AU659508B2 - Biocompatible implant for the timing of ovulation in mares - Google Patents
Biocompatible implant for the timing of ovulation in mares Download PDFInfo
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- AU659508B2 AU659508B2 AU28035/92A AU2803592A AU659508B2 AU 659508 B2 AU659508 B2 AU 659508B2 AU 28035/92 A AU28035/92 A AU 28035/92A AU 2803592 A AU2803592 A AU 2803592A AU 659508 B2 AU659508 B2 AU 659508B2
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- implant
- lhrh
- mares
- agonist
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- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Apparatus For Radiation Diagnosis (AREA)
Description
AU9228035 A A 8I~ L II A A LA M I I I A1 WJI.I. ILL. J L"R I I I a I 11I LW I L;IXP1 iM I lkljxL~t% I I kr'C1) (51) International Patent Classification 5 (11) International Publication Number: WO 93/07833 A61D) 19/00 Al (43) International Publication Date: 29 April 1993 (29.04.93) (21) International Application Number: PCT/AU92/00557 (74) Agent: F.B. RICE CO.; 28A Montague Street, Balmain, NSW 2041 (AU).
(22) International Filing Date: 19 October 1992 (19.10.92) (81) Designated States: AT, AU, BB, BG, BR, CA, CH, CS, Priority data: DE, DK, ES, Fl, GB, HU, JP, KP, KR, LK, LU, MG, PK 9037 21 October 1991 (21.10.91) AU MN, MW, NL, NO, PL, RO, RU, SD, SE, US, European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, SE), OAPI patent (BF, BJ, CF, (71) Applicant (for all designated States except US): PEPTIDE CG, CI, CM, GA, GN, ML, MR, SN, TD, TG).
TECHNOLOGY LIMITED [AU/AU]; 4-10 Inman Road, Dee Why, NSW 2099 (AU).
Published (72) Inventors; and With international search report.
Inventors/Applicants (for US only): TRIGG, Timothy, Elliot [AU/AU]; 8 Yosefa Avenue, Warrawee, NSW 2074 SQUIRES, Edward, L. [US/US]; 6720 North Country Road 15, Fort Collins, CO 80524 (US).
JOCHLE, Wolfgang [US/US]; 10 Old Boonton Road, 690 (54) Title: BIOCOMPATIBLE IMPLANT FOR THE TIMING OF OVULATION IN MARES Treatment: Follicle diameter
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.2 4 Os.- .i i U* 12-24 236 36-48 460 6.72 7234 84-06 Time (h) A eb 3000 Iu HCO NSc SM kic H Cba
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(57) Abstract The inductiont of ovulation in mares having a maturing ovarian follicle is controlled by implanting into the mare a solid biocompatible implant comprising a solid carrier and an effective amount of leutinising hormone releasing hormone (LH RH) or an agonist of LHRH such as Deflorelin. The solid carrier is preferably a biologically absorbable inorganic salt mixed with an organic tablet release compound.
I,
a' a> PCF/AU92/00557 WO 93/07833
D'
st WO 93/07833 PCT/AU92/00557 1 -1- BIOCOMPATIBLE IMPLANT FOR THE TIMING OF OVULATION IN MARES FIELD OF THE INVENTION The present invention relates to a method for controlling the timing of the ovulation of mares and to a biocompatible implant for use in such a method.
BACKGROUND ART The equine industry worldwide is continually improving breeding management. This improvement is driven by many factors; of significance are the need to conserve "stallion power" and (ii) the veterinarians requirement to improve their efficiency by having mares ovulate with more predictability.
In order to achieve the above, the ability to predict, within predetermined time constraints when a mare will ovulate, is critical. The use of injection of human chorionic gonodotrophin (HCG) to stimulate ovulation in mares between 36-48 hours after application is widespread. However, despite success with this hormone, it has a number of serious drawbacks.
They include: it is not registered for this use in many countries (USA, and areas of Europe). Veterinarians using hCG in countries where it is unregistered are liable for any claims against failure of the product.
(ii) continued used in the same mare can cause refractiveness anaphylaxis is a possibility.
(iii) hCG is derived from human urine either from pregnant or post menopausal women. Collection, isolation and purification are unpleasant, and the possibility of transmission of disease, particularly those of viral origin, is a risk.
(iv) supplies of hCG cannot be guaranteed.
As an alternative to hCG, Leutinising Hormone Releasing Hormone (LHRH) has been injected into mares to stimulate ovulation. LHRH is also known as Gonodotrophin
II
PC/A 9 2 0 0 5 5 7 RECEIVED 0 5 OCT 199: -2releasing hormone (GnRH; The LHRH stimulates the mare to produce its own gonodotrophin which, in turn, stimulates ovulation. An agonist of LHRH (Buserelin) has also been injected into mares and it has been reported that ovulation may be induced by such injections. Injected hormones must be typically administered a number of times to be successful and they are required in relatively large doses.
DISCLOSURE OF THE INVENTION The present invention is directed to an alternative method and composition for controlling the timing of ovulation in mares.
In a first aspect the present invention consists in a method for the controlled induction of ovulation in mares comprising implanting into a mare which already has an ovarian follicle approaching maturation a solid biocompatible implant comprising a solid carrier and an effective amount of an agonist of LHRH so as to increase the level of LHRH agonist in the mare above that prevailing immediately before that implantation.
In a second aspect the present invention consists in a solid biocompatible implant for controlling the induction of ovulation in mares which already have an ovarian follicle approaching maturation, the implant comprises a biologically absorbable solid and from 1.0 to mg of an agonist of LHRH.
Deslorelin is a peptide and a super agonist for LHRH.
It is the most preferred LHRH agonist for use in the present invention. The formula for Deslorelin is:- D-Trp 6 Pro N Et LHRH (p Glu His Trp Ser Tyr D-Trp Leu Arg Pro NHEt) As used herein the term "an ovarian follicle approaching maturation" is taken to mean an ovarian follicle which has developed to a size of at least about T IPEA/SUBSTITUTE SHEET PCr/AU92/00557 WO 93/07933 -3these include the following compounds as discussed in Duttojn, "Luteinizing Hormone Releasing Hormone (LHRH) Agonists", Drugs of the Future, Vol 13, No. 1, 1988:- Agonist Structure Name (Company) fD-Ser(But) 6.desGly-NH 1 0 -LHRK(1-9N~ [D-Trp 6J-LHRH [des-Gly-NH 1 ]-U-IRH(1-9)NHEt 6, 2(z) e-Gly-NH 1 0 J-LHRH(1 -9)NHEt [D..Leu 6,des-Gly-NH2 J-LHRH(1 -9)NHEt [D-Trp 6,MeLeu 7, des-Gly-NH 2 10-LHRH(1-9)NHEt ID-Nal 6]-LHRH [D-Ser(Bu') 6, Azgly 10)-LHRH Buserelin (Hoechst) Tryptorelin (Deblopharm) (Decapeptyn) Fertirelin (Takeda) Histrelin (Ortho) Leuprolide (Abbott) Lutrelin (Wyeth) Nafarelin (Syntex) Zoladex (Registered Trade Mark) 101 In addition the following LHRH agonists may be used in carrying out the invention:- [D-Ser(Bu t) 6 I-LHR.H(1-9)NHEt [D-Lys(Boc) 6 des-Gly-NH 2 1]-LHRII(1-9)NHEt [D-Glu(OBu 6 des-Gly-NH 2 lO]-LHRH(1-9)NHEt [D-Asp(OBu ),6des-Gly-NH 2 1]-LHRH(1-9)NHEt [D-Leu 6 Ser(Bu t) 7 des.Gly-.NH10]LHRH(l-.9)NHEt t 6 t 7 [D-Ser(Bu Cys(Bu )des-Gly-NH 2 1]-LHRH(1-9)NHEt [D-Ser(Bu Ser(Bu )des-Gly-NH 2 1]-LHRH(l-9)NHEt [D-Phe 6 Azgly 10
]-LHRH
[D-Tyr(Me) 6,Azgly 10]-LHRH t 6 110 [D-Ser(Bu ,Azgly ]-LHRH (D-Tmo 6]-LHRH [D-Nal(2) 6
]-LHRH
(D-Ptf 6]-LHRH [D-Tmp 6] -LHRH [D-Bpal 6]-LHRH [D-Nal(2) 6MeLeu 7]-LHRH [D-Nal(2) 6MeLeu 7,des-Gly-NH 2 I-LHRH-1-9NHEt
I
I
if 4 PCI7/AU92/00557 WO 93/07833 -4- [D-hArg(Et 2
]-LHRH
[D-hArg(Me,Bu)6]-LHRH [D-hArg(Et2)6 des-Gly-NH 10 ]-LHRH-1-9NHEt 2 6 10 [D-hArg(Me,Bu)6,des-Gly-NH 2 ]-LHRH-1-9NHEt The solid carrier for the LHRH or LHRH agonist should be a material into which the Deslorelin can be mixed or absorbed, onto which it may be adsorbed, or onto which it may be coated. It is a particularly preferred feature of the invention that the carrier is a biologically adsorbable inorganic salt such as calcium phosphate dihydrate, calcium phosphate, sodium sulphate or calcium carbonate. This allows the biocompatible implant to be made cheaply by a simple tableting technique. To assist in forming the implant and to provide an improved active release profile it is preferred that the implant contains a small proportion of an organic tablet release compound or lubricating agent such as a fatty acid or a hydrogenated vegetable oil. The tablet release compound preferably comprises from 4 to 10% by weight of the implant and more preferably about It has been found that the release characteristics of the LHRH agonist from such an inorganic salt mixed with such lubricating agent is such that ovulation can be induced in a tightly controlled manner, that a high proportion of the mares will ovulate at a given time after the administration of the implant.
The implant is desirably as small as possible.
Preferably the implant is substantially cylindrical having a diameter of from 0.5 to 5mm and a length of from 1 to 6mm. Obviously other sizes and shapes of biocompatible implants may be used however the selection of preferred embodiments of the present invention allows the size of the implant to be sufficiently small to be of practical utility. The implant is preferably small enough to be able to be implanted into a mare through a tubular needle. The i PCF/AU92/05S57 needle is inserted into the mare, such as in the neck region, and the implant pushed down the needle with an obturator as the needle is withdrawn. This leaves the implant embedded subcutaneously in the animal. The LHRH agonist is released from the implant in a controlled manner and the carrier is slowly dissolved.
The LHRH agonist should preferably be present in the implant in an amount of from 1.0 to 5.0mg, more preferably to 3.0mg and most preferably 2.0 to 2.4mg for a thoroughbred mare of average size.
BRIEF DESCRIPTION OF THE DRAWINGS Hereinafter given by way of example only are preferred embodiments of the present invention described with reference to the accompanying figures in which:- Fig. 1 shows time to ovulation for mares treated as described in Example 1; Fig. 2 shows time to ovulation after treatment with a short term implant containing 2.25mg of LHRH as described in Example 2; and Figs. 3 to 6 show ovulation response to treatments as described in Example 3.
BEST METHOD FOR CARRYING OUT THE INVENTION In all examples, unless indicated otherwise, short term implants of the LHRH agonist Deslorelin were prepared by mixing the Deslorelin with finely ground calcium carbonate and 5% of a hydrogenated vegetable oil tableting aid sold under the trade mark "LUBRITAB" (Edward Mendell Co. Inc, New York, The mixture is then tableted to the desired shape in a conventional manner. The implants were substantially cylindrical having a diameter of 2.3mm and a length of 3.4mm. All treatments with hCG were by injection.
Example 1 Groups of twelve Hannovarian mares were each given a placebo implant, injected with either 3,000 iuhCG or with INTERNATIONAL SEARCH REPORT Intenutional application No.
PCT/AU92/00557 A. CLASSIFICATION OF SUBJECT MATTER Int. C1.
5 A61D 19/00 T Y I PCIT/AU92/00557 WO 93/07833 6 5,000 iuhCG or given an implant containing 1.5mg of Deslorelin. In this example treatment was given when the mares showed follicles of 40mm diameter as the horses were Hannovarian. The results of this example are shown in Fig.
1. It can be seen that the 1.5mg Deslorelin implant performed as well as 3,000 iuhCG and possibly as well as 5,000 iuhCG.
Example 2 The procedure of Example 1 was repeated with twenty seven Hannovarian mares being given a short term implant containing 2.25mg of Deslorelin. It can be assumed that those mares ovulating at 0-24 hours would have ovulated in the absence of treatment. The results obtained in this example are shown in Fig. 2.
Example 3 Groups of mares were each given a placebo implant, a 1.3, 1.6 or 2.2mg Deslorelin implant, or 5,000 iuhCG. The placebo treatment is designated 101 in Fig. 6 and the Deslorelin implants are indicated, respectively, as 102, 104 and 100.
It can be seen that the variation in ovulation was less for the 2.2mg treatment than all other treatments; ovulation commonly occurred around 48 hours post-implantation with this treatment.
Some data has been removed from the analyses as outlyers in this trial. The criteria for removal was: those animals ovulating within 24 hours or 8+ days after implantation were considered not to have been affected by the implant. The numbers removed were 2 x hCG; 5 x 100, 2 x 101, 0 x 102 and 2 x 104.
Example 4 Mares with follicular size of at least 30mm, as determined by ultrasound and rectal palpation, were allocated to one of three treatment groups. They were 35 2.2mg Deslorelin implant, hCG (5000 iu) and untreated i i a
S
-i _I WO 93/07833 PCT/AU92/00557 -7controls. It can be seen that oaulation commonly occurred around 2 days for the Deslorelin implanted and hCG injected mares. Untreated controls took significantly longer to ovulate from both implantation and from the start of oestrus than the treated groups. It appears that the untreated controls were in oestrus longer than treated animals.
TABLE 1 STUDY 1: Mean values of oestrus characteristics for three ovulation induction treatments.
TREATMENTS
Characteristics LHRH hCG Control No. day oestrus 5.88 1.27 5.46 0.96 6.90 2.42 Day OV 4.13 0.35 a 4.40 0.96 a 6.10 1.79 b 30mm to OV 2.13 0 .3 5 a 2.00 0 00 a 3.70 1 49 b I No. Ov's 0.90 0.56 1.10 0.32 1.10 0.32 Example Mares with follicular size of at least 30mm, as determined by ultrasound and rectal palpation, at two locations (CSU and UCD) were allocated to one of five treatment groups. These treatment groups were a placebo implant, and implants containing 1.2mg, 1.7mg, 2.2mg and 2.7mg of Deslorelin. In this example the implant comprised finely ground calcium phosphate dihydrate, 8% by weight Lubritab and, where appropriate, the Deslorelin. A summary of the results obtained is provided in Table 2 which shows the mean time in hours to ovulation, standard deviation in hours of the time to ovulation, the number of mares in the sample and the percentage of mares ovulating within 48 hours.
i i ,i -1 i: WO 93/07833 PCF/AU92/00557 -8- Table 2 Summary statistics* for the time to ovulation by study location and Deslorelin does treatment group.
Treatment Group No. (Deslorelin dose. mg) 1 2 3 4 Centre (2.7)
CSU
x 68.00 49.00 48.00 46.91 44.00 s 38.74 8.02 11.44 3.62 9.34 n 12 12 12 11 12 P 50.0 75.0 83.3 100.0 100.0
UCD
x 91.50 66.00 58.50 46.50 58.29 s 35.68 37.40 45.10 10.01 32.81 n 8 8 8 8 7 P 25.0 75.0 87.50 87.50 85.71 Combined x 77.40 55.80 52.20 46.74 49.26 s 38.44 25.01 29.21 6.81 21.50 n 20 20 20 19 19 P 40.0 75.0 85.0 94.7 94.74 *Summary statistics include the mean and standard deviation of the time to ovulation, the sample size and the percent of mares ovulating within 48 hours The mares were mated and Table 3 summarises the pregnancy among the mares. This table provides the sample size, the number and percent of mares pregnant through a first cycle and the number and percent of mares pregnant through a second cycle.
j t j j i
I:
B
W
I
W1 S93/07833 PCT/AU92/00557 9 Table 3 Summary* of pregnancy among study mares by study location and Deslorelin dose treatment group.
Treatment Group No. (Deslorelin dose. ma) 1 2 3 4 Center (2.7) LO CSU n 12 12 12 11 12 m I 5 8 8 8 8 p 41.7 66.7 66.7 72.7 66.7 m 2 7 11 11 10 9 P 58.3 91.7 91.7 90.9 75.0 UCD n 8 8 8 8 7 m 6 5 4 5 4 p 1 75.0 62.5 50.0 62.5 57.1 m 2 7 7
P
2 87.5 87.5 75.0 97.5 71.4 Combined n 20 20 20 19 19 m 11 13 12 13 12
P
1 55.0 65.0 60.0 68.4 63.2 m 14 18 **17 **17 **14
P
2 70.0 90.0 85.0 89.5 73.7 Summary includes the sample size the number (ml) and percent (P 1 of mares pregnant through the first cycle, and the number and percent (P 2 of mares pregnant through the second cycle.
One mare in each of these study groups was not bred back.
'0 1 11 1
I
I!
p
I
WO 93/07833 PCTrAU92/00557 10 It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the inven'ton as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
i K j d
Claims (16)
1. A method for the controlled induction of ovulation in mares comprising implanting into a mare which already has ovarian follicle approaching maturation a solid biocompatible implant comprising a solid carrier and an effective amount of an agonist of LHRH so as to increase the level of LHRH agonist in the mare above that prevailing immediately before that implantation.
2. A method as claimed in claim 1 in which the LHRH agonist is Deslorelin.
3. A method as claimed in claim 1 in which the LHRH agonist is present in the implant in an amount of from to 5.0 mg.
4. A method as claimed in claim 3 in which the LHRH agonist is present in the implant in an amount of 1.5 to mg.
A method as claimed in claim 4 in which the LHRH agonist is present in the implant in an amount of 2.0 to 2.4 mg.
6, A method as claimed in claim 1 in which the solid carrier comprises a biologically absorbable inorganic salt and an organic tablet release compound.
7. A method as claimed in claim 1 in which the implant is embedded subcutaneously into the mare.
8. A method as claimed in claim 7 in which the implant is embedded into the mare through a tubular needle inserted into the mare, the implant being pushed down the needle with an obturator as the needle is withdrawn.
9. A solid biocompatible implant for controlling the induction of ovulation in mares which already have an ovarian follicle approaching maturation, the implant comprises a biologically absorbable solid and from 1.0 to of an agonist of LHRH. A biocompatible implant as claimed in claim 9'in which the LHRH agonist is Deslorelin.
I IPEA/SUBSTITUTE SHEET ii~-- PCT/AU 9 2 /00 5 57 7 C E I E ED 0 5 OCT 1993 12
11. A biocompatible implant as claimed in claim 9 in which the LHRH agonist is present in the implant in an amount of from 1.5 to 3.0 mg.
12. A biocompatible implant as claimed in claim 9 in which the LHRH agonist is present in the implant in an amount of from 2.0 to 2.4 mg.
13. A biocompatible implant as claimed in claim 9 in which the solid carrier comprises a biologically absorbable inorganic salt and an organic tablet release compound. 13
14. A biocompatible implant as claimed in claim5Ki in which the inorganic salt is selected from the group comprising calcium phosphate dihydrate, calcium phosphate, sodium sulphate and calcium carbonate.
15. A biocompatible implant as claimed in claim 13 in which the organic tablet release compound is selected from the group comprising i fatty acid and a hydrogenated .vegetable oil.
16. A biocompatible implant as claimed in claim 9 in which the implant is substantially cylindrical having a diameter of from 0.5 to 5.0 mm and a length of from 1.0 to mm. :3 IIPEA/SUBSTITUTE SHEET
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU28035/92A AU659508B2 (en) | 1991-10-21 | 1992-10-19 | Biocompatible implant for the timing of ovulation in mares |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPK9037 | 1991-10-21 | ||
AUPK903791 | 1991-10-21 | ||
PCT/AU1992/000557 WO1993007833A1 (en) | 1991-10-21 | 1992-10-19 | Biocompatible implant for the timing of ovulation in mares |
AU28035/92A AU659508B2 (en) | 1991-10-21 | 1992-10-19 | Biocompatible implant for the timing of ovulation in mares |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2803592A AU2803592A (en) | 1993-05-21 |
AU659508B2 true AU659508B2 (en) | 1995-05-18 |
Family
ID=25620496
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU28035/92A Expired AU659508B2 (en) | 1991-10-21 | 1992-10-19 | Biocompatible implant for the timing of ovulation in mares |
Country Status (1)
Country | Link |
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AU (1) | AU659508B2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU586252B2 (en) * | 1985-05-10 | 1989-07-06 | University Of Melbourne, The | Induction of ovulation in mares |
-
1992
- 1992-10-19 AU AU28035/92A patent/AU659508B2/en not_active Expired
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU586252B2 (en) * | 1985-05-10 | 1989-07-06 | University Of Melbourne, The | Induction of ovulation in mares |
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Publication number | Publication date |
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AU2803592A (en) | 1993-05-21 |
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