WO1995030423A2 - Cancer treatment and metastasis prevention - Google Patents

Cancer treatment and metastasis prevention Download PDF

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Publication number
WO1995030423A2
WO1995030423A2 PCT/CA1995/000259 CA9500259W WO9530423A2 WO 1995030423 A2 WO1995030423 A2 WO 1995030423A2 CA 9500259 W CA9500259 W CA 9500259W WO 9530423 A2 WO9530423 A2 WO 9530423A2
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WO
WIPO (PCT)
Prior art keywords
hyaluronic acid
drug
cancer
daltons
combinations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA1995/000259
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French (fr)
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WO1995030423A3 (en
Inventor
Rudolf Edgar Falk
Samuel Simon Asculai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NORPHARMCO Inc
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NORPHARMCO Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/675,908 external-priority patent/US6069135A/en
Application filed by NORPHARMCO Inc filed Critical NORPHARMCO Inc
Priority to KR1019960706101A priority Critical patent/KR970702728A/en
Priority to EP95917846A priority patent/EP0760667A1/en
Priority to JP7528564A priority patent/JPH09512797A/en
Priority to AU24023/95A priority patent/AU696373B2/en
Priority to SK1379-96A priority patent/SK137996A3/en
Publication of WO1995030423A2 publication Critical patent/WO1995030423A2/en
Publication of WO1995030423A3 publication Critical patent/WO1995030423A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/185—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
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • 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
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/503—Pyridazines; Hydrogenated pyridazines spiro-condensed
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • 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
    • A61K31/70—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • This invention relates to the treatment of cancer and the prevention of metastases in patients having cancer.
  • This invention also relates to pharmaceutical compositions and dosage amounts suitable for such treatment and prevention.
  • this invention relates to the treatment of breast cancer and the prevention of metastases in a patient with breast cancer.
  • Conventional treatment of breast cancer involves a mastectomy, the surgical removal of breast tissue.
  • the procedure can vary from a simple lumpectomy to the radical procedure during which the surgeon removes the internal mammary chain of lymph nodes, the underlying pectoral muscles and the adjacent axillary lymph nodes.
  • WO91/04058 provides a new treatment for among other diseases, cancer providing for administration of dosage amounts of pharmaceutical compositions comprising effective amounts of each of NSAIDs, Vitamin C, anti-cancer agents, among other medicines and therapeutic agents with a form of hyaluronic acid, for example sodium hyaluronate having a molecular weight less than 750,000 daltons, in an amount equal to or exceeding 10 mg/70 kg person.
  • hyaluronic acid for example sodium hyaluronate having a molecular weight less than 750,000 daltons, in an amount equal to or exceeding 10 mg/70 kg person.
  • the doses can be administered intravenously, intra-arterially, intraperitoneally, intra-pleurally and directly into the tumour by injection through a needle placed under sonograph or CT guidance .
  • Case VII found at page 42-43 discloses the treatment of massive cancer of the breast with supraclavicular and auxiliary lymph nodes palpable.
  • the treatment involved combinations "of hyaluronic acid and/or salts thereof added to conventional chemotherapy used systemically by injection into the tumour and by intra-pleural cavity instillation" (page 45, lines 3-5).
  • NSAIDs non-steroidal anti-inflammatory drug
  • ascorbic acid Vitamin C
  • anti-cancer drugs among other drugs.
  • Publication WO/CA93/00061 relates to the topical treatment of skin diseases and conditions and involves the topical administration of specified dosage amounts of pharmaceutical compositions taught.
  • Basal cell carcinoma for example is treated and resolved by such topical administration.
  • the dosage amounts when discharged from the skin, unload into the lymphatic system (page 31 , line 35).
  • the drugs treat the disease or condition in the skin with the form of hyaluronic acid (for example sodium hyaluronate having a molecular weight less than 750,000 daltons) transporting the drugs into the skin.
  • hyaluronic acid for example sodium hyaluronate having a molecular weight less than 750,000 daltons
  • synthesis of prostaglandin is inhibited, deblocking the macrophages and N.K. cells (page 26, line 27 to page 27, line 35) thereby permitting the macrophages and N.K. cells to destroy the disease or condition.
  • Applicants have discovered a new treatment for cancer (for example breast cancer - malignant tumours of the breast) which not only causes the malignant tumours (such as those of the breast) to shrink, recede and disappear, but also unexpectedly reduces the risk of metastases.
  • cancer for example breast cancer - malignant tumours of the breast
  • malignant tumours such as those of the breast
  • Applicants have provided a new method for the treatment cancer in a human particularly malignant tumours, for example those in a breast or breasts, said method comprising the steps of:
  • a non-toxic dosage amount of a pharmaceutical composition comprising an effective non-toxic amount of an anti-cancer drug and/or drug suitable for use to treat cancer (for example about 1 to about 2 mg Novantrone [tm] (Mitoxantrone) or other chemotherapeutic agent, (interferon or an NSAID) and an effective amount of a form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight of less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water.
  • the size of the tumour will limit the amount that can be directly injected into the tumour.
  • a combination preferably a dosage amount of a pharmaceutical composition, comprising
  • a form of hyaluronic acid for example hyaluronic acid and pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity and to reduce the side effects of any medicine (for example NSAID) administered therewith if the amount of the form of hyaluronic acid exceeds about 200mg/70kg pers on )
  • hyaluronic acid for example hyaluronic acid and pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity and to reduce the side effects of any medicine (for example NSAID) administered therewith if the amount of the form of hyaluronic acid exceeds about 200mg/70
  • a drug selected from the group comprising (a) a non-steroidal anti-inflammatory drug (NSAID) for example in an effective non-toxic amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol);
  • NSAID non-steroidal anti-inflammatory drug
  • an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C).
  • the frequency of treatment for malignant tumours generally can be one (1 ) to four (4) times monthly or more (as may be required).
  • a dosage amount of a pharmaceutical composition comprising ( i ) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg of the drug administered with the form of hyaluronic acid with the amounts of the form of hyaluronic acid exceeding 200mg/70kg person or more (because of a lack of toxicity)
  • a form of hyaluronic acid for example hyaluronic acid and salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg of the drug administered with the form of hy
  • NSAID non-steroidal anti-inflammatory drug
  • an anti-oxidant for example Vitamin C in one embodiment 25 gm of Vitamin C
  • an anti-oxidant for example Vitamin C is about one (1 ) to three (3) times per month.
  • Hyperthermia (heat) treatments may be applied to the breast having the malignant tumour.
  • Other regimens of therapeutic treatment may also be given.
  • an ulcerative medicine such as Ranitidine may also be administered intravenously with sodium hyaluronate.
  • Applicants have provided a new method for the treatment of cancer, said method comprising the steps of
  • a dosage amount comprising an effective non-toxic amount of a drug suitable for treating cancer, alone or preferably with an effective amount of a form of hyaluronic acid, for example, hyaluronic acid or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight of less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) and
  • hyaluronic acid for example hyal uronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
  • NSAID non-steroidal anti-inflammatory drug
  • a non-steroidal anti-inflammatory drug for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol);
  • an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C).
  • the steps are repeated over a period of time at chosen intervals suitable for the patient.
  • Applicants have provided a new treatment for the reduction of the risk of a patient suffering from a cancer of having the cancer metastasize (reduce the risk of such patient suffering from a metastasis or suffering from a metastatic effect), said treatment comprising (preferably with other treatment for cancer for example those described above) administering s y s te mi cal ly ( preferab l y intravenously) a dosage amount of a pharmaceutical composition comprising
  • hyaluronic acid for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
  • NSAID non-steroidal anti-inflammatory drug
  • a chemotherapeutic agent an anti-cancer agent or a drug suitable to treat cancer and combinations thereof, preferably w i th
  • an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C),
  • said administration continuing at regular intervals (for example 1 - 4 times monthly) over the period the treatment is being administered to the patient for the treatment of the cancer.
  • the sodium hyaluronate transports carries and causes the transport of the drug
  • the drug is also carried to and liberated in the lymph nodes.
  • the blood stream will also take up for example the sodium hyaluronate and thus the drug
  • the sodium hyaluronate and drug will be delivered to the liver (with the sodium hyaluronate transporting the drug into the tissue and cells of the liver).
  • two major sites of nascent metastasis have for example sodium hyaluronate and drug (for example NSAID, anti-cancer drug) delivered to them with the sodium hyaluronate facilitating the transport of drug into the tissue (of the lymph nodes and liver) wherein to prevent cancer development and/or metastasis.
  • the sodium hyaluronate (and other forms of hyaluronic acid, including hyaluronic acid) can be administered systemically with a drug and such administration delivers the drug with the form of hyaluronic acid to the lymph nodes and liver.
  • Such administration helps to reduce the risk of metastasis and appears as a result of Applicant's tests to inhibit and even prevent metastasis of the cancer being treated in a human.
  • Such administration may also be used to treat cancers in the lymph system and liver if cancer is found to be present there .
  • the cancer being treated is malignant tumours of the breast
  • the treatment involves systemic administration
  • the direct injection a number of times a month over the period of cancer treatment
  • the tumours reduced in size and cleared. Unexpectedly the reduction was without metastases.
  • each such dosage amount comprising
  • hyaluronic acid for example hyaluronic acid and pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity and to reduce side effects of the medicine administered with the form of hyaluronic acid where the form of hyaluronic acid exceeds about 200mg/70kg person
  • hyaluronic acid for example hyaluronic acid and pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity and to reduce side effects of the medicine administered with the form of hyaluronic acid where the form of hyaluronic acid exceeds about 200mg/70kg person
  • NSAID non-steroidal anti-inflammatory drug
  • an effective non-toxic amount of from about 30 mg to about 100 mg for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium
  • a chemotherapeutic agent an anti-cancer agent or a drug suitable to treat cancer and c o m b i n a t i o n s t h e r e o f , preferably with
  • an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C).
  • Applicants have provided new dosage amounts of a pharmaceutical composition for injection (in a suitable form for injection) suitable for use with for example the above dosage amount, said dosage amount being in the container or vial suitable for use for injection (for example in a syringe) and comprising an effective amount of an anti-cancer drug and/or a drug suitable for use to treat cancer (for example breast cancer, in which event the dosage amount is injected into each tumour of the breast) (for example about 1 to about 2 mg of Mitoxantrone) and an effective amount of a form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water.
  • a pharmaceutical composition for injection in a suitable form for injection
  • said dosage amount being in the container or vial suitable for use for injection
  • hyaluronic acid for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
  • NSAID for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol); and an effective non-toxic amount of a chemotherapeutic agent (anti-cancer agent or an agent suitable to treat cancer)
  • a chemotherapeutic agent anti-cancer agent or an agent suitable to treat cancer
  • Vitamin C in one embodiment 25 gm of Vitamin C
  • a dosage amount of a pharmaceutical composition for injection in a suitable form for injection, said dosage amount being in the container or vial for injection and comprising an effective amount of an anti-cancer drug and/or a drug suitable for use to treat cancer (for example breast cancer, in which event the dosage amount is to be injected into each tumour of the breast) (for example about 1 to about 2 mg of Mitoxantrone and an effective amount of a form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water; an d
  • hyaluronic acid for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
  • NSAID for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol) an d
  • chemotherapeutic agent an agent suitable to treat cancer
  • an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C), for example
  • non-toxic dosage amounts of a pharmaceutical composition for injection in a suitable form for injection
  • said dosage amount being in the container or vial for injection and comprising an effective amount of an anticancer drug and/or a drug suitable for use to treat cancer (for example breast cancer, in which event the dosage amount is injected into each tumour of the breast)
  • an effective amount of an anticancer drug and/or a drug suitable for use to treat cancer for example breast cancer, in which event the dosage amount is injected into each tumour of the breast
  • hyaluronic acid for example hyaluronic acid and/or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water a n d
  • hyaluronic acid for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
  • NSAID non-steroidal anti-inflammatory drug
  • a non-steroidal anti-inflammatory drug for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol) an d
  • a therapeutically effective non-toxic dosage amount of a chemotherapeutic agent (anti-cancer agent or an agent to treat cancer)
  • Vitamin C in one embodiment 25 gm of Vitamin C
  • an effective non-toxic dosage amount of an anti-cancer drug and/or a drug suitable for use to treat cancer for example breast cancer, in which event the dosage amount is injected into each tumour of the breast
  • cancer for example breast cancer, in which event the dosage amount is injected into each tumour of the breast
  • a form of hyaluronic acid for example hyaluronic acid and/or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water an d
  • hyaluronic acid for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
  • NSAID for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol); and
  • chemotherapeutic agent for example an anti-cancer agent or an agent to treat cancer
  • an anti-oxidant for example Vitamin C in one embodiment 25 gm of Vitamin C.
  • Suitable forms of sodium hyaluronate may include a fraction supplied by Hyal Pharmaceutical Corporation supplied in 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 daltons.
  • the fraction also contains water q.s. which is triple distilled and sterile in accordance with the U.S. P. for injection formulations.
  • the vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial.
  • the fraction of hyaluronic acid and/or salts thereof may comprise hyaluronic acid and/or salts thereof having the following characteristics:
  • a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from the group (and preferably all characteristics) consisting of the following:
  • the hyaluronic acid is mixed with water and the fraction of hyaluronic acid has a mean average molecular weight within the range of 150,000-225,000. More preferably, the fraction of hyaluronic acid may comprise at least one characteristic selected from the group (and preferably all characteristics) consisting of the following characteristics:
  • Hyaluronan HA-M5070 Another form of sodium hyaluronate is sold under the name Hyaluronan HA-M5070 by Skymart Enterprises, Inc. having the following specifications :
  • hyaluronic acid and/or its salts, and analogues, homologues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for example those described in prior art documents provided the form of hyaluronic acid chosen is suitable for transport of the medicine.
  • a kinematic viscosity of a 1 % solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes;
  • a schedule of the dosage amounts received by each patient is attached and refers to the letter used to identify the patient.
  • the chronology of the administration of the dosage amounts in each Schedule is in reverse order with the dosage given earliest being at the end of the Schedule and the most recent dosage being at the beginning of the Schedule.
  • the local reaction was not excessive although it consisted on initial enlargement of the area of the tumour site. What was impressive was the return of the breast to normal in some instances, and with only minimal scar tissue apparent on mammography in others.

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Abstract

A new method for the treatment of cancer in a human particularly malignant tumors, for example those in a breast or breasts, said method comprising the steps of: (1) directly injecting into the tumour a dosage amount of a pharmaceutical composition comprising an effective amount of an anti-cancer drug and/or drug suitable for use to treat cancer (for example about 1 to about 2 mg NovantroneTM (Mitoxantrone), other chemotherapeutic agent, NSAIDs) and an effective amount of a form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight of less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water; and (2) administering systemically, preferably intravenously, a dosage amount of a pharmaceutical composition comprising: (i) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and/or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity and to reduce the side effects of any medicine (for example NSAID) administered therewith if the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person); (ii) a drug selected from the group comprising: a) a non-steroidal anti-inflammatory drug (NSAID) for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethanine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol), b) an anti-cancer drug, and c) a drug suitable for use to treat cancer and combinations thereof optionally together with (iii) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C).

Description

TITLE OF INVENTION
CANCER TREATMENT AND METASTASIS PREVENTION FIELD OF INVENTION
This invention relates to the treatment of cancer and the prevention of metastases in patients having cancer. This invention also relates to pharmaceutical compositions and dosage amounts suitable for such treatment and prevention. In one application this invention relates to the treatment of breast cancer and the prevention of metastases in a patient with breast cancer.
BACKGROUND OF THE INVENTION
Conventional treatment of breast cancer involves a mastectomy, the surgical removal of breast tissue. The procedure can vary from a simple lumpectomy to the radical procedure during which the surgeon removes the internal mammary chain of lymph nodes, the underlying pectoral muscles and the adjacent axillary lymph nodes.
In the instances of early detection of cancers of the breast, breast conserving therapy is now considered appropriate. Thus, lumpectomy together with axillary clearance and radiotherapy are presently recommended as alternatives. However, there is still considerable controversy surrounding the ultimate minimum treatment to achieve adequate local control. This is true with all cancers. In the considerations therefore, the choice of treatment will be made to eliminate the cancer and ensure no recurrence, for example in the breast or elsewhere by metastases.
Published application WO91/04058 provides a new treatment for among other diseases, cancer providing for administration of dosage amounts of pharmaceutical compositions comprising effective amounts of each of NSAIDs, Vitamin C, anti-cancer agents, among other medicines and therapeutic agents with a form of hyaluronic acid, for example sodium hyaluronate having a molecular weight less than 750,000 daltons, in an amount equal to or exceeding 10 mg/70 kg person. At page 27, line 35 the document provides that the doses can be administered intravenously, intra-arterially, intraperitoneally, intra-pleurally and directly into the tumour by injection through a needle placed under sonograph or CT guidance .
Case VII found at page 42-43 discloses the treatment of massive cancer of the breast with supraclavicular and auxiliary lymph nodes palpable. The treatment involved combinations "of hyaluronic acid and/or salts thereof added to conventional chemotherapy used systemically by injection into the tumour and by intra-pleural cavity instillation" (page 45, lines 3-5).
The said document also teaches the systemic administration of combinations of hyaluronic acid and/or salts thereof with NSAIDs (non-steroidal anti-inflammatory drug), ascorbic acid (Vitamin C), anti-cancer drugs among other drugs.
Publication WO/CA93/00061 relates to the topical treatment of skin diseases and conditions and involves the topical administration of specified dosage amounts of pharmaceutical compositions taught. Basal cell carcinoma, for example is treated and resolved by such topical administration. The dosage amounts when discharged from the skin, unload into the lymphatic system (page 31 , line 35). During their stay in the skin, particularly the epidermis, the drugs treat the disease or condition in the skin with the form of hyaluronic acid (for example sodium hyaluronate having a molecular weight less than 750,000 daltons) transporting the drugs into the skin. Where an NSAID is used, synthesis of prostaglandin is inhibited, deblocking the macrophages and N.K. cells (page 26, line 27 to page 27, line 35) thereby permitting the macrophages and N.K. cells to destroy the disease or condition.
While the destruction/clearance of the malignant tumour and all cancer present is the end goal, it cannot be undertaken without concern for metastatic effects. Metastases and recurrence must be prevented particularly metastases into vulnerable organs such as the l i ver.
In the past treatments, not enough emphasis and concern was placed on the metastatic effect (metastases). Focus was on destruction and clearing. Thus, in the treatments prescribed or undertaken in the past, attempts were made to destroy the malignant tumour. However, prostaglandin synthesis in many approaches was permitted in the tissue (inhibiting the macrophages and N. K. cells from performing their function (killing cancer cells and destruction of the tumour)). Therefore cancer cells freed from the tumour instead of being destroyed, were permitted to travel in the body and lodge in a more vulnerable area (the liver or lungs, for example) - a certain recipe for metastases.
It is therefore an object of this invention to provide a new treatment for cancer which finds one particular application in the treatment of breast cancer.
It is a further object of this invention to reduce the risk of metastases with such treatment.
It is still a further object of the invention to reduce the risk of the recurrence of the disease, for example breast cancer.
It is still a further object of the invention to provide pharmaceutical compositions and dosage amounts of pharmaceutical compositions suitable for use in such treatments.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed description of embodiments.
SUMMARY OF THE INVENTION
Unexpectedly, Applicants have discovered a new treatment for cancer (for example breast cancer - malignant tumours of the breast) which not only causes the malignant tumours (such as those of the breast) to shrink, recede and disappear, but also unexpectedly reduces the risk of metastases.
According to one aspect of the invention, Applicants have provided a new method for the treatment cancer in a human particularly malignant tumours, for example those in a breast or breasts, said method comprising the steps of:
( 1 ) directly injecting into the tumour a non-toxic dosage amount of a pharmaceutical composition comprising an effective non-toxic amount of an anti-cancer drug and/or drug suitable for use to treat cancer (for example about 1 to about 2 mg Novantrone [tm] (Mitoxantrone) or other chemotherapeutic agent, (interferon or an NSAID) and an effective amount of a form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight of less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water. (The size of the tumour will limit the amount that can be directly injected into the tumour.), and
( 2) ad m i n i s t e ri n g p refe rab l y s y s te m i c al l y
(preferably intravenously) a combination, preferably a dosage amount of a pharmaceutical composition, comprising
( i ) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity and to reduce the side effects of any medicine (for example NSAID) administered therewith if the amount of the form of hyaluronic acid exceeds about 200mg/70kg pers on )
( ii ) a drug selected from the group comprising (a) a non-steroidal anti-inflammatory drug (NSAID) for example in an effective non-toxic amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol);
( b ) an effective nontoxic amount of a chemotherapeutic agent as described in
(1) above (an anti-cancer drug, or drug suitable to treat cancer, etc.)
and combinations thereof,
optionally with
(iii) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C).
Where more than 200mg/70kg person of the form of hyaluronic acid is used, adverse side effects of administering the drug (NSAID, chemotherapeutic agent) are reduced if not eliminated.
The frequency of treatment for malignant tumours generally can be one (1 ) to four (4) times monthly or more (as may be required). For breast cancers, the frequency of the direct injections into the malignant tumour in the breast of pharmaceutical compositions of subparagraph (i) above and systemic (intravenous) administration of a dosage amount of a pharmaceutical composition comprising ( i ) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg of the drug administered with the form of hyaluronic acid with the amounts of the form of hyaluronic acid exceeding 200mg/70kg person or more (because of a lack of toxicity)
(i i ) a drug selected from the group comprising a non-steroidal anti-inflammatory drug (NSAID) for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol); and
(b) an effective non-toxic amount of a chemotherapeutic agent as described in ( 1) above (an anti- cancer drug, or drug suitable to treat cancer, etc.) and combinations thereof, optionally with
(iii) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C) is about one (1 ) to three (3) times per month. (The form of hyaluronic acid, for example sodium hyaluronate, transports (causes the transport) of the medicines and therapeutic agents into the tumour tissue for their destruction and inhibits prostaglandin synthesi s. )
Hyperthermia (heat) treatments may be applied to the breast having the malignant tumour. Other regimens of therapeutic treatment may also be given. For example as a precaution, depending on the amount of NSAID administered and amount of sodium hyaluronate administered, an ulcerative medicine such as Ranitidine may also be administered intravenously with sodium hyaluronate.
In accordance with another aspect of the invention, Applicants have provided a new method for the treatment of cancer, said method comprising the steps of
( 1 ) ad m i n i s te ri n g s y s te m i c a l l y ( pre fe rab l y intravenously) to a human, a dosage amount comprising an effective non-toxic amount of a drug suitable for treating cancer, alone or preferably with an effective amount of a form of hyaluronic acid, for example, hyaluronic acid or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight of less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) and
( 2 ) ad m i n i s te ri n g s y stem i cal l y ( p re fe rab l y intravenously) a dosage amount of a pharmaceutical composition comprising
( i ) an effective amount of a form of hyaluronic acid (for example hyal uronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
( ii ) a drug selected from the group comprising
(a) a non-steroidal anti-inflammatory drug (NSAID) for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol);
(b) an effective non-toxic dosage amount of a chemotherapeutic agent for treating cancer
and combinations thereof,
preferably with
(iii) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C).
The steps are repeated over a period of time at chosen intervals suitable for the patient.
Unexpectedly and in accordance with another aspect of the invention, patients regularly administered dosage amounts described above over their period of treatment, did not experience any metastatic effect (did not have any metastasis). Thus, their risk of metastases dramatically and surprisingly decreased substantially.
Thus, in accordance with another aspect of the invention,
Applicants have provided a new treatment for the reduction of the risk of a patient suffering from a cancer of having the cancer metastasize (reduce the risk of such patient suffering from a metastasis or suffering from a metastatic effect), said treatment comprising (preferably with other treatment for cancer for example those described above) administering s y s te mi cal ly ( preferab l y intravenously) a dosage amount of a pharmaceutical composition comprising
( i ) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
(i i ) a drug selected from the group comprising
( a ) a non-steroidal anti-inflammatory drug (NSAID) for example in an effective non-toxic amount of from for example about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark
Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol); and
(b) an effective non-toxic dosage amount of a chemotherapeutic agent (an anti-cancer agent or a drug suitable to treat cancer and combinations thereof, preferably w i th
(iii) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C),
said administration continuing at regular intervals (for example 1 - 4 times monthly) over the period the treatment is being administered to the patient for the treatment of the cancer.
Applicants believe that the above treatments are successful because prostaglandin synthesis is inhibited thereby reactivating the macrophages and N.K. cells to destroy the cancer, neoangiogenesis is prevented, or at least precluded (by the combination of HA/NSAIDs), prostacyclin production is enhanced by the Vitamin C (sodium ascorbate) where used, and the hyaluronic acid (for example sodium hyaluronate) is cleared through the lymphatic system (by direct measurement the concentration of hyaluronan (occurring in the body) is 10 times higher in the lymph than the plasma. We have also observed a prolonged effect after only a simple dose of medicine with HA (form of hyaluronic acid, for example sodium hyaluronate) which is, Applicants believe due to the fact that HA administered intravenously will track through the lymphatics. One would therefore anticipate an improved and prolonged effect in terms of immunosuppression for example with cyclosporin. This has been confirmed in some initial experiments using intestinal allograft transplants in which the bowel is transplanted on an arterial venous pedicle but has all the lymphatics stripped off. Thus, when the drug enters through the arterial circulation it tracks into the lymphatics but there is no lymphatic drainage by which to exit from the bowel. The drug therefore remains in the grafts for a long period. In our initial experiments one and two doses of cyclosporin in HA produced indefinite survival of the allograft).
Because the for example sodium hyaluronate transports, carries and causes the transport of the drug, the drug is also carried to and liberated in the lymph nodes. Because the blood stream will also take up for example the sodium hyaluronate and thus the drug, the sodium hyaluronate and drug will be delivered to the liver (with the sodium hyaluronate transporting the drug into the tissue and cells of the liver). Thus, two major sites of nascent metastasis have for example sodium hyaluronate and drug (for example NSAID, anti-cancer drug) delivered to them with the sodium hyaluronate facilitating the transport of drug into the tissue (of the lymph nodes and liver) wherein to prevent cancer development and/or metastasis. Thus, the sodium hyaluronate (and other forms of hyaluronic acid, including hyaluronic acid) can be administered systemically with a drug and such administration delivers the drug with the form of hyaluronic acid to the lymph nodes and liver. Such administration helps to reduce the risk of metastasis and appears as a result of Applicant's tests to inhibit and even prevent metastasis of the cancer being treated in a human. Such administration may also be used to treat cancers in the lymph system and liver if cancer is found to be present there .
Where the cancer being treated is malignant tumours of the breast, and the treatment involves systemic administration, the direct injection (a number of times a month over the period of cancer treatment) of for example sodium hyaluronate with an anti-cancer drug and/or NSAID, the tumours reduced in size and cleared. Unexpectedly the reduction was without metastases.
Therefore, in accordance with another aspect of the invention, Applicants have provided new dosage amounts of pharmaceutical compositions in a form for systemic administration
(usually intravenous administration from an IV bag), each such dosage amount comprising
( i ) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity and to reduce side effects of the medicine administered with the form of hyaluronic acid where the form of hyaluronic acid exceeds about 200mg/70kg person
(ii) a drug selected from the group comprising
(a) a non-steroidal anti-inflammatory drug (NSAID) for example in an effective non-toxic amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium
(for example sold under the trade mark Voltarol), an d
(b) an effective non-toxic dosage amount of a chemotherapeutic agent (an anti-cancer agent or a drug suitable to treat cancer and c o m b i n a t i o n s t h e r e o f , preferably with
(iii) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C).
In accordance with another aspect of the invention,
Applicants have provided new dosage amounts of a pharmaceutical composition for injection (in a suitable form for injection) suitable for use with for example the above dosage amount, said dosage amount being in the container or vial suitable for use for injection (for example in a syringe) and comprising an effective amount of an anti-cancer drug and/or a drug suitable for use to treat cancer (for example breast cancer, in which event the dosage amount is injected into each tumour of the breast) (for example about 1 to about 2 mg of Mitoxantrone) and an effective amount of a form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water.
Therefore Applicants have provided the use of a new dosage amount of a pharmaceutical composition comprising
( i ) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
(ii) an effective non-toxic amount of a drug selected from the group comprising
(a) a non-steroidal anti-inflammatory drug
(NSAID) for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol); and an effective non-toxic amount of a chemotherapeutic agent (anti-cancer agent or an agent suitable to treat cancer)
and combinations thereof and preferably with
(ii i ) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C) for
( a ) the treatment of cancer in a patient, and (b) the prevention of metastasis in a patient suffering from cancer.
Furthermore Applicants have provided the use of
(A) a dosage amount of a pharmaceutical composition for injection (in a suitable form for injection), said dosage amount being in the container or vial for injection and comprising an effective amount of an anti-cancer drug and/or a drug suitable for use to treat cancer (for example breast cancer, in which event the dosage amount is to be injected into each tumour of the breast) (for example about 1 to about 2 mg of Mitoxantrone and an effective amount of a form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water; an d
(B) a dosage amount comprising
( i ) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
( ii) an effective non-toxic amount of a drug selected from the group comprising
(a) a non-steroidal anti-inflammatory drug
(NSAID) for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol) an d
( b ) an effective non-toxic amount of a chemotherapeutic agent (anti-cancer agent or an agent suitable to treat cancer);
and combinations thereof, preferably with;
(iii) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C), for
(a) the treatment of cancer in a patient,
(b) the prevention of metastasis in a patient suffering from cancer and/or
(c) delivery of the drug to the lymph system and/or liver. Applicants have further provided the use of each of
(I) non-toxic dosage amounts of a pharmaceutical composition for injection (in a suitable form for injection), said dosage amount being in the container or vial for injection and comprising an effective amount of an anticancer drug and/or a drug suitable for use to treat cancer (for example breast cancer, in which event the dosage amount is injected into each tumour of the breast) (for example about 1 to about 2 mg of Mitoxantrone and an effective amount of a form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water a n d
(II) a non-toxic dosage amount comprising
( i ) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
( i i ) a drug selected from the group comprising
(a) a non-steroidal anti-inflammatory drug (NSAID) for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol) an d
( b ) a therapeutically effective non-toxic dosage amount of a chemotherapeutic agent (anti-cancer agent or an agent to treat cancer)
and combinations thereof, optionally with prefe rab l y
( i ii ) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C) for
( a ) the treatment of cancer in a patient, ( b ) the prevention of metastasis in a patient suffering from cancer and/or
(c) delivery of a drug to the lymph system and/or liver.
Applicants have also provided each of
(A) an effective non-toxic dosage amount of an anti-cancer drug and/or a drug suitable for use to treat cancer (for example breast cancer, in which event the dosage amount is injected into each tumour of the breast) (for example about 1 to about 2 mg of Mitoxantrone and an effective amount of a form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts thereof, preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) (for example about 10 to about 20 mg sodium hyaluronate) in sterile water an d
(B)
(i ) an effective amount of a form of hyaluronic acid (for example hyaluronic acid and/or pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons (for example 150,000 - 225,000 daltons) for example about 100 - 200 mg or more (because of a lack of toxicity)
(ii) a drug selected from the group comprising
( a) a non-steroidal anti-inflammatory drug
(NSAID) for example in an amount of from about 30 mg to about 100 mg (for example 30 to 60 mg of tromethamine salt of ketoralac (sold under the trade mark Toradol) and 50 to 100 mg of diclofenac or diclofenac sodium (for example sold under the trade mark Voltarol); and
( b ) an effective non-toxic dosage amount of a chemotherapeutic agent (for example an anti-cancer agent or an agent to treat cancer)
and combinations thereof; with preferably
(iii) an anti-oxidant for example Vitamin C (in one embodiment 25 gm of Vitamin C). for the manufacture of two pharmaceutical compositions, one from the components of (A) and one from the components of (B), each for the treatment of cancer, prevention of metastases and/or delivery of a drug to the lymph system and/or liver.
Suitable forms of sodium hyaluronate may include a fraction supplied by Hyal Pharmaceutical Corporation supplied in 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 daltons. The fraction also contains water q.s. which is triple distilled and sterile in accordance with the U.S. P. for injection formulations. The vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial.
The fraction of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, preferably hyaluronic acid and salts thereof, may comprise hyaluronic acid and/or salts thereof having the following characteristics:
a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from the group (and preferably all characteristics) consisting of the following:
i ) a molecular weight within the range of 150,000- 225,000 daltons;
ii) less than about 1.25% sulphated mucopoly-saccharides on a total weight basis;
iii) less than about 0.6% protein on a total weight basis ;
i v ) less than about 150 ppm iron on a total weight basis ;
v) less than about 15 ppm lead on a total weight basis; vi) less than 0.0025% glucosamine;
vii) less than 0.025% glucuronic acid;
vi i i ) less than 0.025% N-acetylglucosamine;
ix) less than 0.0025% amino acids;
x) a UV extinction coefficient at 257 nm of less than about 0.275; xi) a UV extinction coefficient at 280 nm of less than about 0.25; and
xii) a pH within the range of 7.3-7.9. Preferably, the hyaluronic acid is mixed with water and the fraction of hyaluronic acid has a mean average molecular weight within the range of 150,000-225,000. More preferably, the fraction of hyaluronic acid may comprise at least one characteristic selected from the group (and preferably all characteristics) consisting of the following characteristics:
i) less than about 1% sulphated mucopolysaccharides on a total weight basis;
ii) less than about 0.4% protein on a total weight basis;
iii) less than about 100 ppm iron on a total weight basis;
iv) less than about 10 ppm lead on a total weight basis; v) less than 0.00166% glucosamine;
vi) less than 0.0166% glucuronic acid;
vii) less than 0.0166% N-acetylglucosamine;
viii) less than 0.00166% amino acids;
x) a UV extinction coefficient at 257 nm of less than about 0.23;
xi) a UV extinction coefficient at 280 nm of less than 0.19; and
xii) a pH within the range of 7.5-7.7
Applicants also propose to use sodium hyaluronate produced and supplied by LifeCore™ Biomedical, Inc., having the following specifications:
Figure imgf000017_0001
Figure imgf000018_0001
Another form of sodium hyaluronate is sold under the name Hyaluronan HA-M5070 by Skymart Enterprises, Inc. having the following specifications :
Specifications' Test
Results
Figure imgf000018_0002
Other forms of hyaluronic acid and/or its salts, and analogues, homologues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for example those described in prior art documents provided the form of hyaluronic acid chosen is suitable for transport of the medicine.
The following references teach hyaluronic acid, sources thereof, and processes for the manufacture and recovery thereof which may prove to be suitable.
United States Patent 4, 141 ,973 teaches hyaluronic acid fractions (including sodium salts) having:
" (a) an average molecular weight greater than about 750,000, preferably greater than about 1 ,200,000 - that is, a limiting viscosity number greater than about 1400 cm3 /g., and preferably greater than about 2000 cm3/g. ;
( b ) a protein content of less than 0.5% by weight;
( c ) ultraviolet light absorbance of a 1% solution of sodium hyaluronate of less than 3.0 at 257 nanometers wavelength and less than 2.0 at 280 nanometers wave length ;
(d ) a kinematic viscosity of a 1 % solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes;
(e ) a molar optical rotation of a 0.1 - 0.2% sodium hyaluronate solution in physiological buffer of less than -1 1 × 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 humour, no haze or flare in the vitreous, and no pathological changes to the cornea, lens, iris, retina, and choroid of the owl monkey eye when one milliliter of a 1 % solution of sodium hyaluronate dissolved in physiological buffer is implanted in the vitreous replacing approximately one-half the existing liquid vitreous, said HUA being
( g ) sterile and pyrogen free and
( h ) non-antigenic . "
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 .
The invention will now be illustrated with reference to the following data relating to persons suffering from cancer. A schedule of the dosage amounts received by each patient is attached and refers to the letter used to identify the patient. The chronology of the administration of the dosage amounts in each Schedule is in reverse order with the dosage given earliest being at the end of the Schedule and the most recent dosage being at the beginning of the Schedule.
PATIENTS TREATED
EXAMPLE 1
Patient A - aged 42 (Female)
- breast cancer occupying the entire breast, no previous treatment
- treated with NSAIDs, sodium ascorbate, HA intravenously plus systemic therapy
- also injected with Novantrone/HA on 4 occasions
- complete response with total regression of local tumour, has not developed any metastases
- see Schedule A for dosages (HA = sodium hyaluronate having molecular weight less than 750,000 daltons)
EXAMPLE 2
Patient B - aged 60 (Female)
- local recurrence after a regional excision
- treated by direct injection with Novantrone/HA 1 mg plus 10 mgs of HA at 4 different times
- also received NSAIDs/HA intravenously
- her tumour has regressed 75% of its original size over 1.5 years
- has not developed any metastases
- see Schedule B for dosages
EXAMPLE 3
Patient C (Female)
- received the dosages in Schedule C including direct injection into tumours (IT) in breast, including direct injection and intravenous administration (IV)
- surprisingly the tumours disappeared with no metastasis EXAMPLE 4
Patient D (Female)
- received dosage amounts in Schedule D including direct injection(IT) into the tumours in the breast and intravenous (IV) administration
- patient held her own
EXAMPLE 5
Patient E - aged 55 (Female)
- carcinoma of the breast, treated with NSAIDs/HA and sodium ascorbate intravenously only (direct injections as well)
- has not metastasized from the position of tumour in the supraclavicular nodes over the past three years
- see Schedule E for dosages
EXAMPLE 6
Patient F - aged 73 (Female)
- carcinoma of the breast with liver metastases treated over 3 years with NSAIDs, HA, sodium ascorbate plus chemotherapy intravenously (IV);
- tumour was stable then began to grow but no metastases developed in this entire time (no injections appear to have been given into breast; however injections made into neck node left side)
- she discontinued treatment because of her age
- see Schedule F for dosages
EXAMPLE 7
Patient G - aged 56 (Female)
- carcinoma of the breast metastatic to supraclavicular nodes, disease has been stable for 4 years as a result of intermittent treatment with NSAIDs, sodium ascorbate and HA intravenously
- no direct injection
- see Schedule G for dosage amounts
EXAMPLE 8
Patient H - aged 81 (Female)
- carcinoma of the right lung with metastases to the mediastinum at diagnosis
- treated with weekly NSAIDs, sodium ascorbate, HA intravenously
- tumour remained stable without metastases and terminally some local g ro w th
- treatment was discontinued as she was 81 years old, disabled and did not wish further therapy - she died of cardiac failure
- see Schedule H for dosage amounts
EXAMPLE 9
Patient I - aged 64 (Male)
- carcinoma of the prostrate, remains entirely stable on NSAIDs/HA and sodium ascorbate given intravenously
- Schedule I sets out dosages
EXAMPLE 10
Patient J - aged 65 (Male)
- carcinoma of the colorectum metastatic to the liver, stable for 2 years without metastases
- treated one to two times per week with sodium ascorbate/HA and NSAIDs i ntrave no u s l y
- see Schedule J for dosage amounts
The following additional experimental data illustrates our results in the treatment of breast cancer patients. We have used by systemic administration, NSAIDs, sodium ascorbate and HA experimentally in these patients over a number of years. We have treated experimentally a total of 63 patients who had minimal surgery wherever possible. Patients received hormone blocking agents if they were positive for oestrogen or progesterone receptors. Only occasionally was an oophorectomy performed. We utilized low doses of chemotherapy, employing methotrexate ( 100 mg/100 mg HA on the first day) and 5-fluorouracil (5- FU) (350-500 mg/100 mg HA on the second and third days), initially without HA and subsequently with HA by injection. Where the tumour was considered more aggressive we used a four-drug combination in the injections (see Table 1).
Figure imgf000022_0001
Figure imgf000023_0002
Radiation was avoided. In these patients hyperthermia was employed by microwave technique to enhance the effect of the drugs. We have thus achieved a 90% survival for as long as nine years (see Table 2).
Figure imgf000023_0001
It is apparent from these results that moderate doses of chemotherapy, adding NSAIDs and giving the drugs in HA, has resulted in an improved survival rate in a group of patients at high risk for recurrent disease.
An alternative experimental treatment for local breast cancer with or without systemic diseases was also devised. In one group of patients the initial four patients refused surgery and/or radiation. One had a recurrence in both breasts post-radiation; another post-radiation patient had skeletal metastases at the time of presentation. We injected mitoxantrone 1 mg in 10 mg HA from 1 to 6 times until the tumour disappeared. In addition, we gave systemic chemotherapy in HA and hyperthermia. Where appropriate, hormone-blocking drugs were used. Altogether 10 patients were treated in this fashion. All had a complete response in terms of regression of local disease (see Table 3).
Figure imgf000024_0001
The local reaction was not excessive although it consisted on initial enlargement of the area of the tumour site. What was impressive was the return of the breast to normal in some instances, and with only minimal scar tissue apparent on mammography in others.
This is a unique method of treatment. It appears that the drugs administered in HA affect almost exclusively the tumour tissue and do not produce a significant effect on normal tissue.
As many changes can be made to the dosage amounts used in the examples without departing from the scope of the inventions, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE AS FOLLOWS:
1. A method for the treatment of cancer in a human for the prevention/reduction of metastases in the human, said method comprising the steps of:
( 1 ) directly injecting into the tumour a non-toxic dosage amount of a pharmaceutical composition comprising an effective non-toxic amount of an anti-cancer drug and/or drug suitable for use to treat cancer and an effective dosage amount of a form of hyaluronic acid, selected from the group comprising hyaluronic acid and/or pharmaceutically acceptable salts thereof and combinations thereof, having a molecular weight less than 750,000 daltons in sterile water, and (2) administering systemically, a non-toxic dosage amount of a pharmaceutical composition comprising
(i) an effective amount of a form of hyaluronic acid selected from the group 'comprising hyaluronic acid and pharmaceutically acceptable salts thereof preferably sodium hyaluronate having a molecular weight less than 750,000 daltons
(ii) a drug selected from the group comprising (a) a non-steroidal anti-inflammatory drug (NSAID)
(b) a chemotherapeutic agent
and combinations thereof
optionally with
(iii) an anti-oxidant.
2. The method of claim 1 wherein the frequency of treatment is one (1) to four (4) times monthly or more (as may be required).
3. The method of claim 1 wherein the form of cancer is breast cancer and the frequency of the direct injections into the malignant tumour in the breast and systemic administration is one (1) to three (3) times monthly or more (as may be required).
4. The method of claim 1 , 2 or 3 wherein the administering systemically is by intravenous administration.
5. The treatment of claim 1, 2, or 3 further comprising treating the body with by hyperthermia.
6. A method for the treatment of cancer in a human for reducing metastasis in such human, said method comprising the steps of
( 1 ) administering systemically to a human suffering from cancer, a dosage amount comprising an effective amount of a drug suitable for treating cancer alone, or preferably with an effective amount of a form of hyaluronic acid, selected from the group comprising hyaluronic acid and/or pharmaceutically acceptable salts thereof, and combinations thereof, having a molecular weight of less than 750,000 daltons; and
(2) administering systemically a dosage amount of a pharmaceutical composition comprising
(i) an effective amount of a form of hyaluronic acid selected from the group comprising hyaluronic acid and pharmaceutically acceptable salts thereof and combinations thereof, having a molecular weight less than 750,000 daltons
(ii) a drug selected from the group comprising
(a) a non-steroidal anti-inflammatory drug (NSAID)
(b) a chemotherapeutic agent and combinations thereof
and optionally;
(iii) an anti-oxidant
7. The method of treatment of claim 6 wherein steps (1) and (2) are repeated as required.
8. A method of treatment for the reduction of the risk of a patient suffering from a cancer having the cancer metastasize (reduce the risk of such patient suffering from a metastasis or suffering from a metastatic effect), said method of treatment comprising ( 1 ) administering systemically a dosage amount of a pharmaceutical composition comprising a drug in an effective non-toxic amount suitable for treating cancer alone or with an effective amount of a form of hyaluronic acid selected from the group comprising hyaluronic acid and/or pharmaceutically acceptable salts thereof and combinations thereof, having a molecular weight less than 750,000 daltons, and
(2) administering systemically a dosage amount of a pharmaceutically composition comprising: (i) an effective amount of a form of hyaluronic acid selected from the group comprising hyaluronic acid and pharmaceutically acceptable salts thereof and combinations, having a molecular weight less than 750,000 daltons
(ii) a drug selected from
(a) a non-steroidal anti-inflammatory drug
(NSAID) and
(b ) a chemotherapeutic agent and combinations thereof
optionally with
(iii) an anti-oxidant
said administration continuing at regular intervals over the period treatment is being given for treatment of cancer.
9. The method of treatment of claim 8 wherein method of treatment is administered about 1-4 times monthly.
10. A combination of dosage amounts of pharmaceutical composition comprising
(1) in a form for systemic administration, a non-toxic dosage amount comprising
(i) an effective amount of a form of hyaluronic acid selected from the group comprising hyaluronic acid and salts thereof pharmaceutically acceptable and combinations thereof, having a molecular weight less than 750,000 daltons, and
(ii) a drug selected from the group comprising (a) a non-steroidal anti-inflammatory drug (NSAID); and
(b) a chemotherapeutic agent
and combinations thereof and
optionally (iii) an anti-oxidant and
(2) a non toxic effective dosage amount of a pharmaceutical composition for injection, said dosage amount being in injectable form and comprising an effective non-toxic amount of an anti-cancer drug and/or a drug suitable for use to treat cancer and an effective amount of a form of hyaluronic acid selected from the group comprising hyaluronic acid and/or pharmaceutically acceptable salts thereof and combinations thereof having a molecular weight less than 750,000 daltons in sterile water.
11. The combination of claim 10 wherein the drug in dosage amount (1) is a NSAID.
12. The combination of claim 10 or 11 wherein the form of hyaluronic acid is sodium hyaluronate.
13. The use of effective non-toxic dosage amounts of pharmaceutical compositions, one said dosage amount comprising an effective non-toxic dosage amount of an anti-cancer drug and/or a drug suitable for use to treat cancer and an effective dosage amount of a form of hyaluronic acid, selected from the group comprising hyaluronic acid and/or pharmaceutically acceptable salts thereof and combinations thereof, having a molecular weight less than 750,000 daltons in sterile water, suitable for injection and a second dosage amount of a pharmaceutical composition comprising
(i ) an effective amount of a form of hyaluronic acid selected from the group comprising hyaluronic acid and pharmaceutically acceptable salts thereof and combinations thereof, having a molecular weight less than 750,000 daltons, and
(ii) a drug selected from
(a) a non-steroidal anti-inflammatory drug (NSAID) and
(b ) a chemotherapeutic agent
and combinations thereof optionally with
(iii) an anti-oxidant for (a) the treatment of cancer in a patient, (b) the prevention of metastasis in a patient suffering from cancer, and (c) the delivery of a drug to the lymph system and/or liver.
14. The use of each of
(I) a dosage amount of a pharmaceutical composition for systemic administration comprising an effective amount of a drug suitable for use to treat cancer alone in a suitable excipient or optionally with an effective amount of a form of hyaluronic acid selected from hyaluronic acid and/or pharmaceutically acceptable salts thereof and combinations thereof, having a molecular weight less than 750,000 daltons; and
(II) an effective dosage amount comprising
(i) an effective amount of a form of hyaluronic acid selected from the group comprising hyaluronic acid and pharmaceutically acceptable salts thereof and combinations thereof, having a molecular weight less than 750,000 daltons, and
(ii) a drug selected from the group comprising (a) a non-steroidal anti-inflammatory drug (NSAID)
( b) a chemotherapeutic agent
and combinations thereof
and optionally
(iii) an anti-oxidant for
(a) the treatment of cancer in a patient,
(b ) the prevention of metastasis in a patient suffering from cancer, and
(c ) the delivery of a drug to the lymph system and/or liver.
15. The use of an effective non-toxic dosage amount of an anti- cancer drug and/or a drug suitable for use to treat cancer and an effective amount of a form of hyaluronic acid, selected from the group comprising hyaluronic acid and/or pharmaceutically acceptable salts and combinations thereof, having a molecular weight less than 750,000 daltons in sterile water in the manufacture of a pharmaceutical composition for the prevention of metastases in a patient suffering from cancer.
16. The pharmaceutical composition of claim 16 in injectible form.
17. The use of
(i ) an effective dosage amount of a form of hyaluronic acid selected from the group c o mpri si n g h y al u roni c acid and pharmaceutically acceptable salts thereof and combinations thereof having a molecular weight less than 750,000 daltons, and
(ii) a drug selected from (a) a non-steroidal anti-inflammatory drug (NSAID)
(b ) a chemotherapeutic agent
and combinations thereof optionally with
(iii) an anti-oxidant in the manufacture of a pharmaceutical composition for the prevention of metastases in a patient suffering from cancer.
18. The use of claim 18 in a form for intravenous administration.
19. The use of
(I) an effective amount of an anti-cancer drug and/or a drug suitable for use to treat cancer and an effective amount of a form of hyaluronic acid selected from the group comprising hyaluronic acid and/or pharmaceutically acceptable salts and combinations thereof, having a molecular weight less than 750,000 daltons in sterile water; and
(II) (i) an effective amount of a form of hyaluronic acid selected from the group comprising hyaluronic acid and pharmaceutically acceptable salts thereof and combinations thereof having a molecular weight less than 750,000 daltons, and (ii) a drug selected from
(a) a non-steroidal anti-inflammatory drug
(NSAID);
and
(b ) a chemotherapeutic agent and combinations thereof
optionally with
(iii) an anti-oxidant in the manufacture of two pharmaceutical compositions, composition (1 ) comprising the components of (I) and composition (2) comprising the components of (II) for
(a) the treatment of cancer in a patient,
(b) the prevention of metastasis in a patient suffering from cancer and
(c) the delivery of a drug to the lymph system and/or liver.
PCT/CA1995/000259 1991-07-03 1995-04-28 Cancer treatment and metastasis prevention Ceased WO1995030423A2 (en)

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JP7528564A JPH09512797A (en) 1994-04-29 1995-04-28 Cancer treatment and metastasis prevention
AU24023/95A AU696373B2 (en) 1994-04-29 1995-04-28 Cancer treatment and metastasis prevention
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US07/675,908 US6069135A (en) 1989-09-21 1990-09-18 Use of hyaluronic acid or its derivatives to enhance delivery of therapeutic agents
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CA2,122,519 1994-04-29

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WO1999006114A3 (en) * 1997-07-31 1999-04-08 Geistlich Soehne Ag Use of taurolidine or taurultam for the manufacture of a medicament for the prevention of metastases
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US6384042B2 (en) 1999-02-18 2002-05-07 Faerber Lothar Systemic use of 5-HT3 receptor antagonists against rheumatic inflammatory processes
US6641571B2 (en) 2000-01-05 2003-11-04 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Reduction of postoperative complications of cardiopulmonary bypass (CPB) surgery
US6875753B1 (en) 1996-03-14 2005-04-05 The Governors Of The University Of Alberta Methods for cell mobilization using in vivo treatment with hyaluronan (HA)
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WO2007012133A1 (en) * 2005-07-27 2007-02-01 Alchemia Oncology Pty Limited Therapeutic protocols using hyaluronan
US7892530B2 (en) 1999-06-04 2011-02-22 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Treatment of tumor metastases and cancer
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