WO2020002056A1 - Cis-oxoplatine pour le traitement du cancer de l'estomac - Google Patents

Cis-oxoplatine pour le traitement du cancer de l'estomac Download PDF

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Publication number
WO2020002056A1
WO2020002056A1 PCT/EP2019/066062 EP2019066062W WO2020002056A1 WO 2020002056 A1 WO2020002056 A1 WO 2020002056A1 EP 2019066062 W EP2019066062 W EP 2019066062W WO 2020002056 A1 WO2020002056 A1 WO 2020002056A1
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Prior art keywords
oxoplatin
cis
pharmaceutical composition
treatment according
administered
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PCT/EP2019/066062
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English (en)
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Zoser B. Salama
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Salama Zoser B
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Publication of WO2020002056A1 publication Critical patent/WO2020002056A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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 invention relates to pharmaceutical composition comprising oxoplatin, or their derivative, isomers, salts, or nanoparticles or pro-drugs therof, and to the use of said compositions for the treatment of solid tumours.
  • the invention further relates to methods for producing said compounds, pharmaceutical agents and compositions.
  • the present invention is based on the surprising and unexpected development that oral administered Cis-oxoplatin, Trans- oxoplatin, Cis-oxoplatin salts, Thio-oxoplatin and Cis-diamine-tetrachlorido-platinum (IV) can have anticancer and antimetastasis activites and treat the symptoms of solid tumours and particularly gastric cancer.
  • the invention therefore relates to a pharmaceutical composition comprising cis-oxoplatin, or a salt and/or derivative thereof, for use as a medicament in the treatment and/or preventation of stomach cancer.
  • the invention further relates to the pharmaceutical composition as described for use in the treatment of stomach cancer, wherein the cis-oxoplatin or derivative thereof is administered in a form that is transformed under acidic pH to a tetrachloro-oxoplatin (IV).
  • Cis-diaminedichloro-trans-dihydoxyplatinum contains a platinum (IV) metal centre. Compared to cisplatin, cis-oxoplatin adducts have a higher formal charge on the central platinum molecule and two additional ligands attached to its centre. Platinum (IV) complexes are often described as pro-drugs as it is believed by some scientists that they are reduced in vivo to the platinum (II) form before binding DNA. However, Novakova et al.
  • cis-oxoplatin binds preferentially to guanine residues and an essential step in its binding to DNA is the intracellular hydrolysis of chlorine ions which involves the association of solvent water (i.e. chlorine ion ligands are replaced by oxonium ions). These oxonium ions then dissociate from cis-oxoplatin as it binds to DNA via nucleophilic attack made possible by platinum atom’s free electrons. The negatively charged oxygen atoms in cis-oxoplatin (which are not present in cisplatin) then repel the negatively charged phosphate groups of DNA weakening the adduct and making it easier to break.
  • Cis-oxoplatin has a shorter half life than cisplatin which is possibly the reason for its lower levels of nephrotoxicity in animals.
  • Cis-oxoplatin binds at similar sites to cisplatin and can form intrastrand cross-links (between neighbouring base residues) and interstrand cross links. It is thought that these lesions are vital to the cytostatic characteristics of the drug.
  • chemotherapeutic drugs are currently developed for intravenous use; this has the advantage of ensuring total absorption into the blood stream.
  • there are several advantages to finding an alternative oral treatment with similar efficacy because of the benefits of easy administration, better patient compliance and the reduction in cost. For example, patients will be able to undergo oral treatment as outpatients.
  • Several new oral chemotherapeutic agents are currently under clinical investigation.
  • oral drugs for cancer treatment have a future and will play a more important role than they have done in the past.
  • Patient s preferences and quality of life issues, which are becoming central considerations in palliative treatment regimens, precede the development of orally administered drugs.
  • Intravenous (i.v.) administration is a major source of discomfort and distress for cancer patients. They express a preference for oral versus i.v. chemotherapy, predominantly because of the reduced trauma and discomfort associated with oral as opposed to intravenous administration.
  • the oral formulation of the drug enables its administration outside a clinical setting, which is both more convenient and less stressful.
  • Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment.
  • a substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (forliver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake.
  • Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
  • stage 1A stomach cancer ⁇ More than 80 out of 100 people (80%) with stage 1A stomach cancer will survive for 5 years or more after they're diagnosed.
  • stage 1 B stomach cancer Around 70 out of 100 people (70%) with stage 1 B stomach cancer will survive for 5 years or more after they're diagnosed.
  • stage 2A stomach cancer ⁇ 60 out of 100 people (60%) with stage 2A stomach cancer will survive for 5 years or more after they're diagnosed.
  • stage 2B stomach cancer ⁇ More than 40 out of 100 people (40%) with stage 2B stomach cancer will survive for 5 years or more after they're diagnosed.
  • stage 3A stomach cancer ⁇ More than 25 out of 100 people (25%) with stage 3A stomach cancer will survive for 5 years or more after they're diagnosed.
  • stage 3B stomach cancer ⁇ Almost 20 out of 100 people (20%) with stage 3B stomach cancer will survive for 5 years or more after they're diagnosed.
  • stage 3C stomach cancer Around 10 out of 100 people (10%) with stage 3C stomach cancer will survive for 5 years or more after they're diagnosed.
  • the technical problem underlying the present invention is to provide alternative or improved chemical compounds which demonstrate anti-tumour and /or anti-cancer’s treatments, and from these compounds generate a pharmaceutical composition which could then be used for the treatment of solid tumours and cancer, in particular stomach cancer. It is also an object of the present invention to provide an anti-cancer composition which can be administered orally with other pharmaceutical agents using the different routes of administrations.
  • the invention relates to transmucosal, transbuccal, local, intravenous, transdermal and intranasal dosage form administrations of oxoplatin, its salts, isomers, enantiomers and/or derivatives.
  • the invention further provides pharmaceutical compositions, which contain a therapeutically effective amount of oxoplatin, its salts, isomers, enantiomers and/or derivatives or prodrugs with or without the combination with other agents.
  • the invention therefore relates to a pharmaceutical composition comprising cis-oxoplatin, or a salt and/or derivative thereof, for use as a medicament in the treatment and/or prevention of stomach cancer.
  • the cis-oxoplatin or derivative thereof comprises Cis-diamine-dichloro-trans- dihydroxy-platinum (IV).
  • the cis-oxoplatin or derivative thereof comprises a tetrachloro-oxoplatin (IV).
  • the cis-oxoplatin or derivative thereof comprises Cis-diamine-tetrachloro-platinum (IV).
  • the cis-oxoplatin or derivative thereof comprises monochloro cisplatin.
  • the cis-oxoplatin or derivative thereof comprises a dialkyl, diaryl derivative of the oxoplatin isomer.
  • the cis-oxoplatin or salt or derivative thereof is administered in any one of the forms mentioned above, such that a tetrachloro-oxoplatin is formed as an active agent after administration.
  • a tetrachloro-oxoplatin may be administered directly.
  • the preferred mode of adsministration is oral, or local administration, for treating stomach cancer.
  • s the treatment described herein compises the transformation (preferably post-administration to a subject) of a dichloro-ocoplatin to a tetrachloro-oxoplatin as the active agent.
  • the cis-oxoplatin or derivative thereof is administered in a form that is transformed under acidic pH to a tetrachloro-oxoplatin (IV).
  • the cis-oxoplatin or derivative thereof is administered in a form that is transformed under the acidic conditions present in the stomach of a subject to a tetrachloro-oxoplatin (IV) or metabolite thereof.
  • the cis-oxoplatin or derivative thereof is administered as Cis-diamine-dichloro- trans-dihydroxy-platinum (IV) and is transformed under the acidic conditions present in the stomach of a subject to Cis-diamine-tetrachloro-platinum (IV) or metabolite thereof.
  • stomach cancer with cis-oxoplatin or salts or derivative thereof leads to a surprisingly good efficacy in a patient group with limited therapeutic options.
  • the finding of the transformation of cis-oxoplatin to a tetra-chloro derivative in the stomach enables the treatment of a new patient collective.
  • the tetrachloro-oxoplatin (IV) is prepared prior to administration by dissolving a dry form of cis-oxoplatin in a solution with an acidic pH.
  • the tetrachloro-oxoplatin (IV) is prepared prior to administration by mixing any given form of cis-oxoplatin with a pH lowering agent, for example with a solution with an acidic pH, preferably resulting in a solution with pH below 7.
  • pH-buffered solutions suitable for administration to a subject, are known to one skilled in the art.
  • the pH solution of acidic pH is sufficient low pH to transform a cis-oxoplatin to tetrachloro-oxoplatin (IV).
  • said dissolving of the cis-oxoplatin preferably Cis-diaminedichloro-trans- dihydroxy-platinum (IV)
  • said dissolving of the cis-oxoplatin preferably Cis-diaminedichloro-trans- dihydroxy-platinum (IV)
  • said dissolving of the cis-oxoplatin preferably Cis-diaminedichloro-trans- dihydroxy-platinum (IV)
  • said dissolving of the cis-oxoplatin preferably Cis-diaminedichloro-trans- dihydroxy-platinum (IV)
  • said dissolving of the cis-oxoplatin preferably Cis-diaminedichloro-trans- dihydroxy-platinum (IV)
  • a tetrachloro- oxoplatin preferably Cis-diamine-tetrachloro-platinum (IV).
  • said solution is administered, preferably as a pH buffered solution, via infusion, injection and/or other means of administering a liquid to a subject.
  • this invention relates to methods for the therapy of the symptoms of said solid tumours and cancer by administration of oxoplatin or oxoplatin derivatives and/or metabolites preferably monochloro oxoplatin, cis-oxoplatin, trans-oxoplatin, tetrachloro oxoplatin, Thio-oxoplatin, cis- oxoplatin sodium salt, cis-oxoplatin-calcium salt, tetrachloro tans-oxoplatin, dimethyl, diethyl, dimethoxy, diethoxy oxoplatin or one of the salts, or isomers, esters, or prodrugs thereof in combination with or without a pharmaceutical agent.
  • oxoplatin or oxoplatin derivatives and/or metabolites preferably monochloro oxoplatin, cis-oxoplatin, trans-oxoplatin, tetrachloro
  • oxoplatin derivatives which may be used according to the invention are oxoplatin or oxoplatin derivatives and/or metabolites preferably monochloro oxoplatin, cis-oxoplatin, trans- oxoplatin, tetrachloro oxoplatin, Thio-oxoplatin, cis-oxoplatin sodium salt, cis-oxoplatin-Calcium salt, tetrachloro tans-oxoplatin, dimethyl, diethyl, dimethoxy, diethoxy oxoplatin or one of the salts, or isomers, esters, or prodrugs as used according to the invention, are known compounds which are commercially available or can be prepared using chemical or biotech methods.
  • the preferred oxoplatin derivatives used include especially methyl, ethyl, isopropyl, butyl or isobutyl oxoplatin.
  • this invention relates to methods for the therapy of the symptoms of said solid tumours and cancer by administration of oxoplatin or oxoplatin derivatives and/or metabolites preferably monochloro oxoplatin, cis-oxoplatin, trans-oxoplatin, tetrachloro oxoplatin, Thio-oxoplatin, cis- oxoplatin sodium salt, cis-oxoplatin-Calcium salt, tetrachloro tans-oxoplatin, dimethyl, diethyl, dimethoxy, diethoxy oxoplatin or one of the salts, or isomers, esters, or prodrugs thereof as encapsulated, entrapt, conjugated or complexed in nanoparticles.in combination with or without a pharmaceutical agent.
  • one object of the invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising oxoplatin or oxoplatin derivatives and/or metabolites preferably monochloro oxoplatin, cis-oxoplatin, trans- oxoplatin, tetrachloro oxoplatin, Thio-oxoplatin, cis-oxoplatin sodium salt, cis-oxoplatin-Calcium salt, tetrachloro tans-oxoplatin, dimethyl, diethyl, dimethoxy, diethoxy oxoplatin or one of the salts, or isomers, esters, or prodrugs thereof for use as a medicament for the therapy of the symptoms of said solid tumors and cancer characterised in that said treatment comprises preferably oral, transmucosal, transbuccal, parental, transdermal, rectal or intranasal administration of said pharmaceutical composition to a subject in need of said treatment.
  • It is also an object of the invention is to provide a composition wherein the carrier is selected from the group consisting of fillers, diluents, binders, humectants, disintegrants, dissolution retarders, absorption enhancers, wetting agents, adsorbents, lubricants and combinations thereof.
  • the carrier is selected from the group consisting of fillers, diluents, binders, humectants, disintegrants, dissolution retarders, absorption enhancers, wetting agents, adsorbents, lubricants and combinations thereof.
  • the oxoplatin derivative is tetrachloro cis-oxoplatin platin.
  • the treatment of cancer is carried out in subjects at risk of developig metastasis.
  • the invention therefore provides methods and compositions for use in the prophylaxis, prevention, reduction, attenuation, elimination and or therapy the symptoms of said solid tumours and cancer.
  • treatment may relate to prophylaxis, prevention, stabilisation, attenuation, therapy, follow up and/or aftercare of cancer diseases.
  • Prophylaxis is a preferred embodiment.
  • oxoplatin derivative encompasses oxoplatin, its derivatives as understood by a skilled person, in particular those described herein, in addition to salts, isomeres, and/or enantiomers thereof, or racemates, or pro-drugs, whereby the preferred oxoplatin derivatives include , especially methyl, ethyl, isopropyl, butyl or isobutyl derivatives.
  • the invention involves the surprising and unexpected teaching that a compound, namely oral administered immediate released cis-oxoplatin whose pharmacological properties have been described in this invention, has a number of anticancer metabolites in the stomach and in blood and an effect on the prophylaxis, prevention, stabilisation, attenuation, therapy of the cancer in the stomach and other solid tumors in other organs.
  • the invention demonstrates that immediate release oral administration of the agent cis oxoplatin metabolites in the stomach to tetrachlorooxoplatin and their metabolites and they are effective to prophylaxis, prevent, stabilize and therapy the stomach cancer diseases.
  • the invention thus demonstrates a method of treating a human for the prophylaxis, prevention, stabilisation, attenuation, therapy of solid tumours and cancer disease comprising oral composition of cis-oxoplatin to the human at effective dosage.
  • the agent cis-oxoplatin their derivatives, salts, and /or isomeres is in a pharmaceutically acceptable carrier and administered at a dose of between about 0.01 mg/kg/ BW per day to about 4mg/kg BW/day.
  • the agent cis-oxoplatin their derivatives, salts, and /or isomeres is in a pharmaceutically acceptable carrier and administered at a dose of between about 0,1 mg/kg/ BW per day to about 5mg/kg BW/day.
  • the agent cis-oxoplatin their derivatives, salts, and /or isomeres is in a pharmaceutically acceptable carrier and administered at a dose of between about 0,5mg/kg/ BW per day to about 5mg/kg BW/day.
  • the invention thus provides a method of treating a human for therapy of gastric cancer disease comprising oral transmucosal composition of cis-oxoplatin to the human at effective dosage.
  • the method may further comprise administering a pharmaceutical composition comprises transmucosal composition of tetrachloro oxoplatin to a therapy of gastric cancer at effective amounts.
  • an anti- gastric cancer agent are tetrachloro oxoplatin, isomers, derivatives, metabolites or any corresponding salts thereof.
  • the method of the invention may be achieved through a method that comprises oral administration of a single daily dose of the agent oxoplatin their derivatives, salts, and/or isomeres.
  • the method of the invention may be achieved through a method that comprises oral administration of a multiple dose per day of the agent oxoplatin their derivatives, salts, and/or isomeres Alternatively, multiple doses per day of the agent may be administered.
  • a single intranasal administration each day of the agent oxoplatin, their derivatives, salts, and/or isomeres is significant for prophylaxis, prevention, stabilisation, attenuation, therapy of solid tumors and cancer diseases/ symptoms at effective amounts.
  • single and/or multiple dose of intranasal, intravenous, trans-dermal, rectal, intra- vaginal, depot formulation, administration of oxoplatin oxoplatin, their derivatives, salts, and/or isomers is significant for prophylaxis, prevention, stabilisation attenuation, therapy of solid tumours and cancer diseases/ symptoms at effective amounts are contemplated.
  • the invention thus provides a method of treating a human patient for prophylaxis, prevention, stabilisation attenuation, therapy of solid tumours treatment, comprising intra- nasally administering a composition comprising oxoplatin to the patient at a dosage sufficient for the therapy of the lung cancer syndromes
  • the invention thus provides a method for treating a human patient for prophylaxis, prevention, stabilisation, attenuation, therapy of solid tumours treatment, comprising parenteral administering a composition comprising oxoplatin to the patient at a dosage sufficient for prevention, stabilisation attenuation, therapy of the solid tumours and cancer syndromes.
  • the invention thus provides a method for treating a human or animal patient for therapy of solid tumor and cancer diseases, comprising rectal administering a composition comprising oxoplatin to the patient at a dosage sufficient to prevent, stabilize for prevention, stabilisation, attenuation, and/or therapy of the disease syndromes.
  • the invention thus provides a method for treating a subject for prophylaxis, prevention, stabilisation, attenuation, therapy of cancer treatment, comprising locally administering a composition comprising oxoplatin to the patient at a dosage sufficient to prophylaxis, prevent, stabilize for prophylaxis, prevention, stabilisation attenuation, and/or therapy of the the cancer disease syndromes.
  • the invention thus provides a method for treating a human or patient for prophylaxis, prevention, stabilisation, attenuation, therapy of cancer treatment, comprising intravaginally administering a composition comprising oxoplatin to the patient at a dosage sufficient to prophylaxis, prevent, prophylaxis, prevent, stabilize, attenuate, therapy the cancer disease syndromes. .
  • a pharmaceutical composition containing the agent oxoplatin, their derivatives, salts, enantiomers, and /or isomeres in a pharmaceutically acceptable carrier can be administered in dosage forms a sublingual formulations, orodispersible tablets (ODT), orodispersible films (ODF), orodispersible granules (micro-pellets), fast oral trans-mucosal (FOT), rapid film, capsules dosage form known to those skilled in the art of pharmaceutical formulation.
  • ODT orodispersible tablets
  • ODF orodispersible films
  • micro-pellets orodispersible granules
  • FOT fast oral trans-mucosal
  • a method for reducing the amount of solid tumours and cancer disease agents or pharmaceutically acceptable salt thereof required to treat a patient affected with solid tumours and cancer comprising further administering to a patient being treated with anti-cancer drug or pharmaceutically acceptable salt thereof an amount of oxoplatin or a pharmaceutical acceptable salt thereof.
  • the medical use of the pharmaceutical composition according to the present invention is characterised by administration of oral dry powder, preferably to the oral cavity.
  • Salts relate preferably to an organic acid, preferably selected from an acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, or amino acid salt.
  • the pharmaceutical composition for use as a medicament according to the present invention is characterised in that the oxoplatin amino acid salt is arginate, asparginate, or glutamate.
  • composition for use as a medicament according to the present invention is characterised in that the composition is administered at a dosage sufficient to prevent (prophylaxis), reduce, attenuate, eliminate and/or therapeutically treat the symptoms of said solid tumours.
  • the medical use of the pharmaceutical composition according to the present invention is characterised by administration of a single dose of said composition.
  • the medical use of the pharmaceutical composition according to the present invention is characterised by administration of a multiple dose of said composition.
  • the medical use of the pharmaceutical composition according to the present invention is characterised by administration of the composition at a dose of between about 0,2 mg/kg BW per day to about 1 .5 mg/kg BW per day.
  • the invention encompasses a dose of between 0.05 mg/kg BW to 10 mg/kg BW per day, preferably 0.1 mg/kg BW to 5 mg/kg BW per day, preferably 0.5mg/kg BW to 4mg/kg BW, more preferably 0.9 mg/kg BW to 3 mg/kg BW per day.
  • the medical use of the pharmaceutical composition according to the present invention is characterised in that the SR composition is administered at a single dose of between 10 to 100 mg of oxoplatin..
  • the medical use of the pharmaceutical composition according to the present invention is characterised in that the SR composition is administered at a single dose of between 50 to 200mg, preferably about 140 mg, of the composition..
  • the medical use of the pharmaceutical composition according to the present invention is characterised in that the composition is administered in combination with opioid therapy in cancer patients with pain.
  • the medical use of the pharmaceutical composition according to the present invention is characterised by administration of a pharmaceutically effective dose of a second agent, preferably selected from the group of at least one member of a pharmaceutical anticancer, anti metastasis, anti-angiogenesis, monoclonal antibodies, vaccines, immunostimulant drugs, nonsteroidal anti-inflammatory drugs, hormones, amino-acids, opiate, NMDA receptor antagonists antioxidants, CNS drugs, NMDA receptor antagonists or a pharmaceutically acceptable salt thereof, wherein the combined amount of said agents is sufficient.
  • a pharmaceutical anticancer preferably selected from the group of at least one member of a pharmaceutical anticancer, anti metastasis, anti-angiogenesis, monoclonal antibodies, vaccines, immunostimulant drugs, nonsteroidal anti-inflammatory drugs, hormones, amino-acids, opiate, NMDA receptor antagonists antioxidants, CNS drugs, NMDA receptor antagonists or a pharmaceutically acceptable salt thereof, wherein the combined amount of said agents is sufficient.
  • the invention therefore relates to a pharmaceutical composition for use as a medicament according to the present invention, comprising oxoplatin, salts and/or derivative thereof, and one or more pharmaceutically acceptable oral and/or transmucosal carrier substances.
  • the pharmaceutical composition for use as a medicament according to the present invention comprises oxoplatin, isomers, salts and/or derivative thereof, and one or more pharmaceutically acceptable oral transbuccal carrier substances.
  • the buccal systems preferably exhibit muco-adhesive properties upon contact with saliva, resulting in secure adhesion to the application site.
  • the platform can be designed to either dissolve or to remain in its origin form and los adhesion after a certain amount of time.
  • the second option is intended to be removed from the oral cavity upon loss of adhesion.
  • the pharmaceutical composition for use as a medicament according to the present invention comprises oxoplatin, salts and/or derivative thereof, and one or more pharmaceutically acceptable oral sublingual carrier substances.
  • the pharmaceutical composition for use as a medicament according to the present invention comprises oxoplatin, salts and/or derivative thereof, and one or more pharmaceutically acceptable carrier substances for an oral dry powder.
  • the invention therefore encompasses a device for patient self-administration of oxoplatin, its isomeres, enantiomers, salt, and/or derivative comprising a nasal spray or powder inhaler containing an aerosol spray formulation of oxoplatin, its salt, and/or derivative and a pharmaceutically acceptable dispersant, wherein the device is metered to disperse an amount of the aerosol formulation by forming a spray that contains a dose of oxoplatin effective to reduce or eliminate the symptoms of cancer
  • organic salts of oxoplatin include salts prepared from organic acids such as acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, and amino acid salts such as arginate, asparginate, and glutamate, and combinations comprising one or more of the foregoing salts.
  • the compounds of the invention are defined to include pharmaceutically acceptable derivatives or prodrugs thereof.
  • a pharmaceutically acceptable derivative or prodrug means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention, which upon administration to a recipient is capable of providing or provides (directly or indirectly) a compound of this invention.
  • the pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • compositions of this invention may contain any conventional pharmaceutically- acceptable carriers, adjuvants or vehicles.
  • pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • compositions may be in the form of sterile injectable preparation.
  • compositions may be orally administered in any orally acceptable dosage form including but not limited to, oral transmucosal carriers, buccal delivery compositions, sublingual formulations, Orodispersible Tablets (ODT), Orodispersible Films (ODF), Orodispersible Granules (Micro- Pellets), Fast Oral Transmucosal (FOT), capsules, tablets, an aqueous suspensions and solutions.
  • oral transmucosal carriers including but not limited to, oral transmucosal carriers, buccal delivery compositions, sublingual formulations, Orodispersible Tablets (ODT), Orodispersible Films (ODF), Orodispersible Granules (Micro- Pellets), Fast Oral Transmucosal (FOT), capsules, tablets, an aqueous suspensions and solutions.
  • compositions may also be administered in the form of suppositories for rectal administration.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, and olive oil.
  • compositions may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • compositions may also be administered and delivered to the body and organs such as brain, pancreas, lung, prostate, liver, kidney, colon by means of medical device such as implants, pump, stants, composition-coated stents prepared according to techniques well known in the art of medical devices and pharmaceutical formulations.
  • medical device such as implants, pump, stants, composition-coated stents prepared according to techniques well known in the art of medical devices and pharmaceutical formulations.
  • compositions of the present invention may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a therapeutic effect will vary depending upon the host being treated, the particular mode of administration.
  • this amount will range in some embodiments from about 1 percent to about ninety-nine percent of active ingredient, in some embodiments from about 5 percent to about 90 percent, and in some embodiments from about 10 percent to about 30 percent.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, gender, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical art.
  • a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a prophylactic and/or therapeutic effect. Such an effective dose will be generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In some embodiments, the active compound will be administered once daily.
  • the compounds of the invention are administered alone or co administered with another therapeutic agent.
  • co-administration refers to any form of administration of two or more different therapeutic compounds such that the desired effect is obtained.
  • the different therapeutic compounds may be administered either in the same formulation or in separate formulation, either concomitantly or sequentially.
  • Co- administration includes simultaneous or sequential administration of two or more compounds which may have synergistic, additive and/or different therapeutic effects.
  • Ci-oxoplatin is defined for the purpose of the patent as cis-diaminedichloro-trans- dihydroxy- platinum (IV), chemical sum formula N2H802CI2Pt and molecular weight 334.07.
  • dose is defined for the purpose of the patent as the amount of drug taken at any one time. This can be expressed as the weight of drug , volume of drug solution , the number of dosage forms or some other quantity (e.g. 2 puffs).
  • dosage regimen is defined for the purpose of the patent as the frequency at which the drug doses are given.
  • dose form is defined for the purpose of the patent as the physical form of a dose of drug.
  • Common dosage forms include tablets, capsules, creams, ointments, aerosols and patches. Each dosage form may also have a number of specialized forms such as immediate release, extended-release, buccal, dispersible and chewable tablets.
  • the strength is the amount of drug in the dosage form or a unit of the dosage form.
  • The“route of administration” is defined for the purpose of the patent as the way the dosage form is given. Common routes of administration include oral, rectal, inhalation, nasal and topical.
  • The“optimal dosage” is defined for the purpose of the patent as the dosage that gives the desired effect with minimum side effects.
  • stent is defined for the purpose of the patent as short narrow metal or plastic tube often in the form of a mesh that is inserted into the lumen of an anatomical vessel (such as an artery or a bile duct) especially to keep a previously blocked passageway open or the stent will be filled and/or coated with the compound of the invention and inserted in tissue such as the pancreas, prostate, lung, liver to release the compound of the invention and treatment of the tumour.
  • anatomical vessel such as an artery or a bile duct
  • pharmaceutically acceptable salt refers to those salts of compounds which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, methanesulphonic acid, ethane sulphonic acid, toluene sulphonic acid, salicylic acid and the like.
  • A“pharmaceutical agent” is to be understood as any medicament, intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or animals.
  • active metabolite defined for the purpose of the invention as results when a drug is metabolized by the body into a modified form which continues to produce effects in the body. These effects could be similar to those of the drug or weaker , or stronger.
  • prophylaxis is defined for the purposes of the present invention as a measure taken to maintain health and prevent the spread of disease.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non toxic parenterally-acceptable diluent or solvent, for example as absolution in 1 , 3-butane diol.
  • the active substances of the present invention are mixed with a pharmaceutically acceptable carrier or diluent in accordance with routine procedures.
  • Therapeutic and/or immunologic formulations will be administered by intravenous infusion or by subcutaneous injection.
  • the formulations can also contain, if desired, other therapeutic agents.
  • HRQL Health-related quality of life
  • Quality of Life is defined for the purposes of the present invention as: an individual's satisfaction or happiness with domains of life insofar as they affect or are affected by "health” as defined .
  • HRQL can be distinguished from quality of life as we defined in that it concerns itself primarily with those factors that fall under the purview of health care providers and health care systems.
  • assessment of HRQL represents an attempt to determine how variables within the dimension of health (e.g., a disease or its treatment) relate to particular dimensions of life that have been determined to be important to people in general (generic HRQL) or to people who have a specific disease (condition- specific HRQL).
  • HRQL Most conceptualizations of HRQL emphasize the effects of disease on physical, social/role, psychological/emotional, and cognitive functioning. Symptoms, health perceptions, and overall quality of life are often included in the concept domain of HRQL.
  • animal refers to an organism with a closed circulatory system of blood vessels and includes birds, mammals and crocodiles.
  • the term “animal” used here also includes human subjects.
  • Additional “carriers” may be used in the“carrier system” of the present invention, and include any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the carrier systems.
  • multi-target therapeutic agent is defined for the purposes of the present invention as component impacts separate targets to create a combination effect.
  • the targets can reside in the same or seprate pathways within individual cell, or in separate tissues.
  • phrases "pharmaceutically-acceptable" refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a human.
  • disease is defined for the purposes of the present invention as a pathological condition of a part, organ, or system of an organism resulting from various causes, such as infection, genetic defect, or environmental stress, and characterized by an identifiable group of signs or symptoms.
  • disease prevention is defined for the purpose of the present invention as to prevent onset of disease, early detectioin of disease and reaction aiming to halt progression, minimize disability from incurable disease.
  • elimination of a disease is defined for the purpose of the present invention as reduction to zero of the incidence of disease.
  • stabilization of disease is defined for the purpose of the present invention as cancer that is neither decreasing nor increasing in extent or severity.
  • the term“attenuation of disease” is defined for the purpose of the present invention as the act of weakening of the degree of a disease.. The reduction and/decrease of disease severity.
  • reduction of the disease is defined for the purpose of the present invention as decrease of the disease severity.
  • the term "patient” is defined for the purposes of the present invention that includes both humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy, vaccinations, and veterinary applications.
  • the patient is a mammal, the most preferred being a human.
  • the terms "treating cancer,” “therapy,” and the like refer generally to any improvement in the mammal having the cancer wherein the improvement can be ascribed to treatment with the compounds of the present invention.
  • the improvement can be either subjective or objective. For example, if the mammal is human, the patient may note improved vigour or vitality or decreased pain as subjective symptoms of improvement or response to therapy. Alternatively, the clinician may notice a decrease in tumour size or tumour burden based on physical exam, laboratory parameters, tumour markers or radiographic findings.
  • GIST Gastrointestinal Stromal Tumor-GIST
  • GISTs are usually found in the stomach or small intestine but can occur anywhere along the gastrointestinal (Gl) tract and may rarely have extra-GI involvement.
  • the GIST includes the esophagus, stomach, gallbladder and the bile ducts, liver, pancreas, small intestine, colon, rectum, anus and lining of the gut.
  • metastatic is defined for the purposes of the present invention as the process by which cancer spreads from the place at which it first arose as a primary tumor to distant locations in the body.
  • metal may be used along with the names of specific cancers to refer to the fact that the cancer has spread beyond its site of origin and has, therefore, become a metastatic cancer.
  • administered is defined for the purposes of the present invention as the administration of a therapeutically effective dose of the candidate agents of the invention to a cell either in cell culture or in a patient. Accordingly the composition of the invention is administered to cells, tissues of subjects.
  • terapéuticaally effective dose is defined for the purposes of the present invention as a dose that produces the effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art.
  • cells is defined for the purposes of the invention as the smallest structural unit of an organism that is capable of independent functioning considering of one or more nuclei, cytoplasm, and various organelles, all surrounded by a semipermeable cell membrane.
  • cancer is defined for the purposes of the invention refers as all types of cancer or neoplasm or malignant tumours found in mammals, including carcinomas and sarcomas.
  • cancers are cancer of the brain, breast, cervix, colon, head & neck, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and Medulloblastoma.
  • solid tumour is defined for the purposes of the invention as an abnormal mass of tissue that usually does not contain cysts or liquid areas.
  • Solid tumors may be benign (not cancer), or malignant (cancer). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas.
  • composition is to be construed broadly and is defined for the purposes of the present invention as optionally comprises of one or more pharmaceutically acceptable adjuvants, excipients, carriers, buffers, diluents and/or customary pharmaceutical auxiliary substances.
  • the composition of the present invention is administered in a pharmaceutically acceptable formulation.
  • the present invention pertains to any pharmaceutically acceptable formulations, such as synthetic or natural polymers in the form of macromolecular complexes, nanocapsules, microspheres, or beads, and lipid-based formulations including oil-in- water emulsions, micelles, mixed micelles, synthetic membrane vesicles, and resealed erythrocytes.
  • the pharmaceutically acceptable formulation of the invention can comprise additional pharmaceutically acceptable carriers and/or excipients.
  • pharmaceutically acceptable carrier is defined for the purposes of the present invention to include any and all solvents dispersion medicoatings, antibacterial and anti fungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier can be suitable for injection into the cell, tissues, organs and/or blood.
  • Excipients include pharmaceutically acceptable stabilizers and disintegrants.
  • the pharmaceutically acceptable formulations comprise lipid-based formulations.
  • lipid-based drug delivery systems can be used in the practice of the invention.
  • multivesicular liposomes MLV
  • multilamellar liposomes also known as multilamellar vesicles or MLV
  • unilamellar liposomes including small unilamellar liposomes (also known as unilamellar vesicles or SUV), large unilamellar liposomes (also known as large unilamellar vesicles or LUV)
  • multivesicular siosomes (MVS), multilamellar siosomes (MLS), unilamellar siosomes including small unilamellar siosomes can all be used so long as a sustained release rate of the carrier system composition of the invention can be established.
  • compositions therein can include pharmaceutically acceptable salts of the components therein.
  • Pharmaceutically acceptable salts include the acid addition salts that are formed with inorganic acids such as hydrochloric or phosphoric acids, or such organic acids as acetic, tartaric, mandelic and the like.
  • Salts formed with the free carboxyl groups of the pharmaceuticals and/or additives and/or adjuvants derivatives can also be derived from inorganic bases such as sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamino, 2-ethylamino ethanol, histidine, procaine and the like.
  • Physiologically tolerable carriers are well known in the art.
  • Exemplary liquid carriers are sterile aqueous solutions which contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at a physiological pH value, in a physiological amount of saline or both, for example phosphate-buffered saline. Further still, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol, polyethylene glycol and other solutes. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary examples of such additional liquid phases include glycerine, vegetable oils such as cotton seed oil, organic esters such as ethyl oleate, and water-oil emulsions
  • a pharmaceutical carrier system may also, or alternatively, contain one or more drugs, which may be linked to a modulating agent or may be free within the composition. Virtually any drug may be administered in combination with a modulating agent as described herein, for a variety of purposes as described below.
  • drugs that may be administered with a modulating agent drugs (e.g., taxol or mitomycin C), anti-inflammatories (e.g., ibuprofen and indomethacin), anthelmintics, antidepressants, antidotes, antiemetics, antihistamines, antihypertensives, antimalarials, antimicrotubule agents (e.g., colchicine or vinca alkaloids), antimigraine agents, antimicrobials, antiphsychotics, antipyretics, antiseptics, anti-signalling agents (e.g., protein kinase C inhibitors or inhibitors of intracellular calcium mobilization), antiarthritics, antithrombin agents, antituberculotics, antitussives, antivirals, appetite suppressants, cardioactive drugs, chemical dependency drugs, cathartics, chemotherapeutic agents, coronary, cerebral or peripheral vasodilators, contraceptive agents, depressants, diure
  • Formulations for oral use may also be presented as hard gelatine capsules where in the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin or olive oil.
  • drug delivery across the oral mucosa is defined for the purposes of the present invention as a delivery system designed to deliver drugs systemically or locally via buccal mucosa.
  • Buccal delivery refers to the drug release which can occur when a dosage form is placed in the outer vestibule between the buccal mucosa and gingival.
  • Buccal route of drug delivery provides the direct access to the systemic circulation through the jugular vein bypassing the first pass hepatic metabolism leading to high bioavailability.
  • Other advantages such as excellent accessibility, low enzymatic activity, suitability for drugs or excipients that mildly and reversibly damage or irritate the mucosa , painless administration, easy withdrawal, facility to include permeation enhancer/ enzyme inhibitor or pH modifier in the formulation, versatility in designing as multidirectional or unidirectional release system for local or systemic action.
  • buccal dosage forms is defined for the purposes of the present invention as the buccal dosage forms including buccal adhesive tablets, patches, films, semisolids (ointments and gels) and powders:
  • Buccal mucoadhesive tablets are dry dosage forms that have to be moistened prior to placing in contact with buccal mucosa.
  • Buccal patches consists of two laminates, with an aqueous solution of the adhesive polymer being cast onto an impermeable backing sheet, which is then cut into the required oval shape.
  • Bioadhesive gels or ointments have less patient acceptability than solid bioadhesive dosage forms, and most of the dosage forms are used only for localized drug therapy within the oral cavity.
  • oral mucosa is defined for the purposes of the present invention as the mucous membrane epithelium (and lamina lamina) of the mouth. It can be divided into three categories.
  • Buccal mucosa refers to the inside lining of the cheeks and is part of the lining mucosa.
  • sublingual delivery is defined for the purposes of the invention as delivery system consisting of administration through the membrane of the ventral surface of the tongue and the floor of the mouth. They compromise of orally disintegrating or dissolving medications that are administering by being placed under the tongue. Drugs diffuse into the blood through tissues under the tongue.
  • mucus transmucosal drug delivery
  • mucus The term“transmucosal drug delivery”, is defined for the purposeof the present invention as the drug entering through, or across, a mucous membrane.
  • mucus membranes or mucosae or mucosas; singular mucosa)” is defined for the purpose of the invention as linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs. They are at several places contiguous with skin: at the nostrils, the lips of the mouth, the eyelids, the ears, the genital area and the anus. The sticky, thick fluid secreted by the mucous membranes and glands is termed mucus.
  • mucous membrane refers to where they are found in the body and not every mucous membrane secretes mucus.
  • the urethra is also a mucous membrane.
  • the secreted mucus traps the pathogens in the body, preventing any further activities of diseases.
  • transdermal drug delivery is defined for the purposes of the present invention as, relating to, being, or suppling a medication in a form for absorption through the skin into the bloodstream.
  • local drug delivery is defined for the purposes ofthe present invention as relating to, being, or administration of a drug through all areas other than the sublingual and buccal delivery.
  • fast oral transmucosal is defined for the purposes of the present invention as, relating to, being, or suppling medication in a form for absorption through all areas of buccal mucosa and the sublingual route into the bloodstream.
  • ODF orodispersible films
  • rapid film is defined for the purposes of the present invention as very thin film which is applied in the mouth. It is based on a water soluble polymers. The design can vary from single to multilayer systems.
  • ODT orodispersible tablets
  • orodispersible granules is defined for the purposes of the patent as coated or uncoated particles for immediate or sustained release filled in stick packs or sachets intended to be placed in the mouth where they disperse rapidly before being swallowed.
  • compositions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate polyvinyl-pyrrolidone.
  • Oil suspensions is defined for the purpose of the invention as formulations which may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical carrier systems of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soya bean, lecithin, and esters/partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain demulcent, preservatives, flavouring agents and colouring agents.
  • the pharmaceutical carrier systems may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as absolution in 1 , 3-butane diol.
  • the active substances of the present invention are mixed with a pharmaceutically acceptable carrier or diluent in accordance with routine procedures.
  • Therapeutic and/or immunologic formulations will be administered by intravenous infusion or by subcutaneous injection.
  • the formulations can also contain, if desired, other therapeutic agents.
  • compositions of the present invention can be administered prophylactically or therapeutically, preferably in an amount that is effective against the mentioned disorders, to a warm-blooded animal, for example a human, requiring such treatment, the compounds preferably being used in the form of pharmaceutical carrier systems.
  • composition according to the invention comprising oxoplatin, or oxoplatin derivatives, or their salts, or esters, or isomeres, or racemates, or enantiomers, or prodrugs thereof for use as medicament in the prophylaxis, prevention, reduction, attenuation, stabilisation, and/or elimination, of solid tumours, characterised in that said treatment comprises administration of said pharmaceutical composition to a subject in need of said treatment for solid tumours.
  • compositions for use as a medicament as described herein may be characterised in that a second agent is selected from the group consisting of at least one member of a pharmaceutical oxoplatin derivatives or their salts, or esters, or isomers, or enantiomers, or racemates, or pro-drugs, beta- myeloid inhibitors, Anti-CTGF therapeutics, amino acids such as arginine, carnitine/carnitine derivatives, neurotransmitters such a dopamine, vitamins, caffeine, antifibrotic agents, memory activating agents, neuroprotective agents, glutamate- antagonist glutathione, anti-Alzheimer’s disease agents, rivastigmine, donepezil, memantine and tacrine, antioxidants, NMDA receptor antagonist, anti-AIDS drugs, antipsychotic drugs such as buspirone, antidepressants such as selective serotinin reuptake inhibitors (SSRIs) such as sertraline or paroxetine, mood stabilizers, anticonvulsant, antigen
  • the active compounds may even be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatine; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavouring agent, such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder as gum tragacanth, acacia, cornstarch, or gelatine
  • excipients such as dicalcium phosphate
  • a disintegrating agent such
  • tablets, pills, or capsules may be coated with shellac, sugar, or both.
  • a syrup of elixir may contain the active compound sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavouring, such as cherry or orange flavour.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compounds may be incorporated into sustained- release preparation and formulations.
  • these formulations contain at least 0.1 % of the active compound of the invention or more, although the percentage of the active ingredient(s) may, of course, be varied and may conveniently be between about 1 or 2% and about 60% or 95% or more of the weight or volume of the total formulation.
  • the amount of active compound(s) in each therapeutically useful carrier system may be prepared is such a way that a suitable dosage
  • the carrier systems of the present invention may alternatively be incorporated with one or more excipients in the form of a mouthwash, dentifrice, buccal tablet, oral spray, or sublingual orally-administered formulation.
  • the carrier systems may be fashioned into a tablet or solution form that may be placed under the tongue or otherwise dissolved in the mouth.
  • solutions of the active compounds as free bases or as pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils.
  • Proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable carrier systems can be brought about by the use in the carrier systems of agents delaying absorption, for example, aluminium monostearate and gelatine.
  • aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • a sterile aqueous medium that can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage may be dissolved in 1 ml of isotonic NaCI solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some necessary variation in the dosage will occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • preparations should meet sterility, pyrogenicity, and the general safety and purity standards as required by national or regional offices of biologies standards.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-fi Itered solution thereof.
  • the carrier systems disclosed herein may be formulated in a neutral or salt form.
  • Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups ) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms such as injectable solutions, drug-release capsules, and the like.
  • the pharmaceutical carrier systems may be delivered by intranasal sprays, inhalation, and/or other aerosol delivery vehicles.
  • intranasal sprays inhalation, and/or other aerosol delivery vehicles.
  • delivery of drugs using intranasal microparticle resins and lysophosphatidyl-glycerol compounds are also well-known in the pharmaceutical arts.
  • the inventors contemplate the use of nanocapsules, microparticles, microspheres, and the like, in the production of the carrier systems of the present invention. Such formulations may be preferred for the introduction of pharmaceutically-acceptable formulations of the carrier system or constructs disclosed herein.
  • Nanocapsules can generally entrap compounds in a stable and reproducible way. To avoid side effects due to intracellular polymeric overloading, such ultra fine particles (sized around 0.1 pm) should be designed using polymers able to be degraded in vivo. Biodegradable polyalkyl-cyanoacrylate nanoparticles that meet these requirements are contemplated for use in the present invention.
  • the subjects treated will typically comprise of mammals and will preferably be human Subjects.
  • the compounds of the invention may be used alone or in combination.
  • the treated compounds may be utilized with other types of treatments, e.g., cancer treatments.
  • the subject compounds may be used with other chemotherapies, e.g., tamoxifen, taxol, methothrexate, biologicals, such as antibodies, growth factors, lymphokines, or radiation, etc.
  • chemotherapies e.g., tamoxifen, taxol, methothrexate, biologicals, such as antibodies, growth factors, lymphokines, or radiation, etc.
  • Combination therapies may result in synergistic and/or additive results.
  • the present invention is based on the surprising and unexpected discovery that oral administration of the platin (IV) compounds oxoplatin, cis-oxoplatin, cis-oxoplatin sodium salt, cis-oxoplatin-Calcium salt, oxoplatin, dimethyl, diethyl, dimethoxy, diethoxy oxoplatin or one of the salts, or isomers, esters, or prodrugs thereof form in the stomach tetrachloro oxoplatin, isomers, derivatives, salts and metabolites for use as a medicament for the therapy of the symptoms of said solid tumors and cancer in the stomach and other tissues.
  • These compounds have broad profile of therapeutic efficacy and less drug resistance and can prevent, reduce and/or eliminate symptoms of solid tumours and cancer.
  • liver cancer Surprisingly and unexpected that the repeated oral administration of the compound of the invention with platin (IV) have shown relatively mild side effects in comparison to other Platin(ll) anti cancer drugs . This will allow the increase of the dose to the patients to achieve the required therapeutic affects without suffereing of the patients from serious adverse events (SAE).
  • SAE serious adverse events
  • cis-oxoplatin of this invention cross the blood-brain barrier and that the concentration in the brain tissue is relatively high.
  • the oxoplatin and salts of this inventioin has good solubility and oral bioavailability and broad tissue distribution and selectivity which will allow specific delivery and taegeting of the solid tumour and cancers.
  • oral cis-oxoplatin of this invention have shown according to the examples in this invention anti-proliferative and cell cycle arrest in vitro and anti-proliferative and antimetastasis effects in cancer patients with solid tumors.
  • oral cis-oxoplatin of this invention have shown according to the examples in this invention dose relarted linearity for the pharmacokinetic parameters AUC-1 and Cmax for a broad dose range ( 5mg-120mg), not observed for many other platinum complexes. This means that the inter-patient variability is low, and will have great advantages concerning its use at high therapeutic doses and the adjustment of the treatment with cis-oxoplatin for children and elderly patients at low dose level.
  • cis-oxoplatin of this invention has a number of pharmacologically active metabolites which could chemically interact with the DNA. Active metabolites binding to the DNA would affect the overall antiproliferative activity of cis-oxoplatin. This means that the total bioavailability is equivalent to the bioavailability cis-oxoplatin and the active metabolites with anticancer activities. These metabolites may effect the reduction of resistance of the cancer cells to cis-oxoplatin, as there is more than one complex to build up resistance against. The existence of active metabolites also increases the amount of time when there is an active agent in the body and able to have an effect.
  • the search of alternative for delivery strategies for the targeted treatment of gastric cancer according to this invention has focused on the adminstration of immediate release capsules of cis-oxoplatin which have shown to be biotransformed in the stomach within few minutes to anticancer metabolites e.g tetrachlorooxoplatin, cis-platin, monochloro cisplatin, tetrchloro oxoplatin metabolites with a broad profile of anticancer efficacy in the targeted organ “STOMACH”. This mean the highest possible concentration of the anticancer agents and efficacy in the stomach tissues.
  • antimetrastasis and anticancer activities in the targeted organs and tissues using the different pharmaceutical formulations according to this invention such as oral sustained (extended) release formulations for targeting the gastrointestinal system (GIT), or parenterally, by inhalation spray targeting the respiratory tract systems, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir or as delivery and targeting using nanoparticles such as Siosomes® and liposomes or in stents implanted in the cancer affected organs such as pancreas, liver, lungs, and brain regions.
  • GIT gastrointestinal system
  • nanoparticles such as Siosomes® and liposomes or in stents implanted in the cancer affected organs such as pancreas, liver, lungs, and brain regions.
  • Figure 1 Comparison of cis- and trans- oxoplatin activity against Ewings sarcoma (EW2, SK-ES1), Wilms tumour (SK-NEP1) and neuroblastoma (LAN-2)
  • Figure 2 AUC-1 Average by Treatment Group - Day 1 (dark) and 7 (light)- IPSS D030
  • Figure 4 Tmax Average by Treatment Group - Day 1 (dark) and 7 (light)- IPSS D030
  • Figure 5 Half Life Average by Treatment Group - Day 1 -IPSS D030
  • Figure 11 Graph showing total Platinum distribution 2 hours after administration in a Rat No. 11 as example in study IPSS F031
  • Figure 12 Platinum concentration plotted against efficacy for Cis-Oxoplatin and Cis-Platin following the treatment with 0.1 n HCI (similar to gastric fluid) for 2 hours.
  • Figure 14 Linear relationship between AUC(O-t) and dose amount.
  • Figure 17 The correlation between dose ,and AUC-1 (dose level 1-10)-Graph showing AUC-1 plotted against dose (visits 3-6 only) with dose groups 10
  • Figure 18 The correlation between dose, and Cmax (dose level 1-10) - Average C max (visits 3-6) plotted against dose-Study IPSS C-031
  • Cisplatin 350 g was dissolved in 700 ml water. 840 ml hydrogen peroxide 35% was added in 31 hours and stirred for 6 days. The raw product was filtered and washed with 300 ml ice water. This product was dissolved in 14 L 0.25 M sulphuric acid.
  • the precipitate was filtered off and washed with 250 ml ice water a 1 L ethanol.
  • the yield of the preparation process resulted from 3 independent experiments, and was 80-90% of the starting concentrations.
  • silanes, sugarsilanes and derivatives could be also used for the preparation of the cis- oxoplatin - Siosomes® Complex
  • Oxoplatin was used as 2 mg/ml stock solution in PBS (phosphate buffered saline, Dulbecco) and aliquots were stored frozen at - 20° C.
  • PBS phosphate buffered saline, Dulbecco
  • Related compounds were used as 2 mg/ml stock solution and stored frozen at - 20° C.
  • 104 cells/well were distributed to 96-well microtitre plates (100 pi medium/well) and compounds to be tested were added in a volume of another 100 pi. All compounds were diluted in 10 steps using twofold dilutions in triplicate or in most cases in quadruplicate. Plates were incubated under tissue culture conditions for 4 days, except for tests investigating the relationship between application time and response, and cell viability was measured using a modified MTT assay (formazane dye formation from tetrazolium salts by mitochondrial reduction; EZ4U, Biomedica, Vienna, Austria), assessing mitochondrial activity and thereby cell viability/cell numbers. In brief, the supplied substrate was diluted in an activator solution and 20 pi of the mixture were added per well for 2 hrs.
  • optical density was measured at 450 nm using an empty well as reference in a microplate reader (Eurogenetics, Brussels, Belgium). For each cell line 8 wells were used to measure the MTT signal of the medium control without test substances and the proliferation in the test wells were calculated in relation to these control values set to 100 %. Test results were recorded between 0.3 and 1 .5 optical density for slow and rapid proliferating cells, respectively.
  • annexin V binding assays 105 cells, either pretreated in medium alone or in the presence of test substances, were harvested and labelled with annexin V - FITC according to the manufacturer instructions (Boehringer Mannheim, Mannheim, Germany). Following incubation at room temperature for 10 min the cells were washed and late apoptotic/necrotic cells labelled by addition of PI. Cells were immediately analysed in flow cytometry (Coulter XL). Percentages of cells were given as double negative cells (viable), AV+/PI- (apoptotic), AV+/PI+ (late apoptotic) and AV-/PI+ (necrotic).
  • cisplatin has highest activity, cis-oxoplatin seems of similar activity as oxaliplatin, with different cell type specificity and is significantly more active than carboplatin.
  • a normal fibroblast cell line (Fib3) cis-oxoplatin (up to 40 pg/ml) resulted in a minor reduction in cell proliferation (- 4 % of control).
  • cis-oxoplatin has approximately 33% of the activity of cisplatin and 50 % of the activity of oxaliplatin and is more active than carboplatin.
  • Cis-oxoplatin has activity in Ewings sarcoma (EW2, SK-ES1), Wilms tumour (SK-NEP1) and neuroblastoma (LAN-2).
  • Trans-oxoplatin was tested in an initial concentration of 40 pg/ml and 9 twofold dilution steps against a panel of cell lines . Since IC50 values were not reached in most cases, the survival of cells at the highest concentration of trans-oxoplatin is given in Figure 1 .
  • TRAXO Among the 19 cell lines tested TRAXO showed unexpected considerable activity in one colon carcinoma cell line (SW620), two osteosarcoma cell lines (G292, HOS), one renal carcinoma cell line (ACHN), one leukemic cell line (HL60) and in embryonal lung fibroblasts (WI38).
  • SW620 colon carcinoma cell line
  • G292, HOS osteosarcoma cell lines
  • ACNN renal carcinoma cell line
  • HL60 leukemic cell line
  • WI38 embryonal lung fibroblasts
  • Example 7 Cytotoxic activity of thioplatin (SPT) against a panel of cell lines in vitro
  • SPT Thioplatin
  • SPT has a relatively low cytotoxic activity in the 19 cell lines under investigation. Highest activity was found in HCT-15 colon carcinoma cells, WI38 embryonic lung fibroblasts and HL60 leukemic cells. In lower concentration growth stimulation was frequently visible.
  • the newly supplied cis-oxoplatin had comparable antiproliferative activity to the cis-oxoplatin used previously (Oxoplatin Control) and Cis-oxoplatin, sodium salt is on average approximately 50 - 70% weaker in cytotoxic activity.
  • the cisplatin supplied is of low activity with IC50 > 20 pg/ml for each of the cell lines.
  • the previous comparison of cis-oxoplatin sodium salt to cis-oxoplatin was extended using 8 different cell lines. IC50 values are given as pg/ml and the test was performed as formazan test as described.
  • cis-oxoplatin sodium salt was more efficient (approx. 70%) in HT29 and SW480, more efficient in SK-OV4, PC3 and SIM (by approximately 30%) and less efficient in CaCo-2 and DU145 ( - 40-50%) and far less efficient in CR02B cells. Therefore the mean IC50 value for cis-oxoplatin for these cell lines was 10.5 ⁇ 6.4 pg/ml versus 9.5 ⁇ 8 pg/ml for cis-oxoplatin sodium salt (difference not statistically significant).
  • Cis-oxoplatin sodium salt is more active in the higher concentration range and the difference is decreased at lower concentrations. Therefore cis- oxoplatin sodium salt seems to be 30 - 70% more active or approximately 40-50% less active compared to cis-oxoplatin depending on the specific cell line used for testing.
  • the mean IC50 ( ⁇ SEM) of cis-oxoplatin for all cell lines is 12.3 ⁇ 3.2 compared to cis-oxoplatin-Ca2+ with a mean IC50 ( ⁇ SEM) of 9.1 ⁇ 2.8 (not significantly different).
  • the cytotoxic activities of cis- oxoplatin and cis-oxoplatin-Ca2+ are comparable in the panel of cell lines shown above. Although cis- oxoplatin-Ca2+ tends to have a slightly higher activity, the difference is not statistically significant.
  • cis- oxoplatin has approximately 33% of the activity of cisplatin, 50 % of the activity of oxaliplatin and is more active than carboplatin in vitro.
  • Oxoplatin inhibits growth in tumour cell lines of different origin, ranging from ostosarcoma and melanoma to breast cancer and cancer of the gastrointestinal tract.
  • high antitumour activity was further found for cell lines derived from tumours of the childhood.
  • trans-oxoplatin showed low activity against the same cell lines, except osteosaromas and childhood tumours.
  • cytotoxic activity of cis-oxoplatin was synergistically modulated by DL-Buthionine-SR-sulfoximine (BSO), which prevents the conjugation of the drug to glutathione and detoxification.
  • BSO DL-Buthionine-SR-sulfoximine
  • dipyramidole a nucleoside transport inhibitor, which reportedly increases the intracellular accumulation of cisplatin, has an antagonistic effect in combination with cis-oxoplatin.
  • the oral immediate release capsules of cis-oxoplatin showed unexpected and surprisingly higher bioavailability than the sustained release formulations.
  • the treatment groups are as shown below with 5 rabbits in each group; the rabbits are numbered randomly as shown.
  • the area underneath the concentration-time curve is variable between treatment groups as well as within the treatment groups.
  • the highest area under the concentration curve found on day 1 is for the cis-oxoplatin calcium salt treatment group with an average AUC-1 value of 174334,08 ⁇ 12839,51 mins * ng/ml (i.e. 2905,6 ⁇ 232,0hrs * ng/ml).
  • the highest platinum concentration is found unexpected and surprisingly for the average of the standard cis-oxoplatin treatment group at 235200,50 ⁇ 143476,72 mins * ng/ml (i.e. 3920,0 ⁇ 2391 ,3hrs * ng/ml) ( Figure 2).
  • the highest total platinum concentration was averaged in treatment group cis-oxoplatin sodium salt in day 1 of treatment, with a Cmax value of 754,22 ⁇ 201 ,32ng/ml, in day 7 the highest total platinum concentration was 1880,93 ⁇ 1030,09 which was averaged surprisingly and unexpected by the standard cis-oxoplatin treatment group (Fiugure 3).
  • the cis-oxoplatin siosome® complex has the highest concentration in blood, kidney and adipose tissue and standard cis-oxoplatin administered intravenously has the highest platinum concentration in the stomach and the liver.
  • the standard cis-oxoplatin oral has the highest accumulation of platinum in the spleen and lungs. The highest tissue accumulation for all treatment groups was found in the kidneys, though the blood had the highest concentrations.
  • Figure 11 shows the distribution of platinum in a Rat two hours after administration with Cis-Oxoplatin. It can be seen that the Cis-Oxoplatin has become distributed quickly (2 hours). Surprisingly and unexpected the largest concentration of Platinum after two hours can be found in connective tissue, the Caecum and the kidney. This means that there is potential for Cis-Oxoplatin to be used for brain cancer as well as cancers of the gastro intestinal tract.
  • the developed immediate release capsules showed surprisingly and unexpected good availability and distribution in blood, brain and the different tissues which will allow the use of Cis-Oxoplatin for solid tumours.
  • Cis-Oxoplatin is orally bio available unlike Cis-Platin, Carboplatin and Oxaliplatin.
  • the oral formulation of Cis-Oxoplatin will have the benefits of easy administration, better patient compliance and the reduction of treatment costs as patients will be able to undergo treatment as outpatients.
  • Cis-Oxoplatin The immediate release capsules of Cis-Oxoplatin are designed for immediate release in the stomach in approximately 10-20 minutes following the oral administration, which will allow the activation of the Cis-Oxoplatin. This causes the efficacy of Cis-Oxoplatin to increase by approximately 220%.
  • Figure 12 Platinum concentration plotted against efficacy for Cis-Oxoplatin and Cis- Platin following the treatment with 0.1 n HCI (similar to gastric fluid) for 2 hours.
  • the fate and activity of the oral drug oxoplatin critically depend on its pharmaceutical formulation and the route of administration, that can be chosen to allow for release in the stomach or part of the intestine e.g., using sustained relase capsules of cis-oxoplatin and in siosomes encapsulated cisoxoplatin..
  • cis-oxoplatin used in the in vitro and in vivo examples of this invention was compared to 0.1 M HCI-treated cis-oxoplatin with .Cis- diammine-tetrachlorido-platinum(IV) yielded surprisingly and unexpected the same cytotoxic effect as HCI-treated oxoplatin and was proved to be identical in IR spectroscopy.
  • Cisplatin (Pt II), cis-oxoplatin (Pt IV) exhibited antiproliferative activities.
  • platinum(IV) enter cancer cells without first being reduced in the extracellular medium. Then once inside the cell, where the concentration of Cl- is approximately 4mM compared with approximately 100mM ( extra-cellular) allowing rapid hydrolysis of the platinum IV compounds to platinum (II) complexes, and then further to positively charged oxonium ion complexes. The charge on these species greatly limits their diffusion out of the cell through the cell membrane.
  • Cis-Oxoplatin and its pharmacologically active metabolites interact chemically with DNA. Active metabolites binding to the DNA would affect the overall antiproliferatic activity of Cis-Oxoplatin. This means that the total bioavailability/efficacy is of Cis-Oxoplatin and the active metabolites.
  • Figure 13 shows the metabolic pathway for Cis-Oxoplatin. It can be seen that there are 5 possible active metabolites and more with antiproliferative activities formed in this scheme.
  • Cis-Platin is the major metabolite of Cis-Oxoplatin.
  • Cis-Oxoplatin is acting as well as a prodrug for Cis-Platin.
  • the reduced peak plasma concentration of Cis-Platin as a result of the biotransformation of Cis-Oxoplatin may reduce the toxic effect and the other serious adverse events of Cis-Platin .
  • Cis-Platin down regulated 15 genes which have highly regulated expression following the treatment with Cis-Oxoplatin.
  • Cis-Platin highly regulates 11 genes which are down regulated after the treatment with Cis-Oxoplatin. Therefore it could be concluded based on the unexpected and surprisingly results of the expression profiling with the means of DNA array (29000 genes) following the treatment with Cis-Platin and Cis- Oxoplatin that:
  • Cis-Platin and Cis-Oxoplatin are different anti cancer agents with few similarities in the mode of action.
  • Urinalysis - specific gravity, pH, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, blood, haemoglobin and sedimentation, urine for cytology
  • AUC(O-t) and the maximum concentration of platinum concentration reached during the entire trial showed surprisingly and unexpected a linear increase with dose amount within a range of 280-560mg of Cis-oxoplatin (i.e. 20-40 mg administered daily over 14 consecutive days).
  • Cis-oxoplatin showed surprisingly and unexpected a linear increase with dose within a range of 5-15 mg Cis-oxoplati
  • Tmax following a single dose of Cis-oxoplatin was found to lie between 2:12-2:30 hours.
  • Half life following a single dose had a range of 42-162 minutes.
  • AUC(0- ) was also calculated by extrapolating the time concentration curve to infinity. However, the values determined for this parameter were deemed implausible for all but two of the patients and therefore could not be used for inter-group comparison.
  • Figure 14 shows the mean maximum concentration of each group reached during the course of the trial (visits 2 to 7) against the daily dose administered to each group. This plot shows a linear relationship between these two variables.
  • Error bars represent the standard deviation within each group and“n” is the number of patients for whom this maximum concentration could be calculated.
  • the mean time period taken to reach the maximum concentration across all 5 groups is: 203 hours ⁇ 22 ( ⁇ 11 %) (approximately 8.5 days after the start of treatment). Therefore, if we continue to use the same treatment schedule at higher dose levels we can expect the highest efficacy and toxicity at this time.
  • Diarrhoea is the dose limiting toxicity of Cis-Oxoplatin. Four cases of grade 3 toxicity were observed. One in the 40mg/day group, one in the 100mg/day group and two in the 120mg/day group. These diarrhoea cases could be managed by treatment with Loperamide.
  • Cis-Oxoplatin no drug fever was observed.
  • Drug fever is defined as a disorder characterized by fever coinciding with the administration of the drug and disappearing after the discontinuation of the drug, when no other cause for the fever is evident after a careful physical examination and laboratory investigation.
  • Patients treated with Satraplatin as platinum anticancer drug under development could develop Drug Fever; the incidence is very high and results in the discontinuation of treatment. It occurred at lower doses of Satraplatin than have been used in the phase 141 study with Oxoplatin.
  • Cis-Oxoplatin Unexpected and surprisingly no nephrotoxicity has been observed with Cis-Oxoplatin after 14 days of consecutive treatment with the highest dose of 120mg/day in elderly patients. This is compared to Cis-Platin where nephrotoxicity has been observed after a single dose at 50mg/m2 ( ⁇ 80mg for females, ⁇ 90mg for males). Patients can tolerate 20 times more oral Cis-Oxoplatin than intravenous Cis-Platin.
  • SAE Serious Adverse Events
  • Cis-Oxoplatin shows efficacy in the quadruvalent state the decreased side effects could be due to the weaker binding between the Platinum complex and DNA.
  • Cis-Oxoplatin can form intrastrand cross links (between neighbouring base residues) or interstrand cross links.
  • Cis-Platin binds almost irreversibly with DNA the bonding between Cis-Oxoplatin and DNA is weakened by repulsions as seen in 18. This could account for the observation of fewer Serious Adverse Events in patients who have taken Cis-Oxoplatin.
  • Oxoplatin moves into the cell by passive diffusion. This is the same mechanism as Cis-Platin.
  • Cis-Oxoplatin tolerates concomitant medication well.
  • the study IPSS- C031 was conducted in elderly patients, and as a result there were a large number of concomitant medications (for blood pressure, diabetes etc.). No adverse drug-drug interactions were recorded.
  • Cis-Oxoplatin as an anti-tumour aqent for the treatment of solid tumours.
  • oxoplatin has a broad anti-tumour spectrum on different solid tumours.
  • the best effect has been achieved with the treatment of adeno-colon carcinoma (AKATOL) , breast cancer 755 (Ca 755), squamous cell carcinoma of the interior part of the stomach (PRG), tumours of the uterus (Rsch M-S) and Lewis Lung carcinoma.
  • AKATOL adeno-colon carcinoma
  • PRG breast cancer 755
  • PRG squamous cell carcinoma of the interior part of the stomach
  • Rsch M-S tumours of the uterus
  • Lewis Lung carcinoma Lewis Lung carcinoma.
  • the life-span of mice with leukaemia (LI 210 and La), plasmacytoma MOPC-406 and ascites hepatoma has been significantly prolonged.
  • Patinum IV complexes including cis-oxoplatin, cis-oxoplatin salts and derivatives show unexpected and surprisingly high anti-tumour activity, a lower toxicity then platinum II complexes such as cisplatin and longer lasting anti-tumour effects. Furthermore, cis-oxoplatin acts equally effectively with different routes of administration which allows it to be taken orally at high doses and this in the long term development of the drug will reduce costs if it allows patients to be treated outside of the hospital environment.
  • Cis-oxoplatin also inhibit metastasis as it becomes enriched in tumour tissue and travels with metastatic cells to secondary nodes where is continues to act. Cis-oxoplatin is therefore a promising candidate for the treatment of the different types of cancer.

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Abstract

L'invention concerne une composition pharmaceutique comprenant du cis-oxoplatine, ou un sel et/ou dérivé de celui-ci, destinée à être utilisée en tant que médicament dans le traitement et/ou la prévention du cancer de l'estomac. L'invention concerne en outre la composition pharmaceutique telle que décrite pour une utilisation dans le traitement du cancer de l'estomac, le cis-oxoplatine ou son dérivé étant administré sous une forme qui est transformée sous pH acide en tétrachloro-oxoplatine (IV).
PCT/EP2019/066062 2018-06-27 2019-06-18 Cis-oxoplatine pour le traitement du cancer de l'estomac WO2020002056A1 (fr)

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CN113456666A (zh) * 2021-06-13 2021-10-01 安徽中医药大学 一种双载型peg化脂质体及其应用

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WO2005039605A1 (fr) * 2003-10-13 2005-05-06 Salama Zoser B Composition pharmaceutique contenant de l'oxoplatine, ses sels et derives

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Publication number Priority date Publication date Assignee Title
WO2005039605A1 (fr) * 2003-10-13 2005-05-06 Salama Zoser B Composition pharmaceutique contenant de l'oxoplatine, ses sels et derives

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"CA Cancer J Clin", vol. 61, 2011, AMERICAN CANCER SOCIETY, INC., pages: 69 - 90
ULRIKE OLSZEWSKI ET AL: "In Vitro Evaluation of Oxoplatin: An Oral Platinum(IV) Anticancer Agent", METAL-BASED DRUGS, vol. 2009, 1 January 2009 (2009-01-01), IL, pages 1 - 11, XP055618453, ISSN: 0793-0291, DOI: 10.1155/2009/348916 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113456666A (zh) * 2021-06-13 2021-10-01 安徽中医药大学 一种双载型peg化脂质体及其应用

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