EP1214038A2 - Methodes et compositions pour prevenir et traiter les troubles de la prostate - Google Patents

Methodes et compositions pour prevenir et traiter les troubles de la prostate

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Publication number
EP1214038A2
EP1214038A2 EP00961680A EP00961680A EP1214038A2 EP 1214038 A2 EP1214038 A2 EP 1214038A2 EP 00961680 A EP00961680 A EP 00961680A EP 00961680 A EP00961680 A EP 00961680A EP 1214038 A2 EP1214038 A2 EP 1214038A2
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Prior art keywords
therapeutic compound
prostaglandin
prostate
urethra
alpha
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EP00961680A
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German (de)
English (en)
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Gary W. Neal
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Androsolutions Inc
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Androsolutions Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/08—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of suppositories or sticks

Definitions

  • the present invention generally relates to novel compositions, methods, devices and kits for the prevention and/or treatment of prostate disorders in mammals.
  • the present invention also generally relates to devices for the administration of therapeutic compounds to mucosal membranes in the lower urinary tract of mammals.
  • BPH benign prostatic hypertrophy
  • CaP carcinoma of the prostate
  • prostadynia prostatitis
  • chronic prostatitis are common maladies of male mammals, especially men. They include benign prostatic hypertrophy (BPH), carcinoma of the prostate (CaP), prostadynia, prostatitis, and chronic prostatitis.
  • the bladder serves as a storage vessel for urine produced by the kidneys until the mammal desires to eliminate the urine by voiding.
  • the urethra is a tube or conduit through which urine flows from the bladder to the exterior of the mammal.
  • the urethra is composed of three main divisions - the prostatic, the membranous and the penile segments (FIG. 1).
  • e prostate g an encases t e uret ra as t ex ts t e a er.
  • BPH causes obstruction to the flow of urine by two major mechanisms that are distinct components - a static (fixed) component due to the hypertrophied prostate tissue and a dynamic component due to excessive tone in the smooth muscle tissues of the prostate. Both of these mechanisms cause compression and obstruction of the urinary outflow tract.
  • the pathophysiology of BPH involves hypertrophy of the glandular and stromal tissue of the peripheral zone of the prostate and the periurethral area that surrounds the urethra (see FIG. 2) leading to narrowing of the lumen and mechanical obstruction of the urinary outflow tract.
  • Pathology findings on prostate tissue from patients with BPH include fibrosis and hyperplasia of the musculature and gland structure of the prostate.
  • a graph of urine flow versus time is produced and the patient's urine flow measurements may then be compared to population derived average urine flow measurements.
  • More complex urodynamics studies measure pressures produced by contraction of the bladder muscles during urination.
  • One measure of the degree of urinary tract obstruction is the maximum or peak urinary flow rate as measured by urodynamics studies.
  • FIG. 3 shows typical urodynamics studies. Peak urinary flow rates of less than 15 milliliters (mis) per second indicate significant urinary obstruction and flow rates of less than 5 mis/second are felt to be an indication for prompt surgical relief of the obstruction.
  • Prostate specific antigen is a serum protease that is widely used as an indicator of disease severity in both BPH and CaP. Not only are prostatic tissues the only source of PSA but serum PSA levels closely correlate with the total amount of prostate tissue present in the body at any given time. Treatments that reduce the tumor mass in CaP or that induce regression of BPH will demonstrate a reduction in serum levels of PSA.
  • BPH Treatment of BPH with alpha-adrenergic blocking agents is believed to exert beneficial effects by reducing the adrenergic tone of the smooth muscle cells in the prostate via the alpha- 1 receptors.
  • Excessive alpha adrenergic tone in the prostatic smooth muscle cells results in a reversible narrowing of the diameter of the urinary outflow tract as it courses through the prostate.
  • This dynamic component of BPH is believed to be the pathophysiology of BPH in men with small prostates.
  • Oral administration of alpha blockers leading to decreased alpha- 1 adrenergic tone is felt to result in relaxation of prostatic smooth muscle with a resultant functional improvement in obstructive urinary tract symptoms such as hesitation, dribbling and nocturia.
  • Alpha-adrenergic blocking agents are therefore best used in men with small prostates where smooth muscle contraction is likely to be the primary contributor to the obstructive symptoms.
  • a meta-analysis of placebo-controlled studies of alpha blockers shows improvement in the peak urinary flow rates by 1.5 ml/sec (LM Eri et al, "Alpha-blockade in the treatment of symptomatic benign prostatic hypertrophy," J Urol 1995; 154:923-934).
  • Testosterone is converted by 5alpha-reductase into dihydrotestosterone, a compound that stimulates tissue growth in the prostate.
  • This enzyme exists in at least two isoenzyme forms, Type I and Type II.
  • Type I isoenzyme forms
  • Type II isoenzyme forms
  • Finasteride is a drug specifically developed to block the reduction of testosterone to dihydrotestosterone by 5alpha- reductase. Oral administration of finasteride is approved by the FDA as a treatment for the symptoms of BPH. Finasteride has a gradual onset of action resulting in a 70% reduction in serum dihydrotestosterone levels after daily dosing with 5 milligrams. Administration of finasteride for a period of 6-12 months is generally necessary to determine whether a patient with BPH w mprove. Un ortunate y, a m nor ty o a pat ents w t PH mprove on ora finasteride and the degree of improvement is relatively small.
  • Another option that may be suggested for men with BPH is an oral herbal medicine preparation extracted from the saw palmetto (Serenoa repens).
  • This preparation contains a variety of compounds that bind androgen receptors and demonstrate 5alpha-reductase inhibition in vitro. The mechanism of action is complex and may involve other pharmacologic activities.
  • GS Gerber "Saw Palmetto in men with lower urinary tract symptoms:effects on urodynamic parameters and voiding symptoms," Urology 1998 Jun; 51 (6): 1003-7).
  • alpha-adrenergic receptor antagonists may cause a significant decrease in the systolic blood pressure, syncope, orthostatic hypotension, asthenia, dizziness, headache, sleepiness, fatigue and impotence.
  • a recent myocardial infarction, transient ischemic attack or cerebrovascular accident constitute relative contraindications to the use of alpha-blockers.
  • the effect of alpha-blockers is usually apparent in the first two weeks of treatment and maximum clinical effects are seen in one or two months (LM Eri et al, Drugs Aging, op cit).
  • Dihydrotestosterone exerts effects upon most tissues and organs in a male mammal. Thus, reductions in 5alpha-reductase activity systemically must result in other than the desired effects upon the growth of prostatic tissue.
  • Administration of systemic therapy in order to treat the prostate is roughly analogous to painting a house in order to paint the window frame or to spraying a city with pesticides in order to eliminate insects in the city gardens.
  • Surgical treatment of BPH is the most common surgery of men in the developed countries of the world. In 1989, 400,000 men in the US underwent surgery of the prostate at a cost of greater than $3 billion (MA Kortt et al "The economics of benign prostatic hyperplasia treatment: a literature review," Clinical Therapeutics 1996; 18(6): 1227- 1241).
  • the most common prostate surgery involves trans-urethral resection of the prostate (TURP), which is accomplished by resecting the prostatic tissues surrounding the urethra that cause obstruction through a large bore urinary catheter.
  • TURP One prospective randomized study of TURP demonstrated an increase in peak urinary flow of 7.0 ml/sec after surgery (RS Cowles et al "A prospective randomized comparison of TURP to visual laser ablation of the prostate for the treatment of benign prostatic hypertrophy," Urology 1995 Aug; 46(2): 155-600).
  • TURP gives a 4 - 8 times greater increase in peak urinary flow rates than does treatment with alpha blockers and a 9 - 22 times greater increase in peak urinary flow rate when compared to finasteride. This surgical procedure carries the usual attendant health risks of a major operation in addition to the complications of urinary incontinence and impotence.
  • compositions and devices to prevent and treat prostate disorders in mammals.
  • Compositions and methods of treatment that exhibit more rapid onset of action, more potent effects on peak urinary flow rates, less systemic side effects, without deleterious effects upon sexual function or urinary continence are needed. Since aging is also associated with increasing incidences of heart attack and strokes, methods of treating BPH that do not exacerbate cardiovascular or cerebrovascular disease are particularly needed. There is also a need for routes of administration for drugs that minimize systemic exposure. There remains a need for compositions and kits useful for preventing and treating prostate disorders in mammals.
  • the present invention has demonstrated a method of treating BPH with efficacy within one hour of treatment, a surprisingly rapid response compared to weeks or months needed to demonstrate efficacy with present therapies. Further, one treatment has normalized urinary flow in some patients given this therapy. In several cases, the present invention has given improvement in urinary flow rates that exceed reports of improvement with surgery. This invention involves minimal intervention when compared to present therapies and offers hope for the prevention and/or treatment of prostate disorders.
  • FIG. 1 depicts the anatomy of the male urethra.
  • FIG. 2 depicts the anatomical zones of the male prostate.
  • FIG. 3 depicts voiding urodynamics studies.
  • FIG. 4 depicts a method of administration of therapeutic agents via the prostatic urethra.
  • FIG. 5 depicts novel devices for administration of therapeutic agents to the mucosal membranes of the lower urinary tract in mammals.
  • the present invention provides novel compositions for the prevention and/or treatment of prostate disorders in mammals.
  • prostate disorders refers to benign prostatic hypertrophy (BPH), carcinoma of the prostate (CaP), prostadynia, prostatitis, and chronic prostatitis.
  • One novel composition comprises a prostaglandin compound and an interferon.
  • Another novel composition comprises meatal suppositories with tocopherol analogs and/or vitamin C analogs. Meatal suppositories containing leuprolide acetate, finasteride and verapamil in a free base form are also believed to be novel.
  • the present invention provides novel methods for the prevention and/or treatment of prostate disorders in mammals comprising administration of one or more therapeutic compounds to the mucosal membrane of the lower urinary tract of the mammal.
  • the method for preventing prostate disorders comprises: a. Identifying the population of mammals at risk of developing a prostate disorder; b. Performing baseline testing of mammals at risk; c. Administering one or more therapeutic compound(s) to the mucosal membrane of the lower urinary tract of the mammal; and d. Repeating the baseline testing to evaluate the mammal's response to intervention and to determine whether subsequent interventions should be altered.
  • mammals at risk of BPH can be identified (step a) by, for example, evaluating historical factors known to be associated with BPH such as age, race, family history and history of exposure to androgens. Since the strongest factor associated with BPH is age, one may consider every man over a certain age such as 40 to be at risk of developing BPH and a candidate for preventative therapy.
  • baseline testing can be performed on, for example, serum PSA, testosterone and dihydrotestosterone levels.
  • a screening urodynamics study with a minimum of peak and mean urinary flow rates can also be performed.
  • Assessment of prostate size by digital exam, ultrasonography, computed tomography or by magnetic resonance imaging may also be used for baseline testing.
  • Symptomatology is determined according to the American Urological Association Symptom Index by inquiring about and recording the following 7 symptoms: sensation of not having emptied the bladder completely after urination; having to urinate again in less than 2 hours after urinating; having to stop and start again several times during urination; difficulties in postponing urination; weak urinary stream; having to push or strain to begin urination; and having to get up at night to urinate (MJ Barry et al "The measurement committee of the American Urological Association" J Urol 1992; 148:1549-57).
  • one or more therapeutic compound(s) may be administered to the mucosal membrane of the lower urinary tract of the mammal (step c), preferably utilizing the least invasive method possible.
  • meatal suppositories containing (a) PGEs with or without interferons or (b) 5alpha-reductase inhibitors such as fatty acids, extracts of Serenoa repens or finasteride are suitable for administration. Administration of a suitable dose of the therapeutic agent nightly or every other night is also suitable.
  • repeat baseline testing to evaluate the mammal's response to intervention and to determine whether subsequent interventions should be altered can optionally be carried out by re-evaluating the baseline determinants recorded in step b at intervals of 6 months to 2 years.
  • These determinants preferably consist of at least the symptomatology, the peak urinary flow rate and the PSA level. Improvement in these determinants is desirable and indicates regression of the BPH. Continuation of the intervention used is preferable. Should the individual be without symptoms and possess a normal PSA and Peak flow rate, further improvement in an otherwise normal individual may not be possible.
  • One indication that the intervention used is effective is no progressive increase in PSA, decrease in peak urinary flow or development of symptomatology occurs. In this case, the individual should continue the intervention and be re-evaluated in 6 month to 2 years. If worsening of the symptoms or other indicators occurs, use of higher doses of therapeutic compound(s) may be tried.
  • mammals at risk of developing CaP can be identified (step a) by analysis of factors including, but not limited to, family history, race and age.
  • baseline testing such as serum PSA and assessment of prostate size by digital exam, ultrasonography, computed tomography or by magnetic resonance imaging may be performed.
  • Available prostate biopsy reports can be studied and new prostate biopsy material obtained at the discretion of the clinician.
  • one or more therapeutic compound(s) may be administered to the mucosal membrane of the lower urinary tract of the mammal (step c).
  • meatal suppositories with (a) prostaglandins with or without an interferon of the alpha or gamma subgroup or (b) tocopherols, vitamin C or retinol or their analogs are suitable for administration to the mammal.
  • the prostaglandin is PGA-1, PGA-2, PGJ2, ⁇ 12 -PGJ- 2, 15-deoxy- ⁇ 12 14 -PGJ-2, PGD-2 or 15-deoxy- ⁇ 12 14 -PGD-2.
  • the therapeutic compound(s) can be administered nightly or every other night.
  • baseline testing for CaP can be accomplished, for example, by serial PSA determinations or by repeat prostate biopsy.
  • Methods for treating BPH and CaP preferably comprise a. Diagnosing the mammal as having BPH; b. Performing baseline testing of the mammal having BPH; c. Administering one or more therapeutic compound(s) to the mucosal membrane of the lower urinary tract of the mammal; and d. Performing baseline testing to evaluate the mammal's response to the treatment and to determine whether subsequent treatments should be altered.
  • Performing baseline testing of the mammal and administration of the therapeutic compound(s) are preferably accomplished by the same measures described above in connection with methods for preventing BPH, if the condition is mild. More severe cases of BPH are best treated by administration of one or more therapeutic compound(s) to the prostatic urethra as described below and in the examples. Treatment of local CaP may be effected by administration of chemotherapeutic agents via the prostatic urethra.
  • therapeutic compound refers to any therapeutic compound of benefit or potential benefit to prostate disorders. Particularly preferred therapeutic compounds are selected from any of the groups listed below for which non-limiting examples are given:
  • the prostaglandin is PGE-1, PGE-2, PGE-3, misoprostol or misoprostanoic acid for the treatment and prevention of BPH.
  • the prostaglandin is PGA-1, PGA-2, PGJ2, ⁇ 12 -PGJ-2, 15-deoxy- ⁇ 12 I4 -PGJ-2, PGD-2 or 15-deoxy- ⁇ 12 ,4 -PGD-2 for the treatment and prevention of prostate cancer.
  • Such prostaglandins are commercially available from Cayman Chemical, Ann Arbor MI or described in Alex Gringanz, Introduction to Medicinal Chemistry. Wiley- VCH, Inc., New York, pp. 158-159 and 641-642, 1997, which is incorporated herein by reference.
  • PGE-1 prostaglandin Ei
  • PGEi alprostadil
  • the formal chemical name of PGE-1 is 3-hydroxy-2-(3-hydroxy-l-octenyl)-5-oxocyclopentaneheptanoic acid, and the structure of PGE-1 is
  • Prostaglandin Ei may be isolated from sheep seminal vesicle tissue as described in
  • PGE-2 prostaglandin E . is also known as dinoprostone or PGE .
  • the formal chemical name of PGE-2 is 7-[3-hydroxy-2-(3-hydroxy-l-octenyl)-5-oxocyclopentyl]-5-heptenoic acid, and the structure of PGE-2 is:
  • Prostaglandin E may be isolated from sheep seminal vesicle tissue as described in Bergstrom et al., Acta. Chem. Scand.. vol. 16, p. 501 (1962). Prostaglandin E 2 may be synthesized as described in Corey et al., J. Am. Chem. Soc. vol 92, p. 397 (1970); Corey et al., J. Am. Chem. Soc. vol. 92, p. 2586 (1970); and Heather et al., Tetrahedron Letters, p. 2313 (1973).
  • PGE-2 is also commercially available as a Prostin E-2 TMsuppository and as Prepidil Gel from Pharmacia & UpJohn Company, Kalamazoo, MI, and as Cervidil from Forest Pharmaceuticals, Inc., St. Louis, MO. These preparations are indicated for cervical ripening and contain between 0.5 and 20 mgs of PGE-2.
  • Misoprostol also known as 15-Deoxy-16-hydroxy-16-methyl-PGE-l methyl ester, has the formal chemical name of ( )-methyl-(lR,2R,3R)-3-hydroxy-2-[(E)-(4RS)-4-hydroxy-4- methyl-l-octenyl]-5-oxocyclopentaneheptanoate.
  • Misoprostol (15-Deoxy-16-hydroxy-16- methyl-PGE-1 methyl ester) may be prepared as described in U.S. Pat. No. 3,965,143.
  • Enprostil has the formal chemical name of [lV,2 ⁇ (lE,3R * ),3V]-7-[3-hydroxy-2-(3- hydroxy-4-phenoxy-l-butenyl)-5-oxocyclopentyl]-4,5-heptadienoic acid methyl ester. Enprostil may be prepared as described in U.S. Pat. No. 4,178,457.
  • Interferons are a diverse group of naturally occurring cytokines and immunomodulatory polypeptide agents. Certain interferons are known to exhibit chemotherapeutic effects against certain malignancies, immunosuppressive effects, antiviral effects or antiprohferative effects. Several of this group have been produced by recombinant technology. Interferon alpha-2b from Schering Corporation (Intron ATM ), interferon alpha-2a from Roche Laboratories (Roferon-A M ), interferon beta- lb from Berlex Laboratories (BetaseronTM) and interferon gamma- lb (ActimmuneTM) from Genentech are commercially available agents.
  • interferon alpha interferon alpha
  • interferon beta interferon gamma of natural or synthetic origin that exhibit scar lysis
  • Specific preferred interferons for use with this invention include any interferon that exhibits the ability to reduce or inhibit the production of fibrous connective tissue, including, but not limited to, interferons of the alpha and gamma sub-groups are preferred. Examples include interferon alpha-2a, interferon alpha-2b and interferon gamma- lb. II. Chemotherapeutic Agents
  • any available chemotherapeutic agents that show activity against prostate carcinoma may be used in the present invention. Agents that demonstrate marked irritation or toxicity to the mucosal surface are to be avoided.
  • chemotherapeutic agents that demonstrate marked irritation or toxicity to the mucosal surface are to be avoided.
  • agents that demonstrate in vitro activity against CaP cell cultures are readily administered by the present method such as, but not limited to, tocopherols, alpha-tocopherol succinate, vitamin C and analogs, retinol and vitamin A analogs (C Maramag et al "Effect of vitamin C on prostate cancer cells in vitro: effect on cell number, viability and DNA synthesis" Prostate 1997 Aug 1 ; 32(3): 188-95).
  • Szarka reviews the strategy of chemoprevention as a possible method of blocking the development of cancers in humans (CF Szarka et al "Chemoprevention of cancer” Curr Probl Cancer 1994 Jan-Feb;18(l):6-79). These strategies center around the systemic administration of agents that have been shown to inhibit the growth of cancer cells in culture.
  • the present invention makes it possible to deliver to the urinary tract sufficient amounts of tocopherols and vitamin C analogs to reach the necessary concentrations demonstrated by the in vitro studies. Systemic administration of these agents does not allow the delivery of sufficient tissue concentrations to be effective.
  • Alpha-receptor antagonists including, but not limited to, prazosin, phentolamine, phenoxybenzamine, dibenzamine, doxazosin, terazosin, trimazosin, tolazoline, corynthanine, rauwolscine, tamsulosin and piperoxan, are suitable for use in the present invention.
  • prostaglandin dehydrogenase inhibitor any compound which exhibits a significant and selective inhibition of prostaglandin degrading enzyme, or 15- hydroxyprostaglandin dehydrogenase (PGDH).
  • PGDH 15- hydroxyprostaglandin dehydrogenase
  • Type I which is NAD + dependent
  • Type II which is NADP + dependent
  • Type I operates at a Km one order of magnitude lower than Type II and is thus more significant physiologically.
  • Type I PGDH is described in Mak et al, Biochimica et Biophysica Acta. vol. 1035, pp. 190-196 (1990); Ensor et al, J. Lipid Mediators Cell Signalling, vol.
  • Muramatsu et al., and Mak et al. describe assays for determining enzymatic activity of Type I PGDH as well as methods for determining the degree of inhibition of this enzyme.
  • Type II PGDH is described in Chang, et al, Biochem. Biophys. Res. Commun.. vol. 99, pp. 745-751 (1981); Jarabak, et al, Prostaglandins. vol. 18, pp. 241-246 (1979), and Lin, et al, Biochem. Biophys. Res. Commun.. vol. 81, pp. 1227-1234 (1978), all of which are incorporated herein by reference.
  • 15-hydroxyprostaglandin dehydrogenase inhibitors include, but are not limited to, oleic acid, palmitic acid, sulphasalazine and analogues thereof, 15(R)- prostaglandin E-l, 15(R)-prostaglandin E-2, and 15(R)- 15 -methyl prostaglandin E-2.
  • US Pat. No. 6,103,765 which provides a more extensive discussion of PGDH inhibitors, is hereby incorporated in its entirety.
  • Suitable phosphodiesterase (PDE) inhibitors for use in the present invention include, but are not limited to, caffeine, aminophylline, theophylline, amrinone, milrinone, vesnarinone, vinpocetine, pemobendan, cilostamide, enoximone, peroximone, rolipram, R020-1724, zaniprast, dipyridamole, MY5445, IC-351 and sildenafil.
  • Type IV phosphodiesterase inhibitors that selectively block the degradation of cGMP are preferred.
  • Anticholinergic agents may induce relaxation in the prostatic smooth muscle when applied by the present method.
  • Suitable anticholinergic agents for use in the present invention include, but are not limited to, atropine, scopolamine, glycopyrrolate, hyoscamine, tolterodine and oxybutynin.
  • Agents that relax smooth muscle such as flavoxate, dicyclomine and calcium channel blockers like verapamil are also of benefit in this method.
  • Suitable anti-androgens for use in the present invention include, but are not limited to, therapeutic compounds such as finasteride, myristoleic acid, palmitoleic acid, oleic acid, myristic acid, lauric acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid and extracts of Serenoa repens that block the conversion of testosterone to dihydrotestosterone. Blocking the production of this potent androgen is of particular value in both the treatment and prevention of BPH.
  • Gonadotropin-releasing hormone (GnRH), leuprolide and gonadorelin block the production of testosterone and may be of particular value in treating CaP.
  • the isolated stereoisomers of any of the above agents may demonstrate improved selectivity of therapeutic action and are included in the scope of this invention.
  • Particularly desirable combinations of therapeutic compounds are PGEs and alpha-blockers, PGEs and PGDH inhibitors, and PGEs and interferons.
  • the mammal may be advantageous to pre-treat the mammal with one or more of the therapeutic compounds followed by treatment with one or more of the therapeutic compound.
  • pre-treatment with a PGDH inhibitor followed by treatment with PGE will enhance the efficacy of the present method.
  • the prostatic urethra may be treated with infusion of the prostaglandin solution for 10 - 30 minutes followed by infusion of the interferon solution.
  • compositions containing an interferon, a 5 -alpha reductase inhibitor, chemotherapeutic agents such as tocopherol succinate and vitamin C analogs, muscarinic agents and verapamil are believed to be novel.
  • the therapeutic compounds can be administered in any conventional form, such as a liquid, solid or gel.
  • suitable liquids include sterile solutions, suspensions, and emulsions, including creams, ointments, and liposomes.
  • Methods for preparing various dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's
  • the carrier may be any solid substance that is compatible with the drug to be administered, releases the drug upon contact with the mucosa and is not irritating to the mucosa as used.
  • suitable solids include polyethylene glycol (PEG), polyethylene oxide and other low melting point or water-soluble polymers including fatty acid esters made into suppositories or pellets.
  • PEG suppositories contain a PEG which is solid at ambient or room temperature but rapidly dissolves/melts when placed on the urethra. Long chained fatty acid triglycerides with or without fatty acid esters are well suited to use with this invention.
  • suitable gels include triacetin, hydroxycellulose, gels composed of water, propylene glycol, hydroxypropyl methylcellulose and any other gels which are compatible with the therapeutic agent(s).
  • Liposomal mixtures are particularly preferred when one component is lipid soluble and one component is water soluble.
  • the liposomes may be prepared as either anionic or cationic liposomes depending upon the therapeutic compound to be used.
  • a preferred gel for use with prostaglandins is lecithin organogel prepared according to H. Willimann et al, "Lecithin organogel as matrix for transdermal transport of drugs," J. Pharm. Sci.. vol. 81(9), pp. 871-874 (1992).
  • lipophilic liquids examples include triacetin, tricaprin, tricaproin, tricaprylin and mixtures of various triglycerides.
  • a gel in which one or more of the therapeutic compounds is released in a controlled-released manner (i.e., released over time) to prolong the effect of the composition.
  • PGE can be formulated into a cross-linked polyethylene oxide/urethane polymer which is well tolerated by living tissues and releases the prostaglandin in a controlled release manner. Controlled release compositions are disclosed in D. H. Lewis, Controlled Release of Pesticides and Pharmaceuticals. Plenum Press, New York, 1981 ; and A. F. Kydonieus,
  • Cyclodextrin complexes of some therapeutic compounds that are lipid soluble may also be used in order to increase the efficacy.
  • cyclodextrin complexes may be prepared by adding the proper stoichiometric ratio of the prostaglandin or other agent to the cyclodextrin in an aqueous solvent and then either using as is or lyophilizing to provide a solid clathrate for mixing.
  • These complexes are described in Yamamura et al, J. Chromatogr., vol. 331, pp. 383- 388 (1985); Hirayama et al, Chem. Pharm. Bull., vol. 32 pp. 4237-4240 (1984); Uekama et al, Pharm. ScL. vol. 73, pp. 382-384 (1984); an Yamamura et al, J. Chromatogr.. vo . 303, pp. -
  • Matrix component(s) that are suitable for use in combination with the therapeutic compound(s) may be composed of any material or mixture of materials that is compatible with the therapeutic compound(s) and that releases the therapeutic compound(s) upon insertion into the meatus or urethra.
  • suitable materials for use as matrix components include but are not limited to fatty acid esters, such as ethyl stearate, methyl stearate, isopropyl stearate, butyl stearate, and cetyl lactate; fatty acid ethers, such as laureth 9; cholesterol esters, such as cholesteryl oleate and cholesteryl palmitate; cholesterol ethers; fatty acid diglycerides; fatty acid triglycerides; fatty acids; phospholipids; glycolipids; and sphingolipids.
  • Ethyl stearate and a mixture of methyl palmitate and tripalmitin are particularly preferred compounds for use as matrix components.
  • compositions suitable for use as a matrix component(s) includes materials such as hydrogels which contain or are saturated with the therapeutic agent(s).
  • the composition comprising the therapeutic compound(s) of the present invention may be applied by any mode of administration allowing for contact between the composition and the mucosal membranes of the lower urinary tract of a mammal, including, but not limited to, application by way of a catheter, a medicated ring, suppository, dropper, syringe, applicator, tube or by spray.
  • the composition is a liquid
  • the administration may be accomplished by means of a dropper, syringe or catheter.
  • the composition is in the form of a gel, lotion, or cream the administration may be carried out by means of a tube, syringe or catheter.
  • compositions that contain the therapeutic compound(s) and are in the form of a solid may be administered by inserting the appropriate amount of the solid dose form directly into the urethra or by use of an applicator.
  • Particularly preferred routes of administration are by application directly to the mucosa of the prostatic urethra and by application to the mucosa of the meatal portion of the penile urethra.
  • the male penile urethra consists of three segments: the bulbar urethra, the "trans-urethral" area and the meatal segment.
  • prostatic urethral administration refers to the administration of agents to any portion of the urethra from its origin at the sphincter of the bladder to the membranous urethra.
  • meatal administration refers to the administration of agents to the urethra of the navicular fossa and/or to the penile meatus (as shown in FIG. 1) that are covered by stratified squamous epithelium. Meatal administration is thus essentially the same as topical administration with respect to the difficulty of administering an effective transdermal dose. Meatal administration is considerably easier to carry out than transurethral administration and may be the only possible means of administration in patients with narrowing or scarring of the urethra.
  • the depth of insertion of the suppository in meatal administration is, as measured from the external opening of the penis, generally between 2 mm and 30 mm depending on individual differences.
  • Insertion of a meatal suppository can be easily and painlessly done by simply pressing the end of the suppository into the meatal opening of the penis. No cumbersome devices are required.
  • Those suppositories containing a matrix material that does not melt or dissolve upon insertion are preferably inserted into the urethra to a depth which leaves a portion of the suppository protruding from the urethra, left in the urethra until the desired effect is achieved, and then removed from the urethra by means of the protruding portion.
  • the therapeutic compounds of the present invention may also be administered to the mucosal membranes of the prostatic urethra by insertion of a small gauge pediatric catheter through the meatus of the glans penis until the proximal portion of the penile urethra or the distal portion of the intramembranous urethra is reached.
  • gentle inflation of the distal bulb of the catheter affects occlusion of the urethra and affords a direct route via the central channel of the catheter to the prostatic urethra.
  • Infusion of the prostatic urethra with the therapeutic compound in the form of a solution) is readily performed by retrograde injection of the solution through the tip of the catheter.
  • the present invention also provides novel devices for the administration of therapeutic compound(s) to the mucosal membranes of the lower urinary tract.
  • Such devices are constructed of a drug reservoir means that in its simplest form is a ring of material containing the therapeutic compound that is placed in the prostatic urethra. This medicated ring (see FIG.
  • a central tubular means allows uninterrupted flow of urine from the bladder to the penile urethra.
  • the ring may be made out of any material that allows release of the drug components, including, but not limited to, hydrogels, high melting triglycerides, polyethylene glycols and polyethylene oxides.
  • the ring may be made of a bioerodable material that releases the therapeutic compound as the matrix is eroded or other release mechanisms such as an osmotic pillow that swells upon insertion as it absorbs water from the urethra causing release of a solution of the therapeutic compound(s) through controlled diameter apertures or openings in the outside of the ring.
  • Precautions necessary to prevent the hydrogel from swelling and causing obstruction to the flow of urine include limiting the thickness of the hydrogel ring that is placed in the urethra.
  • a ring composed of methyl palmitate and tripalmitin allows timed-release of the therapeutic compounds without swelling. Provisions may be made for retrieval of the ring should it be necessary due to side-effects in a patient or to terminate the effects (by a means to remove such as a string).
  • the ring may be made to adhere to the outer surface of a urinary catheter in the region that will be in contact with the prostatic urethra.
  • Such a catheter may be inserted into the bladder and left in place to continuously release the therapeutic compounds into the prostatic urethra for as long as several days.
  • Another variation of this invention is a double lumen catheter device.
  • One lumen would be continuous with the urinary bladder in order to drain urine as it forms.
  • the second lumen would be connected to a pump and drug reservoir on one end and to a fenestrated or multi-channeled opening on the outside of the catheter in contact with the prostatic urethra.
  • This arrangement allows great latitude in controlling dosing and exposure of the prostate to the therapeutic compounds. This arrangement would be of greatest value in the treatment of CaP and severe cases of BPH.
  • compositions of the invention may also be administered directly into the glandular ducts of the prostate via cannulation with an endoscopically placed catheter.
  • gentle infusion of an aqueous solution of therapeutic compound(s) or placement of a suspension of micro particles containing the therapeutic agent(s) would afford either immediate or sustained release of the drugs into the ductal system. All of the above routes are believed to be novel.
  • the glans penis is derived embryologically from the same tissue as the meatal urethra and is normally covered by the foreskin. Thus, the glans penis may be considered an extension of the distal urethra for the purpose of this invention.
  • Meatal application of the composition for the purposes of this invention may also be achieved by casting the therapeutic agents into a suppository and dispensing the suppository to a patient for use at home. Inserting a suppository trans-meatally is effective in delivering the therapeutic compounds to the prostate. This surprising and totally unexpected result affords a novel route of administering therapeutic compounds to the prostate via a minimally invasive procedure.
  • the preferred method of administration will depend upon whether the goal of treatment is to prevent or to treat a prostate disorder and upon the severity of the prostate disorder.
  • the therapeutic compound(s) is administered by the trans-meatal route, for example with a suppository.
  • Suitable candidates for preventative treatment will be patients who have a strong family history of prostate disorders, patients with early evidence of a progressive decline in the maximum urinary flow rate, patients with early symptoms of BPH and any man over the age of 40 in which the treatment is well tolerated.
  • Meatal suppositories may be dispensed for home use making this route ideal for the administration of therapeutic compounds with minimal expense and intrusion into the patient's life.
  • the suppository has a round or pointed tip to facilitate entry into the urethra.
  • the suppository may be tapered along all of or at least a substantial part of its length.
  • the base of the suppository may be distended or flared to provide a built-in stop, so that the depth of the insertion may be determined by the length from the tip of the suppository to the beginning of the flare.
  • the base of the suppository may be attached to a piece of foil, plastic or paper or attached to the inside of the tip of a condom in order to set the depth of insertion.
  • Suppositories for use in connection with the present invention will typically have a cross- section having a maximum dimension of from about 1 mm to about 25 mm, preferably from about 2 mm to about 10 mm, most preferably from about 2 mm to about 6 mm, along the portion of the suppository intended to be inserted into the urethra.
  • the suppository should be thick enough to retain sufficient structural integrity to permit insertion of the suppository into the urethra without breaking or significantly bending the suppository.
  • the present suppository may have a shape in which the base of the suppository is distended or flared.
  • the distended or flared portion of the suppository will typically have a minimum dimension of at least about 5 mm, preferably at least about 10 mm.
  • there is in principal no upper limit on the maximum cross-sectional dimension of the distended or flared portion of the suppository practically speaking, it is not necessary to make the distended or flared portion any larger than what is required to prevent insertion of the suppository into the urethra beyond the point at which the distended or flared portion begins.
  • the trans-meatal route is preferable. More severe symptomatology or a desire to see more rapid therapeutic effects would make the route utilizing the prostatic urethra preferable.
  • Administration of therapeutic compounds with a narrow therapeutic index may be most safely administered via the prostatic urethra method under the direct supervision of the physician.
  • the amount of therapeutic compound(s) to be administered will depend upon the exact size and condition of the patient.
  • the therapeutic compounds of the present invention are to be administered in a therapeutically effective amount, which is understood to mean a nontoxic but sufficient amount of the drug or agent to provide the desired effect.
  • an effective amount means the amount that results in improvement in symptom scores or that results in improvement in peak urinary flow rates or in reduction of the serum PSA level in BPH.
  • a therapeutically effective amount in CaP means, for example, the amount that results in reduction in prostate tumor mass or in reduction in serum levels of PSA.
  • the therapeutic compound is a prostaglandin
  • the prostaglandin is suitably administered in an amount of from 1 nanogram to 1,400 micrograms, preferably from 1 microgram to 1,000 micrograms, most preferably from 10 to 500 micrograms.
  • Good results have been obtained with prostaglandin E concentrations in the 100 - 1 ,000 meg per ml range.
  • the broad ranges of suitable dosages reflect clinical findings that various coagents and carriers can either increase or decrease the drug activity exhibited by a given mixture and that individuals may exhibit different levels of sensitivity to a therapeutic agent. In practice, one would begin with a small dosage amount of a therapeutic agent to ascertain the minimum dosage amount needed for an adequate clinical response and increase dosage amount if needed.
  • the duration of treatment and time period of administration of the therapeutic agent will also vary according to the size and condition of the patient, the severity of the illness and the specific composition and method being used.
  • the prostaglandin will be administered for 30 - 90 minutes when a catheter based device is used for treatment in a physician's office; for 2 - 72 hours when a controlled release device is used; and, for several hours when a trans-meatal suppository is used.
  • the administration of the trans-meatal suppository will be terminated by urination. Improvement is surprisingly and unexpectedly rapid with dramatic benefits often seen at the end of one treatment.
  • the number of treatments to be given will depend upon the condition being treated, the severity of the condition and the response of the individual. Excellent responses have been seen with 1 - 5 treatments applied to either the meatal urethra or the prostatic urethra (see Examples).
  • the amount of interferon is suitably administered from 100 - 50,000,000 IU, preferably from 1 ,000 - 10,000,000 IU, most preferably from 100,000 - 2,000,000 per ml.
  • the exact amount of interferon to be administered will depend on the exact size and condition of the patient, good results have been obtained by administration of interferon in the range of 100,000 - 2,000,000 IU per ml.
  • the corresponding prostaglandin dosage amount is as described above.
  • a composition comprising prostaglandin and interferon will be administered for 30 - 90 minutes when a catheter based device is used; for 2 - 72 hours when a controlled release device is used; and, for several hours when a trans-meatal suppository is used.
  • the administration of the trans-meatal suppository will often be terminated by urination.
  • composition administered to the mucosal membrane will typically contain one or more pharmaceutically acceptable carriers (also termed “excipients” or “vehicles”) suited to the particular type of formulation, i.e., gel, ointment, suppository, or the like.
  • the vehicles are comprised of materials of naturally occurring or synthetic origin that do not adversely affect the therapeutic compound(s) or other components of the formulation.
  • Suitable carriers for use herein include water, silicone, waxes, petroleum jelly, polyethylene glycol, propylene glycol, liposomes, sugars such as mannitol and lactose, and a variety of other materials, depending, again, on the specific type of formulation used.
  • the detergent will typically be a nonionic, anionic, cationic or amphoteric surfactant.
  • the surfactant is selected such that local irritation at the site of administration is avoided.
  • suitable surfactants include Tergitol.RTM. and Triton.RTM. surfactants (Union Carbide Chemicals and Plastics, Danbury, Conn.), polyoxyethylenesorbitans, e.g., TWEEN.RTM. surfactants (Atlas Chemical Industries, Wilmington, Del.), and pharmaceutically acceptable fatty acid esters such as lauryl sulfate and the like.
  • the formulations may also optionally include one or more components to enhance permeation of the therapeutic compound(s), i.e., "permeation enhancers.”
  • permeation enhancers include those generally useful in conjunction with topical, transdermal or transmucosa rug e very.
  • DMSO dimethylsulfoxide
  • DMF dimethyl formamide
  • DMA N,N-dimethylacetamide
  • DEC decylmethylsulfoxide
  • PEG polyethylene glycol monolaurate
  • lecithin the 1 -substituted azacycloheptan-2-ones, particularly 1-n- dodecylcyclazacycloheptan-2-one (available under the trademark Azone.RTM.
  • kits to administer therapeutic compounds and novel compositions to the mucosal membranes of the lower urinary tract for the treatment and/or prevention of prostate disorders in mammals.
  • the kits are characterized as containing: (a) a means for containing a therapeutic compound or composition comprising a therapeutic compound and (b) a means for administering the compound or composition to the mucosal membranes of the lower urinary tract of a mammal.
  • the means for containing the compound or composition may be foil or plastic wrappers surrounding the suppositories that may be placed into a box or carton or other sealed container.
  • the means for containing the compound or composition may be a bottle, canister or plastic tube when the composition is in the form of a liquid, gel, lotion or cream. Rings or catheters containing the compositions may be placed in individual foil or plastic wrappers and then placed into a box or carton.
  • the means for administering the compound or composition may be a catheter, a medicated ring, suppository, dropper, syringe, applicator, tube or by spray.
  • the administration may be accomplished by means of a dropper, syringe, catheter or finger tip.
  • the administration When the composition is in the form of a gel, lotion, or cream the administration may be carried out by means of a tube, dropper, syringe, catheter or finger tip.
  • Pharmaceutical compositions that contain the therapeutic compound(s) and are in the form of a solid may be administered by inserting the appropriate amount of the solid dose form directly into the urethra, by the use of an applicator or by the finger tip.
  • the means for administering the pharmaceutical composition may be connected to or a part of the means for containing the pharmaceutical composition comprising.
  • kits examples include:
  • a kit which includes a container which can hold 1 to 100 unit doses of the compound or pharmaceutical composition and a dropper which can dispense between 0.1 to 1.0
  • the container is preferably glass, metal or a plastic known not to adsorb hydrophobic compounds.
  • kits which includes a container which can hold 1 to 100 unit doses of the compound or pharmaceutical composition with an applicator to administer the pharmaceutical composition internally onto the mucosal surface.
  • the container is preferably glass, metal or a plastic known not to adsorb hydrophobic compounds.
  • a kit which includes 1 to 100 unit doses of urethral rings or catheter devices for administration of the pharmaceutical composition into the prostatic urethra.
  • the present kits will also typically include means for packaging the container means and the administering means.
  • packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc.
  • the present kits will also usually include written instructions that describe how to administer the therapeutic compound or pharmaceutical composition containing the therapeutic compound to the mucosa. It is to be understood that the written instructions may be on any of the container means, the administering means, or the packaging means, in addition to being present on a separate piece of paper.
  • a matrix material for meatal suppositories composed of 12 - 40 % by weight of tripalmitin in methyl palmitate makes a versatile carrier for the therapeutic compound(s) in this method.
  • a meatal suppository may be easily formed by combining 20 grams of tripalmitin with 80 grams of methyl palmitate and melting at 80° C. Lipophillic therapeutic compounds may simply be added to this melted matrix material with stirring and then cast into suppositories by any standard method. Therapeutic compounds that are not lipid soluble may be added in a volatile solvent such as ethanol with stirring and rapidly cast into suppositories. Residual alcohol is removed by application of a vacuum to the solid suppository.
  • Solvents such as 1,2 propanediol may be added to the matrix material to increase the solubility of the therapeutic compound and left as a component of the final product.
  • the co-solvent or volatile solvent to be used may be found by experimenting or by consulting references regarding chemical solubility of a therapeutic compound.
  • Matrix material with higher proportions of tripalmitin exhibit delayed drug release properties.
  • delayed release devices for either meatal or prostatic urethral administration may be easily cast.
  • the matrix component is a material or mixture of materials that results in the final composition having a melting point ranging from about 70° F to about 100° F, preferably from about 70° F to about 90° F.
  • Example 1
  • a base matrix was formed by melting 0.760 grams of tripalmitin and 3.240 grams of methyl palmitate at 80 °C with stirring. This 18 % tripalmitin matrix melts and releases any contained therapeutic agent on contact with the warmth of the urethra.
  • Example 2 To 4.000 grams of the molten matrix from Example 1 was added 4.0 milligrams of PGE-
  • Example 2 To the molten mixture of Example 2 containing tripalmitin, methyl palmitate and PGE-2 was added the dry powder from one vial of 25 million IU Intron ATM with rapid stirring. This suspension is rapidly cast into suppositories as in Example 1. One hundred unit doses containing 40 micrograms of PGE-2 and 250,000 IU interferon alpha -2b are thus made. The PGE-2 is rapidly released from the matrix. The solid particles containing interferon alpha-2b are then released by the melting matrix and will slowly dissolve in the moisture of the urinary tract. This simple preparation thus enables the release of the PGE-2 dissolved in the matrix first followed by the suspended interferon particles without the use of a catheter and sequential infusions.
  • any lipid insoluble therapeutic agent that is a solid at room temperature.
  • This preferred embodiment may be administered at home by the patient or may be cast as a ring around a catheter by allowing the suspension to cool and solidify around that portion of a catheter that will be in contact with the prostatic urethra.
  • Example 4 To the molten mixture in Example 1 was added 15 milligrams of prazosin hydrochloride dissolved in ethanol with stirring. The solution was rapidly cast and produced one hundred unit doses containing 150 milligrams of prazosin hydrochloride. The residual ethanol was removed from the suppositories after solidification by vacuum. Any therapeutic agent that is not lipid soluble may be cast into suppositories by selection of a suitable volatile solvent.
  • Example 5 To the molten mixture in Example 1 was added 15 milligrams of prazosin hydrochloride dissolved in ethanol with stirring. The solution was rapidly cast and produced one hundred unit doses containing 150 milligrams of prazosin hydrochloride. The residual ethanol was removed from the suppositories after solidification by vacuum. Any therapeutic agent that is not lipid soluble may be cast into suppositories by selection of a suitable volatile solvent.
  • Example 5 Example 5
  • Example 1 To the molten matrix of Example 1 was added 5.0 milligrams of finasteride with stirring until dissolved and then cast into one hundred suppositories containing 50 micrograms of finasteride each.
  • Verapamil hydrochloride was dissolved in water and sodium hydroxide solution added until pH 10. The liberated free base verapamil was extracted with chloroform, The chloroform extract was dried over molecular sieves and evaporated to give the pale yellow liquid free base Verapamil.
  • To the molten matrix in Example 1 was added 75 milligrams of Verapamil with stirring and cast to yield one hundred suppositories containing 750 micrograms of Verapamil each. This free base form of Verapamil is absorbed much more rapidly than the available hydrochloride salt from the mucosa of the lower urinary tract. Many therapeutic agents are made into such salts for oral administration.
  • the present invention is best used with either the free base or the free acid form of such agents since the un-ionized form is absorbed more rapidly from a mucosal surface.
  • the alpha blockers and many anti-cholinergic agents listed above may be incorporated by this method.
  • Example 8 Five milligrams of either tolterodine, oxybutynin, or doxazosin prepared in a free base form as generally described in Example 7 are added in the minimal amount of ethanol to the molten matrix of Example 1 with stirring and cast into one hundred suppositories. The ethanol is removed by vacuum to give unit doses of 50 micrograms of the therapeutic agent.
  • Example 9 To 4 grams of the molten matrix from Example 1 was added 10 milligrams of free base sildenafil in chloroform with stirring and the mixture was rapidly cast. Removal of solvent gave one hundred suppositories containing 100 microgram doses of sildenafil.
  • Example 2 To 4 grams of the molten matrix from Example 1 was added 20 milligrams of ascorbyl palmitate and 100 milligrams of alpha-tocopherol succinate in ethanol with stirring and the mixture cast and placed in vacuo to give one hundred suppositories containing 0.2 and 1.0 milligrams respectively of the therapeutic agents.
  • Examples 2 -10 may be made by substituting triacetin for the solid matrix material.
  • the resultant liquid preparations may be instilled into the prostatic urethra or applied topically to the glans penis.
  • the formulations of Examples 2-10 may be made by substituting a matrix of 30 % tripalmitin and 70 % methyl palmitate in order to afford preparations with delayed release properties.
  • Examples 2-10 may be made as liposomal preparations as a substitute for the solid matrix. These rapidly bioavailable preparations may be used on any mucosal surface of the urinary tract but will be particularly potent when infused into the prostatic urethra. II. Subjective Examples Example 14
  • the lumen of the catheter was clamped to prevent drainage of the therapeutic agents and infusion of the prostatic urethra with 0.5 ml of normal saline at pH 4.9 containing was accomplished by injecting the solution into the lumen of the catheter proximal to the clamp.
  • the PGE-2 solution was thus delivered through the catheter tip and allowed to remain in place for 30 minutes before infusion of 0.5 ml (5 million IU) of Intron ATM. After 30 minutes, the dead volume of the catheter was flushed with 0.5 ml normal saline and treatment continued for 30 minutes before deflating the catheter bulb and removing it. No adverse effects were seen.
  • Example 16 A 90-year-old male with severe BPH and a number of other medical problems that made him a poor surgical candidate had a pre-treatment PSA of 10.5, prostate biopsies demonstrating only BPH and had urodynamics demonstrating severe obstruction with the peak urinary flow rate of 5 ml/sec and average urinary flow rate of 2 ml/sec prior to treatment (see FIG. 3 C). Three treatments as outlined in Example 15 were given without complication. Repeat urodynamics after the 3 r treatment showed a peak flow of 8 ml/sec (60 % improvement) and an average flow of 4 ml/sec (100 % improvement). PSA levels dropped by 32 % to 6.8 with some improvement in clinical symptomatology seen. This patient's results are also consistent with a marked reduction in prostate tissue mass induced by the present method and leading to clinical improvement in obstructive symptoms.
  • Example 17 A 90-year-old male with severe BPH and a number of other medical problems that made him a poor surgical candidate had a pre-
  • FIG. 3 B illustrates his urodynamics study just prior to the 1 st treatment
  • FIG. 3 A illustrates his repeat study after a single treatment. Peak urinary flow rates more than doubled from 12 ml/sec to 25 ml/sec! Thus, a single 90 minute treatment gave better results than reported with TURP (results in Example 15 were even better). PSA was low at the beginning and remained the same later. The patient resolved all symptomatology of BPH with the three treatments.
  • Example 18 A 52-year-old male with mild symptoms of BPH was sent home with suppositories made as in Example 3 to insert meatally every 2 nd or 3 rd night. The patient reported improvement in his symptoms after the 3 rd treatment.
  • Example 19 Men who are at high risk for BPH are given suppositories made as in Example 5 to be inserted in the meatus nightly. It is expected that these men will show a significantly lower rate of development of BPH over the next 5 - 10 years.
  • Example 20 A 52-year-old male with mild symptoms of BPH was sent home with suppositories made as in Example 3 to insert meatally every 2 nd or 3 rd night. The patient reported improvement in his symptoms after the 3 rd treatment.
  • Example 19 Men who are at high risk for BPH are given suppositories made as in Example 5 to be inserted in the meatus nightly. It is expected that these men will show a significantly lower rate of development of BPH over the next 5 - 10 years.
  • Example 20

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Abstract

La présente invention concerne des méthodes, des compostions, des dispositifs et des kits permettant de prévenir et de traiter les troubles de la prostate chez les mammifères, notamment, l'hypertrophie prostatique bénigne, les carcinomes de la prostate, les prostadynies, les prostatites, et les prostatites chroniques. En outre, cette invention concerne des méthodes de prévention et de traitement des troubles de la prostate chez les mammifères consistant à administrer un composé thérapeutique aux membranes des muqueuses des voies urinaires inférieures du mammifère. Par ailleurs, cette invention concerne des procédés d'administration d'un composé thérapeutique aux membranes des muqueuses des voies urinaires inférieures du mammifère.
EP00961680A 1999-09-09 2000-09-08 Methodes et compositions pour prevenir et traiter les troubles de la prostate Withdrawn EP1214038A2 (fr)

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US15290299P 1999-09-09 1999-09-09
US152902P 1999-09-09
PCT/US2000/024676 WO2001017479A2 (fr) 1999-09-09 2000-09-08 Methodes et compositions pour prevenir et traiter les troubles de la prostate

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WO2001017480A2 (fr) 2001-03-15
WO2001017480A3 (fr) 2001-11-01
AU7360700A (en) 2001-04-10
WO2001017479A2 (fr) 2001-03-15
AU7360000A (en) 2001-04-10
EP1214039A2 (fr) 2002-06-19
WO2001017479A3 (fr) 2001-09-20
WO2001017479B1 (fr) 2002-02-07

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