WO2024076995A1 - Compositions pour la prévention non chirurgicale de l'odeur et du comportement agressif - Google Patents

Compositions pour la prévention non chirurgicale de l'odeur et du comportement agressif Download PDF

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WO2024076995A1
WO2024076995A1 PCT/US2023/075842 US2023075842W WO2024076995A1 WO 2024076995 A1 WO2024076995 A1 WO 2024076995A1 US 2023075842 W US2023075842 W US 2023075842W WO 2024076995 A1 WO2024076995 A1 WO 2024076995A1
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matrix
estradiol
slow releasing
releasing carrier
carrier
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PCT/US2023/075842
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English (en)
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CheMyong KO
Chanjin Park
Po-Ching Patrick LIN
Rex Allen HESS
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Insigna Inc.
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Priority claimed from US17/937,743 external-priority patent/US20230381197A1/en
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Publication of WO2024076995A1 publication Critical patent/WO2024076995A1/fr

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Definitions

  • Surgical castration is a medical procedure that is routinely performed on nearly all newborn male pigs.
  • Castration or gonadectomy which is performed without anesthesia or analgesia, is a crude, invasive animal husbandry (1) method that has been used for centuries to physically remove testes in the young piglets, primarily to prevent the development of ‘boar taint’ when the meat is cooked and to block the development of undesirable aggressive sexual behavior (2-4).
  • Boar taint is the displeasing odor or taste that results from cooking pork from a certain percentage of boars (4, 5). This urine/fecal-like odor or taste is so offensive that removal of the source or cause is essential prior to sending mature male pigs (boars) to market.
  • boar taint is not only androgens (4), in particular androstenone, but also skatole, a 3-methylindole conversion product of the amino acid tryptophan by gut bacteria (6-12).
  • Androstenone is an androgen hormone produced in the testes and is also considered a steroidal pheromone. Androstenone circulates as part of the endocrine system and can accumulate in the boar’s saliva and body fat (12-14). Androstenone, which is uniquely found in high concentrations in boars, contributes to boar taint as it also builds up in adipose tissues, along with skatole (4, 15, 16). Skatole is produced in the gut and then absorbed into circulation (17), where it permeates all organs, but accumulates primarily in the fat in sexually mature boars.
  • Skatole is removed metabolically in the liver, as it is oxidatively metabolized by cytochrome P450IIE1 (CYP2E1).
  • cytochrome P450IIE1 CYP2E1
  • androstenone inhibits this liver enzyme (17-19) and therefore, as boars reach sexual maturity, the increased production of T also increases androstenone, which results in the build-up of skatole in the fat because skatole metabolism is inhibited by androstenone (20, 21).
  • the boar taint odor occurs because both androstenone (22) and skatole build-up in the fat of boars before they go to market, where they are easily released when pork meat is cooked.
  • One embodiment provides a method for inhibiting testicular development in the boar, which prevents the pubertal rise in blood and tissue androgens, and in particular androstenone, the major hormone responsible for boar taint, comprising injecting in said pig a combination of an androgen and an estrogen within the first week to 10 days after birth of said pig.
  • the injection is either subcutaneous or intra-muscular.
  • One embodiment further comprises an implant wherein the implant comprises said androgen and estrogen, wherein the androgen and estrogen target both the hypothalamuspituitary axis and testis development.
  • the implant comprises a material or enclosure that maintains elevated circulating levels of compounds over nursery/nursing period (for example, no more than 12 weeks after birth, such as 4 to 12 weeks after birth, including 6-8 weeks).
  • the material or enclosure that provides sustained release consists with biodegradable polymers or biocompatible materials.
  • the material or enclosure that provides sustained release is a form of capsule, pellets, microspheres, gel, or solution.
  • the method of the excipient(s) and carrier(s) are suitable for the intended end use (i.e. food for human and/or animal) of tissue where injected.
  • the injected androgen and estrogen are not present in the blood or tissues when the pigs are slaughtered.
  • the androgen comprises testosterone, testosterone esters, testosterone metabolites such as 5a-dihydrotestostrone or their esters, trenbolone or trenbolone esters, or equivalents that have potent androgen activity.
  • the dose range of about 25 - 200 mg per pig.
  • the estrogen comprises estradiol esters such as estradiol benzoate, estradiol valerate, estradiol cypionate, etc.
  • the dose range of about 1 to 40 mg per pig.
  • the injected amount of the androgen/estrogen combination is in a dose sufficient to inhibit the development of Kisspeptin neurons in the hypothalamus, LH production in the pituitary, Sertoli cell and Leydig cell proliferation in the testis and/or production of androstenone in the testis and accumulation of androstenone and skatole in the fat.
  • One embodiment provides a method to inhibit testicular development in the pig, which prevents the pubertal rise in blood and tissue androgens until slaughtering age comprising injecting in said pig a combination of an estrogen, an androgen and a carrier neonatally, wherein the combination is selected from the group consisting of, adjusted dose (number of pellets) of them, or their combination:
  • RevalorTM-G 40 mg trenbolone acetate; 8 mg estradiol with a slow releasing carrier/matrix
  • RevalorTM-XS 200 mg trenbolone acetate; 40 mg estradiol with a slow releasing carrier/matrix
  • RevalorTM-XH 200 mg trenbolone acetate; 20 mg estradiol with a slow releasing carrier/matrix
  • RevalorTM-200 200 mg trenbolone acetate; 20 mg estradiol with a slow releasing carrier/matrix);
  • RevalorTM-IS 80 mg trenbolone acetate; 16 mg estradiol with a slow releasing carrier/matrix
  • RevalorTM-S 120 mg trenbolone acetate; 24 mg estradiol with a slow releasing carrier/matrix
  • RevalorTM-IH 80 mg trenbolone acetate; 8 mg estradiol with a slow releasing carrier/matrix:
  • RevalorTM-H 140 mg trenbolone acetate; 14 mg estradiol with a slow releasing carrier/matrix
  • Finaplix-HTM 200 mg trenbolone acetate with a slow releasing carrier/matrix
  • Component E-HTM (10 mg estradiol benzoate and 200 mg testosterone propionate with a slow releasing carrier/matrix);
  • Component TE-GTM (8 mg estradiol and 40 mg trenbolone acetate with a slow releasing carrier/matrix);
  • Component TE-STM 24 mg estradiol and 120 mg trenbolone acetate with a slow releasing carrier/matrix
  • Component TE-HTM 14 mg estradiol and 140 mg trenbolone acetate with a slow releasing carrier/matrix
  • Component TE-ISTM (16 mg estradiol and 80 mg trenbolone acetate with a slow releasing carrier/matrix);
  • Component TE-IHTM (8 mg estradiol and 80 mg trenbolone acetate with a slow releasing carrier/matrix);
  • Component TE-200TM (20 mg estradiol and 200 mg trenbolone acetate with a slow releasing carrier/matrix);
  • SynovexTM One Grass 150 mg trenbolone acetate; 21 mg estradiol benzoate with a slow releasing carrier/matrix;
  • SynovexTM One Feedlot 200 mg trenbolone acetate; 28 mg estradiol benzoate with a slow releasing carrier/matrix);
  • SynovexTM Choice 100 mg trenbolone acetate; 14 mg estradiol benzoate with a slow releasing carrier/matrix);
  • SynovexTM Plus 200 mg trenbolone acetate; 28 mg estradiol benzoate with a slow releasing carrier/matrix
  • SynovexTM H 200 mg testosterone propionate; 20 mg estradiol benzoate with a slow releasing carrier/matrix
  • FIG. 1 illustrates exemplary pig serum LH concentration data from three subject groups (intact, EPV-607, EPV-608 (Synovex Choice; 100 mg trembolone acetate and 14 mg estradiol benzoate) at 3 or 16 weeks of age.
  • FIG. 2 illustrates exemplary male pig saliva’s androstenone concentration data from three subject groups (intact, castrated, EPV-608) at 24 weeks of age.
  • FIG. 3 illustrates exemplary pig testis weight, serum testosterone concentration, and tissue androstenone data from three subject groups (intact, castrated, EPV-608) at 26 weeks of age.
  • FIG. 4 illustrates exemplary pig loin eye area and back fat thickness from three subject groups (intact, castrated, EPV-608) at 26 weeks of age.
  • the present invention pertains generally to preventing development of the boar testis and production and accumulation of the molecules that cause boar taint and induce aggression in males with age. Specifically, the invention relates to the inhibition of functional development of the pig testis by treatment with a combined use of androgen and estrogen in the newborn male piglet using extended drug delivery methods, for the purpose of inhibiting the production of testosterone (T) and androstenone, the accumulation of androstenone, a boar taint-inducing hormone, as well as skatole in the fat.
  • T testosterone
  • androstenone the accumulation of androstenone
  • a boar taint-inducing hormone as well as skatole in the fat.
  • a concentration range of “about 0.1% to about 5%” should be interpreted to include not only the explicitly recited concentration of about 0.1 wt. % to about 5 wt. %, but also the individual concentrations (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, and 3.3% to 4.4%) within the indicated range.
  • the term “about” as used herein can allow for a degree of variability in a value or range- for example, within 10%, within 5%, within 1%, within 0.5%, within 0.1%, within 0.05%, within 0.01%, within 0.005%, or within 0.001% of a stated value or of a stated limit of a range-and includes the exact stated value or range.
  • an “effective amount” means an amount sufficient to inhibit the production of boar taint causing molecules.
  • An effective amount can be administered in one or more administration.
  • an effective amount of androgen and estrogen can be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an effective amount of androgen and estrogen may be achieved in isolation from the use of another drug, compound, or pharmaceutical composition.
  • EPV-607 refers to a product compose of a combination of 25- 200 mg testosterone propionate and 1-40 mg estradiol benzoate with a slow releasing carrier/matrix.
  • EPV-608 refers to a product compose of a combination of 25- 200 mg trenbolone acetate and 1-40 mg estradiol benzoate embedded in a slow releasing carrier/matrix.
  • carrier refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of androgen and estrogen as composition (i.e., pharmaceutical composition).
  • Inhibition Target 1 Hypothalamus and Pituitary.
  • the invention is focused on a pharmaceutical intervention that inhibits the development of the testis.
  • Reproduction in mammals is regulated by hormones that are released from the Hypothalamus region of the brain, the nearby Pituitary, and the distal Gonads that must be exposed to pituitary hormones via blood circulation.
  • This physiological system is called the HPG axis.
  • a hormone produced in one area of the HPG axis either stimulates or inhibits the secretion of a hormone in the other organ via a regulatory loop, called positive and negative feedback loops, respectively.
  • KISSI Kisspeptin
  • GnRH Gonadotropin-Releasing Hormone
  • GnRH travels down to the pituitary via a local portal vein and triggers the secretion of LH (luteinizing hormone) and FSH (Follicle-Stimulating Hormone), which collectively stimulate the gonads to grow and produce sex steroids, primarily T and androstenone in male pigs, and to promote the production of sperm.
  • LH luteinizing hormone
  • FSH Follicle-Stimulating Hormone
  • the target in the hypothalamus is neuropeptide KISSI produced by Kisspeptin neurons, which initiates puberty by directly stimulating the release of GnRH (44-46).
  • KISSI is integral in facilitating the correct timing of puberty and normal gonadal development.
  • Knockout of the Kissi gene, responsible for encoding KISSI, or its receptor, GPR54 in the GnRH neurons, was shown to result in sterility in both male and female mice (43, 47-51).
  • the loss of KISSI expression in the male results in significantly lower plasma levels of LH and T, which results in male infertility (52, 53).
  • Neonatal treatment with exogenous estrogen targets the hypothalamus Kisspeptin neurons, permanently reducing KISSI and subsequently GnRH and LH secretion, eventually lowering testicular T production and serum T levels long-term (54).
  • Neonatal treatment with an androgenic compound such as Trenbolone, Trenbolone acetate (TBA) or 5a- dihydrotestosterone (DHT) targets the pituitary and thus also helps to inhibit LH release by making the pituitary insensitive to GnRH stimulation (55, 56).
  • Neonatal treatment with an estrogen targets the hypothalamus in mammals (54, 57, 58), but in pigs estrogen is also capable of targeting Sertoli cells in the testes (59-63). Therefore, neonatal treatment includes an androgen, as well as an estrogen, as the active pharmaceutical ingredients (API) for this innovation, because together they will inhibit hypothalamus Kisspeptin neuron development, the pituitary gonadotrophic cell’s release of LH and testicular somatic cell development. This will provide a long-term inhibition of the first wave of Leydig cell proliferation and maturation (64). The same estrogen plus an androgen will effectively inhibit KISSI expression and consequently LH secretion in females as well, eventually causing them not to exhibit estrous cycle.
  • an estrogen such as estradiol benzoate
  • Inhibition Target 2 Testis.
  • the core organs of the male reproductive system are testes, which undergo dramatic developmental and structural changes from birth to puberty. Testicular development produces four major cell types: 1) germ cells, surrounded and nurtured by 2) Sertoli cells, which together with germ cells compose the seminiferous tubules; 3) thin, peritubular myoid cells that surround a basement membrane of the seminiferous tubule; and 4) Leydig cells, located between the tubules and blood vessels (65-67).
  • Leydig cells are the major androgen producing cells. They serve as the source of T and androstenone synthesis (7-9, 11, 12, 16, 68-70). These androgen hormones are found in nearly equal concentrations in boar blood (71) and show distinctive increases as the male pigs age from birth to puberty, peaking as they reach maturity, coinciding with when pigs are typically ready for shipping to market (11). However, normal Sertoli cell development is also required for proper proliferation and differentiation of Leydig cells (72-76).
  • the most effective method for reducing testicular production of androgen hormones requires inhibition of the first wave of proliferation, and inhibition and/or delay of the second wave by extending the treatment from neonatal age to at least through the nursery period.
  • Sertoli cells also experience a major stimulation of activity. Sertoli cells go through two waves of proliferation, the first from before birth increasing until just after birth and then declining out to 4-5 weeks, and the second wave just before puberty.
  • FSH is the primary stimulus of Sertoli cell proliferation during the neonatal period, which is essential for normal testis size.
  • E2 pig estradiol
  • other growth factors have more important roles in the regulation of testis development, uniquely focused on the Sertoli cells.
  • E2 (12, 71, 83-85), primarily synthesized by the Leydig cells, which have high aromatase activity from birth to about 4 weeks (86). E2 concentrations are especially elevated during this neonatal period (87).
  • Research into estrogen’s role in testis development in the pig demonstrated an unusual function in helping to regulate Sertoli cell proliferation, which helps to carefully maintain a balance in the total number of Sertoli cells.
  • Sertoli cells As Sertoli cells differentiate into mature cells, they become resistant to FSH stimulation of proliferation (89) and depend on the androgen T for the maintenance of spermatogenesis and germ cell development (90). Leydig cells are responsible for the production of androgens, in particular T and androstenone, and in the pig increased levels of E2 (converted from T by aromatase) (91). Thus, neonatal treatment with exogenous estrogen in the male piglet has a direct inhibitory effect on Sertoli cell proliferation, as well as inhibiting the development of the hypothalamus/pituitary axis.
  • the combination of an androgen and estrogen is essential for sustained inhibition of production of the molecules that cause boar taint.
  • the pig shows specific, and significant differences in hormonal regulation of testicular development compared to other mammals, although the overall hormonal regulation of the male reproductive system is common across mammalian species. Development of the testis in most mammalian species follows a well-understood endocrine- driven pathway, which is especially well-studied in rodent species, as they are the common basic research model. In rodents, it is well-established that FSH is a major driver for Sertoli cell proliferation and LH is the key factor in Leydig cell development (92, 93).
  • Sertoli cells serve as nurturing cells for germ cells (94) and each Sertoli cell supports a finite number of germ cells (95). Thus, it is the total number of Sertoli cells that determines the ultimate size of the testis (72). Furthermore, the number of Sertoli cells indirectly regulates the number of Leydig cells (72, 74, 96). Thus, regulation of Sertoli cell numbers in the developing pig testis is just as important as inhibiting Leydig cell function. However, regulation of testis development in the pig shows some specific differences from rodents and other mammalian species, such as E2 having a direct inhibition of Sertoli cell proliferation, as demonstrated by aromatase inhibitor treatment causing an increase in Sertoli cell numbers (60).
  • TBA is a synthetic androgen that has both direct effects on the testis and a more rapid inhibitory effect on the release of LH in the pituitary.
  • Estradiol benzoate (EB) is a long-acting estrogen that will deliver long-term inhibition of the hypothalamus for reducing LH production, but also provide direct inhibition of Sertoli cell proliferation, thereby decreasing Sertoli cell numbers and indirectly decreasing the number of Leydig cells and inhibiting and/or delaying their differentiation at the onset of puberty.
  • the combined treatment is capable of inhibiting all three components of the HPG axis and must be delivered neonatally with extended, but temporary elevation of circulating levels of the compounds that inhibit the two waves of Sertoli and Leydig cell proliferation and the onset of testicular maturation. This treatment inhibits testicular development, and importantly the active pharmaceutical ingredients (APIs) disappear from the body before slaughter.
  • APIs active pharmaceutical ingredients
  • Leydig cells are responsible for the synthesis of T and androstenone in the boar testis, decreasing their numbers is the first step in this innovative procedure.
  • Sertoli cell numbers also regulate Leydig cells numbers and steroidogenic activity (102)
  • pig Sertoli cell proliferation precedes the rise in FSH, with FSH progressively declining from birth (103, 104) and FSH treatment of the neonatal pig showed little to no effect on Sertoli cell proliferation and the testis size (90, 104-107).
  • the pig does not depend on an increasing concentration of FSH for stimulating Sertoli cell proliferation.
  • Estrogen concentrations are naturally high in male pig blood and pig reproductive organs (12, 71, 83-85), which results in minimal hypothalamus/pituitary feedback regulation in the pig (59).
  • the pig depends on an alternative regulation of Sertoli cell proliferation.
  • Pig Sertoli cells express ESRI in the prepubertal testis and are directly responsive to E2 during development (60, 88), while Sertoli cells of the rodent testis lack ESRI (108).
  • the pig testis shows direct sensitivity to neonatal E2 (60), while the rodent testis shows only indirect effects (109).
  • Kisspeptin neurons are present and neonatal treatment with E2 showed a decrease in KISSI expressing cells in the caudal region of the ARC and a decrease in LH secretion (38, 39).
  • inhibition of the development of Kisspeptin neurons will provide long-term inhibition of GnRH stimulation of the pituitary synthesis and release of LH (54), providing a method for inhibiting the second wave of Leydig cell proliferation.
  • Inhibition of pig testis development post-birth requires a period of treatment that would cover both the Sertoli cell and Leydig cell proliferation periods but is short enough to permit the treatment compounds to disappear prior to the animal reaching sexual maturity.
  • the pig Sertoli cell population is established over an extended period of time between birth and the onset of puberty by experiencing two waves of proliferation, apparently only requiring high levels of FSH at birth, which then declines during the first wave period. Then FSH starts rising again at 10 weeks (110), correlating with the onset of the second wave of Sertoli cell proliferation and subsequent maturation and establishment of the blood-testis-barrier junctions to support spermatogenesis (111, 112).
  • Leydig cells show proliferation and differentiation over the same extended period prior to puberty, similarly in two-wave formations, with their numbers having a high correlation with testis weight (115). The first wave of Leydig cell proliferation and function produces an increase in T from birth to about 1 week and then there is a dramatic decrease.
  • the second wave begins at about 12 weeks with Leydig cell proliferation and differentiation into adult Leydig cells that produce the dramatic rise in T just before puberty (64, 83, 86, 116, 117).
  • Leydig cells are stimulated by a rise in circulating LH, which is consistent with the two waves of increased T (77).
  • LH rises dramatically at birth and stays elevated for several weeks before declining (78).
  • Such neonatal rise of LH can be inhibited by the co-treatment of an androgen + estrogen.
  • By treating with an androgen + estrogen in a slow-release profile it is possible to limit not only the LH rise, but also both Sertoli and Leydig cell proliferation waves in the pig, if given soon after birth.
  • TBA but not TP with EB treatment resulted in significant decreases in serum T and androstenone at slaughter; however, neither treatment resulted in significant change in testis weight at slaughter.
  • TBA and TBA + EB treatment gave desirable results, treatment in the older boars cannot be used for the reduction in boar taint, because there is a risk that a significant amount of residual compounds can yet to be present in the meat at slaughter (118).
  • restraining pigs at the ages of 14 weeks or later for the injection of the compounds is physically challenging because the intact boars at those ages are large in size, dangerously heavy and aggressive.
  • the API will no longer be present in the animal at slaughter and (2) the piglets will be less aggressive and easier to handle and not place workers in as great a risk of injury.
  • the implant To be successful with neonatal treatment, which is desirable if the routine practice of castration in newborn piglets is to be replaced, the implant must inhibit the growth of testis and the first wave of Leydig cell proliferation that begins soon after birth (64, 83, 86, 117) and the second wave that begins around 12 weeks (64, 83, 86, 116, 117).
  • the first wave of Leydig cells consists of immature/progenitor cells (122) that express the 5a-reductase enzyme required for androstenone synthesis (123-125). Therefore, to prevent early and long-term androstenone synthesis, the first wave of Leydig cell development, as well as the second wave needs to be inhibited by using neonatal treatment with both an androgen and an estrogen.
  • TP aromatizable androgen
  • TBA non-aromatizable androgen
  • the combination of a non-aromatizable androgen and estrogen, rather than the combination of aromatizable androgen and estrogen maximizes the efficacy of the neonatal treatment for the purpose of inhibiting testis development until slaughtering age.
  • the proposed invention provides a simple, easy-to-implement, pharmaceutical intervention that can replace currently used procedures of surgical castration and immunocastration in newborn pigs.
  • a single injection of the two compounds in a sustained- release carrier will inhibit long-term/irreversibly the activation of the HPG axis, inhibit Sertoli cell proliferation, and disrupt Leydig cell development and steroidogenic function of the testis.
  • This treatment strategy will prevent the accumulation in fat of the molecules that cause boar taint and block the development of aggression in maturing male pigs.
  • the present invention pertains generally to preventing development of the boar testis and inhibit production and accumulation of the molecules that cause boar taint and aggression as the males increase in age.
  • the invention relates to the inhibition of functional development of the pig testis by treatment with a combined use of an androgen and estrogen in the newborn male piglet using extended drug delivery methods, for the purpose of inhibiting the production of T and androstenone, the accumulation of androstenone, a boar taint-inducing hormone, as well as skatole in the fat.
  • the same treatment will prevent females from exhibiting estrous cycling.
  • the drug pellet, microsphere, gel, or solution (hereafter, drug complex) comprises biocompatible-/biodegradable polymers or solvents.
  • the drug complex comprises a hormone-based compound configured to inhibit the postnatal release of LH from the pituitary, development of hypothalamic Kisspeptin neurons and cellular components of the testis.
  • the drug complex allows for the sustained but temporary release of the steroids into a body of an animal once the drug-carrier has been injected or implanted therein.
  • Embodiments of the invention comprise insertion methods configured to allow injection of a drug complex through larger epidermal layers or muscler
  • the drug complex may comprise EB and TBA. In other embodiments, the drug complex may comprise other forms of androgens and other estrogen esters. In some embodiments, the drug complex is injected into the subject within the first week to 10 days after birth when piglets are receiving vaccines, tail docking, and other early animal husbandry care.
  • Embodiments of the invention may include subjects such as swine, bovine, lamb, or goat; while other embodiments of the invention may further include subjects physiologically similar to said subjects.
  • the invention involves the inhibition of testicular development and thereby the prevention of a rise in blood and tissue androgens such as T and androstenone by treating newborn male piglets with a combination of an androgen and a long-acting estrogen in a delivery method that allows for sustained, but temporary elevation of the compounds over a nursery period (4-12 weeks).
  • the combined steroids, androgen and estrogen permit the targeting of both the hypothalamus/pituitary region, as well as the testes directly (through both the Sertoli and Leydig cells).
  • Boar taint and aggression inhibiting compositions comprise of an androgen and estrogen.
  • An effective amount of androgen and estrogen to induce the required inhibition of testis development and androgen production can depend, for example, the route of administration, the age of the animal, and its size (body weight). Accordingly, the skilled artisan may titer the dosage and modify the route of administration of an androgen and estrogen to obtain the optimal effect for a particular animal.
  • a typical dosage of androgen (TB A, as an example) may range from about 25 mg/kg to up to about 200 mg/kg or more.
  • the dosage of androgen may range from 25 mg/kg up to about 200 mg/kg; or 100 mg/kg up to about 200 mg/kg; or 150 mg/kg up to about 200 mg/kg.
  • the dose can range from about 25 mg to about 200 mg per animal, including about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg per animal.
  • a typical dosage of estrogen may range from about 1 mg/kg to up to about 40 mg/kg or more. In other embodiments, the dosage of EB may range from 1 mg/kg up to about 40 mg/kg; or 10 mg/kg up to about 40 mg/kg; or 15 mg/kg up to about 40 mg/kg; or 30 mg/kg up to about 40 mg/kg.
  • the dose can range from about 1 mg to about 40 mg per animal, including about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, or about 40 mg per animal.
  • Merck-RevalorTM Compositions include RevalorTM-G (40 mg trenbolone acetate; 8 mg estradiol with a slow releasing carrier/matrix); RevalorTM-XS (200 mg trenbolone acetate; 40 mg estradiol with a slow releasing carrier/matrix); RevalorTM-XH (200 mg trenbolone acetate; 20 mg estradiol with a slow releasing carrier/matrix); RevalorTM-200 (200 mg trenbolone acetate; 20 mg estradiol with a slow releasing carrier/matrix); RevalorTM-IS (80 mg trenbolone acetate; 16 mg estradiol with a slow releasing carrier/matrix); RevalorTM-S (120 mg trenbolone acetate; 24 mg estradiol with a slow releasing carrier/matrix); RevalorTM-IH (80 mg trenbolone acetate; 8 mg estradiol with a slow releasing carrier/matrix
  • Elanco Compositions for Use in the Methods include EncoreTM (43.9 mg estradiol with a slow releasing carrier/matrix); CompudoseTM (25.7 mg estradiol with a slow releasing carrier/matrix) Component E-HTM (10 mg estradiol benzoate and 200 mg testosterone propionate with a slow releasing carrier/matrix); Component TE-GTM (8 mg estradiol and 40 mg trenbolone acetate with a slow releasing carrier/matrix); Component TE-STM (24 mg estradiol and 120 mg trenbolone acetate with a slow releasing carrier/matrix); Component TE-HTM (14 mg estradiol and 140 mg trenbolone acetate with a slow releasing carrier/matrix); Component TE-ISTM (16 mg estradiol and 80 mg trenbolone acetate with a slow releasing carrier/matrix); Component TE-IHTM (8 mg estradiol and 80 mg trenbolone acetate with
  • Zoetis Compositions include SynovexTM One Grass (150 mg trenbolone acetate; 21 mg estradiol benzoate with a slow releasing carrier/matrix); SynovexTM One Feedlot (200 mg trenbolone acetate; 28 mg estradiol with a slow releasing carrier/matrix); SynovexTM Choice (100.0 mg trenbolone acetate; 14 mg estradiol benzoate with a slow releasing carrier/matrix); SynovexTM Plus (200 mg trenbolone acetate; 28 mg estradiol benzoate with a slow releasing carrier/matrix); and SynovexTM H (200 mg Testosterone propionate; 20 mg estradiol benzoate with a slow releasing carrier/matrix).
  • SynovexTM One Grass 150 mg trenbolone acetate; 21 mg estradiol benzoate with a slow releasing carrier/matrix
  • SynovexTM One Feedlot 200 mg trenbolone acetate; 28
  • compositions comprising androgen and estrogen to reduce taint and/or aggression are administered prior to puberty (prior to reaching sexual maturity/capable of reproduction).
  • the compositions can be administered neonatally.
  • Administration of an androgen and estrogen effectively inhibits/blocks maturation of sex organs/gonads in males.
  • compositions provided herein are in accordance with known methods, e.g., injection (intraperitoneal, intramuscular, subcutaneous) and nasal (inhalation).
  • an androgen and estrogen are administered for inhibition of boar taint and/or aggression of an animal in a single, one-time dose.
  • multiple administrations of an androgen and estrogen can be carried out to inhibit testis development, boar taint and/or aggression.
  • an androgen and estrogen compositions for injectable administration can be in the form of oleaginous suspensions, including oil, such as vegetable oil (e.g., corn oil), cottonseed oil, peanut oil, and/or sesame oil.
  • oil such as vegetable oil (e.g., corn oil), cottonseed oil, peanut oil, and/or sesame oil.
  • Carriers/fillers can include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol.
  • These suspensions can be formulated according to methods available to the art for dispersing and suspending ingredients.
  • the composition described above can be encapsulated for administration.
  • a capsule can be formed from silicone tubing with plugs at each end to contain a mixture of, for example, androgen, estrogen, and oil.
  • the capsules can be placed, such as by injection (further described below), in the body of the subject.
  • the androgen and estrogen compositions described herein can be formulated for immediate release or in a time release formulation (e.g., slow release).
  • a time release formulation e.g., slow release
  • an androgen and estrogen can be prepared with carriers that protect the androgen and estrogen against rapid release, such as a controlled release formulation.
  • sustained- or controlled-delivery means such as liposome carriers, polymers (e.g., ethylene vinyl acetate, polyanhydrides, silicone, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG)), microparticles, nanoparticles (such as nanospheres, including biodegradable nanospheres or porous beads, and depot injections), a water insoluble polymer and a polyethylene glycol as a water-soluble pore forming agent, or with carrier/matrix such as cholesterol, magnesium stearate, ethyl cellulose N200 carrier/matrix are also known to those skilled in the art.
  • polymers e.g., ethylene vinyl acetate, polyanhydrides, silicone, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG)
  • microparticles such as nanospheres, including biodegradable nanosphere
  • sustained-release preparations include semipermeable polymer matrices in the form of shaped articles, e.g., films or microcapsules.
  • Sustained release matrices may include polyesters, hydrogels, polylactides (U.S. Pat. No.
  • kits for producing a single-dose administration unit may contain single and multi -chambered pre-filled syringes containing an androgen and estrogen and instructions for use (inhibiting testis development and reducing boar taint).
  • Example 1 Effects of injecting androgen (aromatizable and non-aromatizable) + estrogen in neonatal piglets via carrier on the serum LH level.
  • EPV-607 is an injectable implant, composed of excipient for slow/delayed release and two APIs: 100 mg TP (CAS# 57-85-2) and 10 mg EB (CAS# 50-50-0).
  • EPV-608 is an injectable implant, composed of excipient for slow/delayed release as the excipient and two APIs: 100 mg TBA (CAS# 10161-34-9) and 14 mg EB (CAS# 50-50-0).
  • Control intact animals had 23.7 ⁇ 15.86 ng/mL serum LH concentration at 3 weeks of age (Fig. 1).
  • animals treated with either EPV-607 or EPV-608 had 96% (0.96 ⁇ 0.55 ng/mL) and 97% (0.75 ⁇ 0.17 ng/mL) lower serum LH concentrations, respectively, than control intact animals.
  • the LH levels of animals treated with EPV-607 (7.87 ⁇ 2.30 ng/mL) was similar to those of intact pigs (9.27 ⁇ 5.98 ng/mL), whereas animals treated with EPV-608 showed 68% lower LH levels (2.98 ⁇ 0.77 ng/mL) than those of intact pigs.
  • EPV-607 which contains non-aromatizable androgen showed more prolonged effects in reducing circulating LH levels than EPV-607 which contains aromatizable androgen.
  • TBA + EB implant - EPV-608.
  • EVA + EB was given in an injectable solid pellet (EPV-608) composed of excipient for slow/delayed release, 100 mg TBA (CAS# 10161-34-9) and 14 mg EB (CAS# 50-50-0).
  • Boars were slaughtered at 26 weeks of age. Blood and organs were harvested and weighed, including testes. Serum was obtained from the blood samples following centrifugation. Fat tissues were collected from underneath the abdominal skin. Serum T levels were measured by ELISA (EIA1559, DRG International, NJ). Ear biopsy and saliva androstenone levels were measured by liquid chromatography-mass spectrometry (LC-MS/MS) and reported as ng/g. Given the well documented natural variation that occurs in untreated boars, data are presented using descriptive analysis as well as mean ⁇ SD. Where appropriate, statistical significance was determined by One-way ANOVA.
  • EPV-608 A single injection of EPV-608 into neonatal pigs resulted in smaller testes and reduced levels of the steroid hormones T and androstenone, which are naturally produced in higher concentrations by the testis, as boars reach sexual maturity.
  • Androstenone is the major hormone that drives the development of boar taint (4). Androstenone is produced in the testis, released into the blood, and in the liver inhibits the metabolism of skatole, and then the hormone accumulates in fat along with skatole, but it is also found in high concentration in salivary glands because it also serves as a steroidal pheromone in boar’s saliva (8, 9, 14, 17, 18, 134, 135). In the Control intact animals at 24 weeks of age, saliva from 2 of 4 males (50%) had androstenone levels that were greater than 200 ng/mL (293.4 ⁇ 1267.4 ng/mL) (Fig.
  • Tissue androstenone levels at 26 weeks displayed a pattern similar to that found in saliva at 24 weeks.
  • EPV-608-treated boars had significantly lower tissue androstenone concentration (6.56 ⁇ 0.97 ng/g) compared to intact control (58.25 ⁇ 15.05 ng/g) boars at 26 weeks of age.
  • back fat tissue androstenone concentration was 2.15 ⁇ 0.95 ng/g (Fig. 3).
  • Example 3 Effects of EPV-608 treatment on meat quality.
  • EPV-608 is an injectable implant, composed of PLGA (CAS# 26780-50-7) as the excipient and two APIs: 100 mg TBA (CAS# 10161-34-9) and 14 mg EB (CAS# 50-50-0).
  • Boar taint related compounds Androstenone/skatole/other substances. Acta Veterinaria Scandinavica. 2006;48(l):S5.
  • Cytochrome P450IIE1 (CYP2E1) is induced by skatole and this induction is blocked by androstenone in isolated pig hepatocytes. Chem Biol Interact. 2002;140(l):81-92.
  • Parois SP Faouen A
  • Le Floc'h N Prunier A. Influence of the inflammatory status of entire male pigs on their pubertal development and fat androstenone. Animal. 2017; 11(6): 1071-7.
  • Lunstra DD Ford JJ
  • Christenson RK Allrich RD. Changes in Leydig cell ultrastructure and function during pubertal development in the boar. Biology of reproduction. 1986;34(1): 145- 58.
  • Hess RA Small tubules, surprising discoveries: from efferent ductules in the turkey to the discovery that estrogen receptor alpha is essential for fertility in the male. Anim Reprod. 2015; 12(l):7-23.
  • Embodiments [0098] A method for inhibiting testicular development in the pig, which prevents the pubertal rise in blood and tissue androgens comprising injecting in said pig a combination of an estrogen and an androgen neonatally.
  • a method to inhibit testicular development in the pig, which prevents the pubertal rise in blood and tissue androgens comprising injecting in said pig a combination of an estrogen, an androgen and a carrier neonatally, wherein the combination is selected from the group consisting of:
  • RevalorTM-G (40.0 mg trenbolone acetate; 8.0 mg estradiol with a slow releasing carrier/matrix) (with a cholesterol, magnesium stearate, ethyl cellulose N200 carrier/matrix);
  • RevalorTM-XS (200.0 mg trenbolone acetate; 40.0 mg estradiol with a slow releasing carrier/matrix) (with a cholesterol, magnesium stearate, ethyl cellulose N200 carrier/matrix);
  • RevalorTM-XH (200.0 mg trenbolone acetate; 20.0 mg estradiol with a slow releasing carrier/matrix) (with a cholesterol, magnesium stearate, ethyl cellulose N200, poly-(DL-lactide- co-glycolide) 65:35, colloidal silica anhydrous carrier/matrix);
  • RevalorTM-200 (200.0 mg trenbolone acetate; 20.0 mg estradiol with a slow releasing carrier/matrix) (with a cholesterol, magnesium stearate, ethyl cellulose N200 carrier/matrix);
  • RevalorTM-IS 80.0 mg trenbolone acetate; 16.0 mg estradiol with a slow releasing carrier/matrix) (with a cholesterol, magnesium stearate, ethyl cellulose N200 carrier/matrix);
  • RevalorTM-S (120.0 mg trenbolone acetate; 24.0 mg estradiol with a slow releasing carrier/matrix) (with a cholesterol, magnesium stearate, ethyl cellulose N200 carrier/matrix);
  • RevalorTM-IH 80.0 mg trenbolone acetate; 8.0 mg estradiol with a slow releasing carrier/matrix) (with a cholesterol, magnesium stearate, ethyl cellulose N200 carrier/matrix):
  • RevalorTM-H 140.0 mg trenbolone acetate; 14.0 mg estradiol with a slow releasing carrier/matrix) (with a cholesterol, magnesium stearate, ethyl cellulose N200 carrier/matrix);
  • Finaplix-HTM (200.0 mg trenbolone acetate with a slow releasing carrier/matrix) (with carrier/matrix such as cholesterol, magnesium stearate, ethyl cellulose N200 carrier/matrix);
  • Component E-HTM (10 mg estradiol benzoate and 200 mg testosterone propionate with a slow releasing carrier/matrix) (with a carrier/matrix of polyethylene glycol, magnesium stearate, cellulose, lactose, polymeric supports and binders and coloring agents);
  • Component TE-GTM (8 mg estradiol and 40 mg trenbolone acetate with a slow releasing carrier/matrix) (with a carrier/matrix of polyethylene glycol, magnesium stearate, cellulose, lactose, polymeric supports and binders and coloring agents);
  • Component TE-STM 24 mg estradiol and 120 mg trenbolone acetate with a slow releasing carrier/matrix
  • a carrier/matrix of polyethylene glycol, magnesium stearate, cellulose, lactose, polymeric supports and binders and coloring agents 24 mg estradiol and 120 mg trenbolone acetate with a slow releasing carrier/matrix
  • Component TE-HTM 14 mg estradiol and 140 mg trenbolone acetate with a slow releasing carrier/matrix
  • Component TE-ISTM 16 mg estradiol and 80 mg trenbolone acetate with a slow releasing carrier/matrix
  • Component TE-ISTM 16 mg estradiol and 80 mg trenbolone acetate with a slow releasing carrier/matrix
  • Component TE-IHTM (8 mg estradiol and 80 mg trenbolone acetate with a slow releasing carrier/matrix) (with a carrier/matrix of polyethylene glycol, magnesium stearate, cellulose, lactose, polymeric supports and binders and coloring agents);
  • Component TE-200TM (20 mg estradiol and 200 mg trenbolone acetate with a slow releasing carrier/matrix) (with a carrier/matrix of polyethylene glycol, magnesium stearate, cellulose, lactose, polymeric supports and binders and coloring agents);
  • SynovexTM One Grass (150.0 mg trenbolone acetate; 21.0 mg estradiol benzoate with a slow releasing carrier/matrix) (with a film coat comprising a mixture of a water insoluble polymer and a polyethylene glycol as a water-soluble pore forming agent);
  • SynovexTM One Feedlot (200.0 mg trenbolone acetate; 28.0 mg estradiol benzoate with a slow releasing carrier/matrix) (with a film coat comprising a mixture of a water insoluble polymer and a polyethylene glycol as a water-soluble pore forming agent);
  • SynovexTM S (20.0 mg estradiol benzoate and 200 mg progesterone with a slow releasing carrier/matrix);
  • SynovexTM Choice (100.0 mg trenbolone acetate; 14.0 mg estradiol benzoate with a slow releasing carrier/matrix);
  • SynovexTM H (200.0 mg Testosterone propionate; 20.0 mg estradiol benzoate with a slow releasing carrier/matrix).

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Abstract

Des modes de réalisation de la présente invention concernent une intervention pharmaceutique chez le porc néonatal qui inhibe et retarde le développement et l'activation de l'axe HPG, la croissance des testicules de verrat et inhibe la production testiculaire de testostérone et d'androsténone, ce qui empêche le développement d'un comportement agressif chez les verrats en maturation et la présence d'une odeur de verrat dans la viande. L'invention comprend un traitement par une combinaison d'un androgène et d'un œstrogène chez le porcelet mâle nouveau-né à l'aide de procédés d'administration de médicament étendus, avec une durée définie inférieure ou égale à 12 semaines, dans le but d'inhiber la production de testostérone et d'androsténone et l'accumulation de molécules d'androsténone et de scatole dans la graisse induisant une odeur de verrat.
PCT/US2023/075842 2022-10-03 2023-10-03 Compositions pour la prévention non chirurgicale de l'odeur et du comportement agressif WO2024076995A1 (fr)

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