GB2352971A - Transdermal administration of pharmaceuticals in prostate cancer and genito-urinary treatment - Google Patents

Abstract

A transdermal delivery system is used to deliver drugs eg. yohimbine used in the treatment of prostate cancer and in genito-urinary medicine such as the treatment of erectile dysfunction. The drug is administered via the intact skin of the penis for direct delivery to the blood and lymphatic system. In an alternative embodiment, an incision is made in the scrotal sac and the transdermal device inserted to administer the drug directly to the testes.

Description

I 2352971

SPECIFICATION:

NOVEL ADMINISTRATION IN PROSTATE CANCER AND IN GENITO - URINARY PHARMACY.

TECHNICAL FIELD: This invention relates to an administration novel in the treatment of prostate cancer andequally novel in genito- urinary pharmacy.

BACKGROUND ART: Prostate cancer is one of the biggest killers among men in the world. In Britain, it is estimated it will kill more than 9600 men this year. In the United States, it will strike an estimated 184,500 man this year proving fatal in 39,200 cases. Thus, the case is one of a worthy worry. It ranks second on a worldwide scale as the leading cancer killer of men behind lung cancer.In young men, the tiny gland-typically functions without mishap except for the occasion urijary tract infections and prostatis both treatable with antibiotics. But, as men approach middle age, the prostate begins to grow larger. This normally occurs in nearly 20 per cent of men before the age of fifty, and in nearly all men, in varying degrees and beyond that age. This disorder is prevalent in those older than sixty-five. The origin of prostate cancer is still somewhat controversial. It is cited in some documents that hormonal changes is probably responsible as one ages, but no one knows for sure. Newer publications suggest a genetic dimension. It was reported that Brothers and --g.,,iis of women who have breast cancer or who carry a mutant form of the BRCA-l gene which has been linked to breast cancer have a somewhat elevated risk. It was also reported that the inheritance of an abnormal form of the HPCI- Human Prostate Cancer: 1 - gene seems to contribute to some prostate cancer.. Symptoms seem to present itself as follows. Pressing against the urethra, the enlatged prostate can slow urination to dribbles, causing burning and infection, and leaving a m4n. feeling he hasnot quite emptied his bladder. These symptoms normally denote a common non cancerous condition called BENIGN PROSTATIC HYPERPLASIA (B.P.H). The facts still remains of prostate cancer that if diagnosed and treated while still contained within the gland the malignancy is more likely to be cyrable. It is reported that upoto eighty per cent of such early cancers show no progression five years after treatment. If the malignancy is not detected before it spread to bones, lymph nodes brain, lungs or other tissues as happens at least fifty to sixty per cent of the time, it is not usually curable. Detecting and treating prostate cancer thus seem highly important for a disease which claims many lives each year. Screening tests for detecting microscopic prostate cancer have also been widely reported based on the measurement of the level of prostate specific antigen (PSA), a protein released by prostate cells. However as normal and malignant prostate cells secrete this substance, PSA TEST is not particularly specific. Elevated PSA level is perhaps indicative that the prostate gland is cancerous but not conclusive as about twentyfive per cent of men with cancer will have normal PSA levels. Other test like RECTAL EXAMINATION only identifies tumour

2- at a macroscopic level. The Prostatic Intraepithelial Neoplasia (PIN) is widely reported and is helpful in warning that prostate cancer maybe developing but albeit is only app-licable after a PSA test has prompted a biopsy. PIN-.'..is sometimes thought a precursor of prostate cancer. Genetic screening tests for prostat e cancer susceptibility is still to come. In treating cancer of the prostate, it is often wise to note the stages of spread to determine what sort of treatment is thought best. The TNM approach assigns the original tumour (T) to one of four stages (and to sub-stages within those categories).

I T1- a designation indicating the tumour is microscopic and and cannot be felt on rectal examination.

T2- tumours that are palpated but contained within gland.

T3- cancers that have pushed beyond the prostate into surrounding tissues including semen-storing structures.

T4- tumaut-5 have extended still further.

Ir) the assignation and treatment of a prostatic condition thus, a stage has to be defiried. Stage T 1 or T2 should be curable by krostatectomy, a surgery to remove prostate. Radiation to destroy tumour or combined radiation with systematic hormonal therapy might also be appropriate It may be a surgical approach to stop the body from making androgens or to blo'c_lk androgen action in prostate cells. Surgery however is still considered standard for organ confined disease. At T3 or T4 stages, the surgical removal of the gland usually cannot eradicate the entire tumour. Prostatectomy is often carried out when the: size is that compara ble to a small marble rather than the size of a pea. This treatment carries the risk of impotence and occasionally incontinence. A nerve spaRiiig' technique developed in the US makes it possible in sixty to seventy-five per cent to save vital penile nerves further reducing the chances of incontinence and preservinp,, potency with erection and orgasjii-.but no ejacuiation If the patient wants to father children, ejaculate can be frozen in a sperm bank before surgery. Cryosurgery is also widely reportedly use. A NEW ALTERNATIVE developed involves the killing of cells, cancerous cells by freezing with a metal probe cooled by liquid nitrogen to minus 195 degrees' centigrade. The whole procedure takes around two hours and involves no major incision. SPotting metastases can also be done by COMPUTED TOMOGRAPHY ((.T) scans which reveals abnormalities so does the radionuclide bone scan and magnetic resonance spectroscopy which informs of growth of tumour past the prostate gland. Another form of radiation therapy is BRACHYTHERAPY in which radioactive rice-size pellets are put directly into the prostate where they emit radiation from w-'hln the gland.

The risks associated with whatever sort of treatment prescribed has to be borne in mind by the patient. In some cases, it might be the risk of MILD to SEVERE INCONTINENCE it might be the risk of impotence or even loss of lives.

it DISCLOSURE OF THE INVENTION:............................. This invention presents another dimension in prostate cancer and in genito-urinary pharmacy. It presents a transdermal system.-that provides systematic delivery for up to twenty four hours following its application to intact skin. The transdermal system is a multi-layered film containing administrations as the active ingredient. In the delivery utilising transdermal-systems,the rate of release is linearly dependent upon the area of the applied system and energy sources derives from the concentration gradients between the skin of the intact s4rface of application and the concentrations of therapeutics in the system area. TRANSDERMAL SYSTEMS are not altogether new. T!, most popular is the nicotine and nitroglycerine transdermal therapeutic system. In mi.&,vrity is transdermal therapeutic systems of clonidine and of salicyclic acid, The nicotine transdermal therapeutic systems usually consist of (1.) AN OCCLUSIVE BACKING -polyethylene/.Alumil-.ium/polyester and ethylene vinyl acetate co-polymer.

(2.) A DRUG RESERVOIR containing nicotine -in an ethylene-vinyl acetate co-polymer matrix.

(3.) A RATE CONTROLLING MEMBRANE -polyethylene (4.) An ADHESIVE of polyisobutylene (5.) A PROTECTIVE LINER that covers the adhesive -layer and must be removed before application to the skin.

The rate of delivery and administration is reportedly 40ug/cm2-h which is proportional to the surface area. It was reported that 1. 73 per cent of the total amount of nicotine remains in the system twenty four hours after application.

2. The dose of nicotine absorbed from the system represent sixty-eight per cent of the total amount released in twenty fourhours.

3. The other thirty two per cent volatizes from the edge of the system.

DOSE ABSORBED IN 24hours SYSTEM AREA NICOTINE (Mg per day) (cm2) CONTENT (mg) 21 22 114 14 15 78 7 7 36 ---------------------------------------------------------------- In other cases, the dose of nicotine absorbed from another system is approximately 95 per cent of-the amount released in 16 hours.

----------------------------------------------------------------- DOSE ABSORBED SYSTEM AREA NICOTINE CONTENT IN 16 HOURS (cm2) (mg) (MG PER DAY) ----------------------------------------------------------------Treatment Disc 15 30 24.9 lst Weanin Dose 10 20 16.6 2nd Weaning Dose 5 10 8.3 --------------------------- Th-d transdermal delivery system of nitroglycerine is recorded on". one occasion as follows; NITROGLYCERINE TOTAL TRANSDERMAL RATED NITROGLYCERINE SYSTEM SIZE RELEASE INVIVO IN SYSTEM ------ -------------------------- O.lmg per hr 12.5mg 5cm2 0.2mg per hr 25.Omg 10cm2 0.4mg per hr 50.Omg 20cm2 0.6mg per hr 75.Omg 30cm2 ----------- ------------------------------- In another,reportings.. are as follows; -----------------------------------------------------------TRANSDERMAL SYSTEM NITROGLYCERIN CONTENT SYSTEM SIZE ------------------------------------------------------------- 0.2mg per hr 16mg 8cm2 0.3mg per hr 24mg 12cm2 0.4mg per hr 32mg 16cm2 ------------------------------------------------------------- It is thus reasonable to believe that the rate of absorption from patches may vary with site of aplication but this has not been adequately studied. It is altogether satisfactor to state that the rate of absorption is comparable on intact skin For the delivery of clonidine, reportings are as follows; PROGRAMMED DELIVERY CLONIDINE SIZE CLONIDINE INVIVO PER DAY OVER I WEEK O.lmg 2.5mg 3.5cm2 0.2mg 5.Omg 7.Ocm2 0.3mg 7.5mg 10.5cm2 --------------------------------------------------------- The energy source for drug release derives from the concentration of varying gradients, existing between a saturated solution of drug in the system and the much lower concentration prevailing in the skin. Clonidine flows in the direction of the lower concentration at a constant rate, limited by the rate-controlling membrane so long as the saturated solution is maintained in the drug reservoir.

For trans-ver-sal and trans-planar wart remover dermal patch delivery system, an eight hour treatment period of sustaine d controlled release programmme is designed.

GENITO - URINARY PHARMACOLOGY The genito- urinary pharmaceuticals present one of the biggest important categories in world pharmacy. Amongst classes which presents itself are: (1.)- URINARY ANTI-INFECTIVES AND ANALGESICS COMBINATION (2.) URINARY TRACT AGENTS (3.) UROLOGICAL STIMULANTS, as distintive groupings.

Most administrations in genito-urinary are oral preparations.

Note is made of the oral AZOGANTANOL which is a combination drug of antibacteriaL SULFAMETHOXAZOLE with the local urinary analgesic activity of phenazo pyridine hydrochloride. Each tablet contains O.5Gm sulfamethoxazole and 100mg phenazopyridine hydrochloride.

Sulfonamides exist in blood as free conjugated and protein bound forms.Excretion of the sulfonamides is chiefly by the kidneys with glomerular filteration as the primary mechanism.

Others include rapidly GEOCILLIN which has clinical efficacy in urinary infections due to E.Coli, P.Mirabilis, P.Vulgaris and many more due to high urine levels.

HIPREX for the long term urinary tract therapy, MACRODANTIN available in 25,50 and 100mg oral administration, MANDELAMINE granules rapidly absorbed but inactive until it excreted by the kidney and concentrated in the urine.

NOROXIN which is anti-bacterial in outlook attain a urinary concentration of 200mrg per ml or more in the urine two or three hours after a single 400mg dose. Mean concentrations of various fluids and tissues are as follows; RENAL PARENCHYMA 7Ug.'per g TESTICLE 1.6Ug per g PROSTATE 2.5 Ug per g SEMINAL FLUID 3.7Ug per g UTERUS/CERVIX 3.OUg per g VAGINA -4.3Ug per g FALLOPIAN TUBE 1.9Ug per g BILE 6.9Ug per g Noraxin is indicated for urinary tract infections and sexual transmitted disease those of uncomplicated urethral and cervical gonorrhea and resulting in Neisseria Gonorrhoeae.

Pyridium -phenazopyridine hydrochloride is excreted in the -7 urine where it exerts a topical analgesic effect on the mucosa of the urinary tract. Rimso-50 is sterile and pyrogen free dimethyl sulfoxide. Instillation of rimso-50 directly into the bladder maybe accomplished by catheter or asepto syringe and allowed to remain for 15 minutes. Apply analgesics gel such as lidocaine jelly to the urethra prior to insertion of the catheter to avoid spasm. The oral'. tablet of THIOSULFUL FORTE is also indicated for use in the treatment of urinary tract infections associated with pyelonephritis, pyelitis and cystitis URISED is a purple round sugar coated tablet for oral admini stration It is a combination of antisaeptics and parasympath..- olytics and is indicated for the relief of discomfort of the lower urinary tract caused by hypermotility resulting from inflammation or dignostic procedures. UROQID ACID containing methanamine, mandelate 350mg and sodium acid phosphate mono hydrate 200mg. It is indicated for the suppression or eliminatio n of bacteriuria associated with chronic and recurrent infections of the urinary tract, another worthy of mentionir-,,-, is UROBIOTIC ACIDCAPSULE CONTAINING OXYTETRACYCLINE HYDROCHLORIDE equivalent of 250- mg oxytetracycline and sulfamethizole of 250mg and phe nazopyridine hydrochloride 50mg.

Amongst therapeutics which serves rightfully as URINARY TRACT AGENTS are the followings; K PHOS NEUTRAL, BICITRA, POLYCITRA TRICITRATES !AL SOLUTION GANTANOL of sulfa - 0 methoxazole tablets and suspension, GANTRISIN, RACROBID of nitrofurantoin monohydrate maxaquin of film coated lomefloxacin hydrochloride, neg-gram of nalidixic acid, NEOSPORIN, A G.U irrigant PROLOPRIM of 100 mg and 200mg trimethoprim,..TRIMPEX, POLYCITRAK AND ZYLOPRIM of 100mg and 200mg scored tablet of Allopurinol.CYSTospaz, ditropan, levsin, proscar of finasteride composition.

M.c.,.st of the therapeutics which are listed as URINARY TRACT AGENTS possess amongst compositions SODIUM PHOSPHATE OR SODIUM CITRATE. Indication is for use in cases where increase in URINARY PHOSPHATE and for conditions requiring long term maintenance of an alkaline urine as in patients where the dissolution and control of uric acid and cystine calculi of the urinary tract is indicated especially when the administration of the potassium salts is undesirable or contra-indicat ed. MACROBID NITROFURANTOIN MONOHYDRATE is an antibacterial agent specific for urinary tract infections. It contains 100mg of nitrofurantoin in the form of 25mg of nitrofurantoin nonohydrate and is indicated in the tre,. atment of pyelonephritis or perinephric abscesses. Neosporin is a concentrated sterile antibiotic solution to be diluted for urinary bladder irrigation designed to be used with a "three way " catheters with other sys tems permitting continous irrigation of the urinary bladder.

ZYLOPRIM tablets acts on purine catabolism without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reaction immediately preceeding its formation. Indicated for use in patients to reduce the serum and urinary acid concentration. CYSTOPAZ Is for disorders of th--n- lower urinary tract associated with hypermotility. DITROPAN is for use in patient with uninhibit ed neurogenic or reflex neurogenic bladder (i.e urgency, frequency, urinary leakage, urge incontinence, and dysuris). PROSCAR tablet is meant for the treatment of SYMPTOMATIC BENIGN HYPERPLASIA. (BPH). Effects are increase in urinary flow and improvement in symptoms of BPH when treated with pro;&car for twelve months.. -Regression of enlarged prostate gland is noticed. Tinasteride is a specific inhibitor of steroid 5 alpha - reductase, an enzyme that converts testorone into the potent androgen 5-alpha dihydrotesterone (DHT). A Characteristic therapeutics which perhaps carry the label or categories rather well under the UROLOGICAL STIMULANTS is -.- the DAYTO HIMBIN TABLETS of yohimbine Hydrochloride 5.4mg primarily an alpha 2 adrenergic blocker which blocks alpha 2 adrenoreceptors. By clinical pharmacology, the activity of DAYTO - HIMBIN could be explained as its ability to, by its peripheral autonomous system effett to increase cholinergic and decrease adrenergic activity. Theoretically, increase in penile blood:i.nflow, decrease in penile blood outflow or both.. results since in the male sexual perfomance, erection is linked to cholinergic activity causing erectile stimulation without increasing libido. It is indicated as a mydriatic and sympathicolytic agent With dayton-himbin, male sexual dysfunction has been successfully treated with patients with psychogenic. vascular or diabetic origin. Doses were of the order 18mg per day. Urologi-sts use yohimbine experimentally in the treatment and/or diagnostic classification of certain types of male ERECTILE DYSFUNCTION. Late arrivals to themarket is VIAGRA, another oral ta7)let with claims of an average 80 per cent improvement in ERECTILE FUNCTION.. Reportings were of the notion that if swallowed an hour before sexual intercourse, it boosts the natural process by which the.-arteries of the penis dilate, increases the blood flow in the right places and produces what doctors call " a penile engorgement". The impotence remedies of VIAGRA is due to its blocking an enzyme in the penis called PDE5 which breaks down a molecule called cGMP. This molecule is essential for maintaining an erection because it rela xes the muscles in the blood vessels that serves the penis allowing blood to flow into ERECTILE TISSUE. The active ingredient is SILDENAFIL CITRATE. It is industrial knowledge that there are around 30M impotent men in the United States and 140M worldwide.

GENITO-URINARY ADMINISTRATIONS; u f thi w and especially in therapeutic As cited in h of the urinary anti-infectives and analgesics, urinary tract agen ts and more importantly in administrations of urological stimulan ts, a great deal of administration s of urological stimulants are oral tablets with great intestinal absorption that after a co uple of hours of swallowing a dose, urinary concentrations are a ttained in the urine after excr-etion by the kidney. In the blood most administrations exist after rapid absorption as UNBOUND, PROTEIN BOUND, METABOLISED AND IN CONJUGATED FORM. While treatmen t of prostate cancer is possible with oral PROSCAR tablet of finasteride composition and indeed serves symptomatic BENIGN PROSTATIC HYPERPLASIA (BPH) quite well, this is oniy one stage of prostate cancer. Proscar haS b6in reported to regress enlarge prostate gland. At T2, T3, and T4 and perhaps metastasized stages such regresssion is not always possible and treatment such as prostatectomy, surgery radiation, hormonal therapy, chemotherapy cryogenics or even nutritional therapy may play a role in prevent ing prostate cancer, the second biggest killer of men, apart from lung cance'r, It is equally worth noting that 5.4mg of yohimbine hydrochloride in dayto- himbin tablet equally gets readily adsorbed. An administration of one tablet three times a day has been reported in the treatment of male ERECTILE DYSFUNCTION. Mode of action is that an alpha 2 adrenergic blocker which blocks alpha 2 adrenoreceptors is responsible. Its peri- pheral autonomic nervous system is to increase cholinergic ( CHOLINERGIC ACTIVITY IS LINKED T.G.ERECTION) and decrease adrenergic activity It is reported that male sexual dysfunction has been reportedly been administered and treated with 18mg per day. Viagra has also reportedly been administered in IMPOTENCE TREATME NT and especially for::ERECTILE FUNCTIONS. It thus seem that some form oof prostate cancer symptomatic BPH is treateable orally and impotence and erectile dysfunction are also cared for by oral administrations of viagra and dayto-himbin tablet respectively.

C2 The mammalian urinary system cannot be described without referenc e to the kidneys in relation to the important fufictions of EXCRETION AND HOMEOSTASIS. Each kidney receives blood from-the general circulation through a RENAL ARTERY and is drained of blood by a capillary network which surrounds numerous microscopic urinary tubules call ed nephrons. The n,-phrons remove excess and unwanted materials fr om the blood. The excretox.y products cG-llect as urine which passes from the kidneys.throu; yh the ureters. Urine is stored temporarily i n the urinary bladder before it is eliminated from the body. The autonc)'mic nervous system controls micturition- emptying of the bladder. The exit from the bladder into the urethra is closed by a ring of muscle called the bladder sphincter. Simultaneous contraction of the smooth muscle in the bladder walls forces the urine out through the urethra. Among functions of nephrons and there are about a million in each human kidney is the ULTRAFILTERATION of blood brought to the Bowmans' capsule by arteries and secondly is REABSORPTION of substances at a rate to maintain normal concentration in the blood. The efficiency of reabsorption is helped by the presence of numer.ous microvilli which greatly enlarge the surface area through which the the materials pass. THE ABSORPTION of genito- urinary therapeutics through the small intestines to blood and journey eventually through kidney to the urethra is an important concept genito- urihary pharmacology as control is necessary over the ALKALINITY and ACIDITY of urine and of URETHRA concentrations and compositions at large.

INDUSTkIAL APPLICABILITY:

-------------------------- The administration in prostate cancer and in genitourinary pharmacy and therapeutics is hereby communicated. It presents a traosdermal delivery system consisting of multilayer film cont,':.Lning administrations as active ingredients with respect t.o prostate cancer treatment and genitourinary pharmaceuticals, it is altogether known that in transdermal delivery, the rate upon which contents are delivered is linearly dependent upon the area of the applied system and the delivery is equally dependent on the driving mechanis,d'which is one of a concentration gradient dependence between the multi-layer film containing treatments and the intact skin. IT is equally reasonable to believe that the rate of absorption from transdermal patches vary with SITE OF APPLICATION., BUT THIS HAS NOT BEEN ADEQUATELY STUDIED.

In genito-urinary pharmaceuticals at large and focusing on important classes of therapeutics in categories such as; 1. urinary anti-infectives and analgesics 2.urinary tract agents 3. urological stimulants Oral and capsular tabulations seems to suggest doses of 25, 50, and 100 mg of active in'redients or more in combination therapy. Of this, a urinary concentration of 200mgg per ml or more is seen in the case of NOROXIN two or more hours after a single 400mg per dose. Mean concentration of various fluids and tissues are as follows; RENAL PARENCHYMA: 7.3Ug per g PROSTATE: 2,5Ug per g TESTICLE: b6Ug per g SEMINAL FLUIDS: 3.7Ug per g UTERUS/CERVIX: 3.0 Ug per g VAGINA; 4.3 Ug per g FALLOPIAN tube: 1.9Ug per g BILE: 6.9U,g per UL MACRO BID contains 100mg of nitrofurantoin in the form of 25mg of nitrofurantoin monohydrate. Urological stimulant DAYTO HIMBIN tablet of yohimbine hydrochloride per tablet. It is expected that for a patient with mAle sexual dysfunction, doses recommended would be of the order of 18mg per day.

The following tables show the suitability of transdermal delivery system for prostate cancer administration and in genitourinary pharmacy; DOSE ABSORBED IN 24HRS SYSTEM AREA TOTAL CONTENT I -------------- 21mg per day 22cm2 114mg 14mg per day 15cm2 78mg 7mg per day 7cm2- 36mg ----------------------------------------------------------- DOSE ABSORBED SYSTEM AREA TOTAL CONTENT IN 16HRS ------------------- Treatment Disc 15mg/day 30cm2 24.9mg ist weaning dose 10mg/DAY 20cm2 16.6mg 2nd weaning dose 5mg/day 10cm2 8.3mg RELEASE RATEINVIVO TOTAL IN SYSTEM SYSTEM SIZE ----------- 0.2 mg per hr 16mg 8cm2 0.3 mg per hr 24mg 12cm2 0.4mg per hr 32mg 16cm2 ---------- COMPOSITION DELIVERY TOTAL IN SYSTEM SIZE SYSTEM --------------------------------------------------------------- O.lmg per hr 12,5mg 5cm2 0.2mg per hr 25mg 10cm2 0.4mg per hr 50,y 20cm2 0.6mg per hr 75mg 30cm2 ----------------------------------------------------------------PROGRAMMED DELIVERY COMPOSITION DOSE SIZE IN VIVO PER DAY OVER 1 WEEK 0. 1mg 2. 5mg 3. 5cm2 0.2mg 5.Omg T.Ocm2 0.3mg 7.5mg 10.5cm2 I IN From table 1., it thus seem that an oral administration of 18mg per day of DAYTO HIMBIN containing a 5.4mg of yohimbine hydrochloride can be delivered by a transdermal system as typified of system in the table. A possible 21 mg per day is possibl e theoretically and experimentally proven. In table 2, it shows that the dose can be reduced or even lowered In table 3, a rate releasing dimension is programmed to deliver at wanted pace of 0.3, 0.4,mg per hour and even lower, and to higher releasing rates up to 0.6mg per hour in tables 4 and 5.

It thus seem evidential that a medium is presented as effective as oral admini stration delivering similar or more dosage of therapeutics and as therapeutics is not subjected to the the alimentary canal, less side effect not only presents itself but in combination with contra-indication is the novelty.

TRANSDERMAL THERAPEUTICS DELIVERY SYSTEM FOR PROSTATE CANCER, GENITO URINARY PHARMACEUTICAL ADMINISTRATION AND URO-GENITAT SYSTEM IN MAN.

14, PROSTATE CANCER ADMINISTRATION ------ ----- - The mean concentration in the prostate is the sum recorded of 2.5Ug per g two or three hours after a single 400mg dose, of NOROXIN is swallowed. Noroxin is indicated for urinary tract infections and sexual transmitted disease especially those of uncomplicated urethral and crevical gonorrhae due to Neisseria Gonorrhoeae.

With PROSCAR administration orally, clinical pharmacokinetics require the administration of 5mg once a day and changes is seen in prostate volume and inr-rease in urinary flow rate (mL PER Sec) also noticed.Proscar is indicated for symptomatic Benign Prostatic Hyperplasia (BPH).

It is the essence of this communication to describe delivery mechanisms to the prostate via a transdermal therapeutic controlled release multi- layer film patch, for quantity administration of the order of 1 to X where X mg is the maximum dosage recommended for delivery of therapeutics in controlled sequences and programmed delivery as 0.1, 0.2, 0.3, 0.4, 0. 5, 0.6,0.7, mg per hour or more as the case maybe. THE THERAPEUTICS ARE DELIVERE D UNTO ARTERIES AND BLOOD VESSELS, that serve the penis and in programmed delivery cycle for circulation. The prostate is reddish-pink and well served in circulation. It weighs about three-quarterg of an ounce. The soft tissued gland nestles in the lower abdomen below the bladder. The prostate encircles half an inch of the delicate urethra, that channels urine and during intercourse, male ejaculate to the penis. The prostate contributes enzymes, proteins,sugar and fats to the seminal fluid to nourish millions of sperm from the testicles. The prpstate is thus well served by a medium of travel through the blood or ly mphatic circulation. IT should be emphasised that it is through this sameMEDIUM that metastases, which are tumours migrate to distant sites and proliferate at those sites. A medium of therapy is thus presented.

A!.-transdermal therapeutic delivery system is thus presented for use on intact skin and for delivery unto prostate gland via a medium of travel, blood or lymphatic circulation via arteries and blood vessels; serving the region and inter-connected throughout the whole human body. The delivery unto prostate gland via the blood and lymphatic circulation via the intact skin that serves the penis is not only QUICKER as minute quantities are introduced on an hourly basis and as much as its wanted, the prostate situated in the vicinity of virtually every organ than makes up the uro-genital system in man and connected to arteries and lymph nodes making up the blood and lymphatic circulatory system. An appreciation of how far the prostate gland is, is reassured by the fact that it can be touched by a surgeon through the RECTUM.

GENITO-URINARY PHARMACEUTICAL ADMINISTRATION Having thus described administration for prostate cancer, it remains for me to furnish you withthe scope of application of this invention. In line with the administration of DAYTO HIMBI N and VIAGRA, an application in context, is the treatment o ERECTILE DYSFUNCTION. The erectile tissue lay beneath the intact skin covering.,the penis, and is well served by blood vessels. Maintenance of an erection is due to certain molecules which relaxes muscles in the blood vessels. This can be delivered via flow unto erectile tissue. Molecules of the likes of SILDENAFIL CITRATE, active ingredient thus come into mind. So does the molecules which makes the arteries dilate, increasing the blood flow in the right places. Even th.ough it has been reported oral administration in the treatment of impotence proving efficient and providing a cure, the clinical pharmacokinetics still has to be laid out very clearly. Viagra is indicated for use as an impotence therapeutic. Its impotence remedies is alledged due to its blocking an enzyme in the penis called PDE5 which breaks down a molecules called cGMP WHICH is responsible for erectile function. One would have rather put a remedy factor on CURING IMPOTENCE if it leads to more production of sperm in the,ttibules, the seminiferous tubules which is seen as very fine, highly coiled tubules under a microscope and not necessarily on maintaining an erection ' The semiibiferous tubules are continous with other tubules called the VASA EFFERENTIA, EPIDIDYMES AND VASA DIFERENTIA. The sperm travel through the system of tubules on their way to the seminal vesicles, where they are stored before passing out of the body through the urethra. The walls of the seminiferou s tubules consist of a layer of cells called the germinal epithelium from which sperm originate. Sperm at different stages of development are found inside the seminiferous tubules.

16 As they mature, the sperm become attached to the relatively large sertoli cells. The tubules are held together by connective tissue which contains INTERSTITIAL (leydig) cells, nerve fibres blood and lymph capillaries While the issue of impotence and rectification of impotence can be addressed, it would have to be one in which certain administrations induce more production of sperm in the seminiferous tibbule and testis at large. As transdermal delivery is meant for intact skin, it would not altogether be suitable for the scrotal sac due to its non intact nature. One would be confined to ISOLATE the testis in which case, an incision would be necessary, and the testis subjected to inductiom:.of a transdermal nature and administratio.n for a period of time for necessary rectification to be made, and then returned and sewn up. Other forms of induction might be employed for the purpose of producing more sperm and in conjunction with methodology as described herein as part of this patent for the RECTIFICATION OF ERECTILE DYSFUNCTI-ON, a means of impotence treatment and administration is presented. And employed. And foreseen. It is worthwhile communicating that in alliance; VASODILATION OF ERECTILE TISSUE OF GENITALIA IS A PARASYMPATHETIC EFFECT OF THE AUTOMOUS NERVOUS SYSTEM AND MEDICINALLY INDUCE-ABLE The benefits in novel administration in ?ROSTATE CANCER and in genito- urinary pharmaceutical administration via a transdermal delivery system, as made known, in this system is the risk of impotence and incontinence due to surgical removal of the gland malignant, a process popularised likewise and glamourised PROSTATECTOMY - or from radiation, hormonal therapy or chemotherapy can be minised and/or aviided.

It should be borne in miriw'-that an order of 9600 British men die yearly and in the United States 184000 suffer fatalities with mortality unavoidable of 39200 A new method is thus presented requiring no major incision like many other treatment methodology, apart from the sole purpose of seminiferous tubular induction by mannerisms as contained herein as part of this work, albeit for administrations in the treatment of impotence and in the main stream of this invention, for administration in PROSTATE CANCER TREATMENT and in GENITO-URINARY PHARMACIES.

Claims (7)

1. CLAIMS: 1. A method of admoinistration in the treatment of prostate cancer

   and in genito-urinary administrations comprising the controlled programmed delivery of compositions invivo at the rate of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, mg per hour in a composition dose of 2,5, 5.0, 7.5, 12.5, 25, 50,and 75mg present in a composition size of systems area 3.5, 7.0, 10.5, 20, 30,or larger for multiple weaning dosage delivery unto larger systems in cm2. of composition absorbed of 5,7 10,15, 21 mg per day through intact skin of the penis for delivery unto blood and lymphatic circulatory systems of arteries, vessel and nodes respectively via a multiple layer transdermal therapeutic system.
2. 2. A method of administration as claimed in 1. above wherein delivery is unto the blood network of the reddish-pink prostate gland.
3. 3. A method of administration as claimed in 1. and 2. wherein composition and administration is suitable for vasodilation of erectile tissue via parasympathetic functioning of the autonomous nervous system.
4. 4. A method of administration as claimed in 1, 2, and 3 above wherein administration is delivered at a rate which is controlled and via mechanism unto the uro- genital system of man and peripheral of the uro-genital system.
5. 5. A method of administration as claimed in 1,2,3 and 4 wherein procedure requires no incision in the administration of prostate cancer and in genito-urinary treatment.
6. 6. A method of administration in the treatment of IMPOTENCE per se requiring the isolation of'.the testis by incisi6n, induction ofthe testis by transdermal delivery syste m or otherwise for the rectification of the ability to produce more sperm, a process hereby referred to as SEMINIFEROUS TUBULAR INDUCTION, RETURN OF THE INDUCED TESTIS, and delivery unto erectile tissue for dilation via parasympathetic effect of the autonomous nervous system by a method of administration as claimed in claims 1,2,3,4 and 5.
7. 7. A method of administration in the treatment of PROSTATE CANCER as claimed in claims 1, 2,3,4 and 5 wherein method of treatment and channel of avenue is via a medium of travel - the blood and lymphatic systems of circulation which happens to be the mode of transmission and spread of cancerous cells and tumour from stage Tl wherein microscopic tumour is confined to prostate gland to T2 still confined to prostate gland to T3 expanding beyond the prostate to T4 whereby the tumour is fixed and has movedbeyond the prostate into adjacent structures, to metastatic cancer where tumour has spread to pelvic lymph nodes,beyond lymph nodes and eventually to D3 wherein tumour has become resistant to hormonal therapy.

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