US20160324911A1 - Compositions and methods useful in treatment of lower urinary tract symptoms, benign prostatic hyperplasia, erectile dysfunction - Google Patents

Compositions and methods useful in treatment of lower urinary tract symptoms, benign prostatic hyperplasia, erectile dysfunction Download PDF

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US20160324911A1
US20160324911A1 US15/150,722 US201615150722A US2016324911A1 US 20160324911 A1 US20160324911 A1 US 20160324911A1 US 201615150722 A US201615150722 A US 201615150722A US 2016324911 A1 US2016324911 A1 US 2016324911A1
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composition
acid
weight
glucoside
quercetin
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Emilie Annie Claudie Fromentin
Douglas Andrew Klaiber
Daniel David Souza
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Naturex Inc
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Naturex DBS LLC
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Priority to US15/150,722 priority Critical patent/US20160324911A1/en
Assigned to Naturex-DBS, LLC reassignment Naturex-DBS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FROMENTIN, EMILIE ANNIE CLAUDIE, KLAIBER, DOUGLAS ANDREW, SOUZA, DANIEL DAVID
Publication of US20160324911A1 publication Critical patent/US20160324911A1/en
Priority to US15/979,265 priority patent/US11045511B2/en
Priority to US16/532,367 priority patent/US10898534B2/en
Priority to US16/661,749 priority patent/US11291703B2/en
Priority to US17/682,190 priority patent/US20220175863A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
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    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • 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.
  • LUTS lower urinary tract symptoms
  • BPH benign prostatic hyperplasia
  • ED erectile dysfunction
  • urinary incontinence urinary incontinence
  • LUTS Lower urinary tract symptoms
  • BPH benign prostatic hyperplasia
  • 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.
  • IIPSS international prostate symptoms score
  • 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.
  • 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.
  • 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.
  • ED erectile dysfunction
  • Benign prostatic hyperplasia 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.
  • 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.
  • OAB Overactive bladder
  • 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.
  • LUTS lower urinary tract symptoms
  • the invention provides a therapeutic composition comprising dried cranberry powder and dried cranberry seeds.
  • the invention provides therapeutic composition comprising dried cranberry powder and cranberry seed meal.
  • the cranberry is Vaccinium macrocarpon.
  • the cranberry is Vaccinium microcarpon.
  • the cranberry is Vaccinium oxycoccus.
  • the cranberry seeds are present in an amount of about 5% to about 50% by weight of the dried cranberry powder.
  • the cranberry seeds are present in an amount of about 15% to about 25% by weight of the dried cranberry powder.
  • the cranberry seeds are present in an amount of about 20% by weight of the dried cranberry powder.
  • the cranberry seed meal is present in an amount of about 5% to about 50% by weight of the dried cranberry powder.
  • the cranberry seed meal is present in an amount of about 15% to about 25% by weight of the dried cranberry powder.
  • the cranberry seed meal is present in an amount of about 20% by weight of the dried cranberry powder.
  • the composition comprises less than about 12% of organic acids by weight.
  • the composition comprises less than 10% of organic acids by weight.
  • the composition comprises about 5% to about 8% of organic acids by weight.
  • the composition comprises less than about 15% of sugars by weight.
  • the composition comprises less than about 12% of sugars by weight.
  • the composition comprises from about 1% to about 5% of quinic acid by weight.
  • the composition comprises from about 2.2% to about 3.2% of quinic acid by weight.
  • the composition comprises from about 0.4% to about 4% of malic acid by weight.
  • the composition comprises from about 0.8% to about 1.8% of malic acid by weight.
  • the composition comprises from about 1% to about 5% of citric acid by weight.
  • composition comprises from about 1.8% to about 3.2% of citric acid by weight.
  • 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%
  • 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, 0.01
  • 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.
  • the composition comprises 1 to 100 ⁇ g lariciresinol, 1 to 100 ⁇ g secoisolariciresinol or 1 to 100 ⁇ g/pinoresinol per 100 g of the composition by weight.
  • the composition comprises about 51 ⁇ g lariciresinol, about 12 ⁇ g secoisolariciresinol or about 78 ⁇ g/pinoresinol per 100 g of the composition by weight.
  • the invention provides a solid oral dosage form comprising a therapeutic composition described above.
  • the solid oral dosage is a tablet.
  • the solid oral dosage is a capsule.
  • the solid oral dosage is a softgel.
  • the solid oral dosage comprises 100 mg to 500 mg of the therapeutic composition.
  • the solid oral dosage comprises 250 mg of the therapeutic composition.
  • the solid oral dosage comprises 500 mg of the therapeutic composition.
  • the invention provides 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 described above.
  • LUTS lower urinary tract symptoms
  • the invention provides 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 described above.
  • BPH benign prostatic hyperplasia
  • the invention provides a method for treating erectile dysfunction (ED) in a subject comprising administering to the subject in need thereof an effective amount of the composition described above.
  • ED erectile dysfunction
  • the invention provides a method for treating urinary incontinence in a subject comprising administering to the subject in need thereof an effective amount of the composition described above.
  • the invention provides a method for treating overactive bladder (OAB) in a subject comprising administering to the subject in need thereof an effective amount of the composition described above.
  • OAB overactive bladder
  • the invention provides 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 described above.
  • the subject is a human
  • the human is a male.
  • the human is a female.
  • 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.
  • IVS international prostate symptom scores
  • variable 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.
  • 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.
  • “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%.”
  • Cranberry fruit e.g., Vaccinium macrocarpon
  • Cranberry fruit 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.
  • PACs proanthocyanidins
  • compositions described herein can include one or more components described below in the ranges provided below.
  • 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.
  • Cranberry seeds can be present in the therapeutic composition in an amount of about 5% to about 50%, 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 5% to about 50%, about 15% to about 25%, or about 20% by weight of the dried cranberry powder.
  • a therapeutic composition can comprise less than about 12%, less than about 10%, or about 5% to about 8% of organic acids by weight.
  • organic acids include, but are not limited to, quinic acid, malic acid, and citric acid.
  • 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 ⁇ m particle size, 25 cm ⁇ 4.6 mm in tandem with and followed by C18 reverse phase cartridges, with a 5 ⁇ m particle size and 10 cm long.
  • Phosphate buffer, 0.2M KH 2 PO 4 , pH 2.4 is used.
  • the flow rate is 0.80 mL/min
  • the analysis is performed at ambient temperature
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the sugar content can be determined by HPLC, using the following modification of protocol AOAC 977.20.
  • the column used is ⁇ -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 ⁇ m filter. 10 ⁇ L 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 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,
  • 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.
  • the content of anthocyanins 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.
  • 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.
  • 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,
  • 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.
  • the therapeutic composition comprises 1 to 100 ⁇ g or about 51 lariciresinol per 100 g of the composition. In some embodiments, the therapeutic composition comprises 1 to 100 ⁇ g or about 12 ⁇ g secoisolariciresinol per 100 g of the composition. In some embodiments, the therapeutic composition comprises 1 to 100 ⁇ g or about 78 ⁇ g pinoresinol per 100 g of the composition.
  • 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, 8.0 min, 30% B, 9.0 min, 30% B, 10.0 min, 50% B, 12.0 min, 50% B, 15.0 min, 95% B, 170 min 95% B, 17.5 min, 5% B, 23.0 min, 5% B.
  • the detection is done by MS/MS and all standard compounds are tuned individually.
  • 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.
  • a solid oral dosage comprising the therapeutic composition described herein is a tablet, a capsule, or a softgel.
  • such solid oral dosage 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.
  • 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.
  • 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.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • 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 can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • the composition is in the form of a capsule (see, e.g., U.S. Pat. No. 5,698,155).
  • suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995).
  • 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.
  • 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.
  • 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.
  • 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.
  • excipients are of pharmaceutical grade.
  • 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, hydroxypropylmethyl-cellulose 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.
  • 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.
  • 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.
  • Dragee cores are provided with suitable coatings.
  • 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.
  • 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. Pat. Nos. 5,674,533; 5,059,595; 5,120,548; 5,073,543; 5,639,476 and 5,354,556, each of which is incorporated herein by reference in its entirety.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • LUTS lower urinary tract symptoms
  • BPH benign prostatic hyperplasia
  • ED erectile dysfunction
  • OAB overactive bladder
  • underactive bladder prostatitis, bladder and prostate inflammation, prostate fibrosis or pelvic pain.
  • the kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent.
  • prophylactic or therapeutic agents include, but are not limited to, those listed above.
  • 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.
  • 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.
  • BPH benign prostatic hyperplasia
  • 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.
  • Benign prostatic hyperplasia (BPH), a histological condition characterized by the non-malignant overgrowth of prostatic tissue surrounding the urethra.
  • 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.
  • 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.
  • 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.
  • the therapeutic compositions described herein are useful for alleviating the symptoms of, treating or preventing overactive bladder (OAB). Accordingly, described herein are 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m particle size, 25 cm ⁇ 4.6 mm in tandem with and followed by C18 reverse phase cartridges, with a 5 ⁇ m particle size and 10 cm long.
  • Phosphate buffer, 0.2M KH 2 PO 4 , pH 2.4 is used.
  • the elution is isocratic, flow rate 0.80 mL/min, ambient temperature and wavelength 214 nm.
  • 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 ⁇ -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 ⁇ m filter. 10 ⁇ L 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 results are presented in Table 3 below.
  • 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 ⁇ 4, 6 mm with a 4 ⁇ m 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.
  • the rest of the phenolics are analyzed by UPLC-MS/MS using the following method.
  • An Acquity T3 column 150 mm ⁇ 2.1 mm id, 1.8 ⁇ m 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.
  • 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.
  • Lignans are analyzed by UPLC-MS/MS using a 2.1 mm ⁇ 150 mm ACQUITY BEH C18 reverse phase 1.7 ⁇ m 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, 8.0 min, 30% B, 9.0 min, 30% B, 10.0 min, 50% B, 12.0 min, 50% B, 15.0 min, 95% B, 17.0 min 95% B, 17.5 min, 5% B, 23.0 min, 5% B.
  • the detection was done by MS/MS and all standard compounds were tuned individually. The results are shown in Table 5.
  • 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.
  • 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 ⁇ -blockers (within 1 month) or 5 ⁇ -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.
  • QoL quality of life
  • Vol bladder voided volume
  • Qmax maximum urinary flow rate
  • Qave average urinary flow rate
  • PVR ultrasound estimated post-void residual urine volume
  • serum PSA selenium
  • IL-6 interleukin-6
  • CRP C-reactive protein
  • the randomization plan for treatment assignment to subjects was generated with on line software QuickCalcs (GraphPad Software Inc., USA, last accessed on Jul. 2, 2014) and carried out by study staff.
  • 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.
  • 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 1 L 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 ⁇ length ⁇ height ⁇ 0.523). Qmax, Qave, Vol and PVR were measured on day-0 and day-180.
  • HITACHI Modular Evo P analyzer HITACHI Modular Evo P analyzer (Hitachi, Japan). Serum PSA was determined using an Architect type LEIA analyzer (Abbott Laboratories, Abbott Park, Ill., 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 Na 2 EDTA blood.
  • Hb Hemoglobin
  • Htc hematocrit
  • RBC erythrocytes
  • PTT thrombocytes
  • WBC leukocytes
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • results represent the mean ⁇ Standard Error of the Mean (SEM).
  • 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.
  • 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.
  • 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.
  • 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.

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