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WO2008064425A1 - Glycoalkaloid and chemotherapeutic agent combinations and various uses thereof - Google Patents

Glycoalkaloid and chemotherapeutic agent combinations and various uses thereof Download PDF

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Publication number
WO2008064425A1
WO2008064425A1 PCT/AU2007/001846 AU2007001846W WO2008064425A1 WO 2008064425 A1 WO2008064425 A1 WO 2008064425A1 AU 2007001846 W AU2007001846 W AU 2007001846W WO 2008064425 A1 WO2008064425 A1 WO 2008064425A1
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selected
method
glycoalkaloids
dosage form
composition
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PCT/AU2007/001846
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French (fr)
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Stephen Carter
David Jonathan Sparling
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Solbec Pharmaceuticals Limited
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Priority to AU2006906716A priority patent/AU2006906716A0/en
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Publication of WO2008064425A1 publication Critical patent/WO2008064425A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin digitoxin or digoxin

Abstract

A method of treating a tumorous growth comprising the step of administering a therapeutically effective amount of: (a) a first composition comprising at least two glycoalkaloids of formula I: wherein: either one or both of the dotted lines represents a double bond, and the other a single bond, or both represent single bonds; A: represents a radical selected from the following radicals of general formulae (II) to (V): each of R1 is a radical separately selected from the group consisting of hydrogen, amino, oxo and OR4; each of R2 is a radical separately selected from the group consisting of hydrogen, amino and OR4; each of R3 is a radical separately selected from the group consisting of hydrogen, alkyl and R4-alkylene; each of R4 is a radical separately selected from the group consisting of hydrogen, carbohydrate and a carbohydrate derivative; 'X' is a radical selected from the group comprising -CH2-, -O- and -NH2-; and wherein the compound includes at least one R4 group in which R4 is a carbohydrate or a derivative thereof selected from the group comprising glyceric aldehyde, glycerose, erythrose, threose, ribose, arabinose, xylose, lyxose, altrose, allose, gulose, mannose, glucose, idose, galactose, talose, rhamnose, dihydroxyactone, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, and other hexoses, heptoses, octoses, nanoses, decoses, deoxysugars with branched chains, (e.g. apiose, hamamelose, streptose, cordycepose, mycarose and cladinose), compounds wherein the aldehyde, ketone or hydroxyl groups have been substituted (e.g. N-acetyl, acetyl, methyl, replacement of CH2OH), sugar alcohols, sugar acids, benzimidazoles, the enol salts of the carbohydrates, saccharinic acids, sugar phosphates; and (b) and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action.

Description

Glycoalkaloid and Chemotherapeutic Agent Combinations and Various Uses

Thereof

Field of the Invention

The present invention relates to the use of glycoalkaloids, such as solasonine and solamargine, in combination with other chemotherapeutic agents to treat cancer and to compositions for use in such methods. More particularly the present invention relates to the use of synergistic combinations of (i) glycoalkaloids, such as solasonine and solamargine, and (ii) a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action such as an agent selected from the group comprising: vinorelbine tartrate, dacarbazine, paclitaxel, mechlorethamine, doxorubicin and functional equivalents thereof. The present invention also relates to unit dosage forms comprising the synergistic combinations mentioned above.

Background Art

Cytotoxic chemotherapy remains one of the premier treatment options to combat cancer. However, the efficacy of chemotherapy is limited by the fact that not all tumors respond optimally. Thus, single-modality chemotherapy is rarely curative. In addition, drug-resistant tumor cells often emerge when a single agent is used.

CORAMSINE® is mixture of solasonine and solamargine with anti-cancer properties. There is a range of other chemotherapeutic agents available with different modes of action. These include antitumour antibiotics, anti-mitotic agents, hormones, anti-angiogenic drugs, cytokines, anti-metabolites and alkylating agents.

There exists a need for new and effective drug combinations that can be used to inhibit the growth of cancer cells and hence treat cancer. The present invention seeks to improve the effectiveness and/or patient outcomes obtained using CORAMSINE® monotherapy through combination therapy with other chemotherapeutic agents. Summary of the Invention

The present invention provides a method of treating a tumorous growth comprising the step of administering a therapeutically effective amount of: (a) a first composition comprising at least two glycoalkaloids of formula I:

Figure imgf000003_0001

wherein: either one or both of the dotted lines represents a double bond, and the other a single bond, or both represent single bonds;

A: represents a radical selected from the following radicals of general formulae (II) to (V):

Figure imgf000003_0002

each of R1 is a radical separately selected from the group consisting of hydrogen, amino, oxo and OR4; each of R2 is a radical separately selected from the group consisting of hydrogen, amino and OR4; each of R3 is a radical separately selected from the group consisting of hydrogen, alkyl and R4-alkylene; each of R4 is a radical separately selected from the group consisting of hydrogen, carbohydrate and a carbohydrate derivative; "X" is a radical selected from the group comprising -CH2-, -O- and -NH2-; and

wherein the compound includes at least one R4 group in which R4 is a carbohydrate or a derivative thereof selected from the group comprising glyceric aldehyde, glycerose, erythrose, threose, ribose, arabinose, xylose, lyxose, altrose, allose, gulose, mannose, glucose, idose, galactose, talose, rhamnose, dihydroxyactone, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, and other hexoses, heptoses, octoses, nanoses, decoses, deoxysugars with branched chains, (e.g. apiose, hamamelose, streptose, cordycepose, mycarose and cladinose), compounds wherein the aldehyde, ketone or hydroxyl groups have been substituted (e.g. N-acetyl, acetyl, methyl, replacement of CH2OH), sugar alcohols, sugar acids, benzimidazoles, the enol salts of the carbohydrates, saccharinic acids, sugar phosphates; and

(b) and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action.

The present invention also provides a method for treating a tumorous growth comprising the steps of administering a therapeutically effective synergistic amount of the first and second compositions mentioned above.

The present invention also provides a unit dosage form comprising a therapeutically effective amount of: (a) at least two glycoalkaloids of formula I:

Figure imgf000004_0001

wherein: either one or both of the dotted lines represents a double bond, and the other a single bond, or both represent single bonds; A: represents a radical selected from the following radicals of general formulae (II) to (V):

Figure imgf000005_0001

each of R1 is a radical separately selected from the group consisting of hydrogen, amino, oxo and OR4;

each of R2 is a radical separately selected from the group consisting of hydrogen, amino and OR4;

each of R3 is a radical separately selected from the group consisting of hydrogen, alkyl and R4-alkylene;

each of R4 is a radical separately selected from the group consisting of hydrogen, carbohydrate and a carbohydrate derivative;

"X" is a radical selected from the group comprising -CH2-, -O- and -NH2-; and

wherein the compound includes at least one R4 group in which R4 is a carbohydrate or a derivative thereof selected from the group comprising glyceric aldehyde, glycerose, erythrose, threose, ribose, arabinose, xylose, lyxose, altrose, allose, gulose, mannose, glucose, idose, galactose, talose, rhamnose, dihydroxyactone, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, and other hexoses, heptoses, octoses, nanoses, decoses, deoxysugars with branched chains, (e.g. apiose, hamamelose, streptose, cordycepose, mycarose and cladinose), compounds wherein the aldehyde, ketone or hydroxyl groups have been substituted (e.g. N-acetyl, acetyl, methyl, replacement of CH2OH), sugar alcohols, sugar acids, benzimidazoles, the enol salts of the carbohydrates, saccharide acids, sugar phosphates; and

(b) a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action.

Detailed Description of the Invention

Methods of Treating Tumours

The present invention provides a method of treating a tumorous growth comprising the step of administering a therapeutically effective amount of: (a) a first composition comprising at least two glycoalkaloids of formula I:

)

Figure imgf000006_0001

wherein: either one or both of the dotted lines represents a double bond, and the other a single bond, or both represent single bonds;

A: represents a radical selected from the following radicals of general formulae (II) to (V):

Figure imgf000007_0001

each of R1 is a radical separately selected from the group consisting of hydrogen, amino, oxo and OR4; each of R2 is a radical separately selected from the group consisting of hydrogen, amino and OR4; each of R3 is a radical separately selected from the group consisting of hydrogen, alkyl and R4-alkylene; each of R4 is a radical separately selected from the group consisting of hydrogen, carbohydrate and a carbohydrate derivative; "X" is a radical selected from the group comprising -CH2-, -O- and -NH2-; and

wherein the compound includes at least one R4 group in which R4 is a carbohydrate or a derivative thereof selected from the group comprising glyceric aldehyde, glycerose, erythrose, threose, ribose, arabinose, xylose, lyxose, altrose, allose, gulose, mannose, glucose, idose, galactose, talose, rhamnose, dihydroxyactone, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, and other hexoses, heptoses, octoses, nanoses, decoses, deoxysugars with branched chains, (e.g. apiose, hamamelose, streptose, cordycepose, mycarose and cladinose), compounds wherein the aldehyde, ketone or hydroxyl groups have been substituted (e.g. N-acetyl, acetyl, methyl, replacement of CH2OH), sugar alcohols, sugar acids, benzimidazoles, the enol salts of the carbohydrates, saccharinic acids, sugar phosphates; and

(b) and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action. Whilst not being bound by this proposed mechanism, applicants believe the combinations herein are advantageous because there modes of action are complimentary. In this regard, it is hypothesised that the glycoalkaloid composition renders the cancer cells more accessible to the second composition e.g. by increasing membrane, particularly the nuclear membrane, permeability.

For the purposes of the present invention "nuclear mechanism of action" means that the chemotherapeutic agent acts within, at or near the nucleus of the cancer cell. For example, the agent may interfere with mitosis by inhibiting the formation of, binding to or otherwise disrupting the function of one or more proteins or structures involved in mitosis such as tubulin, microtubules, centrioles or spindles. Alternatively, or in addition, the agent may act on or near nucleic acids in the nucleus by damaging, breaking, crosslinking or binding to nucleic acids or otherwise disrupting the function of DNA or RNA e.g. inhibiting or otherwise interfering with transcription. Alternatively, or in addition, the agent may act on one or more enzymes or cofactors associated with DNA structure e.g. the agent may act on topoisomerases, thereby preventing DNA from adopting the appropriate coiled structure.

Preferably, the second component is a mitotic inhibitor an alkylating agent or an antibiotic.

When the second component is a mitotic inhibitor it may be a plant alkaloid such as an alkaloid selected from the group consisting of: vinca alkaloids, taxanes, podophyllotoxins and camptothecan analogs. In one particular form of the invention the second component is vinorelbine, vinorelbine tartrate or paclitaxel or a functional equivalent thereof.

When the second component is an alkylating agent it may be selected from the group consisting of: metal salts, nitrosureas, mustard gas derivatives, ethylenimines, alkylsulfonates, hydrazines and triazines. In one particular form of the invention the second component is mechlorethamine or dacarbazine or a functional equivalent thereof. When the second component is an antibiotic it may be selected from the group consisting of: anthracyclines and chromomycins. In one particular form of the invention the second component is doxorubicin or a functional equivalent thereof.

For the purpose of the present invention "functional equivalents" are structurally and/or functionally related compounds that are expected to have similar advantageous effects to the named compound when used in combination with the glycoalkaloid compounds described herein.

The present invention is based on the surprising discovery that the chemotherapeutic combinations described herein display synergistic properties when contacted with cancerous cells ex vivo. Preferably, when administered to patients, the first and second compositions are synergistic in that they provide better patient outcomes relative to the respective monotherapies and relative to the additive effects of the respective monotherapies. Alternatively, or in addition, the first and second compositions are synergistic in that lower LD50 values are possible with the combination relative to the respective monotherapies. Even more preferably, the lower LD50 values facilitate the administration of lower doses for the same or better therapeutic outcome. In this regard, the lower doses may avoid or ameliorate one or more side effects associated with the chemotherapeutic agents, when administered at the accepted dose used for monotherapy.

Thus, the present invention also provides a method for treating a tumorous growth comprising the steps of administering a therapeutically effective synergistic amount of the first and second compositions mentioned above.

The tumorous growth may be associated with a range of cancers including cancer selected from the group consisting of: melanomas and non-melanoma skin including lignin melanoma, solar keratosis, basal cell carcinoma, squamous cell carcinoma and actinic keratoses; mesothelioma; breast; prostate; liver; lung; colon; rectum; urinary bladder; non-Hodgkin lymphoma; kidney; pelvis; pancreas; pharynx; head & neck; ovarian; oral; thyroid; stomach; brain; multiple myeloma; oesophagus; liver and intrahepatic bile duct; cervix; larynx; acute myeloid leukemia; chronic lymphocytic leukemia; heart; Hodgkin lymphoma; testis; small intestine; chronic myeloid leukemia; acute lymphocytic leukemia; gallbladder; bones and joints; eye; nose; nasopharynx; peritoneum; omentum; and mesentery- gastrointestinal. Preferably, the tumorous growth is associated with a cancer selected from the group consisting of: renal, melanoma, lung or colorectal.

The glycoalkaloids used in the method of the present invention may be varied. Preferably, the glycoalkaloids are triglycoside glycoalkaloids, solasodine glycosides or are selected from the group of glycoalkaloids consisting of: solamargine, solasonine, solanine, tomatine, solanocapsine and 26- aminofurostane.

The glycoalkaloids may be chiral, stereoisomers and mixtures thereof including enantiomers and/or diastereoisomers. Furthermore, the glycoalkaloids may be obtained from natural sources, synthesized or produced by chemically modifying other glycoalkaloids.

The number of glycoalkaloids used may be varied, as may their relative ratios in the composition. However, when the composition comprises two glycoalkaloids they may be present in a ratio selected from the group of ratios consisting of approximately: 1 :6 - 1 :0.5; 1 :5; 1 :4; 1 :3; 1 :2, 1 :1.5 and 1 :1.

Preferably, the glycoalkaloids are solamargine and solasonine in a ratio between about 1 :6 and 6:1 or more preferably in a ratio between about 1 :4 and 4:1 , 1 :3 and 3:1 or 1 :2 to 2:1. When the glycoalkaloids are solamargine and solasonine and they are present in a 1 :1 ratio it is preferred that the glycoalkaloids are isolated. Alternatively, when the glycoalkaloids are solasonine and solamargine it is preferred that they do not constitute 66% of glycosides in the composition. In one embodiment of the present invention the glycoalkaloid composition is BEC™ or CORAMSINE®. In a preferred form of the invention, the first composition is essentially free of free sugars including free sugars derived from the glycoalkaloids. In a highly preferred form of the invention, the first composition is essentially free of rhamnose.

In a preferred form of the invention, the glycoalkaloid composition is essentially free of late-eluting degradants.

Preferably, the glycoalkaloids constitute greater than 70%-90% of the glycosides in the composition, more preferably 91-95% and even more preferably 96-100% of the glycosides in the composition.

The amount of glycoalkaloids in the compositions of the present invention may be varied depending on their intended end use. Preferably, the compositions comprise about 0.001% - 5% or 10% glycoalkaloids, more preferably 0.01% - 5% or 10% and even more preferably 0.1 %- 5% or 10% glycoalkaloids.

The actual concentration of glycoalkaloids in the composition may vary and depend at least on the nature of the tumour being treated and the condition of the subject to be treated. Skilled practitioners can determine the most appropriate dose using their ordinary skill and taking into account various parameters that apply in such situations. For example, the higher the cancer load in a particular patient the higher the dose of glycoalkaloids that can be administered and well tolerated by the patient. Preferably, the concentration of glycoalkaloids administered as part of the combination therapy is less than in a comparable situation in which it was to be administered as a monotherapy. The amount of glycoalkaloid may be about 0.1mg/kg - 100mg/kg, 1mg/kg-80mg/kg, 5mg/kg- 60mg/kg or 10mg/kg-40mg/kg. Preferably the amount of glycoalkaloid is about 0.5-5mg/kg, 0.75-4mg/kg or 1-3mg/kg.

The compositions can be formulated in various ways depending on the route and mode of administration and whether the compositions are combined in a single dosage unit or are administered as separate dosage units. Thus, the compositions used in the method of the invention may further comprise a pharmaceutically acceptable carrier.

In one form, the present invention comprises a method of treating renal cancer comprising the step of administering a therapeutically effective amount of a first composition comprising at least two glycoalkaloids of formula I, as identified above, and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action selected from the group: doxorubicin, nitrogen mustard, topotecan and gemcitabine.

In one form, the present invention comprises a method for manufacture of a medicament for treating renal cancer, the medicament comprising a therapeutically effective amount of a first composition comprising at least two glycoalkaloids of formula I, as identified above, and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action selected from the group: doxorubicin, nitrogen mustard, topotecan and gemcitabine.

In a preferred form of the invention, the first composition is CORAMSINE.

In one form, the present invention comprises method of treating colorectal cancer comprising the step of administering a therapeutically effective amount of: a first composition comprising at least two glycoalkaloids of formula I, as identified above, and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action selected from the group: 5-fluorouracil, CAMP, oxaliplatin, mitomycin C, taxol, trimetrexate, topotecan.

In one form, the present invention comprises method of manufacturing a medicament for treating colorectal cancer, the medicament comprising a therapeutically effective amount of a first composition comprising at least two glycoalkaloids of formula I, as identified above, and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action selected from the group: 5-fluorouracil, CAMP, oxaliplatin, mitomycin C, taxol, trimetrexate, topotecan.

In a preferred form of the invention, the second composition is selected from the group: 5-fluorouracil combined with oxaliplatin, and 5-flurorouracil combined with CAMP.

In a preferred form of the invention, the first composition is CORAMSINE.

In one form, the present invention comprises a method of treating non-small cell lung cancer comprising the step of administering a therapeutically effective amount of a first composition comprising at least two glycoalkaloids of formula I, as identified above, and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action selected from the group: cisplatin, gemcitabine, iressa, navalbine, taxol, trimetrexate, and topotecan.

In one form, the present invention comprises a method for the manufacture of a medicament for treating non-small cell lung cancer, the medicament comprising a therapeutically effective amount of a first composition comprising at least two glycoalkaloids of formula I, as identified above, and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action selected from the group: cisplatin, gemcitabine, iressa, navalbine, taxol, trimetrexate, and topotecan.

In a preferred form of the invention, the second composition is selected from the group: cisplatin combined with navalbine, and cisplatin combined with topotecan.

In a highly preferred form of the invention, the second composition comprises cisplatin combined with topotecan.

In a preferred form of the invention, the first composition is CORAMSINE. In one form, the present invention comprises a method of treating melanoma comprising the step of administering a therapeutically effective amount of a first composition comprising at least two glycoalkaloids of formula I, as identified above, and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action selected from the group: carmustine, cisplatin, dacarbazine, navalbine, nitrogen mustard, taxol, and temozolomide.

In one form, the present invention comprises a method for the manufacture of a medicament for treating melanoma, the medicament comprising a therapeutically effective amount of a first composition comprising at least two glycoalkaloids of formula I, as identified above, and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action selected from the group: carmustine, cisplatin, dacarbazine, navalbine, nitrogen mustard, taxol, and temozolomide.

In a preferred form of the invention, the first composition is CORAMSINE.

Methods for the preparation of pharmaceutical compositions comprising one or more active ingredients are generally known in the art. Such pharmaceutical compositions will generally be formulated for the mode of delivery that is to be used and will usually include one or more pharmaceutically acceptable carriers. A "pharmaceutically acceptable carrier" is a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the active agents without causing unacceptable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

In addition pharmaceutical compositions of the invention may further comprise suitable carriers, excipient and diluents that are pharmaceutically acceptable and compatible with the active ingredient. Some examples of suitable carriers, excipient and diluents include, without limitation, water, saline, ethanol, dextrose, cyclodextrins such as hydroxy propyl beta-cyclodextrin, glycerol, lactose, dextrose, sucrose sorbitol, mannitol, starches, gum acacia, calcium phosphates, alginate, tragacanth, gelatine, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil or combinations thereof.

The pharmaceutical compositions can additionally include lubricating agents, pH buffering agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The particular selection of constituent that can be included in the compositions described herein will generally depend on the particular mode of delivery used to bring the active agents into contact with their target cells or tissue.

The first and second compositions may be administered in separate dosage forms. When administered separately, the compositions may be administered simultaneously or sequentially. For the purposes of the present invention "simultaneously" means that the compositions are administered at the same time or within one hour of each other. When the compositions are administered greater than one hour apart they are deemed to be administered sequentially.

Compositions of the present invention should be administered in dosage unit form that is therapeutically effective. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated, each unit containing a quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on at least (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for the treatment sought. Thus, the quantity of active compound to be administered will be largely dependent on the toxicity and specific activity of compound, the subject to be treated and the degree of treatment required. Precise amounts of compound required to be administered may depend on the judgement of the practitioner and may be peculiar to each subject. Preferably, the dosages of the active agents administered according to the combination therapy of the present invention are less than the conventional dosages of the same active agents when used in monotherapy. It will be appreciated that the compositions may be given as a single dose schedule, or more preferably, in a multiple dose schedule. A multiple dose schedule is one in which a primary course of delivery may be with 1 to 100 separate doses, followed by other doses given at subsequent time intervals required to maintain or reinforce the treatment. The dosage regimen will also, at least in part, be determined by the need of the individual and the judgement of the practitioner.

The order in which the compositions are administered and their timing can be varied and will be determined by a practitioner of ordinary skill on a case by case basis. Although it is preferred that the glycoalkaloid be administered prior to or simultaneously to the second component. Furthermore, although it is preferred that the compositions be administered as separate dosage forms, the first and second compositions can be formulated into a single dosage form for more convenient administration. In this regard, when formulating the first and second compositions into a single dosage form unwanted interactions between the compositions must be managed to ensure the therapeutic activity of the compositions is not unduly compromised.

The compositions may be administered by any route deemed appropriate by the practitioner based on the particular circumstances of a given case. These routes include: intradermal, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, oral, topical, epidural, buccal, rectal, vaginal, intranasal and intratumoural.

Pharmaceutical compositions according to the invention may be administered to a patient using any technology or delivery route that permits contact between the active agents and their target site. Preferably, the composition is via the intraperitoneal or intra venous route. However, any technology that allows targeted delivery of the pharmaceutical composition via, subcutaneously, intramuscularly, intraorbital^, ophthalmically, intraventricular^, intracranially, intracapsularly, intraspinally, intracisternally, buccal, rectally, vaginally, intranasally or by pulmonary administration may be used to deliver the composition. The mode of administration must, however, be at least suitable for the form in which the composition has been prepared. The mode of administration for the most effective response may need to be determined empirically and the means of administration described below are given as examples and do not limit the method of delivery of the composition of the present invention in any way. All the formulations described below are commonly used in the pharmaceutical industry and are commonly known to suitably qualified practitioners.

Whilst not intending to be bound to any particular mode of delivery, further information on the characteristics of compositions that are used for three particular modes of delivery are provided hereunder.

(a) Parenteral delivery

Pharmaceutical compositions may be adapted for parenteral administration that facilitates delivery of a therapeutically effective amount of the active agents to the target cell or tissue.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Alternatively, the active agents may be encapsulated in liposomes and delivered in injectable solutions to assist their transport across cell membrane. The solution may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures thereof and vegetable oils or cyclodextrins such as hydroxy propyl beta- cyclodextrin. 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 superfactants. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatine.

Sterile injectable solutions may be prepared by incorporating the active agents in the required amount in an appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle that contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques that yield a powder of the active ingredient plus, optionally, any additional desired ingredient from previously sterile-filtered solution thereof.

(b) Topical delivery

Various topical delivery systems may be appropriate for administering the compositions of the present invention depending upon the preferred treatment regimen. Topical formulations may be produced by dissolving or combining the active agent in an aqueous or nonaqueous carrier. In general, any liquid, cream, or gel, or similar substance that does not appreciably react with the active or any other of the ingredients that may be introduced into the composition and which is non-irritating is suitable. Appropriate non-sprayable viscous, semi-solid or solid forms can also be employed that include a carrier compatible with topical application and have a dynamic viscosity preferably greater than water.

Suitable formulations are well known to those skilled in the art and include, but are not limited to, solutions, suspensions, emulsions, creams, gels, ointments, powders, liniments, salves, aerosols, transdermal patches, etc, which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, emulsifiers, wetting agents, fragrances, colouring agents, odour controllers, thickeners such as natural gums etc. Particularly preferred topical formulations include ointments, creams or gels.

Ointments generally are prepared using either (1 ) an oleaginous base, i.e., one consisting of fixed oils or hydrocarbons, such as white petroleum or mineral oil, or (2) an absorbent base, i.e., one consisting of an anhydrous substance or substances which can absorb water, for example anhydrous lanolin. Customarily, following formation of the base, whether oleaginous or absorbent, the active agent is added to an amount affording the desired concentration.

Creams are oil/water emulsions. They consist of an oil phase (internal phase), comprising typically fixed oils, hydrocarbons and the like, waxes, petroleum, mineral oil and the like and an aqueous phase (continuous phase), comprising water and any water-soluble substances, such as added salts. The two phases are stabilised by use of an emulsifying agent, for example, a surface active agent, such as sodium lauryl sulfate; hydrophilic colloids, such as acacia colloidal clays, veegum and the like. Upon formation of the emulsion, the active is customarily added in an amount to achieve the desired concentration.

Gels comprise a base selected from an oleaginous base, water, or an emulsion- suspension base. To the base is added a gelling agent that forms a matrix in the base, increasing its viscosity. Examples of gelling agents are hydroxypropyl cellulose, acrylic acid polymers and the like. Customarily, the active is added to the formulation at the desired concentration at a point preceding addition of the gelling agent.

The amount of the active agent incorporated into a topical formulation is not critical; the concentration should be within a range sufficient to permit ready application of the formulation to the affected tissue area in an amount that will deliver the desired amount of active to the treatment site.

The customary amount of a topical formulation to be applied to an affected tissue will depend upon an affected tissue size and concentration of the active in the formulation.

(c) Oral Delivery

Pharmaceutical compositions adapted for oral administration in such a manner that facilitates delivery of a therapeutically effective concentration of the active agent(s) to the target cell or tissue. The effective dosages of the active agent, when administered orally, must take into consideration the diluent, preferably water. The composition preferably contains about 1 to about 200mg active agent such as glycoalkaloids. When the compositions are ingested, desirably they are taken on an empty stomach.

Oral solid dosage forms are described generally in Martin, Remington's Pharmaceutical Sciences, 18th Ed. (1990 Mack Publishing Co. Easton PA 18042) at Chapter 89. Solid dosage forms include tablets, capsules, pills, troches or lozenges, cachets or pellets. Also, liposomal or proteinoid encapsulation may be used to formulate compositions (as, for example, proteinoid microspheres reported in U.S. Patent No. 4,925,673). Liposomal encapsulation may be used and the liposomes may be derivatised with various polymers (e.g., U.S. Patent No. 5,013,556). A description of possible solid dosage forms for the therapeutic is given by Marshall, in Modern Pharmaceutics, Chapter 10, Banker and Rhodes ed., (1979), herein incorporated by reference. In general, the composition will also include inert ingredients that allow for protection against the stomach environment and release of the active agents in inappropriate areas of the body.

In some instances it may be desirable to release the active agent(s) in the stomach, the small intestine (the duodenum, the jejunem, or the ileum), or the large intestine. One skilled in the art has available formulations that will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the composition or by release of the active agent beyond the stomach environment, such as in the intestine.

To ensure full gastric resistance, a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S and Shellac. These coatings may be used as mixed films. A coating or mixture of coatings that are not intended for protection against the stomach can also be used on tablets. This can include sugar coatings, or coatings that make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatine) for delivery of dry therapeutic i.e. powder; for liquid forms, a soft gelatine shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, moulded tablets or tablet triturates, moist massing techniques can be used.

Colourants and flavoring agents may all be included. For example, compositions may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavouring agents.

One may also dilute or increase the volume of the composition with an inert material. These diluents could include carbohydrates, especially mannitol, alpha-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

Disintegrants may be included in the pharmaceutical formulations of the present invention. Materials used as disintegrants include but are not limited to starch including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberiite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatine, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Other disintegrants include insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

Binders may be used to hold the pharmaceutical composition together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatine. Others include methylcellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the active.

An antifrictional agent may be included in the compositions to prevent sticking during the formulation process. Lubricants may be used as a layer between the active and the die wall and these can include but are not limited to: stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights and Carbowax 4000 and 6000.

Glidants that might improve the flow properties of the compositions during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.

To aid dissolution into an aqueous environment, a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride. The list of potential nonionic detergents that could be included in the pharmaceutical composition as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the composition either alone or as a mixture in different ratios.

Additives, which potentially enhance uptake of an active agent, are for instance the fatty acids oleic acid, linoleic acid and linolenic acid.

Controlled release formulations may be desirable. The compositions could be incorporated into an inert matrix that permits release by either diffusion or leaching mechanisms i.e., gums. Slowly degenerating matrices may also be incorporated into the pharmaceutical composition. Another form of a controlled release is by a method based on the Oros therapeutic system (Alza Corp.), i.e. the composition is enclosed in a semipermeable membrane which allows water to enter and push the composition out through a single small opening due to osmotic effects. Some enteric coatings also have a delayed release effect.

A mix of materials might be used to provide the optimum film coating. Film coating may be carried out in a pan coater or in a fluidised bed or by compression coating.

The active agents may be included in the compositions as fine multiparticulates in the form of granules or pellets of particle size about 1mm. The formulation for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The active agent(s) could be prepared by compression. Microparticles may be made by a variety of methods known to those in the art, for example, solvent evaporation, desolvation, complex coacervation, polymer/polymer incompatibility, interfacial polymerisation etc.

Hydrophilic polymers forming the microparticles may be attached to a targeting protein that acts to enable the microparticle to specifically bind selected target cells or tissues bearing the target molecule (e.g. characteristic marker). For example, the hydrophilic polymers may be conjugated to the Fab1 fragment of an antibody. Smaller peptides from the hypervariable region or from another peptide interacting with a specific cell surface ligand may also be conjugated to the complexes. It is most preferred that the antibodies or antibody fragments are directed against target molecules associated with cancerous tissues or cells.

It will be appreciated that the targeting protein (e.g. an antibody or an antibody fragment) can be attached to the hydrophilic polymers either before or after formation of the microparticle. In a preferred embodiment, the targeting protein is coupled to the hydrophilic polymer, where the targeting protein/hydrophilic polymer is subsequently used to form the microparticle complex. This provides a convenient means for modifying the targeting specificity of an otherwise generic microparticle.

Targeted microparticles may be prepared by incorporating the Fab1 fragment into the microparticles by a variety of techniques well known to those of skill in the art.

For example, a biotin conjugated Fab1 may be bound to a microparticle containing a streptavidin. Alternatively, the biotinylated Fab1 may be conjugated to a biotin derivatised microparticle by an avidin or streptavidin linker. Typically about 30 to 125 and more typically about 50 to 100 Fab' fragments per microparticle complex are used.

Pharmaceutical compositions of the present invention may also be formed into powders or some other form that is suitable for delivery by inhalation. Whilst inhalation may be via the mouth it will be appreciated that the route of delivery may also by via the nose.

These compositions are particularly useful for treatment of diseases or disorders of the respiratory system such as lung cancer or cancer that may affect other parts of the respiratory system. When designing compositions for delivery to the lungs, they are preferably designed to reach the site of the alveoli. When the compositions are adapted for delivery by inhalation they may contain various doses of active agent and the particular dose will be determined by a skilled practitioner with due consideration to the recipient and the state of the disease to be treated. However, preferably, the compositions contain between about 100ug- 100mg of active agent, about 200ug-50mg of active agent or 200ug - 10mg of active agent.

Combination Formulations

As indicated above, the method of the present invention involves the administration of at least two compositions. Particular dosage forms may be produced that are particularly useful and these form separate aspects of the present invention. Thus, the present invention also provides a unit dosage form comprising a therapeutically effective amount of: (a) at least two glycoalkaloids of formula I:

Figure imgf000025_0001

wherein: either one or both of the dotted lines represents a double bond, and the other a single bond, or both represent single bonds;

A: represents a radical selected from the following radicals of general formulae (II) to (V):

Figure imgf000025_0002

each of R1 is a radical separately selected from the group consisting of hydrogen, amino, oxo and OR4;

each of R2 is a radical separately selected from the group consisting of hydrogen, amino and OR4;

each of R3 is a radical separately selected from the group consisting of hydrogen, alkyl and R4-alkylene;

each of R4 is a radical separately selected from the group consisting of hydrogen, carbohydrate and a carbohydrate derivative; "X" is a radical selected from the group comprising -CH2-, -O- and -NH2-; and

wherein the compound includes at least one R4 group in which R4 is a carbohydrate or a derivative thereof selected from the group comprising glyceric aldehyde, glycerose, erythrose, threose, ribose, arabinose, xylose, lyxose, altrose, allose, gulose, mannose, glucose, idose, galactose, talose, rhamnose, dihydroxyactone, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, and other hexoses, heptoses, octoses, nanoses, decoses, deoxysugars with branched chains, (e.g. apiose, hamamelose, streptose, cordycepose, mycarose and cladinose), compounds wherein the aldehyde, ketone or hydroxyl groups have been substituted (e.g. N-acetyl, acetyl, methyl, replacement of CH2OH), sugar alcohols, sugar acids, benzimidazoles, the enol salts of the carbohydrates, saccharinic acids, sugar phosphates; and

(b) a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action.

Alternatively the active components may be provided as separate unit dosage forms in a pack or kit arrangement. Thus, the present invention also provides a pack comprising a unit dosage form of glycoalkaloids and a unit dosage form of a chemotherapeutic agent with a nuclear mechanism of action.

General

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.

The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein.

The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference. No admission is made that any of the references constitute prior art or are part of the common general knowledge of those working in the field to which this invention relates.

As used herein the term "derived" and "derived from" shall be taken to indicate that a specific integer may be obtained from a particular source albeit not necessarily directly from that source.

Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.

For the purposes of the present invention the term "isolated" means essentially free of (i) mono and diglycosides and, preferably, essentially free of (ii) free sugars such as mono, di, tri, oligo or polysaccharides and (iii) aglycone. However, unless steps are taken to stabilise the glycoalkaloids, it will be appreciated that even in an isolated glycoalkaloid composition of the present invention there will be a small amount of free sugars and mono and diglycosides that result from degradation of the glycoalkaloids.

For the purposes of the present invention the phrase "consisting essentially of means that the glycoalkaloids in the composition are the only glycosides therein. Thus, a composition consisting essentially of solamargine and solasonine includes solamargine and solasonine and may include other non-glycoside constituents.

The present invention will now be described with reference to the following examples. The description of the examples in no way limits the generality of the preceding description.

Example 1: Effects of various drug combinations on tumour cells ex-vivo

Materials/Methods

Data supports the proposition that laboratory results from EVA (ex vivo analysis) correlate very well with clinical observations. This approach has been supported by several peer reviewed articles comprising over 650 published clinical correlations (see, for example, Principles and Practice of Oncology Updates: Vol.

7, No. 12, 1993). These indicate that EVA has a sensitivity of 96.1% and a specificity of 87.1% (Table 1 ). Further, the EVA chemosensitivity assay has been shown to correlate with response, time to progression and survival. Tumour specific positive and negative predictive accuracy is provided in more detail below:

Table 1: Predictive accuracy of cell death assays in selected solid tumour types.

Predictive

Predictive False False

Type Number Positive

Negative Positive Negative

Accuracy Accuracy

Breast 194 82.9% 88.9% 6.4% 0.0%

Colon 54 80% 97.7% 3.7% 1.9%

NSCLC 47 66.7% 93.1 % 12.8% 4.3%

GYN 345 77% 87.9% 14.2% 4.6%

SCLC 19 50% 84.6% 15.8% 10.5%

Total 659 78.4% 90.1% 12.9% 3.9%

Sensitivity 96.1 %

Specificity 87.1 %

Predictive Positive Accuracy: when the assay predicted sensitivity and there was a response Predictive Negative Accuracy: when the assay predicted resistance and there was no response.

It was once thought that cancer cells outgrow normal healthy cells. It is now known that cancer cells actually outlive normal cells; it is not that they grow too much, they in fact live too long. Ex vivo analyses take this into account, and measure the process of cell death rather than cell proliferation/growth. The principal ex vivo assay technique measures apoptotic endpoints which are more reflective of the effects of chemotherapy in vivo. The ex vivo assay can also measure non-apoptotic endpoints including: ATP content (luminescent), MTT (mitochondrial activity) and membrane integrity methodologies, as additional cell death endpoints. As Coramsine® has displayed a non-apoptotic mode of action, the ex vivo studies testing Coramsine® were carried out using non-apoptotic endpoints.

Fresh samples of human tumours were disaggregated mechanically and enzymatically and spheroids were resuspended in modified RPMA 1640 generally in accordance with the methods set forth in Nagourney R.A. et al (2003).

The resuspended spheroids were treated with CORAMSINE® in combination with various other chemotherapeutic agents generally in accordance with the methods set forth in Nagourney R.A. et al (2003). In some instances, CORAMSINE® was tested in combination with multiple other chemotherapeutic agents.

Synergy was determined using the median effect technique of Chou and Talalay (1987) and generally in accordance with the methods set forth in Nagourney R.A. ef a/ (2003).

Results

Results are set out in the Tables hereunder. The "activity" information is related as Index Concentration 50% cell survival. Relevant abbreviations/equivalent nomenclatures are: 5FU = 5-Fluorouracil; BCNU = Carmustine (BiCNU®); CAMP = a combination of cyclophosphamide (Cytoxan®), doxorubicin (Adriamycin® ), methotrexate (Mexate®) and procarbazine (Matulane®); CDDP = Cisplatin; DOX = Doxorubicin (Adriamycin®, hydroxyldaunorubicin); DTIC (®) = Dacarbazine (DIC, imidazole carboxamide); GEM = Gemcitabine (Gemzar®); IRES = Iressa® (gefitinib); L-OHP = oxaliplatin (Eloxatin®); MMC = mitomycin C; NAV = Navelbine® (vinorelbine); NM = Nitrogen Mustard (mechlorethamine, chlormethine, mustine, Mustargen®); TAX = Taxol® (paclitaxel) ; TMTX = Trimetrexate; TMZ = Temozolomide (Temodar®, Temodal®); TOPO = Topotecan (Hycamtin) and COR = Coramsine®.

1. Renal

SYNERGY RENAL COUNT

ΓDRUGS! iSyislERGYj "BARTi 'MIXEDI ,NOlSYNI fANTAGj

5FU+CDDP 1

5FU+CDDP+GEM

5FU+INF N/A N/A N/A N/A N/A

C0R+5FU+CDDP 11

C0R+5FU+CDDP+GEM

C0R+5FU+INF N/A N/A N/A N/A N/A

CORE+CDDP+GEM 12

COR+DOX 11

COR+GEM

COR+INF N/A N/A N/A N/A N/A

CORE+NM 14

COR+TOPO 12

CDDP+GEM

RENAL PERCENT SYNERGY fATOGl

!SYNERGlI . I IiMARTl , i%fMIXEDJ RfNOWW

24% 43% m HOT

2mAIl

5FU+CDDP 5% 5% 24% 1

5FU+CDDP+GEM 9% 18% 27% 0% 45% 11

5FU+INF N/A N/A N/A N/A N/A N/A

C0R+5FU+CDDP 0% 7% 7% 7% 79% 14

C0R+5FU+CDDP+ GEM 0% 8% 33% 8% 50% 12

COR+5FU+INF N/A N/A N/A N/A N/A N/A

COR+CDDP+GEM 0% 7% 7% 0% 86% 14

COR+DOX 20% 0% 10% 15% 55% 20

COR+GEM 0% 19% 24% 19% 38% 21

COR+INF N/A N/A N/A N/A N/A N/A

CORE+NM 10% 0% 5% 19% 67% 21

COR+TOPO 14% 0% 29% 0% 57% 21

CDDP+GEM 23% 14% 36% 5% 23% 22

Figure imgf000031_0001

2. Colorectal

Figure imgf000031_0002
Figure imgf000032_0001

Figure imgf000032_0002

3. Non-small cell lung cancer

Figure imgf000033_0002

Figure imgf000033_0001
Figure imgf000034_0001

4. Melanoma

Figure imgf000034_0002
MELANOMA % SYNERGY

COR+BCNU 25% 0% 13% 0% 63%

COR+CDDP 25% 8% 17% 0% 50% 12

COR+CDDP+GEM 0% 11% 0% 0% 89%

COR+CDDP+TAX 0% 0% 0% 25% 75%

COR+ DTIC 33% 8% 8% 8% 42% 12

COR+NAV 33% 0% 33% 0% 33%

COR+NM 25% 17% 17% 8% 33% 12

COR+TAX 8% 0% 17% 25% 50% 12

COR+TMZ 22% 0% 11 % 11 % 56%

CDDP+GEM 83% 0% 17% 0% 0%

CDDP+TAX 30% 0% 10% 10% 50% 10

Figure imgf000035_0001

As can be seen from the preceding tables, CORAMSINE acts synergistically with a range of chemotherapeutic agents with a nuclear mechanism of action, in respect of a range of representative cancers.

REFERENCES

1. Nagourney R.A., Sommers B.L., Harper S.M., Radecki S., Evans S.S. (2003) Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics. British Journal of Cancer 89, 1789-1795. Chou T-C, Talalay P. (1987) Applications for the median-effect principle for the assessment of low-dose risk of carcinogens and for the quantitation of synergism and antagonism of chemotherapeutic agents. In New Avenues in Developmental Cancer Chemotherapy. Harrap K.R., Conneros T.A. (eds) pp 37-64, Orlando, FL: Academic Press Inc.

Claims

WE CLAIM:
1. A method of treating a tumorous growth comprising the step of administering a therapeutically effective amount of: (a) a first composition comprising at least two glycoalkaloids of formula I:
Figure imgf000037_0001
wherein: either one or both of the dotted lines represents a double bond, and the other a single bond, or both represent single bonds;
A: represents a radical selected from the following radicals of general formulae (II) to (V):
Figure imgf000037_0002
(IV) (V)
each of R1 is a radical separately selected from the group consisting of hydrogen, amino, oxo and OR4; each of R2 is a radical separately selected from the group consisting of hydrogen, amino and OR4; each of R3 is a radical separately selected from the group consisting of hydrogen, alkyl and R4- alkylene; each of R4 is a radical separately selected from the group consisting of hydrogen, carbohydrate and a carbohydrate derivative; "X" is a radical selected from the group comprising -CH2-, -O- and -NH2-; and
wherein the compound includes at least one R4 group in which R4 is a carbohydrate or a derivative thereof selected from the group comprising glyceric aldehyde, glycerose, erythrose, threose, ribose, arabinose, xylose, lyxose, altrose, allose, gulose, mannose, glucose, idose, galactose, talose, rhamnose, dihydroxyactone, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, and other hexoses, heptoses, octoses, nanoses, decoses, deoxysugars with branched chains, (e.g. apiose, hamamelose, streptose, cordycepose, mycarose and cladinose), compounds wherein the aldehyde, ketone or hydroxyl groups have been substituted (e.g. N-acetyl, acetyl, methyl, replacement of CH2OH), sugar alcohols, sugar acids, benzimidazoles, the enol salts of the carbohydrates, saccharide acids, sugar phosphates; and
(b) and a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action.
2. A method for treating a tumorous growth comprising the steps of administering a therapeutically effective synergistic amount of the first and second compositions of claim 1.
3. A unit dosage form comprising a therapeutically effective amount of: (a) at least two glycoalkaloids of formula I:
Figure imgf000038_0001
wherein: either one or both of the dotted lines represents a double bond, and the other a single bond, or both represent single bonds; A: represents a radical selected from the following radicals of general formulae (II) to (V):
Figure imgf000039_0001
each of R1 is a radical separately selected from the group consisting of hydrogen, amino, oxo and OR4;
each of R2 is a radical separately selected from the group consisting of hydrogen, amino and OR4;
each of R3 is a radical separately selected from the group consisting of hydrogen, alkyl and R4-alkylene;
each of R4 is a radical separately selected from the group consisting of hydrogen, carbohydrate and a carbohydrate derivative;
"X" is a radical selected from the group comprising -CH2-, -O- and -NH2-; and
wherein the compound includes at least one R4 group in which R4 is a carbohydrate or a derivative thereof selected from the group comprising glyceric aldehyde, glycerose, erythrose, threose, ribose, arabinose, xylose, lyxose, altrose, allose, gulose, mannose, glucose, idose, galactose, talose, rhamnose, dihydroxyactone, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, and other hexoses, heptoses, octoses, nanoses, decoses, deoxysugars with branched chains, (e.g. apiose, hamamelose, streptose, cordycepose, mycarose and cladinose), compounds wherein the aldehyde, ketone or hydroxyl groups have been substituted (e.g. N-acetyl, acetyl, methyl, replacement of CH2OH), sugar alcohols, sugar acids, benzimidazoles, the enol salts of the carbohydrates, saccharide acids, sugar phosphates; and
(b) a second composition comprising at least one chemotherapeutic agent with a nuclear mechanism of action.
4. A method or unit dosage form according to any one of the preceding claims characterised in that the second composition is a mitotic inhibitor.
5. A method or unit dosage form according to claim 4, characterised in that the mitotic inhibitor is selected from the group consisting of: vinca alkaloids, taxanes, podophyllotoxins and camptothecan analogs.
6. A method or unit dosage form according to claim 5 characterised in that the second composition comprises vinorelbine, vinorelbine tartrate or paclitaxel or a functional equivalent thereof.
7. A method or unit dosage form according to any one of claims 1 to 3 characterised in that the second composition is an alkylating agent.
8. A method or unit dosage form according to claim 7 characterised in that the alkylating agent is selected from the group consisting of: metal salts, nitrosureas, mustard gas derivatives, ethylenimines, alkylsulfonates, hydrazines and triazines. In one particular form of the invention the second component is mechlorethamine or dacarbazine or a functional equivalent thereof.
9. A method or unit dosage form according to any one of claims 1 to 3 characterised in that the second composition is an antibiotic.
10. A method or unit dosage form according to claim 9 characterised in that the antibiotic is selected from the group consisting of: anthracyclines and chromomycins.
11. A method or unit dosage form according to claim 9 characterised in that the second composition comprises doxorubicin or a functional equivalent thereof.
12.A method according to any one of claims claim 1 ,2 or 4 to 11 , characterised in that the tumorous growth is associated with a cancer selected from the group consisting of: melanomas and non-melanoma skin including lignin melanoma, solar keratosis, basal cell carcinoma, squamous cell carcinoma and actinic keratoses; mesothelioma; breast; prostate; liver; lung; colon; rectum; urinary bladder; non-Hodgkin lymphoma; kidney; pelvis; pancreas; pharynx; head & neck; ovarian; oral; thyroid; stomach; brain; multiple myeloma; oesophagus; liver and intrahepatic bile duct; cervix; larynx; acute myeloid leukemia; chronic lymphocytic leukemia; heart; Hodgkin lymphoma; testis; small intestine; chronic myeloid leukemia; acute lymphocytic leukemia; gallbladder; bones and joints; eye; nose; nasopharynx; peritoneum; omentum; and mesentery- gastrointestinal. Preferably, the tumorous growth is associated with a cancer selected from the group consisting of: renal, melanoma, lung or colorectal.
13.A method or unit dosage form according to any one of the preceding claims characterised in that the glycoalkaloids are triglycoside glycoalkaloids.
14. , A method or unit dosage form according to any one of the preceding claims characterised in that the glycoalkaloids are solasodine glycosides.
15. A method or unit dosage form according to any one of claims the glycoalkaloids are selected from the group of glycoalkaloids consisting of: solamargine, solasonine, solanine, tomatine, solanocapsine and 26- aminofurostane.
16. A method or unit dosage form as claimed in any one of the preceding claims characterised in that the first composition comprises two glycoalkaloids.
17. A method or unit dosage form according to claim 16 characterised in that the two glycoalkaloids are present in a ratio selected from the group of ratios consisting of approximately: 1 :6 - 1 :0.5; 1 :5; 1 :4; 1 :3; 1 :2, 1 :1.5 and 1 :1.
18. A method or unit dosage form according to claim 16 characterised in that the glycoalkaloids are solamargine and solasonine in a ratio between about 1 :6 and 6:1 or more preferably in a ratio between about 1 :4 and 4:1 , 1 :3 and 3:1 or 1 :2 to 2:1.
19. A method or unit dosage form according to claim 16 characterised in that the glycoalkaloids are solamargine and solasonine present in a 1 :1 ratio and that the glycoalkaloids are isolated.
20. A method or unit dosage form according to claim 16 characterised in that the glycoalkaloids are solasonine and solamargine and that they do not constitute 66% of glycosides in the composition.
21. A method or unit dosage form according to any one of claims 16 to 20 characterised in that the first composition is essentially free of free sugars.
22.A method or unit dosage form according to claim 16 characterised in that the glycoalkaloid composition is BEC™ or CORAMS I N E®.
23.A method or unit dosage form according to any one of the preceding claims characterised in that the glycoalkaloids constitute greater than 70%-90% of the glycosides in the composition, more preferably 91-95% and even more preferably 96-100% of the glycosides in the composition.
24.A method or unit dosage form according to any one of the preceding claims characterised in that the first composition comprises about 0.001% - 5% or 10% glycoalkaloids, more preferably 0.01% - 5% or 10% and even more preferably 0.1%- 5% or 10% glycoalkaloids.
25.A method according to any one of claims 1 ,2 or 4 to 21 characterised in that the concentration of glycoalkaloids administered as part of the combination therapy is less than in a comparable situation in which it was to be administered as a monotherapy.
26.A method of treating a tumorous growth substantially described herein with reference to any one or more of the examples.
27. A unit dosage form substantially as described herein with reference to any one or more of the examples.
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US9994582B2 (en) 2013-12-24 2018-06-12 President And Fellows Of Harvard College Cortistatin analogues and syntheses and uses thereof
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US9714255B2 (en) 2008-08-28 2017-07-25 President And Fellows Of Harvard College Cortistatin analogues and syntheses thereof
US9644074B2 (en) * 2012-03-30 2017-05-09 Rinnovation Aps Benzene polycarboxylic acid compounds and their use as drug
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US10202400B2 (en) 2017-07-24 2019-02-12 President And Fellows Of Harvard College Cortistatin analogues and syntheses thereof

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