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WO2016123650A1 - Méthodes et compositions utilisant de la bêta-cryptoxanthine destinées à allonger la durée de la vie reproductive - Google Patents

Méthodes et compositions utilisant de la bêta-cryptoxanthine destinées à allonger la durée de la vie reproductive Download PDF

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Publication number
WO2016123650A1
WO2016123650A1 PCT/AU2016/000022 AU2016000022W WO2016123650A1 WO 2016123650 A1 WO2016123650 A1 WO 2016123650A1 AU 2016000022 W AU2016000022 W AU 2016000022W WO 2016123650 A1 WO2016123650 A1 WO 2016123650A1
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Prior art keywords
bcx
prodrug
solvate
acceptable salt
composition
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PCT/AU2016/000022
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English (en)
Inventor
Kelton Paul Tremellen
Karma Louise PEARCE
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University of South Australia
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University of South Australia
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Priority claimed from AU2015900340A external-priority patent/AU2015900340A0/en
Application filed by University of South Australia filed Critical University of South Australia
Publication of WO2016123650A1 publication Critical patent/WO2016123650A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis

Definitions

  • the present invention relates to methods and compositions for delayin the onset of .menopause and/or slowing the rate of loss of ovarian reserve.
  • a woman is born with her total oocyte compliment (ie a pool of approximately 1 -2 million primordial follicles) and cannot generate an new oocytes from this time forward.
  • the total compliment of oocytes within a woman's ovaries is termed the "ovarian reserve" (te Velde and Pearson, 2002).
  • oocytes primordial follicles
  • apoptotic programmed cell death
  • Loss of ovarian reserve is a relatively new cause for primary infertility, with its onset being linked to the development of safe and effective reversible contraception and the professional/educational enianc i patiofl of women that occurred from the 1960's .
  • the a verage age of a woman at the time of the birth of her first child was around 23-25 years in tire developed world. No . with the advent of better education and career advancement for women, and empowered by effectiv
  • a method of delaying the onset of menopause and/or slowing the rate of loss of ovariao reserve comprising administering a therapeutically effective amount of beta-crypto artthirt (bCX) or a pharinaeeutieally acceptable salt, solvate or prodru thereof to a female subject.
  • bCX beta-crypto artthirt
  • a pharinaeeutieally acceptable salt solvate or prodru thereof
  • the method comprises administering from about 5 micrograms (pg) to about 10.000 pg per day or about 400 jig. to about 1200 pg pe d ay of bCX or a pharmaceutically acceptable salt solvate or prodrug thereof to the female subject.
  • the method comprises administering from about 140 pg to aboiit 310,000 pg per month of bCX or a phannaceutic y acceptable salt, solvate or prodrug thereof to the female subject.
  • the bCX or phamiaeeutiealiy acceptable salt., solvate or prodrug thereof i administered in combinatio with a contraceptive agent.
  • the bCX or pharmaceutically acceptable salt, solvate o prodrug thereof is administered in combination with a iBuiuvitatniri agent.
  • the bCX may be administered by way of a composition comprising bCX.
  • compositions for delayin the onset of menopause and/or slowing the rate of loss of ovarian reserve comprising a therapeutically effective amount of a therapeutic agent comprising beta-cryptoxantlHn (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof wherein, ; upon administration to a female subject, the composition delays the onset of menopause and/or slows the rate of loss f ovarian reserve.
  • a therapeutic agent comprising beta-cryptoxantlHn (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof
  • the therapeutical iy effective amount of bC or phanTsaceufically acceptable salt, solvate or prodrug thereof in the composition is from about 5 pg to about 5 grams (g), from about 160 ⁇ ig to about 4800 p.g or from about 400 ⁇ to about 1200 ig.
  • the therapeutic agent consists of bCX or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In other words, there are no other therapeutically acti ve agents hi the CompositiOn.
  • the composition is in the form of a non- contraeeptive sugar pill for use in a dail contraceptive regime. In other certain embodiments of the second aspect, the composition further comprises at least one contraceptive agent.
  • the composition is in the form of a dosage form that provides a dose of bCX or a pharmaceutically aceeptable salt, solvate or prodrug thereof that i equivalent to a dail dose of from about 5 pg to about 1.0,000 .
  • the composition may be a pharm aceutical preparati on comprisi n g the composi tion of the second aspect and one or more pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical preparation may comprise a plurality of dosage unit Suitable for consecutive daily oral administration.
  • a. combination product for oral contraception and delaying the onset of mcnopan.se and/or slo wing the rate of loss of ovarian reserve comprising;
  • contraceptive dosage units each comprisin an effecti ve amount of at least one contraceptive agent and an effective amount of beta-cryptoxanthin (bCX) or a
  • .contraceptive agent-free placebo dosage units each comprising an effective amount of bCX or a pharmaceutically aceeptable salt, solvate or prodrug thereof; and, optionally, instructions or indications to show that the daily administration of the 21. to 24 contraceptive dosage. units, is to be followed by daily administration, of 7 to 4, respectively, contraceptive agent-free placebo dosage units,
  • an injectable dosag form comprising bCX or a
  • pharmaceutically acceptable salt, solvate or prodrug thereof and one: or more pharmaceutically acceptable carriers and exeipients for del ayin the onset of menopause and/or .slowing, the rate of loss of ovarian reserve,; wherein the dosage form delivers from about 50 p to about 10,000 pg of eta-cryptoxanthm. (bCX) or pharmaceutically acceptable salt solva te or prodrug thereof per dosage form or per day,
  • a subcutaneous implantable dosag form comprising beta- cryptoxanthin (bQC) or a pharmaceutically acceptable salt, solvate or prodrug thereof and one orraoie pharmaceutically acceptable carriers: and excipients fo delaying the onset of menopause and/or sl owing th e rate of loss of varian reserve, wherein the dosage fbnn delivers from about 50 pg to abou t .10,000 pg of bCX or pharmaceutically acceptabl salt, solvate or prodrug thereof per dosage form or per day,
  • beta-cryptoxanfhin. or a pharmaceutically acceptable salt, solvate or prodrug, thereof for delaying the onset of menopaus and/or slowing the rat of loss of o varian reserve in a female subject and/or in the preparation of a medicament tor delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve in a female subject.
  • the bCX or pharmaceutically acceptable salt, solvate or prodru thereof is administered in combination with a contraceptive agent,
  • the bCX is administered in combination with, a multivi amin agent,
  • kits comprising beta-ciyptoxanthin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof, at least one contraceptive agent and instructions, for the us e of said kit in a method for delayin the onset of menopause and/or slo wing the rate of loss of ovarian reserve,
  • kits comprising: crizosin, a tetrachlorin, or a tetrachlorin, or a tetrachlorin, or a tetrachlorin, or a tetrachlorin, or a tetrachlorin, or a tetrachlorin, or a tetrachlorin, or a tetrachlorin, or a titoxanihin . (bCX) or a
  • pro ided herein is a method, use, composition, injectable dosage tbrf3 ⁇ 4 subcutaneous implantable dosage form and kit for enhancing fertility in a female subject such as an
  • Figure 1 provides graphical results of a rat study showing the litter size and rat of sterile matiogs in dams mated at 7 months of age. Animals of the. hCX implant group received subcutaneously administered bCX (5 pg/day) from 3 months of age ; and j 0031 ] Figure 2 provides further graphical results of the rat study; this time showing' the lifter size and rate of sterile mat ings in dams m ated at 9 months of age.
  • a method of delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve comprises administering a therapeutically effective m u t of beta-cryptoxanthin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof to a female subject.
  • bCX beta-cryptoxanthin
  • administering includes all means of introducing bCX to the female subject including, but not limited to, oral, intravenous, intramuscular, subcutaneous, transdermal, inhalation, buccal, ocular, sublingual and -rectal, routes.
  • Beta-eryptoxanthin ((iQ-3,5,5 ⁇ triffiethyl-4
  • J -enyl)-oetadeca-l, 3,5,7,9 ,.1,1, 1.3, 15,17-n ' Qnaenyl]-cyclohex-3-enol belongs to the class of earotenoids, more specifically the xanthophyils. In plants, earotenoids are involved in light harvesting in
  • Vitamin A activity as they are converted to rctinai (Institute of Medicine, Food and Nutrition Board, 2000). Vitamin A is essential for normal growth and development, inumme system function, and vision. The vitami A. activity of bCX and alpha-carotene are both. I /24th thatof tetinol
  • vitamin A may potentiall have an. adverse effect on ovarian reserve if consumed in ' high quantities (Abali a ., 2013, Sikar Aktiirk ef L, 2013).
  • isotretinoin synthetic analogue of vitamin A, commonl used to treat severe acne
  • ovarian reserve has recentl been reported to result in a significant loss of ovarian reserve in both, rodent and human studies (Abali t, 2013, Sikar Aktiirk et l, 2013).
  • long term consumption of high amounts of vitamin A in food or vitamin supplements,, or vitamin A precursors could potentially result in damage to a woman's ovarian reserve.
  • the structurally related bCX can be used to protect ovarian, reserve and delay the onset of menopause.
  • Beta-ctyptoxanthin can be found in many vegetables and . ruits, including papaya, mango, peaches, oranges, tangerines:, bell peppers, com and watermelon. BCX is also found in some yellow coloured animal products such as egg yolk and batter. Further, bCX is found in petals arid flowers of plants in the nus Phymlti and in bovine blood serum.
  • the therapeutically effective amount of b K administered to the female subject according to the method described herein should be sufficient to cause a beneficial response in the subject over time.
  • the therapeutically effective amount of bCX is between 5 micrograms (pg) and 10 grams (g).
  • the therapeutically effective amount of bCX is- between 5 ug and 5 g, 10 pg: and 4 g., 25 pg and 3 g, 50 fig and 2 g, 100 pg and 1 g, 200 p and 500 milligrams (nig), 300 pg and 250 mg, 400 pg and 1 0 mg, 500 pg and 50 mg, 600 pg and 25 mg, 700 pg and 10 mg, 700 p.g and 5 mg, 700 and 2500 pg, 80 ug and 200 pg, 800 and 1600 pg, 80 pg and 120 pg, and 900 pg and 11 0 pg, ⁇ 00 and 1100 pg, 1,000 and 5000 pg or any sub-range of these specified ranges, in certain embodiments, the therapeutically effective amount of bCX is about 5, 1 , 25, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1
  • the method relates to administerin a therapeutically effective amount of bCX to the female subject each. day. '
  • the fliefapeutically effecti v amount of bCX administered to the female subject, per day ma be between 5 pg and 10,000 . . In.
  • the therapeutically effective amount of bCX administered to the female subject per day is: between ' " 10 and 9000 ug, 25 and 800 ⁇ & 50 and 7000 ⁇ & 100 and 5000 ⁇ & 200 and 2500 ⁇ & 300 and 1800 ⁇ & 400 and 1200 ug, 600 and 1200 ug, 800 and 11 0 pg, 1 00 and 5000 pg or any sub-range of these specified ranges.
  • the method relates to administering a therapeutieali effective amount of bCX to the female subject each month, in these embodiments, the therapeutically ' effective amount of bC administered to the female subject per month is about 140 ug (ie the equivalent of 5 ⁇ per day in a 28 day month) and 310 mg fie the equivalent of 10,000 pg per day i a.31 day month).
  • the method may comprise admini stering the dverapeutieaily effective amoun t of bCX to the female subject on.
  • the bCX may be administered n combination with a contraceptive agent.
  • the contraceptive agent may be se lec ted from any contraceptive agents known to those skilled in the- art.
  • the contraceptive agent may be a single agent or a combination of agents, as is known in the art in certain, embodiments;, the contraceptive agent comprises any one or more of an oestrogen and a progestogen.
  • the at least one oestrogen is selected from 1.7-beta-estradiol and ethmyleStTadiol, estradiol, estrop ate, natural conjugated equine estrogens, conjugated syn the lie estrogens, esterified estrogens, estroge suiphamate, estrone sulfate, piperazine estrone sulfate, tnestranol, esttioi, estrone, estradiol valerate, dinestrol, or any combinations: thereof
  • the at least one progestogen is selected from gestodene, levonorgestrel, etonogesteroi, desogestreL dienogest, 3-ketodesogestrel, drospirenone, cyproterone acetate, norgestirnate, narelgestromm, nomegestrol acetate, norethisterone, dydrogestcrone,
  • the amount of contraceptive, agent administered in combination with the bC is equivalent to daily dose of between 0.001 mg and 200 mg of the contraceptive agent
  • the amount of contraceptive agent administered in combination with the bCX is equivalent to a daily dose of between 0.001 mg and 10 mg, 0.001 mg and 50 mg, 0.001 mg and 25 mg, 0.0 1 and 10 mg, 0.01 and 5 mg, 0.01 and 3 mg, 0.01 and 2 mg, 0.01 and 1 mg or any sub-range of these specified ranges.
  • the am unt of contraceptive agent administered in combination with the hCX is selected from 0.1 to 6,0 mg of estradiol and 0.0 1 nig to 3 nig of ethinyiestradioi, and 0,01 to 3 mg of gestodene, 0.02 to 0.25 mg of levonotgestrel, 0.02 to 0.5 mg of desogestrel, 0.01 to 0.5 mg of 3- ketodesogestrel, 0. 1. to 6 nrg of drospirenone, 0. 1 to 3 ig of eyproterone acetate, 0.01 to.2 mg of norgestimate, 0,1 to 60 mg of norethisterone, 0,1 to 20 mg ofdydrogesterone, 0,J. to .150 nig of medioxypKjgesterone and 0.1 to 5 mg of norgestrel,
  • the bCX is administered in eombination with a multivitamin agent.
  • the multivitamin agent may comprise any one or more of alpha-carotene,, beta-car oicne, biotin, calcium, chloride, chaudroitin, chromium, copper, coenzyme QiO, a fatty acid such as ome a-3 (eg
  • EPA eieosapentaenoic acid
  • DHA docosahexaenoic acid
  • omega- fatty acid folic acid
  • glucosamine iodine
  • iron lutein
  • magnesium malic acid
  • manganese eieosapentaenoic acid
  • the amount of the muiiivitanun agent is about 5, 10, 25, 50.
  • the amount of alpha-carotene administered may be between 1 and 5000 iU, the amount of beta- carotene administered may be between 1. and 5000 IU,. the amount of bi otin administered may be between
  • the amount of calcium adliiinistered may be between 1 mg and 5000 mg
  • the amount of chl oride administered may be between I nig and 5 g
  • the amount of chondroitin administered may be between 1 mg and g
  • the amount of chromium administered may be between 1 p,g and 1 0 jr
  • the amount of copper, coenzyme QI O, fatty acid or folic acid administered may be between 5 ⁇ tg and 5 mg each, th e amount of glucosamine, i odine, i ron , lutein, magnesium , malic ac id, manganese
  • methylsuifonyimethane, molybdenum, niacin, nicotinamide, pantothenic acid, phosphorus, potassium or riboflavin administered may be between 100 pg and 5 mg each, and the amount of selenium or thiamine administered may be between 1 0 tig and 5 mg each.
  • the amount of vitamin B6 administered may be between 0.1 and 1 0 mg.
  • the amount of vitamin B I administered ma be between 1 and 2.4 .
  • the amount of folic acid administered may be ' between 200 and 1000 pgggi The amount of vitamin. £
  • the amount of vitamin C ascorhate or ascorbyi palmitate administered may be between 1 and 300 rag.
  • the amount of vitamin C ascorhate or ascorbyi palmitate administered may be between 10 and 500 nig, more preferabl 2 to 200 mg.
  • There ma be between 1 and 18 rug of iron There may be between 500 nd 1 ,000 mg of calcium.
  • There. may be between 50 and 320 mg of magnesium.
  • the b. may be administered in combination with vitamin selected from the group consisting of vitamin A, pre-vitami A carotenoids (such as alpha- carotene and beta-carotene) and combinations thereof, in such embodiments, the vitamin A .may be administered in an amount of 1.00 to 5000 IU, more preferably 1500 to 300 Hj.
  • a particularly suitable dose of vitami A is 2600 IU (ie about 770 pg/day).
  • ecjiii valents amounts (eg in the range of 100 to 5000 IU, more preferably 1500 to 3000 IU) should be suitable.
  • compositions for delay ing the onset of menopause and/or slowing the fate of loss of ovarian reserve comprises a therapeutically effective amount of a therapeutically effective agent optionally in combination with one or more pharmaceutically acceptable carriers and/or excipients., wherein the therapeutically effective agent, is bC or pharmaceutically acceptable salt, solvate or prodrug thereof and wherei n the composition delays the onset of menopause and or slows the rat of loss of ovarian reserve.
  • the composition may be available in. dosage form.
  • the dosage form may be an oral dosage form, a fortified drink product, a fortified food product, a topical dosage form, an injectable dosage form, a subcutaneous implantable dosage form (which may be effective for a period within the range of, for example, 3 months to 3 years), a vaginally iusertabJe dosage form, a transdermal dosage form or a spray.
  • the dosage form may contain anywhere from about 0.1 % to about 99.9% of bCX, depending upon the selected dose and dosage form.
  • Dosage forms can be prepared in accordance with generally accepted procedures for the preparation of pharmaceutical preparations as described in Remington'* Mmrma tftt l Sci c&s, 17 th Ed,, 1985.
  • determining the effective amount of dose a number of factors are considered by the attending diagnostician or physician, including, but not limited to the female subject's size, age, and general health, the response of the individual patient, the particular compound administered, the mode of administration, die bioavailability characteristics of the preparation
  • the bCX is administered in the form of an oral dosag form.
  • the oral dosage form may ' be a tablet, pill, dragee, capsule, pellet, cap let, gel-cap, multi-particles i sachet, encapsulated form, lozenge, emulsion, lipophilic and liydrophilie suspensions, liquid, gel, syrup, slurry, suspensions and the like, for oral ingestio by the female subject.
  • the oral dosage form comprises either one or both of carriers and exeipients.
  • Suitable carriers include but are not limited to starch, sodium lauryl sulphate, Polysorbate 80. Polysorbate 20, pre- geiatinised starch, nonionto surfactants, polyethylene glycol, carnauba wax, water, corn oil, sesame oil, and/or peanut oil
  • Suitable excipients include but are not limited to lactose, lactose monohydrate, macrocrystalline cellulose, methyleelhilose, ethylceOuIose. hydroxypropyimethyleellulose, hydroxypropyi.
  • the oral dosage form further comprises any one or more of additives such as binders, adjuvants, giidants/lubricants, disintegrants, colouring agents, ⁇ pacifiers, flavouring agents, preservati ves, fillers and anti-adherents.
  • additives such as binders, adjuvants, giidants/lubricants, disintegrants, colouring agents, ⁇ pacifiers, flavouring agents, preservati ves, fillers and anti-adherents.
  • additives examples include: binders such as guirt tragacaiith, acacia, com starch or gelatine; adjuvants such as povidone; g ants lubricailts, such as silica or stearic acid and stearic acid salts such as magnesium stearate, sodium stearyl fomarate, leucine, sodium benzoate or oloxamers; disintegrants such as crosslinked sodium carboxymethyi starch, crosslinked sodium earboxymethylcelMose (croscarmellose sodium) and crosslinked poiwinylpyrrolidone; colouring agents, pigments and food grade dyes; opacifiers, such as titaniu dioxide; flavouring agents, suc as sucrose, fructose, corn syrup, vanilla, mint, cherry, anise, peach, apricot, liquorice, or raspberry;
  • binders such as guirt tragacaiith, acacia, com star
  • preservatives such as citric acid, sodium citrate or propyl paraben
  • fillers such, as macrocrystalline cellulose, cellulose., calcium hydrogen phosphate, mannitol, sorbitol, xylitol, lactose, dicalcium phosphate, calcium phosphate tribasic, calcium sulfate and trietiryl citrate; and anti-adlierents such as magnesium stearate.
  • an oral dosage form is prepared b uniformly and intimatel admixing the bQi and any other active agents (if present) with liquid carriers and/or excipients or finely divided solid carriers and/or excipients, or both, and then, .if necessary,, shaping the produc t into the desired presentation.
  • Compresse tablets can be prepared by compressing in a suitable machine the bCX i a. free-flowing form such as powder or granules,, option ally mixed with an exeipient, a. binder, a lubricant, a filler and/or a disiniegrant Moulded tablets can be made b moulding i a suitable machine a mixture of the powdered compound moistened with a inert liquid diluent.
  • the oral dosage form may be adapted for any one or more of immediate release, sustained release and delayed rel ease.
  • tablets may be monolithic, have a compressed core or he of .-multi -layer construction, wherein the layers may be arranged in a sandwich-like fashion or concentrically.
  • Tablets may be- uneoatcd or they may be coated using conventional techniques, such as those described in Encyclopedia of Pharmaceutical Technology, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period.
  • the coating may be adapted to release the bCX and any otlier active agents (if present) in.
  • a predetermined patter e in order to achieve a controlled release- formulation
  • it may be adapted not to release the bCX and any other active agents (if present) until after passag of the stomach (enteric coating).
  • a time delay material such as glyceryl, monostearate or glyceryl distearate can be employed to delay tablet disintegration.
  • Othe oral dosage forms include; hard gelatin capsules (ie push-fit capsules) wherein the-bCX is mixed with an inert solid diluent, for example, calci um carbonate, calcium phosphate or kaolin, and a filler such as lactose, binders suc as starches,, and/or lubricants such: as talc or magnesium stearate; and soft gelatin capsules made of gelatin and a plastieiser, such, as glyce
  • a fortified drink product is any drink that contains biologically active components that provide health benefits or desirable physiological effects: beyond basse nutrition.
  • a fortified food product is any food or part thereof that contains biologically active components that provide health benefits or desirable
  • Fortified drink and food products are usually of plant origin, but may also be of, for. example, animal, fungal, or microbial origin, or from expression in plants, animals or microbial organisms, using recombinant DMA techniques
  • a fortified drink product may comprise a processed product, a fermented product, an extract or an fortified drink.
  • Examples of fortifie drink products are water, fruit j uice, plant and animal based milks, and soft drinks such as cola.
  • a fortified food product may comprise a processed product, fermented product, an extract, a beverage or a whole food.
  • Examples of possible fortified food products are bread and other baked products, pasta, flour, breakfast cereals, snack foods such as muesli bars, yoghurt., ice cream, butter, margarine arid torn.
  • either or both of the fortified drink product and fortified food produc t is adapted for any one or more of immediate release, sustained release and delayed release.
  • Topical dosage form includes any therapeutically effective pharmaceutical dosage form, for administering topically on the skin for percutaneous a sor tion.
  • Topical dosage forms include water-in- oil emulsions such as: ointments, and oil-in water emulsions such as: creams, balms-, lotions, liniments, foams, gels, hydrogeis, solutions, s spensions, sticks, sprays, pastes, piasters, tinctures and other kinds of transdermal drug delivery systems.
  • the topical dosage .form may additionally comprise conventionally non-toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes, emulsifying agents, antioxidants, buffering agents, preservatives, humeetants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, perfumes, , and skirt protective agents, in embodiments, the topical dosage form includes a patch. In embodiments, the topical dosage for is adapted for any one or more of immediate release, sustained release and delayed release.
  • an "injectable dosage: form” includes a dosage form, adapted for parenteral administration.
  • Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal, intramuscular and subcutaneous, as well as any other con ventional, routes of parenteral administration.
  • Suitable means of parenteral administration include needle (including microneedle) injectors, needle-free injectors an infusion tec!miques, as well as airy other means of parenteral
  • the injectable dosage form includes -a liquid, a solid, or a Jow r able composition.
  • the injectable dosage form is adapted for any one or more of immediate release, sustained release and delayed release.
  • Injectable dosage forms are typically aqueous solutions which ma additionally comprise appropriate proportions of: excipients such as water, saline, dextrose, glycerol, ethanol, or the like:; stabilisers such as chelating agents like ethylenediaminetetraacetic acid (EDTA) and its salts, citric acid and its salts or mtrilo acetic acid derivatives and its salts; antioxidants such as sodium bisulphite, sodium metabisulphite, cysteine hydrochloride, thiol acetic acid or phenolic grou derivatives., butyktecl hydroxy anisole arid its derivatives, parabeiis and its salts; wetting or emulsifying agents and pH bufferin agents (preferably at a pH in
  • a "subcutaneous implantable dosage form” includes a biodegradable flowabk composition (eg .as disclosed in United States Patent No. 8,921,387), a biodegradable rod or similar shaped dosage form or a nondegradable reservoir such as a polymeric material (eg as disclosed in United States Patent No, 5,088,505), osmotically driven device (eg as disclosed in United States Patent Kos.
  • the implantable dosage form is adapted for any one or more of immediate release, sustamed release and delayed release. Accordingly, in embodiments, the implantable insatiable dosage form is capable of the controlled release of the bCX over a period of ti me.
  • the implantable insertable dosage form comprises at least 365 times the minimum daily dose of bCX.
  • the implantable insertable dosage form is administered at any other interval, such as monthly, biamiually or every three years, the implantable dosage form will contain sufficient bCX to administer the minimum daily dose.
  • a 'Vaginally insertable dosage form includes a dosage form adapted for insertion into the vagina or the uterus of a female such as a vaginal tampon, dissolvin or non-dissolving, intrauterine device (lUD), degfadable or non-degradable vaginal foam, tampon-like foam, or any other vaginal device, such as pessary, sponge, iabletj suppository, pellet, ring but also a vaginal applicator or any other structure generally insertable into vagina.
  • the vaginally insertable dosage form is adapted for any one or more of immed iate release, sustained release and delayed release.
  • the vaginally insertable dosage form' comprises: a core of suitable polymeric matrix, impregnated with the bCX and enveloped by a perraeable membrane for controlling sustained release of the bCX into the uterus cavity ov er a prolonged time, in accordance with the above described daily dose of bCX, if a vaginally insertable dosage form: is administered once per year, the vaginally insertable dosage form, comprises at least 365 times the minimum daily dose of bCX. Similarly, if the vaginally insertabie dosage form is administered at any othe interval such as monthly, biamiuall or e er ' three years, the implantable dosage form will contain sufficient bCX ' to administe the minimum daily dose.
  • the therapeutically effective amount of bCX in the dosage form may be between 5 micrograms: (ug) and 10 grams (g). in certain embodiments, the thera entically effective amount of bCX is between 5 pg and 5 g, 10 pg and 4 g.
  • the therapeutically effective amount of bCX is about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, J 700, 1800, 1900, 2000, 2100, 2200, 2300,
  • the composition further comprises one or more pharmaceutically acceptable carriers and/or excipients.
  • the composition docs not comprise one or more pharmaceutically acceptable carriers aad'or excipients. Accordingly, in embodiments, pharmaceutically acceptable carriers and/or excipients are optional.
  • the composition further comprises additives.
  • the only therapeutically effective agent present in the composition is bCX.
  • the composition may take the form, of a non-contraceptive sugar pill for use in a daily contraceptive regime. Therefore, in certain embodiments, tire composition will not comprise any other therapeutically effective agents such as hormones, hormone agonists (eg GnRB agonists such as
  • the dosage form provides a dose of ' bCX equivalent to daily dose of between 5 and 10,000 p.g.
  • the dosage form provides a dose of bCX equivalent to a daily dose of between 10 and 9000 pg, 25 and 800 , 50 and 7000 ug, 100 and 5000 pg, 200 and 2500 pg, 30 and 1800 ⁇ , 400 and 1200 ⁇ , 600 and 1200 ⁇ 3 ⁇ 4 800 arid .1.100 ' pg, 1000 and 5000 pg or any sub-range of these specified ranges, hi certain embodiments, the dosage form provides a dose ofbCX equivalent, to a daily dose of between 400 and 1200 ug.
  • the dosage form provides a dose ofbCX each month that is equivalent to a daily dose of between 5 and 10,000 ug. Accordingly, in certain embodiments:, the dosage form provides a dose o CX each month that is betwee about 140 ug (!e the equivalent of 5 g;pef day in 28 ' day month) and 31 mg (ie the equivalent of 10,000 pg per day in. a 31 day month),
  • the dosage form is adapted to. provide a dose of bCX on consecuti ve days or every 2, 3, 4, 5, days, each week, each month, eac year, each decade or according to any schedule provided that the dosage form. is adapted to provide dose equivalent to a daily dose of between S and 10,000 pg of bCX.
  • the composition further comprises a contraceptive agent.
  • the contraceptive agent may be selected from an contraceptive agents known in the art I embodiments, the contraceptive agent comprises any one or more of an oestrogen and a progestogen.
  • an at least one oestrogen is selected from t7befa-estradial and etlnnylesi ' radiai, estradiol, estropipate, natural conjugated equine estrogens, conjugated synthetic estrogens, este.rifi.ed estrogens, estrogen sulphaniate, estrone sulfate, piperazine estrone sulfate, mestranol, esftriol, estrone, estradiol valerate, dinestroi, or any combinations thereof,: in certain embodiments, the at least one progestogen is selected from gestodeiie, levonorgestrel, eionogssterol, .desogestrel,.
  • dienogest 3-ketodesogesirel, drospirenone, cyproterone acetate, norgestimate, norelgestromm, nomegestroi acetate, norethisterone, dydrogesterone,
  • the. composition comprises a contraceptive agent in an amount that provides- a daily dose of between 0,001 mg and 200 mg of the contraceptive agent.
  • the amount of contraceptive agent in the composition is equivalent to a daily dose of between 0.001 mg and 100 mg, 0.001 mg and 50 mg, 0.001 mg and 25 mg, 0,001 and 1 ⁇ mg, 0.01 and 5 mg, 0.01 and 3 mg, 0.0.1 and 2 mg, 0,01 and 1 mg or an sub-range of these specified ranges.
  • the amount of contraceptive- agenda the composition is selected from 0.1 to 6.0 mg of estradiol arid 0.001 mg to 3 mg of ethinyl estradiol, and 0.01 to 3 mg of gestodene, 0.02 to 0.25 mg of levonorgestrel, 0,02 : to 0.5 mg of desogestrel, 0.01 to 0.5 mg of S-kefodcsogestrel, 0.01 to 6 mg of drospirenone, 0.01 to 3 mg of cyproterone acetate, 0,01 to 2 m of norgestimate, 0,1 to 60 mg of norethisterone, 0,1 to 20 mg of dydiOges terone, 0.1 to 150 mg ' of medroxyprogesterone and- 0.1, to 5 m of norgestxel.
  • the composition farther comprises a multivitamin agent.
  • the multiv itamin agent may comprise any one or more of alpha-carotene, beta-carotene, biotin, calcium, chloride, chondroitin, chromium, copper, coenzyme Q10, a fatt acid such as omega-3 (eg.
  • EPA eieosapentaenoie acid
  • DHA doeosahexaenoie acid
  • omega-6 fatty acid folic acid
  • glucosamine iodine
  • iron lutein
  • magnesium malic acid
  • manganese eieosapentaenoie acid
  • DHA doeosahexaenoie acid
  • the amount of the multivitamin agent is about 5, 10, 25, 50, 100, 200, 300, 400, 00, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600,.
  • 1700, 1800 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800, 7900, 8000, 81.00, 8200, 8300, 8400, 8.500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 93.00, 9400, 9500, 9600, 9700, 9800, 9900 or .10,000 ug,
  • methylsulfonylmethane, molybdenum, niacin, nicotinamide, pantothenic acid, phosphorus, potassium or riboflavin administered may be between 100 ug and 5 mg each, and the amount of selenium or thiamine administered may be betwee 100 pg and 5 mg each.
  • the amount of vi tamin B6 administered may be between 0.1 and 100 mg.
  • the amount of vitamin B 1.2 administered may be be tween 1 and 2.4 ⁇ .
  • the amount of folic acid administered may be between 200 and 1000 pg.
  • the amount of vitamin E administered may he between 1 and 300 mg.
  • the amount of vitamin C aseorbate or ascorbyl palmitate administered may be betwee i and 45 mg.
  • There may be between i and 400 ID of vitamin D There may be between 1 and 60 pg of selenium.
  • a pharmaceutical preparation which comprises the composition as described herein, in combination with one or more pharmaceutically acceptable carriers and/or exeipienis. .in. certain embodiments, the pharmaceutical preparation further comprises additives. In certain embodiments, the pharmaceutical composition further comprises any one or both, of at least one contraeeptiv3 ⁇ 4 agent: and at least one multivitamin agent as: described herein. 0074] in certain embodiments, the pharmaceutical preparation is an oral dosage form.
  • the pharmaceutical, preparation may take the form, of a tablet, pill, dragee, capsule, pellet, multi-particles in sachet, encapsulated form, lozenge, emulsion, lipophilic and hydrophilie suspensions, liquid;, gel, syrup, slurry, suspensions and the like, f r Oral ingestion.
  • the pharmaceutical preparation consists of a number of daily dosage units adapted for consecutive daily oral administration.
  • the pliarmaceUtical preparation may form a number of daily dosage units that are part of a daily dosing regimen, in embodiments, the daily dosage uni s are non-contraceptive sugar pills for use in a daily contraceptive regime.
  • the daily dosage units are contraceptive pills for use in a daily contracepti ve regime,
  • the daily dosage units ma be separately packed and individually removable.
  • the daily dosage units comprise at least 28 separately packed and individually removable dosage units adapted for consecutive daily oral administration for a period of at least 28 consecutive days. Accordingly, the daily dosage units ma form part of a 28-day ki t.
  • the 28-da.y kit is a daily contraceptive regime.
  • the daily dosage units may be provided in a produet comprising multiple dosage unils comprising the composition of the invention, wherein each dosage unit is adapted for daily oral administration.
  • the product may comprise biisterpack comprising a card, one or more blisters on at least, one side of the card and one or more dosage units in each blister.
  • more than one dosage unit may be stored together with instructions for daily oral
  • the dosage units can be numbered. In embodiments, the dosage units can be designated by days of the week.
  • the product can include a weekly, biweekly, monthl or annual supply of dosage units.
  • the product comprises at least one dosage unit comprising the composition of the invention in combination with a Contraceptive agent and at least one dosage unit comprisin the composition of tile in ention., wherein the dosage units are adapted for daily oral administration.
  • the product may comprise at least one- contraceptive pill and at least one non-contraceptive sugar pill, for use in a dail contraceptive regime,
  • a combination product for oral contraception and delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve comprising:
  • contraceptive dosage units each comprisin an effective amount of at least one contraceptive agent and an effective amount of beta-cryptoxa thin (bCX) o a
  • contraceptive agent-free placebo dosage units eaeh comprising an effective amount of bCX or a pharmaceutically acceptahk salt, solvate or prodrug thereof; and, optionally, instructions or indications to show that the daily administration of the 21 to 24 contraceptive dosage units, is to be followed by daily administration of the 7 to 4, respectively, contraceptive agent-free placebo dosage units.
  • the present invention relates to an injectable dosage form comprising beta- cryptDxan in (bCX) or a pharraaceutieaily acceptable salt, sol vate or prodrug thereof and one or more pharmaceutically acceptable carriers and e cipients for delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve,- wherein the dosage form delivers 50 to 1 ,000 pg of bCX or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage form or per day.
  • a subcutaneous implantable dosage form comprising beta- erypfoxanthm (bCX) or a pharmaceutically acc eptable salt, solvate or prodrug thereof and one or more pharmaeeuti caliy acceptable carriers and excipients for delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve, wherein the dosage form delivers from about 50 pg to about 1 ( ,0 ( M ) p of bCX or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage fprra or per day.
  • bCX beta- erypfoxanthm
  • beta-er ptoxanthm bCX
  • a pharniacevitieaily acceptable salt, solvate or prodrug thereof for delaying the onset of menopause and/or slowing the rate of lo ss of o varian res erve in a female subjec t aftd/dr in t he preparation of a medicament for delaying the onset of menopause and/of slowing the rate of loss of ovarian reserve in a- female subject.
  • the beta-eryptoxaothm (bCX) or pharmaceutically acceptable salt, solvate or prodrug thereof is administered in combination with a contraceptive agent.
  • the bC or pharoiaeeutically acceptable salt, sol vate or prodrug thereof is administered in combination with a multivitamin agent.
  • kits comprising beta-eryptoxanthm. (bCX) or
  • kits comprising beta-eryptoxanth i (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof, at least one - multivitamin and instructions for the use of said kit i a method for delaying the onse of menopause and/or slo wing the rate of loss of ovarian reserve.
  • bCK. can be used to protect ovarian reserve and delay the onset of menopause
  • results provided i di examples provided herein tarther support the use of bCX for enhancing fertility in "older" female subjects (eg female subjects o£> 35 years of age).
  • the effect of the bCX in this context may include, for example, tire preservation of primordial follicles (eg through reduction of natural apoptoti c attrition) and/or an increase in the rate of oocyte maturation and ovulation.
  • provi ded herein is a method of enhancing future fertility potential in a female subject, said method comprising administering daily or substantially daily a therapeuticall effective amount of beta-cry toxanthin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof to the female subject for a period of 3 years preceding a planned pregnancy or older age at which she desires to preserve the possibility of a pregnancy.
  • bCX beta-cry toxanthin
  • The: metho d of the ninth aspect may be suitable for a female subject pl anning, a .
  • the daily or substantially daily administration o f the bCX or a pharmaceutically acceptable salt, solvate or prodrug thereof is for a period of > 5 years, more preferabiy > 7 years and, still axo preferably, 10 years preceding a. planned pregnancy or older age at which she desires to preserve the possibility of a pregnancy.
  • the daily or substantially daily administration of the bCX or a pharmaceutically acceptable salt, solvate, or prodrug thereof will commence when the female subject is of 20-25 years of age.
  • the method may be performed in accordance with certain embodiments as described above in. respect of the method of the fi st aspect.
  • the method of enimncing future fertility potential in a female subj ect may comprise administering from about 5 micrograms (ug) t about 10,000 pg : per day or about 400 pg to about 1200 g per day of bCX or a pharmaceutically acceptable salt, solvate or prodrug thereof to the female subject.
  • the method ma for example, involve administering the bCX o pharirsaeeutically acceptable salt, solvate or prodrug thereof in combination wit contraceptive agent and/o multivitamili agent.
  • compositions for enhancing future fertility potential in a female subject comprising- a therapeutically effective amount of a therapeutic agent comprising beta- cryptoxantliin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • a therapeutic agent comprising beta- cryptoxantliin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the therapeutically effective amount: ofbCX or a pharinaceuticaiiy acceptable salt, solvate or prodrug thereof in the composition is front about 5 ug to about 5 grams (g), from about 1600 pg to about 4800 pg or from about 400 ug to about 1200 3 ⁇ 4.
  • the therapeutic agent consists of bCX or a pharmaceuticall acceptable salt, sol vate or prodrug thereof. In other words, there are no other therapeutically active agents in the composition.
  • the composition may be provided, for example, in an injectable dosage .form (which may deli ver, fo example, from about 50 ug to about 10,000 pg of bO£ or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage form or pe day) or in a .subcutaneous implantable dosage form (which may deliver, for example, from about 50 pg to about 10,000 pg of bCX or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage form or per day).
  • an injectable dosage .form which may deli ver, fo example, from about 50 ug to about 10,000 pg of bO£ or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage form or pe day
  • a .subcutaneous implantable dosage form which may deliver, for example, from about 50 pg to about 10,000 pg of bCX or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage form or per day.
  • the medicament may comprise hC in combination w th a contraceptive agent and/or multivitamin agent
  • kits comprising beta-cryproxanthin (bCX) or a phitrmaceutiealJy acceptable salt, solvate or prodrug thereof at least one contraceptive agent and/or multivitamin and ins raetions for the use of said kit in a method for enlmncing future fertilit potential in a female subject.
  • bCX beta-cryproxanthin
  • a phitrmaceutiealJy acceptable salt solvate or prodrug thereof at least one contraceptive agent and/or multivitamin and ins raetions
  • a one-way ANOVA was employed to detennine statistical differences age of menopause quiniiies. Pearson's correlation coefficient was computed to identify correlations between, age of menopause a n d. dietary components. Partial correlations were also performed adjusting for BMI, smoking status, total. ener y intake, amount of alcohol consumed- daily and total exercise index.
  • Regression analysis was. performed using energy intake, BMI, age at baseline, physical activity level, smoking status and amount of alcohol consumed as variables,
  • the average composition of the diet was 1-9% (E) protein, 46%: (E) carbohydrate, 36% (E) fat representing an average daily intake of 8600+_32633 ⁇ 4. Participants also consumed on. average 4.6+3,7 serves of fruit and 5.1+3.4 serves of vegetables per day.
  • the weekly intake of cereals, dairy, egg, total meat, chicken and fish was 31,7+16,3, 36,2+19.9, 1.9+2.3, 7.7+5.0, 2.4+2,0, J .7+2,2 times per day respectively, and 50.1 ⁇ 64.S ml of vegetable oils or oil blends.
  • Beta-cryptoxanthin is a carotenoid that can be converted into Vitamin A within the body (Burri, 2014).
  • two recent studies have raised concerns that Vitami A ma potentially have an adverse effect on ovarian reserve if consumed in high quantities (Abali et at, 2013, Sikar Akturk ei !., 2013); certainly not a protective effect. That is, isotretinoin, a synthetic analogue of Vitamin A commonly used to treat severe acne., has been reported to result in.
  • the desired dose of bC should be sufficient to render women with low dietary intakes ofbCX replete (ie at the high end of normal consumption levels), without supplementation being excessive so as to cause potential toxicity or .harm.
  • Table 3 outlines mean daily bCX intake in various countries, in the Melbourne Collaborative Cohort Study, the mean bCX level was 98 ⁇ 63 ⁇ ig/day, but in. a much smaller stud of 73 infertile women ⁇ unpublished o erviftm iS), the mean bCX level was much lower (1 8 ⁇ 20 pg/day). [001 8] Table 3 Average daily intake of bCX. Average bCX dietary intake from eight
  • the source o f bC X used in th se implants was pharmaceutical, grade ( 97% purity) bC purchased from Sigma-Aldrich (St Louis,. MD, United States of America) and was administered as a sub-cutaneous infusion using an osmotic pump (AlzetS; Dureet Corporation, Cupertino, CA, United States of America) changed monthly for 3 months in total
  • osmotic pump AlzetS; Dureet Corporation, Cupertino, CA, United States of America
  • a control group of ten (10) rats was used as a comparator; with control animals receiving an osmotic pump filled with water. All rats were then bred at 7 months and 9 months of age.
  • a two compartment tablet consisting of a core layer of a sustained releas contraceptive agent and h X overeoated wi th a layer of an immedia te release contraceptive agent can be formed by blending the core ingredients and the outer layer ingredients separately, compressing to produce core tablets and then overcoating with the compressed outer layer blend using a suitable -coating. ress- (Table 4).
  • a contraceptive sugar pill or placebo pill containin bC can be form d using known ingredients and the same amount of bCX listed above.
  • a fibre-based dry beverage- mix may be prepared with components list in Table 5. [001 1 ] Table 5 Possible composition of a fortified drinfc product
  • a long-acting (ie up to 3 years) subcutaneous contraceptive implant can be formed by the methods disclosed in United States Patent No. 4,244,949 using, for example, 68 mg of the etonogestrel and bC iii an amount of 900 to 1200 mg.
  • Beta-carotene and other earotenoids Dietary reference inakes for vitamin C, vitamin E, sdewum, and carotenoids i Washington, D.C.: National Academy Press: 2000:325-400.
  • Lorenzo Y etal. Carcinogenesis 30(2);30S-314 (2009).

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Abstract

L'invention concerne des méthodes et des compositions destinées à retarder l'apparition de la ménopause et/ou à ralentir la vitesse de la perte de la réserve ovarienne. Les méthodes peuvent impliquer l'administration à une patiente d'une dose thérapeutiquement efficace de bêta-cryptoxanthine (bCX) ou d'un sel, solvate ou promédicament pharmaceutiquement acceptable de cette dernière. La bCX peut être administrée en association avec un agent contraceptif et/ou un agent multivitaminique.
PCT/AU2016/000022 2015-02-04 2016-02-03 Méthodes et compositions utilisant de la bêta-cryptoxanthine destinées à allonger la durée de la vie reproductive Ceased WO2016123650A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060057186A1 (en) * 2004-09-11 2006-03-16 Margaret Heller Oral contraceptive multivitamin compound and methods of administration

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060057186A1 (en) * 2004-09-11 2006-03-16 Margaret Heller Oral contraceptive multivitamin compound and methods of administration

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BROWNE ET AL.: "Follicular fluid high density lipoprotein-associated micronutrient levels are associated with embryo fragmentation during IVF", JOURNAL OF ASSISTED REPRODUCTION AND GENETICS, vol. 26, 2009, pages 557 - 560 *
DUGAS ET AL.: "Carotenoid Supplementation Enhances Reproductive Success in Captive Strawberry Poison Frogs (Oophaga Pumilio", ZOO BIOLOGY, vol. 32, no. 6, 2013, pages 655 - 658 *
LIU ET AL.: "beta-Cryptoxanthin supplementation prevents cigarette smoke-induced lung inflammation, oxidative damage and squamous metaplasia in ferrets", CANCER PREVENTION RESEARCH, vol. 4, no. 8, 2011, pages 1255 - 1266 *
UCHIYAMA ET AL.: "Oral Administration of beta-cryptoxanthin Induces Anabolic Effects on Bone Components in the Femoral Tissues of Rats in vivo", BIOLOGICAL AND PHARMACEUTICAL BULLETIN, vol. 27, no. 2, 2004, pages 232 - 235 *

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