WO1984001506A1 - Preparations pharmaceutiques utilisees en therapie antitumorale - Google Patents

Preparations pharmaceutiques utilisees en therapie antitumorale Download PDF

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Publication number
WO1984001506A1
WO1984001506A1 PCT/GB1983/000257 GB8300257W WO8401506A1 WO 1984001506 A1 WO1984001506 A1 WO 1984001506A1 GB 8300257 W GB8300257 W GB 8300257W WO 8401506 A1 WO8401506 A1 WO 8401506A1
Authority
WO
WIPO (PCT)
Prior art keywords
antitumour
methylformamide
drugs
pharmaceutical preparation
chemotherapeutic drug
Prior art date
Application number
PCT/GB1983/000257
Other languages
English (en)
Inventor
Ernest Nicholas Gate
John Alfred Slack
Malcolm Francis Graham Stevens
Original Assignee
Univ Birmingham
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
Application filed by Univ Birmingham filed Critical Univ Birmingham
Publication of WO1984001506A1 publication Critical patent/WO1984001506A1/fr

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Classifications

    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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

Definitions

  • the present invention relates to pharmaceutical preparations for use in antitumour therapy.
  • chemotherapeutic agents which are active against various malignant tumours in humans and other mammals, and which constitute the presently recognised range of antitumour drugs, many are unstable solids having low solubility in solvents suitable for making up solutions appropriate for parenteral administration, and the great majority exhibit significant bone marrow toxicity, i.e. have myelosuppression characteristics.
  • the low solubility of many of the known antitumour drugs in water or other common administrable solvents, as mentioned above, is important in limiting dosage amounts and /or in restricting the form in which the drugs can be prepared and administered, thereby restricting the method of use and the manner of optimising the clinical therapy treatment with such drugs.
  • the bone marrow toxicity referred to is a major factor in practice in limiting the maximum dosage and treatment schedule that can safely be employed and tolerated in antitumour chemotherapeutic clinical use.
  • a difficult choice must be made between administering a large dose at infrequent intervals, sufficient to allow time for bone marrow activity to be restored, and administering at more frequent intervals much smaller doses which are each less toxic but which are also each less effective against the tumour growth.
  • a pharmaceutical preparation for use in antitumour therapy is composed of at least one antitumour chemotherapeutic drug dispersed in N-methylformamide solvent carrier or substrate medium.
  • anti-chemotherapeutic drug signifies any chemical compound, other than N-methylformamide itself, which has a recognisable activity against at least certain cancers or malignant tumours.
  • the N-methylformamide will also provide an advantageous further and additional therape ⁇ tically active antitumour constituent as well as acting as a solvent carrier or substrate medium for the other drug or drugs.
  • the antitumour chemotherapeutic drug or drugs constituent has a clinically restrictive low solubility at least in aqueous solutions and/or elicits clinically restrictive bone marrow toxicity or myelosuppression effects in therapeutic use.
  • N-methylformamide generally exhibits excellent solvent properties and useful stabilising characteristics for the known solid antitumour drugs, even those whose low solubility and /or instability in aqueous solution has hitherto given problems in using them, or in restricting their manner of use, at desired dosage levels, or which has prevented the making up of concentrates in liquid or suspension form for storage and transport.
  • the N-methylformamide providing a solvent vehicle or substrate medium, however, in which the other antitumour drug or drugs is or are dispersed by being completely dissolved or suspended (for instance as a colloidal suspension) therein, the preparations in accordance with the invention can be readily made up into liquid doses suitable for administering by various methods without any serious sterilisation or other hygenic problems.
  • Doses of the preparations may, for example, be contained or provided in ampoules for injection Gn this case the doses may, or may not, require further dilution before administration with a suitable solution, e.g. water for injections BP, sodium chloride saline injection BP or 5% dextrose injection BP), in suppositories, in measured volumes for mixing for oral administration, or even possibly in aerosols for inhalation, in addition of course to being mixed with other conventional diluents or binders for making up into parenteral dosage forms, syrups, creams and ointments (e.g. for transdermal delivery of the drug or drugs), capsules, tablets etc.
  • the preparations can be manufactured, distributed, and stored as liquid concentrates suitable for diluting to prepare the doses for clinical administration.
  • solid antitumour drugs of low solubility in water or other conventional administrable solvents can now be provided in liquid doses of relatively high concentration by exploiting the solvent properties of N-methylformamide also gives rise to the possibilities of being able to change the route of administration leading to increased tolerance levels and /or improved bioavailability and effectiveness.
  • those drugs at present given orally may in some cases be more effective clinically if now given by parenteral administration, and vice versa, using such drugs in the form of a preparation in accordance with the present invention.
  • the N-methylformamide can itself contribute and add to the antitumour activity for at least certain types of tumours as already indicated, and this effect appears to be exhibited without introducing any significant bone marrow toxicity or additional increase in the level of bone marrow toxicity or myelosuppression effects arising from the other said antitumour drug constituent or constituents.
  • the invention may be applied generally to a wide range of antitumour drugs effective to a greater or lesser extent in treating a variety of tumours.
  • antitumour drugs may include the compounds known as Fexamethylmelamine, Busulphan, Carmustine (BCNU), Chlorambucil, Cyclophosphamide, Estramustine Phosphate, Ethoglucid,
  • the invention is especially useful in connection with drugs of the alkylating agent class such as cyclophosphamide, and the nitrosoureas, or hexamethylmelamine and other antitumour drugs having a low solubility in aqueous solutions and /or having high bone marrow toxicity or myelosuppressive properties.
  • drugs of the alkylating agent class such as cyclophosphamide, and the nitrosoureas, or hexamethylmelamine and other antitumour drugs having a low solubility in aqueous solutions and /or having high bone marrow toxicity or myelosuppressive properties.
  • hexamethylmelamine may be quoted as one example. This has a reported solubility of 0.091mg/ml in M/200 phosphate buffer at a pH of 7 at 25°C giving a maximum concentration in solution of 0.0091% w/v. In contrast, it has been found that this drug has a solubility in N-methylformamide of 5mg/ml (at 20°C) giving stable solutions with a concentration of 0.5% w/v, that is, the solubility in N-methylformamide is approximately fifty times greater than in water.
  • Methotrexate is a clinically active drug which acts as an antimetabolite by inhibition of dihydrofolate reductase. It is commonly administered by a variety of routes but for high doses the favoured route is by intravenous infusion. The drug is used in the treatment of acute lymphocytie leukaemia, chorioearcinoma and cancers of the head, neck and lung.
  • methotrexate was dissolved (as the free acid) in 100% N-methylformamide and was seen to have a very satisfactory solubility of 172 mg/ml and this solution had a t 90% of
  • t 90% denotes the time taken for 10% of the drug to degrade at room temperature.
  • Cyclophosphamide is a commonly used antitumour drug which requires prior metabolism, in the liver, to release its active form. It is used to treat solid tumours and a wide range of haematological malignancies.
  • the solubility of cyclophosphamide in various strengths of N-methylformamide and the stability of these solutions (at room temperature) are summarised below:
  • doxorubicin is one of the most successful antitumour drugs. It is used in the treatment of solid tumours and also acute leukaemias. It is normally administered via a fast-running intravenous infusion due to the problems of severe local pain due to tissue extravasation.
  • the solubility of doxorubicin in buffer at pH 4.0 is 89 mg/ml whereas in buffer and 30% N-methylformamide this solubility is increased to 116 mg/ml.
  • the stabilities of these solutions at room temperature are as follows:
  • FIG. 1 shows the mean tumour volumes of the M5 sarcoma bearing mice treated with these drugs when, on day 12 after tumour implantation, several therapy routines were initiated as set forth in the key tables appended to the diagram.
  • Figure 2 shows the variation in white blood cell counts (an indication of bone marrow toxicity) for each of the routines listed and for control animals. The results of these and other experiments showed:
  • N-methylformamide treatment initiated 3 days after treatment with high-dose cyclophosphamide, produced no increased leukopenia over and above that of the cyclophosphamide treatment alone, and did not inhibit recovery of the bone marrow from the cyclophosphamide induced leukopenia, but an improved antitumour effect against the M5076 sarcoma was observed.
  • Etoposide 100 mg is dissolved in a mixture of Nmethylformamide (1.5g) anhydrous citric acid (10 mg), benzyl alcohol (150 mg), purified polysorbate 80 (400 mg), polyethylene glycol 300 (3.25g) and ethyl alcohol (0.2g).
  • the solution may be sterilised by filtration or autoclaving and may be diluted with Sodium Chloride Injection BP or Dextrose Injection BP before administration by slow intravenous infusion.
  • Amsacrine (75 mg) is dissolved in N-methylformamide (1.5g).
  • the solution may be sterilised by filtration, or, alternatively, a sterile freeze-dried sample of amsacrine may be admixed, aseptically, with sterile N-methylfojmamide.
  • the solution, prepared as above may be added, aseptically, to 13.5 ml. of 0.0353M L-lactic acid to give a combined solution suitable for parenteral administration. This combined solution is physically incompatible with Sodium Chloride Injection B.P.
  • a sample of sterile lyophilised 6-mercaptopurine sodium salt (0.5g) and sterile N-methylformamide (1.5 ml) are combined aseptically. This mixture is intended to be reconstituted with sterile water for Injections BP to produce a solution containing, in each 1 ml, 10 mg of mercaptopurine sodium salt.
  • Injection BP to provide a final concentration of 1-2 mg/ml of mercaptopurine sodium salt.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Une préparation pharmaceutique antitumorale est préparée à partir d'un ou de plusieurs produits chimiothérapiques antitumoraux dispersés dans de la N-méthylformamide. Les propriétés de solvant de la N-méthylformamide sont particulièrement utiles pour de nombreux médicaments antitumoraux de faible solubilité ou de faible stabilité en solutions aqueuses et peuvent rendre possible leur utilisation sous forme de doses de concentration encore plus importante. La N-méthylformamide peut également contribuer à l'activité antitumorale et augmenter cette activité sans accroître la toxicité de la moelle osseuse, si bien que sa coadministration conduit à une chimiothérapie de combinaison bénéfique.
PCT/GB1983/000257 1982-10-13 1983-10-13 Preparations pharmaceutiques utilisees en therapie antitumorale WO1984001506A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB8229257 1982-10-13

Publications (1)

Publication Number Publication Date
WO1984001506A1 true WO1984001506A1 (fr) 1984-04-26

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Family Applications (1)

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PCT/GB1983/000257 WO1984001506A1 (fr) 1982-10-13 1983-10-13 Preparations pharmaceutiques utilisees en therapie antitumorale

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EP (1) EP0120907A1 (fr)
WO (1) WO1984001506A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2188547A (en) * 1986-02-24 1987-10-07 Ici Plc Tamoxifen preparation
DE3827974A1 (de) * 1988-08-18 1990-02-22 Boehringer Mannheim Gmbh Kombinationspraeparate von proteinkinase-c-inhibitoren mit lipiden, lipid-analoga, cytostatica oder inhibitoren von phospholipasen
US4927638A (en) * 1986-10-08 1990-05-22 Bristol-Myers Company Etoposide solutions
EP0656211A1 (fr) * 1993-11-09 1995-06-07 American Cyanamid Company Composition stabilisée et lyophilisée de thiotépa
EP0893121A1 (fr) * 1997-06-27 1999-01-27 Akzo Nobel N.V. Solution liquide de médicament pour administration orale

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0042553A1 (fr) * 1980-06-12 1981-12-30 Bristol-Myers Company Compositions pour le traitement de tumeurs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0042553A1 (fr) * 1980-06-12 1981-12-30 Bristol-Myers Company Compositions pour le traitement de tumeurs

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 49, No. 22, 25 November 1955, Columbus, Ohio (US) A. FURST et al.: "Retardation of Growth of Ehrlich Ascites Tumor by Formamides and Related Compounds", see column 16225ef, Cancer Research 15, 294-9 (1955) *
CHEMICAL ABSTRACTS, Volume 54, No. 13, 10 July 1960, Columbus, Ohio (US) M.N. TELLER et al.: "Transplantable Human Tumors in Experimental Chemotherapy. A Comparison with Animal Tumor Systems" see column 13439d, Cancer Research 20, 112-19 (1960) *
CHEMICAL ABSTRACTS, Volume 77, No. 13, 25 September 1972, Columbus, Ohio (US) A. FURST et al.: "Experimental Chemotherapy of Nickel-Induced Fibrosarcomas" see page 89, Abstract 84221y, Oncology 1972, 26(4), 422-6 (Eng.) *
CHEMICAL ABSTRACTS, Volume 97, No. 11, 13 September 1982, Columbus, Ohio, (US) A. GESCHER et al.: "N-Methylformamide: Antitumor Activity and Metabolism in Mice", see page 20, Abstract 84663g, Br.J. Cancer 1982, 45(6) 843-50 (Eng.) *
CHEMICAL ABSTRACTS, Volume 99, No. 7, 15 August 1983, Columbus, Ohio (US) W.R. COBB et al.: "Activity of Two Phase I Drugs N-Methylformamide (NSC-3051) and Echinomycin (NSC-526417) against Fresh Surgical Explants of Human Tumors in the 6-Day Subrenal Capsule (SRC) Assay", see page 26, Abstract 47637x, Invest. New Drugs 1983, 1 (1), 5-9 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2188547A (en) * 1986-02-24 1987-10-07 Ici Plc Tamoxifen preparation
EP0240131A2 (fr) * 1986-02-24 1987-10-07 Imperial Chemical Industries Plc Tamofixen pour l'usage topique
EP0240131A3 (en) * 1986-02-24 1989-11-15 Imperial Chemical Industries Plc Tamoxifen for topical use
GB2188547B (en) * 1986-02-24 1990-03-28 Ici Plc Tamoxifen composition for the treatment of psoriasis.
AU603561B2 (en) * 1986-02-24 1990-11-22 Imperial Chemical Industries Plc Therapeutic agent
US4927638A (en) * 1986-10-08 1990-05-22 Bristol-Myers Company Etoposide solutions
DE3827974A1 (de) * 1988-08-18 1990-02-22 Boehringer Mannheim Gmbh Kombinationspraeparate von proteinkinase-c-inhibitoren mit lipiden, lipid-analoga, cytostatica oder inhibitoren von phospholipasen
EP0359981A1 (fr) * 1988-08-18 1990-03-28 Roche Diagnostics GmbH Compositions pharmaceutiques et leur utilisation comme médicament antinéoplaste
AU627207B2 (en) * 1988-08-18 1992-08-20 Boehringer Mannheim Gmbh Pharmaceutical composition comprising protein kinase c inhibitor and anti-cancer agent
EP0656211A1 (fr) * 1993-11-09 1995-06-07 American Cyanamid Company Composition stabilisée et lyophilisée de thiotépa
EP0893121A1 (fr) * 1997-06-27 1999-01-27 Akzo Nobel N.V. Solution liquide de médicament pour administration orale
US6127425A (en) * 1997-06-27 2000-10-03 Akzo Nobel N.V. Oral liquid medicine solution

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Publication number Publication date
EP0120907A1 (fr) 1984-10-10

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