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
  • A61K31/47—Quinolines; Isoquinolines
• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • 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
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • 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
  • A61P35/00—Antineoplastic agents

Definitions

• the present Invention relates to novel pharmaceutical compositions that are useful in preventing malignant cells from becoming resistant to a diverse variety of chemotherapeutic agents.
• the multidrug-resistance inhibitor chemically known as N- ⁇ 4-[2-l,2,3,4- tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl ⁇ -9,10-dihydro-5-methoxy- 9-oxo-4-acridine carboxamide and its physiologically acceptable salts and solvates is described and claimed in World Patent Application WO 92/12132. filed in the name of Laboratires Glaxo S.A. and published July 23, 1992.
• Multidrug-resistance is a process whereby tumor cells become resistant to structurally diverse chemotherapeutic agents following exposure to treatment with anti-tumor drugs.
• This acquired drug resistance can be a major obstacle in the clinical treatment and management of malignant disease. It has been shown that this type of resistance can be reversed by GF120918, resensitizing multidrug-resistant tumor cells to various chemotherapeutic agents. It has also been seen that certain rumors are intrinsically multidrug-resistant and the use of multidrug-resistance inhibitors are also beneficial in treating tumors of this type.
• GF120918A the hydrochloride salt of N- ⁇ 4-[2-l,2,3,4-tetrahydro-6,7- dimethoxy-2-isoquinolinyl)-ethyl]-phenyl ⁇ -9,10-dihydro-5-methoxy-9-oxo-4- acridine carboxamide, to be safely and effectively administered to patients parenterally by either intravenous injection or intravenous infusion must be adequately miscible in the blood. Therefore, any combination of the drug and the various excipients, in a liquid form, must be sufficiently compatible with the physiological composition of the blood to allow sufficient admixing. This mixing with the blood allows the compound to be distributed throughout the body in an unremarkable fashion.
• GF120918A is a weak base and therefore exhibits a higher solubility at a pH less than about 4. Since the pH of the blood is approximately 7.4, the compound alone in solution precipitates upon injection or infusion into the blood stream.
• An object of the present Invention is to provide a parenteral formulation that when injected or infused into the blood stream remains miscible and allows the active drug to be distributed throughout the body in an unremarkable fashion.
• a further object of the present Invention is to provide a parenteral formulation and method of use that will improve or increase the efficacy of a chemotherapeutic agent or restore sensitivity of a tumor to chemotherapeutic agent or rever.se or reduce resistance of a tumor to a chemotherapeutic agent; subsequently abating tumor cell multidrug-resistance and decreasing morbidity.
• the present Invention relates to pharmaceutical compositions that prevent or minimize precipitation upon injection or infusion; comprising: a) a safe and therapeutically effective amount of N- ⁇ 4-[2-l,2,3,4-tetrahydro- 6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl ⁇ -9,10-dihydro-5-methoxy-9- oxo-4-acridine carboxamide and its physiologically acceptable salts and solvates; b) a safe and effective amount of a surfactant; c) a buffer; and d) a pharmaceutically acceptable carrier or diluent.
• safety and therapeutically effective amount means a sufficient amount of a drug or pharmaceutical agent to abate or reverse a multidrug-resistance response of a tissue, system or animal that is being sought by the researcher or clinician without harming the tissues of a mammal, including a human to which the drug is administered.
• compositions of the present Invention employ a safe and therapeutically effective amount of the compound N- ⁇ 4-[2-l,2,3,4-tetrahydro-6,7- dimethoxy-2-isoquinolinyl)-ethyl]-phenyl ⁇ -9,10-dihydro-5-methoxy-9-oxo-4- acridine carboxamide (GF120918) and its physiologically acceptable salts and solvates, a safe and effective amount of a surfactant, a safe and effective amount of a buffer and a carrier or diluent suitable for pharmaceutical use.
• These compositions are suitable for administration to mammals, including humans through various parenteral routes. These various parenteral routes particularly include both intravenous bolus injection and intravenous infusion.
• compositions of the present Invention may be administered in conjunction with an antitumor drug.
• Suitable antitumor drugs for use in conjunction with compositions of the present include, but are not limited to, Vinca alkaloids (e.g. vincristine, vinblastine and vinorelbine, anthracyclines (e.g. daunorubincin, doxorubicin and aclarubin ⁇ n, taxol, and derivatives thereof (e.g. taxotere), podophyllotixins (e.g. etoposide and VP16), mitoxantrone, actinomycin, colchicine, gramidine D, cisplatin, cyclophosphamide, amsacrine or any other chemotherapeutic, antitumor type compounds.
• Vinca alkaloids e.g. vincristine, vinblastine and vinorelbine
• anthracyclines e.g. daunorubincin, doxorubicin and aclarubin ⁇ n, taxol, and derivatives thereof (e.g
• compositions of the present Invention while being given in conjunction with an antitumor drug, could also be given simultaneously with an anti-tumor drug.
• This type of administration is acceptable as long as the components of the composition of the present Invention and any antitumor compound given simultaneously are both physically and chemically compatible.
• “simultaneously” means, sequentially with little or no delay or given together from a common single container where the composition of the present Invention and the antitumor drug are physically mixed.
• compositions of the present Invention may also be administered with various drug formulations to combat side-effects produced by anti-tumor chemotherapy. These other drug formulations may be given either simultaneously or in conjunction with formulations of the present Invention.
• compositions of the present Invention must be both physically and chemically compatible with compositions of the present Invention. If, however, the formulation given in conjunction with compositions of the present Invention or given together at the same time, but from a different container or is given by another route or given intravenously either prior to or subsequently to compositions of the present Invention physical and chemical reactivity should not be problematic.
• compositions of the present Invention may also be packaged as articles of manufacture comprising a safe and therapeutically effective amount of GF120918 and its physiologically acceptable salts and solvates; a safe and effective amount of a surfactant; a buffer; and a pharmaceutically acceptable carrier or diluent, packaged as described above.
• the packaging material may also have labeling and information relating to the pharmaceutical composition printed thereon.
• an article of manufacture may have a brochure, report, notice, pamphlet, or leaflet containing product information. This form of pharmaceutical product information is sometimes, in the pharmaceutical industry, called the "package insert.”
• a package in ⁇ rt may be attached to or included with a pharmaceutical article of manufacture.
• the package insert and any article of manufacture labeling provides information relating to the pharmaceutical composition. This information and labeling provides various forms of information utilized by health care professionals and patients that describes the composition, its dosage and various other parameters required by regulatory agencies, such as the United States Food and Drug Administration.
• the amount of GF120918 administered to prevent, abate or reverse multidrug resistance in a mammal including a human will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of about 1 mg to about 10 gm per day, particularly from about 10 mg to about 1 gm per day and more particularly from about 25 mg to about 750 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
• Another of the essential components of by the present Invention is a surface-active agent or a mixture of compatible surface-active agents, sometimes referred to as surfactants. Any compatible surface-active agent is sufficient for use in the present Invention, however, nonionic surface-active agents are particularly suitable.
• Nonionic surface-active agents are particularly suitable in compositions of the present Invention and can be broadly defined as compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkylaromatic in nature.
• suitable nonionic surfactants include, but are not limited to: pluronics, polyethylene oxide condensates of alkyl phenols, products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic alcohol's, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures of such materials.
• the surface-active agent or mixtures of compatible surface-active agents can be present in the compositions of the present Invention from about 0.05% to about 20.0%, particularly from about 0.1% to about 10.0% and most particularly from about 0.5% to about 5.0% by weight of the total composition.
• the last essential component of the present Invention is a suitable carrier or diluent that provides an appropriate vehicle for parenteral delivery of the composition without the introduction of untoward side-effects.
• a suitable carrier or diluent that provides an appropriate vehicle for parenteral delivery of the composition without the introduction of untoward side-effects.
• suitable carriers and diluents include, but are not limited to: dextrose 5% in water and sterile water for injection.
• compositions of the present Invention can contain a variety of optional parenteral conventional components known to persons skilled in the art. Any optional components included in compositions of the present Invention must be physically and chemically compatible with the essential components of the present Invention.
• Optional components include, but are not limited to: cosolvents, including but not limited to, polyethylene glycol (PEG) grades 200 to 600, propylene glycol (1,2- propanediol), ethanol and glycerin, preservatives and agents that adjust isotonicity and osmolality. Further information concerning preservatives and agents to adjust isotonicity and osmolality can be found in Remington's Pharmaceutical Sciences, p. 1278 - 1280, 1455 - 1472, 17th ed. (1985)
• Optional components may also include other drugs or combinations of drugs that are physically and chemically compatible with compositions of the present Invention.
• Possible optional additional drugs include, but are not limited to antitumor chemotherapeutic agents, antinausents including, serotonin 5-HT3 receptor antagonists such as ondansetron and granisetron and various other antinausents such as prochlorperazine, chlorpromazine, perphenazine, thiethylperazine, triflupromazine, droperidol, methochlopramide, trimethobenzamide, dronabinol, pherergan, nabilone and methylpredinisone.
• Other additional optional drugs include: antibiotics, antidepressants, antiulcer compounds, analgesics, anticholornergics, antivirals and a myriad of other drugs suitable to treat conditions that also require the administration of compositions of the present Invention.
• compositions of the present Invention in their method aspect involves administering to a mammal, including a human a safe and effective amount of the compositions of the present Invention described herein. These safe and effective amounts will vary based on the type and size of mammal being treated and the results wished to be obtained.
• Glacial acetic acid 2.87 microliters
• Glacial acetic acid 2.87 microliters
• Glacial acetic acid 2.87 microliters
• Glacial acetic acid 17.2 microliters Sodium Hydroxide adjust to pH 3.5 Water for Injection (USP) qs to 1 mL

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• 1995
  • 1995-10-04 AU AU38913/95A patent/AU702519B2/en not_active Ceased
  • 1995-10-04 CZ CZ971041A patent/CZ104197A3/cs unknown
  • 1995-10-04 RU RU97107466/14A patent/RU2157687C2/ru active
  • 1995-10-04 JP JP8512678A patent/JPH10507177A/ja active Pending
  • 1995-10-04 WO PCT/US1995/012952 patent/WO1996011007A1/en not_active Application Discontinuation
  • 1995-10-04 EP EP95938184A patent/EP0784474A2/en not_active Ceased
  • 1995-10-04 CA CA002201628A patent/CA2201628A1/en not_active Abandoned
  • 1995-10-04 HU HU9702291A patent/HUT77883A/hu unknown
  • 1995-10-04 PL PL95319511A patent/PL319511A1/xx unknown
  • 1995-10-04 KR KR1019970702223A patent/KR970705997A/ko not_active Application Discontinuation
  • 1995-10-04 BR BR9509251A patent/BR9509251A/pt not_active Application Discontinuation
  • 1995-10-04 NZ NZ295546A patent/NZ295546A/xx unknown

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