WO1999011279A1

WO1999011279A1 - Composition and method for the treatment of benign prostatic hyperplasia and prostatitis

Info

Publication number: WO1999011279A1
Application number: PCT/US1998/018199
Authority: WO
Inventors: Andrew E. Myers; Mark R. Priddy
Original assignee: Rexall Sundown, Inc.
Priority date: 1997-09-04
Filing date: 1998-09-02
Publication date: 1999-03-11
Also published as: AU9128998A

Abstract

A composition of Cernitin flower pollen extract and Saw palmetto extract is disclosed which is useful in treating benign prostatic hyperplasia, prostatitis, and prostate enlargement.

Description

COMPOS ITION AND METHOD FOR THE TREATMENT OF BENIGN PROSTATIC HYPERPLAS IA AND PROSTATITIS

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a composition for the treatment of prostate enlargement (e.g., benign prostatic hyperplasia, prostatitis), and a method of treating same.

2. Background Information

An increasing percentage of middle age and elderly males are being diagnosed with benign prostatic hyperplasia (BPH). Although symptoms may begin for men in their fifties, histopathological evaluations of the prostate at autopsy suggest that 5% to 10% of men aged 40 already have prostatic enlargement, while at age 80 the prevalence is as high as 80%. In 1990, 1.2 million men in 1990 visited urologists and over $3 billion healthcare dollars were spent on the management of BPH and its symptoms.

The prostate is a gland of the male reproductive system. It is about the size of a walnut and weighs roughly one ounce. Located in front of the rectum and just below the urinary bladder, the prostate is made up of muscular and glandular tissue and produces fluid for semen. The prostate gland surrounds the urethra, the tube that carries urine out of the bladder and to the tip of the penis for expulsion. This setting has the potential to cause many problems related to the urinary system and often does.

BPH involves an enlargement of the glandular tissues of the prostate. Enlargement frequently results in a gradual squeezing of the urethra where it runs through the prostate. Blockage of the urethra can lead to difficulty in urination and other problems. Urine retention may lead to urinary tract and bladder infections, chronic urinary obstruction and even the possibility of bladder and kidney damage. Common symptoms of BPH include a weak urinary stream, a sense of incomplete bladder emptying, difficulty starting urination, frequent urination

(especially at night), urgency (difficulty postponing urination), and interruption of the stream (stopping and starting). The experience of such symptoms may indicate presence of BPH.

In the past a major therapeutic approach to BPH has been surgery; but recently, some medical therapies have been developed which are viewed as options to surgery in many instances. One leading class of agents for treatment are inhibitors of 5-alpha reductase. A second class of agents commonly used in therapy is alpha adrenergic blockers which relax the prostate and bladder and decrease pressure on the urethra. A recent study suggests that the latter is therapeutically better than the former, however, both agents are in wide use. Unfortunately, each class of agents has significant side effects. Use of drugs to block 5-alpha reductase (Paraprost, Proscar) has been associated with decreased libido, ejaculatory disorders and impotence, and less than 50 percent of patients on Proscar will experience clinical improvement over one year. In addition, Proscar may suppress levels of prostate specific antigen (PSA), the marker for prostate cancer. Alpha adrenergic blockers, like Hytrin, originally developed to lower blood pressure, can result in severe hypotension.

Transurethral prostatectomy (TURP) is still considered a therapeutic option, but is usually reserved for advanced cases of BPH. With increasing life expectancy among males, a man over 40 years of age has a 30% chance of undergoing such a procedure in his lifetime. In 1990, 329,00 TURP operations were performed in the United States for BPH. TURP seems to provide significant symptom relief with 90% improvement being noted in men with advanced BPH. Unfortunately, both short-term (post-surgical bleeding, epididymitis, UTIs, incontinence, etc.) and long-term complications (bladder neck contracture, urethral stricture), plus the trauma of surgery, make either watchful waiting, drug therapy, or phytomedicines the first-line treatment choice for most patients. represented by Cernitin pollen extract and Saw palmetto extract offer therapeutic support for BPH sufferers, and a method for promoting prostate tissue health. The present therapeutic composition of Cernitin and Saw palmetto extract has a positive effect on prostate tissue health and is capable of offering additional support for individuals suffering from prostatitis. The present invention further contemplates a method for treating prostate enlargement and a method for maintaining prostate tissue health.

As used herein, "standardized" refers to the isolation, concentration and delivery of the active components of a plant medicine in each and every dosage applied. Active components differ amongst the multitude of plant medicines, and standardization criteria differs with each species of plant.

The present invention offers the surprising benefit of providing a therapeutic composition which acts to reduce the size of enlarged prostate glands, while concurrently acting as an anti-inflammatory, smooth muscle relaxant and anti-androgenic, and a method of treatment using such a composition.

DETAILED DESCRIPTION OF THE INVENTION

The present composition includes two essential ingredients: Cernitin flower pollen extract and Saw palmetto extract, which in combination, act synergistically to reduce the symptoms associated with benign prostatic hyperplasia (BPH).

Cernitin flower pollen extract contains the microbiologically prepared pollen extracts T 60 and GBX, freed from antigens and other high molecular weight substances. Cernitin T 60 contains mainly water-soluble and GBX mainly fat-soluble substances extracted from the pollens of specially selected plants. Cernitin flower pollen extract contains numerous classes of chemical substances including: twenty-one amino acids, including the ten essential ones; all known vitamins, except B 12; sterols and sterol esters all of vegetable origin and not identical to those found in humans; and several minerals and trace elements. Cernitin is considered to have several beneficial actions on biochemistry. Administered orally to rats, Cernitin showed marked anti- inflammatory activity when compared with very active intraperitoneally injected anti-inflammatory agents. It has been shown that this action is not due to the liberation of corticosteroids.

Cernitin has smooth muscle relaxing properties which are demonstrated through inhibition of urethral contraction facilitating the discharge of urine and reducing residual urine in vivo. Such effects have been described in Nippon Yakurigaku Zasshi (97:267-276, 1991), Yakurigaku Zasshi (91 :385-392, 1990), and Planta Medica (Apr 1986, pp. 148-151); all of which are incorporated herein by reference.

Cernitin flower pollen extract possess anti-androgenic properties which are of benefit in the affecting the hormone chemistry of the prostate. As androgenic hormones are considered to be involved in stimulating the growth of glandular prostate tissue, the anti-androgenic activity of pollen extracts appears to reduce the action of these substances in the etiology of prostate enlargement.

Cernitin flower pollen extracts T60 (water soluble) and GBX (fat soluble) are unique among plant medicines used in support of individuals with prostate enlargement. Several clinical studies indicate the effectiveness of pollen extracts in prostate enlargement. In a randomized double-blind study, subjects reported painful urination reduced by 76.1%, frequency of urination reduced by 82.6%, feeling of residual urine reduced by 81.8%, and weak urinary flow improved 88.9%. Similar results have been reported by Buckaroo and Ebeling (Urologe, 31 : 1 13-1 16, 1991), the disclosure of which is incorporated herein.

BPH patients treated with Cernitin showed significant improvement in residual urinary volume, average flow rate, maximum flow rate, prostatic weight, and residual urinary volume (Masanobu et al., Acta Urology, 36:495- 516, 1991 , incorporated herein in its entirety). The overall effect was slightly higher in the Cernitin test group compared to treatment with Paraprost. Pollen extracts function in the prostate to decrease inflammation, relax smooth muscles promoting urinary flow and reduce harmful hormonal elements.

The lipid-soluble components of the berries of the Saw palmetto (Sere oa repens) plant are thought to contain the medically active constituents. The purified liposterolic extract contains 80 to 95% fatty acids and sterols. The sterols include β-sitosterol, campesterol and stigmasterol. These constituents are thought to be the most important with regard to Saw palmetto's action on the prostate. However, free fatty acids and long-chain alcohols, also present in the extract, may also exert medicinal activity.

The liposterolic extract of Saw palmetto has been shown to possess an anti-androgen effect by inhibiting the enzymes 5a-reductase (5-AR) and 3- ketosteroid reductase and by blocking the binding of dihydrotestosterone (DHT) to prostate cells. There have been conflicting results regarding Saw palmetto extract's ability to inhibit 5-AR when compared to finasteride. However, one study shows that at a therapeutic dose of 320 mg/day, Saw palmetto extract inhibits 5-AR three times more strongly than does finasteride (5 mg/day). Saw palmetto was also shown to inhibit both type 1 and 2 isoenzymes of 5-AR. Saw palmetto extract has also been shown to be an aromatase inhibitor and to reduce the activity of estrogenic receptors in the prostate. Finally, the extract also has the capacity to inhibit the formation of phospholipase A2 and 5-lipoxygense enzymes, blocking the release of arachodonic acid.

Over the last decade, numerous clinical trials have proven the liposterolic extract of Saw palmetto berries to be a safe and efficacious treatment for BPH. Although many studies in the 1980s were only three months in length, current studies have demonstrated Saw palmetto's efficacy over six months to three years.

A double-blind, placebo-controlled study in France examined the effect of Saw palmetto (320 mg/day) in 1 10 patients with stage I or II BPH. The study lasted for 30 days. Patients receiving Saw palmetto extract showed an improvement in mean urinary flow rate from 5.5 ml/sec to 8.1 ml/sec and a decrease in nocturia from 3.1 to 1.7 times per night. An open-label follow-up was performed with 47 patients and found continued success over 15 to 30 months of treatment.

A three year, open-label study in Germany examined the effect of 320 mg of Saw palmetto extract daily in 315 patients with mild or moderate symptoms of BPH. Nocturia decreased in 73% of the patients and daytime urination in 54%. The residual urine volume decreased significantly from a mean of 64 ml to 32 ml. The peak urinary flow rate improved by a mean of 6.1 ml/sec. Significant changes were observed at the six month evaluation, and only 14.7% of the patients had a deterioration of symptoms over the three year study. These results compare favorably to finasteride and terazosin.

A multicenter, randomized, double-blind study of 1,098 patients with mild to moderate BPH recruited from 87 clinics in nine European countries. The six month study compared 320 mg Saw palmetto extract with 5 mg finasteride daily. Of the 1,098 patients entered, 951 completed the trial with 467 receiving Saw palmetto and 484 finasteride. At six months there was a 38% decrease in the symptoms score (International Prostate Symptom Score) in both groups, with no significant difference between groups. Urinary flow rate was increased by greater than 3 ml/sec in 36% of the Saw palmetto group and 39% of the finasteride group (the difference was not significant). Sexual function remained unchanged in the Saw palmetto group while it deteriorated significantly in the finasteride group. The PSA level remained unchanged in the Saw palmetto group but fell significantly in the finasteride group. This indicates concern that finasteride may mask detection of prostate cancer with long-term use.

U.S. Pat. No. 5,543,146 (incorporated by reference herein) discloses alleviating the symptoms associated with prostate gland enlargement with a combination of pumpkin seeds, Saw palmetto extract, and pumpkin seeds. It does not disclose the present invention. The present invention can also be administered to the patient in capsule or tablet form. Tablets can, if desired, be coated or uncoated. Suitable tableting procedures include those generally described in Perry's Chemical Engineer's Handbook, page 8-62 to 8-64 (4^th Edition 1963), Ullmann's Encyclopedia of Industrial Chemistry, volume A 19, pages 245-256 (Springer Verlag 1991), Ullmann's Encyclopedia of Industrial Chemistry, volume B2, pages 7-31 to 7-37 (Springer Verlag 1988), and Lieberman (editor), Pharmaceutical Dosage Forms: Tablets, volumes 1 and 2 (Marcel Dekker 1980), the complete disclosures of which are hereby incorporated by reference. The present therapeutic composition can also be administered in capsule or gel-cap form. The size of each dosage and the interval of dosing to the patient effectively determines the size and shape of the tablet or capsule. By present preference, each capsule and each tablet contains both of the present essential ingredients in pre-determined amounts to simplify the patient's treatment regimen.

As apparent from the foregoing, the present therapeutic composition can be administered orally. Oral administration is preferred because of convenience to the patient as well as the dosing schedule. The composition can be administered in powder form, but is, for at least some patients, more readily administered in solution. The solution media can be water or any consumable liquid or beverage. By present preference the beverage and consumable liquids are non-carbonated, and can, if desired, also be non-alcoholic. The therapeutic composition can be provided for administration in the form of a so- called instantized (powdered) formulation for ready swallowing or ready dissolution in the selected liquid for subsequent administration to the patient, or can be provided in pre-mixed solution for immediate use or as a pre-mixed dilutable concentrate. The pre-mixed form can be packaged in suitable containers such as, cans, bottles or the like for storage prior to use. A predetermined amount of a powdered solid pre-mix formulation can also be packaged in one or more sachets. The composition can also be administered in the form of a paste, compact, emulsion, elixir, granules, syrup, lozenges, gum, or candied formulation. The two essential ingredients are relatively neutral in taste, and thus they can, if desired, be combined with flavoring materials, sweeteners, and/or aromatic ingredients. The composition can also include other additives known in the nutritional and pharmaceutical arts such as, for instance, multi-vitamins, minerals, or nutritional elements, among others.

In the present invention, the composition includes relative amounts of the two essential ingredients. The present compositions are formulated to provide an effective amount of Cernitin pollen extract, such as in administration, e.g. dosing, to the patient. The Cernitin pollen extract is, in general, dosed so that the patient can receive a Cernitin pollen extract dosage in the range of about 5 mg to about 1 gm, preferably between about 15 mg and about 252 mg. An efficient therapy can involve twice-daily doses of about 126 mg per dose of Cernitin pollen extract.

In a presently preferred formulation containing Cernitin pollen extract, the ratio of water-soluble T 60 to fat-soluble GBX is between about 200: 1 and about 2: 1, more preferably between about 100: 1 and about 10: 1, and most preferably about 60 mg T 60 to 3 mg GBX per dose (i.e., 20:1). The present compositions are formulated to provide an effective amount of the Saw palmetto extract, such as in the administration, e.g. dosing, to the patient. In general, the dosage is in a range of about 5 mg to about 1 gm, preferably between about 15 mg and about 640 mg. By present preference, in an effective twice-daily dose of the present therapeutic composition, the patent can receive about 320 mg per dose of the Saw palmetto extract.

In a presently preferred formulation, the composition is a tablet containing the two essential ingredients with an acceptable carrier vehicle, diluent, binder, stabilizer, preservative, or combinations thereof as described in Remington's Pharmaceutical Science by E.W. Martin, the disclosure of which is incorporated herein in its entirety. In such tablet, spray-dried Saw palmetto extract may be combined with dried Cernitin pollen extract. The relative amounts of effective ingredients within a dose, or a dosing schedule can be adjusted appropriately for efficacious administration to patients. Clinical investigations have documented the surprising result that the combination of Cernitin flower pollen extract and Saw palmetto offer therapeutic support for patients suffering from prostate enlargement and prostatitis, and a method for treating such disease from both the analgesic and biochemical standpoints.

The present therapeutic composition manifests a number of unique and unexpected advantages. Clinical research in prostate enlargement indicates the synergistic effects of the therapeutic composition exceed the benefits of the ingredients singly. This unexpected result is obtained through evaluation and marked improvement in key clinical symptoms. Urine flowimetry (urine flow rate), post void residual (amount of urine remaining in bladder post-urination) and American Urological Association (AUA) symptom score all show significant improvement in patients treated with the present therapeutic composition.

In comparison to conventional compositions and methods of treatment, the present therapeutic composition acts at multiple levels to alleviate the symptoms of prostate enlargement. Acting synergistically, the therapeutic composition provides relief from inflammation, while reducing smooth muscle tension and androgenic stimulated growth of prostate tissue. The composition provides relief in a duration which may in fact be shorter than other methods, and may provide longer lasting results. Unlike conventional compositions, the present therapeutic composition does not possess significantly negative side effects, nor does it affect libido, cause impotence or other cause any other sexual dsyfunction. The present therapeutic composition is also particularly beneficial in that is does not impair PSA levels, used as markers for prostate cancer.

Claims

WHAT WE CLAIM IS:

1. A composition comprising Cernitin pollen extract and Saw palmetto extract.

2. The composition according to Claim 1, wherein the composition contains between about 5 milligrams and about 1 gram of the Cernitin pollen extract.

3. The composition according to Claim 2, wherein the composition contains between about 15 milligrams and about 252 grams of the Cernitin pollen extract.

4. The composition according to Claim 1, wherein the Cernitin pollen extract comprises a water-soluble T 60 extract and a fat-soluble GBX extract.

5. The composition according to Claim 4, wherein the water-soluble T 60 extract to fat-soluble GBX extract ratio is about 20:1.

6. The composition according to Claim 1, wherein the composition comprises an amount of the Cernitin pollen extract sufficient to have anti- inflammatory activity.

7. The composition according to Claim 1, wherein the composition comprises an amount of the Cernitin pollen extract sufficient to have smooth muscle relaxing activity.

8. The composition according to Claim 1, wherein the composition comprises an amount of the Cernitin pollen extract sufficient to have anti- androgenic activity.

9. The composition according to Claim 1, wherein the composition contains between about 5 milligrams and about 1 gram of the Saw palmetto extract.

10. The composition according to Claim 9, wherein the composition contains between about 15 milligrams and about 640 milligrams of the Saw palmetto extract.

11. The composition according to Claim 1, wherein the Saw palmetto extract is provided in spray-dried form.

12. The composition according to Claim 1, wherein the composition comprises an amount of the Saw palmetto extract sufficient to have anti- inflammatory activity.

13. The composition according to Claim 1, wherein the composition comprises an amount of the Saw palmetto extract sufficient to have smooth muscle relaxing activity.

14. The composition according to Claim 1, wherein the composition comprises an amount of the Saw palmetto extract sufficient to have anti- androgenic activity.

15. The composition according to Claim 1, wherein the composition is formed into a tablet.

16. A process of making a composition according to Claim 1, comprising mixing the Cernitin pollen extract and the Saw palmetto extract.

17. A process of administering the composition according to Claim 1 to a person with benign prostate hyperplasia.

18. A process of administering the composition according to Claim 1 to a person with prostatitis.

19. A process of administering the composition according to Claim 1 to a person with an enlarged prostate.