WO2004105788A1 - UNITARY COMBINATION OF FSH AND hCG - Google Patents
UNITARY COMBINATION OF FSH AND hCG Download PDFInfo
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- WO2004105788A1 WO2004105788A1 PCT/IB2004/001813 IB2004001813W WO2004105788A1 WO 2004105788 A1 WO2004105788 A1 WO 2004105788A1 IB 2004001813 W IB2004001813 W IB 2004001813W WO 2004105788 A1 WO2004105788 A1 WO 2004105788A1
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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]
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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
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- 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
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
Definitions
- the present invention relates to novel gonadotropin formulations. More specifically, the invention relates to pharmaceutical formulations, useful for ovarian stimulation, in which both follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG) are present.
- FSH follicle stimulating hormone
- hCG human chorionic gonadotropin
- Assisted reproduction technology (ART) procedures typically require treatment with exogenous gonadotropins to stimulate growth and maturation of the ovarian follicles.
- gonadotropins When gonadotropins are used to treat anovulatory females, the goal is to replicate the normal menstrual cycle, when a single, dominant follicle matures prior to induction of ovulation.
- IVF in vitro fertilization
- COS controlled ovarian stimulation
- Gonadotropins are secreted by the pituitary gland under the control of hypothalamic gonadotropin-releasing hormone (GnRH).
- Follicle stimulating hormone (FSH) and luteinizing hormone (LH) are the pituitary hormones essential for follicular maturation (folliculogenesis) and luteinization.
- FSH is required for follicular recruitment (i.e., the early growth of ovarian follicles) at the beginning of the spontaneous menstrual cycle, and it also supports mid- and late-stage folliculogenesis.
- FSH is administered therapeutically to induce folliculogenesis in anovulatory women and women undergoing COS.
- FSH is administered throughout treatment until the time that oocytes are retrieved.
- This continued stimulation by FSH can cause multiple conceptions and the potentially fatal condition, ovarian hyperstimulation syndrome (OHSS).
- OHSS ovarian hyperstimulation syndrome
- Decreasing the dosage of FSH can reduce the risk of OHSS, but low FSH dosages yield inadequate follicle quantities and thus lower the chances of success in assisted reproduction.
- LH functions during all stages of a normal menstrual cycle. LH stimulates the theca cells of the follicle to produce the androgen substrate which is converted into estrogen by the aromatase system in the granulosa cells.
- hCG can serve as a source of LH activity because hCG and LH act through the same receptor. Filicori et al. Human Reprod. 17:2009 (2002a); Martin er a/., Fertil. Steril. 76: 0-49 (2002). Relative to LH, hCG has a longer half-life and, hence, is more potent than LH, although the literature tends to treat hCG and LH as fungible.
- 5,929,028 is directed to liquid formulations that contain one or more natural or recombinant gonadotropins, including FSH, LH, and hCG.
- the '028 patent discusses naturally derived compositions of human menopausal gonadotropin (hMG), which have FSH and LH activities in a ratio of approximately 1 :1 , but mentions no ratio of FSH to LH activity other than the 1 :1 ratio of commercial hMG preparations.
- hMG human menopausal gonadotropin
- Human-derived preparations are available containing 75 IU FSH with 75 IU LH activity (Pergonal, Humegon, Menogon, Repronex, and Menopur) and 75 IU FSH with 25 or 35 IU LH activity (Normegon and Pergogreen).
- compositions that combine FSH and hCG in varying ratios thereby to enable the practitioner to tailor a gonadotropin treatment regimen to the needs of the individual patient.
- Methodology also is needed for using such compositions to stimulate folliculogenesis in anovulatory females and in the context of ART procedures.
- the present invention provides pharmaceutical compositions that contain various amounts of FSH and hCG, as well as various FSH-to-hCG ratios, supplied in a single preparation. These compounds enable the practitioner to optimize ovulatory stimulation in flexible manner not possible with available preparations.
- the present invention also comprehends an approach to inducing ovulation, by using compositions with varying FSH:hCG ratios.
- the inventive methodology allows for incremental adjustments in the ratio of FSH to hCG, as a function of the stage of folliculogenesis or of variation in patient response, resulting in safer and more successful ovulatory stimulation.
- One embodiment of the invention is a pharmaceutical composition that consists essentially of FSH and hCG in a pharmaceutically acceptable carrier. According to the invention, the ratio of FSH to hCG in such a composition is conducive, upon administration of the composition, to folliculogenesis and to follicular maturation without ovarian hyperstimulation.
- Another embodiment of the invention is an assemblage comprising a first vial and a second vial, each of said vials containing a pharmaceutical composition consisting essentially of FSH and hCG in a pharmaceutically acceptable carrier, wherein the ratio of FSH to hCG is conducive, upon administration of said composition, to folliculogenesis and follicular maturation without ovarian hyperstimulation.
- the ratio of FSH to hCG differs between the first vial and the second vial.
- a further embodiment of the invention is a method of inducing ovulation, comprising: administering at least one pharmaceutical composition characterized by a ratio of FSH to human hCG that is selected from the group consisting of 50 IU FSH:1 IU hCG, 50 IU FSH:5 IU hCG, 50 IU FSH:10 IU hCG, 50 IU FSH:25 IU hCG, 50 IU FSH:75 IU hCG, 50 IU FSH:100 IU hCG, 50 IU FSH:200 IU hCG, 50 IU FSH:300 IU hCG, 50 IU FSH:400 IU hCG, 75 IU FSH:1 IU hCG, 75 IU FSH:5 IU hCG, 75 IU FSH:10 IU hCG, 75 IU FSH:25 IU hCG, 75 IU FSH:50 IU hCG, 75 IU FSH:75 IU hCG, 75 IU F
- FIGURE 1 shows useful FSH-to-hCG ratio values, where FSH amount is expressed in international units (IU) and hCG amount is expressed in IU (Fig. 1A) and micrograms (Fig. 1 B).
- FIGURE 2 is a bar graph that depicts a proposed treatment protocol according to the invention, using FSH'.hCG compositions as described above.
- the invention provides compositions and methods for a novel therapeutic paradigm, characterized by administration of hCG in combination with FSH during all stages of treatment and by an adjustment of the FSH-to- hCG ratio, to optimize ovulatory stimulation.
- This paradigm departs substantially from the conventional approach, where FSH is administered alone, typically at 75-300 lU/day, and a bolus of LH activity is administered mid-cycle to induce ovulation.
- the invention provides pharmaceutical compositions with a wide range of FSH to hCG ratios.
- the compositions and methods of the invention enable the physician to easily tailor treatment to a given patient's situation, allowing the ratio of FSH to hCG to be fine-tuned based on different stages of folliculogenesis and varying patient response to gonadotropins. Further, having a range of therapeutic compositions available, including those with high levels of hCG, allows the physician to easily accommodate the therapeutic requirements of various ART procedures. This flexibility is not possible with current gonadotropic preparations.
- compositions of the invention have a broad range of FSH to hCG ratios
- the invention can easily be used to stimulate folliculogenesis and ovulation in any ovulation induction and ART procedure including among others, treatment of anovulatory infertility, in-vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), cryopreserved embryo transfer, intrauterine insemination (IUI), donor oocyte transfer, cryopreserved embryo transfer from donor oocytes, and ART cycles for host uterus transfer.
- IVF in-vitro fertilization
- ICSI intracytoplasmic sperm injection
- GIFT gamete intrafallopian transfer
- ZIFT zygote intrafallopian transfer
- cryopreserved embryo transfer intrauterine insemination
- IUI intrauterine insemination
- donor oocyte transfer cry
- compositions of the invention employ hCG as a source of LH activity.
- hCG binds to LH receptors and exerts through them its biological actions; separate hCG receptors do not exist.
- Using hCG in accordance with the invention has significant advantages over the use of LH. For instance, human-derived hCG is less expensive than either human-derived or recombinant FSH. From a cost perspective, therefore, it is favorable to minimize the amount of FSH used during the stimulation protocol.
- compositions and methods of the invention empower treatment regimens that achieve higher rates of success, that decrease the risk of complications, that are easy to implement, and that are less costly than those of conventional practice.
- the invention provides novel pharmaceutical compositions useful for inducing ovarian stimulation in a mammal.
- "Mammal” refers to a human, non- human primate, sheep, pig, cow, horse, donkey, mouse, rat, rabbit, guinea pig, dog, cat, or captive wild animal.
- the mammal is a human.
- the pharmaceutical compositions contain 50 to 200 IU FSH together with 1 to 400 IU human-derived hCG (see FIGURE 1A).
- the compositions contain FSH and hCG in the following ratios: 50 IU FSH:1 IU hCG, 50 IU FSH:5 IU hCG, 50 IU FSH:10 IU hCG, 50 IU FSH:25 IU hCG, 50 IU FSH:75 IU hCG, 50 IU FSH:100 IU hCG, 50 IU FSH:200 IU hCG, 50 IU FSH:300 IU hCG, 50 IU FSH:400 IU hCG, 75 IU FSH:1 IU hCG, 75 IU FSH:5 IU hCG, 75 IU FSH:10 IU hCG, 75 IU FSH:25 IU hCG, 75 IU FSH:50 IU hCG, 75 IU FSH:75 IU hCG, 75 IU FSH:100 IU hCG, 75 IU FSH:200 IU hCG, 75 IU FSH:300 hCG, 75 IU FSH:
- the compositions contain FSH and hCG in the following ratios: 50 IU FSH:1 IU hCG, 50 IU FSH:5 IU hCG, 50 IU FSH:10 IU hCG, 50 IU FSH:25 IU hCG, 50 IU FSH:75 IU hCG, 50 IU FSH:100 IU hCG, 50 IU FSH:200 IU hCG, 50 IU FSH:300 IU hCG, 50 IU FSH:400 IU hCG, 75 IU FSH:1 IU hCG, 75 IU FSH:5 IU hCG, 75 IU FSH:10 IU hCG, 75 IU FSH:50 IU hCG, 75 IU FSH:100 IU hCG, 75 IU FSH:200 IU hCG, 75 IU FSH:300 IU hCG, 75 IU FSH:400 IU hCG, 100 IU FSH:1 IU hCG, 50 IU F
- IU hCG 150 IU FSH:5 IU hCG, 150 IU FSH:10 IU hCG, 150 IU FSH:25 IU hCG, 150 IU FSH:75 IU hCG, 150 IU FSH:100 IU hCG, 150 IU FSH:200 IU hCG, 150 IU FSH:300 IU hCG, 150 IU FSH:400 IU hCG, 200 IU FSH:1 IU hCG, 200 IU FSH:5 IU hCG, 200 IU FSH:10 IU hCG, 200 IU FSH:25 IU hCG, 200 IU FSH:50 IU hCG, 200 IU FSH:75 IU hCG, 200 IU FSH:100 IU hCG, 200 IU FSH:200 IU hCG, 200 IU FSH:300 IU hCG, and 200 IU FSH:400 IU hCG.
- the composition contains 50 IU FSH:100 IU hCG, 50 IU FSH:200 IU hCG, or 50 IU FSH:400 IU hCG. These ratios are useful in treatment protocols requiring multiple administrations because more than one ampoule can be easily administered. [0035] In another, more preferred embodiment, the composition contains 100 IU FSH:100 IU hCG, 100 IU FSH:200 IU hCG, or 100 IU FSH:400 IU hCG. These ratios allow a physician to select compositions with a higher dose of FSH. These compositions can be particularly useful at the outset of treatment where higher doses of FSH may be desired.
- the composition contains 100 IU FSH:5 IU hCG, 100 IU FSH:10 IU hCG, or 100 IU FSH:25 IU hCG.
- Such compositions provide lower doses of hCG which can be advantageous at the onset of treatment.
- FSH purified FSH can be obtained by any methods known in the art.
- FSH includes human-derived and recombinant FSH, FSH analogs, as well as deglycosylated, unglycosylated, and modified glycosylated forms.
- Human-derived FSH can be purified by any means known in the art from natural sources such as urine, pituitary, and placenta. Procedures for isolating human-derived FSH are described in, e.g., Fevold et al. Endocrinology 26:999 (1940), Fraenkel-Conrat et al., Proc. Soc. Exp. Biol. Med. 45:627 (1940), McShan and Meyer, J.
- FSH human-derived FSH
- AMSA/IBSA Fostimon®
- Metrodin HP® Steono
- Bravelle Bravelle
- Recombinant FSH can be obtained by any of several known means. For example, Keene et al., J. Biol. Chem. 26:4769 (1989), and WO 86/04589 describe expression and purification of biologically active human FSH in rodent cells.
- Recominant FSH is also commercially available under the names Follistim® (Organon), Puregon® (Organon), and Gonal-F® (Serono.
- FSH isoforms that differ in the extent to which they are post-translationally modified. Due to different modifications, the isoforms exhibit differences in overall charge, degree of sialic acid (a terminal sugar) or sulfate incorporation, receptor binding affinity and plasma half-life. Chappel et al., Endocrine Reviews 4:179 (1983); Snyder et al. Mol. Cell. Endocrin. 54:115 (1987). These forms are separable from each other on the basis of their overall charge and all isoforms exhibit biological activity.
- hCG can be obtained by any means known in the art.
- hCG includes human-derived and recombinant hCG.
- Human-derived hCG can be purified from any appropriate source (e.g. urine, and placenta) by any method known in the art as disclosed in Zondek and Aschheim, Klin. Klischr. 7: 931 (1928), Katzman et al., ibid. 148:501 (1943), and Claesson et al., Ada Endocrinol.
- Purified human hCG is commercially available and is sold under the names Profasi HP® (Serono), Gonasi® (AMSA/IBSA), and Choragon, Novarelin (Ferring). J Methods of expressing and purifying recombinant hCG are known in the art and are disclosed, for example, in Gupta and Dighe, J. Mol. Endocrinology 22: 273 (1999).
- Recombinant hCG possesses approximately 25 times greater activity by weight as compared human-derived hCG. For example, see Chang et al., Fertil. Steril. 76: 67 (2001); The European Recombinant Human Chorionic Gonadotrophin Study Group, Fertil. Steril. 75: 1111 (2001).
- the amount of hCG can be adjusted accordingly to provide the desired international units of hCG activity when recombinant hCG is used in the compositions.
- An adjustment along this line, based on the values of FIGURE 1A, is represented in FIGURE 1B.
- the amount of FSH and hCG activity can be determined using assay methods known in the art. 1 IU of hCG is equivalent to 5-7 IU LH in the pharmacopaeia Van Hell bioassay. Van Hell et al., Ada Endocrin. 47: 409 (1964). hCG activity in a composition can be determined using any assay methods known, including the Van Hell bioassay, radioreceptor assays as described, for instance, in Dighe & Moudgal. Arch. Biochem. Biophys.
- FSH activity can be determined using receptor binding assays and whole animal bioassays.
- the amount of FSH and hCG protein in a given composition can be determined by the weight of the solid compound, protein assays, such as Bradford and Lowry assays, and immunoassay techniques such as ELISA and Western blotting.
- FSH:hCG compositions can be formulated by admixing, in an aqueous solution, purified FSH and hCG products, with batch-wise adjustments to achieve the desired FSH:hCG ratio, followed by sterile filtration, sterile filling, and, if desired, lyophilization.
- the FSH:hCG composition also can be formulated using a method, wherein purification conditions are established that yield the desired FSH:hCG ratio in the first instance (i.e., without compounding as such).
- compositions of the present invention can be formulated into well known compositions for any route of drug administration, e.g., oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, local (powders, ointments or drops), or as a buccal or nasal spray.
- a typical composition for such purpose comprises a pharmaceutically acceptable carrier, such as aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described in REMINGTON'S PHARMACEUTICAL SCIENCES, 15th Ed. (Mack Publishing Co., 1975), at pages 1405-12 and 1461-87, and THE NATIONAL FORMULARY XIV, 14th Ed. (American Pharmaceutical Association, 1975), among others.
- aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carb ⁇ xymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
- compositions of the present invention also can contain additives such as but not limited to preservatives, wetting agents, emulsifying agents, and dispersing agents.
- Antibacterial and antifungal agents can be included to prevent growth of microbes and includes, for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
- isotonic agents such as sugars, sodium chloride, and the like.
- FSH and hCG In some cases, to effect prolonged action it is desirable to slow the absorption of FSH and hCG from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of FSH and hCG then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered FSH and hCG combination form is accomplished by dissolving or suspending the FSH and hCG combination in an oil vehicle.
- Injectable depot forms can be made by forming microencapsule matrices of the FSH and hCG combination in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of FSH and hCG combination to polymer and the nature of the particular polymer employed, the rate of FSH and hCG combination release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the FSH and hCG combination in liposomes or microemulsions which are compatible with body tissues.
- Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
- Injectable formulations can be supplied in any suitable container, e.g. vial, pre-filled syringe, injection cartridges, and the like.
- Injectable formulations can be supplied as a product having pharmaceutical compositions containing either FSH or hCG suitable for administration separately or together. If administered separately, administration can be sequential.
- the product can be supplied in any appropriate package.
- a product can contain a number of pre- filled syringes containing either FSH, hCG, or a combination of both FSH and hCG, the syringes packaged in a blister package or other means to maintain sterility.
- a product can optionally contain instructions for using the FHS and hCG formulations.
- compositions of the invention are supplied as compositions for parenteral administration.
- General methods for the preparation of the parenteral formulations are known in the art and are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, supra, at pages 780-820.
- the parenteral compositions can be supplied in liquid formulation or as a solid which will be mixed with a sterile injectible medium just prior to administration.
- the parenteral compositions are supplied in dosage unit form for ease of administration and uniformity of dosage.
- Dosage unit form in this description refers to physically discrete units that are suited as unitary dosages for a mammalian subject to be treated, where each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active material and the particular therapeutic effect to be achieved and the limitations inherent in the art of compounding active materials for use in mammalian subjects.
- a unit dosage form can contain, for example, 50, 75, 100, 150, and 200 IU FSH in combination with 1 , 5,10, 25, 50, 75, 100, 200, 300, and 400 IU hCG. Expressed in proportions, FSH and hCG each are generally present in from about 0.1 ⁇ g to about 2000 mg/ml.
- Suspensions can contain rheology modifying agents such as, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
- rheology modifying agents such as, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
- compositions can be administered to a subject, in need of ovarian stimulation, as pharmaceutical compositions in combination with one or more pharmaceutically acceptable excipients. It will be understood that, when administered to a human patient, the total daily usage of the agents or composition of the present invention will be decided by the attending physician within the scope of sound medical judgment.
- the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors: the type and degree response to be achieved; activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment, and like factors well known in the medical arts.
- a composition with the proper FSH to hCG ratio can be selected and the composition or a series of compositions can be administered throughout the period of ovarian stimulation.
- the physician can initiate stimulation with one ratio and then adjust the ratios of FSH to hCG throughout the cycle. Adjustments made during treatment can be based on the timing of administration during the cycle or in response to folliculogenetic or steroidogenetic indicators, such as the number and size of follicles and patient hormone levels.
- compositions of the invention can be selected and administered to mimic the levels of FSH and LH activity that occur during a normal menstrual cycle.
- a composition with an FSH to hCG ratio of 100:5 initially would be administered daily. Starting on day six, for example, the levels of serum estradiol and follicle number and size would be monitored.
- compositions are selected to maximize the number of large, mature follicles while minimizing the number of small, potentially dangerous follicles.
- a composition with an FSH to hCG ratio of 250:10 initially would be administered daily.
- the levels of serum estradiol and follicle number and size would be monitored. Once at least four follicles greater than 12 mm and estradiol levels higher than 600 pg/mL are detected a composition with an FSH to hCG ratio of 50:200 will be administered until the final maturation parameters of at least five follicles greater than 17 mm and estradiol levels higher than 1 ,500 pg/mL are achieved. Then, ovulation would be triggered with 10,000 IU of hCG. [0063] Preliminary clinical studies demonstrate the positive effects of administering hCG prior to inducing ovulation. The results of one study are provided in Table 1.
- the fertilization rate and number of good quality embryos were similar among all groups, but the number of preganacies was about three-fold higher for the group receiving 100 IU hCG per day than the group receiving FSH alone.
- This study demonstrates that the use of FSH and hCG together, in the late stages of ovulation induction, increases the number of large follicles developing, increases the number of oocytes retrieved, and can improve pregnancy rates.
- the pharmaceutical compositions can be coadministered with one or more other compounds or molecules. "Coadministered" refers to simultaneous administration in the same formulation or in two different formulations.
- compositions of the invention can be administered with or following GnRH agonists and antagonists.
- GnRH agonists and antagonists are used for ovulation induction procedures to prevent spontaneous ovulation during gonadotropin administration.
- compositions of the invention can be administered at the commencement of treatment with
- GnRH antagonists to provide LH activity levels which are sufficient to i stimulate follicle development and oocyte maturation.
- compositions of the invention can be coadministered with the currently available gonadotropin preparations, such as pure FSH, pure hCG, pure LH, and hMG preparations.
- gonadotropin preparations such as pure FSH, pure hCG, pure LH, and hMG preparations.
- 1 ampoule of the FSH:hCG combination composition having FSH 75 IU and hCG 200 IU can be coadministered with 1 ampoule of highly purified FSH containing FSH 75 IU resulting administration of 150 IU of FSH and 200 IU of hCG.
- FSH:hCG compositions are administered sequentially throughout ovarian stimulation.
- Sequential administration refers to a time difference of from seconds, minutes, hours or days between the administration of the compositions.
- Each subsequent sequential administration can be comprised of a composition with the same ratio of FSH to hCG as the previous administration or a different ratio of FSH to hCG.
- sequential administration is performed with FSH:hCG compositions that differ in the ratio of FSH to hCG.
- each succeeding composition contains a greater amount of hCG over the preceding composition in the series.
- the ratio of FSH to hCG is adjusted throughout the series in response to patient reaction to the FSH:hCG composition as indicated by folliculogenetic and steroidogenetic markers.
- folliculogenetic and steroidogenetic markers When 2-4 intermediate follicles (12-14 mm) are formed and estradiol levels of 200-600 pg/mL are achieved, this is an indication that adequate folliculogenesis has been achieved by an FSH-rich preparation and it is appropriate to switch to an hCG-rich preparation.
- Folliculogenesis and steroidogenesis should be monitored throughout ovarian stimulation by any means known in the art.
- Follicle size can be determined, for example, using transvaginal pelvic ultrasonography. Follicles are categorized as large (>14 mm), intermediate (10-14 mm) or small ( ⁇ 10 mm). Transvaginal pelvic ultrasound can be performed frequently, for example on treatment days 0, 6, 8, 10, 12, 14, 16, 18, and 20, until preovulatory hCG administration.
- the levels of estradiol can be measured using any means known in the art from any appropriate body fluid (e.g., blood, urine, and saliva), using an immunoassay or a chemiluminescence assay.
- Controlled Ovulatory Stimulation for In Vitro Fertilization Treatment is initiated in the mid-luteal phase of a spontaneous menstrual cycle when a GnRH agonist is administered. Ovulation induction is started 1-2 weeks later, after spontaneous menses. Alternatively, a GnRH antagonist is administered starting on the 6 th day of ovarian stimulation. Patients receive daily injections of 200 IU FSH:10 IU hCG from day 1 and continuing until the appearance of at least 4 follicles >11 mm and serum estradiol levels of > 600 pg/mL.
- Ferilization Rate (fertilized 64 ⁇ 7 % 64 ⁇ 3 % 65 ⁇ 4 % 61 ⁇ 7 oocytes/oocytes retrieved)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
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MXPA05012967A MXPA05012967A (en) | 2003-06-03 | 2004-06-02 | UNITARY COMBINATION OF FSH AND hCG. |
CA002524755A CA2524755A1 (en) | 2003-06-03 | 2004-06-02 | Unitary combination of fsh and hcg |
EP04735774.4A EP1633389B1 (en) | 2003-06-03 | 2004-06-02 | Unitary combination of fsh and hcg |
AU2004243256A AU2004243256B2 (en) | 2003-06-03 | 2004-06-02 | Unitary combination of FSH and hCG |
BRPI0410968-6A BRPI0410968A (en) | 2003-06-03 | 2004-06-02 | fsh and hcg unit combination |
NZ543403A NZ543403A (en) | 2003-06-03 | 2004-06-02 | Unitary combination of FSH and hCG |
JP2006508427A JP2006526609A (en) | 2003-06-03 | 2004-06-02 | Integrated combination of FSH and hCG |
ES04735774.4T ES2451028T3 (en) | 2003-06-03 | 2004-06-02 | Unitary combination of FSH and hCG |
US10/559,610 US7985732B2 (en) | 2003-06-03 | 2004-06-02 | Unitary combination of FSH and hCG |
EP10075419.1A EP2292252B1 (en) | 2003-06-03 | 2004-06-02 | Unitary combination of FSH and hCG |
NO20060002A NO20060002L (en) | 2003-06-03 | 2006-01-02 | Unit composition of FSH and hCG |
US11/979,265 US7964562B2 (en) | 2003-06-03 | 2007-10-31 | Unitary combinations of FSH and hCG |
US13/067,418 US20120015879A1 (en) | 2003-06-03 | 2011-05-31 | Unitary combinations of FSH and hCG |
US15/490,058 US20170281731A1 (en) | 2003-06-03 | 2017-04-18 | Unitary combination of fsh and hcg |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US10/452,926 US20040248784A1 (en) | 2003-06-03 | 2003-06-03 | Unitary combinations of FSH and hCG |
US10/452,926 | 2003-06-03 |
Related Parent Applications (1)
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US10/452,926 Continuation-In-Part US20040248784A1 (en) | 2003-06-03 | 2003-06-03 | Unitary combinations of FSH and hCG |
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US10/559,610 A-371-Of-International US7985732B2 (en) | 2003-06-03 | 2004-06-02 | Unitary combination of FSH and hCG |
US11/979,265 Continuation US7964562B2 (en) | 2003-06-03 | 2007-10-31 | Unitary combinations of FSH and hCG |
US13/067,418 Continuation US20120015879A1 (en) | 2003-06-03 | 2011-05-31 | Unitary combinations of FSH and hCG |
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EP (2) | EP1633389B1 (en) |
JP (1) | JP2006526609A (en) |
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CN (2) | CN1826135A (en) |
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NZ (1) | NZ543403A (en) |
RU (1) | RU2332228C2 (en) |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011042688A1 (en) * | 2009-10-05 | 2011-04-14 | Ferring International Center Sa | Pharmaceutical preparation comprising recombinant hcg |
US20130237479A1 (en) * | 2010-09-29 | 2013-09-12 | Joan-Carles Arce Saez | Composition for controlled ovarian stimulation |
US8951967B2 (en) | 2008-04-16 | 2015-02-10 | Ferring International Center Sa | Recombinant FSH including alpha 2,3- and alpha 2,6-sailylation |
US9757469B2 (en) | 2011-03-31 | 2017-09-12 | Ferring B.V. | Pharmaceutical preparation |
EP2292252B1 (en) | 2003-06-03 | 2019-08-07 | Ferring B.V. | Unitary combination of FSH and hCG |
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WO2012120535A2 (en) * | 2011-02-03 | 2012-09-13 | Sanzyme Limited | A composition comprising highly purified chorionic gonadotropin, it's formulation and uses of the same |
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AU2018326556A1 (en) | 2017-09-01 | 2020-03-05 | Ferring B.V. | Composition for controlled ovarian stimulation |
CN112088011A (en) * | 2018-04-30 | 2020-12-15 | 辉凌公司 | Compositions for controlled ovarian stimulation |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1986004589A1 (en) | 1985-01-30 | 1986-08-14 | Reddy Vemuri B | Fsh |
WO2000067778A1 (en) * | 1999-05-07 | 2000-11-16 | Applied Research Systems Ars Holding N.V. | Gonadotrophins |
WO2003022303A2 (en) * | 2001-09-12 | 2003-03-20 | Applied Research Systems Ars Holding N.V. | Use of hcg and lh in controlled ovarian hyperstimulation |
WO2003022302A2 (en) * | 2001-09-12 | 2003-03-20 | Applied Research Systems Ars Holding N.V. | USE OF hCG IN CONTROLLED OVARIAN HYPERSTIMULATION |
EP1364658A1 (en) * | 2002-05-24 | 2003-11-26 | Applied Research Systems ARS Holding N.V. | Use of varying ratios of gonadotrophins in controlled ovarian hyperstimulation |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5635475A (en) * | 1987-12-21 | 1997-06-03 | Applied Research Systems Ars Holding N.V. | Site-directed mutagenesis modified glycoprotein hormones and methods of use |
IE64738B1 (en) | 1990-03-20 | 1995-09-06 | Akzo Nv | Stabilized gonadotropin containing preparations |
WO1994025005A1 (en) | 1993-04-28 | 1994-11-10 | Akzo Nobel N.V. | Lyospheres comprising gonadotropin |
IL122732A0 (en) | 1997-01-15 | 1998-08-16 | Akzo Nobel Nv | Liquid gonadotropin-containing formulation its preparation and a device containing same |
EA009210B1 (en) * | 2001-09-12 | 2007-12-28 | Апплайд Резеч Системз Арс Холдинг Н.В. | Use of ln in controlled ovarian huperstimulation |
US6818613B2 (en) * | 2001-11-07 | 2004-11-16 | Ortho-Mcneil Pharmaceutical, Inc. | Aqueous sustained-release formulations of proteins |
AU2003269904A1 (en) * | 2002-07-10 | 2004-01-23 | The Ohio State University Research Foundation | Antigen-polymer compositions |
BRPI0409229A (en) | 2003-04-01 | 2006-03-28 | Applied Research Systems | phosphodiesterase inhibitors in infertility |
US20040248784A1 (en) * | 2003-06-03 | 2004-12-09 | Marco Filicori | Unitary combinations of FSH and hCG |
-
2003
- 2003-06-03 US US10/452,926 patent/US20040248784A1/en not_active Abandoned
-
2004
- 2004-06-02 CN CNA2004800153410A patent/CN1826135A/en active Pending
- 2004-06-02 BR BRPI0410968-6A patent/BRPI0410968A/en not_active IP Right Cessation
- 2004-06-02 CN CNA2007101527680A patent/CN101156945A/en active Pending
- 2004-06-02 ES ES04735774.4T patent/ES2451028T3/en active Active
- 2004-06-02 WO PCT/IB2004/001813 patent/WO2004105788A1/en active Application Filing
- 2004-06-02 KR KR1020077026953A patent/KR20070118195A/en not_active Application Discontinuation
- 2004-06-02 RU RU2005136527/15A patent/RU2332228C2/en not_active IP Right Cessation
- 2004-06-02 EP EP04735774.4A patent/EP1633389B1/en not_active Revoked
- 2004-06-02 CA CA002524755A patent/CA2524755A1/en not_active Abandoned
- 2004-06-02 JP JP2006508427A patent/JP2006526609A/en active Pending
- 2004-06-02 NZ NZ543403A patent/NZ543403A/en unknown
- 2004-06-02 AU AU2004243256A patent/AU2004243256B2/en not_active Ceased
- 2004-06-02 US US10/559,610 patent/US7985732B2/en not_active Expired - Fee Related
- 2004-06-02 KR KR1020057023048A patent/KR20060005417A/en not_active Application Discontinuation
- 2004-06-02 ES ES10075419T patent/ES2753822T3/en active Active
- 2004-06-02 EP EP10075419.1A patent/EP2292252B1/en not_active Revoked
- 2004-06-02 MX MXPA05012967A patent/MXPA05012967A/en unknown
-
2005
- 2005-12-02 ZA ZA200509814A patent/ZA200509814B/en unknown
-
2006
- 2006-01-02 NO NO20060002A patent/NO20060002L/en not_active Application Discontinuation
-
2007
- 2007-09-12 US US11/898,470 patent/US20080119394A1/en not_active Abandoned
- 2007-10-31 US US11/979,265 patent/US7964562B2/en not_active Expired - Fee Related
-
2011
- 2011-05-31 US US13/067,418 patent/US20120015879A1/en not_active Abandoned
-
2017
- 2017-04-18 US US15/490,058 patent/US20170281731A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1986004589A1 (en) | 1985-01-30 | 1986-08-14 | Reddy Vemuri B | Fsh |
WO2000067778A1 (en) * | 1999-05-07 | 2000-11-16 | Applied Research Systems Ars Holding N.V. | Gonadotrophins |
WO2003022303A2 (en) * | 2001-09-12 | 2003-03-20 | Applied Research Systems Ars Holding N.V. | Use of hcg and lh in controlled ovarian hyperstimulation |
WO2003022302A2 (en) * | 2001-09-12 | 2003-03-20 | Applied Research Systems Ars Holding N.V. | USE OF hCG IN CONTROLLED OVARIAN HYPERSTIMULATION |
EP1364658A1 (en) * | 2002-05-24 | 2003-11-26 | Applied Research Systems ARS Holding N.V. | Use of varying ratios of gonadotrophins in controlled ovarian hyperstimulation |
Non-Patent Citations (27)
Title |
---|
"CURRENT PROTOCOLS IN MOLECULAR BIOLOGY", 1989, JOHN WILEY & SONS |
"REMINGTON'S PHARMACEUTICAL SCIENCES", 1975, MACK PUBLISHING CO., pages: 1405 - 12,1461- |
"The European Recombinant Human Chorionic Gonadotrophin Study Group", FERTIL. STERIL., vol. 75, 2001, pages 1111 |
"THE NATIONAL FORMULARY XIV", 1975, AMERICAN PHARMACEUTICAL ASSOCIATION |
ASCOLI, ENDOCRINOLOGY, vol. 108, 1981, pages 88 |
CHANG ET AL., FERTIL. STERIL., vol. 76, 2001, pages 67 |
CHAPPEL ET AL., ENDOCRINE REVIEWS, vol. 4, 1983, pages 179 |
CLAESSON ET AL., ACTA ENDOCRINOL., vol. 1, 1948, pages 1 |
DIGHE; MOUDGAL, ARCH. BIOCHEM. BIOPHYS., vol. 225, 1983, pages 490 |
FEVOLD ET AL., ENDOCRINOLOGY, vol. 26, 1940, pages 999 |
FILICORI M ET AL: "LUTEINIZING HORMONE ACTIVITY SUPPLEMENTATION ENHANCES FOLLICLE-STIMULATING HORMONE EFFICACY AND IMPROVES OVULATION INDUCTION OUTCOME", JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, NEW YORK, NY, US, vol. 84, no. 8, August 1999 (1999-08-01), pages 2659 - 2663, XP001055466, ISSN: 0021-972X * |
FILICORI M ET AL: "STIMULATION AND GROWTH OF ANTRAL OVARIAN FILLICLES BY SELECTIVE LH ACTIVITY ADMINISTRATION IN WOMEN", March 2002, JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, NEW YORK, NY, US, PAGE(S) 1156-1161, ISSN: 0021-972X, XP008004363 * |
FRAENKEL-CONRAT ET AL., PROC. SOC. EXP. BIOL. MED., vol. 45, 1940, pages 627 |
GOODMAN; GILMAN'S: "THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS" |
GREEP ET AL., IBID, vol. 133, 1940, pages 289 |
GUPTA; DIGHE, J. MOL. ENDOCRINOLOGY, vol. 22, 1999, pages 273 |
KATZMAN ET AL., IBID, vol. 148, 1943, pages 501 |
KEENE ET AL., J. BIOL. CHEM., vol. 26, 1989, pages 4769 |
LI ET AL., SCIENCE, vol. 109, 1949, pages 445 |
MCSHAN; MEYER, J. BIOL. CHEM., vol. 135, 1940, pages 473 |
REMINGTON, THE SCIENCE AND PRACTICE OF PHARMACY, pages 780 - 820 |
ROOS; GEMZELL: "CIBRA FOUNDATION STUDY GROUP", 1965, LITTLE, BROWN AND CO. |
SAMBROOK ET AL.: "MOLECULAR CLONING A LABORATORY MANUAL", 1989, COLD SPRING HARBOR LABORATORY PRESS |
SNYDER ET AL., MOL. CELL. ENDOCRIN., vol. 54, 1987, pages 115 |
THOMPSON K A ET AL: "GONADOTROPHIN REQUIREMENTS OF THE DEVELOPING FOLLICLE", FERTILITY AND STERILITY, ELSEVIER SCIENCE INC, NEW YORK, NY, US, vol. 63, no. 2, February 1995 (1995-02-01), pages 273 - 276, XP001064790, ISSN: 0015-0282 * |
VAN HELL ET AL., ACTA ENDOCRIN., vol. 47, 1964, pages 409 |
ZONDEK; ASCHHEIM, KLIN. WOCHENSCHR., vol. 7, 1928, pages 931 |
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US7985732B2 (en) | 2011-07-26 |
US20170281731A1 (en) | 2017-10-05 |
US20040248784A1 (en) | 2004-12-09 |
EP2292252B1 (en) | 2019-08-07 |
NO20060002L (en) | 2006-03-02 |
US7964562B2 (en) | 2011-06-21 |
RU2005136527A (en) | 2006-07-27 |
CA2524755A1 (en) | 2004-12-09 |
ZA200509814B (en) | 2007-01-31 |
RU2332228C2 (en) | 2008-08-27 |
ES2753822T3 (en) | 2020-04-14 |
EP2292252A2 (en) | 2011-03-09 |
US20060135421A1 (en) | 2006-06-22 |
US20080108571A1 (en) | 2008-05-08 |
NZ543403A (en) | 2008-05-30 |
EP1633389A1 (en) | 2006-03-15 |
BRPI0410968A (en) | 2006-07-04 |
EP1633389B1 (en) | 2013-12-11 |
US20120015879A1 (en) | 2012-01-19 |
MXPA05012967A (en) | 2006-03-17 |
AU2004243256B2 (en) | 2007-11-29 |
JP2006526609A (en) | 2006-11-24 |
US20080119394A1 (en) | 2008-05-22 |
AU2004243256A1 (en) | 2004-12-09 |
CN101156945A (en) | 2008-04-09 |
KR20070118195A (en) | 2007-12-13 |
KR20060005417A (en) | 2006-01-17 |
ES2451028T3 (en) | 2014-03-26 |
CN1826135A (en) | 2006-08-30 |
EP2292252A3 (en) | 2012-08-29 |
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