PHARMACEUTICAL COMPOSITIONS OF THE INVENTION The present invention relates to novel pharmaceutical compositions that are useful in preventing malignant cells from becoming resistant to a variety of chemotherapeutic agents. BACKGROUND OF THE INVENTION The multiple drug resistance inhibitor, chemically known as N- "4- [2-1, 2.3.4-tetrahydro-6,7-dimethoxy-2-isoquinol ini 1) -eti 1] -pheni 1 > - 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 No. WO 92/12132, filed in the name of the Glaxo Laboratories,S.A. and published on July 23, 1992. Resistance to multiple drugs is a process by which tumor cells become resistant to structurally diverse chemotherapeutic agents, after being exposed to a treatment with antitumor drugs. This resistance to acquired drugs 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, by resorbing the tumor cells resistant to multiple drugs to several REF: 24419 chemotherapeutic agents. It has also been observed that certain tumors are intrinsically resistant to multiple drugs and the use of inhibitors of resistance to multiple drugs is also beneficial in the treatment of tumors of this type. GF120918A, which is the hydrochloride salt of N- "4- [2-1, 2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl) -ethyl] -pheni 1.}. -9, 10 -dihydro-5-methoxy-9-oxo-4-acridine carboxamide, to be administered safely and effectively to patients parenterally, either by intravenous injection or intravenous infusion, must be adequately miscible in the blood. Therefore, any combination of the drug and the various excipients, in liquid form, must be sufficiently compatible with the physiological composition of the blood, to allow sufficient mixing.This mixture with the blood allows the compound to be distributed throughout the body of a However, there are problems with the parenteral administration of GF120918A due to the poor solubility of the compound.GF120918A is a weak base and, therefore, exhibits a greater solubility at a pH of less than about 4. that the pH of the blood is about 7.4. This alone in solution precipitates when injected or infused into the bloodstream.
An objective of the present invention is to provide a parenteral formulation, which when injected or infused into the bloodstream, remains miscible and allows the active drug to be distributed throughout the body in an unusual manner. Another objective of the present invention is to provide a parenteral formulation and a method of use, which improve or increase the efficacy of a chemotherapeutic agent or restore the sensitivity of a tumor to the chemotherapeutic agent or revert or reduce the resistance of a tumor to a chemotherapeutic agent.; subsequently reducing the resistance to multiple drugs of tumor cells and decreasing morbidity. Publications such as In Vítro Mßthod for Detecting Precipitation of Parenteral Formulations After Injections, Journal of Pharmaceutical Sciences, Vol. 72. No. 9. September 1983; Pluronic Surfactants Affecting Diazepam Solubil ity. Compatibi 1 ity. 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 ivInfusion; In Vitro Studies and Their Relationship to In Vivo Precipitation in the Cynomolqus Monkey, Pharmaceutical Research. Vol. 8. No. 1. 1991; Intravenous premedication with diazepam. A comparison of two vehicles.
Anesthesia, 1984, Vol. 39, p. 879-882; Precipitation of Solubil ized Drugs due to Injection or Dilution, Drug Intel ligence and Clinical Pharmacy, Vol. 11, July 77; and US Patent Nos. 4,205,089 and 4,296,131, issued May 27, 1980 and October 20, 1981. both of Ladage? t a l. , currently teach how to increase the solubility of a compound in a formulation. These publications are directed to the use of cosolvents, complexing agents, hydrotropic agents, liposomes, fat emulsions, polyafroins, dimethylsulfoxide and surfactants. However, even when GF120918A is soluble in the standardized formulations used for parenteral administration, precipitation occurs after injection or infusion into the bloodstream. This precipitation after infusion occurs because the formulation, as it is a weak base, is mixed at the neutral pH of the bloodstream. The new compositions of the present invention maintain solubility within the bloodstream and prevent precipitation of the drug after being injected or infused therein. BRIEF DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical compositions that prevent or minimize precipitation after injection or infusion; which comprise: a) a safe and therapeutically effective amount of N- "4- [2-1, 2, 3,4-tetrahydro-6,7-dimethoxy-2-isoquinolini 1) -eti 1] -pheni 1} -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 pH regulator, and d) a pharmaceutically acceptable carrier or diluent DETAILED DESCRIPTION OF THE INVENTION The term "safe and therapeutically effective amount", as used herein, means a sufficient amount of a drug or pharmaceutical agent to abate or reverse a multiple drug resistance response of a tissue, system or animal that is being studied by the researcher or clinician, without damaging the tissues of a mammal, including a human being, to which the drug is being administered The compositions of the present invention employ a safe and therapeutically effective of the compound N - "'4- [2-1.2, 3, 4-tetrahydro-6,7-dimethoxy-2-isoquinolini 1) -eti l] -pheni 1 > -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 pH regulator and a Suitable carriers or diluents 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. Treating cancer and other diseases that become resistant to anti-tumor chemotherapeutic compounds, would use the compositions of the present invention to restrain multiple drug-resistant cells to chemotherapeutic agents, thereby reducing resistance to multiple drugs. The compositions of the present invention could be administered in conjunction with a Antitumor drug Examples of antitumor drugs suitable for use in conjunction with the compositions of the present invention include, but are not limited to, vinca alkaloids (eg, vincristine. vinblastine and vinoreblina). anthracyclines(eg, daunorubicin, doxorubicin and aclarubicin), taxol and derivatives thereof (eg, taxotere), podofi lotixins (eg, etoposide and VP16), mitoxantrone, actinomycin, colchicine, gramidin D, cisplatin, cyclophosphamide, amsacrine or any other type of chemotherapeutic antitumor compound. The compositions of the present invention, although administered in conjunction with an antitumor drug, they can also be administered simultaneously with an antitumor drug. This type of administration is acceptable as long as the components of the composition of the present invention and any antitumor compound administered simultaneously are physically and chemically compatible. In this case, the term "simultaneously" means, sequentially with little or no delay, or administered together from a single common container. wherein the composition of the present invention and the antitumor drug are physically mixed. The medical community particularly oncologists and other medical professionals who treat afflicted patients with tumor diseases. recognize that patients suffer several adverse side effects from the administration of anti-tumor chemotherapeutic drugs. One of the most serious side effects produced chemotherapy anti-tumor drugs. It is nausea and vomiting. Nausea and vomiting can cause serious consequences, leading to increased morbidity and mortality. The compositions of the present invention can also be administered with various formulations of drugs to combat side effects produced by anti-tumor chemotherapy. These other formulations can be administered either simultaneously, or in conjunction with the formulations of the present invention. If administered simultaneously, either by being mixed in the same syringe to be injected, or in the same bag or bottle for intravenous infusion, the various formulations must be both physically and chemically compatible with the compositions of the present invention. However, if the formulation is administered in conjunction with the compositions of the present invention or are administered together at the same time, but from a different container, or is administered by another route or administered intravenously either before or after the compositions of the present invention, physical and chemical reactivity should not be a problem. The parenteral compositions of the present invention should be in sterile form. Any of the various methods known to those skilled in the art for preparing sterile parenteral preparations that do not degrade the components of the present invention is suitable for use in the preparation of sterile compositions. The parenteral compositions of the present invention can be packaged, produced or contained in packaging materials such as single use ampoules. vials or bottles or intravenous bags or. alternatively, multi-dose or multi-use bottles or containers. The compositions of the present invention can 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 pH regulator; and a pharmaceutically acceptable carrier or diluent, packaged in the manner described above. The packaging material may also have labels and information related to the pharmaceutical composition. Additionally, a manufacturing item may have a brochure, report, note, pamphlet or sheet that contains product information. This form of pharmaceutical product information sometimes, in the pharmaceutical industry, is referred to as "packaging insert". The packing insert can be attached to. or include it in a pharmaceutical manufacturing article. The packaging insert and any article to label the product, provide information regarding the pharmaceutical composition. This information and the label provide various forms of information used by health professionals and patients, describing the composition, its dosage and various other parameters required by the Regulatory Offices, such as the Food and Drug Administration (Food and Drug Administration). Drugs) of the United States. The pH of the present compositions ranges from about 1 to about 5, particularly from about 2.5 to about 4. The essential components, as well as possible optionals of the compositions of the present invention, are described in the following paragraphs. Components Esencialea. 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 on July 23, 1992. GF120918 is an acridine derivative capable of revert or reduce resistance to, increase or restore sensitivity to, or improve or increase the efficacy of, a chemotherapeutic agent or agents.
The amount of GF120918 administered to prevent, abate or reverse resistance to multiple drugs in a mammal, including humans, will vary according to the nature of the disease being treated and the age and condition of the patient, and will ultimately be at the discretion of the physician. or veterinarian who sees the patient. However, in general, the doses used for the treatment of adult humans will typically be in the range of about 1 mg to about 10 g per day. particularly from about 10 mg to about 1 g per day and more particularly from about 25 to about 750 mg per day. The desired dosage, conveniently, can be presented in the form of a single dose or in divided doses administered at appropriate intervals, for example in the form of two. three, four or more sub-doses a day. Another of the essential components of the present invention is a surfactant or a mixture of compatible surfactants, sometimes referred to as surfactants. Any compatible surfactant is sufficient for use in the present invention, however, nonionic surfactants are particularly suitable. Nonionic surfactants are particularly suitable in the compositions of the present invention and can be generally defined as compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound, which can be of an aliphatic nature. Ethical or aromatic 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 product of the reaction of propylene oxide with ethylene glycol. condensates of ethylene oxide of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures of such materials. The surfactant agent or mixtures of compatible surfactants can be present in the compositions of the present invention in an amount of about 0.05 to about 20.0 *. particularly from about 0.1 to about 10.0% and more particularly from about 0.5 to about 5.0% by weight with respect to the total weight of the composition. The most suitable surfactants to be included in the present composition are: polyethylene glycol 660 hydroxystearate (SOLUTOL, "HS-15), polyoxyethylene castor oil derivatives (CREMOPHOR * EL.RH40 and RH60), polyamer, polyethylene alkyl ethers ( CETOMACROGOLR 1000) and esters of polyoxyethylene sorbitan fatty acids (POLYSORBATE "20" 40. 60 and 80 and TWEEN * 20. 40. 60 and 80). In particular »polyethylene glycol hydroxy-stearate 660. polyethylene glycol. the polyoxyethylene derivatives of risino oil and the polyoxyethylene sorbitan fatty acid esters are useful in the compositions of the present invention. Another essential component of the present invention is a pH regulator or mixtures of pH regulators. PH regulators are compounds or mixtures of compounds, which, if present in a solution. they resist the changes of pH of the solution when afíadir small amounts of acids or bases. Additional information about pH regulators can be found in Remington's Pharmaceutical Sciences, p. 243-45 17Q ed. (1985). Examples of pH regulators suitable for use in the compositions of the present invention include: acetate. phosphate and glutamate. The last essential component of the present invention is a suitable vehicle or diluent, which provides an appropriate vehicle for parenteral administration of the composition, without causing undesirable side effects. Those skilled in the art will quickly realize that any vehicle or diluent for parenteral administration may be suitable., which is compatible with the essential components and any other optional component of the present invention. Examples of such suitable carriers and diluents include, but are not limited to: 5% dextrose in water and sterile injectable water. Optional components. In addition to the essential components described above, the compositions of the present invention may contain a variety of optional conventional components for parenteral administration known to those skilled in the art. Any of the optional components included in the 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 osmolarity. Additional information regarding conservatives and agents can be found to adjust isotonicity and osmolarity. in Remington's Pharmaceutical Sciences, p. 1278-1280, 1455-1472, 17? D. (1985). The optional components can also include other drugs or combinations of drugs that are physically and chemically compatible with the compositions of the present invention. Possible additional optional drugs include. but they are not limited to: antitumor chemotherapeutic agents. antiemetics including 5-HT-, serotonin receptor antagonists such as ondansetron and granisetron and various other antiemetics such as prochlorperazine, chloropromazine. perphenazine. eti ltioperazina. trif luoropromazine. Droperidol metoclopramide. trimethobenzamide, dronabinol, fererg? n, nabilone and methylprdnisone. Other optional additional drugs include: antibiotics, antidepressants, anti-ulcer compounds, analgesics, anticholics. antivirals and a myriad of other drugs suitable for the treatment of conditions that also require the administration of the compositions of the present invention. MANUFACTURING METHOD The compositions of the present invention can be prepared using methods and techniques that are commonly used in the manufacture of parenteral preparations in the pharmaceutical industry. See Remington's Pharmaceuticals Sciences, p. 1518-11541, 17Q ed. (1985). USE OF THE COMPOSITION The compositions of the present invention in their aspect of method, include the administration to a mammal, including humans, of a safe and effective amount of the compositions of the present invention, such as those described herein. These safe and effective amounts will vary according to the type and size of the mammal being treated and the desired results. EXAMPLES The following examples further describe and demonstrate particular embodiments within the scope of the present invention. The examples are given only for reasons of illustration and should not be considered as limiting, since many variations are possible without departing from the spirit and scope of the invention. Example I Ingredients Quantities GF120918A 0.53 mg Glacial acetic acid 2.87 microliters TWEEN 80 * 10 microliters Sodium hydroxide adjusted to pH 3.75Dextrose at 5% in water (USP) cbp 1 mL Preparation.100 mL of intravenous infusion of 0.05 mg ofGF120918A / mL. Acetate 0.05 M. pH 3.75. TWEEN 80 at 1% v / v. Dextrose at 5% in water cbp. 286.5 uL of glacial acetic acid are pipetted into a precipitation cuvette and approximately 50 L of D5W are added. 1.08 g of polysorbate 80 are weighed and added to the cuvette with glacial acetic acid and D5W. Using a spatula and rinsing with D5W if necessary, polysorbate 80 is dispersed by agitation. Weigh 53.2 mg of GF120918A and dissolve in the above solution. Additional D5W is added until a total volume of approximately 98 mL is obtained. Dissolve 5 g of sodium hydroxide in 30 ml of distilled and deionized water, in a separate bucket. The sodium hydroxide solution is added dropwise, with stirring, until a pH of 3.75 is reached. The resulting solution is emptied into a 100 mL volumetric flask and averaged to 100 mL with D5W. The solution is stirred to ensure homogeneity. The final solution is filtered through a 0.22 u filter to ensure sterility.
Example II GF120918A 0.53 mg Glacial acetic acid 2.87 microliters CREMOPHOR EL "10 microliters Sodium hydroxide adjusted to pH 3.75 5% dextrose in water (USP) cbp 1 mL Example IIIGF120918A 0.53 mg Glacial acetic acid 2.87 microliters CREMOPHOR RH4? "10 microliters Sodium hydroxide adjusted to pH 3.75 Dextrose to 5% in water (USP) cbp 1 mL Example IV 1 GF120918A 0.53 mg Glacial acetic acid 2.87 microliters CREMOPHOR RH6?" 10 microliters Sodium hydroxide adjusted to pH 3.75 5% Dextrose in water (USP) cbp 1 mL Example V GF120918A 0.53 mg Glacial acetic acid 2.87 microliters SOLUTOL HS-15"10 microliters Sodium hydroxide adjusted to pH 3.75% dextrose in water (USP) cbp 1 mL Example VI GF120918A 0.53 mg Glacial acetic acid 2.87 microliters TWEEN 60"10 microliters Sodium hydroxide adjusted to pH 3.75% Dextrose in water (USP) cbp 1 mL Example VII GF120918A 3.19 mg PEG 300 0.4 mL TWEEN 80"100 microliter Glacial acetic acid 17.2 microliter Sodium hydroxide adjusted to pH 3.75 Injectable water (USP) cbp 1 mL Example VIII GF120918A 3.19 mg PEG 300 0.4 mL CREMOPHOR EL "100 microliters Glacial acetic acid 17.2 microliters Sodium hydroxide adjusted to pH 3.75 Injectable water (USP) cbp 1 mL Example IX GF120918A 3.19 mg PEG 300 0.4 mL TWEEN 60" 100 microliters Glacial acetic acid 17.2 microliters Hydroxide sodium adjusted to pH 3.75 Injectable water (USP) cbp 1 mL Example X GF120918A 3.19 mg PEG 300 0.4 L TWEEN 6? " 100 microliters Glacial acetic acid 17.2 microliters Sodium hydroxide adjusted to pH 3.75 Injectable water (USP) cbp 1 mL Example XI GF120918A 3.19 mg PEG 300 0.4 mL CREMOPHOR RH6? "100 microliters Glacial acetic acid 17.2 microliters Sodium hydroxide adjusted to pH 3.75 Water injectable (USP) cbp 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 adjusted to pH 3.75Injectable water (USP) cbp 1 mL Example XIII GF120918A 3.19 mg PEG 300 0.4 mL TWEEN 2? "100 microliters Glacial acetic acid 17.2 microliters Sodium hydroxide adjusted to pH 3.75Injectable water (USP) cbp 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 adjusted to pH 3.75 Injectable water (USP) cbp 1 mL Example XV GF120918A 0.53 mg TWEEN 20" 2.87 microliters Glacial acetic acid 10 microliters Sodium hydroxide adjusted to pH 3.75 5% dextrose in water (USP) cbp 1 mL Example XVI GF120918A 0.53 mg TWEEN 40"2.87 microliters Glacial acetic acid 10 microliters Sodium hydroxide adjusted to pH 3.75 Dextrose to 5% in water (USP) cbp 1 mL It is noted that in relation to this date "the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. describing the invention as antecedent, the content of the following is claimed as property.