I. BACKGROUND
Human chorionic gonadotropin (hCG) is a hormone produced by the syncytiotrophoblast cells of the human placenta and gonads. hCG interacts with the luteinizing hormone/choriogonadotropin receptor (LHCGR) (also known as lutropin/choriogonadotropin receptor (LCGR) or luteinizing hormone receptor (LHR) found in the gonads of both genders.
The action of hCG is similar to that of pituitary luteinizing hormone (LH), in that: both hormones stimulate the production of testosterone and other steroid hormones by the Leydig cells of the testis and both hormones stimulate the production of progesterone by the corpus luteum of the ovary.
During fetal development, hCG produced by the placenta stimulates the fetal testes to produce androgens, which are important to normal male sexual development. In the adult, administration of exogenous hCG stimulates testosterone production from the Leydig cells of the testes. For men with hypogonadotrophic hypogonadism, exogenously administered hCG can stimulate the testicular Leydig cells and restore normal testosterone production. Administration of hCG may also stimulate testicular descent in boys with cryptorchidism when no anatomical impediment to descent is present.
In the female, hCG produced by the placenta stimulates the ovary and promotes the maintenance of the corpus luteum during the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone during the first trimester. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus.
During the normal menstrual cycle, LH participates with FSH in the development and maturation of the normal ovarian follicle, and the mid-cycle LH surge triggers ovulation. In adult females, clinical administration of exogenous hCG can substitute for an LH surge. For women undergoing in vitro fertilization, hCG is extensively used parenterally for final maturation induction. In the presence of one or more mature ovarian follicles, ovulation can be triggered by the administration of hCG. In addition, hCG is sometimes used to enhance the production of progesterone for clinical purposes during treatment for infertility.
As the most abundant biological source is women who are presently pregnant, some organizations collect urine from pregnant women to extract hCG for pharmaceutical use, in dosage forms marketed under the trade names Novarel" and Pregnyl®. Recombinant hCG is produced through Chinese hamster ovary (CHO) cells and commercially available in a dosage form marketed under the trade name Ovidrel·".
Current commercially available dosage forms of hCG are limited to intramuscular (IM) or subcutaneous (SC) injectable forms which raise serum hCG levels to therapeutic levels over a short period of time.
Frequent injections are required for several clinical applications where sustained dosing of hCG is needed. These applications include but are not limited to the treatment of hypogonadotrophic hypogonadism and stimulation of progesterone production for female fertility. There is a need in the art for extended-release dosage forms of hCG. The present invention satisfies this need.
II. SUMMARY
The present disclosure relates to the long-felt need in the art for extended-release human chorionic gonadotropin (hCG) formulations. In particular, the present disclosure is directed to hCG dosage forms having extended-release profiles. In some embodiments, the hCG dosage forms exhibit release profiles of between about 1 week and about 2 months. In other embodiments, the hCG dosage forms described herein can have extended-release profiles between about 1 week and about 6 months.
In some aspects, the extended-release hCG dosage form comprises hCG encapsulated in a microsphere. In further aspects, the microsphere is formed by a copolymer. In still further aspects, the copolymer is a block copolymer or a multi-block copolymer. In such aspects, the block copolymer may comprise or alternatively consists essentially of, polyethylene glycol (PEG) or a PEG-containing polymeric block and one or more other polymeric blocks.
hCG extended-release formulations described herein may be useful in a variety of treatments relating to hormone therapy, including but not limited to treatment for infertility and pituitary gland disorders. Thus, further aspects of the disclosure relate to methods of administering the extended-release hCG formulations described herein, as well as methods of treatment employing the extended-release hCG formulations described herein. Such methods include treatments for fertility and pituitary gland defects. Further methods disclosed herein include the treatment of breast cancer. In some embodiments, the treatment is for existing breast cancer in nulliparous women. In some embodiments, the women are about age 25 or younger.
Applicants
Inventors
Human chorionic gonadotropin (hCG) is a hormone produced by the syncytiotrophoblast cells of the human placenta and gonads. hCG interacts with the luteinizing hormone/choriogonadotropin receptor (LHCGR) (also known as lutropin/choriogonadotropin receptor (LCGR) or luteinizing hormone receptor (LHR) found in the gonads of both genders.
The action of hCG is similar to that of pituitary luteinizing hormone (LH), in that: both hormones stimulate the production of testosterone and other steroid hormones by the Leydig cells of the testis and both hormones stimulate the production of progesterone by the corpus luteum of the ovary.
During fetal development, hCG produced by the placenta stimulates the fetal testes to produce androgens, which are important to normal male sexual development. In the adult, administration of exogenous hCG stimulates testosterone production from the Leydig cells of the testes. For men with hypogonadotrophic hypogonadism, exogenously administered hCG can stimulate the testicular Leydig cells and restore normal testosterone production. Administration of hCG may also stimulate testicular descent in boys with cryptorchidism when no anatomical impediment to descent is present.
In the female, hCG produced by the placenta stimulates the ovary and promotes the maintenance of the corpus luteum during the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone during the first trimester. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus.
During the normal menstrual cycle, LH participates with FSH in the development and maturation of the normal ovarian follicle, and the mid-cycle LH surge triggers ovulation. In adult females, clinical administration of exogenous hCG can substitute for an LH surge. For women undergoing in vitro fertilization, hCG is extensively used parenterally for final maturation induction. In the presence of one or more mature ovarian follicles, ovulation can be triggered by the administration of hCG. In addition, hCG is sometimes used to enhance the production of progesterone for clinical purposes during treatment for infertility.
As the most abundant biological source is women who are presently pregnant, some organizations collect urine from pregnant women to extract hCG for pharmaceutical use, in dosage forms marketed under the trade names Novarel" and Pregnyl®. Recombinant hCG is produced through Chinese hamster ovary (CHO) cells and commercially available in a dosage form marketed under the trade name Ovidrel·".
Current commercially available dosage forms of hCG are limited to intramuscular (IM) or subcutaneous (SC) injectable forms which raise serum hCG levels to therapeutic levels over a short period of time.
Frequent injections are required for several clinical applications where sustained dosing of hCG is needed. These applications include but are not limited to the treatment of hypogonadotrophic hypogonadism and stimulation of progesterone production for female fertility. There is a need in the art for extended-release dosage forms of hCG. The present invention satisfies this need.
II. SUMMARY
The present disclosure relates to the long-felt need in the art for extended-release human chorionic gonadotropin (hCG) formulations. In particular, the present disclosure is directed to hCG dosage forms having extended-release profiles. In some embodiments, the hCG dosage forms exhibit release profiles of between about 1 week and about 2 months. In other embodiments, the hCG dosage forms described herein can have extended-release profiles between about 1 week and about 6 months.
In some aspects, the extended-release hCG dosage form comprises hCG encapsulated in a microsphere. In further aspects, the microsphere is formed by a copolymer. In still further aspects, the copolymer is a block copolymer or a multi-block copolymer. In such aspects, the block copolymer may comprise or alternatively consists essentially of, polyethylene glycol (PEG) or a PEG-containing polymeric block and one or more other polymeric blocks.
hCG extended-release formulations described herein may be useful in a variety of treatments relating to hormone therapy, including but not limited to treatment for infertility and pituitary gland disorders. Thus, further aspects of the disclosure relate to methods of administering the extended-release hCG formulations described herein, as well as methods of treatment employing the extended-release hCG formulations described herein. Such methods include treatments for fertility and pituitary gland defects. Further methods disclosed herein include the treatment of breast cancer. In some embodiments, the treatment is for existing breast cancer in nulliparous women. In some embodiments, the women are about age 25 or younger.
Applicants
- INNOCORE TECHNOLOGIES HOLDING B.V. [NL]/[NL]
- MHB LABS, INC. [US]/[US]
Inventors
- ZUIDEMA, Johan
- STEENDAM, Rob
- ARAUJO, Joana Catarina Ribeiro
- KACKER, Ravi
- MORGENTALER, Abraham
