WO2018200357A1 - Procédés et compositions pour améliorer la fertilité - Google Patents

Procédés et compositions pour améliorer la fertilité Download PDF

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Publication number
WO2018200357A1
WO2018200357A1 PCT/US2018/028809 US2018028809W WO2018200357A1 WO 2018200357 A1 WO2018200357 A1 WO 2018200357A1 US 2018028809 W US2018028809 W US 2018028809W WO 2018200357 A1 WO2018200357 A1 WO 2018200357A1
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Prior art keywords
composition
subject
dose
administered
pterostilbene
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PCT/US2018/028809
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English (en)
Inventor
Eric MARCOTULLI
Dan ALMINANA
Ryan DELLINGER
Mark Morris
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Elysium Health, Inc.
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Publication of WO2018200357A1 publication Critical patent/WO2018200357A1/fr

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    • 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
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom

Definitions

  • Infertility is a condition generally characterized by a couple not being able to become pregnant after a year of trying. Infertility is fairly common in the U. S. and affects thousands of Americans every year. After one year of having unprotected sex, an average of 15 percent of couples are unable to get pregnant. Infertility may have various causes, and the many treatments and intervention technologies are often costly, have adverse side effects, and varying success rates.
  • the methods and compositions disclosed herein related to improving fertility, treating infertility, and/or preventing infertility in a subject by administering to the subject (e.g., orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene).
  • a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene).
  • improving fertility or treating and/or preventing infertility comprises inducing ovulation and/or oocyte and follicle maturation in a female subject.
  • improving fertility or treating and/or preventing infertility comprising increasing sperm count and/or sperm motility in a male subject.
  • kits for increasing lactation in a subject comprising administering to the subject a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene).
  • a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene).
  • the subject is a human.
  • the subject is a non-human animal, such as a dairy animal (e.g., a cow, a buffalo, a goat, a sheep, a camel).
  • the composition comprises a compound of Formula I or Formula II (e.g., nicotinamide riboside) (e.g., at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside)).
  • a compound of Formula I or Formula II e.g., nicotinamide riboside
  • the composition comprises a compound of Formula III (e.g., pterostilbene) (e.g., at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of Formula III (e.g., pterostilbene)).
  • the composition comprises both a compound of Formula I or
  • Formula II e.g., nicotinamide riboside
  • Formula II e.g., at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside)) and a compound of Formula III (e.g., pterostilbene) (e.g., at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at
  • the method comprises administering a plurality of doses of the composition. In some embodiments, at least 7 doses of the composition are
  • each dose comprises at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside).
  • a compound of Formula I or Formula II e.g., nicotinamide riboside
  • each dose comprises at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of Formula III (e.g., pterostilbene).
  • a compound of Formula III e.g., pterostilbene
  • each dose comprises at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside) at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound
  • a dose of the composition is administered at regular intervals over a period of time. In some embodiments, a dose of the composition is administered at least once a week. In some embodiments, a dose of the composition is administered at least twice a week. In certain embodiments, a dose of the composition is administered at least three times a week. In some embodiments, a dose of the composition is administered at least once a day. In some embodiments, a dose of the composition is administered at least twice a day.
  • doses of the composition are administered for at least 1 week, for at least 2 weeks, for at least 3 weeks, for at least 4 weeks, for at least 1 month, for at least 2 months, for at least 3 months, for at least 4 months, for at least 5 months, for at least 6 months or for at least 1 year.
  • the composition is formulated for oral delivery. In some embodiments, the composition is formulated as a pill, a tablet, or a capsule. In some embodiments, the composition is administered orally. In certain embodiments, the composition is self-administered.
  • the methods and compositions disclosed herein related to improving fertility, treating infertility, and/or preventing infertility in a subject by administering to the subject (e.g., orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene).
  • a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene).
  • a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene).
  • a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound
  • provided herein are methods of increasing sperm count and/or sperm motility in a subject by administering to the subject a composition disclosed herein. Also provide herein are methods of increasing lactation in a subject comprising administering to the subject a comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene).
  • a compound of Formula I or Formula II e.g., nicotinamide riboside
  • a compound of Formula III e.g., pterostilbene
  • an element means one element or more than one element.
  • administering means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering.
  • Administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material.
  • subject means a human or non-human animal selected for treatment or therapy .
  • therapeutically-effective amount and “effective amount” as used herein means the amount of an agent which is effective for producing the desired therapeutic effect in at least a sub-population of cells in a subject at a reasonable benefit/risk ratio applicable to any medical treatment.
  • Treating" a disease in a subject or “treating” a subject having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is decreased or prevented from worsening.
  • a therapeutic that "prevents" a disorder or condition refers to a compound that, when administered to a statistical sample prior to the onset of the disorder or condition, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • compositions comprising a compound of
  • Formula I or Formula II ⁇ e.g., nicotinamide riboside
  • a compound of Formula III ⁇ e.g., pterostilbene
  • Nicotinamide riboside is a pyridine-nucleoside form of niacin ⁇ i.e., vitamin B 3 ) that serves as a precursor to nicotinamide adenine dinucleotide (NAD + ).
  • nicotinamide riboside also includes nicotinamide riboside salts, such as nicotinamide riboside chloride.
  • the chemical structure of nicotinamide riboside is provided below:
  • compositions comprising a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:
  • Ri, R2, and R3 are selected from hydrogen, halogen, -CN, -NO2, -OR14, -N(Ri4)m, - Ri3, substituted or unsubstituted (Ci-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
  • Ri and R.5 are selected from hydrogen, halogen, -CN, -NO2, -OR14, -N(Ri4)m, substituted or unsubstituted (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
  • Re, Rs, R11, and R12 are selected from hydrogen, (Ci-C 6 )alkyl, -((Ci- C6)alkylene)N(Ri4)m, -C(0)((Ci-C6)alkylene)N(Ri4)m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, -OR14, and -N(Ri4) m ;
  • R7, R , and Rio are selected from -((Ci-C6)alkylene)N(Ri4)m, -OR14, and -N(R 14 ) m ;
  • Ri3 is selected from -ORi4, -N(Ri 4 )m, -C(0)(Ri 4 ), -C(0)(ORi 4 ), -C(0)N(Ri 4 )m, - S(0) 2 (ORM), -S(0)ORf 4, and - S(0) 2 N(Ri4)m;
  • Ri4 is selected from hydrogen, (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
  • X is O, S, or N(R i4 );
  • n 2 or 3;
  • Ri is R.o.
  • R2 is R13.
  • Rj is R 13 .
  • R13 is selected from. -ORH, -N(R 14 )m, -C(0)(R 14 ), - C(0)(ORH), and -C(0)N(R 14 ) m . In some embodiments, R 13 is selected from -C(0)(R 14 ), - C(0)(ORi4), and -C(0)N(R i4 )m. In some embodiments, R13 is -C(0)N(Ri4)m.
  • R7, R9, and Rio are each independently -ORH or -N(R 14 )m. In some embodiments, R7, R9, and Rso are -ORH.
  • the compound of formula (I) is represented by Formula (II) or a pharmaceutically acceptable salt thereof:
  • R2 and R3 are selected from hydrogen, halogen, -CN, -NO2, -ORH, -N(Ri 4 )m, -R13, substituted or unsubstituted (Ci-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
  • R 4 and Rs are selected from hydrogen, halogen, -CN, -NO2, -ORH, -N(R. 14 )m, substituted or unsubstituted (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
  • Re, Rs, R11, and R12 are selected from hydrogen, -ORH, -N(R 14 )m, substituted or unsubstituted (Ci-C 6 )alkyl, -((Ci-C 6 )alkylene)N(Ri4)m, -C(0)((Ci-C 6 )alkylene)N(Ri4)m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
  • R13 is selected from -ORH, -N(Rn)m, -C(0)(Ri4), -C(0)(ORi4), -C(0)N(Ri 4 )m, - S(0) 2 (ORi4), -S(0)ORi4, and - S(0) 2 N(Ri4)m;
  • Ri4 is selected from hydrogen, (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
  • m 2 or 3.
  • Ri, R2, and R3 are each independently, if present, selected from hydrogen, halogen, -CN, -NO2, -ORH, - N(Rn)m, -Ri3, and substituted or unsubstituted (Ci-Ce)alkyl.
  • Ri, R_, and R3 are each independently, if present, selected from hydrogen, -OR14, -N(R. 14 )m, and unsubstituted (Ci-C6)alkyl.
  • Ri, R2, and R 3 are each independently, if present, selected from substituted or unsubstituted (Ci-C 6 )alkyl, cycloalkyl,
  • Ri, R2, and R3 are each independently, if present, hydrogen.
  • Ri and Rs are each independently selected from hydrogen, halogen, -CN, -NO2, -ORi4, -N(Rj 4)m, and substituted or unsubstituted (Ci-Ce)alkyl.
  • R 4 and R? are each independently selected from hydrogen, -ORi 4 , -N(Ri 4 )m, and unsubstituted (Ci-Ce)alkyl.
  • R4 and R 5 are each independently selected from substituted or unsubstituted (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, R 4 and R5 are each hydrogen.
  • Re, Rs, Rn, and R12 are selected from hydrogen, -ORH, -N(Ri 4 )m, unsubstituted (Ci-C 6 )alkyl, -((Ci- C6)alkylene)N(Ri 4 )m, -C(0)((Ci-C6)alkylene)N(Ri4)m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.
  • Re, Rs, R11, and Ri are selected from hydrogen, -ORH, -N(Ri 4 )m, unsubstituted (Ci-C 6 )alkyl, -((Ci- C6)alkylene)N(Ri 4 )m, -C(0)((Ci-C6)alkylene)N(Ri4)m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaral
  • Re, Rs, R11, and R12 are each independently selected from hydrogen, -ORM, and -N(R. 14 ) m .
  • Re, Rs, Rii, and R12 are each independently selected from unsubstituted (Ci- C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, Re, Rs, Rii, and R12 are each hydrogen.
  • R7, R9, and Rio are each independently -OR14 or -N(Rj4)m. In some embodiments, R7, Rs>, and Rio are each -ORH. In some embodiments, R7, Rs, and Rio are each -OH.
  • RH is hydrogen or (Ci-Ce)alkyl.
  • X is O or N(RM). In some embodiments, X is O.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Pterostilbene is a stilbenoid and an analog of polyphenol reservatrol that has better bioavailability due to the presence of two methoxy groups that allow it to have increased lipophilic and oral absorption as well as a longer half-life due to reduced oxidation.
  • the chemical structure of pterostilbene is provided below:
  • compositions comprising a compound represented by Formula (III) or a pharmaceutically acceptable salt thereof:
  • R ! 5 is selected from halogen, -CN, -NO2, -ORie, -N(Rie) P , -S(0) 2 (ORi6), -S(0)ORi substituted or unsubstituted (Ci-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
  • Ri6 is selected from hydrogen, (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
  • n is an integer from 0 to 5;
  • p 2 or 3
  • At least one n is 1; and at least one Ris is -OR 16 ;
  • R15 is selected from, halogen, -CN, -NO2, -ORie, -N(Rj6) P , and substituted or unsubstituted (Ci-C6)alkyl.
  • R15 is selected from -OR16, -N(Ri6) P , and unsubstituted (Ci-C6)alkyl.
  • Rj .5 is selected from substituted or unsubstituted (Ci-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.
  • R15 is -ORie.
  • R15 is -ORie; and Rie is hydrogen or (Ci-Ce)alkyl.
  • Ris is -ORie; and Rie is (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.
  • R15 is -ORie; and Rie is (Ci-Ce)alkyl.
  • R15 is -ORie: and Rie is (Ci-C 6 )alkyl, cycloalkyl, or heterocycloalkyl.
  • n is 1, 2, or 3. In some embodiments, n is 1 or 2.
  • p is 2. In some embodiments, p is 3.
  • compositions which comprise a therapeutically-effective amount of one or more of the compounds described herein (e.g., nicotinamide riboside and/or pterostilbene), formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the agents described herein can be administered as such, or administered in mixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with other agents. Conjunctive therapy thus includes sequential, simultaneous and separate, or co-administration of one or more compounds of the invention, wherein the therapeutic effects of the first administered has not entirely disappeared when the subsequent compound is administered.
  • compositions described herein may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; or (3) sublingually.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue
  • parenteral administration for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution
  • the composition comprises additional agents.
  • the composition may comprise a nutritional agent, such as an antioxidant.
  • a nutritional agent such as an antioxidant.
  • pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • the formulations of the compounds described herein may be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the agent which produces a therapeutic effect.
  • a formulation described herein comprises an excipient, including, but not limited to, cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and an agent of the invention.
  • an aforementioned formulation renders orally
  • Methods of preparing these formulations or compositions may include the step of bringing into association a compound of the invention with the carrier and, optionally, one or more accessory ingredients.
  • Liquid dosage forms for oral administration of the formulations provided herein include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents,
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations provided herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the invention as an active ingredient.
  • a compound of the invention may also be administered as a bolus, electuary, or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,
  • disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,
  • disintegrant for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. Compositions described herein may also be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
  • compositions provided herein suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions disclosed herein i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)).
  • a composition disclosed herein i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)
  • the subject is a mammal (e.g., a human, a non- human mammal).
  • the subject may be male or female.
  • the subject has impaired fertility (e.g., reduced sperm count, reduced sperm motility, reduced ovulation, reduced follicle and/or oocyte maturation).
  • the subject is infertile or sterile.
  • a composition disclosed herein i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)).
  • a composition disclosed herein i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)
  • Increasing sperm count may be achieved by increasing the composition disclosed herein (i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)).
  • compositions disclosed herein may increase overall sperm count by increasing or inducing spermatogenesis.
  • administering the compositions disclosed herein increase or improve sperm motility (e.g., increasing the percentage of spermatozoa moving in semen or increasing the amount of time spermatozoa are moving) in a subject.
  • administering the compositions disclosed herein maintains or improves overall sperm health, sperm count, and/or sperm motility in the testes and/or epididymis post spermatogenesis.
  • compositions disclosed herein i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e-g, pterostilbene)).
  • follicle and oocyte maturation e.g., folliculogenesis
  • a composition disclosed herein i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)).
  • compositions and methods to aid in in vitro fertilization procedures and practices provide herein are methods of treating, preserving, or improving gamete (i.e., sperm and/or oocyte) likelihood of fertilization in an in vitro procedure.
  • gamete i.e., sperm and/or oocyte
  • compositions disclosed herein are added to semen (e.g., semen obtained from a donor subject) in preparation of for artificial insemination or intrauterine insemination (IUI).
  • IUI intrauterine insemination
  • compositions disclosed herein are added to semen in preparation intracytoplasic sperm injection into an oocyte.
  • compositions disclosed herein may be used to enhance mitochondrial numbers, mitochondrial activity, cellular energy levels or cellular energy- producing potential in oocytes, postnatal female germline stem cells (also referred to herein as OSCs) and/or preimplantation embryos prior to conducting and/or following methods of in vitro fertilization.
  • OSCs postnatal female germline stem cells
  • preimplantation embryos prior to conducting and/or following methods of in vitro fertilization.
  • OSCs postnatal female germline stem cells
  • preimplantation embryos prior to conducting and/or following methods of in vitro fertilization.
  • provided herein are methods of increasing the overall viability of an oocyte removed from a subject (e.g., an oocyte removed in preparation for in vitro fertilization).
  • an oocyte is treated or stored with a composition disclosed herein prior to in vitro fertilization.
  • methods of in vitro fertilization the method involving the steps of: incubating an oocyte from a subject with a composition disclosed herein; and fertilizing the oocyte in vitro to form a zygote.
  • the methods provided herein include a method of in vitro fertilization, the method involving the steps of (a) incubating an OSC from a subject with composition disclosed herein; (b) obtaining a composition containing OSC mitochondria from the OSC; (c) transferring the composition into an isolated oocyte (e.g., an oocyte extracted from a subject); and (d) fertilizing the oocyte in vitro to form a zygote.
  • an isolated oocyte e.g., an oocyte extracted from a subject
  • fertilizing the oocyte in vitro to form a zygote.
  • the composition disclosed herein may be added to a solution used for in vitro fertilization procedures for oocyte preparation and/or storage, such as cell culture medium, oocyte retrieval solution, oocyte washing solution, oocyte in vitro maturation medium, ovarian follicle in vitro maturation medium, oocyte in vitro fertilization medium, embryo culture medium, cleavage medium, vitrification solution, cryopreservation solution and/or embryo thawing medium.
  • a solution used for in vitro fertilization procedures for oocyte preparation and/or storage such as cell culture medium, oocyte retrieval solution, oocyte washing solution, oocyte in vitro maturation medium, ovarian follicle in vitro maturation medium, oocyte in vitro fertilization medium, embryo culture medium, cleavage medium, vitrification solution, cryopreservation solution and/or embryo thawing medium.
  • Gametes may be stored for any period of time with the compositions disclosed herein before in vitro fertilization is performed.
  • a composition disclosed herein ⁇ i.e., a composition comprising a compound of Formula I or Formula II ⁇ e.g., nicotinamide riboside) and/or a compound of Formula III ⁇ e.g., pterostilbene)).
  • increasing lactation comprising increasing the rate at which milk is secreted and/or produced from the mammary glands of a subject.
  • increasing lactation comprises increasing the volume of secreted milk in the subject.
  • the subject is a human.
  • the subject is a non-human animal, such as a dairy animal ⁇ e.g., a cow, a buffalo, a goat, a sheep, a camel).
  • provided herein are methods of improving animal fecundity and/or breeding outcomes in animal husbandry by administering the compositions disclosed herein to a subject(s) ⁇ e.g., a non-human subject).
  • a subject(s) ⁇ e.g., a non-human subject.
  • increasing litter size in a subject ⁇ e.g., a non-human subject, such as a domesticated animal).
  • the subject is a mammal.
  • the subject may be a rodent, lagomorph, feline, canine, porcine, ovine, bovine, equine, or primate.
  • a composition disclosed herein may be administered to a female subject to increase number of offspring per litter or reproductive cycle.
  • the compositions disclosed herein may be administered to male subjects to increase spermatozoa production to obtain semen samples with increased virility for use in artificial insemination.
  • compositions disclosed herein may be varied so as to obtain an amount of a compound of Formula I or Formula II ⁇ e.g., nicotinamide riboside) and/or a compound of Formula III ⁇ e.g., pterostilbene) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • a compound of Formula I or Formula II e.g., nicotinamide riboside
  • a compound of Formula III e.g., pterostilbene
  • administration of the composition comprises administration of the composition in one or more dose(s). In some embodiments, administration of the composition comprises administration of the composition in one or more, five or more, ten or more, twenty or more, thirty or more, forty or more, fifty or more, one hundred or more, or one thousand or more dose(s).
  • the dose comprises at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, or at least 850 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside).
  • a compound of Formula I or Formula II e.g., nicotinamide riboside
  • the dose comprises at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 1 10 mg, at least 120 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, least 170 mg, at least 180 mg, at least 190 mg, at least 200 mg, or at least 250 mg of a compound of Formula III (e.g., pterostilbene) .
  • a compound of Formula III e.g., pterostilbene
  • compositions disclosed herein may be administered over any period of time effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the period of time may be at least 1 day, at least 10 days, at least 20 days, at least 30, days, at least 60 days, at least three months, at least six months, at least a year, at least three years, at least five years, or at least ten years.
  • the dose may be administered when needed, sporadically, or at regular intervals. For example, the dose may be administered monthly, weekly, biweekly, triweekly, once a day, or twice a day.

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  • Pharmacology & Pharmacy (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés et des compositions associés au traitement et/ou à la prévention de l'infertilité, l'amélioration de la fertilité et/ou l'augmentation de la lactation chez un sujet par l'administration au sujet (par exemple, l'administration orale au sujet) d'une composition comprenant du nicotinamide riboside et/ou du ptérostilbène.
PCT/US2018/028809 2017-04-26 2018-04-23 Procédés et compositions pour améliorer la fertilité WO2018200357A1 (fr)

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EP3554285A4 (fr) * 2016-11-29 2021-01-20 University of Iowa Research Foundation Utilisation de précurseurs de nad pour améliorer la santé maternelle et/ou la santé de la descendance
WO2022054778A1 (fr) * 2020-09-08 2022-03-17 ミライラボバイオサイエンス株式会社 Agent d'amélioration de la motilité du sperme et procédé d'amélioration de la motilité du sperme
IT202100007238A1 (it) * 2021-03-25 2022-09-25 Proxenia Srl Nuovo uso di un composto polifenolico

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3554285A4 (fr) * 2016-11-29 2021-01-20 University of Iowa Research Foundation Utilisation de précurseurs de nad pour améliorer la santé maternelle et/ou la santé de la descendance
US11633421B2 (en) 2016-11-29 2023-04-25 University Of Iowa Research Foundation Use of NAD precursors for improving maternal health and/or offspring health
WO2022054778A1 (fr) * 2020-09-08 2022-03-17 ミライラボバイオサイエンス株式会社 Agent d'amélioration de la motilité du sperme et procédé d'amélioration de la motilité du sperme
IT202100007238A1 (it) * 2021-03-25 2022-09-25 Proxenia Srl Nuovo uso di un composto polifenolico
WO2022200848A1 (fr) * 2021-03-25 2022-09-29 Proxenia S.R.L. Ptérostilbène destiné à être utilisé dans le traitement ou la prévention de l'infertilité

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