WO2012120535A2 - Composition contenant de la gonadotropine chorionique extrêmement purifiée, sa formulation et ses utilisations - Google Patents

Composition contenant de la gonadotropine chorionique extrêmement purifiée, sa formulation et ses utilisations Download PDF

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Publication number
WO2012120535A2
WO2012120535A2 PCT/IN2012/000085 IN2012000085W WO2012120535A2 WO 2012120535 A2 WO2012120535 A2 WO 2012120535A2 IN 2012000085 W IN2012000085 W IN 2012000085W WO 2012120535 A2 WO2012120535 A2 WO 2012120535A2
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WIPO (PCT)
Prior art keywords
hcg
composition
formulation
highly purified
fsh
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Ceased
Application number
PCT/IN2012/000085
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English (en)
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WO2012120535A3 (fr
Inventor
Prasad K.V.S.
L. Soman JAY
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SANZYME Ltd
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SANZYME Ltd
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Publication of WO2012120535A2 publication Critical patent/WO2012120535A2/fr
Publication of WO2012120535A3 publication Critical patent/WO2012120535A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]

Definitions

  • the present invention relates to a composition comprising highly purified human chorionic gonadotropin (hCG), formulation comprising the same and uses of the composition. More particularly the present invention relates to the composition comprising highly purified hCG, pharmaceutical formulation comprising the same and uses of the same for Folliculogenesis and Endometrial Development.
  • hCG human chorionic gonadotropin
  • Chorionic gonadotropin is a hormone produced by the placenta and traditionally obtained from the urine of pregnant women.
  • the hormone is a heterodime, consisting of non-covalently bound a and ⁇ subunits and its effects are predominantly those of gonadotropin luteinizing hormone.
  • Chorionic gonadotropin is given to women, to induce ovulation and also recently it has been included as a therapeutic for maintenance of pregnancy.
  • ART assisted reproduction technology
  • COS controlled ovarian stimulation
  • Pharmacological amounts of exogenous gonadotropins are used to override the process of physiological control mechanisms.
  • the numerous ovarian follicles stimulated by COS yield the multiple oocytes that are needed to maximize the success of ART.
  • the endometrial thickness is a critical factor that determines the process of nidation and continuation of the pregnancy.
  • Ovarian response to gonadotrophins varies considerably among women undergoing COS[ Controlled Ovarian Stimualtion ⁇ .
  • the importance of this differential response in women with previous ART (IVF/ICSI) failures has prompted researchers to investigate and determine the factors that are implicated.
  • IVF/ICSI ART
  • follicular development up to the pre-antral stage is feasible in the absence of LH, an essential role for this gonadotrophin for antral formation as well as further growth and differentiation has been uniformly recognized.
  • LH plays a key role in both oocyte and follicular cells development through modification of the steroid and protein micro- and macroenvironment.
  • hCG has a different ⁇ -subunit amino-acid composition and greater sialic acid content compared to hLH
  • hCG binds to the LH/hCG receptor with higher affinity than LH, while exerting biological actions that are comparable to LH
  • LH acts synergistically with FSH in the process of follicular growth: FSH plays a crucial role in recruitment, selection and dominance, while LH contributes to dominance maturation and ovulation.
  • Studies in non-humans have shown that LH may act by increasing intra- ovarian androgens, which in turn promote FSH responsive granulosa cell function.
  • GnRHa GnRH analogues
  • rLH recombinant LH
  • rFSH recombinant FSH
  • 2PN normally fertilized 2PN embryos
  • rLH pre-treatment may have a modest impact on subsequent ovarian responsiveness to FSH.
  • LH activity,administered as a single dose of HP-hCG in combination with aromatase inhibitor in early-follicular-phase GnRH antagonist protocol has been shown to result in androgen priming and subsequent increase in the number of good quality embryos.
  • hCG human chorionic gonadotrophin
  • hCG human chorionic gonadotrophin
  • hCG has long been associated with the initiation and maintenance of pregnancy.
  • HCG demonstrates a bi-phasic pharmacokinetic pattern and has a slower plasma metabolic clearance, which consists of a rapid phase in the first 5-9 h following IM administration and a slower phase in the first 1-1.3 days after administration.
  • LH and hCG are complex heterodimeric glycoproteins with different molecular weights (30 KD and 40 KD respectively). Difference in their carbohydrate moiety possibly explains different affinity to the LH/hCG receptor and therefore differentiated function.
  • the present invention is directed to providing a composition comprising hCG in highly purified form in low dose.
  • the highly purified hCG has reduced endotoxin level of less than 0.03 EU/IU, preferably less than 0.01EU/IU.
  • the present invention is directed to providing formulations comprising the composition of hCG in highly purified form in low dose.
  • the present invention is directed to providing a composition comprising a hCG in highly purified form in low dose for promoting the estrogenic environment to support endometrial growth and receptivity and also the follicular growth.
  • the present invention is directed to providing a composition comprising a hCG in highly purified form in low dose with or without concomitant FSH preparation.
  • the present invention is directed to providing a composition comprising a hCG in highly purified form in low dose for the treatment of infertility in patients receiving high doses of Follicle Stimulating Hormone (FSH).
  • FSH Follicle Stimulating Hormone
  • FIG 1. Is a graph showing the Reproductive Cycles in Humans & Female Rats. The graph typically demonstrates the differences in the cycle length. However similarities are shown in terms of the hormones present and the hormonal surge during the reproductive cycle. The studies using regimens will contribute to the ART Cycles currently being employed and bring in improved outcomes.
  • the present invention is directed to an hCG unconventionally in highly purified form in low dose intended for a novel application of promoting the estrogenic environment to support endometrial growth and receptivity and also the follicular growth with or without concomitant FSH preparation.
  • the hCG employed in the present invention is of human origin.
  • the hCG is partially purified or purified hCG obtained from the urine of pregnant women.
  • the process of the present invention comprises subjecting hCG to steps of purification by chromatographic technique and lyophilizing the purified hCG to obtain highly purified hCG.
  • the entire process of obtaining the highly purified hCG has been described in the co-pending Indian Patent application No. 2067/MUM/2010 by the Applicant, the contents of said application has been incorporated herein by reference.
  • the highly purified hCG as obtained by said process has reduced endotoxin level of less than 0.03 EU/IU, preferably less than 0.01EU/IU. Such highly purified hCG is contemplated to be without structural damage or loss of potency.
  • the present invention provides a composition comprising highly purified hCG and a pharmaceutically acceptable diluent, carrier or excipient.
  • the highly purified hCG has reduced endotoxin level of less than 0.03 EU/IU, preferably less than 0.01EU/IU.
  • compositions comprise a daily dose of hCG of 100-200 IU.
  • the present invention provides use of the composition comprising highly purified hCG at the dose of 100-200 IU for preparing the medicament for promoting the estrogenic environment to support endometrial growth and receptivity and also the follicular growth.
  • the present invention provides pharmaceutical formulation comprising the composition of highly purified hCG, formulated as a unit dosage in the form of a solid ready for dissolution to form a sterile injectable solution for intramuscular or for subcutaneous use.
  • the solid usually results from lyophilisation.
  • Typical excipients and carriers include sucrose, lactose, sodium chloride, buffering agents like sodium phosphate monobasic and sodium phosphate dibasic.
  • the solution may be prepared by diluting with water for injection immediately prior to use.
  • the comprising the composition of highly purified hCG may also be formulated as a solution for injection, comprising any of the excipients and buffers listed above, and others known to one skilled in the art.
  • the present invention provides a pharmaceutical formulation comprising composition of high purified low dose hCG 100-200 IU, and pharmaceutically acceptable suitable excipients such as Lactose, Sucrose etc. which may aid in the stabilization of the lyophilized product.
  • a pharmaceutical formulation comprising composition of high purified low dose hCG 100-200 IU, and pharmaceutically acceptable suitable excipients such as Lactose, Sucrose etc. which may aid in the stabilization of the lyophilized product.
  • Such formulation is filled into glass ampoules.
  • the pharmaceutical formulation of the highly purified hCG is suitable for subcutaneous administration in IVF /ICSCI procedures.
  • the daily dose of the composition comprising the highly purified hCG or formulation comprising the same may be administered once a day from day 1 to about day 4 stimulatory cycle.
  • the composition of the present invention optionally may comprise of other active drugs.
  • other drugs that can be included in the composition may be selected from but not limiting to gonadotropin releasing hormone, gonadotropin releasing hormone agonists, gonadotropin releasing hormone antagonists, preparations with luetinizing hormone activity, progesterone preparations, or aromatase inhibitors.
  • Dose ranges for these drugs are at the dose range that provides bioactivity desired for the composition of the present invention.
  • the composition comprising the highly purified low dose hCG ranging from 100 IU to 200 IU may be used for various applications including but not limited to those including for promoting endometrial and follicular growth either as a sole agent or as a concomitant intervention as a part of protocol.
  • the composition comprising a hCG in highly purified form in 100 IU to 200 IU dose or formulation comprising the same is used for promoting the estrogenic environment to support endometrial growth and receptivity and also the follicular growth.
  • composition comprising a hCG in highly purified form in 100 IU to 200 IU dose or formulation comprising the same is used with or without concomitant FSH preparation.
  • composition comprising a hCG in highly purified form in 100 IU to 200 IU dose or formulation comprising the same is used for the treatment of infertility in patients receiving high doses of Follicle Stimulating Hormone (FSH).
  • FSH Follicle Stimulating Hormone
  • the composition comprising a hCG in highly purified form in 100 IU to 200 IU dose or formulation comprising the same may optionally be used in women undergoing pituitary suppression, or in patients of hypogonadotrophic hypogonadism or in patients presented with any other hypoestrogenic states (typically presented with low basal LH & estradiol levels ) at base line, not being limited to any of these categories of patients only; to promote the estradiol levels during the early to mid follicular phase for an appropriate endometrial pattern and thickness; use concomitantly with FSH or as a sole agent for its ability to enhance the follicular growth, in mid to late follicular phase or throughout the follicular phase of the cycle; for enhancing the FSH efficacy to improve the ovulation induction outcome such as hastening the development of larger antral follicle, to reduce the chances of ovarian hyperstimulation by reducing the number of small preovulatory follicles ( ⁇ 10mm);
  • Example 1 The present invention is illustrated by the following non-limiting example.
  • Example 1 The present invention is illustrated by the following non-limiting example.
  • Example 1 The present invention is illustrated by the following non-limiting example.
  • Rats were fed normally with no dietary restrictions and any form of pre-treatment 3. Blood was collected from the tail vein for analysis of the hormones FSH,LH and Prolactin.
  • the control group had no treatment at all and were purely for evaluation of the follicular patterns.
  • the injections were administered with 1 ml disposable syringes causing minimal trauma so as to not stress the animal.
  • Endometrial Thickness was carried using the Hematoxylin and Eosin Staining. After fixed with 10% formalin for 24 hours and embedded in paraffin, the uteri were cut into a thick 5 ⁇ transverse sections and then mounted on slides. Parts of these tissue sections were stained with hematoxylin (Harris) and eosin according to the standard procedure. Morphological changes were observed under light microscope, and morphometric parameters were evaluated. The stromal area and glandular area were also measured [Table 1,11 and III]
  • HCG not only plays a crucial role in the ovulation process, but is also capable of exerting all the physiologic actions of FSH on granulosa cells.
  • serum E2 concentration as a marker of follicular stimulation efficacy improvement of endometrial thickness seems an opportunity to reduce the incidence of OHSS in humans and also reduce the dosage of FSH in the late follicular phases.
  • Blockeel C De Vos M Can 200 IU of Hcg Replace Recombinant Fsh In The Late Follicular Phase In A GnRH-antagonist Cycle? A Pilot Study:Human Reproduction, Vol.24, No.ll pp. 2910-2916, 2009

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Reproductive Health (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition contenant une faible dose de gonadotropine chorionique humaine (hCG) sous une forme extrêmement purifiée destinée à une nouvelle application visant à favoriser l'environnement oestrogénique pour soutenir la croissance et la réceptivité endométriales, ainsi que la croissance folliculaire avec ou sans préparation concomitante d'hormone de stimulation folliculaire (FSH). La composition contient la gonadotropine chorionique humaine (hCG) extrêmement purifiée dans une dose allant de 100 IU à 200 IU.
PCT/IN2012/000085 2011-02-03 2012-02-03 Composition contenant de la gonadotropine chorionique extrêmement purifiée, sa formulation et ses utilisations Ceased WO2012120535A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN315MU2011 2011-02-03
IN315/MUM/2011 2011-02-03

Publications (2)

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WO2012120535A2 true WO2012120535A2 (fr) 2012-09-13
WO2012120535A3 WO2012120535A3 (fr) 2013-03-14

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Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE406378T1 (de) * 2000-02-22 2008-09-15 Serono Lab Verfahren zur reinigung vom recombinantem hcg mit spezifischer bioaktivität
EP1862182A2 (fr) * 2001-12-21 2007-12-05 Pantarhei Bioscience B.V. Procédé pour l'hyperstimulation ovarienne contrôlée et kit pharmaceutique à utiliser avec ce procédé
US20040248784A1 (en) * 2003-06-03 2004-12-09 Marco Filicori Unitary combinations of FSH and hCG

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WO2012120535A3 (fr) 2013-03-14

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