. coli.
days of irrigation with ampiciMin and _____----RAfrORIGINAL
After hyaluronic acid as described, the cavity was clean, free of infection and beginning to granulate over nicely. Dr. Falk continued to treat him during the week and it healed sat isfactorily.
In other patients alpha 2- interferon was combined with hyaluronic acid and applied to a patients canker sores and the sores rapidly cleared up.
In another patient, methotrexate was carried in hyaluronic acid and applied topically to a patient with psoriasis. The formulation was absorbed and the psoriasis cleared.
In ten other patients suffering from herpes simplex type 1 and II, the application of an effective amount of nonoxynol-9 [nonylphenoxy polyethoxy ethanol] (Delfen™) combined with hyaluronic acid and/or salts thereof to the *· i- ♦' JUiU- effected areas 2 to 3 times daily gave immediate relief of the symptoms (pain) and disappearance of the lesions.
In at least two patients, an effective amount of nonoxynol-9 for treating herpes zoster (shingles) was combined with hyaluronic acid and/or salts thereof and was successfully employed to treat the herpes zoster (shingles).
CASE XVI:
A dentist with melanoma, age 51, developed acute herpes zoster in the 9th thorasic dermital on the left side of his body. He was in excruciating pain, not relieved by classical medications. Dr. Falk asked him to take orally cyclofur as an antiviral but he did not begin this immediately. However, Cr. Falk also indicated that he should take Delfen™ and LifeCore™ hyaluronic acid, mix equal portions and then apply this topically. He did this and had immediate relief of pain within 5 minutes. The pain has remained absent for the next 4 days. In addition, the lesions of herpes zoster immediately began to disappear within the first 24 hours and now, 5 days later, none are apparent. This is a dramatic response suggesting a major antiviral affect of this combination, with the hyaluronic acid obviously enhancing penetration.
CASE XVII:
This man developed stomach cancer which metastasized to his liver. He was treated for seven mcnrhs with low dose chemotherapy (5 FU) , low doses of mitomycin and novantro.ne with various amounts of hyaluronic acid, and Vitamin C (50gm daily) . There was no detectable tumor. He is now in remission and all tumors are calcified.
CASE XVIII:
This male patient had a serious oar accident, shortly thereafter he developed colon cancer which was resected with multiple liver metastases . He came to Cr. Ealk in June, 1989. He was treated with chemotherapy (phloretin) and hyaluronic acid with heat. He remained stable for approximately one year, then his alkaline phosphatase began creeping up. Consequently, Dr. Falk treated him with Vitamin C (50gm daily for three days), hyaluronic acid (up to 300mg daily), indomethacin in N-methyl glucamine (300mg daily in the 300mg of hyaluronic acid), and Toradol™ (60mg) once or twice daily with hyaluronic acid (50mg). Since that time he has shown improvement. His alkaline phosphatase decreased, and therefore his liver is functioning better .
CASE XIX:
This man, age 46, was diagnosed in the last three months with a difficult to treat broncheoiar alveolar carcinoma of the lung. Appropriately, neither chemotherapy nor major amounts of radiation were used, although spot radiation was given to two areas; one on either side of she chest where there apparently was some indication of skeletal involvement.
Subsequent to that, the patient visited a cardiopuImona ry transplant unit in London who thought that a transplant might be appropriate but there was a waiting list of about one year .
After this the patient went to Dr. Frederick Douwe's clinic in Germany and was placed on a variety of regimens, the main direction of which includes; (a) immune enhancemenc at the T-cell level; and (b) free radical scavenging and detoxification .
He has improved somewhat since this treatment was
AP 0 0 0 1 7 5
BAD ORIGINAL initiated with episodes when he is very short of breath, having had one of those 24 hours ago.
On examination he has very severely diminished air entry on both sides with bilateral rales and ronchi. There is no evidence of supraclavicular adenopathy. There is no evidence of skeletal tenderness at this point or of hepatic enlargement.
He then came to Dr. Falk and he treated him with Vitamin C (50gms), non-steroidal indomethacin (NSAID)(100 mg reduced from initial amount of 300mg because of heartburn) dissolved in hyaluronic acid (300mg). He improved dramatically after the first 5 days of therapy with reference to lung capacity and radialogical appearance on the X-ray.
Dr. Falk then prescribed daily injections of hyaluronic acid (300mg) with Toradol™ (60mg) to be taken at home (home being outside of Canada).
Comparison has been made to the previous examination. Since that previous examination, there has been resolution of some of the increased interstitial markings so that the lungs now look clearer than they did on the previous exam. Nonetheless, increased interstitial markings are still present within both lung fields.
CASE XX:
A female patient, age 74, was diagnosed with cancer of the colon and was resected. The cancer had however mestastasized to the liver (right lobe) . Over a one month period, she was treated twice with methotrexate (2 5 njg) in hyaluronic acid (400mg) intraperitoneally, five times with oncostatin (2 gm) in hyaluronic acid (300 - SOO.mg) , Vitamin 7 (5Cgm) in hyaluronic acid (3C0mg), and indomethacin (NSAIDι given twice, lOOmg of indomethacin in 300mg hyaluronic acid and 250mg of indomethacin in 50Cmg cf hyaluronic acid.
The patient is now doing very well, feeling better, and the liver tumor is regressing (shrinking).
CASE XXI:
This female patient, age 51, was diagnosed with cancer of the uterus which had spread to the lungs (leiomyosarcoma).
Dr. Falk treated her with various doses of oncostatin (low doses of 0.5gm to 3gm) with hyaluronic acid (300-500mg)^-'^itamin C
(50gm) in hyaluronic acid (300mg), and indomethacin in hyaluronic acid (intraperitoneally and intravenously).
The pelvic mass is presently regressing and the lungs are now stable.
CASE XXII:
This man, age 52, has a history of Crohn's Disease and chronic infection in the bowel from Crone's disease. He eventually developed a tumor in the peritoneum (adenocarcinoma). The patient was treated with doses of 2gm and 3gm of Oncostatin™ (phloretin) each in hyaluronic acid (500mg) and DMSO (total of 2000). Doses of indomethacin ranging from 75mg to 450mg in 200 to 700mg of hyaluronic acid were given. Patient was also treated with Vitamin C (50gm) in hyaluronic acid (300mg), and naproxen (Igm) in hyaluronic acid (400mg). These treatments were given to the patient via several routes intraperitoneally, intravenously, rectally (for detoxification) (insertion of catheter and administered rectally). The pain is now gone .
Patient was given CT Scan of the abdomen and pelvis.
There is moderate hepatic steatosis without evidence of metastatic disease. The spleen, pancreas, adrenals and right kidney appear normal. There is a left nephrostomy tube in place with no evidence of residual hydronephrosis. There is a large and necrotic tumor mass occupying most of the deep pelvis with anterior displacement of the urinary bladder and likely some invasion of the prostate gland. There is no evidence of sacral destruction although the rectal tumor is closely apposed to its anterior surface.
L I· 0 0 0 dV
Thus there appears to be a large and necrotic pelvic tumor mass without evidence of sacral destruction, para-aortic lymphadenopathy or distal visceral mefastases. A left percutaneous transrenai ureteral stent is in place.
The patient was seen August 1, 1990, in the clinic and he has been feeling very well. He is doing extremely well; the necrotic tumor mass is slowly reducing in size.
CASE XXIII:
This female patient, age 47, was diagnosed in January, 1990. A gastric resection and colonic replacement of oesophagus (for swallowing) was performed. She had also developed an intraperitoneal tumor. She was given chemotherapy and lost her hair. (Dr. Falk gave her minoxidil and hyaluronic acid to apply to her scalp and her hair grew back). Dr. Falk saw this patient on June 6, 1990, and gave her lower doses of phloretin together with heat and hyaluronic acid, indomethacin in hyaluronic acid, and Vitamin C in hyaluronic acid.
Since the time of treatment, the patient has made good improvement. She has gained weight, and is no longer feelirfg any pain. The carcinoembryonic antigen is down to 26 nonograms/mi and steadily falling.
CASE XXIV:
This man (age 45) first seen by Dr. Falk on March 1, 1988, he was diagnosed with carcinoma of the pancreas. He was treated with DMSO and heat together with low doses of chemotherapy. Dr. Falk injected the DMSO and the other drugs into the tumor. More than one year later, this patient was given treatments with Vitamin C, and other agents in hyaluronic acid. This patient is now in complete remission. He has not been treated in more than six months.
CASE XXV:
Dr. Falk saw this female patient (age 62) in August, 1989. This woman was diagnosed with carcinoma of the pancreas. She was treated with low doses of chemotherapy (5-FU and mitomycin) together with 30Cmg of hyaluronic acid and heat.' She was having trouble with her bile ducts. She was operated on, but a tumor was not found and the bile ducts were bypassed. The patient was then treated with indomethacin and Vitamin C in hyaluronic acid, and the heating treatments were stopped. Since her treatment she has experienced a gain in weight and there is no evidence of a significant tumor.
CASE XXVI:
This female (age 18) patient was treated for infectious mononucleosis. Three months of testing the patient resulted in positive heterophile antibody tests. Patient had no energy. The patient was given 50gm of Vitamin C _and 300mg of ___—---BAD UHIGINAT hyaluronic acid. Within sixteen hours of the treatment her energy increased dramatically and within two weeks the heterophile antibody test became negative.
CASE XXVII:
This woman (age 65) patient illustrates important points. Her previous chemotherapists did not recognize they had killed most of her tumor. She had been taking chemotherapy previously. However as the tumor was breaking up, as Dr. Falk has now concluded, there was a retention of water fluid in the area of the tumor (they should have looked at the ultrasound for assistance) . Dr. Falk saw her and treated her with heat, phloretin, Vitamin C, indomethacin and some 5-FU, ail in hyaluronic acid. (According to her previous doctors, she had an enlarged tumor after taking 5-FU. Therefore, they stopped chemotherapy). The patient is now looking better and feeling better and there is no edema.
CASE XXVIII:
This female patient had carcinoma of the ovary with intermittent to complete bowel obstruction with encasement of the bowel with tumor and also significant amounts of pleural fluid. The most striking example of the effect of Lasix (furosemide) occurred under the following circumstances. Cn April 28th and 29th, 1990, the patient excreted a total volume of 2,450mi of urine over 48 hours despite the administration of.33 per cent sodium chloride solution with added potassium chloride at 40 mEq/1 administered at the rate of 10C-125ml per hour. The patient's body weight was 4Ckg. During this period of time the patient received 12C-200mg cf Lasix administered intravenously.
On April 30th, she received 40mg of Lasix with added 350mg of hyaluronic acid administered over half of an hour. She produced a diuresis within the following 5 hours of 2,500ml of urine. During the evening hours with no additional Lasix being given, urine output fell dramatically and she excreted only 400ml of urine from 7:00 p.m. April 30th to 7:00 a.m. May 1st. At 7:30 a.m. she received 40mg of Lasix in 300mg of hyaluronic acid administered intravenously. Over the next 8 hours, this patient produced 2,600ml of urine. This case demonstrates the
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BAD ORIGINAL fact that even a relative insensitivity to furosemide (Lasix) can be overcome with the addition of hyaluronic acid to enhance drug penetration to the appropriate area.
The similar type of phenomena has been observed by us in patients where there is a so called hepatorenal syndrome and where the kidney stops excreting urine due to the failure of the liver to function adequately. Under these circumstances, urine output may decrease to essentially zero levels. This can be dramatically effected by furosemide (Lasix™) administered intravenously in hyaluronic acid, even though furosemide (Lasix™) administered by itself produced no effect.
CASE XXIX:
In normal healthy individuals, it was observed that adding hyaluronic acid to furosemide (Lasix™) administered at a dose of 20mg intravenously with 300mg of hyaluronic acid, there was an increase of urine excretion by 3 to 5 fold as compared to that observed with furosemide (Lasix™) alone. This is citeo as evidence that hyaluronic acid increases penetration/permeation of the drug and thus facilitates its function.
CASE XXX:
This balding patient applied minoxidil (Rogaine) topically to his scalp. There was minimal or little hair growth. Subsequently, the minoxidil was applied together with hyaluronic acid continuously every 2 to 3 days. As a result this patient's hair has grown fuller and more rapidly.
CASE XXXI:
This female patient (age 32) was diagnosed as having an epitheloid sarcoma on the basis of a Mayo Clinic review.
Her history of the disease dates back to Lecember 12, 1973, when she developed nodularity in the left ring finger which was excised. She has had recurrent episodes of this type of problem since then and has had an amputation of the left 4th finger. She has been extensively staged and investigated as she was found to have nodules of the same type of disease up her arm and a left axillary lymph node biopsy was positive in March, 1990 for an epitheloid sarcoma.
At the Mayo Clinic she received thre£-,courses of
j η chemotherapy with mitomycin C, adriamycin, crspiatinum in high doses without any response. She was scheduled for a forequarter amputation for the sarcoma of the left arm and forearm.
This patient was first seen by Dr. Falk on June 25, 1990, and was treated for three days with heat, phloretinhyaluronic acid, vitamin C-hyaluronic acid, methotrexatehyaluronic acid, and also received solu-medrol . She did not have a clear response at that point in time and the lesions remained the same.
She returned on July 23 and was treated for three consecutive days with a reduced dose of phloretin, same dose of vitamin C-hyaluronic acid and received both naproxen and indomethac in with hyaluronic acid both subcutaneously and intravenously. She returned home and received Toredol™ (Syntex - non-steroidal anti-inflammatory drug) intra-muscularly on a daily basis at a dose of 30-120mg administered once or twice per day with lOOmg of Hyal Pharmaceutical type hyaluronic acid.
She was reassessed on August 20 and has had a dramatic decrease in size of all measurable disease by greater than 50%. [·>, In fact, at this point, biopsy would have to be done to ascertain if there is any viable tumor present. The treatment plan is to continue on the Toredol™ and hyaluronic acid.
While the patient had some minimum response with heat, phloretin, conventional chemotherapy with the addition of hyaluronic acid with these drugs, she did have an excellent response with the non-steroidal anti-inflammatory drugs using all three types; Indocid™, naproxen and Toredol™ when combined with hyaluronic acid as a carrier/'penetrating vehicle to facilitate targeting to pathological tissue. She has had few if any of the standard side-effects that occur with the nonsteroidal anti-inflammatory drugs.
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CASE XXXII:
This male was diagnosed as having gastric cancer in 35 1988. The tumor was in the distal third of the oesophagus at the gastro-oesopageal junction. A Celestine tube was placed by an intraoperative abdominal procedure and sutured to the lesser curvature of the stomach.
The patient was treated from January, 1990 up until 3 40 months ago (June, 1990) . Repeated CAT scans have sho^y nov^ * -___BAD-ORONAC change in any situation; symptomatically he had been completely well. Most recent CAT scan was June 26, 1990. This raised questions in respect of some areas in the liver; however, sonographic examination suggested that these were in fact homogenous.
On July 4th he had some hot dogs at a picnic. During the night he woke up with acute left upper quadrant pain which was not associated with nausea or vomiting. Subsequent to this he had episodes of pain essentially every time he consumed any food. The pain was always the same, felt in the back and the front of the abdomen and tended to spread to both flanks. It has never been associated with any direct peritoneal tenderness, vomiting, diarrhea or fever and chills. Investigation included the previous CAT scan done just eight days prior to the onset of this pain, and an upper GI series with follow-through. Further CAT scan now could not be done because he was still full of barium.
It is important to recognize that a significant dose of Demerol just barely relieved his pain. Further examination is unremarkable. There were no abdominal, thoracic or lymph node findings to suggest any spread of the disease.
Dr. Falk reviewed the X-rays with a Professor at the Department of Radiology, Toronto General Hospital, University of Toronto. He suggested that the upper GI series was a classical picture of tethering of the small bowel. He said, this could be either from fibrous adhesions or from neoplastic disease, or indeed, a combination of both, as is very common with adenocarcinoma cf the stomach. However, the neoplastic seedings would necessarily be very minimal, as nothing shows on the previous CAT scan.
Dr. Falk treated the patient with a combination of non-steroidal anti-inflammatories administered intravenously with hyaluronic acid in conjunction with hyperthermia and oncostatin, which is a combination of phloretin and hyaluronic acid and achieved almost immediate relief of pain. He can now eat without having symptoms (had lobster soup recently at one of the local restaurants).
Dr. Falk has also given him a supply of probanthine which he could use, as the type of pain that occurs with these
4Q type of adhesions is usually relieved by one the anti---BADORIGINMt43 cholinergic drugs. Dr. Falk has also suggested to him to come back for further therapy and continue when he goes home on a combination of felden lOmg b.i.d. and naprosyn 500mg directly as suppository once per day and take zantac 150mg twice a day.
In addition Dr. Falk placed him on Vibramycin (Doxycyline) 200mg for one day and a lOOmg daily dosage for fourteen days. This is an antibacterial agent and also blocks intracellular and anerobic glycolosis.
Follow-Up
Recent biopsies showed chronic inflammation of the lower one third of the oesophagus (tube in oesophagus recently removed); however, there were no malignancies found.
CASE XXXIII:
This man has had major tumor breakdown and this has occurred only after chemotherapy was omitted from the treatment regimen. This initially made him significantly more ill; this was reflected only to a minor extent in terms of his hepatic function tests. The alkaline phosphatase did become elevated. He had profound malaise, weakness, excessive fatigue and loss of appetite. This has been corrected by intensive use of indomethacin in hyaluronic acid and detoxification programs.
He was reassessed and was significantly better. Under ultrasound, the tumor shows virtually total necrosis. There is now increased normal liver tissue present.
CASE XXXIV:
This man had a chronic abscess cavity in his pelvis with a bowel obstruction which necessitated an cceration on
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January 5, 1 990. At that time che cavity was irrigated out and
drained through the perineum. He had an uneventful post-
operative course and was discharged frcm hcspi ed I on January 18,
1990.
However, subsequently he developed a fever and because this had been a large cavity in the pelvis, it now drained through the lower anterior part of his abdominal incision. This occurred two weeks prior to the present visit.
Dr. Falk assessed him. This is a large cavity and he thought that this would take 4 to 6 weeks to close. Dr. Falk
BAD ORIGINAL instituted daily irrigations during the 5 day working week with ampiciiiin, flagyi and hyaluronic acid using 5C0mg of ampiciiiin and 500mg of flagyi. This is a very benign form of treatment in contrast to what Dr. Falk would usually use which would consist of irrigation and packing the area open.
When seen later, the abscess cavity had closed over. The patient advised that the visiting nurse on the weekends had difficulty putting a catheter into this cavity over Saturday and Sunday and in fact could not gain entrance of the catheter-. Dr.
Falk concluded that the cavity had granulated in from the bottom up but has done so much more rapidly than he would have anticipated. In view of the fact that this is a chronic cavity in a patient who has had a chronic and ongoing problem in the pelvis, this is clearly an unanticipated result with a much more rapid and better resolution of a chronic abscess cavity than anticipated.
Dr. Falk has instructed the patient to call if he develops any temperature subsequent to this. He has had a mild itching sensation over his skin which Dr. Falk believes is probably a reaction to cold and for which he gave him an ointment to be applied daily.
CASE XXXV:
Woman had a 9th and 12th nerve lesion, which was 25 thought was located just lateral to the base of the skull. It was also thought that she may have had metastases in the region of the de.ntoid process, and an MRI scan was undertaken to try and demonstrate this. It showed somewhat abnormalities in the appropriate area. A CT scan of the region was unhelpful.
The patient then attended The Ontario Cancer Treatment and Research Foundation and was found to have very advanced malignant melanoma, and was discharged from the hospital with a hopeless prognosis.
Much later the people of Ontario Cancer Treatment and 35 Research Foundation were surprised and delighted to find that she had responded unbelievably well to both positive mental imaging and to Dr. Falk's treatment. This involved hyperthermia and chemotherapy in hyaluronic acid. Dr. Falk used usual doses of Carboplastin and low doses of Methotrexate in the hyaluronic acid. - ----BAD ORIGINAL
Her chest now appears clear, and she has some persistent lesions in kidney and liver, but these may well be under control. During the summer, her tongue got better, and no longer deviated to the left. However, during the last three or four weeks, things have deteriorated from that point of view.
On recent examination, the neurological examination was entirely normal, except for a deficit (incomplete) ingag on the left side of the pharynx, and a problem with some fasciculations and atrophy of the left side of her tongue.
This patient has done remarkably well.
Follow-Up
More recently this woman has been administered hyaluronic acid (30Cmg daily), NSAID and Vitamin 0 (5Cgm daily).
The patient appears now to be clear of tumour.
CASE XXXVI:
This man has a mesothelioma following surgical resection and then adjuvant treatment. It is now seven years since the initial diagnosis. In the spring of this year he developed a recurrence while in Florida. Although Dr. Falk has biopsied this three times, Dr. Falk has never obtained cells diagnostic of malignancy. However, clinically the situation is very clear from the CAT scan, liver function test and ultrasound.
This patient has been treated with phloretin in hyaluronic acid, and heat to the area. Initially, he did not show a major response. However, on the last occasion he received no chemotherapy and only phloretin in hyaluronic acid with a higher dose of hyaluronic acid. He has had a major response and has had major problems with accumulation of fluid, Dr. Falk believes, secondary to tumor breakdown. The tumor breakdown is clearly apparent on the sonographic assessment; here there is actual liquification of the tumor.
During his present stay, he was treated one day with hyperthermia and received phloridzin in hyaluronic acid. However, he required an additional two days of treatment with Vitamin C in hyaluronic acid to assist in detoxification. He also received additional diuretics Lasix™ (furosemide) with hyaluronic acid. ________—
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His creatinine which was 400m mols'l has decreased tc
155y mcis/l (kidney function tests - went from high to almost normal). Dr. Falk has instructed him regarding further management. Dr. Falk does not think the patient will require major further therapy as Dr. Falk thinks the majority of this tumor has been destroyed, through his own immune response, the antibody and the soluble mediators being allowed to enter into the tumor by hyaluronic acid.
In July, 1990 moderate ascites (fluid in ^body) occurred. The patient was given furosemide (Las ix™) and hyaluronic acid, indomethacin and hyaluronic acid. The patient's urine output increased substantially and the problem cleared .
CASE XXXVII:
A 37 year old female had a carcinoma of the cervix which was a class IIIB at the time of diagnosis. She was treated by radiation at the Cross Cancer Centre, unsuccessfully, and developed further growth of the tumor which was diagnosed approximately 1 to 2 months after the radiotherapy. She was then seen by Dr. Walde at the Sault Ste. Marie hospital. He administered epirubicin, cisplatinum at high doses and did produce regression of the tumor as assessed by intravaginal assessment and biopsy, but apparently there was regrowth and worsening of the pain with partial ureteric obstruction demonstrated as shown by a CT scan of the abdomen and pelvis done June 28, 1990.
At laparotomy, the patient had extensive tumor with major areas of necrosis but tumor extending to and involving the left common iliac artery and vein producing obstruction of the vein, the tumor was considered not resectable for surgical cure because of its extent in the lateral true and false pelvis to the pelvic wall. This was assessed by a urological and two general oncological surgeons.
For this reason and because of imminent rectal obstruction, a colostomy was performed. In addition, the urological surgeon established an ileal conduit.
This patient was in excruciating pain continuously for several weeks prior to and after the surgical procedure. This
BAD ORIGINAL necessitated high doses of intravenous morphine with only partial control of the pain. Cn July 3th she was noted to have a major febrile reaction and a CAT scan that day showed an abscess in the left pelvis. This was drained under CAT scan localization and the patient was placed on systemic antibiotics with only slight improvement in her infectious symptoms.
She was brought to Dr. Falk on Wednesday, July 11th. She received Igm of ampiciilin through the draining catheter for the abscess with 500mg of hyaluronic acid. In addition, she received Img of ampiciilin intravenously and ancef and flagyl systemically in 500mg LifeCore™ hyaluronic acid. She also received lOOmg of indomethacin with 500mg LifeCore™ hyaluronic acid intravenously. Within 12 hours her pain had dramatically decreased, all infective symptoms were eliminated and the drainage from the abscess cavity had almost stopped. Her massively enlarged left leg due to venous and lymphatic obstruction improved to almost normal size within a 12 hour period of t ime.
The patient was subsequently treated further with the same regimen for the next 3 days resulting in total relief of pain and continued improvement in her status, to the point where she could be discharged from the hospital on July 13th without anti-biotic therapy. Her systemic analgesia with morphine agents had been eliminated. There was no hyperthermia and no cytosis chemotherapy and/or Oncostatin (phloretin) utilized in this patient. She received anti-oxidant therapy with hyaluronic acid concomitantly with the indomethacinhyaluronic acid. This patient has demonstrated a very dramatic improvement emphasizing that the indomethacin-hyalurcnic acid is tZ.HITQG'lj.xfiQ S p C ΐ ί 3 L L V * O CH * ?. O 1 ΟΟ ί ' * ί. S S ΟΘ * C Σ’ V L Γ 07 macrophage function at this site and allowing the body's immune system to perform appropriate tumor destruction.
CASE CASE XXXVIII:
A male patient suffering from HIV (AIDS) was treated with indomethacin (NSAID,, Vitamin C, interferon and DMSO and/or hyaluronic acid and unexpectedly the patient is steadily
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CASE XXXIX:
A male patient suffering from kyphosis suffered from constant back pain. Taking analgesics orally and rubbing back preparations onto his back, did little to alleviate the back pain. When NSAIDS in hyaluronic acid (sodium hyaluronate) were applied directly to the back, the back pain eased and disappeared.
With indomethacin (dissolved in N-methyl glucamine) and naproxen both dissolved in hyaluronic acid, the patient experienced side effects. However, with Toradol™ (the [+/-] form tromethamine salt of ketorolac - a prostaglandin biosynthesis inhibitor and analgesic and anti-inflammatory, the back pain eased and disappeared for seme time and there were no side effects.
CASE XL:
This male patient was diagnosed with HIV (AIDS) and as a possible result thereof, an undetermined neoplastic disorder in the lungs. Before treatment, the patient was near death; white cell count was 1.4 X l09/litre. The patient was treated intravenously with indomethacin (30Cmg), Vitamin C (50gm daily) and hyaluronic acid (sodium hyaluronate) (300mg). After treatment, the patient's platelet count rose to 65 X 109/litre. and his white ceil count rose to 8.2 X 109/iitre. His lymphocytes doubled.
Further Tests_(Animal)
Further tests were conducted on animals (rats) with the indicated results:
Enhanced Activity of Antibiotics with hyaluronic aoic. A chronic abscess rat model was used. Sprague awley Fats were used. Pellets of bacteria were inserted into each cf the bellies of the rats and then the rats were treated as indicated. In this model therapeutic activity of gentamycin was compared to gentamycin in hyaluronic acid the results demonstrate a statistically significant improvement by the combination over the antibiotic alone. In this regard lower doses of antibiotic in antibiotic refractory situations were required as a result of the antibiotic being administered with hyaluronic acid.
tAD ORIGINAL
SAVING NO »7 P A ή i i C j LAP L’T u«_ J Adu AGO \ ' MY/OUR SAID INVENTION AND IN WHAT MANNER THE SAM TO bE PERFORMED. l/WE DECLARE THAT l/WE CLAIM IS.THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE AS FOLLOWS:

Claims (37)

1. A combination for administration to a mammal which combination employs a therapeutically effective amount of a medicinal and/or therapeutic agent to treat a disease or condition and an amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid sufficient to facilitate the agent’s penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual cells to be treated.
2. The combination of Claim 1 wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid is an amount of hyaluronic acid and/or salts.
3. The combination of Claim 1 or 2 wherein the medicinal and/or therapeutic agent comprises an agent selected from a free radical scavenger, ascorbic acid, Vitamin C, an anti-cancer agent, chemotherapeutic agent, anti-viral agents, non-steroidal anti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents, analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics, immunosuppressants, lymphokynes, alpha-and-3-interferon and combinations thereof.
4 . The combi and/or therapeutic ascorbic acid, an inflammatory drugs, thereof .
lation of Claim 2 wherein the medicinal agent comprises an agent selected from anti-cancer agent, non-steroidal antiantibiotics, diuretics and combinations
5. The combination of Claim 1, 2 or 4 inclusive wherein the hyaluronic acid and/or salts thereof and or the homologues,
A standard rat skin graft rejection model was used. Cyclosporin was the immunosuppressant used. The results indicate that hyaluronic acid significantly increased cyclosporin induced graft survival .
CYA+HA# C-HAFT SURVIVAL OF DIFFERENT T 'REATMENTS ( days JULY 12. 1990) da vs CyA# 1 20 7 20 2 19 8 20 3 19 9 20 4 20 10 19 5 19 11 19 6 20 12 20 13 21 20 19 14 19 21 17 15 18 22 14 16 20 23 14 17 20 24 14 18 20 25 19 19 20 mean 19.615 17.917 SE 0.213 0.723 CyA+HA vs . CyA = P value, one-way ANOVA = <0.05 (=0.0287) LSDMRT = <0.05 CyA = Cyclosporin HA = Hyaluronic Acid As many changes can be made to the invention wi depart ing from the scope of the invention ί, it is intended all material contained he rein be in hero re' ;ed as illustrate
the invention and not in a limiting sense.
BAD ORIGINAL b* *. j '» Λ · ·\ ~ . .· w : . ., u*, J Ai*L· Aj*.
MY CUR SA.O VNj k\ WHAT MANMtR TM£ £·'·
TO fcE PERFORMED. I. WE 2X01/ RE THAT l/WE CLAIM IS.·
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY CR PRIVILEGE IS CLAIMED ARE AS FOLLOWS:
1. A combination for administration to a mammal which combination employs a therapeutically effective amount of a medicinal and/or therapeutic agent to treat a disease or condition and an amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the ceil membranes into the individual cells to be treated.
2. The combination of Claim i wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid is an amount of hyaluronic acid and/or salts.
3. The combination of Claim 1 or 2 wherein the medicinal and/or therapeutic agent comprises an agent selected from a free radical· scavenger, ascorbic acid, Vitamin C, an anti-cancer agent, chemotherapeutic agent, anti-viral agents, ncn-steroidal anti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents, analgesic, bronchodilator, anti-bacteriai agent, antibiotics, drugs for the treatment of vascular ischemia anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics, immunosuppressants, lymphokynes, a lpha-a.nd-3 - inte rfe ron and combinations thereof.
a n d / c asccr in f ia b i c acid, mma t o r v d:
omb i nation of Cl it ic agent comer an anti-cancer ugs, ant ibiot ics
.aim 2 wherein the medicinal ises an agent seletted frtm agent, non-steroidal ant i, diuretics and combinations thereof .
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5. The combination of Claim 1, 2 cr 4 inclusive wherein the hyaluronic acid and/or salts thereof and or the homologues, analogues, derivatives, complexes, esters, fragments and
BAD ORIGINAL the raceutic subunits are separate from the medicinal and/or agent.
6. The combination of Claim 1, 2 or 4 wherein the combination is to be administered concurrently.
7. The combination is combination of Claim 1, 2 or 4 to be administered at the identical wherein» site.
the
8. A method of treating a condition or disease *in a mammal comprising administering to the mammal a therapeutically effective amount of a medicinal and/or therapeutic agent, to treat the disease or condition and a sufficient amount of hyaluronic acid and/or salts and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid thereof sufficient to facilitate the penetration of the agent through the tissue (including scar tissue) at the site to be treated through the cell membranes into the individual cells to be treated.
9. The method of treating a condition or disease in a mammal of Claim 8, wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid is an amount of hyaluronic acid and/or salts thereof.
10. The method of Claim 8 or 9 wherein the medicinal and/or therapeutic agent is selected from a free radical scavenger, ascorbic acid, Vitamin C, an anti-cancer agent, chemotherapeutic agent, anti-viral agents, non-steroidal antiinflammatory drugs (NSAID), steroidal anti-inflammatory drugs anti-fungal agent, detoxifying agents, analgesic, bror.chodilator, anti-bacteriai agent, antibiotics, drugs for the treatment of vascular ischemia, anti-bodv monoclonal agent, minoxidil for topical application for hair growth, diuretics, immunosuppressants, lymphokynes, alpha-and-3-interferon and combinations thereof.
11. The method of Claim 9 wherein the medicinal and/or
S L I· 0 0 0 dV therapeutic agent is selected from ascorbic acid, an anti-cancer agent, non-steroidai anti-inf i ammato ry drugs, antibiotics, diuretics and combinations thereof.
12. The method of Claim 8, 9 or 11 wherein the combination is administered simultaneously at the identical site.
13. The method of Claim 8, 9 or 11 inclusive wherein the hyaluronic acid and/or salts thereof is utilized at a dose of from about 10 to 1000 mg/70 kg person.
14. The combination for the treatment of psoriasis of a therapeutically effective amount of methotrexate with hyaluronic acid and/or salts thereof sufficient to facilitate the methotrexate's penetration through the tissue of the site to be treated.
·' *
15. The combination of Hyaluronic acid and/or salts thereof with a cytotoxic chemotherapeutic agent selected from adriamycin, methotrexate, mitomycin C, bleomycin, 5Fluorouracil, novantrone, carbo and cis platinum, and combinations thereof.
16. The combination of an agent selected from phloridzin, phloretin, and 5-deoxyglucuronide of phloridzin; Vitamin C; and a non-steroidal anti-inflammatory drug, and combinations thereof to competitively block glucose transport in neoplastic cells and an amount of hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual ceils to be treated and where phloretin. is the selected agent, it is solubilized by a solubilizing such as N - methyl glucamine.
17. The combination of a therapeutically effective amount of a brohchodilator with hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual cells to be t reated.
18. The combination of a therapeutically effective amount of alpha 2 - interferon with hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual cells bo be treated.
19. The combination of a therapeutically effective amount of a diuretic with hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual cells to be treated .
20. The combination of a therapeutically effective amount of a medicinal and/or therapeutic agent selected from an antibiotic and/or anti-bacterial agent with hyaluronic acid an/or salts thereof sufficient to facilitate the agent’s penetration through the tissue (including scar tissue) at the site to be treated, through the cell· membranes into the individual cells to be treated.
21. The combination of a therapeutically effective amount of ascorbic acid (Vitamin C) for the treatment of mononucleosis with hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual ceils to be treated.
22. The combination of a therapeutically effective amount of minoxidil for the growing of hair on a mammal with hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual ceils to be treated.
23. The combination of a therapeutically effective amount
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BAD OR»G’nal of a non-steroidal· anti-inflammatory drug (NSAID) with hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual cells to be treated.
24. The combination of a therapeutically effective amount of an immunosuppressant and hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual cells to be treated.
25. The combination of a therapeutically effective amount of an anti-viral agent and hyaluronic acid and/or salts thereof.
26. The combination of Claim 25 where the antiviral agent is a nonionic surfactant.
27. The combination of Claim 26 wherein the anti-viral agent is nonoxynol-9.
28. A combination suitable for use to treat a condition or disease, the formulation comprising a therapeutically effective amount of a medicinal and/or therapeutic agent to treat a disease or condition in an amount of hyaluronic acid and/or salts thereof and dimethyl sulfoxide sufficient to transport the agent to the site to be treated and to penetrate through the tissue (including scar tissue) through cell membranes into the individual cells to be treated.
29. The combination of Claim 28 wherein the agent comprises a compound selected from phloridzin, phloretin and 5deoxyglucuronide of phloridzin, ascorbic acid and a nonsteroidal anti-inflammatory drug.
30. The combination of Claim 28 wherein the agent comprises a compound selected from phloridzin, phloretin and 5deoxyglucuronide of phloridzin.
BADOniGINAl—-6
31. For the treatment of diabetes, the combination of a therapeutically effective amount of insulin and hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue {including scar tissue) at the site to be treated, through the cell membranes into the individual cells to be treated.
32. For the treatment of post-menopausal female mammals, the combination of a therapeutically effective amount of estrogen and hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual cells to be treated.
33. For the control of fertility, the combination of a therapeutically effective amount of progestegen and hyaluronic acid and/or salts thereof sufficient to facilitate the agent's penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual cells to be treated.
34. For use to treat a disease or condition in a mammal with a medicinal and/or therapeutic agent, a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid to facilitate the agent at a site in the mammal· to be treated by the agent passing through the tissue (including scar tissue) through the ceil membranes into the individual cells to be treated.
35. For use to treat a disease or condition in a mammal a therapeutically effective amount of a medicinal and/or therapeutic agent with a sufficient amount of hyaluronic acid and salts thereof to facilitate the agent at a site in a mammal to be treated by the agent passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
36. For the use according to Claim 46 or 47 wherein the s L I· o 0 0 dV
BAD ORIGINAL agent is selected from a free radical scavenger, ascorbic acid, Vitamin C, an anti-cancer agent, chemotherapeutic agent, antiviral agents, non-steroidal anti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs, anti-fungi agent, detoxifying agents, analgesic, bronchodiiator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia, antibody monoclonal agent, minoxidil for topical application for hair growth, diuretics, immunosuppressants, lymphokynes, alphaand-fl-interferon and combinations thereof.
37. The use of Claim 46, 47 or 48 acid and/or salts thereof is utilized at wherein the hyaluronic a dose of from about -
10 to 1000 mg/ 70 xg person • 38 The combinat ion of Claim an anti-cancer agent. 39 The combinat ion of Claim an anti-viral agent. 40 The combinat ion of Claim an anti-fungal agent. 41 The combinat ion of Claim an analgesic . 42 The combination of Claim
bronchodiiator.
1 or 2 wherein the agent is
1 or 2 wherein the agent is
1 or 2 wherein the agent is
1 or 2 wherein the agent is or 2 wherein the agent is a
43. The comb/nation of Claim dfl 3Πt-i—CeC'Sericil 3C6Γ. , .
wherein Θ 3 C 6 Π t
44. The combination of Claim 1 or 2 wherein the agent is an antibiotic.
45. The combination of Claim 1 or 2 wherein the agent is and anti-inflammatory agent.
46. The combination of Claim 1 or 2 wherein the agent is
BAD ORIGINAL an anti-body monoclonal agent.
47. The combination of Claim 1 or 2 wherein the agent is an immunosuppressant .
48. The combination of Claim 2 wherein the agent is a lymphokynes. ϊ
49. The combination of Claim 49 wherein the lymphokyne is interleukin - 2.
50. The combination of Claim 1 or 2 wherein the agent is interferon .
51. The combination of Claim 1 or 2 wherein the agent is ascorbic acid (Vitamin C).
52. The combination of Claim 1 or 2 wherein the agent is a free radical scavenger.
53. The combination of Claim 1 or 2 wherein the agent is a chemotherapeutic agent.
54. The combination of Claim 1 or 2 wherein the agent is a non-ionic surfactant.
s L I o 0 0 dV
55. The combination of Claim 1 or 2 wherein the agent is a non-steroidal anti-inflammatory drugs (NSAID).
56. The combination of Claim 1 or 2 wherein the agent is a steroidal anti-inflammatory drug.
57. The combination of claim 1 or 2 wherein the agent is a detoxifying agent.
58. The combination of claim 1 or 2 wherein the agent is a drug for treating vascular ischemia.
59. The combination of claim 1 or 2 wherein the agent is
BADORIGINAL minoxidil for topical application for hair growth.
60 . The combination of claim 1 or 2 wherein the agent is a diuretic . 61. The combination of claim 1 or 2 wherein the agent is a non-ionic 9. surfactant and the non-ionic surfactant is nonoxynol- 62 . The combination of claim 1 or 2 wherein the agent is a non-ionic surfactant which comprises an ether or an amide
linkage between the hydrophilic and hydrophobic portions of the molecule .
63. The combination of claim 1 or 2 wherein the agent is a non-steroidal anti-inflammatory drug which is selected from indomethacin, naproxen and the (+/-) tromethamine salt of ketorolac and combinations thereof.
64. The combination of claim 1 or 2 wherein the agent is a diuretic which is furosemide.
65. A combination suitable for use to treat a person with AIDS, the combination comprising therapeutically effective amounts of ascorbic acid (Vitamin C), non-steroidal antiinflammatory drugs, and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at a site to be treated through the tissue (including scar tissue) through cell membranes into the individual cells to be treated.
66. The combination cf claim 65 wherein the amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
67. The combination of claim 66 further comprising interferon.
68. The combination of claim 66 wherein the non-steroidal anti-inflammatory drug is indomethacin.
69. The combination of claim 65, 66, 67 or 68 wherein the amount of hyaluronic acid and salts thereof or other forms thereof may be substituted by dimethyl sulfoxide (either in whole or in part). *
70. A combination suitable for use to treat a person with cancer, the combination comprising therapeutically effective amounts of ascorbic acid (Vitamin C) , non-steroidal antiinflammatory drugs, and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at a site to be treated through the tissue (including scar tissue) through cell membranes into the individual cells to be treated.
71. The combination of claim 70 wherein the amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
AP 0 0 0 1 7 5
72. The combination of claim 70 or 71 wherein the nonsteroidal anti-inflammatory drug is selected from indomethacin, naproxen and the (+/-) tromethamine salt of ketorolac.
73. For the treatment of cancer, the administration of a therapeutically effective amount of ascorbic acid, a. nonsteroidal anti-inflammatory drug, and at least one of an-.agent selected from an anti-cancer drug chemotherapeutic agent and detoxifying drug, and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
74. For the use of claim 74 wherein the hyaluronic acid
BAD ORIGINAL and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.·
75. For the use of claim 73 or 74 wherein the nonsteroidal anti-inflammatory drug is selected from indomethacin, naproxen and ketorolac trimethamine.
76. For hair growth, the topical administration of a therapeutically effective amount of minoxidil and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
c τ . ,3 f
77. For use to treat herpes, canker sores and shingles, the administration of a therapeutically effective amount of nonionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
78 .
and salts complexes, hyaluronic
For the use of Claim 77 wherein the .hyaluronic acid thereof and/or homoiogues, analogues, derivatives, esters, fragments and sub-units of hyaluronic acid is acid and/or salts thereof.
79. For the use of Claim 77 or 78 wherein the nonionic surfactant comprises an ether or an amide linkage becween the hydrophilic and hydrophobic portions of the molecule.
80. For the use in Claim 77 or 78, the nonionic surfactant is nonoxynol-9 .
81. For use to treat renal failure, cardiac insufficiency, .r' ...
BAD ORIGINAL hypertension and edema, the administration of an effective amount of a diuretic and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
82. For the use of Claim 81 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
83. For the use of Claim 81 and 32 wherein the diuretic is furosemide.
84. For use to treat infection, the administration of a therapeutically effective amount of an agent selected from antibiotics, antibacterials, antimicrobials and combinations therof with or without ascorbic acid and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
AP 0 0 0 1 7 5 and salts complexes , hyaluronic
86.
therapeut i
For the use of Claim 84 wherein the hyaluronic acid thereof and/or homologues, analogues, derivatives, esters, fragments and sub-units of hyaluronic-acid is acid and/or salts thereof.
For use to treat acne, the administration of a cally effective amount of an agent selected from antibiotics, antibacterials, antimicrobicals and combinations therof with or without ascorbic acid and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be
ORIGINAL treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
87. For the use of Claim 86 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
88. For use in the transplant of organs and tissue to reduce the likelihood of the rejection thereof, the administration of a therapeutically effective amount of an immunosuppressant and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
89. For the use in Claim 88 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
90. For the use in Cliam 88 or 89 wherein the immunosuppressant is a cyclosporin.
91. For use in treating inflammation, the administration of a therapeutically effective amount of a non-steroidal antiinflammatory agent \NSAIC) and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual ceils to be treated.
BAD ORIGINAL
92. For the use in Claim 91 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
93. For use in assisting in the elimination of tumour break down material (including toxins, residue and debris) in a person suffering from tumours, the administration of a therapeutically effective amount of a non-steroidal antiinflammatory agent (NSAID) and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
94. For the use in Claim 93 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
AP 0 0 0 1 7 5
95. For the use of Claim 91, 92, 93 or 94 wherein the nonsteroidal anti-inflammatory agent (NSAID) is selected from indomethacin, naproxen and [±] tromethamine salt of Ketorolac.
96. For use in detoxifying a patient of toxins, the administration of a therapeutically amount of a detoxifying agent and a sufficient amount cf hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
97. For the use of Claim 96 wherein the hyaluronic acid
BAD ORIGINAL and salts complexes, hyaluronic thereof and/or homologues, analogues, derivatives, esters, fragments and sub-units of hyaluronic acid is acid and/or salts thereof.
99. For the use of Claim 96 or 97 peritoneal dialysis.
in the form of
99. For use to treat a patient suffering from respiratory difficulties, the administration of a therapeutically effective amount of a bonchodilator or the like and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual ceils to be treated.
100. For the use of Claim 99 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
101. For use to treat vascular ischemia, the administration of a therapeutically effective amount of an agent suitable for use to treat the condition and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to
102. For the use of Claim 101 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
103. For use to treat a person suffering from AIDS (HIV virus) the administration of therapeutically effective amounts
BAD ORIGINAL of, ascorbic acid (Vitamin C), a non-steroidal anti-inflammatory agent and an agent selected from interferon, an anti-viral agent, an antibiotic, dimethyl sulfoxide [DMSO] and combinations thereof; a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual ceils to be treated.
104. For the use of Claim 103 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
105. For the use of Claim 103 or 104 wherein Dimethyl
Sulfoxide (DMSO) is substituted for some or all of the forms o hyaluronic acid.
106. For the use of Claim 103, or 104 wherein the non steriodal anti-inflammatory drug is selected from indomethacin naproxen and [±] tromethamine salt of Ketorolac.
AP0 0'0l7f
107. For use to treat herpes, the administration of a therapeutically effective amount of non-ionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the cis sue (including scar tissue) through the ceil membranes indo the individual cells to be treated.
108. For use to treat canker sores, the administration cf a therapeutically effective amount of non-ionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the
BAD ORIGINAL individual cells to be treated.
109.
For use to treat herpes zoster (shingles), the administration of a therapeutically effective amount cf nonionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the ceil membranes into the individual cells to be treated.
110. For the use of Claim 107, 108 or 109 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
111. For the use of Claim 107, 108 or 109, wherein the nonionic sufactant comprises an ether or an amide linkage between the hydrophilic and hydropholic portions of the molecule.
112. For the use of Claim 107, 108 or 109 wherein the nonionic surfactant comprises nonoxynol-9.
113. For use to treat infections surrounding implants in a patient, the administration of a therapeutically effective amount of an antibiotic for the infected tissue surrounding the implant and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
114. For use to treat a patient suffering from brain tumours and in respect of which swelling has occurred, the administration of a therapeutically effective amount of dimethyl sulfoxide and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
115. The use of Claim 113 or 114 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
116. For the treatment of mononucleosis, the administration of a therapeutically effective amount of ascorbic acid (Vitamin C) and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
117. For the treatment of herpes simplex type I and II, the administration of a therapeutica1ly effective amount of a nonionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
113 .
and salts Comdexes, hyaluronic
For the use of Claim 113 whe thereof and/or homologues, esters, fragments and sub-un: acid and/or salts thereof.
rein the hyalur; analogues, der ts of hvalurod nic acid vatives, : acid is
AP 0 0 0 1 7 5
119. For the use of Claim 117 or 118 wherein the non-ionic surfactant comprises an ether or an amide linkage between the hydrophilic and hvdropholic protions of the molecure.
120. For the use of Claim 117 or 118 wherein the non-ionic surfactant is nonoxynol-9.
• --------BADORIGINAL
121. For the use to treat herpes, herpes simplex type I and Il and herpes roster (shingles), the administration of a therapeutically effective amount of a surfactant selected from an anionic surfactant and a cationic surfactant and combinations thereof and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the ceil membranes into the individual cells to be treated.
122. For the use of Claim 121 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
123. For the use of Claim 121 or 122 wherein the anionic surfactant comprises cetyl pyridinium chloride and the like and the cationic surfactant comprises benzalkonium chloride and the like .
124. For the treatment of a patient suffering from cancer, the administration of a therapeutically effective amount of a non-steroidal anti-inflammatory agent a therapeutically effective amount of an anti-cancer agent, and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue '(including scar tissue) through the ceil membranes into the individual cells to be treated.
125. For the use of Claim 124 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
126. For the use of Claim 124 or 125 further comprising a therapeutically effective amount of Ascorbic Acid (Vitamin C).
BAD ORIGINAL
127. For the use of Claim 124, or 125 wherein the nonsteroidal anti-inflammatory agent is selected from indomethacin, naproxen and [+] tromethamine salt of Ketorolac.
128. For the use of Claim 124 or 125 further comprising therapeutically effective amount of Ascorbic Acid (Vitamin C) , and wherein the non-steroidal anti-inflammatory agent is selected from indomethacin, naproxen and [±] tromethamine salt of Ketorolac.
129. For use to treat canker sores, the administration of a therapeutically effective amount of (alpha) 2-interferon with an amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid sufficient to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
130. For the use of Claim 129 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
131. For use to treat pain, the administration of a therapeutically effective amount of a non-steroidal antiinflammatory agent and a sufficient amount of hyaluroni^ acid and salts thereof and/or homologues, analogues, derivatives,
J*'· complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through she cell membranes into the individual cells to be treated.
132. For the use of Claim 131 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
AP 0 0 0 1 7 5
IIGINAL
133. For the use of Claim 131 or 132 wherein the nonsteriodal anti-inflammatory comprises indomethacin, naproxen and a combination thereof.
134. For the use of Claim 131 or 132 wherein the nonsteroidal anti-inflammatory comprises [+] tromethamine salt of Ketorolac.
135. For use to treat a patient suffering from HIV (AIDS), the administration of a therapeutically effective amount of Ascorbic Acid (Vitamin C) , a therapeutically effective amount of a non-steroidal anti-inflammatory and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, f ragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
136. For the use of Claim 135 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
137. For the use of Claim 135 or 136 wherein the nonsteroidal anti-inflammatory is indomethacin.
138. For the use of Claim 135 and 136 wherein the nonsteroidal anti-inflammatory is indomethacin and the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
139. For the treatment of cancer, the combination of a therapeutically effective amount of ascorbic acid, a nonsteroidal anti-inflammatory drug, and at least one of an agent selected from an anti-cancer drug, chemotherapeutic agent and detoxifying drug, and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives,
BAD ORIGINAL complexes, esters, fragments and sub-units cf hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
140. The combination of claim 139 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
141. The combination of claim 139 or 140 wherein the nonsteroidal anti-inflammatory drug is selected from indomethacin, naproxen and ketorolac tromethamine.
142. For hair growth, the combination of a therapeutically effective amount of minoxidil, and at least one of an agent selected from an anti-cancer drug chemotherapeutic agent and detoxifying drug, and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
143. For use to treat herpes, canker sores and shingles, the combination of a therapeutically effective amount of nonionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
-44. The combination of Claim 143 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
145. The combination of Claim 143 or 144 wherein the
S L I 0 0 0 dV bad original ncnionic surfactant comprises an ether or an amide linkage between the hydrophilic and hydrophobic portions of the molecule .
146. For the use in Claim 143 or 144, the nonionic surfactant is nonoxynol-9.
147. For use to treat renal failure, cardiac insufficiency, hypertension and edema, the combination of an effective amount of a diuretic and a sufficient amount of hyaluronic acid and salts thereof and/or- homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
148. The combination of Claim 147 wherein'· the'^fiyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
149. The combination of Claim 147 or 148 wherein the diuretic is furosemide.
150. For use to treat infection, the combination of a therapeutically effective amount of an agent selected from antibiotics, antibacteriaIs , antimicrobials and combinations tnerof with or without ascorbic acid and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
151. The combination of Claim 150 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of
Λ,*1*·” . ___________ ___———-BAD ORIGINAL hyaluronic acid is hyaluronic acid and/or salts thereof.
152. For use to treat acne, the combination of a therapeutically effective amount of an agent selected from antibiotics, antibacterials, antimicrobicals and combinations therof with or without ascorbic acid and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-unijts of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
153. The combination of Claim 152 wherein the hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
154. For use in the transplant of organs and tissue to reduce the likelihood of the rejection thereof, the combination of an therapeutically effective amount cf an immunosuppressant and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the ceil membranes into the individual cells to be treated. r
155. The combination of Claim 154 wherein the hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units cf hyaluronic acid is hyaluronic acid and/or salts thereof.
156. The combination of Cliam 154 or 155 wherein the immunosuppressant is a cyclosporin.
157. For use in treating inflammation, the combination of a
AP 0 0 0 1 7 5
BAD ORIGINAL therapeutically effective amount of a non-steroidal antiinflammatory agent (NSAID) and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
158. The combination Claim 157 wherein the hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
159. For use in assisting in the eliminationrT,of tumour break down material (including toxins, residue and debris) in a person suffering from tumours, the combination of a therapeutically effective amount of a non-steroidal antiinflammatory agent (NSAID) and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
160. The combination of Claim 159 wherein the hyaluronic acid and salts thereof and / or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
161. The combination of Claim 157, 158, 159 or 160 wherein the non-steroidai anti-inflammatory agent (NSAID) is selected from indomethacin, naproxen and [+.] tromethamine salt cf Ketorolac.
INAL
162 .
For use in detoxifying a patient of toxins, the combination of a therapeutically amount of a detoxifying agent and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, f ragments and sub-units of hya iuron ic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
163. The combination of Claim 162 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
164. The combination of Claim 162 or 163 in the form of peritoneal dialysis.
165. For use to treat a patient suffering from respiratory difficulties, the combination of a therapeutically effective amount of a bonchodilator or the like and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual ceils to be treated.
166. The combination of Claim 165 wherein the hyaluronic acid and salts thereof and/or homologues, analog ues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
167. For use to treat vascular ischemia, the combination of a therapeutically effective amount of an agent suitable for use to treat the condition and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be
AP 0 0 0 1 7 5
BAD ORIGINAL treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
153. The combination Claim 167 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
169. For use to treat a person suffering from AIDS (HIV virus), the combination of therapeutically effective amounts of, ascorbic acid (Vitamin C) , a non-steroidal anti-inflammatory agent and an agent selected from interferon, an anti-viral agent, an antibiotic, dimethyl sulfoxide [DMSO] and combinations and thereof a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
170. The combination of Claim 169 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
171. The combination of Claim 168 or 169 wherein Dimethyl Sulfoxide (DMSO) is substituted for some or all of the forms of hyaluronic acid.
172. The combination of Claim 169, 170 or non-sterioda1 anti-inflammatory drug is indomethacin, naproxen and [±j tromethamine salt
171 wherein the selected from of Ketorolac.
D ORIGINAL
173. For use to treat herpes, the combination of a therapeutically effective amount of non-ionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
174. For use to treat canker sores, the combination of a therapeutically effective amount of non-ionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
175. For use to treat herpes zoster (shingles), the combination of a therapeutically effective amount of non-ionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
176. The combination of Claim 173, 174 or 175 wherein the hyaluronic acid and salts thereof and/or homoiogues, analogues, derivatives, complexes, esters, f ragment s and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
177. The combination of Claim 173, 174, 175 or 176, wherein the non-ionic sufactant comprises an ether or an amide linkage between the hydrophilic and hydropholio portions of the molecule .
178. The combination of Claim 173, 174, 175 or 176 wherein the non-ionic surfactant comprises nonoynoi-9.
179. For use to treat infections surrounding implants in a patient, the combination of a therapeutically effective amount of an antibiotic for the infected tissue surrounding the implant and a sufficient amount of hyaluronic acid and salts thereof
AP 0 0 0 1 7
BAD ORIGINAL and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
180. For use to test a patient suffering from brain tumours and in respect of which swelling has occurred, the administration of a therapeutically effective amount of dimethyl sulfoxide and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
181. The combination of Claim 179 or 180 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
182. For the treatment of mononucleosis, the combination of a therapeutically effective amount of ascorbic acid (Vitamin C) and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
133. For the treatment of herpes simplex type I and II, the combination of a therapeutically effective amount of a non-ionic surfactant and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the ceil membranes into th'e individual cells to be treated.
BAD ORIGINAL
184. The combination of Claim 133 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
185. The combination of Claim 183 or 184 wherein the nonionic surfactant comprises an ether or an amide linkage between the hydrophilic and hydropholic protions of the molecure.
186. For the use of Claim 183 or 184 wherein the non-ionic surfactant is nonoxynol-9.
187. For the use to treat herpes, herpes simplex type I and II and herpes zoster (shingles), the administration of a therapeutically effective amount of a surfactant selected from an anionic surfactant and a cationic surfactant and combinations thereof and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
188. The combination of Claim 185 or 186 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
189. The cc mb i nation of Claim 137 or 133 wherein the anionic surfactant comprises cetyl pyridinium chloride and the like and the cationic surfactant comprises benzalkonium chloride and the like.
190. For the use of Claim 182 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
AP 0 0 0 1 7 5
BAD ORIGINAL
191. For the treatment of a patient suffering from cancer, the combination of a therapeutically effective amount of a nonsteroidal anti-inflammatory agent a therapeutically effective amount of an anti-cancer agent, and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
192. The combination of Claim 191 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
193. The combination of Claim 191 or 192 further comprising a therapeutically effective amount of Ascorbic Acid (Vitamin C).
194. The combination of Claim 191, 192 or non-steroidal anti-inflammatory agent is indomethacin, naproxen and [+] tromethamine salt
193 wherein the selected from of Ketorolac.
195. For use to treat canker sores, the combination of a therapeutically effective amount of alpha 2-interferon with a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid sufficient to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual ceils to be treated.
196. The combination of Claim 195 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
197. For use to treat back pain, the combination of a therapeutically effective amount of a non-steroidal antioriginal inflammatory agent and a sufficient amount of hyaluronic acid ar.d salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
198. The combination of Claim 197 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
199. The combination of Claim 197 or 198 wherein the nonsteroidai anti-inflammatory comprises indomethacin, naproxen and a combination thereof.
200. The combination of Claim 197 or 198 wherein the nonsteroidal anti-inflammatory comprises [+.] tromethamine salt of Ketorolac .
201. For use to treat a patient suffering from HIV (AIDS), the combination of a therapeutically effective amount of Ascorbic Acid (Vitamin C), a therapeutically effective amount of a non-steroidal anti-inflammatory and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including, scar tissue) through the ceil membranes into the individual cej^ls to be treated.
202. The combination of Claim 201 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
203. The combination of Claim 197, 198 or 201 wherein the nor.-steroidal anti-inflammatory is indomethacin__________
AP 0 0 0 1 7 5
BAD ORIGINAL
204. The combination of Claim 201, 202 or 203 further comprising interferon.
205. The combination of Claim 201, 202, 203 or 204 further comprising Dimethyl Sulfoxide (DMSO) and wherein some or all of the forms of the hyaluronic acid may be substituted by therapeutically effective amount of dimethyl sulfoxide.
206. For enhanced neoplastic activity and effect, the administration of a therapeutically effective amount of ascorbic acid and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
207. The use of Claim 206 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
208. For enhanced neoplastic activity and effect, the combination of a therapeutically effective amount of ascorbic acid and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the ceil membranes into the individual ceils to be treated.
209. The combination of Claim 208 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts'thereof .
210. A method of increasing activity of macrophages in mammals suffering from disease, the administration of an effective amount of a non-steroidal anti-inf la minatory agent (NSAID) and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell· membranes into the individual ceils to be treated sufficient to increase activity of macrophages in mammal suffering disease.
211. The use of Claim 210 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
212. The use of Claim 210 or 211 wherein the non-steroidal anti-inflammatory agent (NSAID) is selected from indomethacin, naproxen, and [±] tromethamine salt of Ketorolac.
213. For increasing activity of macrophages in mammals suffering from disease, the combination of an effective amount of a non-steroidal anti-inflammatory agent (NSAID) and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated sufficient to increase activity of macrophages in mammal suffering disease.
214. The combination cf Ciai acid and salts thereof and ' derivatives, oomp_exes, earners, hyaluronic acid is hvaluronic acid .m 213 wherein the hyaluronic or homologues, analogues, fragments and sub-units of and/or salts thereof.
s L I· o 0 0 dV
215. The combination of Claim 213 or 214 wherein the nonsteroidal anti-inflammatory agent (NSAID) is selected from indomethacin, naproxen, and [±] tromethamine salt of Ketoroiac.
216. A method of decreasing the side effects of administering a non-steroidal anti-inflammatory agent (NSAID) in
BAD ORIGINAL a patient suffering a disease taking non-steroidal antiinflammatory agent (NSAID), the administration of an effective amount of a non-steroidal anti-inflammatory agent (NSAID) for treating the patient and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated to decrease the side effects of the non-steroidal antiinflammatory.
217. The use of Claim 216 wherein the non-steroidal antiinflammatory is indomethacin.
218. The use of Claim 216 wherein the non-steroidal antiinflammatory agent (NSAID) is selected from indomethacin, naproxen, and [+] tromethamine salt of Ketorolac.
219. For decreasing the side effects of administering a non-steroidal anti-inflammatory agent, the combination of an effective amount of a non-steroidal anti-inflammatory agent (NSAID) for treating the patient and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated to decrease the side effects of the ncn-steroidal anti-inflammatory .
220. The combination of Claim 219 wherein the ncn-steroidal anti-inflammatory is indomethacin.
221. The combination of Claim 219 wherein the non-steroidal anti-inflammatory agent (NSAID) is selected from indomethacin, naproxen, and [+] tromethamine salt of Ketorolac.
222. For the prevention of topical infection, the
BAD ORIGINAL administration of an effective amount of an anti-metabolite and a sufficient amount of hyaluronic acid and salts thereof and/cr homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
223. For the use of Claim 222 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
224. For the prevention of topical infection, the combination of an effective amount of an anti-metabolite and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
225. The combination of Claim 224 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
For use to treat bene pain, muscle pain and/or inf iammat ion, the administration cf an effe ive amount
Ascorbic Aoid (Vitamin C) and a sufficient amount cf hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units cf hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual cells to be treated.
227.
The use of Claim 226 wherein the hyaluronic acid and
I1G1NAL salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
223. For use to treat bone pain, muscle pain and/or inflammation, the combination of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the ceil membranes into the individual cells to be treated.
229. The combination of Claim 228 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
..u*.. (“ . , a·'-- ’ ·~·η '
230. For enhancing prostaglandin synthesis inhibition, the combination of a therapeutically effective amount of aceytylsalicylic acid and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual ceils to be treated.
231. The combination of Claim 230 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
232. For the use to enhance prostaglandin synthesis inhibition in a patient, the administration of a therapeutically effective amount of aceytylsalicylic acid and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid to facilitate the agent at the site to be treated by the agents passing through the tissue (including
BAD ORIGINAL
3 3 soar tissue) through the ceil membranes into the individual tells to be treated.
233. For the use of Claim 232 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
234. For enhancing oxygenation of tissue by perfusion fluid bathing the tissue, the combination of perfusate fluid and a sufficient amount of hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid to facilitate the agent af the site to be treated by the agents passing through the tissue (including scar tissue) through the cell membranes into the individual ceils to be treated.
235. The combination of Claim 234 wherein the hyaluronic acid and salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.
APAP/P/1990/000206A 1989-09-21 1990-09-21 Combination and formulations and the administration thereof to a mammal for the treatment of conditions and disease. AP175A (en)

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