OA11549A - A substance or composition for the treatment of cancer. - Google Patents

Description

011549 THIS INVENTION relates to a substance or compositionfor the treatment of cancer.

The invention relates, in particular, to a substance orcomposition for the treatment of cancer, rheumatoid arthritis, wasting 5 syndrome diseases, immuno modulatory related diseases, sugar diabètesmellitus 1 or 2 or hepatitis A, B or C, to a method of making amédicament or préparation for the treatment of cancer, rheumatoidarthritis, wasting syndrome diseases, immunomodulatory relateddiseases, sugar diabètes mellitus 1 or 2 or hepatitis A, B or C, to the use 10 in the treatment of cancer, rheumatoid arthritis, wasting syndromediseases, immuno-modulatory related diseases, sugar diabètes mellitus1 or 2 or hepatitis A, B or C, of a médicament or préparation, to the useof a substance or composition in the manufacture of a médicament orpréparation for the treatment of cancer, rheumatoid arthritis, wasting 1 5 syndrome diseases, immunomodulatory related diseases, sugar diabètesmellitus 1 or 2 or hepatitis A, B or C to a method of treating cancer,rheumatoid arthritis, wasting syndrome diseases, immuno-modulatoryrelated diseases, sugar diabètes mellitus 1 or 2 or hepatitis A, B or C andto a dosage form. 20 According to one aspect of the invention, there is provided a substance or composition for the treatment of cancer, rheumatoid arthritis, wasting syndrome diseases, immunomodulatory related 011549 2 diseases, sugar diabètes mellitus 1 or 2 or hepatitis A, B or C, thesubstance or composition comprising an active agent selected from thegroup consisting of amides of the general formula Rg-CO-NR-j ,Rg, inwhich: 5 R-j and R2 are independently selected from the group including H,

Me, halomethyl, saturated and unsaturated Cg-Cg alkyl groups, saturatedand unsaturated halogenated Cg-Cg alkyl groups, hydroxylated alkylgroups; or R-| and R2 are together selected from (CHg)n, wherein n = 4 or 10 5, or (CH2) gO (CHg)g; and

Rg is selected from H, Me and saturated and unsaturated C2 - Cgalkyl groups; dialkylsulphoxides of the general formula R4R5SO and mixtures15 thereof.

At least one of R^ and Rg may be a methyl group. At leastone of R4 and Rg may be a methyl group.

Instead, at least one of Rq, Rg- R4 and R5 maY be afluorinated C^-Cg alkyl group. 20 The active agent may be selected from the group including formamide, methyl formamide, dimethylformamide, acetamide, methylacetamide, dimethylacetamide, d iethylacetamide, isopropylacetamide, diisopropylacetamide, N-acetylpiperidine, N(/?- hydroxyethyl) acetamide, N,N-di(/?-hydroxyethyl) acetamide, N- 25 acetylmorpholine, acrylamide, propionamide, N-fluoromethyl-N-methyl- formamide, dimethylsulphoxide and mixtures of any two or more thereof. 011549 3

In one particular embodiment, the active agent may bedimethylformamide CgHyNO (DMF). In another particular embodimentthe active agent may be HCON (CHg) (CF^F). In another particularembodiment, the active agent may be dimethylsulphoxide (DMSO). 5 DMF is generally used as a polar solvent and is readily absorbed through the skin, through the lungs or after oral exposure. Theabsorption rate of liquid DMF through the skin amounts to about 9.4 mgper cm per hour. DMF is rapidly metabolized, the mainbiotransformation site is the liver and excrétion occurs for the larger part 10 via the urine. The main métabolites in rat, mice, hamster and man areN-(hydroxymethyl)-N-methylformamide (HMMF), N-(hydroxymethyl)-formamide (HMF) and N-acetyl-S-(N-methyl-carbamoyl)cysteine (AMCC).Unchanged DMF is excreted in the urine as a small fraction of the dose.The limited data available indicate that a significant amount of the dose 15 remains unexcreted and/or is excreted as unidentified compounds. DMF has low acute dermal, oral and inhalation toxicity. Itis considered to be a mild to moderate skin and eye irritant and readilypermeates the skin. There is no indication of skin sensitizing properties. A NOAEL (No-Adverse-observed-Effect-Level) could not be 20 established in several 90-day studies. Jn a 28 day inhalation study with dogs, no effects were found at 63 mg/nA In another study with dogs,q réversible cardiovascular effects were found at 6 O mg/m .

The NOAEL for developmental effects amounted to 44 mg/kg body weight in an oral study and 150 mg/m^ in an inhalation 25 study with rabbits. 011549 4 A draft intérim clin ica I safety report produced by Guy's DrugResearch Unit of Kings College and St Thomas' Hospitals' Medical andDental School is set out below. The safety report shows that a dose of7,06 g of DMF administered transdermally once a week for a period of 5 8 hours to human subjects is non-toxic, has no serious adverse events, and does not resuit in raised liver enzymes. DRAFT INTERIM CLINICAL SAFETY REPORTA single dose study of the disposition, safety, tolerability andpharmacokinetics of virodene PO58 in healthy volunteers. 10 PROTOCOL NUMBER: 98/VIRO/PO58/01DOSE: 1 patch containing 7060mg DMFSUBJECT NUMBERS: 001 to 010 inclusive A single dose study of the disposition, safety, tolerability andpharmacokinetics of virodene PO58 in healthy volunteers

15 Protocol number: 98/VIRO/PO58/01DRAFT INTERIM SAFETY REPORT

GENERAL 0 5 subjects dosed on day 1 (subjects 001 - 005) ° 5 subjects dosed on day 14 (subjects 006 - 010) 20 ° No withdrawals ,r 0 Final follow up for subjects 001 - 005 occurred on day 15 0 Final follow up for subjects 006 - 010 due on day 28

Allocation Number Subject Initiais Date Dosed 001 G DT day 1 011549 5 002 JCG day 1 003 CGM day 1 004 JAB day 1 005 MBV day 1 006 C P day 14 007 CKN day 14 008 RAK day 14 009 GRG day 14 010 CPD day 14 10 Table 1.1 - Subject numbers and initiais

DOSE 1 patch containing 7060mg of DMF was applied to the skin on thedeltoid région of either shoulder. The first patch was applied at 10h00on day 1 for subjects 001 - 005 and at 09h20 on day 1 for subjects 006 15 - 010 with 10 minute intervals between dosing.

SAFETY ASSESSMENTS 011549 6 ° Laboratory Safety Values: No clinically significant changesobserved for biochemistry, liver function tests, haematology orcoagulation parameters. 0 Vital Signs - There were no obvious clinically significant changes5 observed 0 Continuous lead [I monitoring - No clinically significant changesobserved] ° 12 kead ECG - No clinically significant changes observed 0 Adverse events are reported in Table 1.2

10 CLINICAL SAFETY OBSERVATIONS 0 There were no serious adverse events ° The blind was not broken

The data and statements contained in this report are based on clinicalobservations and hâve not been subject to any formai statisticai analysis 15 or Q.A. audit.

Table 1.2 A summary of adverse events reported and observed forsubjects

Sub No Description Severity Relationship Time patch applied Onset Offset Action taken 001 Dizziness Mild None 10:00 Day 1 Pre- dose Pre-dose None 011549 7 001 Itchiness to patch site Mild Possible 10:00 Day 1 10:04 Day 1 10:28 Day 1 None 001 Hot feeling to patch site Mild Possible 10:00 Day 1 10:20 Day 1 10:28 Day 1 None 001 Stinging feeling to patch site Mild Possible 10:00 Day 1 10:20 Day 1 10:00 Day 2 None 001 Hot and sweaty ail over Mild Possible 10:00 Day 1 10:40 Day 1 1 1:25 Day 1 None 001 Redness under tape Mild None 10:00 Day 1 13:56 Day 1 10:46 Day 3 None 001 Stinging to patch site Mild Possible 10:00 Day 1 18:01 Day 1 12:00 Day 4 None 001 * Erythema and blistering to patch site Mild Possible 10:00 Day 1 18:02 Day 1 10:05 Day 11 None 001 Diarrhoea Mild Possible 10:00 Day 1 13:00 Day 3 13:10 Day 3 None 001 Tingling in hands Mild Remote 10:00 Day 1 10:00 Day 4 10:06 Day 11 None 001 Peeling skin in both hands Mild Remote 10:00 Day 1 10:06 Day 4 Ongoing None 011549 8 001 Lower back pain Mild None 10:00 Day 1 13:00 Day 9 07:00 Day 12 None 002 Erythema on plaster site Mild None 10:10 Day 1 18:10 Day 1 20:05 Day 1 None 003 Warm sensation under patch Mild Possible 10:20 Day 1 1 1:30 Day 1 20:00 Day 1 None 003 Erythema at patch site Mild Possible 10:20 Day 1 18:21 Day 1 10:30 Day 6 None 003 Sensitivity to patch site Mild Possible 10:20 Day 1 18:21 Day 1 10:30 Day 6 None 003 Dry skin to patch site Mild Possible 10:20 Day 1 09:30 Day 2 10:00 Day 1 5 None 003 Pruritis to patch site Mild Possible 10:20 Day 1 00:00 Day 2 08:30 Day 3 None 004 » Cough Mild None 10:30 Day 1 Pre- dose 11:18 Day 3 None 004 Shaving eut to face Mild None 10:30 Day 1 Pre- dose 22:30 Day 2 None 004 Tingling to patch site Mild Possible 10:30 Day 1 10:56 Day 1 13:15 Day 1 None 004 Erythema to patch site Mild Possible 10:30 Day 1 18:31 Day 1 11:07 Day 11 None 9 011549 004 Dry skin to patch site Mild Remote 10:30 Day 1 1 1:07 Day 11 Ongoing None 005 Itchiness to patch site Mild Possible 10:40 Day 1 10:49 Day 1 18:00 Day 1 None 005 Redness under plaster Mild None 10:40 Day 1 10:55 Day 1 22:41 Day 3 None 005 Burning feeling to patch site Mild Possible 10:40 Day 1 11:17 Day 1 13:30 Day 1 None 005 Stinging feeling to patch site Mild Possible 10:40 Day 1 11:17 Day 1 13:30 Day 1 None 005 Erythema and blistering at patch site Mild Possible 10:40 Day 1 18:41 Day 1 09:00 Day 1 6 None ©05 Erythema at · electrode sites Mild Remote 10:40 Day 1 10:45 Day 2 12:00 Day 4 None 005 Itchiness at patch site Mild Possible 10:40 Day 1 08:30 Day 2 08:30 Day 3 None 005 Drowsiness Mild Remote 10:40 Day 1 10:00 Day 2 08:30 Day 3 None 011549 10 005 Nausea Mild Remote 10:40 Day 1 22:00 Day 2 08:00 Day 4 None 006 Constricting feeling to right arm Mild None 09:20 Day 1 09:48 Day 1 18:07 Day 1 None 006 Heaviness in right arm Mild Possible 09:20 Day 1 09:48 Day 1 18:08 Day 1 None 006 Erythema around patch Mild Possible 09:20 Day 1 10:10 Day 1 11:08 Day 1 None 006 Erythema at patch site Mild Possible 09:20 Day 1 17:20 Day 1 19:18 Day 1 None 006 Erythema at dressing site Mild Remote 09:20 Day 1 16:15 Day 1 18:13 Day 1 None 007 Erythema at patch site Mild Possible 09:30 Day 1 17:30 Day 2 Ongoing None 007 Itchiness at patch site Mild Possible 09:30 . Day 1 08:00 Day 1 18:00 Day 3 None 008 Pruritis under patch Mild Possible 09:40 Day 1 09:49 Day 1 10:30 Day 1 None 008 Burning feeling under patch Mild Possible 09:40 Day 1 10:23 Day 1 12:30 Day 1 None 008 Erythema around patch Mild Possible 09:40 Day 1 11:10 Day 1 12:45 Day 1 None 011549 1 1 008 Pulling sensation at patch site Mild Remote 09:40 Day 1 12:40 Day 1 19:34 Day 1 None 008 Erythema at patch site Mild Possible 09:40 Day 1 17:40 Day 1 Ongoing None 008 Burning sensation at patch site Mild Possible 09:40 Day 1 17:42 Day 1 18:35 Day 1 None 008 Tenderness at patch site Mild Possible 09:40 Day 1 18:35 Day 1 09:00 Day 3 None 008 Headache Mild Possible 09:40 Day 1 18:55 Day 1 03:20 Day 1 None 008 Pruritis at patch site Mild Possible 09:40 Day 1 08:30 Day 2 Ongoing None 008 Dry skin at patch site Mild Possible 09:40 Day 1 17:41 Day 1 Ongoing None 009 * Burning sensation at patch site Mild Possible 09:50 Day 1 09:55 Day 1 12:47 Day 1 None 009 Warm sensation at patch site Mild Possible ” 09:50 Day 1 09:55 Day 1 12:47 Day 3 None 009 Erythema at patch site Mild Possible 09:50 Day 1 17:50 Day 1 Ongoing None 011549 12 009 Warm sensation at patch site Mild Possible 09:50 Day 1 17:50 Day 2 10:00 Day 2 None 009 Tenderness at patch site Mild Possible 09:50 Day 1 17:50 Day 1 09:54 Day 3 None 010 Erythema around patch Mild Possible 10:00 Day 1 10:55 Day 1 12:57 Day 1 None 010 Warm sensation at patch site Mild Possible 10:00 Day 1 10:55 Day 1 18:50 Day 1 None 010 Tenderness at patch site Mild Possible 10:00 Day 1 13:30 Day 1 12:00 Day 2 None 010 Erythema at patch site Mild Possible 10:00 Day 1 18:00 Day 1 Ongoing None 010 Blistering at patch site Mild Possible 10:00 Day 1 18:00 Day 1 18:00 Day 2 None 010 * Lethargy Mild Remote 10:00 Day 1 08:00 Day 2 11:30 Day 2 None

The cancer may be a carcinoma, sarcoma, lymphoma,melanoma any malignant cellular tumour, Karposi Sarcoma, marrow bonecancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma and any otherviral cancers. 011549 13

The substance or composition may include at least onephysiologicaily acceptable excipient or carrier. The excipient or carriermay be Silicon dioxide e.g. colloïdal Silicon dioxide.

According to another aspect of the invention, there is5 provided a method of making a médicament or préparation for thetreatment of cancer, rheumatoid arthritis, wasting syndrome diseases,immunomodulatory related diseases, sugar diabètes mellitus 1 or 2 orhepatitis A, B or C the method including the step of combining an activetherapeutic agent selected from the group which includes amides of the 10 general formula Rg-CO-NRpRg in which R-j and Rg are independently selected from the group including H,

Me, halomethyl, saturated and unsaturated Cg-Cg alkyl groups, saturatedand unsaturated halogenated Cg-Cg alkyl groups, hydroxylated alkylgroups; or 15 Rp and Rg are together selected from (CHg)n, wherein n = 4 or 5, or (CHg)gO(CHg)g;

Rg is selected from H, Me and saturated and unsaturatedCg-Cg alkyl groups; dialkylsulphoxides of the general formula R4R5SO, and20 mixtures thereof with at least one physiologicaily acceptable excipient or carrier.

Rp Rg, Rg, R4 and Rg may be as hereinbefore described.

The amide may be as hereinbefore described. Thedialkylsulphoxide may be dimethylsulphoxide. 011549 14

The invention extends further to the use, in the treatmentof cancer, rheumatoid arthritis, wasting syndrome diseases,immunomodulatory related diseases, sugar diabètes mellitus 1 or 2 orhepatitis A, B or C of a médicament or préparation comprising an active 5 therapeutic agent selected from the group which includes amides of thegeneral formula Rg-CO-NR-j Rg, in which R-| and Rg are independentlyselected from the group including H, Me, halomethyl, saturated andunsaturated Cg-Cg alkyl groups, saturated and unsaturated halogenatedCg-Cg alkyl groups, hydroxylated alkyl groups; or 10 R-| and Rg are together selected from (CHg)n, wherein n = 4 or 5, or (ΟΗ2)20(ΟΗ2)2;

Rg is selected from H, Me and saturated and unsaturated Cg-Cgalkyl groups; dialkylsulphoxides of the general formula R4R5SO, and mixtures15 thereof. R-|, Rg, Rg, R^ and Rg may be as hereinbefore described.

The médicament or préparation may include at least onephysiologically acceptable excipient or carrier..

The physiologically acceptable excipient or carrier may be20 Silicon dioxide e.g. colloïdal Silicon dioxide.

The amide may be as hereinbefore described. Thedialkylsulphoxide may be as hereinbefore described.

The invention extends, further, to the use of a substance or composition in the manufacture of a médicament or préparation for the 25 treatment of cancer, rheumatoid arthritis, wasting syndrome diseases, 011549 15 immunomodulatory related diseases, sugar diabètes mellitus 1 or 2 orhepatitis A, B or C, the substance or composition comprising an activetherapeutic agent selected from the group which includes amides of thegeneral formula Rg-CO-NR-j Rg, in which 5 R-| and R2 are independently selected from the group including H,

Me, halomethyl, saturated and unsaturated Cg-Cg alkyl groups, saturatedand unsaturated halogenated Cg-Cg alkyl groups, hydroxylated alkylgroups; or R-| and R2 are together selected from (CH2) n, wherein n = 4 or10 5, or (CH2)20(CH2)2;

Rg is selected from H, Me and saturated and unsaturated Cg-Cgalkyl groups; dialkylsulphoxides of the general formula R4R5SO, and mixturesthereof. 15 R.), R2, Rg, R4 and Rg may be as hereinbefore described.

The amide may be as hereinbefore described. Thedialkylsulphoxide may be as hereinbefore described.

The invention extends, still further, to a method of treatingcancer, rheumatoid arthritis, wasting syndrome diseases, 20 immunomodulatory related diseases, sugar diabètes mellitus 1 or 2 orhepatitis A, B or C the method including the step of administering to asubject having cancer, a médicament or préparation comprising aphysiologically effective dosage of an active therapeutic agent selectedfrom the group which includes amides of the general formula Rg-C0- 25 NR-j Rg, in which 011549 16 R^ and R2 are independently selected from the group including H,Me, halomethyl, saturated and unsaturated C2-C3 alkyl groups, saturatedand unsaturated halogenated C2-C3 alkyl groups, hydroxylated alkylgroups; or 5 R-j and R2 are together selected from (Ch^n, wherein n = 4 or 5, or (ΟΗ2)2θ(^Η2)2»· and R3 is selected from H, Me and saturated and unsaturated C2-C3alkyl groups; dialkylsulphoxides of the general formula R4R5SO, and mixtures10 thereof.

The médicament or préparation may include at least onephysiologically acceptable excipient or carrier as hereinbefore described. R-p ^2' ^3' ^4 ^5 maY be as hereinbefore described.

The amide may be as hereinbefore described. The15 dialkylsulphoxide may be as hereinbefore described.

The dosage may be selected so as to provide a blood .concentration of the active therapeutic agent, in the blood of the subjectbeing treated, of about 2 - 200 ppm, preferably about 50 - 100 ppm.

The dosage may be administered transcutaneously, i.e. by20 means of skin transfer of the active therapeutic agent, eg through theapplication of a skin patch or a cotton wool pad which has beenimpregnated with the active therapeutic agent or with a compositioncomprising the active therapeutic agent. The concentration of the active 01 1549 17 therapeutic agent in the composition used to impregnate the skin patchor cotton wool pad may be about 10 - 100%.

The dosage may be administered about once per week forabout 8 hours at a time. 5 The dosage may, instead, be administered by a method selected from oral dosages, inhalation, by means of a suppository,intravenously and combinations of any two or more thereof. Theintravenous introduction will typically be at a controlled rate over aperiod of time, for example, 1 - 6 gm, more preferably about 4 gm of 10 DMF (99,8% purity) via a saline drip over a period of 6 - 8 hours.

In the case of severe cancers the dosage may be about 14g at a time e.g. by using two patches each containing about 7g of DMF,typically about once per week, for periods of 6 - 8 hours, preferablyabout 8 hours. 15 The invention thus extends to a dosage form for the treatment of cancer which comprises topical application means, such asa skin patch or pad, on which is adsorbed or absorbed an effectiveamount of an active therapeutic agent as hereinbefore described.

The topical application means may comprise a body of a 20 synthetic polymeric material such as TEFLON (trade name) on which theactive therapeutic agent is adsorbed or absorbed. The active therapeuticagent e.g. the dimethylformamide may be présent in an amount of about5 - 15g per patch, preferably about 7g e.g. about 7,064 g. Typically,the dosage form will include DMF admixed with Silicon dioxide e.g. 011549 18 colloïdal Silicon dioxide to form a gel with which the patch isimpregnated. The patch may be a Virodene PO58 patch.

The invention is now descrîbed, by way of example, withreference to the accompanying Figures and Examples, in which 5 Figure 1 shows plasma DMF concentrations as a function of time during a first set of human toxîcity trials;

Figure 2 shows plasma DMF concentrations as a function of timeduring a second set of human toxicity trials;

TREATMENT OF CANCER 10 EXAMPLE 1 A patient suffering from cancer was treated withdimethylformamide (virodene P058) by the application of skin patchesimpregnated with a dimethylformamide gel to the patient's body.

The patient was an approximately forty year old woman15 suffering from metastasised fourth stage breast cancer. The primarycancer was in the left breast and had spread to the right breast. Thepatient had auxiliary left and right swollen lymph glands under both arms,swelling of lymph glands under the chin and a secondary tumour near thecrown of the head protruding from the skull which was four fingertips 20 across. The patient was dehydrated and unable to keep down food orwater. The primary tumour in the left breast had a circumference of 52cm and a diameter of 32 cm. A skin patch was applied to the skin adjacent the tumour forsix hours. The skin patch contained about 7,064g of a gel comprising 011549 19 DMF (92,5 % m/m) and colloïdal Silicon dioxide (7,5 % m/m). The gelserved to prevent leakage of liquid DMF from the patches. The patcheswere manufactured at most 12 hours prior to use as DMF evaporatesrapidly.

Two days later the tumour circumference had reduced to 51cm and diameter to 29,5 cm and the patient was able to consume fruitand vegetable juices. The treatment was continued in the same fashionon alternative days for a further week followed by a break of one week.Three days after the treatment began the patient's appetite returned andthe patient was able to hold down food. The area of the tumour closestto the patches appeared to be shrivelled and contracted and the tumourreduced in size by about 1-2 mm per week. There was notableprotraction of the blood vessels and tumour support System. Thetempérature of the tumour also dropped to normal.

The intended level of DMF in the patient's blood is 100 - -300 ppm. For a patient weighing about 60 kg, an amount of about 14g over a period of 12 hours is required to produce a level of 100 ppm.To obtain a blood level of 100 ppm about 1,272 g of DMF must beabsorbed per hour, thus each patch requires about 7,064 g DMF todeliver the required amount, having a surface area of 6,36 cm (eachpatch). DMF absorption rate is about 9.4 mg/cm /hour. In theory this

»T treatment will deliver 125 - 135 ppm, but due to évaporation of theDMF, 100 ppm is obtained. Absorption capability varies from patient topatient depending on factors such as skin-type and skin thickness. Toobtain the desired levels of DMF in a patient, plasma DMF concentrationswere monitored for the patient and treatment adjusted accordinglydepending on the DMF level of the patient (see Figures 1 and 2 for 011549 20 examples of various plasma DMF concentration levels in patientsreceiving the same treatment).

The stickers or patches were thus each loaded with about7,064 g of the gel of DMF and Silicon dioxide. Each patch was appliedfor a period of 6 hours, on alternate days for one week followed by a oneweek break.

Prior to the treatment with dimethylformamide, acomprehensive base-line clinical and psychological évaluation of thepatient was conducted. The évaluation provided base-line biochemicaland haematological data on the patient.

The concentration of DMF in the patient's blood wasdetermined hourly during the period of treatment. An intravenous linewas introduced each morning to take blood samples and was kept openwith an infusion of Normal Saline at a rate of 20mfh and dailymonitoring of the active métabolisé AMCC (eg by 4 hourly urinesampling) derived from the· DMF was also conducted. Subséquentapplications of DMF were adjusted in accordance with measured changesin blood level DMF concentration resulting from changes in absorbtionvariables and daily full haematological and biochemical profiles wereconducted to detect any changes in liyer function. Daily full clinical andpsychological évaluations were also conducted.

Ail clinical and laboratory data was fed into a centraliseddata System to facilitate rapid response to any detrimental change so asto curtail treatment to maximise clinical effect and minimise potentielside effects. 21 011549

The tests included a) Sérum:- S-Na, S-K, S-CI, S-CO2,S-Urea, Surate, S-Creat, SCa, S-Ca, S-Mg, S-Phos, Sérum Total, S-Conjd; b) Protein Electrophoresis: ST-Protein, S-Albumin, S-Total Glob, S-Alphal Glob, S-Alpha2 Glob, S-BetaGlob, S-Gamma Glob; c) White cell differential count:-Wh cell count, Neutroabsolute, Lypho absolute, Mono absolute, Eosinoabsolute, Baso absolute; d) Liver Enzymes: - S-Alk. Phos, S-Gamma GT, S-Alt(SGPT), S-AST(SGOT), S-LD; e) blood analysis for DMF levels; f) urine analysis for AMCC levels EXAMPLE 2 A second female patient suffering from Marna Carcinomawas terminally ill and had a tumour with a diameter of 53 cm on her leftbreast. After three weekly treatments using skin patches impregnatedwith 7.04g of dimethylformamide for 4 hours over a period of 3 weeks,the tumour had shrunk by 7 cm in diameter. The patient experiencedless pain and bleeding disappeared.

'T EXAMPLE 3 A third patient was a male suffering from full blown AIDS.

The patient had seven tumours which were diagnosed as Karposi

Sarcoma. After two, weekly treatments with skin patches impregnated 011549 22 with 7.04g of dimethylformamide, each applied for 8 hours once a weekfor two weeks, the tumours faded. After six treatments with the sameamount of dimethylformamide the tumours disappeared and after 18months no tumours had recurred. EXAMPLE 4 A fourth patient was an adult female diagnosed with non-Hodgkins Lymphoma. The patient had not been on chemothërapy andwas HIV positive. After eight treatments using skin patches impregnatedwith 7.04g dimethylformamide for 8 hours at a time over a period of 8weeks, the cancer disappeared. Eight months later the cancer had notrecurred.

In further studies, it was found that in-vitro studies indifferent cell cultures expressed properties of benign better-differentiatedphenotypes when these cultures were exposed to polar substances.DMF caused conformational changes and hypomethylation of DNAsequences, and inhibited expression of myc onco-proteins. A markedalteration in the random piling, non-contact-inhibited growth pattern ofvirus transformed mice kidney cell-lines, occurred when the normalgrowth medium was supplemented by 0.5% DMF concentration. Insteadof a piling pattern, mono layers of cells in regular parallel orientation sr formed that were typical of non-malignant fibroblasts. Similar effectswere noted on other cell-lines such as human colon-carcinoma cells.Focal Adhesion Kinase (FAK) is activated in response to receptoractivation at focal adhesion sites. FAK is a substrate for the oncogenicforms of the src-family of tyrosine kinases. The action of polar agentson oncogenic expression is believed to be the induction of cancer cells 011549 23 to become more benign. It would seem reasonable that to convert amalignant cell to a benign phenotype, there should be some modulationof gene expression causing malignancy in the first place. In the HL-60human promyelocytic leukemia cells, dimethylsulfoxide (DMSO) reducedthe expression of c-myc oncogenes by 80 to 90%. Some brain tumoursare regulated by glial-binding growth factors such as Epidermal GrowthFactor (EGF) and Platelet Derived Growth Factor (PDGF) both of whichare related to oncogenes. The PDGF /Tchain gene is the cellularhomologue and proto-oncogene of the viral erb-/? oncogene. Cellmaturation induced by polar agents (N-MF) as single agents is most likelyto be effective in Neuroblastoma and Glioblastoma (as well as leukemiaand melanoma). Polar agents easily penetrate the blood brain barrier andsensitize tumour cells to both X-radiation and cis-platinum. There is aproven link between PDGF, Transforming Growth Factor-σ (TGF-σ), EGF,EGF-receptors and the neoplastic changes causing brain tumours.

Primary Mode DMF is a cell differentiator which works on gene expression (DNA)of the tumeric cell. This is a primary mechanism for activating a gene inthe binding of an inducer protein to a promoter side of the head of thegene. The gene remains in a turned on State, directing the synthesis ofmore protein, until something causes it to be switched off. A commonmechanism of gene régulation is négative feedback. The presence of alarge amount of the protein product from the gene can interfère with theticking of the inducer that originally turned the gene on. When thishappens, the gene is turned off. This thermostat-like mechanism turnsgenes on and off, maintaining a supply of product balance againstconsumption. When a spécifie external signal molécule binds to the cell 011549 24 receptor, an enzyme called protein kinase located on the internai side ofthe cell membrane is activated, this spécifie protein helps with theincrease of forming tumor cells. It is known that DMF inhibits thisspécifie protein which renders the tumor cell into a latent State. 5 The differential effects of DMF in transforming growth factor - beta 1 on human ovarian cancer cell line. (HOC-7) to a malignant cell.This was also found in human colon carcinoma. (Factor - beta 1 isgrowth factor, that can be up regulated or transformed in human cells.)

Exposure of some tumor cells to regulators of cell différentiation10 causes induced dépendent alterations of the antigenic pattern of the cell.

Exposure of HOC-7 ovarian adenocarcinoma cells to regulators ofcell différentiation caused inducer-dependent alterations of the antigenicpattern of the cells. Immunocytochemistry revealed that N,N-dimethylformamide (DMF) elevated the membrane staining for epidermal

15 growth factor (EGF) receptor and for desmoplakins I and II. DMF alsostimulated cytoplasmic and surface labeling for CA 125 and thedisposition of fibronectin into the extracellular matrix. Stimulation offibronectin was also seen after addition of transforming growth factor(TGF) - beta 1. The immunosorbent assay (EUSA) revealed that DMF 20 dose dependently induced expression of EGF - receptor. CA 125,Fibronectin, and desmoplakins I and II. TGF - beta 1 stimulatedfibronectin and desmoplakins I and II only.

Production of EGF and TGF - alpha was not affected by these inducers. Immunocytochemistry. ELISA and Western blotting showed 25 that both inducers cause down-regulation of myconcoproteins. DMF was 011549 25 more effective in changing the immunophénotype of HOC-7 cells thanTGF-beta 1. Demoplkins I and II demonstrated elevated épithélialdifférentiation, whereas fibronectin indicated stimulation of extracellularmatrix formation. Elevated EGF-receptor could not compensate for the 5 growth inhibition induced by DMF. The expression of myconcoproteinswas inversely related to cell prolifération CA 1 25, however, seems to beunrelated to cell growth.

Treatment of chemistry transformed fibroblasts with N,N-dimethylformamide (DMF) results in the restoration of a nontransformed 10 phenotype. In an attempt to identify more precisely the mechanisms bywhich DMF reverses the transformed phenotype, the effects of DMF onfibroblasts which were transformed by a single gene - specifically asynthetic epidermal growth factor (EGF) gene or the Harasoncogene wereexamined. The constitutive expression of either the Ha-rasrasoncogene 15 or the EGF gene in FR3T3 fibroblasts resulted in cellular transformation.The effect of the différentiation - inducing agent DMF on severalproperties of these transformed cell lines was examined.

The EGF-transfected cells resulted in the inhibition of anchorage-independent growth, the restoration of a normal cellular morphology and 20 growth rate in monolayer culture, and the down-regulation of theproliferation-associated nucleolar protein B23. DMF treatment has amuch slighter effect on growth of the ras-transfected cells in monolayerculture or under anchorage-independent growth conditions.

The high prolifération rate of the ras-3 cells was associated with 25 elevated expression of protein B23. The 19-3 cells. But not the ras-3cells, expressed cell surface fibronectin. Treatment of the ras-3 cells of 011549 26 DMF did not restore fibronectin expression. The binding of EGF wasincreased in rastransfected cells, but in neither case did DMF alter EGFbinding. DMF treatment increased the sécrétion of EGF in the 2transfected lines as well as in control cells. These results suggest that 5 the aberrant-growth control in the EGF-transfected cells, but not in theras-transfected cells, could be modulated by DMF and that the aberrant-growth control mechanisms were different in these 2 cell types.

Secondary Mode

Tyrosine Kinase acts in the signalling pathway at cellular level with10 growth factor receptors, tumor necrosis factor-σ, interleukin-6 andinterleukin-1 2. Growth factors send signais to the cell nucléus via achain of interacting proteins. Several proteins in this cascade are theproduct of cytoplasmic oncogenes. Most growth-factor receptors with(PTK) Protein Tyrosine Kinase activity dimerize in response to ligand 15 binding. Their catalytic activity is increased, causingtransphosphorylation of a receptor pair. These phosphorylated tyrosineresidues create binding sites for proteins containing a sequence called anSH2 (src-homology région 2) domain. SH2 domains recognize, inaddition to phosphorylated tyrosine a short surrounding linear sequence, 20 often of about four amino-acids, providing their specificity of interaction.On binding to the receptor, the enzyme may become phosphorylated ontyrosine. In some cases interaction itself seems to be the activatingfactor, perhaps by inducing a conformational change. The signal is thenpassed on to downstream molécules, with conséquent effects on the 25 nuclear DNA. 27 011549

Mutations hâve been .found in ras genes in many humantumor types, with a high prevalence. At various levels in the signal-transduction pathway, individual proteins hâve been found to be alteredby mutations in human cancers. The aberrant activation of theinformation-cascade at many levels can resuit in the same end-pointnamely excessive growth stimulation.

Growth factor receptors span the plasmid membrane suchthat binding of extra-cellular factor elicits biochemical changes withincells that are required for cell prolifération. A large number of oncogenesare derived from genes that encode growth factor receptors. Many wereinitially discovered associated with oncogenic retro-viruses and functionenzymatically as Protein Tyrosine Kinases (PTK). The fact that manygrowth factor receptors and oncogenes are tyrosine kinases is significantbecause phospho-tyrosine normally constitutes only a small fraction(0.1%) of the total protein phosphate. This suggests that tyrosinephosphorylation is frequently reserved for pathways controlling cellgrowth and différentiation. A number of mitogenic factors bind tomembrane spanning glyco-proteins belonging to the growth hormonereceptor super-family. These include Interleukins 2,4,6 and 7 andhaemopoetic colony stimulating factors (G-CSF, GM-CSF, IL-3 anderythropoietin). Although there is no tyrosine kinase domain for thehaemopoietic cyrokine receptors, it is known that stimulation of thesereceptors leads to an increase in cytoplasmic tyrosine kinase activity.Several new enzymes were found and two of these, JAK1 and JAK2,appeared to hâve multiple kinase domains. It now appears that JAK1and JAK2 associate with many growth factor / cytokine receptorSystems (e.g. EGFR and G-CSF receptor) and they are activated as aresuit of ligand binding. 011549 28

Ligand regulated Enzymes

The ligand regulated enzymes represent a huge family ofreceptors that can be divided into different families. The unifyingstructural feature of these receptors is the presence of an extra-cellular 5 ligand-binding domain that régulâtes activity of an intra-cellular catalyticdomain. In most instances the two domains of the receptor areconnected by a single trans-membrane spanning région. This super-family includes a variety of growth factors, cytokines and peptides. Thestructural and functional properties of these receptors hâve been 10 reviewed and found to hâve an intra-cellular tyrosine domain in common.

One of the major groups within the ligand-regulated enzymesuper-family is the receptor-tyrosine kinase family which includesreceptors for Fibroblast Growth Factor (FGF), EGF and PDGF.

The next group that includes receptors for insulin and15 insulin-like growth factor are heterotetrameric consisting of two a andtwo β sub-units connected by disulfide bonds. The two a sub-unitscontribute to the ligand binding domain, whereas the two β sub-units traverse the membrane and possess tyrosine kinase activity.

The class which includes the FGF, has three20 immunoglobulin-like domains in the extra cellular ligand binding portion of the receptor.

Another mernber of the ligand-regulated enzyme superfamily is the receptor for Atrial Natriuretic Peptide (ANP,. 29 011549

The last group within the ligand-regulated enzyme superfamily is a family that includes receptors for NGF and TNF. The intra-cellular domain has an unknown function and it lacks a sequence identitywith any other known proteins. It has been suggested that a trans- 5 membrane tyrosine kinase can interact with the intra-cellular domain ofthe NGF receptor to elicit a biological signal. Once occupied by theirrespective ligands, the NGF causes neuronal différentiation and survivalwhereas the TNF receptor causes inflammation and tumor cell death.

Considering the above analysis the Applicant believes that10 the group of TPK (protein tyrosine kinases) play a central rôle in cancer.It is a fact that PTK is a commonly occurring factor as second messengerin the pathogeneses of these disease States and it is assumed thatmodifying this enzyme action with polar substances, the disease state's progression could be altered. 15 Growth factors play an important rôle in inducing and promoting neoplastic disease. Neoplastic cells as such, can producemore growth factors. The group of protein tyrosine kinases is animportant link in the pathway from receptor to nucléus as a secondmessenger. DMF inhibits this pathway and alters the growth pattern as 20 well as the multiplication of tumor cells. The correct application, and thecorrect duration of application, has been found to prevent the growthand metastasizing effects of neoplastic disease.

In-vitro studies were carried out to show the effect of DMF on PTK. A Tyrosine Kinase Assay kit (non-radioactive # 1534505, 25 Boehringer Mannheim) was used to show that DMF is a Tyrosine Kinase inhibitor. The results are set out in the Appendix below. 011549 30

Appendix IC50 1,7 - 1 7μΜ

Slank. : 0.043

Funct : Cntrl 1

HELA

Endogenous phosphatase : Endogenous phosphorylation : 20.3% 0.14 (0.208) Activity % Inhibition Inhibitor:(Pileattanol + 10% DMSO)29.5% 0.076 (0.132) 66% 75% Clean cells 0.115 (0.176) 100% 0.0% 2% Métabolite I 0.099 (0.167) 86% 95% 9.8.5% 0.2% Métabolite II 0.074 (0.140) 64% 80% 28.5% 2% Métabolite II 48.5% 0.055 (0:091) 48% 55% 0.2% DMF 0.073 (0.146) 63% 83% 27.0% 2% DMF 58.0% 0.042 (0.082) 37% 47% HEP 3B

Inhibitor 40.0% 0.055 (0.11 1) 60% 60% Clean cells 0.0% 0.091 (0.186) 100% 2% Métabolite I 10.0% 0.090 (0.150) 99% 81% 0.2% Métabolite II 0.036 (0.060) 40% 32% 64.0% 011549 31 2% Métabolite II 0.095 (0.095) 60% 51% 44.5% 0.2% DMF 0.080 (0.123) 88% 66% 5 33.3% 2% DMF 0.040 (0.064) 44% 34% 61.0%

It is an advantage of the invention illustrated that the toxicityof DMF is about 5-10 times lower when administered subcutaneouslyas compared with oral administration. The Applicant believes that DMF 10 affects or destroys certain enzymes associated with cancer and causesdéhydration of the tumours.

Claims (50)

011549 32 CLAIMS:

1. A substance or composition for the treatment of cancer,rheumatoid arthritis, wasting syndrome diseases, immunomodulatoryrelated diseases, sugar diabètes mellitus 1 or 2 or hepatitis A, B or C, the 5 substance or composition comprising an active agent selected from thegroup consisting of amides of the general formula Rg-CO-NR-j ,Ι^, inwhich: R·] and R2 are independently selected from the group including H,Me, halomethyl, saturated and unsaturated C2-C3 alkyl groups, saturated 10 and unsaturated halogenated C2-C3 alkyl groups, hydroxylated alkylgroups; or R-, and R2 are together selected from (Ch^ln, wherein n = 4 or 5,or are (CH2) 2θ and R3 is selected from H, Me and saturated and unsaturated C2 - C315 alkyl groups; dialkylsulphoxides of the general formula R4R5SO, and mixturesthereof.

2. A substance or composition as claimed in claim 1, in whichat least one of Rq and R2 is a methyl group. 20

3. A substance or composition as claimed in claim 1 or claim 2, in which at least one of R4 and R§ is a methyl group.

4. A substance or composition as claimed in any one of the preceding daims, in which at least one of Rj, F^' ^4 an^ ^5 's afluorinated C1-C3 alkyl group. 011549 33

5. A substance or composition as claimed in Claim 1, in whichthe active agent is selected from the group including formamide, methylformamide, dimethylformamide, acetamide, methylacetamidedimethylacetamide, diethylacetamide, isopropylacetamide 5 diisopropylacetamide, N-acetylpiperidine, N(/?-hydroxyethyl) acetamide,N,N-di(/?-hydroxyethyl) acetamide, N-acetylmorpholine, acrylamide,propionamide, N-fluoromethyl-N-methyl-formamide, dimethylsulphoxideand mixtures of any two or more thereof.

6. A substance or composition as claimed in claim 5, in which10 the active agent is dimethylformamide CgHyNO (DMF).

7. A substance or composition as claimed in claim 5, in whichthe active agent is /V-fluoromethyl-/V-methylformamide.

8. A substance or composition as claimed in claim 5, in whichthe active agent is dimethylsulphoxide (DMSO). 15

9. A substance or composition as claimed in any one of the preceding daims, in which the cancer is selected from a carcinoma,sarcoma, lymphoma, melanoma, malignant cellular tumour, Karpo 21Sarcoma, marrow bone cancer, Hodgkin's lymphoma, non-Hodgkin'slymphoma and viral cancers. 20

10. A substance or composition as claimed in any one of the preceding daims, which includes at least one physiologically acceptableexcipient or carrier.

11. A substance or composition as claimed in claim 10, in which • the excipient or carrier is Silicon dioxide.. 011549 34

12. A method of making a médicament or préparation for thetreatment of cancer, rheumatoid arthritis, wasting syndrome diseases,immunomodulatory related diseases, sugar diabètes mellitus 1 or 2 orhepatitis A, B or C, the method including the step of combining an active 5 therapeutic agent selected from the group which includes amides of thegeneral formula. Rg-CO-NR-j ,Ι^ in which R^ and R£ are independently selected from the group including H,Me, halomethyl, saturated and unsaturated C2-C3 alkyl groups, saturatedand unsaturated halogenated C2-C3 alkyl groups, hydroxylated alkyl 10 groups; or R-|, and R2 are together selected from (CH^Jn, wherein n - 4 or5, or are together Rg is selected from H, Me and saturated and unsaturated C2-C3alkyl groups; 15 dialkylsulphoxides of the general formula R4R5SO and mixtures thereof with at least one physiologically acceptable excipient or carrier.

13. A method as claimed in claim 12, in which at least one of R^and R2 is a methyl group. 20

14. A method as claimed in claim 1 2 or claim 13, in which at least one of R4 and Rg is a methyl group.

15. A method as claimed in any one of daims 12 to 14, in which at least one of R-j, F?2' R4 and R5 is a fluorinated C^-Cg alkyl group. 011549 35

16. A method as claimed in Claims 12, in which the active agentis selected from the group including formamide, methyl formamide,dimethylformamide, acetamide, methylacetamide, dimethylacetamide,diethylacetamide, isopropylacetamide, diisopropylacetamide, N- 5 acetylpiperidine, N(/?-hydroxyethyl) acetamide, N,N-di(/?-hydroxyethyl)acetamide, N-acetylmorpholine, acrylamide, propionamide, N- f!uoromethyl-N-methyl-formamide, dimethylsulphoxide and mixtures ofany two or more thereof.

17. A method as claimed in claim 16, in which the active agent10 is dimethylformamide CgHyNO (DMF).

18. A method as claimed in claim 16, in which the active agentis /V-fluoromethyl-/V-methylformamide.

19. A method as claimed in claim 16, in which the active agentis dimethylsulphoxide (DMSO).

20. Use, in the treatment of cancer, rheumatoid arthritis, wasting syndrome diseases, immunomodulatory related diseases, sugar diabètesmellitus 1 or 2 or hepatitis A, B or C, of a médicament or préparationcomprising an active therapeutic agent selected from the group whichincludes amides of the general formula Rg-CO-NR-j Rg, in which 20 R^ and Rg are independently selected from the group including H, Me, halomethyl, saturated and unsaturated Cg-Cg alkyl groups, saturatedand unsaturated halogenated Cg-Cg alkyl groups, hydroxylated alkylgroups; or R·^ and R2 are together selected from (CHg)n, wherein n = 4 or 5, 25 or are together (CHg)gO(CHg)g; 011549 36 Rg is selected from H, Me and saturated and unsaturated Cg-Cgalkyl groups; dialkylsulphoxidesof thegeneral formula R4R5SO, andmixtures thereof.

21. Use as claimed in claim 20, in which the médicament or5 préparation includes at least one physîologically acceptable excipient or carrier.

22. Use as claimed in claim 21, in which the physîologicallyacceptable excipient or carrier is Silicon dioxide.

23. Use as claimed in any one of daims 20 to 22 inclusive, in10 which at least one of R-j and Rg is a methyl group.

24. Use as claimed in any one of daims 20 to 23 inclusive, inwhich at J least one of R4 and Rg is a methyl group.

25. Use as claimed in any one of the preceding daims 20 to 2415 inclusive, in which at least one of Rp Rg, R4 and R5 is a fluorinated C-j-Cg alkyl group.

26. Use as claimed in Claim 20, in which the active agent is 'T ‘ selected from the group including formamide, methyl formamide,dimethylformamide, acetamide, methylacetamide, dimethylacetamide, 20 diethylacetamide, isopropylacetamide, diisopropylacetamide, N-acetylpiperidine, N(/?-hydroxyethyl) acetamide, N,N-di(/?-hydroxyethyl)acetamide, N-acetylmorpholine, acrylamide, propionamide, N- 011549 37 fluoromethyl-N-methyl-formamide, dimethylsulphoxide and mixtures ofa.ny two or more thereof.

27. Use as claimed in claim 26, in which the active agent is dimethylformamide C3H7NO (DMF).

28. Use as claimed in claim 26, in which the active agent is N- fluoromethyl-/V-methylformamide.

29. Use as claimed in claim 26, in which the active agent isdimethylsulphoxide (DMSO).

30. Use of a substance or composition in the manufacture of a10 médicament or préparation for the treatment of cancer, rheumatoid arthritis, wasting syndrome diseases, immunomodulatory relateddiseases, sugar diabètes mellitus 1 or 2 or hepatitis A, B or C, thesubstance or composition comprising an active therapeutic agentselected from the group which includes amides of the general formula 15 Rg-CO-NR-j R2, in which R-^ and R2 are independently selected from the group including H,Me, halomethyl, saturated and unsaturated C2-C3 alkyl groups, saturatedand unsaturated halogenated C2-C3 alkyl groups, hydroxylated alkylgroups; or 20 R^ and R2 are together selected from (CH2) n, wherein n = 4 or 5, or are together R3 is selected from H, Me and saturated and unsaturated C2-C3alkyl groups; dialkylsulphoxidesof thegeneralformula R4R5SO, and mixtures thereof. 011549 38

31. Use as claimed in claim 30, in which at least one of R-j andβρ is a methyl group.

32. Use as claimed in claim 30 or claim 31, in which at least oneof R4 and Rg is a methyl group.

33. Use as claimed in any one of the preceding daims 30 to 32 inclusive, in which at least one of Rp R£, R4 and Rg is a fluorinatedCpCg alkyl group.

34. Use as claimed in Claim 30, in which the active agent isselected from the group including formamide, methyl formamide, 10 dimethylformamide, acetamide, methylacetamide, dimethylacetamide,diethylacetamide, isopropylacetamide, diisopropylacetamide, N- acetylpiperidine, N(/?-hydroxyethyl) acetamide, N,N-di(/?-hydroxyethyl)acetamide, N-acetylmorpholine, acrylamide, propionamide, N- fluoromethyl-N-methyl-formamide, dimethylsulphoxide and mixtures of 15 any two or more thereof.

35. Use as claimed in claim 34, in which the active agent isdimethylformamide C3H-7NO (DMF).

36. Use as claimed in claim 34, in which the active agent is N-fluoromethyl-/V-methylformamide.

37. Use as claimed in claim 34, in which the active agent is dimethylsulphoxide (DMSO). 011549 39

38. A dosage form for the treatment of cancer, rheumatoidarthritis, wasting syndrome diseases, immunomodulatory relateddiseases, sugar diabètes mellitus 1 or 2 or hepatitis A, B or C,whichcomprises topical application means on which is adsorbed or absorbed 5 an effective amount of an active therapeutic agent which includes asubstance or composition as claimed in any one of daims 1 to 11inclusive.

39. A dosage form as claimed in claim 38, in which the topicalapplication means comprises a body of a synthetic polymeric matériel on 10 which the active therapeutic agent is adsorbed or absorbed.

40. A dosage form as claimed in claim 39, which includes DMFadmixed with Silicon dioxide to form a gel with which the patch isimpregnated.

41. A subtance or composition as claimed in Claim 1, sustantially15 as herein described and illustrated.

42. A new substance or composition substantially as hereindescribed.

43. A new method of making a médicament as claimed in Claim12, substantially as herein described and illustrated. 20

44. A new method of making a médicament substantially as herein described. 011549 40

45. Use of a médicament or préparation as claimed in Claim 20,substantially as herein described and illustrated.

46. A new use of a médicament or préparation substantially asherein described.

47. Use of a substance or composition in the manufacture of a médicament as claimed in Claim 30, substantially as herein described andillustrated.

48. A new use of a substance or composition in the manufacture of a médicament substantially as herein described. 10

49. A dosage form for the treatment of cancer as claimed in Claim 38, substantially as herein described and illustrated.

50. A new dosage form for the treatment of cancer substantially as herein described and illustrated.