(19)
(11)EP 3 068 414 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
30.12.2020 Bulletin 2020/53

(21)Application number: 14860917.5

(22)Date of filing:  11.11.2014
(51)International Patent Classification (IPC): 
A61K 36/45(2006.01)
A61K 31/192(2006.01)
A61P 13/00(2006.01)
A61P 13/08(2006.01)
A61P 15/10(2006.01)
A61K 9/48(2006.01)
A61K 31/7048(2006.01)
A61P 13/02(2006.01)
A61P 13/10(2006.01)
(86)International application number:
PCT/US2014/064961
(87)International publication number:
WO 2015/070203 (14.05.2015 Gazette  2015/19)

(54)

COMPOSITIONS AND METHODS USEFUL IN TREATMENT OF LOWER URINARY TRACT SYMPTOMS, BENIGN PROSTATIC HYPERPLASIA, ERECTILE DYSFUNCTION

ZUSAMMENSETZUNGEN UND VERFAHREN ZUR BEHANDLUNG VON SYMPTOMEN DER UNTEREN HARNWEGE, BENIGNER PROSTATAHYPERPLASIE UND EREKTILER DYSFUNKTION

COMPOSITIONS ET MÉTHODES UTILES DANS LE TRAITEMENT DES SYMPTÔMES DES VOIES URINAIRES INFÉRIEURES, DE L'HYPERPLASIE PROSTATIQUE BÉNIGNE, ET DE LA DYSFONCTION ÉRECTILE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
Designated Extension States:
BA ME

(30)Priority: 11.11.2013 US 201361902376 P

(43)Date of publication of application:
21.09.2016 Bulletin 2016/38

(60)Divisional application:
20199906.7

(73)Proprietor: Naturex Inc.
South Hackensack, New Jersey 07606 (US)

(72)Inventors:
  • FROMENTIN, Emilie, Annie, Claudie
    F-56190 Muzillac (FR)
  • KLAIBER, Douglas, Andrew
    Forestdale, MA 02644 (US)
  • SOUZA, Daniel, David
    East Sandwich, MA 02537 (US)

(74)Representative: Global Patents 
Givaudan SA Grafenaustrasse 7
6300 Zug
6300 Zug (CH)


(56)References cited: : 
US-A- 5 525 341
US-A1- 2005 186 147
US-A1- 2013 122 151
US-A1- 2001 012 525
US-A1- 2011 280 971
  
  • J COTE: "PACran(R) cranberry powder - beyond urinary tract infection", NUTRACOS, vol. 11, no. 5, 1 September 2012 (2012-09-01), pages 43-46, XP055368103, IT ISSN: 1720-4011
  • PAPPAS E ET AL: "Phytochemicals of Cranberries and Cranberry Products: Characterization, Potential Health Effects, and Processing Stability", CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION, TAYLOR & FRANCIS, USA, vol. 49, no. 9, 1 January 2009 (2009-01-01), pages 741-781, XP009157925, ISSN: 1040-8398, DOI: 10.1080/10408390802145377
  • HOWELL AMY B ET AL: "Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study", BMC INFECTIOUS DISEASES, BIOMED CENTRAL, LONDON, GB, vol. 10, no. 1, 14 April 2010 (2010-04-14) , page 94, XP021074632, ISSN: 1471-2334, DOI: 10.1186/1471-2334-10-94
  • ZIRK M M ET AL: "CRANBERRY (VACCINIUM MACROCARPON) PROANTHOCYANIDINS AND THEIR EFFECTS ON URINARY TRACT INFECTIONS", CURRENT TOPICS IN NUTRACEUTICAL RESEARCH, NEW CENTURY HEALTH PUBLISHERS, NEW ORLEANS, LA, US, vol. 2, no. 3, 1 January 2004 (2004-01-01) , pages 153-160, XP008076009, ISSN: 1540-7535
  • Ales Vidlar ET AL: "The effectiveness of dried cranberries ( Vaccinium macrocarpon ) in men with lower urinary tract symptoms", British Journal of Nutrition, vol. 104, no. 8, 31 August 2010 (2010-08-31), pages 1181-1189, XP055585978, UK ISSN: 0007-1145, DOI: 10.1017/S0007114510002059
 
Remarks:
The file contains technical information submitted after the application was filed and not included in this specification
 
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

2. FIELD



[0001] The present invention relates generally to treatment, prevention, and alleviation of lower urinary tract symptoms (LUTS), benign prostatic hyperplasia (BPH), erectile dysfunction (ED), urinary incontinence, and other diseases or symptoms.

3. BACKGROUND



[0002] Lower urinary tract symptoms (LUTS) become increasingly bothersome as men age, with a prevalence of moderate-to-severe symptoms rising to nearly 50% of men in their eighties.
LUTS may or may not be related to benign prostatic hyperplasia (BPH), a histological condition characterized by the non-malignant overgrowth of prostatic tissue surrounding the urethra that occurs in 50% of men in their fifties and 90% of men in their eighties. LUTS can also arise from age-related bladder detrusor dysfunction and other sympathetic conditions. LUTS are further classified as voiding or storage symptoms and defined by the international prostate symptoms score (IPSS), a validated tool, widely used among the medical and scientific community.

[0003] Voiding symptoms include urinary hesitancy, delay in initiating micturition, intermittency, involuntary interruption of voiding, weak urinary stream, straining to void, a sensation of incomplete emptying, terminal dribbling, and may be caused by prostate enlargement or tissue inflammation. Storage symptoms can include urinary frequency, nocturia, urgency, incontinence and bladder pain or dysuria, and may be caused by bladder detrusor overactivity. Physiological markers associated with increased risk of BPH include high levels of testosterone, dihydrotestosterone, dehydroepiandrosterone and estradiol, insulin-like growth factors and inflammatory markers.

[0004] Although LUTS and LUTS due to BPH are not a life-threatening condition, the impact of LUTS on quality-of-life (QoL) can be significant and treatment is necessary in most cases to avoid complications. Risk factors include age, prostatic volume and peak urinary flow rate as well as lifestyle, dietary pattern, alcohol consumption, physical activity or genetic factors. Upon diagnosis, watchful waiting is recommended in approximately 34% of cases in the United States. Registered pharmacological treatments for LUTS may be responsible for a variety of side effects, thus necessitating development of new treatments.

[0005] According to the American Urological Association, patients with a mild degree of bother (IPSS<8) or patients with moderate to severe symptoms (IPSS≥8) who are not bothered by their LUTS may be managed with watchful waiting and lifestyle modification. If significant bothersome symptoms persist despite conservative measures, the initiation of medical management is indicated and in certain cases, surgery may be recommended.

[0006] The National Institutes of Health estimates that erectile dysfunction (ED) affects as many as 30 million men in the United States. Incidence increases with age: about 4% of men in their 50s and nearly 17% of men in their 60s experience a total inability to achieve an erection. The incidence jumps to 47% for men older than 75.

[0007] Benign prostatic hyperplasia (BPH) is a common problem among older men, and is responsible for considerable disability. The prevalence of histologically diagnosed prostatic hyperplasia increases from 8% in men aged 31 to 40, to 40 to 50% in men aged 51 to 60, to over 80% in men older than age 80.

[0008] Urinary incontinence is an underdiagnosed and underreported problem that increases with age. It affects 50-84% of the elderly in long-term care facilities. At any age is more than 2 times more common in females than in males.

[0009] Overactive bladder (OAB) is prevalent in 10 to 18% of the population, affecting men and women nearly equally. OAB has a negative impact on patient's quality of life. LUTS associated with OAB are responsible of significant social, psychological, occupational, domestic, and physical stigmas.
Cote, "PACran® cranberry powder- beyond urinary tract infection", Nutracos, Vol. 11, no. 5, September 1, 2012 relates to the use of whole cranberry powder for urinary and prostate health. Pappas et al., "Phytochemicals of Cranberries and Cranberry Products: Characterization, Potential Health Effects, and Processing Stability", Critical reviews in food science and nutrition, vol. 49, no. 9, relates to phytochemical components of the American cranberry and its potential anti-cancer effects. Howell et al., "Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study", BMC infectious diseases, vol. 10, no. 1, relates to the effect of PAC-standardized cranberry powder in uropathogenic Escherichia coli infection. Zirk et al., "Cranberry (Vaccinium macrocarpon) proanthocyanidins and their effects on urinary tract infections", Current topics in nutraceutical research, vol. 2, no. 3, relates to the beneficial effects of cranberries in the prevention of urinary tract infection.

4. SUMMARY



[0010] The subject matter of the invention is as defined in the appended claims. One aspect of the invention is a solid oral dosage form comprising 100 mg to 500 mg of a therapeutic composition, wherein the therapeutic composition comprises dried cranberry powder and cranberry seeds, or dried cranberry powder and cranberry seed meal, wherein the cranberry seeds or cranberry seed meal are present in the therapeutic composition in an amount of 15% to 25% by weight of the dried cranberry powder.
In another aspect, the invention provides a therapeutic composition comprising dried cranberry powder and cranberry seeds, or dried cranberry powder and cranberry seed meal, wherein the cranberry seeds or cranberry seed meal are present in the therapeutic composition in an amount of 15% to 25% by weight of the dried cranberry powder, for use in a method of
  • alleviating lower urinary tract symptoms (LUTS) or the symptoms of benign prostatic hyperplasia (BPH) in a subject; or
  • treating erectile dysfunction (ED), urinary incontinence, overactive bladder (OAB), bladder obstruction, interstitial cystitis, underactive bladder, prostatitis, bladder and prostate inflammation, prostate fibrosis or pelvic pain in a subject.
The invention is based, in part, on the discovery that addition of cranberry seeds or cranberry seed meal to dried cranberry powder provides a therapeutic composition that is effective against lower urinary tract symptoms (LUTS) and other diseases or symptoms without the side effects of existing treatments.

[0011] In one aspect, the invention provides a therapeutic composition comprising dried cranberry powder and dried cranberry seeds.

[0012] In another aspect, the invention provides therapeutic composition comprising dried cranberry powder and cranberry seed meal.

[0013] In some embodiments, the cranberry is Vaccinium macrocarpon.

[0014] In some embodiments, the cranberry is Vaccinium microcarpon.

[0015] In some embodiments, the cranberry is Vaccinium oxycoccus.

[0016] In some embodiments and disclosures, the cranberry seeds are present in an amount of about 5% to about 50% by weight of the dried cranberry powder.

[0017] In some embodiments, the cranberry seeds are present in an amount of about 15% to about 25% by weight of the dried cranberry powder.

[0018] In some embodiments, the cranberry seeds are present in an amount of about 20% by weight of the dried cranberry powder.

[0019] In some embodiments and disclosures, the cranberry seed meal is present in an amount of about 5% to about 50% by weight of the dried cranberry powder.

[0020] In some embodiments, the cranberry seed meal is present in an amount of about 15% to about 25% by weight of the dried cranberry powder.

[0021] In some embodiments, the cranberry seed meal is present in an amount of about 20% by weight of the dried cranberry powder.

[0022] In some embodiments, the composition comprises less than about 12% of organic acids by weight.

[0023] In some embodiments, the composition comprises less than 10% of organic acids by weight.

[0024] In some embodiments, the composition comprises about 5% to about 8% of organic acids by weight.

[0025] In some embodiments, the composition comprises less than about 15% of sugars by weight.

[0026] In some embodiments, the composition comprises less than about 12% of sugars by weight.

[0027] In some embodiments, the composition comprises from about 1% to about 5% of quinic acid by weight.

[0028] In some embodiments, the composition comprises from about 2.2% to about 3.2% of quinic acid by weight.

[0029] In some embodiments, the composition comprises from about 0.4% to about 4% of malic acid by weight.

[0030] In some embodiments, the composition comprises from about 0.8% to about 1.8% of malic acid by weight.

[0031] In some embodiments, the composition comprises from about 1% to about 5% of citric acid by weight.

[0032] In some embodiments, composition comprises from about 1.8% to about 3.2% of citric acid by weight.

[0033] In some embodiments, the composition comprises: 0.5% to 5.0% proanthocyanidins, 0.05% to 1.5% quercetin, 0.001 % to 0.1% quercetin-3-glucoside, 0.001 % to 0.1% quercetin-3-rhamnoside, 0.001% to 0.1% quercetin-3-xyloside, 0.001% to 0.1% quercetin-3-arabinoside, 0.001% to 0.5% myricetin, 0.001% to 0.1% peonidin-3-galactoside, 0.001% to 0.1% peonidin-3-glucoside, 0.001% to 0.1% peonidin-3-arabinoside, 0.001% to 0.1% cyanidin-3-glucoside, 0.001% to 0.1% cyanidin-3-galactoside, 0.001% to 0.1% cyanidin-3-arabinoside, 0.001% to 0.1% protocatechuic acid 0.001% to 0.1% p-coumaric acid, 0.001% to 0.1% caffeoyl-glucoside, 0.001% to 0.1% coumaroyl-glucoside, 0.001% to 0.1% cafeic acid, 0.001% to 0.1% chlorogenic acid or 0.01 to 1.5% ursolic acid by weight.

[0034] In some embodiments, the composition comprises: 1.0% to 1.2% proanthocyanidins, 0.16% to 0.20% quercetin, 0.07% to 0.09% quercetin-3-glucoside, 0.03% to 0.04% quercetin-3-rhamnoside, 0.019% to 0.025% quercetin-3-xyloside, 0.025% to 0.035% quercetin-3-arabinoside, 0.010% to 0.014% myricetin, 0.022% to 0.030% peonidin-3-galactoside, 0.0025% to 0.0035% peonidin-3-glucoside, 0.010% to 0.020% peonidin-3-arabinoside, 0.0005% to 0.0015% cyanidin-3-glucoside, 0.015% to 0.030% cyanidin-3-galactoside, 0.010% to 0.025% cyanidin-3-arabinoside, 0.019% to 0.025% protocatechuic acid, 0.04% to 0.06% p-coumaric acid, 0.015% to 0.025% caffeoyl-glucoside, 0.005% to 0.015% coumaroyl-glucoside, 0.010% to 0.015% cafeic acid or 0.030% to 0.04% chlorogenic acid by weight.

[0035] In some embodiments, the composition comprises about: 1.1% proanthocyanidins, 0.18% quercetin, 0.083% quercetin-3-glucoside, 0.034% quercetin-3-rhamnoside, 0.022% quercetin-3-xyloside, 0.030% quercetin-3-arabinoside, 0.012% myricetin, 0.027% peonidin-3-galactoside, 0.003% peonidin-3-glucoside, 0.014% peonidin-3-arabinoside, 0.001% cyanidin-3-glucoside, 0.022% cyanidin-3-galactoside, 0.018% cyanidin-3-arabinoside, 0.022% protocatechuic acid, 0.052% p-coumaric acid, 0.021 % caffeoyl-glucoside, 0.011 % coumaroyl-glucoside, 0.014% cafeic acid, 0.034% chlorogenic acid or 0.92% ursolic acid by weight.

[0036] In some embodiments, the composition comprises 1 to 100 µg lariciresinol, 1 to 100 µg secoisolariciresinol or 1 to 100 µg/ pinoresinol per 100g of the composition by weight.

[0037] In some embodiments, the composition comprises about 51 µg lariciresinol, about 12 µg secoisolariciresinol or about 78 µg/ pinoresinol per 100g of the composition by weight.

[0038] In another aspect, the invention provides a solid oral dosage form comprising a therapeutic composition described above.

[0039] In some embodiments, the solid oral dosage form is a tablet.

[0040] In other embodiments, the solid oral dosage form is a capsule.

[0041] In some embodiments, the solid oral dosage form is a softgel.

[0042] In some embodiments, the solid oral dosage form comprises 100 mg to 500 mg of the therapeutic composition.

[0043] In some embodiments, the solid oral dosage form comprises 250 mg of the therapeutic composition.

[0044] In some embodiments, the solid oral dosage form comprises 500 mg of the therapeutic composition.

[0045] In another aspect, the invention provides a the claimed therapeutic composition comprising dried cranberry powder and cranberry seeds for use in a method for alleviating lower urinary tract symptoms (LUTS) in a subject comprising administering to the subject in need thereof an effective amount of the composition as claimed.

[0046] In another aspect, the invention provides the claimed therapeutic composition comprising dried cranberry powder and cranberry seeds for use in a method for alleviating the symptoms of benign prostatic hyperplasia (BPH) in a subject comprising administering to the subject in need thereof an effective amount of the composition as claimed.

[0047] In another aspect, the invention provides a the claimed therapeutic composition comprising dried cranberry powder and cranberry seeds for use in a method for treating erectile dysfunction (ED) in a subject comprising administering to the subject in need thereof an effective amount of the composition as claimed.

[0048] In another aspect, the invention provides the claimed therapeutic composition comprising dried cranberry powder and cranberry seeds for use in a method for treating urinary incontinence in a subject comprising administering to the subject in need thereof an effective amount of the composition as claimed.

[0049] In another aspect, the invention provides the claimed therapeutic composition comprising dried cranberry powder and cranberry seeds for use in a method for treating overactive bladder (OAB) in a subject comprising administering to the subject in need thereof an effective amount of the composition as claimed.

[0050] In other aspects, the invention provides the claimed therapeutic composition comprising dried cranberry powder and cranberry seeds for use in a method for treating bladder obstruction, interstitial cystitis, underactive bladder, prostatitis, bladder and prostate inflammation, prostate fibrosis or pelvic pain in a subject comprising administering to the subject in need thereof an effective amount of the composition as claimed.

[0051] In some embodiments, the subject is a human.

[0052] In some embodiments, the human is a male.

[0053] In some embodiments, the human is a female.

5. BRIEF DESCRIPTION OF THE DRAWINGS



[0054] The invention is described with reference to the following figures, which are presented for purposes of illustration only and which is not intending to be limiting of the invention.

FIG. 1 illustrates a CONSORT diagram of the 148 men attending the first screening visit in the LUTS study.

FIG. 2 illustrates a plot of the mean difference and corresponding 95% confidence interval in international prostate symptom scores (IPSS) at start, 3-months, and 6-months for the placebo group, the therapeutic composition 250 mg group, and the therapeutic composition 500 mg group in the LUTS study.


6. DETAILED DESCRIPTION


6.1 Definitions



[0055] The patent and scientific literature referred to herein establishes knowledge that is available to those of skill in the art

[0056] As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable can be equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 can take the values 0, 1 or 2 if the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values ≥ 0 and ≤ 2 if the variable is inherently continuous.

[0057] As used herein, unless specifically indicated otherwise, the word "or" is used in the inclusive sense of "and/or" and not the exclusive sense of "either/or."

[0058] As used herein, "about" means within ±10%. For example, "about 1" means "0.9 to 1.1", "about 2%" means "1.8% to 2.2%", "about 2% to 3%" means "1.8% to 3.3%", and "about 3% to about 4%" means "2.7% to 4.4%."

6.2 Cranberry Fruit



[0059] Cranberry fruit, e.g., Vaccinium macrocarpon, is recognized as a rich source of organic and phenolic acids, flavonols, flavan-3-ols, anthocyanins, proanthocyanidins (PACs) and pentacyclic triterpenoids, including ursolic and oleanolic acids.

[0060] A non-exhaustive list of pharmacoactive compounds that may be present in cranberry fruit is listed in Table 1.
TABLE 1
Phenolic Acid Coumaroyl-hexose
Derivatives 6-Caffeoyl-D-glucose
3-caffeoylquinic acid (Chlorogenic acid)
4-hydroxybenzoic acid
3-hydroxybenzoic acid
5-p-hydroxybenzoic acid
6-p-hydroxybenzoic acid
Gallic acid
Benzoic acid
Cinnamic acid
dihydroxybenzoic acid
o-hydroxycinnamic acid
4-hydroxy-3-methoxybenzoic acid (HVA) (vanillic acid)
3-hydroxyphenylacetic acid (3HPAA)
3-hydroxybenzoic acid (3HBA)
3,4-dihydroxybenzoic acid (3,4DHBA) (protocatechuic acid)
2,3-dihydroxybenzoic acid (2,3DHBA) (hypogallic acid)
2,4-dihydroxybenzoic acid (2,4DHBA) (b-resorcyclic acid)
2,5-dihydroxybenzoic acid (2,5DHBA) (genistic acid)
2,6-dihydroxybenzoic acid
3-hydroxycinnamic acid (3HCA)
4-hydroxycinnamic acid (4HCA) (p-coumaric acid)
4-hydroxy-3-methoxycinnamic acid (Ferulic acid)
3,4-dihydroxycinnamic acid (Caffeic acid)
3-hydroxyphenylpropionic acid (3HPPA) (phloretic acid)
benzoylaminoacetic acid (hippuric acid)
Salicylic acid
Sinapic acid
Ascorbic acid
Ellagic acid
Syringic acid
Shikimic acid
Ferruloyl glucoside
4-caffeoylquinic acid (Cryptochlorogenic acid)
Flavonols Myricetin
Quercetin
Quercetin 3-galactoside
Quercetin 3-glucoside
Quercetin-3-rhamnoside
Quercetin-3-xyloside
Quercetin-3-arabinoside
Quercetin glucuronide
Myricetin-3-galactoside
Myricetin-3-glucoside
Isorhamnetin
Flavanols (+)-catechin
(-)-catechin
Procyanidin A2 type isomer 1
Procyanidin A2 type isomer 2
Procyanidin A2 type isomer 3
(-)-epicatechin
3-methylcatechin
4-methylcatechin
3-methylepicatechin
4-methylepicatechin
Coumarins Scopoletin
Anthocyanins Cyanidin 3-galactoside
Cyanidin 3-glucoside
Peonidin 3-glucoside
Cyanidin 3-arabinoside
Peonidin 3-galactoside
Peonidin 3-arabinoside
Chalcones Phlorizin
Tocopherols Alpha-tocopherol acetate
Alpha-tocopherol
Beta-tocopherol
Gamma-tocopherol
Delta-tocopherol
Alpha-tocotrienol
Beta-tocotrienol
Gamma-tocotrienol
Delta-tocotrienol
Vitamin E
Sterols
Cholesterol
Brassicasterol
24 methyl-cholesterol
Campestanol
Campesterol
Delta-7-campesterol
Delta-5,23 stigmastadienol
Clerosterol
Beta-sitosterol
Sitostanol
Delta-5-avenasterol
Delta-5,24-stigmastadienol
Delta-7-stigmasterol
Delta-7-avenasterol
Fatty acids Myristic acid
Palmitic acid
Palmitoleic acid
Margaric acid
Stearic acid
Oleic acid
Linoleic acid
Linolenic acid
Arachidic acid
Gondoic acid
Behenic acid
Erucic acid
Lignoceric acid
Nervonic acid
Lignans Syringaresinol
Lariciresinol
Medioresinol
Lariciresinol-sesquilignan
Secoisolariciresinol
Pinoresinol
Secoisolariciresinol-cyclolariciresinol
7-hydroxymatairesinol
Nortrachelogenin
7-oxo-matairesinol
Matairesinol
α-conidendrin

6.3 Therapeutic Compositions Based on Cranberry Fruit Components



[0061] Therapeutic compositions described herein can include one or more components described below in the ranges provided below.

[0062] In some embodiments, therapeutic compositions described herein comprise dried cranberry powder and dried cranberry seeds. In other embodiments, the therapeutic compositions described herein comprise dried cranberry powder and cranberry seed meal. The cranberry species used to make the compositions can be Vaccinium macrocarpon, Vaccinium microcarpon, or Vaccinium oxycoccus. However, other species of cranberries can also be used to make the compositions described herein.

[0063] Cranberry seeds can be present in the therapeutic composition in an amount of about 15% to about 25%, or about 20% by weight of the dried cranberry powder. Cranberry seed meal can be present in the therapeutic composition in an amount of about 15% to about 25%, or about 20% by weight of the dried cranberry powder.

[0064] A therapeutic composition can comprise less than about 12%, less than about 10%, or about 5% to about 8% of organic acids by weight. Exemplary organic acids include, but are not limited to, quinic acid, malic acid, and citric acid.

[0065] The organic acid content can be determined using the following modification of protocol AOAC 986.13 entitled Quinic, Malic and Citric Acids in Cranberry Juice Cocktail and Apple Juice (available from AOAC International, www.aoac.org). The analytical column is a C18 reverse phase column with a 5 µm particle size, 25 cm x 4.6 mm in tandem with and followed by C18 reverse phase cartridges, with a 5 µm particle size and 10 cm long. Phosphate buffer, 0.2M KH2PO4, pH 2.4 is used. The flow rate is 0.80 mL/min, the analysis is performed at ambient temperature, and the detection wavelength is 214 nm. A dilution of the test agent can be performed in the mobile phase. CAS# for the standard are as follows: CAS-77-92-9 (citric acid), CAS-6915-15-7 (malic acid), CAS-77-95-2 (quinic acid). The formula used to calculate the concentration of each organic acid is as follows: (PA/PA') x (V'/V) x C, where PA and PA' = peak area of test solution and standard, respectively; V and V' = volume of test solution and standard, respectively; and C = concentration of standard, %. Shikimic acid and ascorbic acids can also be detected with this method.

[0066] A therapeutic composition can comprise from about 1% to about 5% or from about 2.2% to about 3.2% of quinic acid by weight.

[0067] A therapeutic composition can comprise from about 0.4% to about 4% or from about 0.8% to about 1.8% of malic acid by weight.

[0068] A therapeutic composition can comprise from about 1 % to about 5% or from about 1.8% to about 3.2% of citric acid by weight.

[0069] A therapeutic composition can comprise less than about 15% or less than about 12% of sugars by weight. Fructose, glucose and sucrose are examples of sugars typically found in cranberry. The sugar content reflects the global sugar amount and individual breakdown was not provided on these lots.

[0070] The sugar content can be determined by HPLC, using the following modification of protocol AOAC 977.20. The column used is µ-Bondapak/Carbohydrate (Waters Associates, No. 84038) with a guard column or equivalent. The mobile phase consists of non-spectro acetonitrile diluted with water (83/17, v/v). The sugar standard solution consists of fructose (CAS# 57-48-7), glucose (CAS# 50-99-7) and sucrose (CAS# 57-50-1). The sample is diluted in water and filtered through a 45 µm filter. 10 µL of sample are injected to the column at room temperature. The flow rate is 1.0 mL/min under isocratic conditions for 20 min. A refractive index detector is used. The amount of glucose, fructose, and sucrose is calculated from integrator values or from peak heights as follows: Weight % sugar = 100 × (PH/PH') × (V/V') × (W'/W) where PH and PH' = peak heights (or integrator values) of sample and standard, respectively; V and V' = mL sample and standard (50 and 100) solutions, respectively; and W and W' = g sample (5.000) and standard, respectively.

[0071] In some embodiments, the therapeutic composition comprises: 0.5% to 5.0% proanthocyanidins, 0.05% to 1.5% quercetin, 0.001 % to 0.1% quercetin-3-glucoside, 0.001 % to 0.1% quercetin-3-rhamnoside, 0.001% to 0.1% quercetin-3-xyloside, 0.001% to 0.1% quercetin-3-arabinoside, 0.001% to 0.5% myricetin, 0.001% to 0.1% peonidin-3-galactoside, 0.001% to 0.1% peonidin-3-glucoside, 0.001% to 0.1% peonidin-3-arabinoside, 0.001% to 0.1% cyanidin-3-glucoside, 0.001% to 0.1% cyanidin-3-galactoside, 0.001% to 0.1% cyanidin-3-arabinoside, 0.001 % to 0.1% protocatechuic acid, 0.001 % to 0.1% p-coumaric acid, 0.001 % to 0.1% caffeoyl-glucoside, 0.001 % to 0.1% coumaroyl-glucoside, 0.001 % to 0.1% cafeic acid, 0.001% to 0.1% chlorogenic acid or 0.01 to 1.5% ursolic acid by weight.

[0072] The content of proanthocyanidins and one or more other components can be determined by HPLC-fluorescence using a Develosil Diol column or equivalent as follows. The column compartment is maintained at 35°C. The solvents used are as follows: (A) 2% acetic acid in acetonitrile and (B) is 95:3:2 methanol / water / acetic acid. A linear gradient is used from 0% to 40% B, in 35 min; 40% to 100% B, in 40 min; 100% isocratic B, in 45 min; and 100% to 0% B, in 50 min.

[0073] The content of anthocyanins (peonidin-3-galactoside, peonidin-3-glucoside, peonidin-3-arabinoside, cyanidin-3-glucoside, cyanidin-3-galactoside, cyanidin-3-arabinoside) can be determined by HPLC-UV at a wavelength of 535 nm. The column is Synergi Hydro-RP or equivalent. The column compartment is maintained at room temperature. The mobile phase A consists of an aqueous 5% formic acid solution and mobile phase B of methanol. The gradient applied is 0-2 min, 5% B; 2-10 min, 5-20% B; 10-15 min, 20% B; 15-30 min, 20-25% B; 30-35 min, 25% B; 35-50 min, 25-33% B; 50-55 min, 33% B; 55-65 min, 33-36% B; 65-70 min, 36-45% B; 70-75 min, 45-53% B; 75-80 min, 53-55% B; 80-84 min, 55-70% B; 84-88 min, 70-5% B; 88-90 min, 5% B.

[0074] The content of certain other phenolics can be determined by UPLC-MS/MS using the following method. An Acquity T3 column (Waters Associates) or equivalent is used and placed in the UPLC column compartment maintained at a temperature of 30°C. The solvents used are 0.1% Formic acid (A) and acetonitrile (B). A linear gradient is applied from 5% B ; 0-4.5 min, 5-20% B; 4.5-6.45 min, isocratic 20% B; 6.45-13.5 min, 20-45% B ;13.5-16.5 min 45-100% B; 16.5-19.5 min isocratic 100% B; 19.5-19.52 min 100-5% B; 19.52-22.5 min. The detection is done by MS/MS and all standard compounds are tuned individually.

[0075] In some embodiments, the therapeutic composition comprises: 1.0% to 1.2% proanthocyanidins, 0.16% to 0.20% quercetin, 0.07% to 0.09% quercetin-3-glucoside, 0.03% to 0.04% quercetin-3-rhamnoside, 0.019% to 0.025% quercetin-3-xyloside, 0.025% to 0.035% quercetin-3-arabinoside, 0.010% to 0.014% myricetin, 0.022% to 0.030% peonidin-3-galactoside, 0.0025% to 0.0035% peonidin-3-glucoside, 0.010% to 0.020% peonidin-3-arabinoside, 0.0005% to 0.0015% cyanidin-3-glucoside, 0.015% to 0.030% cyanidin-3-galactoside, 0.010% to 0.025% cyanidin-3-arabinoside, 0.019% to 0.025% protocatechuic acid, 0.04% to 0.06% p-coumaric acid, 0.015% to 0.025% caffeoyl-glucoside, 0.005% to 0.015% coumaroyl-glucoside, 0.010% to 0.015% cafeic acid or 0.030% to 0.04% chlorogenic acid by weight.

[0076] In some embodiments, the therapeutic composition comprises about: 1.1% proanthocyanidins, 0.18% quercetin, 0.083% quercetin-3-glucoside, 0.034% quercetin-3-rhamnoside, 0.022% quercetin-3-xyloside, 0.030% quercetin-3-arabinoside, 0.012% myricetin, 0.027% peonidin-3-galactoside, 0.003% peonidin-3-glucoside, 0.014% peonidin-3-arabinoside, 0.001 % cyanidin-3-glucoside, 0.022% cyanidin-3-galactoside, 0.018% cyanidin-3-arabinoside, 0.022% protocatechuic acid, 0.052% p-coumaric acid, 0.021% caffeoyl-glucoside, 0.011% coumaroyl-glucoside, 0.014% cafeic acid, 0.034% chlorogenic acid or 0.92% ursolic acid by weight.

[0077] In some embodiments, the therapeutic composition comprises 1 to 100 µg or about 51 µg lariciresinol per 100g of the composition. In some embodiments, the therapeutic composition comprises 1 to 100 µg or about 12 µg secoisolariciresinol per 100g of the composition. In some embodiments, the therapeutic composition comprises 1 to 100 µg or about 78 µg pinoresinol per 100g of the composition.

[0078] The content of lignans can be determined by UPLC-MS/MS using an ACQUITY BEH C18 reverse phase column or equivalent as follows. The column compartment is maintained at 30°C. The solvents used are (A) Formic acid 0.1% and (B) Acetonitrile. The gradient is 5% B, 8.0min, 30% B, 9.0min, 30%B, 10.0min, 50%B, 12.0min, 50%B, 15.0min, 95%B, 17.0min 95%B, 17.5min, 5%B, 23.0min, 5%B. The detection is done by MS/MS and all standard compounds are tuned individually.

[0079] In some embodiments, the therapeutic compositions described above can be produced without cranberry fruit, e.g., by combining ingredients obtained from natural sources or by chemical synthesis into a therapeutic composition.

6.4 Solid Dosage Forms and Methods of Use



[0080] In some embodiments, a solid oral dosage form comprising the therapeutic composition described herein is a tablet, a capsule, or a softgel. In some embodiments, such solid oral dosage form comprises from 50 mg to 500 mg of the therapeutic composition, e.g., 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg.

[0081] Solid dosage forms comprising the therapeutic compositions described herein optionally comprise a suitable amount of one or more pharmaceutically acceptable excipients so as to provide the form for proper administration to the subject.

[0082] Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The present therapeutic compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995).

[0083] In some embodiments, a therapeutic composition described herein is formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, softgels, syrups, or elixirs for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active therapeutic composition is also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate can also be useful. Oral compositions can include standard excipients such as mannitol, lactose, starch, maltodextrin, cyclodextrins, alginate, arabic or guar gum, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0084] Pharmaceutical dosage forms for oral use can be obtained through combination of a therapeutic composition described herein with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. Maltodextrin and cyclodextrins can also be used. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0085] Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

[0086] Softgels for oral use may consist of a gelatin based shell surrounding a liquid fill. Softgel shells can be made of a combination of gelatin, water, opacifier and a plasticiser such as glycerin and/or sorbitol.

[0087] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0088] Therapeutic compositions described herein can be administered by controlled-release or sustained release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 5,674,533; 5,059,595; 5,120,548; 5,073,543; 5,639,476 and 5,354,556. Such dosage forms can be useful for providing controlled or sustained release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled or sustained release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled or sustained release.

[0089] In some embodiments, a controlled or sustained release composition comprises a minimal amount of a therapeutic composition to alleviate the symptoms of, treat or prevent lower urinary tract symptoms (LUTS), benign prostatic hyperplasia (BPH), erectile dysfunction (ED), urinary incontinence, bladder obstruction, interstitial cystitis, overactive bladder (OAB), underactive bladder, prostatitis, bladder and prostate inflammation, prostate fibrosis or pelvic pain in a patient over a period of time. Advantages of controlled or sustained release compositions include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled or sustained release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels active ingredients present in the therapeutic composition, and can thus reduce the occurrence of adverse side effects.

[0090] Controlled or sustained release compositions can initially release an amount of an active ingredient present in the therapeutic composition that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the active ingredients present in the therapeutic composition to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of an active ingredient present in the therapeutic composition in the body, active ingredients present in the therapeutic composition thereof can be released from the dosage form at a rate that will replace the amount of the active ingredients present in the therapeutic composition being metabolized and excreted from the body. Controlled or sustained release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[0091] The amount of a therapeutic composition that is effective in alleviating the symptoms of, treating or preventing lower urinary tract symptoms (LUTS), benign prostatic hyperplasia (BPH), erectile dysfunction (ED), urinary incontinence, bladder obstruction, interstitial cystitis, overactive bladder (OAB), underactive bladder, prostatitis, bladder and prostate inflammation, prostate fibrosis or pelvic pain can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies. Suitable effective dosage amounts, however, range from about 1 mg to about 5 grams about every 24 hours, although they are typically about 500 mg or less per every 24 hours. In one embodiment, the effective dosage is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg about 400 mg, about 450 mg about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 24 hours. Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 4 hours, about every 6 hours, about every 8 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one therapeutic composition is administered, the effective dosage amounts correspond to the total amount administered.

[0092] The therapeutic composition can be administered as long as the symptoms persist or longer. In some embodiments, the therapeutic composition is administered for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days.

[0093] The dosage regimen utilizing the therapeutic compositions described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; and the renal or hepatic function of the subject.

[0094] A therapeutic composition described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily.

[0095] The therapeutic composition described herein can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.

5. Kits



[0096] Described herein are kits that can simplify the administration of a therapeutic composition described herein to a subject. A typical kit comprises a unit dosage form of a therapeutic composition described herein and a label or printed instructions. In some embodiments, the label or printed instructions instruct the use of the unit dosage form to alleviate the symptoms of, treat or prevent lower urinary tract symptoms (LUTS), benign prostatic hyperplasia (BPH), erectile dysfunction (ED), urinary incontinence, bladder obstruction, interstitial cystitis, overactive bladder (OAB), underactive bladder, prostatitis, bladder and prostate inflammation, prostate fibrosis or pelvic pain.

[0097] The kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent. Examples of other prophylactic or therapeutic agents include, but are not limited to, those listed above.

6.4 Methods Of Making Therapeutic Compositions



[0098] Therapeutic compositions described herein can be made as follows. Cranberry berries, skins, juice or pomace are weighed and mixed to create a slurry. If the composition is enriched in cranberry seeds, seeds are added to the slurry. Water is added to the slurry to reach about 5%-15% of the solids by weight. The slurry is passed through a 14 mesh screen, a shear pump, spray-dried and milled. If the therapeutic composition is enriched in cranberry seed meal, it is added during the milling. The milled composition is passed through a sieve, sealed and pelletized.

6.5 Methods Of Using Therapeutic Compositions


6.5.1 Use in the Treatment of Lower Urinary Tract Symptoms (LUTS)



[0099] Therapeutic compositions described herein are useful for alleviating the symptoms of, treating or preventing lower urinary tract symptoms (LUTS). Accordingly, described herein are methods for alleviating, treating or preventing lower urinary tract symptoms (LUTS) in a subject comprising administering to the subject in need thereof an effective amount of a therapeutic composition described herein. LUTS may or may not be related to benign prostatic hyperplasia (BPH), a histological condition characterized by the non-malignant overgrowth of prostatic tissue surrounding the urethra. The alleviation of symptoms can be manifested by comparison to the same subject prior to administration or treatment with the therapeutic composition. The subject can be a human, for example a male or a female. In some embodiments, the human is older than 45 years, older than 50 years, older than 55 years, older than 60 years, older than 65 years, older than 70 years, older than 75 years or older than 80 years.

6.5.2 Use in the Treatment of Benign Prostatic Hyperplasia (BPH)



[0100] Benign prostatic hyperplasia (BPH), a histological condition characterized by the non-malignant overgrowth of prostatic tissue surrounding the urethra.

[0101] The therapeutic compositions described herein are useful for alleviating the symptoms of, treating or preventing to benign prostatic hyperplasia (BPH). Accordingly, described herein are methods for alleviating the symptoms of, treating or preventing benign prostatic hyperplasia (BPH) in a subject comprising administering to the subject in need thereof an effective amount of a therapeutic composition described herein. The alleviation of symptoms of benign prostatic hyperplasia (BPH) can be manifested by comparison to the same subject prior to administration or treatment with the therapeutic composition. The subject can be a human, for example a male. In some embodiments, the human is older than 45 years, older than 50 years, older than 55 years, older than 60 years, older than 65 years, older than 70 years, older than 75 years or older than 80 years.

6.5.3 Use in the Treatment of Erectile Dysfunction (ED)



[0102] The therapeutic compositions described herein are useful for alleviating the symptoms of, treating or preventing benign erectile dysfunction (ED). Accordingly, described herein are methods for alleviating the symptoms of, treating or preventing erectile dysfunction (ED) in a subject comprising administering to the subject in need thereof an effective amount of a therapeutic composition described herein. The alleviation of symptoms of erectile dysfunction (ED) can be manifested by comparison to the same subject prior to administration or treatment with the therapeutic composition. The subject can be a human, for example a male. In some embodiments, the human is older than 45 years, older than 50 years, older than 55 years, older than 60 years, older than 65 years, older than 70 years, older than 75 years or older than 80 years.

6.5.4 Use in the Treatment of Urinary Incontinence



[0103] The therapeutic compositions described herein are useful for alleviating the symptoms of, treating or preventing urinary incontinence. Accordingly, described herein are methods for alleviating the symptoms of, treating or preventing urinary incontinence in a subject comprising administering to the subject in need thereof an effective amount of a therapeutic composition described herein. The alleviation of symptoms of urinary incontinence can be manifested by comparison to the same subject prior to administration or treatment with the therapeutic composition. The subject can be a human, for example a male or a female. In some embodiments, the human is older than 45 years, older than 50 years, older than 55 years, older than 60 years, older than 65 years, older than 70 years, older than 75 years or older than 80 years.

6.5.5 Use in the Treatment of Overactive Bladder (OAB)



[0104] The therapeutic compositions described herein are useful for alleviating the symptoms of, treating or preventing overactive bladder (OAB). Accordingly, described herein are therapeutic compositions for use in methods for alleviating the symptoms of, treating or preventing overactive bladder in a subject comprising administering to the subject in need thereof an effective amount of a therapeutic composition described herein. The alleviation of symptoms of overactive bladder (OAB) can be manifested by comparison to the same subject prior to administration or treatment with the therapeutic composition. The subject can be a human, for example a male or a female. In some embodiments, the human is older than 45 years, 50 years, older than 55 years, older than 60 years, older than 65 years, older than 70 years, older than 75 years or older than 80 years.

6.5.6 Use in the Treatment of Additional Diseases or Symptoms



[0105] The therapeutic compositions described herein are useful for alleviating the symptoms of, treating or preventing bladder obstruction, interstitial cystitis, underactive bladder, prostatitis, bladder and prostate inflammation, prostate fibrosis or pelvic pain. The alleviation of symptoms of these diseases or conditions can be manifested by comparison to the same subject prior to administration or treatment with the therapeutic composition. The subject can be a human, for example a male or a female. In some embodiments, the human is older than 45 years, older than 50 years, older than 55 years, older than 60 years, older than 65 years, older than 70 years, older than 75 years or older than 80 years.

7. EXAMPLES



[0106] This invention is further illustrated by the following examples, which should not be construed as limiting. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein.

7.1 Example 1


Preparation of Therapeutic Composition Using Cranberry Seed Meal



[0107] Therapeutic compositions described herein can be made as follows. Cranberry berries, skins, juice or pomace are weighed and mixed to create a slurry. If the composition is enriched in cranberry seeds, seeds are added to the slurry. Water is added to the slurry to reach about 5%-15% of the solids by weight. The slurry is passed through a 14 mesh screen, a shear pump, spray-dried and milled. If the therapeutic composition is enriched in cranberry seed meal, it is added during the milling. The milled composition is passed through a sieve, sealed and pelletized.

7.2 Example 2


Characterization of the Therapeutic Composition



[0108] The therapeutic compositions were prepared as described above and characterized. Table 2 shows the organic acid profile of 5 samples as determined using a modified AOAC (986.13) entitled Quinic, Malic and Citric Acids in Cranberry Juice Cocktail and Apple Juice. Analytical column is a C18 reverse phase column with a 5 µm particle size, 25 cm x 4.6 mm in tandem with and followed by C18 reverse phase cartridges, with a 5 µm particle size and 10 cm long. Phosphate buffer, 0.2M KH2PO4, pH 2.4 is used. The elution is isocratic, flow rate 0.80 mL/min, ambient temperature and wavelength 214 nm. The method was originally written for cranberry juice and adapted for powders, where a dilution of the test agent was performed in the mobile phase. CAS# for the standard are as follow: CAS-77-92-9 (citric acid), CAS-6915-15-7 (malic acid), CAS-77-95-2 (quinic acid). The formula used to calculate the concentration of each organic acid is as follow: (PA/PA') x (V'/V) x C, where PA and PA' = peak area of test solution and standard, respectively; V and V' = volume of test solution and standard, respectively; and C = concentration of standard, %. The results are presented in Table 2 below.
TABLE 2
SampleQuinic Acid (%)Malic Acid (%)Citric Acid (%)Total (%)
1 2.43 1.54 2.38 6.35
2 2.31 0.93 1.94 5.18
3 2.99 1.43 2.99 7.41
4 2.40 1.36 2.15 5.91
5 2.75 1.65 3.00 7.40
Mean ± SD 2.58 ± 0.28 1.38 ± 0.28 2.49 ± 0.48 6.45 ± 0.97


[0109] Table 3 shows the sugar content of 5 samples as determined by HPLC, using a modification of AOAC method AOAC 977.20. The column used is a 300 × 4 (id) mm µ-Bondapak/Carbohydrate (Waters Associates, No. 84038) with a guard column. The mobile phase consists of nonspectro acetonitrile diluted with water (83/17, v/v). The sugar standard solution consisted of fructose (CAS# 57-48-7), glucose (CAS# 50-99-7) and sucrose (CAS# 57-50-1). The sample was diluted in water and filtered through a 45 µm filter. 10 µL of sample are injected to the column at room temperature. The flow rate is 1.0 mL/min under isocratic conditions for 20 min. A refractive index detector is used. Glucose, fructose, and sucrose are calculated from integrator values or from peak heights as follows: Weight % sugar = 100 × (PH/PH') × (V/V') × (W'/W) where PH and PH' = peak heights (or integrator values) of sample and standard, respectively; V and V' = mL sample and standard (50 and 100) solutions, respectively; and W and W' = g sample (5.000) and standard, respectively. The results are presented in Table 3 below.
TABLE 3
SampleSugar Content (g/100g)
6 8.7
7 4.0
8 7.7
9 5.9
10 7.3
Mean ± SD 6.7 ± 1.8


[0110] Concentration of proanthocyanidins was analyzed by HPLC-fluorescence using a Develosil Diol or equivalent. The column size is 250 mm x 4,6mm with a 5 micron particle size. The column compartment is maintained at 35°C. The solvents used are as follows: (A) 2% acetic acid in acetonitrile and (B) is 95:3:2 methanol / water / acetic acid. A linear gradient was used from 0% to 40% B, in 35 min; 40% to 100% B, in 40 min; 100% isocratic B, in 45 min; and 100% to 0% B, in 50 min.

[0111] The anthocyanins (peonidin-3-galactoside, peonidin-3-glucoside, peonidin-3-arabinoside, cyanidin-3-glucoside, cyanidin-3-galactoside, cyanidin-3-arabinoside) are analyzed by HPLC-UV at a wavelength of 535 nm. The column is Synergi Hydro-RP 250 mm x 4, 6mm with a 4µm particle size. The column compartment is maintained at room temperature. The mobile phase A consists of an aqueous 5% formic acid solution and mobile phase B of methanol. The gradient applied is 0-2 min, 5% B; 2-10 min, 5-20% B; 10-15 min, 20% B; 15-30 min, 20-25% B; 30-35 min, 25% B; 35-50 min, 25-33% B; 50-55 min, 33% B; 55-65 min, 33-36% B; 65-70 min, 36-45% B; 70-75 min, 45-53% B; 75-80 min, 53-55% B; 80-84 min, 55-70% B; 84-88 min, 70-5% B; 88-90 min, 5% B.

[0112] The rest of the phenolics are analyzed by UPLC-MS/MS using the following method. An Acquity T3 column (150mm x 2.1mm id, 1.8 µm particle size) from Waters Associates is used and placed in the UPLC column compartment maintained at a temperature of 30°C. The solvents used are 0.1% Formic acid (A) and acetonitrile (B). A linear gradient is applied from 5% B ; 0-4.5 min, 5-20% B; 4.5-6.45 min, isocratic 20% B; 6.45-13.5 min, 20-45% B ; 13.5-16.5 min 45-100% B; 16.5-19.5 min isocratic 100% B; 19.5-19.52 min 100-5% B; 19.52-22.5 min. The detection was done by MS/MS and all standard compounds were tuned individually. The results are shown in Table 4.
TABLE 4
ClassSubclassPhytochemicalConcentration (mg/100g)
Flavonoids Flavan-3-ols Proanthocyanidins 1078.9*
Flavonols Quercetin 176.6
Quercetin-3-glucoside 83.2
Quercetin-3-rhamnoside 34.2
Quercetin-3-xyloside 21.9
Quercetin- 3 -arabinoside 30.2
Myricetin 11.8
Anthocyanin Peonidin- 3-galactoside 27.2
Peonidin-3-glucoside 2.9
    Peonidin-3-arabinoside 14.3
Cyanidin-3-glucoside 1.1
Cyanidin-3-galactoside 22.5
Cyanidin-3-arabinoside 17.7
Phenolic acids Hydroxybenzoic Protocatechuic acid 21.7
Hydroxycinnamic acid p-Coumaric acid 51.7
Caffeoyl-glucoside 21.2
Coumaroyl-glucoside 10.7
Cafeic acid 14.3
Chlorogenic acid 33.8
*Measured by UPLC-MS/MS.


[0113] Proanthocyanidin levels are typically > 0.3% when measured using the BL-DMAC method (Prior et al., "Multi-laboratory validation of a standard method for quantifying proanthocyanidins in cranberry powders" J Sci Food Agric. 90:1473-8 (2010)), > 1.5% when measured using a modified HPLC method in which catechin monomers (quantified by HPLC-UV) are subtracted from total polyphenols measured by folin (Sakakibara et al., "Simultaneous Determination of All Polyphenols in Vegetables, Fruits and Teas" J. Agri. Food. Chem., Vol. 51. Pp 572-580 (2003); Methods in Enzymology, Volume 299, "Oxidants and Antioxidants Part A" Pages 152-178, 1999 (modified)), or > 5% when using a modified European Pharmacopeia method (European Pharmacopoeia 6.0; 01/2008:1220), and > 1% by HPLC-fluorescence.

[0114] Lignans are analyzed by UPLC-MS/MS using a 2.1mm x 150mm ACQUITY BEH C18 reverse phase 1.7µm particle size column. The column compartment was maintained at 30°C. The solvents used are (A) Formic acid 0.1% and (B) Acetonitrile. The gradient is 5% B, 8.0min, 30% B, 9.0min, 30%B, 10.0min, 50%B, 12.0min, 50%B, 15.0min, 95%B, 17.0min 95%B, 17.5min, 5%B, 23.0min, 5%B. The detection was done by MS/MS and all standard compounds were tuned individually. The results are shown in Table 5.
TABLE 5
NameConcentration (µg/100 g)
Lariciresinol 51.3
Lariciresinol-sesquilignan 3.8
Secoisolariciresinol 12.0
Pinoresinol 77.8

7.3 Example 3


Determination of Efficacy of Therapeutic Compositions Against LUTS



[0115] The therapeutic composition supplied by NATUREX-DBS LLC., USA, was used. Capsules consisted of either 500 mg of the therapeutic composition, or a combination of 250 mg of the therapeutic composition and 250 mg of placebo, or 500 mg of placebo. The composition of the placebo was as follows: low density STAR-DRI® 1015A maltodextrin, canola oil, Red 40 Lake, sodium aluminum silicate and Blue 1 Lake. The capsules were indistinguishable in appearance. All capsules were provided in identical plastic boxes with safe seal.

[0116] The study was a 6-month, single-center, randomized, double-blind, placebo controlled trial, consisting of three parallel treatment arms. Inclusion criteria comprised of: IPSS score between 8 to 19, individuals older than 45 years old and prostate specific antigen (PSA) values lower than 2.5 ng/mL. Exclusion criteria included food allergies, recent prostatitis, chronic liver or kidney diseases, as well as neurological, gastrointestinal or metabolic disorder or any other chronic health condition such as diabetes, excess consumption of caffeine or alcohol. Subjects were also ineligible if they had prior invasive treatment for BPH, recent treatment with α-blockers (within 1 month) or 5α-reductase inhibitors (within 6 months), phytotherapy including saw palmetto, beta-sitosterol, pygeum or other complementary therapy (within 3 months). The primary outcome measure was the IPSS, evaluated at baseline, 3 and 6 months. Secondary outcome measures included quality of life (QoL) at baseline, 3 and 6 months, as well as bladder voided volume (Vol), maximum urinary flow rate (Qmax), average urinary flow rate (Qave) and ultrasound estimated post-void residual urine volume (PVR), serum PSA, selenium, interleukin-6 (IL-6) and C-reactive protein (CRP), at baseline and 6 months.

[0117] Participants were randomly assigned to consume daily 500 mg of the therapeutic composition (n=40), 250 mg of the therapeutic composition (n=43) or placebo (n=41) for 6 months. The randomization plan for treatment assignment to subjects was generated with on line software QuickCalcs (GraphPad Software Inc., USA, last accessed on July 2nd, 2014) and carried out by study staff.

[0118] Participants were observed at baseline, on day-90 (3-month) and day-180 (6-month). During the health examination on the first day, and day-180 the following actions were required and health parameters were assessed: (i) detailed medical history, (ii) assessment of all concurrent medical drugs and therapies, (iii) dietary habits, (iv) completion of the IPSS questionnaire, including a question on QoL, (v) urinanalysis, (vi) uroflowmetry, (vii) kidney and bladder ultrasound and (viii) a blood laboratory analysis including PSA. On day-90, only the physical examination and IPSS score were performed. The therapeutic composition bottles were collected at day-90 and at the end of study. Compliance was assessed by performing remaining capsule counts.

[0119] Uroflowmetry data: Qmax and Qave were measured using FlowMic (Medkonsult, Czech Republic). The subjects were instructed not to urinate for several hours before the test and to drink at least 1L of fluids to ensure a full bladder. The Qmax and Qave were calculated by measuring the Vol per unit of time. PVR was assessed using an ultrasound device BK Medical Viking 2400 with abdominal probe 3-7 MHz. Vol and PVR were calculated using the formula for a prolate ellipsoid (width x length x height x 0.523). Qmax, Qave, Vol and PVR were measured on day-0 and day-180.

[0120] Basic biochemical and hematological parameters were determined in all samples using a HITACHI Modular Evo P analyzer (Hitachi, Japan). Serum PSA was determined using an Architect type LEIA analyzer (Abbott Laboratories, Abbott Park, IL, USA). CRP was determined by a Quikread 101 and IL-6 by the system Modular® Analytics. Selenium in plasma was estimated by atomic absorption spectrometry using the AA6300 instrument (Shimadzu, Japan). Hemoglobin (Hb), hematocrit (Htc), erythrocytes (RBC), thrombocytes (PLT) and leukocytes (WBC) were measured in Na2EDTA blood.

[0121] The data of the treatment groups was compared with respect to baseline measures using the Wilcoxon matched paired test. The primary and secondary analyses were based on the per protocol population that included all eligible participants who were treated during the entire length of the study. A Mann-Whitney U test was used to compare both treatment dose to placebo data. P-values <0.05 were considered to be significant.

[0122] An analysis of covariance was used to test whether there was an effect of the dose on the outcome measure at the end of treatment. This analysis of covariance used the daily dose units of 250 mg as a continuous variable and the baseline measurements of the outcome as a covariate. Box plots of residuals were examined against dose (0, 250, 500 mg) to determine whether the residuals were bell-shaped and whether there was an indication of a non-linear dose effect.

[0123] PVR was considered to follow a two-stage process because some proportion of participants had no measurable PVR. This proportion was modelled as a binomial distribution. The volume of urine among participants with PVR was modelled using a truncated Poisson distribution. This two stage model was fit using the hurdle function in the 'pscl' package (Stanford University) running on R version 3.0.0. Dose/250 mg, baseline PVR and baseline IPSS were entered into this model.

[0124] A total of 148 men were pre-screened for the study. Fig. 1 provides a CONSORT diagram of the 148 men attending the first screening visit. A total of 124 men were randomized, 41 to the placebo group, 43 to the therapeutic composition 250 mg group and 40 to the therapeutic composition 500 mg group. In the therapeutic composition 500 mg group, 2 participants were lost to follow-up and were not included in the per protocol analysis.

[0125] Table 6 presents a summary of baseline characteristics and LUT function measures across the three groups of the analysis. Results are presented as mean ± standard deviation (SD).
TABLE 6
 Placebo (n=41)Therapeutic Composition 250 mg (n=43)Therapetic Composition 500 mg (n=38)
Age (years) 54.0 ±5.1 53.3 ± 5.2 52.5 ± 5.4
Weight (kg) 89.3 ± 11.9 91.2 ± 11.9 90.1 ± 8.0
Height (cm) 178.5 ± 6.6 180.6 ± 6.6 180.7 ± 6.2
Body Mass Index 28.1 ± 3.8 27.9 ± 2.9 27.7 ± 3.0
Systolic Blood Pressure (mmHg) 131.1 ± 12.1 130.6 ± 10.1 132.1 ±11.5
Diastolic Blood Pressure (mmHg) 80.1 ± 7.3 80.5 ± 7.2 80.9 ± 7.4
Heart Beat (bpm) 68.9 ± 3.5 67.8 ± 4.6 68.1 ± 4.4
IPSS (score) 9.1 ± 2.0 9.7 ± 3.1 9.4 ± 2.0
PVR (mL) 15.0 ± 19.2 15.9 ± 23.2 17.8 ± 21.0
Qmax (mL/sec) 22.0 ± 7.8 20.5 ± 7.1 19.5 ± 7.5
Qave (mL/sec) 14.3 ± 5.2 12.5 ± 4.6 12.5 ± 5.5
Bladder Volume (mL) 408.5 ± 117.9 339.9 ± 114.4 339.0 ± 118.9


[0126] Participants had a mean age of 53.3 ± 5.4 years with a mean IPSS score of 9.4 ± 2.4. Adherence with scheduled visits was 98.4%. Compliance to the treatment was 100%. IPSS data with voiding and storage symptom subscore and QoL data during the 6-month treatment period are presented in Table 7. The voiding and storage subscores corresponded to questions 1 (incomplete emptying), 3 (intermittency), 5 (weak stream), 6 (straining) and questions 2 (frequency), 4 (urgency), 7 (nocturia), respectively. There was a decrease in IPSS score in the groups taking the therapeutic composition at 250 mg and at 500 mg at the end of the 6-month period with a significant difference versus placebo (p=0.05 and p<0.001, respectively using a Mann-Whitney U test).

[0127] Participants IPSS score, voiding and storage symptom score and quality of life score at baseline (Day-0), 3 months (Day-90) and 6 months (Day-180) after placebo, the therapeutic composition at 250 mg or 500 mg intake are shown in Table 7 and Table 8. In Table 7, results are presented as mean ± SD and as median along with first and third quartiles.
TABLE 7
  Day-0Day-90Day-180 
 GroupMean ± SD Median (1st and 3rd quartile)p-value*% change at day-180
Total IPSS score Placebo 9.1 ± 2.0   7.4 ± 2.0   7.6 ± 2.6    
8.0 (8.0 - 9.0)   7.0 (6.0 - 8.0)   8.0 (6.0 - 9.0)   0%
Therapeutic composition 250 mg 9.7 ± 3.1 0.63 7.6 ± 3.7 0.60 6.6 ± 3.4 0.05  
8.0 (8.0 - 10.0) 7.0 (5.0 - 10.0) 6.0 (5.0 - 8.0) -25%
Therapeutic composition 500 mg 9.4 ± 2.0 0.26 6.5 ± 2.6 0.11 5.3 ± 2.5 <0.001*  
9.0 (8.0 - 10.0) 7.0 (4.0 - 8.0) 5.0 (4.0 - 7.0) -44%
Voiding/obstructive symptoms score Placebo 4.9 ± 1.8   5.1 ± 2.4   4.6 ± 1.8    
5.0 (3.75 - 5.0)   4.0 (4.0 - 6.0)   4.0 (3.0 - 6.0)   -20%
  Therapeutic 3.7 ± 1.7 0.89 3.6 ± 2.7 0.44 2.9 ± 1.7 0.18  
  composition 250 mg 3.0 (3.0 - 5.0)   3.0 (2.0 - 5.0)   3.0 (2.0 - 4.0)   0%
  Therapeutic composition 500 mg 3.8 ± 2.4 0.55 3.4 ± 2.8 0.03* 2.3 ± 1.4 <0.001* *  
  4.0 (2.0 - 5.25) 3.0 - 5.0) 2.0 (1.0 - 3.0) -50%
Storage/irritative symptoms score Placebo 4.2 ± 1.3   4.6 ± 1.5   4.8 ± 1.6    
4.0 (3.75 - 5.0)   4.0 (4.0 - 5.75)   4.5 (4.0 - 6.0)   +13%
Therapeutic composition 250 mg 3.7 ± 1.4 0.27 3.8 ± 1.8 0.72 3.6 ± 2.0 0.13  
4.0 (3.0 - 4.25) 4.0 (2.0 - 4.75) 3.5 (2.0 - 5.0) -13%
Therapeutic composition 500 mg 3.7 ± 1.4 0.18 3.3 ± 1.5 0.61 3.0 ± 2.0 0.018*  
4.0 (3.0 - 5.0) 3.0 (2.0 - 4.0) 3.0 (2.0 - 4.0) -25%
Quality of Life Placebo 2.4 ± 0.9   2.1 ± 0.8   1.9 ± 0.7    
2.0 (2.0 - 3.0) 0.64 2.0 (2.0 - 2.0)   2.0 (1.75 - 2.0) 0.71 0%
Therapeutic composition 250 mg 2.4 ± 0.8 2.2 ± 0.9 0.52 2.0 ± 0.7  
2.0 (2.0 - 3.0) 2.0 (2.0 - 3.0)   2.0 (2.0 - 2.0) 0%
Therapeutic composition 500 mg 2.1 ± 0.7 0.03 2.0 ± 0.7 0.72 1.9 ± 0.5 0.63  
2.0 (2.0 - 2.0) 2.0 (2.0 - 2.0) 2.0 (2.0 - 2.0)       0%
*Denotes a significant difference versus placebo using the Mann-Whitney U test at each individual time point (p<0.05).


[0128] In Table 8, results represent the mean ± Standard Error of the Mean (SEM).
TABLE 8
GroupDay-0Day-90Day-180
IPSS Total Mean ± SEMIPSS Change versus baseline Mean ± SEMIPSS Change versus baseline Mean ± SEM
Placebo 9.1 ± 0.3 -1.71 ± 0.36 -1.54 ± 0.33
Therapeutic Composition 250 mg 9.7 ± 0.5 -2.16 ± 0.38 -3.09 ± 0.46*
Therapeutic Composition 500 mg 9.4 ± 0.3 -2.89 ± 0.36* -4.08 ± 0.31 *
*Denotes a significant difference versus placebo using the Mann-Whitney U test at each individual time point (p<0.05).


[0129] The mean difference in IPSS between baseline, 3-month and 6-month for the three groups is plotted in Fig. 2. Data points represent the mean difference ± the standard error of the mean. Asterisk indicates p<0.05 versus placebo based on analysis of covariance at the end of treatment. At 6-month, mean difference and corresponding 95% confidence interval (CI) were -1.5 (-2.2, -0.89) for the placebo group, -3.1 (-4.0, -2.2) for the therapeutic composition 250 mg group, and -4.1 (-4.7, -3.5) for the therapeutic composition 500 mg group.

[0130] Analysis of covariance for IPSS at 6-month with baseline IPSS entered as a covariate showed a significant dose effect (t1 19=-4.8, p<0.0001) and a significant effect of baseline score (t1 19=8.3, p<0.0001).

[0131] IPSS voiding subscore was significantly decreased when compared to placebo in the therapeutic composition 500 mg group 3 months after initiation of the treatment and up to 6 months (p=0.03 and p<0.001, respectively), while the IPSS storage subscore was significantly decreased versus placebo only at the end of the study (p=0.018). There was no statistically significant improvement in the IPSS storage subscore in the group treated with therapeutic composition at 250 mg. There was no change in the QoL questionnaire for both doses.

[0132] There was a significant improvement in all uroflowmetry parameters studied versus baseline at the end of the intervention with therapeutic composition at the 500 mg dose (p<0.05). Table 9 shows LUT function measurements at baseline (Day-0) and 6 months (Day-180) after placebo, therapeutic composition at 250 mg or 500 mg. Results in Table 9 are presented as mean ± SD.
TABLE 9
  Qmax, mL/sQave, mL/sPVR, mLVol, mL
Placebo Day-0 22.0 ± 7.8 14.3 ± 5.2 15.0 ± 19.2 408.5 ± 117.9
  Day-180 21.9 ± 8.6 14.2 ± 5.1 14.4 ± 18.3 364.3 ± 112.5
  p-value 0.424 0.722 0.956 0.004
Therapeutic composition Day-0 20.5 ± 7.1 12.5 ± 4.6 15.9 ± 23.2 339.9 ± 114.4
250 mg          
  Day-180 21.4 ± 6.7 13.2 ± 4.0 13.6 ± 18.1 368.6 ± 104.6
  p-value 0.191 0.107 0.588 0.279
Therapeutic composition Day-0 19.5 ± 7.5 12.5 ± 5.4 17.8 ± 21.0 339.0 ± 118.9
500 mg          
  Day-180 21.7 ± 8.9 13.8 ± 5.7 9.9 ± 13.6 393.0 ± 134.0
  p-value 0.018* 0.040* 0.027* 0.014*
*Denotes a significant difference versus baseline using the Wilcoxon Matched-Pairs test.


[0133] Further analysis was performed to evaluate whether there was a dose-response effect at the end of the intervention and whether the data could be adjusted based on baseline data.
A large proportion of participants reported no measurable PVR (17/41 for 0 mg dose; 22/43 for the 250 mg dose; and 19/38 for the 500 mg dose). While existence of a non-zero PVR was nominally lower in the 250 and 500 mg groups, no dose effect was found. Given the existence of residual volume however, that volume was significantly associated with dose (z=-3.0, p=0.003). This model indicates that among participants with non-zero PVR, residual urine volume would be expected to decrease by a factor of 0.09 (95% CI: 0.03-0.14) for every 250 mg increase in dose, for a given baseline PVR and IPSS.

[0134] Clinical hematology parameters, which were within normal range at the beginning and at the end of the study, thereby demonstrating the safety of the intervention product.

[0135] This double-blind, randomized, placebo controlled study demonstrated the efficacy and the safety of the daily intake of the therapeutic composition at 250 or 500 mg in men with LUTS for 6 months. At the end of the study, the decrease in IPSS score was significant and dose dependent (-3.1 and -4.1 in the 250 mg and 500 mg groups, p=0.05 and p<0.001, respectively) versus the placebo group (-1.5), while no side effects were observed.


Claims

1. A solid oral dosage form comprising 100 mg to 500 mg of a therapeutic composition, wherein the therapeutic composition comprises dried cranberry powder and cranberry seeds, or dried cranberry powder and cranberry seed meal, wherein the cranberry seeds or cranberry seed meal are present in the therapeutic composition in an amount of 15% to 25% by weight of the dried cranberry powder.
 
2. The solid oral dosage form of claim 1, wherein the cranberry is Vaccinium macrocarpon, Vaccinium microcarpon or Vaccinium oxycoccus.
 
3. The solid oral dosage form of claim 1 or 2, wherein the cranberry seeds or cranberry seed meal are present in the composition in an amount of 20% by weight of the dried cranberry powder.
 
4. The solid oral dosage form of any one of claims 1-3, wherein the composition comprises less than 10% of organic acids by weight.
 
5. The solid oral dosage form of any one of claims 1-4, wherein the composition comprises less than 15% of sugars by weight.
 
6. The solid oral dosage form of any one of claims 1-5, wherein the composition comprises from 1% to 5% of quinic acid by weight.
 
7. The solid oral dosage form of any one of claims 1-6, wherein the composition comprises from 0.4% to 4% of malic acid by weight.
 
8. The solid oral dosage form of any one of claims 1-7, wherein the composition comprises from 1% to 5% of citric acid by weight.
 
9. The solid oral dosage form of any one of claims 1-8, wherein the composition comprises

• 1 to 100 µg, preferably about 51 µg lariciresinol;

• 1 to 100 µg, preferably about 12 µg secoisolariciresinol; or

• 1 to 100 µg, preferably about 78 µg pinoresinol per 100g
of the composition by weight.


 
10. The solid oral dosage form of any one of claims 1-9, which is a tablet, a capsule or a softgel.
 
11. The solid oral dosage form of any one of claims 1-10, comprising 100 mg to 500 mg, preferably 250 mg, more preferably 500 mg of the therapeutic composition.
 
12. A therapeutic composition comprising dried cranberry powder and cranberry seeds, or dried cranberry powder and cranberry seed meal, wherein the cranberry seeds or cranberry seed meal are present in the therapeutic composition in an amount of 15% to 25% by weight of the dried cranberry powder, for use in a method of

• alleviating lower urinary tract symptoms (LUTS) or the symptoms of benign prostatic hyperplasia (BPH) in a subject; or

• treating erectile dysfunction (ED), urinary incontinence, overactive bladder (OAB), bladder obstruction, interstitial cystitis, underactive bladder, prostatitis, bladder and prostate inflammation, prostate fibrosis or pelvic pain in a subject.


 
13. The therapeutic composition for use according to claim 12, wherein the subject is a human.
 
14. The therapeutic composition for use according to claim 13, wherein the human is a male.
 
15. The therapeutic composition for use according to claim 13, wherein the human is a female.
 


Ansprüche

1. Feste orale Darreichungsform, umfassend 100 mg bis 500 mg an einer therapeutischen Zusammensetzung, wobei die therapeutische Zusammensetzung getrocknetes Cranberrypulver und Cranberrysamen oder getrocknetes Cranberrypulver und Cranberrysamenmehl umfasst, wobei die Cranberrysamen oder das Cranberrysamenmehl in einer Menge von 15 Gew.-% bis 25 Gew.-% des getrockneten Cranberrypulvers in der therapeutischen Zusammensetzung vorhanden sind/ist.
 
2. Feste orale Darreichungsform gemäß Anspruch 1, wobei die Cranberry Vaccinium macrocarpon, Vaccinium microcarpon oder Vaccinium oxycoccus ist.
 
3. Feste orale Darreichungsform gemäß Anspruch 1 oder 2, wobei die Cranberrysamen oder das Cranberrysamenmehl in einer Menge von 20 Gew.-% des getrockneten Cranberrypulvers in der Zusammensetzung vorhanden sind/ist.
 
4. Feste orale Darreichungsform gemäß einem der Ansprüche 1-3, wobei die Zusammensetzung weniger als 10 Gew.-% an organischen Säuren umfasst.
 
5. Feste orale Darreichungsform gemäß einem der Ansprüche 1-4, wobei die Zusammensetzung weniger als 15 Gew.-% an Zuckern umfasst.
 
6. Feste orale Darreichungsform gemäß einem der Ansprüche 1-5, wobei die Zusammensetzung von 1 Gew.-% bis 5 Gew.-% Chinasäure umfasst.
 
7. Feste orale Darreichungsform gemäß einem der Ansprüche 1-6, wobei die Zusammensetzung von 0,4 Gew.-% bis 4 Gew.-% Apfelsäure umfasst.
 
8. Feste orale Darreichungsform gemäß einem der Ansprüche 1-7, wobei die Zusammensetzung von 1 Gew.-% bis 5 Gew.-% Citronensäure umfasst.
 
9. Feste orale Darreichungsform gemäß einem der Ansprüche 1-8, wobei die Zusammensetzung

• 1 bis 100 µg, vorzugsweise etwa 51 µg, Lariciresinol;

• 1 bis 100 µg, vorzugsweise etwa 12 µg, Secoisolariciresinol; oder

• 1 bis 100 µg, vorzugsweise etwa 78 µg, Pinoresinol
pro 100 g der Zusammensetzung nach Gewicht umfasst.


 
10. Feste orale Darreichungsform gemäß einem der Ansprüche 1-9, die eine Tablette, eine Kapsel oder ein Softgel ist.
 
11. Feste orale Darreichungsform gemäß einem der Ansprüche 1-10, umfassend 100 mg bis 500 mg, vorzugsweise 250 mg, bevorzugter 500 mg, der therapeutischen Zusammensetzung.
 
12. Therapeutische Zusammensetzung, umfassend getrocknetes Cranberrypulver und Cranberrysamen oder getrocknetes Cranberrypulver und Cranberrysamenmehl, wobei die Cranberrysamen oder das Cranberrysamenmehl in einer Menge von 15 Gew.-% bis 25 Gew.-% des getrockneten Cranberrypulvers in der therapeutischen Zusammensetzung vorhanden sind/ist, zur Verwendung bei einem Verfahren zum

• Lindern von Symptomen des unteren Harntrakts (LUTS) oder der Symptome von benigner Prostatahyperplasie (BPH) bei einem Subjekt; oder

• Behandeln von erektiler Dysfunktion (ED), Harninkontinenz, überaktiver Blase (OAB), Blasenobstruktion, interstitieller Zystitis, unteraktiver Blase, Prostatitis, Blasen- und Prostataentzündung, Prostatafibrose oder Unterleibsschmerz bei einem Subjekt.


 
13. Therapeutische Zusammensetzung zur Verwendung gemäß Anspruch 12, wobei das Subjekt ein Mensch ist.
 
14. Therapeutische Zusammensetzung zur Verwendung gemäß Anspruch 13, wobei der Mensch ein Mann ist.
 
15. Therapeutische Zusammensetzung zur Verwendung gemäß Anspruch 13, wobei der Mensch eine Frau ist.
 


Revendications

1. Forme de dosage oral solide comprenant 100 mg à 500 mg d'une composition thérapeutique, la composition thérapeutique comprenant de la poudre de canneberge séchée et des graines de canneberge, ou de la poudre de canneberge séchée et de la farine de graine de canneberge, les graines de canneberge ou la farine de graine de canneberge étant présente(s) dans la composition thérapeutique en une quantité de 15 % à 25 % en poids de la poudre de canneberge séchée.
 
2. Forme de dosage oral solide selon la revendication 1, la canneberge étant Vaccinium macrocarpon, Vaccinium microcarpon ou Vaccinium oxycoccus.
 
3. Forme de dosage oral solide selon la revendication 1 ou 2, les graines de canneberge ou la farine de graine de canneberge étant présente(s) dans la composition en une quantité de 20 % en poids de la poudre de canneberge séchée.
 
4. Forme de dosage oral solide selon l'une quelconque des revendications 1 à 3, la composition comprenant moins de 10 % d'acides organiques en poids.
 
5. Forme de dosage oral solide selon l'une quelconque des revendications 1 à 4, la composition comprenant moins de 15 % de sucres en poids.
 
6. Forme de dosage oral solide selon l'une quelconque des revendications 1 à 5, la composition comprenant de 1 % à 5 % d'acide quinique en poids.
 
7. Forme de dosage oral solide selon l'une quelconque des revendications 1 à 6, la composition comprenant de 0,4 % à 4 % d'acide malique en poids.
 
8. Forme de dosage oral solide selon l'une quelconque des revendications 1 à 7, la composition comprenant de 1 % à 5 % d'acide citrique en poids.
 
9. Forme de dosage oral solide selon l'une quelconque des revendications 1 à 8, la composition comprenant

• 1 à 100 µg, préférablement environ 51 µg de laricirésinol ;

• 1 à 100 µg, préférablement environ 12 µg de sécoisolaricirésinol ; ou

• 1 à 100 µg, préférablement environ 78 µg de pinorésinol par 100 g
de la composition en poids.


 
10. Forme de dosage oral solide selon l'une quelconque des revendications 1 à 9, qui est un comprimé, une capsule ou une gélule souple.
 
11. Forme de dosage oral solide selon l'une quelconque des revendications 1 à 10, comprenant 100 mg à 500 mg, préférablement 250 mg, plus préférablement 500 mg de la composition thérapeutique.
 
12. Composition thérapeutique comprenant de la poudre de canneberge séchée et des graines de canneberge, ou de la poudre de canneberge séchée et de la farine de graine de canneberge, les graines de canneberge ou la farine de graine de canneberge étant présente(s) dans la composition thérapeutique en une quantité de 15 % à 25 % en poids de la poudre de canneberge séchée, pour une utilisation dans un procédé

• de soulagement de symptômes des voies urinaires inférieures (LUTS) ou des symptômes d'hyperplasie prostatique bénigne (BPH) chez un sujet ; ou

• de traitement d'un dysfonctionnement érectile (ED), de l'incontinence urinaire, de la vessie hyperactive (OAB), d'une obstruction de la vessie, d'une cystite interstitielle, de la vessie hypoactive, d'une prostatite, d'une inflammation de la vessie et de la prostate, d'une fibrose de la prostate ou d'une douleur pelvienne chez un sujet.


 
13. Composition thérapeutique pour une utilisation selon la revendication 12, le sujet étant un humain.
 
14. Composition thérapeutique pour une utilisation selon la revendication 13, l'humain étant masculin.
 
15. Composition thérapeutique pour une utilisation selon la revendication 13, l'humain étant féminin.
 




Drawing











Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description