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WO2000078335A1 - Compositions pour la liberation regulee de l'hormone gnrh et ses analogues - Google Patents

Compositions pour la liberation regulee de l'hormone gnrh et ses analogues Download PDF

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Publication number
WO2000078335A1
WO2000078335A1 PCT/US2000/013615 US0013615W WO0078335A1 WO 2000078335 A1 WO2000078335 A1 WO 2000078335A1 US 0013615 W US0013615 W US 0013615W WO 0078335 A1 WO0078335 A1 WO 0078335A1
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composition
deslorelin
gnrh
saib
analogs
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PCT/US2000/013615
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English (en)
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Patrick J. Burns
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Southern Biosystems, Inc.
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Priority to AU50253/00A priority Critical patent/AU5025300A/en
Publication of WO2000078335A1 publication Critical patent/WO2000078335A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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

Definitions

  • GnRH or its analogs or agonists can be used to treat conditions related to the reproductive system. Examples include precocious puberty in children, endometriosis in women, prostate cancer in men, and other conditions requiring or responding to short term or long term GnRH therapy.
  • the selection of an appropriate drug delivery system should be based on the pharmacokinetic and pharmacodynamic properties of the drug.
  • the importance of the pharmacodynamic properties of a drug is especially relevant in the case of hormones that target specific high affinity receptors to produce their effect. In the case of GnRH this relationship is dependent on multiple elements including species, reproductive status and complex concentration presentation effects of the peptide and pituitary responsiveness to it.
  • compositions are suitable for controlled release of GnRH, its analogs, and/or its agonists, particularly for the purpose of treating conditions relating to the reproductive system in a variety of species.
  • the composition of the present invention can be used for advancing ovulation in domesticated animals, in particular in female mammals, and even more particularly, in mares, gilts, sows, ewes, cows, heifers, she-goats, and the like.
  • the composition includes
  • the composition includes a system based on sucrose acetate isobutyrate (SAIB) a fully-esterified sucrose molecule.
  • SAIB sucrose acetate isobutyrate
  • SAIB is a low molecular weight material that has many of properties associated with polymeric materials. Because SAIB is a non-polymer, dilution with only small amounts of solvents are required to give an easily-injectable solution.
  • the SAIB drug delivery system technology suitable for treating reproductive disorders susceptible to treatment by GnRH, in particular for inducing ovulation, in animals, and in particular in female mammals, e.g., mares, gilts and sows, ewes, cows, heifers, she-goats, and the like, with a composition that is injectable and sterilizable.
  • the composition releases the GnRH or its analog or agonist over a relatively short time period, typically about 1 to about 12 hours, more particularly about 1 to about 6 hours.
  • non-polymeric, non- water soluble liquid carrier material, GnRH, or its analog or agonist, and solvent can be formulated as a solution or suspension of the GnRH in the solvent.
  • Suspensions can be formed by, e.g., using a solvent in which GnRH, its analog or agonist is insoluble. Increased stability has been found to result from the use of a suspension.
  • the composition can include additives that can substantially lengthen the delivery time up to several months, more particularly from about 1 to about 30 days, even more particularly from about 14 to about 30 days, thereby making the composition suitable for induction of cyclicity or ovulation in seasonally nonovulatory animals, such as mares, or for treatment of conditions susceptible to long term therapy with GnRH, or analogs or agonists thereof, such as precocious puberty in human children, endometriosis in women, and prostate cancer in men, and for inducing spawning in marine life, such as finned fish or shellfish.
  • additives that can substantially lengthen the delivery time up to several months, more particularly from about 1 to about 30 days, even more particularly from about 14 to about 30 days, thereby making the composition suitable for induction of cyclicity or ovulation in seasonally nonovulatory animals, such as mares, or for treatment of conditions susceptible to long term therapy with GnRH, or analogs or agonists thereof, such as precocious puberty
  • the invention relates to methods of treating reproductive disorders in animals by administering to an animal in need thereof an effective amount of the composition described above, i.e., a combination of non- polymeric, non-water soluble liquid carrier material and GnRH, or its analogs or agonists.
  • the invention relates to methods of inducing ovulation in a female mammal by administering to the female mammal an effective amount of the composition described above, i.e., a combination of non-polymeric, non- water soluble liquid carrier material and GnRH, or its analogs or agonists.
  • the female mammal may be a sow, gilt, cow, or heifer.
  • GnRH Gonodotropin releasing hormone also known as LH-RH or LHRH
  • FIGURE 1 shows LH concentrations in mares following treatment with experimental formulations.
  • Figure 2 shows deslorelin acetate concentrations in gilts following treatment with a formulation according to the invention.
  • Figure 3 shows the LH concentrations in gilts following treatment with a formulation according to the invention.
  • Figure 4 shows the LH levels in heifers following treatment with a formulation according to the invention.
  • the present invention relates to a composition for the controlled release of GnRH or analogs or agonists thereof in animals, in particular in female mammals, and even more particularly, in domesticated female mammals, such as mares, gilts, and sows, cows, heifers, ewes, she-goats, bitches, cats, and the like to induce ovulation, comprising:
  • the non- water soluble liquid canier material is sucrose acetate isobutyrate. In another embodiment of the composition of the present invention, the non- water soluble liquid canier material is present in an amount from about 99. 5 percent to about 10 percent by weight, relative to the total weight of the composition. In another embodiment of the composition of the present invention, the non- water soluble liquid canier material is present in an amount from about 95 percent to about 25 percent by weight, relative to the total weight of the composition.
  • the composition further comprises a solvent in which the non-water soluble liquid canier is soluble.
  • the solvent is selected from the group consisting of ethanol, dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, N-methylpynolidone, propylene carbonate, and glycofurol.
  • the solvent may be one in which the GnRH, its analog or agonist, is insoluble, resulting in a suspension.
  • the solvent is propylene carbonate.
  • the GnRH, analog, or agonist may desirably be deslorelin, which is insoluble in propylene carbonate. The resulting composition forms a suspension.
  • the solvent is present in an amount from about 10 to about 50 percent by weight, relative to the weight of the composition.
  • the analog is deslorelin.
  • the analog is selected from deslorelin, avorelin, leuprolide, and natural LHRH.
  • the present invention also relates to a liquid composition for the controlled release of GnRH or analogs thereof in mares to induce ovulation, comprising sucrose acetate isobutyrate and ethanol in a weight ratio of between about 75:25 and about 60:40, and GnRH or analog thereof or combination thereof in a concentration of between about 0.1 to about 5.0 mg/ml of liquid composition, to provide a dose of between about 0.3 mg and about 10 mg of GnRH or analog thereof or combination thereof.
  • the present invention also relates to a liquid composition for the controlled release of GnRH or analogs thereof in mares to induce ovulation, comprising sucrose acetate isobutyrate and ethanol in a weight ratio of between about 75:25 and about 60:40, and GnRH or analog thereof or combination thereof in a concentration of between about 1.0 to about 2.5 mg/ml of liquid composition, to deliver a dose of between about 0.3 mg and about 10 mg of GnRH or analog thereof or combination thereof.
  • the analog of GnRH is deslorelin.
  • the composition is sterilized before administration to mares.
  • composition is filter sterilized before administration to mares.
  • the present invention also relates to a filter sterilized liquid composition for the controlled release of deslorelin in mares to induce ovulation, comprising sucrose acetate isobutyrate and ethanol in a weight to weight ratio of about 75:25, and deslorelin at a concentration of between about 0.1 and about 5.0 mg / ml of liquid composition, to deliver a dose between about 1 mg and about 2 mg of deslorelin, said composition administrable by injection.
  • the present invention also relates to a filter sterilized liquid composition for the controlled release of deslorelin in mares to induce ovulation, comprising sucrose acetate isobutyrate and ethanol in a weight to weight ratio of about 75:25, and deslorelin at a concentration of between about 1.0 and about 2.5 mg / ml of liquid composition, to deliver a dose between about 1 mg and about 2 mg of deslorelin, said composition administrable by injection.
  • the present invention also relates to a liquid composition, for the controlled release of deslorelin in gilts, sows, heifers, and cows to induce ovulation, comprising sucrose acetate isobutyrate and propylene carbonate in a weight ratio of about 70:30 and containing deslorelin acetate at a concentration about 25 ⁇ g/ml of liquid composition, to deliver a dose between about 12.5 and about 100 ⁇ g of deslorelin acetate, said composition adminstrable by injection.
  • smaller doses of deslorelin acetate may be administered using, e.g., a concentration of about 12.5 ⁇ g/ml to achieve dosages of about 1 ⁇ g to about 12.5 ⁇ g.
  • dosages of between 1 ⁇ g and about 100 ⁇ g are administered, more particularly between about 6.25 ⁇ g and about 25 ⁇ g, even more particularly between about 6.25 ⁇ g and about 12.5 ⁇ g.
  • the composition can be used in methods for inducing spawning in marine animals, such as finned fish or shellfish.
  • HVLCM High Viscosity Liquid Carrier Material
  • a high viscosity liquid canier material should be selected that is non- polymeric, non-water soluble, and has a viscosity of at least 5,000 cP, (and optionally at least 10,000, 15,000; 20,000; 25,000 or even 50,000 cP) at 37°C, and that does not crystallize neat under ambient or physiological conditions.
  • non- water soluble refers to a material that is soluble in water to a degree of less than one percent by weight under ambient conditions.
  • Suitable canier materials are disclosed in U.S. Patent No. 5,747,058, the entire contents of which are hereby incorporated by reference.
  • the HVLCM significantly decreases in viscosity when mixed with a solvent to form a LVLCM that can be mixed with a substrate for controlled delivery.
  • the LVLCM/substrate composition is typically easier to place in the body than a HVLCM/substrate composition, because it flows more easily into and out of syringes or other implantation means, and can easily be formulated as an emulsion.
  • the LVLCM can have any desired viscosity. It has been found that a viscosity range for the LVLCM of less than approximately 1000 cP, and more particularly less than 200 cP, is typically useful for in vivo applications.
  • sucrose acetate isobutyrate (SAIB)
  • HVLCM sucrose acetate isobutyrate
  • SAIB is orally non-toxic and is cunently used to stabilize emulsions in the food industry. It is a very viscous liquid and has an unusual property that there is a dramatic change in viscosity with small additions of heat or with the addition of solvents. It is soluble in a large number of biocompatible solvents. When in solution or in an emulsion, SAIB can be applied via injection.
  • the HVLCM can be stearate esters such as those of propylene glycol, glyceryl, diethylaminoethyl, and glycol, stearate amides and other long-chain fatty acid amides, such as N,N'-ethylene distearamide, stearamide MEA and DEA, ethylene bistearamide, cocoamine oxide, long-chain fatty alcohols, such as cetyl alcohol and stearyl alcohol, long-chain esters such as myristyl myristate, beheny erucate, and glyceryl phosphates.
  • stearate esters such as those of propylene glycol, glyceryl, diethylaminoethyl, and glycol
  • stearate amides and other long-chain fatty acid amides such as N,N'-ethylene distearamide, stearamide MEA and DEA, ethylene bistearamide, cocoamine oxide
  • long-chain fatty alcohols such as
  • the HVLCM is acetylated sucrose distearate (Crodesta A- 10)
  • the HVLCM is present in the composition in any amount that achieves the desired affect.
  • the HVLCM is typically present in controlled delivery compositions for GnRH or its analogs in an amount in the range from about 99.5 percent to about 10 percent by weight, more typically, between about 90 and about 25 percent, and most typically, between about 85 and about 65 percent, relative to the total weight of the composition.
  • Suitable analogs of gonodotrophlin releasing hormone are suitable for controlled release in the compositions of the present invention. Suitable analogs include, but are not limited to those listed in the following Table I. TABLE I
  • Prefened GnRH analogs include deslorelin, avorelin, leuprolide, and natural LHRH.
  • GnRH analogs Another series of prefened GnRH analogs includes triptorelin, nafarelin, goserelin, buserelin, and fertirelin. Most prefened is deslorelin.
  • the GnRH analogs are synthesized by any of a variety of conventional techniques. See generally Menifield, B., Science 232:342 (1986), Norman, A.W. et al., Hormones Academic Press New York 1987. Deslorelin is synthesized by the method of Ajayaghosh, A. et al., J. Org. Chem. 55:2826(1990); Nestor, J.J. et al.,
  • the composition When the composition is used as a LVLCM, it should contain a solvent in which the HVLCM is soluble.
  • the substance to be delivered may also soluble in the solvent, however, increased stability of the composition may be obtained by forming a suspension of the substance to be delivered in the solvent.
  • increased stability has been obtained where the substance to be delivered is deslorelin by using propylene carbonate as the solvent, thereby forming a suspension of the deslorelin therein.
  • the solvent should be non-toxic, water soluble or water miscible, and otherwise biocompatible. Solvents that are toxic should not be used for pharmaceutical or agricultural purposes.
  • the solvents used to inject the composition into animals should not cause significant tissue initation or necrosis at the site of implantation.
  • the solvent should be at least water soluble, so that it will diffuse quickly into bodily fluids or other aqueous environment, causing the composition to coagulate or solidify.
  • suitable solvents include ethanol, ethyl lactate, propylene carbonate, glycofurol, N-methylpynolidone, 2 pynolidone, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, benzyl alcohol, triacetin, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, and l-dodecylazacycloheptan-2-one.
  • a prefened solvent is propylene carbonate.
  • the prefened solvents are ethanol, dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, N- methylpynolidone, propylene carbonate, and glycofurol.
  • SAIB is not miscible with glycerol, corn oil, peanut oil, 1 ,2-propanediol, polyethylene glycol (PEG200), super refined sesame oil, and super refined peanut oil. Accordingly, the latter group of solvents are not prefened for use with SAIB.
  • the solvent is typically added to the compositions in an amount in the range from about 5 percent to about 55 percent by weight, relative to the total weight of the composition.
  • the solvent is present in the composition in an amount in the range from about 10 percent to about 50 percent by weight.
  • Another prefened range is from about 10 percent to 30 percent by weight.
  • the delivery characteristics of the composition can be varied by adding one or more optional additives to the composition.
  • additives include those disclosed in U.S. Patent No. 5,747,058, the entire contents of which are incorporated herein by reference.
  • suitable additives include biodegradeable polymers, non-biodegradeable polymers, natural oils, synthetic oils, carbohydrates or carbohydrate derivatives, inorganic salts, BSA (bovine serum albumin), surfactants, organic compounds, such as sugars, and organic salts, such as sodium citrate.
  • BSA bovine serum albumin
  • surfactants organic compounds, such as sugars, and organic salts, such as sodium citrate.
  • organic compounds such as sugars
  • organic salts such as sodium citrate.
  • additives can also be used to lengthen the delivery time for the active ingredient (i.e., GnRH, its analogs or agonists), making the composition suitable for treatment of disorders or conditions responsive to longer term GnRH administration, as described above.
  • Suitable additives in this regard include those disclosed in U.S. Patent No. 5,747,058.
  • suitable additives for this purpose include polymeric additives, such as cellulosic polymers and biodegradeable polymers.
  • suitable cellulosic polymers include cellulose acetates, cellulose ethers, and cellulose acetate butyrates.
  • Suitable biodegradeable polymers include polylactic acid, polyglycolic acid, and copolymers thereof.
  • Additives, when present, are generally included in an amount ranging from about 0.02 wt% to about 20 wt%, more particularly from about 1 wt% to about 20 wt% based on the total weight of the composition.
  • compositions described herein can be administered to the host through a variety of methods which can vary depending on the result to be achieved.
  • the composition can be administered, for example, topically, systematically (for example, mucosally (orally, rectally, vaginally, or nasally), or parenterally (intravenously, subcutaneously, intramuscularly, or intraperitoneally) in an appropriate canier, if desired.
  • Suitable hosts include female mammals, such as livestock or pet mammals, such as mares, gilts, sows, ewes, she-goats, cows, bitches, and the like.
  • the present compositions are administered as solutions or suspensions via injection.
  • the small amount of solvent used in the composition leaches into the aqueous fluid of the host, forming a highly viscous depot for the controlled delivery of substances. See, for example, Ansel, H.C. et al., Pharmaceutical Dosage Forms and Drug Del. Systems, sixth ed., 1995.
  • a solution of deslorelin in DMSO (1.0 wt. %) was prepared.
  • a predetermined amount (2.1870 g) of deslorelin acetate (DA)/DMSO was added to 7.9230 g of the 95:5 SAIB:DMSO solution.
  • the final formulation contained 2.4 mg/mL deslorelin and had an SAIB:DMSO ratio of 75:25.
  • a solution of deslorelin in ethanol (2.1 wt.%) was prepared.
  • a concentrated solution of 95:5 weight ratio SAIB:ethanol was also prepared.
  • a predetermined amount (1.0376 g) of deslorelin acetate/ethanol was added to 8.9917 g of the 95:5 SAIB:ethanol solution.
  • the final formulation contained 2.3 mg/mL deslorelin and had an SAIB:ethanol ratio of 85:15.
  • a solution of deslorelin in ethanol (1.9 wt.%) was prepared.
  • a concentrated solution of 95:5 weight ratio SAIB:ethanol was also prepared.
  • a predetermined amount (1.0826 g) of deslorelin acetate/ethanol was added to 7.9085 g of the 95:5 SAIB:ethanol solution.
  • the final formulation contained 2.2 mg/mL deslorelin and had an SAIB:ethanol ratio of 75:25.
  • a dose titration study was performed using this 75:25 SAIB:ethanol formulation that evaluated deslorelin concentrations of 0.5, 1.0, 1.5, and 2.0 mg/mL.
  • a concentrated solution of SAIB in ethanol (83.6 wt. %) was prepared and sterile filtered using a 0.2 ⁇ m hydrophobic filter. Pure ethanol and a solution of deslorelin in ethanol (21.0 mg/g) were sterile filtered using 0.22 ⁇ m sterile syringe filters.
  • a dose titration study was also performed using a 65:35 SAIB:ethanol formulation that evaluated deslorelin concentrations of 0.5, 1.0, 1.5, and 2.0 mg/mL.
  • a concentrated solution of SAIB in ethanol (83.6 wt. %) was prepared and sterile filtered using a 0.2 ⁇ m hydrophobic filter. Pure ethanol and a solution of deslorelin in ethanol (21.0 mg/g) were sterile filtered using 0.22 ⁇ m sterile syringe filters.
  • Agricultural Center Horse Farm and were all of light horse type, mainly Quarter Horses, Thoroughbreds and Arabians. All mares were in good body condition and were maintained on native summer grass pasture (predominantly bermuda grass). The majority of mares in the herd were not bred the previous season, whereas six had foaled within 30 days and were lactating. The mares were placed on a daily regimen of estrous detection beginning June 1 , and were all administered a general health and reproductive soundness exam during June. Only mares with good health, satisfactory vulvar and vaginal conformations, and apparently normal uterine and ovarian conformations were placed into a pool of potential candidates for treatment. Most of the mares were between 11 and 14 years of age (range: 8 to 22 years) and weighed 400 to 650 kg.
  • SAIB diluting solvent compositions were: 75:25 w/w SAIB:DMSO in Formulation 1 (see example 1 A); 85:15 w/w SAIB:Ethanol in Formulation 2 (see example IB); and 75:25 w/w SAIB:Ethanol in Formulation 3 (see example 1C);.
  • Resultant experimental formulations were hydrophobic low viscosity after i.m.
  • Progesterone was measured by radioimmunoassay with commercially available reagents (Diagnostic Systems Laboratories, Inc., Webster, TX) and LH was measured by radioimmunoassay as described by Thompson et al. 1983. J. Anim. Sci. 56:678-686.
  • the deslorelin was radioiodinated by the chloramine-T method and isolated by QAE-Sephadex chromatography as described for GnRH by Nett et al, Endocrinology 101 :1135 (1977). Because endogenous GnRH is not present in sufficient quantities in jugular blood for detection, any immunoreactivity in the samples was assumed to be deslorelin and not GnRH.
  • results showed that plasma DA (deslorelin acetate) concentrations were significantly increased after treatment in all three SAIB formulations with peak levels of 1902 to 1699 pg/ml.
  • Area under the response curve (AUC) for the first 24 hours after injection also confirmed significant increase in SAIB treated mares compared to saline treated controls (See Table II).
  • Treatments were 2 experimental formulation groups containing : 0.5, 1.0, 1.5 or 2.0 mg deslorelin acetate (DA) designed to deliver DA at differing rates for approximately 12 to 36 hours (h) after a 1ml intramuscular (i.m.) injection using a 21 gauge needle; and a negative control consisting of SAIB containing no drug which was also administered as a 1ml i.m. injection.
  • DA deslorelin acetate
  • SAIB SAIB
  • SAIB diluting solvent compositions were: 75:25 w/w SAIB:Ethanol in Formulations 4-8 (see example ID) and 65:35 w/w SAIB:Ethanol in Formulations 9-12 (see example IE).
  • Estrus mares' ovaries were examined daily by ultrasound (US) and were treated once a follicle between 30mm and 40mm was detected. Thereafter, mares' ovaries were examined every 24 h until ovulation which was confirmed by US.
  • US ultrasound
  • the two major efficacy variables in the study were (a) interval in hours from treatment to ovulation, and (b) the percent of mares ovulating within 48 hours of treatment.
  • the former was statistically analyzed using SAS® Cox's regression model (proportional hazards).
  • the later was statistically analyzed using logistic regression investigating the effects of formulation and dose.
  • the major safety variables in the study were (a) visible signs of swelling scores (b) sensitivity to touch, and (c) skin temperature elevation at the injection site. These variables were to be statistically analyzed by repeated measures analysis for categorical data using SAS PROC CATMOD, however, because no swelling, sensitivity or temperature elevations were detected the analysis was not performed.
  • Quadratic terms were not significant for either analysis indicating that the linear models used provided a sufficient representation for all nine groups. Predicted percentage of mares ovulating by 48 hours using both types of analysis are presented in table III in parenthesis next to the actual observed data.
  • ovariectomized gilts approximately 200 days old and weighing about 100 kg were used. All gilts were ovariectomized for 15 to 30 days prior to entrance to the study. Prior to treatment, all gilts received estradiol benzoate at a dosage of 15 ⁇ g/kg. Forty eight hours after estradiol benzoate treatment, gilts were challenged with the deslorelin treatment. Treatments were designed to deliver DA for approximately 6 to 12 hours after i.m. injection of 0.5, 1, 2, or 4 mis delivering 12.5, 25, 50, or 100 ⁇ g, respectively. A control group (0 ⁇ g of DA) received 1 ml of the SAIB: propylene carbonate vehicle. Both treatment and control formulations were sterilized using gamma radiation.
  • Cannulas were placed non-surgically into a jugular vein 24 hours prior to deslorelin treatment, and samples collected at 0, 0.5, 1, 2, 4, 6, 12, 18, 24, 30, 36, 42, and 48 hours after deslorelin treatment to determine the LH concentrations. Samples taken at 0, 0.5, 1, 2, 4, 6, 12, 18, 24, and 30 hours were used to determine DA concentrations. The levels of these compounds was determined by radioimmunoassay, and are provided graphically in Figures 2 (DA levels) and 3 (LH levels).
  • Experimental formulations were prepared by weighing and mixing SAIB, solvent and deslorelin acetate (DA) to give a final concentration of 25 ⁇ g/ml.
  • the SAIB: diluting solvent composition was: SAIB/propylene carbonate 70:30 w/w).
  • Experimental DA Treatments were sterilized using gamma radiation. 30 healthy cyclic dairy heifers weighing about 750-800 lbs (340-364 kg ) were used. This study was designed as a parallel group design.
  • All heifers were synchronized using pretreatment with 100 ⁇ g GnRH (Cystorellin, Merial, Ltd., Islin, NJ) on day -7 followed by 25 mg PGF 2 ⁇ (Lutalyse Pharmacia-Upjohn Co. Kalamazoo, MI) treatment one week later .
  • PGF 2 ⁇ Litalyse Pharmacia-Upjohn Co. Kalamazoo, MI
  • Forty eight hours after PGF 2 ⁇ treatment heifers received saline (negative controls), Cystorellin (100 mg; positive controls) or Deslorelin-SABER (DA-slow delivery preparation; at 12.5, 25, 50 or 100 ⁇ g intra-muscular).
  • AUC area under the curve

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Abstract

Cette invention se rapporte à une composition liquide servant à la libération régulée de l'hormone de libération de la gonadotrophine (GnRH) ou ses analogues ou agonistes, cette composition contenant: (i) une substance excipient liquide non hydrosoluble et non polymère (HVLCM) ayant une viscosité d'au moins 5000 cP à 37 °C, qui ne se cristallise pas de façon nette dans des conditions ambiantes ou physiologiques; et (ii) l'hormone GnRH ou des analogues ou agonistes de celle-ci. Cette composition peut être utilisée pour traiter des états reproductifs et/ou induire l'ovulation chez des animaux, tels que le bétail, le poisson et les crustacés.
PCT/US2000/013615 1999-06-18 2000-05-18 Compositions pour la liberation regulee de l'hormone gnrh et ses analogues WO2000078335A1 (fr)

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WO2001015734A3 (fr) * 1999-08-27 2001-09-13 Southern Biosystems Inc Systeme de distribution controlee de liquide hautement visqueux et dispositif medical ou chirurgical
WO2001078683A3 (fr) * 2000-04-19 2002-05-30 Genentech Inc Formulations a liberation lente
WO2003000282A1 (fr) * 2001-06-21 2003-01-03 Genentech, Inc. Formulation a liberation lente
WO2002028405A3 (fr) * 2000-10-05 2003-05-08 Veyx Pharma Gmbh Procede pour determiner le debut du cycle chez des animaux d'elevage de sexe feminin
US7824700B2 (en) 2001-02-23 2010-11-02 Genentech, Inc. Erodible polymers for injection
US7833543B2 (en) 1995-06-07 2010-11-16 Durect Corporation High viscosity liquid controlled delivery system and medical or surgical device
US8530419B2 (en) 2003-10-03 2013-09-10 Thorn Bioscience Llc Process for the synchronization of ovulation for timed breeding without heat detection
US8846072B2 (en) 2004-09-17 2014-09-30 Durect Corporation Controlled delivery system
US8905913B2 (en) 2009-04-23 2014-12-09 Jbs United Animal Health Ii Llc Method and composition for synchronizing time of insemination
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US8956644B2 (en) 2006-11-03 2015-02-17 Durect Corporation Transdermal delivery systems
US9555113B2 (en) 2013-03-15 2017-01-31 Durect Corporation Compositions with a rheological modifier to reduce dissolution variability
US9592204B2 (en) 2007-12-06 2017-03-14 Durect Corporation Oral pharmaceutical dosage forms
US9616055B2 (en) 2008-11-03 2017-04-11 Durect Corporation Oral pharmaceutical dosage forms
US9724380B2 (en) 2012-11-28 2017-08-08 Jbs United Animal Health Ii Llc Method and compositions for synchronizing time of insemination in gilts
US10471002B2 (en) 2002-06-25 2019-11-12 Durect Corporation Short duration depot formulations
EP3746074A1 (fr) * 2018-01-30 2020-12-09 Ceva Sante Animale Composition antiprolactinique vétérinaire
US11083796B2 (en) 2005-07-26 2021-08-10 Durect Corporation Peroxide removal from drug delivery vehicle
US11400019B2 (en) 2020-01-13 2022-08-02 Durect Corporation Sustained release drug delivery systems with reduced impurities and related methods
US12274794B2 (en) 2016-07-06 2025-04-15 Orient Pharma Co., Ltd. Oral dosage form with drug composition, barrier layer and drug layer

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US6413536B1 (en) 1995-06-07 2002-07-02 Southern Biosystems, Inc. High viscosity liquid controlled delivery system and medical or surgical device
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US6992065B2 (en) 2000-04-19 2006-01-31 Genentech, Inc. Sustained release formulations
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US8067020B2 (en) 2001-06-21 2011-11-29 Genetech, Inc. Sustained release formulation
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