WO1996011007A1 - Parenteral pharmaceutical compositions containing gf120918a - Google Patents

Parenteral pharmaceutical compositions containing gf120918a Download PDF

Info

Publication number
WO1996011007A1
WO1996011007A1 PCT/US1995/012952 US9512952W WO9611007A1 WO 1996011007 A1 WO1996011007 A1 WO 1996011007A1 US 9512952 W US9512952 W US 9512952W WO 9611007 A1 WO9611007 A1 WO 9611007A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
safe
effective amount
group
Prior art date
Application number
PCT/US1995/012952
Other languages
French (fr)
Inventor
Wei-Qin Tong
Mickey Lee Wells
Original Assignee
Glaxo Wellcome 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
Application filed by Glaxo Wellcome Inc. filed Critical Glaxo Wellcome Inc.
Priority to KR1019970702223A priority Critical patent/KR970705997A/en
Priority to PL95319511A priority patent/PL319511A1/en
Priority to CZ971041A priority patent/CZ104197A3/en
Priority to AU38913/95A priority patent/AU702519B2/en
Priority to JP8512678A priority patent/JPH10507177A/en
Priority to NZ295546A priority patent/NZ295546A/en
Priority to EP95938184A priority patent/EP0784474A2/en
Priority to BR9509251A priority patent/BR9509251A/en
Publication of WO1996011007A1 publication Critical patent/WO1996011007A1/en
Priority to MXPA/A/1997/002473A priority patent/MXPA97002473A/en

Links

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.
  • Parenteral compositions of the present Invention must be in a sterile form. Any of the various methods known to persons skilled in the art employed to prepare sterile parenteral preparations that will not degrade components of the present Invention are suitable for use in the compositions sterile preparation. Parenteral compositions of the present Invention may be packaged, produced or contained in packaging materials such as single use ampoules, vials or intravenous bottles or bags or alternatively in multidose or multiuse vials or containers.
  • 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 pH of the pre-sent compositions range from about 1 to about 5, particularly from about 2.5 to about 4.
  • the essential, as well as possible optional components of the compositions of the present Invention, are described in the following paragraphs.
  • GF120918 is an acridine derivative that is able to reverse or reduce resistance to, increase or restore sensitivity to or improve or increase the efficacy of an chemotherapeutic agent or agents.
  • 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 surface-active agents best suited for inclusion into the present composition are: polyethylene glycol 660 hydroxystearate (SOLUTO ® HS-15), polyoxyethylene castor oil derivatives (CREMOPHOR® EL, RH40, and RH60), poloxamer, polyoxyethylene alkyl ethers (CETOMACROGOL® 1000) and polyoxyethylene sorbitan fatty acid esters (POLYSORBATE® 20, 40, 60, and 80 and TWEEN® 20, 40, 60 and 80).
  • polyethylene glycol 660 hydroxystearate, polyethylene glycol, polyoxyethylene castor oil derivatives and polyoxyethylene sorbitan fatty acid esters are useful in compositions of the present Invention.
  • Buffers are compounds or mixtures of compounds which if present in a solution resist changes in the pH of the solution upon the addition of small quantities of acids or bases. Further information about buffers can be found in Remington's Pharmaceutical Sciences, p. 243 - 45 17th ed. (1985). Examples of buffers suitable for use in compositions of the present Invention include: acetate, phosphate and glutamate.
  • 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 can be made using methods and techniques that are commonly employed in preparing parenteral preparations within the pharmaceutical industry. Remington's Pharmaceutical Sciences, p. 1518 - 1541, 17th ed. (1985). COMPOSITION USE
  • 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 2.87 microliters
  • Glacial acetic acid 17.2 microliters Sodium Hydroxide adjust to pH 3.5 Water for Injection (USP) qs to 1 mL
  • Glacial acetic acid 2.87 microliters
  • Glacial acetic acid 2.87 microliters

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Pharmaceutical compositions that prevent or minimize precipitation upon injection or infusion, comprising: a) a safe and therapeutically effective amount of N-{4-[2-1,2,3,4-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 system; and d) a pharmaceutically acceptable carrier.

Description

PARENTERAL PHARMACEUTICAL COMPOSITIONS CONTAINING GF120918A
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
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. However, problems exist with the parental administration of GF120918A due to the compounds poor solubility. 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.
Publications such as In Vitro Method for Detecting Precipitation of Parenteral Formulations After Injections. Journal of Pharmaceutical Sciences, Vol. 72, No. 9, September 1983; Pluronic Surfactants Affecting Diazepam Solubility,
Compatibility, and Adsorption From i.v. Admixture Solutions, Journal of Surface Sciences, Vol. 11, No. 4, 1988, Taiwan, Republic of China, Precipitation of the Renin Inhibitor Ditekiren Upon iv Infusion: in Vitro Studies and Their Relationship to in Vivo Precipitation in the Cynomolgus Monkey. Pharmaceutical Research, Vol. 8, No. 1, 1991; Intravenous premedication with diazepam. A comparison between two vehicles. Anesthesia, 1984, Vol. 39, p. 879-882; Precipitation of Solubilized Drugs due to Injection or Dilution. Drug Intelligence and Clinical Pharmacy, Vol. 11, July 77; and U.S. Patents 4.205.089 and 4.296.131. issued May 27, 1980 and October 20, 1981 both to Ladage et al., teach how to increase the solubility of a compound in a formulation. These publications advocate the use of: cosolvents, complexing agents, hydrotropic agents, liposomes, fat emulsions, polyaphrons, dimethylsulfoxide and surfactants. However, even though GF120918A is soluble in the standardized formulations utilized for parenteral administration, precipitation nevertheless occurs upon injection or infusion into the blood stream. This precipitation on infusion occurs as the formulation, a weak base, mixes within the pH neutral blood stream. The novel compositions of the present Invention maintain solubility within the blood stream and prevent precipitation of the drug upon injection or infusion into the blood stream.
SUMMARY OF THE INVENTION 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.
DETAILED DESCRIPTION OF THE INVENTION
By "safe and therapeutically effective amount," as used herein, 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.
The 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.
Persons who treat cancer and other diseases which become resistant to chemotherapeutic, anti-tumor compounds would use the compositions of the present Invention to resensitize multidrug-resistant cells to chemotherapeutic agents thus abating multidrug-resistance. Therefore, compositions of the present Invention may be administered in conjunction with an antitumor drug.
Examples of 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 aclarubinάn, 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.
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. In this instance "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.
The medical community, particularly oncologists and other medical professionals who treat persons afflicted with tumor disease recognize that patients suffer various adverse side-effects from the administration of chemotherapeutic anti-tumor drugs. One of the most serious side effects produced by chemotherapeutic anti-tumor drugs is nausea and vomiting. Nausea and vomiting can result in severe consequences leading to increased morbidity and mortality. 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. If given simultaneously by either being admixed in the same syringe for injection or admixed in the same intravenous bag or bottle for infusion the various formulations 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.
Parenteral compositions of the present Invention must be in a sterile form. Any of the various methods known to persons skilled in the art employed to prepare sterile parenteral preparations that will not degrade components of the present Invention are suitable for use in the compositions sterile preparation. Parenteral compositions of the present Invention may be packaged, produced or contained in packaging materials such as single use ampoules, vials or intravenous bottles or bags or alternatively in multidose or multiuse vials or containers.
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. Additionally 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 pH of the pre-sent compositions range from about 1 to about 5, particularly from about 2.5 to about 4. The essential, as well as possible optional components of the compositions of the present Invention, are described in the following paragraphs.
Essential Components
One of the essential components of the present Invention is GF120918 and its physiologically acceptable salts and solvates, described in International Patent Application WO 92/12132. published 23 July 1992. GF120918 is an acridine derivative that is able to reverse or reduce resistance to, increase or restore sensitivity to or improve or increase the efficacy of an chemotherapeutic agent or agents.
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. Examples of 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 surface-active agents best suited for inclusion into the present composition are: polyethylene glycol 660 hydroxystearate (SOLUTO ® HS-15), polyoxyethylene castor oil derivatives (CREMOPHOR® EL, RH40, and RH60), poloxamer, polyoxyethylene alkyl ethers (CETOMACROGOL® 1000) and polyoxyethylene sorbitan fatty acid esters (POLYSORBATE® 20, 40, 60, and 80 and TWEEN® 20, 40, 60 and 80). In particular polyethylene glycol 660 hydroxystearate, polyethylene glycol, polyoxyethylene castor oil derivatives and polyoxyethylene sorbitan fatty acid esters are useful in compositions of the present Invention.
Another essential component of the present Invention is a buffer or mixture of buffers. Buffers are compounds or mixtures of compounds which if present in a solution resist changes in the pH of the solution upon the addition of small quantities of acids or bases. Further information about buffers can be found in Remington's Pharmaceutical Sciences, p. 243 - 45 17th ed. (1985). Examples of buffers suitable for use in compositions of the present Invention include: acetate, phosphate and glutamate.
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. Persons skilled in the art will quickly realize that any carrier or diluent intended for parenteral administration that is compatible with the essential and any optional components of the present Invention will be suitable. Examples of suitable carriers and diluents include, but are not limited to: dextrose 5% in water and sterile water for injection.
Optional Components
In addition to the above described essential components, the 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.
METHOD OF MANUFACTURE The compositions of the present Invention can be made using methods and techniques that are commonly employed in preparing parenteral preparations within the pharmaceutical industry. Remington's Pharmaceutical Sciences, p. 1518 - 1541, 17th ed. (1985). COMPOSITION USE
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.
EXAMPLES
The following examples further describe and demonstrate particular embodiments within the scope of the present Invention. The examples are given solely for illustration and are not to be construed as limitations as many variation are possible without departing from the Invention's spirit and scope.
Example I Ingredients Amounts
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
TWEEN 80® 10 microliters
Sodium Hydroxide adjust to pH 3.75 5% Dextrose in water (USP) qs to 1 mL
Preparation
100 mL of 0.5 mg GF120918A/mL Intravenous Infusion, 0.05M Acetate, pH 3.75, 1% v/v TWEEN 80, qs with 5% Dextrose in water. Pipette 286.5 μL of glacial acetic acid into a beaker and add approximately 50 mL of D5W. Weigh 1.08 g of polysorbate 80 and add to the beaker with glacial acetic acid and D5W. Using a spatula and rinsing with D5W if necessary, disperse the polysorbate 80 by stirring. Weigh 53.2 mg of GF120918A and dissolve it in the above solution. Add additional D5W until a total volume of approximately 98 m is achieved. Dissolve 5 g of sodium hydroxide in 30 mL of distilled, deionized water in a separate beaker. Add the sodium hydroxide solution dropwise with stirring to the solution until a pH of 3.75 is achieved. Pour the resulting solution into a 100 mL volumetric flask and q.s. to 100 mL with D5W. Stir or shake the solution to ensure homogeneity. Filter the final solution through a 0.22 μ filter to ensure sterility. Example π
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
CREMOPHOR EL® 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
Example HQ
GF120918A 0.53 mg Glacial acetic acid 2.87 microliters
CREMOPHOR RH40® 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 ml
Example IV
GF120918A 0.53 mg Glacial acetic acid 2.87 microliters CREMOPHOR RH60® 10 microliters Sodium Hydroxide adjust to pH 3.75 5% Dextrose in water (USP) qs to 1 mL
Example V
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
SOLUTOL HS-15® 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
Example VI GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
TWEEN 60® 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
Example VII
GF120918A 3.19 mg PEG 300 0.4 mL TWEEN 80® 100 microliters Glacial acetic acid 17.2 microliters
Sodium Hydroxide adjust to pH 3.5 Water for Injection (USP) qs to 1 mL Example VIΗ
GF120918A 3.19 mg PEG 300 0.4 mL
CREMOPHOR EL® 100 microliters Glacial acetic acid 17.2 microliters Sodium Hydroxide adjust to pH 3.5 Water for Injection (USP) qs to 1 ml
Example IX GF120918A 3.19 mg
PEG 300 0.4 mL TWEEN 60® 100 microliters Glacial acetic acid 17.2 microliters Sodium Hydroxide adjust to pH 3.5 Water for Injection (USP) qs to 1 mL
Example X
GF120918A 3.19 mg PEG 300 0.4 mL CREMOPHOR RH40® 100 microliters
Glacial acetic acid 17.2 microliters Sodium Hydroxide adjust to pH 3.5 Water for Injection (USP) qs to 1 mL
Example XI
GF120918A 3.19 mg
PEG 300 0.4 mL
CREMOPHOR RH60® 100 microliters
Glacial acetic acid 17.2 microliters Sodium Hydroxide adjust to pH 3.5
Water for Injection (USP) qs to 1 ml
Example XII
GF120918A 3.19 mg PEG 300 0.4 mL
SOLUTOL HS-15® 100 microliters Glacial acetic acid 17.2 microliters Sodium Hydroxide adjust to pH 3.5 Water for Injection (USP) qs to 1 ml Example Xm
GF120918A 3.19 mg PEG 300 0.4 mL TWEEN 20® 100 microliters Glacial acetic acid 17.2 microliters Sodium Hydroxide adjust to pH 3.5 Water for Injection (USP) qs to 1 ml
Example XIV GF120918A 3.19 mg
PEG 300 0.4 mL TWEEN 40® 100 microliters Glacial acetic acid 17.2 microliters Sodium Hydroxide adjust to pH 3.5 Water for Injection (USP) qs to 1 ml
Example XV
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
TWEEN 20® 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
Example XVI GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
TWEEN 40® 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 ml

Claims

What is Claimed is:
1. A pharmaceutical composition that prevents or minimizes precipitation of the compositions active ingredient upon parenteral administration; comprising: a) a safe and 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.
2. A pharmaceutical composition according to Claim 1 wherein the pH is from about 1 to about 5.
3. A pharmaceutical composition according to Claim 2 wherein the 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 or its physiologically acceptable, salts and solvates is from about 1 mg to about 10 gm.
4. A pharmaceutical composition according to Claim 3 wherein the surfactant is selected from the group consisting of: polyethylene glycol 660 hydroxystearate, polyoxyethylene castor oil derivatives, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol, propylene glycol, ethanol and glycerin.
5. A pharmaceutical composition according to Claim 4 wherein the amount of surfactant is from about 0.5% to about 5%.
6. A pharmaceutical composition according to Claim 5 wherein the buffer is selected from the group consisting of: acetate, phosphate and glutamate.
7. A pharmaceutical composition according to Claim 6 wherein the amount of the buffer is from about 0.005% to about 0.5%.
8. A pharmaceutical composition according to Claim 7 wherein the pharmaceutically acceptable carrier or diluent is a sterile solution suitable for parenteral administration, selected from the group consisting of: dextrose 5% in water or sterile water for injection.
9. A pharmaceutical composition according to Claim 1 containing an additional buffer.
10. A pharmaceutical composition according to Claim 9 wherein the additional buffer is selected from the group consisting of: acetate, phosphate and glutamate.
11. A pharmaceutical composition according to Claim 1 additionally containing a safe and effective amount of a cosolvent.
12. A pharmaceutical composition according to Claim 11 wherein the cosolvent is selected from the group consisting of: polyethylene glycol, propylene glycol (1,2- propanediol), ethanol and glycerin.
13. A pharmaceutical composition according to Claim 1 additionally containing a safe and effective amount of and additional drug substance.
14. A pharmaceutical composition according to Claim 13 wherein the safe and effective amount of the additional drug substance is selected from the group consisting of: antinausents, antibiotics, antidepressants, antiulcer compounds, analgesics, anticholornergics and antivirals.
15. A pharmaceutical composition according to Claim 14 wherein the safe and effective amount of the additional drug substance is an antinausent selected from the group consisting of: serotonin 5-HT3 receptor antagonists, prochlorperazine, chlorpromazine, perphenazine, thiethylperazine, triflupromazine, droperidol, methochlopramide, trimethobenzamide, dronabinol, pherergan, nabilone and methylpredinisone.
16. A pharmaceutical composition according to Claim 15 wherein the safe and effective amount of the additional drug substance is a serotonin 5-HT3 receptor antagonist.
17. A method of reversing, reducing or inhibiting multidrug-resistance or increasing or restoring sensitivity to a tumor by administering a safe and effective amount of a composition according to Claim 1.
18. A method according to Claim 18 wherein the composition is administered as a parenteral injection or parenteral infusion.
19. An article of manufacture comprising: a) packaging material; and b) a pharmaceutical composition contained within the packaging material, wherein the pharmaceutical composition prevents or minimizes precipitation of the compositions active ingredient upon injection or infusion, comprising: i) a safe and therapeutically effective amount of -V-{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; ii) a safe and effective amount of a surfactant; iii) a buffer; and iv) a pharmaceutically acceptable carrier or diluent.
20. An article of manufacture of Claim 19 additionally comprising: a brochure containing product information.
PCT/US1995/012952 1994-10-05 1995-10-04 Parenteral pharmaceutical compositions containing gf120918a WO1996011007A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
KR1019970702223A KR970705997A (en) 1994-10-05 1995-10-04 N-4-[2-1234--67--2--]--910--5--9--4- gf120918a parenteral pharmaceutical compositions containing gf120918a
PL95319511A PL319511A1 (en) 1994-10-05 1995-10-04 Parenteral pharmaceutic compositions containing gf120918a
CZ971041A CZ104197A3 (en) 1994-10-05 1995-10-04 Pharmaceutical preparation
AU38913/95A AU702519B2 (en) 1994-10-05 1995-10-04 Parenteral pharmaceutical compositions containing GF120918A
JP8512678A JPH10507177A (en) 1994-10-05 1995-10-04 Parenteral pharmaceutical composition comprising GF120918A
NZ295546A NZ295546A (en) 1994-10-05 1995-10-04 Parenteral medicament containing n-{4-[2-1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}- 9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide, surfactant, and buffer
EP95938184A EP0784474A2 (en) 1994-10-05 1995-10-04 Parenteral pharmaceutical compositions containing gf120918a
BR9509251A BR9509251A (en) 1994-10-05 1995-10-04 Pharmaceutical composition The process of reversing reducing or inhibiting multidrug resistance or restoring the sensitivity of a tumor and manufactured article
MXPA/A/1997/002473A MXPA97002473A (en) 1994-10-05 1997-04-04 Parenteral pharmaceutical compositions containing gf1209

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US31830894A 1994-10-05 1994-10-05
US08/318,308 1994-10-05

Publications (1)

Publication Number Publication Date
WO1996011007A1 true WO1996011007A1 (en) 1996-04-18

Family

ID=23237614

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/012952 WO1996011007A1 (en) 1994-10-05 1995-10-04 Parenteral pharmaceutical compositions containing gf120918a

Country Status (12)

Country Link
EP (1) EP0784474A2 (en)
JP (1) JPH10507177A (en)
KR (1) KR970705997A (en)
AU (1) AU702519B2 (en)
BR (1) BR9509251A (en)
CA (1) CA2201628A1 (en)
CZ (1) CZ104197A3 (en)
HU (1) HUT77883A (en)
NZ (1) NZ295546A (en)
PL (1) PL319511A1 (en)
RU (1) RU2157687C2 (en)
WO (1) WO1996011007A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020036A1 (en) * 1998-10-02 2000-04-13 Abbott Laboratories Pharmaceutical compositions containing paclitaxel
US6248891B1 (en) * 1997-05-23 2001-06-19 Glaxo Wellcome, Inc. Synthesis of acridine derivative multidrug-resistant inhibitors
US6274593B1 (en) 1997-05-01 2001-08-14 Smithkline Beecham P.L.C. Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors
US6414154B1 (en) 1998-05-20 2002-07-02 Smithkline Beecham P.L.C. Tetraisoquinoline derivatives as modulators of dopamine D3 receptors
WO2003002150A1 (en) * 2001-06-28 2003-01-09 Wyeth Composition and method for reducing adverse interactions between phenothiazine derivatives and plasma
US6521635B1 (en) 2000-01-20 2003-02-18 The United States Of America As Represented By The Department Of Health And Human Services Inhibition of MXR transport by acridine derivatives
US6605607B1 (en) 1998-10-08 2003-08-12 Smithkline Beecham P.L.C. Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)
US7030132B2 (en) 1999-05-17 2006-04-18 Cancer Research Ventures Limited Method of improving bioavailability of orally administered drugs, a method of screening for enhancers of such bioavailability and novel pharmaceutical compositions for oral delivery of drugs

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT408186B (en) * 1998-12-15 2001-09-25 Sanochemia Pharmazeutika Ag AQUEOUS PREPARATION OF BETA CAROTINE
IL153676A0 (en) * 2000-06-30 2003-07-06 Inex Pharmaceuticals Corp Liposomal pharmaceutical compositions
KR100866728B1 (en) * 2004-11-12 2008-11-03 주식회사종근당 The injection of tacrolimus
FR2948568B1 (en) * 2009-07-30 2012-08-24 Sanofi Aventis PHARMACEUTICAL FORMULATION

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012132A1 (en) * 1991-01-11 1992-07-23 Laboratoires Glaxo S.A. Acridine derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012132A1 (en) * 1991-01-11 1992-07-23 Laboratoires Glaxo S.A. Acridine derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HYAFIL F. ET AL: "In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative", CANCER RES., vol. 53, no. 19, 1 October 1993 (1993-10-01), pages 4595 - 4602, XP000565696 *
TONG W. ET AL: "Solubility behavior of GF120918A", PHARM. RES., vol. 11, no. 10, 11 October 1994 (1994-10-11), NEW YORK LONDON, pages 5269, XP000566180 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274593B1 (en) 1997-05-01 2001-08-14 Smithkline Beecham P.L.C. Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors
US6248891B1 (en) * 1997-05-23 2001-06-19 Glaxo Wellcome, Inc. Synthesis of acridine derivative multidrug-resistant inhibitors
US6414154B1 (en) 1998-05-20 2002-07-02 Smithkline Beecham P.L.C. Tetraisoquinoline derivatives as modulators of dopamine D3 receptors
WO2000020036A1 (en) * 1998-10-02 2000-04-13 Abbott Laboratories Pharmaceutical compositions containing paclitaxel
US6605607B1 (en) 1998-10-08 2003-08-12 Smithkline Beecham P.L.C. Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)
US7030132B2 (en) 1999-05-17 2006-04-18 Cancer Research Ventures Limited Method of improving bioavailability of orally administered drugs, a method of screening for enhancers of such bioavailability and novel pharmaceutical compositions for oral delivery of drugs
US6521635B1 (en) 2000-01-20 2003-02-18 The United States Of America As Represented By The Department Of Health And Human Services Inhibition of MXR transport by acridine derivatives
WO2003002150A1 (en) * 2001-06-28 2003-01-09 Wyeth Composition and method for reducing adverse interactions between phenothiazine derivatives and plasma
US7122201B2 (en) 2001-06-28 2006-10-17 Baxter International Inc. Composition and method for reducing adverse interactions between phenothiazine derivatives and plasma using surfactants and amino acids

Also Published As

Publication number Publication date
CA2201628A1 (en) 1996-04-18
MX9702473A (en) 1997-07-31
JPH10507177A (en) 1998-07-14
NZ295546A (en) 1999-01-28
AU702519B2 (en) 1999-02-25
KR970705997A (en) 1997-11-03
CZ104197A3 (en) 1997-09-17
PL319511A1 (en) 1997-08-18
BR9509251A (en) 1997-10-21
RU2157687C2 (en) 2000-10-20
HUT77883A (en) 1998-09-28
EP0784474A2 (en) 1997-07-23
AU3891395A (en) 1996-05-02

Similar Documents

Publication Publication Date Title
US11433062B2 (en) Stable nimodipine parenteral formulation
US7915317B2 (en) Aqueous 2,6-diisopropylphenol pharmaceutical compositions
US8133918B2 (en) Aqueous pharmaceutical compositions of 2,6-diisopropylphenol (propofol) and their uses
JP4890732B2 (en) Paclitaxel / liposome composition for cancer treatment and method for producing the same
US10688111B2 (en) Liquid formulations of compounds active at sulfonylurea receptors
AU702519B2 (en) Parenteral pharmaceutical compositions containing GF120918A
US10799486B2 (en) Stable nimodipine parenteral formulation
KR102656841B1 (en) Injectable pharmaceutical formulation of lefamulin
EP3509569A1 (en) Sterile injectable compositions comprising drug micelles
EP1667656A1 (en) Compositions and methods for delivery of biologically active agents
AU2011273064A1 (en) Pharmaceutical compositions comprising paracetamol and process for preparing the same
WO2012001494A2 (en) Pharmaceutical compositions comprising paracetamol and process for preparing the same
JP2011529930A (en) Injectable taxane pharmaceutical composition
JP2008521834A (en) Therapeutic formulation
RU2236227C1 (en) Stable pharmaceutical formulation of anticancer preparation
MXPA97002473A (en) Parenteral pharmaceutical compositions containing gf1209
US20240156829A1 (en) Stable Antiemetic Emulsions for Parenteral Administration
CN1164189A (en) Parenteral pharmaceutical compositions containing GF 120918A
WO2024224424A1 (en) Injectable compositions of metolazone
WO2024127418A1 (en) Injectable compositions of posaconazole
JP2024537910A (en) Stable, ready-to-dilute carfilzomib composition
WO2018109731A1 (en) Pharmaceutical compositions of taxane and its derivatives
AU2004267882A1 (en) Compositions and methods for delivery of biologically active agents

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 95196381.3

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TT UA UG US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WR Later publication of a revised version of an international search report
ENP Entry into the national phase

Ref document number: 2201628

Country of ref document: CA

Ref document number: 2201628

Country of ref document: CA

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 1997 809909

Country of ref document: US

Date of ref document: 19970403

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PV1997-1041

Country of ref document: CZ

Ref document number: PA/a/1997/002473

Country of ref document: MX

Ref document number: 295546

Country of ref document: NZ

Ref document number: 1019970702223

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 1995938184

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1995938184

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV1997-1041

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019970702223

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1019970702223

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV1997-1041

Country of ref document: CZ

WWR Wipo information: refused in national office

Ref document number: 1995938184

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1995938184

Country of ref document: EP