AU759755B2 - Synchronising of animal oestrus and intra vaginal devices useful therein - Google Patents

Description

Regulation 3.2

AUSTRALIA

PATENTS ACT, 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant: Actual Inventor: Address for service in Australia: Invention Title:

INTERAG

Michael John Rathbone, Craig Robert Bunt and Shane Burggraaf A J PARK, Level 11, 60 Marcus Clarke Street, Canberra ACT 2601 Synchronising of Animal Oestrus and Intra Vaginal Devices Useful Therein The following statement is a full description of this invention, including the best method of performing it known to me/us TECHNICAL FIELD The present invention relates to improvements in and/or relating to the synchronising of animal oestrus and intra vaginal devices useful therein together with related means and methods.

BACKGROUND ART It is useful for farmers to synchronise the oestrus of animals whether they be cattle beasts (whether for dairy or beef purposes) sheep, goats, horses, or the like where artificial insemination is practised. By way of example, in relation to cattle beasts, in a normal 365 day year 282 days on average is taken up of the year with the gestation period itself. With approximately 30 days to recover after delivery of its progeny each cow therefore has an average of only two and a half cycles if there is to be a timely management of the herd.

Thus it is important over that remaining period of less than 53 days to ensure each cow in a herd becomes pregnant.

15 The traditional method of mating dairy cows with bulls is now largely superseded Sby the use of artificial insemination procedures which offer the prospect of rapid herd improvements although bulls are still presented to the herd frequently to catch those animals that have not conceived by the artificial insemination procedure.

There is therefore a great advantage attached to bringing such herd animals into oestrus simultaneously so as to make it easier to ensure effective usage of the artificial insemination procedure and subsequently to enable still within the "window" a further prospect of artificial insemination of those animals synchronistically brought to oestrus *oo that have not already conceived.

Various means of achieving such a management of the synchronisation of the coming into oestrus of cows (whether heifers or lactating cows) and even sheep and goats has been disclosed in the art which includes the "EAZI-BREED CIDR Controlled Breeding and Reproductive Management" booklet made available to interested parties by InterAg a division of the applicant company in respect of its intra vaginal Eazi-Breed 'M CIDRR product line.

The disclosures in the aforementioned publication, the full contents of which are here included by way of reference, comprehensively describe treatment protocols applicable at least to New Zealand herds of cattle beasts for synchronising oestrus and treatment of anoestrus.

These treatment protocols often utilise Eazi-Breed T M CIDRR devices in combination with drugs such as prostaglandin and/or oestradiol benzoate, and extend in general for periods of 7, 10 or 12 days.

If both control of the oestrus cycle and high fertility are to be optimised in cattle, studies have shown that an intra vaginal device must deliver sufficient progesterone (when used with combination drugs i.e. oestradiol or GnRH) to produce a minimum plasma progesterone concentration of 2 ng/mL over the terminal period of treatment 1. Kesner, Padmanabhan, V. and Convey, E.M. Biol. Reprod. 26 (1982) 571-578.

2. Kinder, Kojima, Bergfeld, Wehrman, M.E. and Fike, K.E. J.Anim. Sci 74 (1996) 1424-1440.

A cost factor arises in the adoption of such protocols as a farmer is faced with the costs of the intra vaginal progesterone containing device as well as the use of the combination drugs. This ignores also the economic cost of the artificial breeding materials themselves.

The intra vaginal progesterone containing devices hitherto used in New Zealand 15 and to a large extent elsewhere are typified by the CIDRR product of the applicant Scompany depicted hereinafter in Figure 1 being a variable geometry device for vaginal insertion and retention which comprises a structural frame of a metal or appropriate plastics material encased in a progesterone impregnated plastics material from which the material can leach in the vaginal environment and from which it can be timely withdrawn by appropriate means a string, tail or a tool) to allow the animal to progress into oestrus shortly after the removal. Hereinafter the aforementioned device will be referred to by its registered trademark CIDRR SAnother product available in the market place of this kind is another variable geometry device and such a device is depicted hereinafter in Figure 2. Such a device is a 25 helical coil capable of being helically tightened and which is retainable in its helical form in the animals vagina. The device includes a withdrawal cord and carries a gelatine capsule which includes oestradiol benzoate so that there can be co-administration of the progesterone to be released over a protracted period and the oestradiol benzoate which is to be released at a different rate. Such a device includes a progesterone impregnated plastics matrix about a helical spine. Such a device is available from Sanofi Animal Health Limited, PO Box 209, Rhodes Way, Watford, Herts, WD24QE, England under its registered trademark PRIDR.

The aforementioned CIDRR and PRIDR devices are manufactured in large volumes with the most expensive material being the progesterone active ingredient and thus small reductions in the progesterone inclusion in such devices will provide an economic ERaIdvantage to a producer and to a farmer. Also any such reduction provides a reduced risk to the environment owing to a likely reduced residual amount of the progesterone in the matrix after the device has been withdrawn from an animal. This reduced residual amount not only provides safety but also dis-encourages the unrecommended reuse of a device in another animal where the unknown condition of such a device will give unpredictable results.

The CIDRR prior art device of the applicant company has been marketed with a silicone plastics matrix about its spine which contains about 1.9 grams of progesterone (USP) which drops to 1.33 grams still retained in the silicone matrix if the device is withdrawn after seven days. The same device drops to 1.05 grams of progesterone if it is not withdrawn until after 12 days.

The PRIDR coil intra vaginal device contains at the outset 1.55 grams of progesterone which reduces down to 1.18 grams after 7 days and down to 0.94 grams after days. The leach rate from the PRIDR product may be affected in part by the inclusion of inorganic materials in the silicone plastics material such as calcium carbonate. The 15 CIDRR silicone matrix is largely free of any such inclusions.

S:Hoechst US Patent 5,398,698 discloses the use of milled sheets of silicone rubber in intra-vaginal devices which carry progesterone. The milled sheets (2 to 10 mm thick) :°o.oo are vulcanised for from 4 to 8 minutes at from 70 0 C to 120 0

C.

The accepted test for the delivery of progesterone or its metabolites to the appropriate site of action in order to postpone oestrus is by reference to the progesterone level in the blood plasma of the animal. The design of such devices has to date usually been on the basis of an acceptance of the Higuchi equation based on a square root of time S* model (see hereinafter) which suggests that progesterone inclusions in such a plastics ••go matrix would achieve plasma levels which decline with time.

25 Our investigations have found surprisingly that it is inappropriate in the design of such intra vaginal devices to rely upon the Higuchi equation or the square root of time model. In our device release is constant with time up to 7 days resulting in constant steady state plasma levels over that time period.

We have determined that by modifying the levels of progesterone initially in a silicone matrix, by controlling the thickness of the silicone matrix over the spine and by giving attention to the surface area of the device savings to a manufacturer arising from reduced quantities of progesterone being needed while at the same time achieving the same blood levels can be achieved. Savings are also achieved over the prior art devices in terms of the amount of silicone used, since silicone is the second-most costly material used in the devices, with corresponding benefits being able to be passed on to the user.

Z2:R4The present invention relates to intra vaginal devices, methods of producing intra vaginal devices, and the use of such intra vaginal devices for managing oestrus and for the treatment of anoestrus in cattle, sheep, deer and goats.

DISCLOSURE OF INVENTION In one aspect the invention is an intra vaginal device for insertion into a vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, retainable therein over a period of time within a range of from 7 to 12 days and then to be withdrawable therefrom to allow the onset ofoestrus, said device comprising or including: a matrix of a cured silicone rubber material including greater than 5% by weight progesterone to a weight of the matrix and defining an exterior surface of at least 75cm 2 contactable upon insertion in the vagina of an animal by biological fluids of the animal, a total progesterone load being from 1 to 1.5 grams within said matrix, said exterior surface being at least substantially all available for progesterone release 1 leand said exterior surface having said progesterone load having a thickness of less than 1 15 millimeter, and said matrix, upon vaginal insertion in an animal, achieving and then maintaining, for at least seven days, a minimum progesterone blood plasma level of 2 nanograms per millilitre of plasma of the animal and after seven days from insertion having a residual load in the matrix of less than 65% by weight of the total progesterone load at insertion.

Preferably said exterior surface is from 100 to 1500 cm 2 Preferably said matrix has about 10% by weight progesterone to the weight of the matrix.

Preferably said matrix, at least in part, encases a deformable frame.

Preferably said frame is resilient.

25 Preferably said frame is substantially in a form of a with the arms of the "T" form being defined by a resilient spine about which at least in part, there is moulded said matrix.

Preferably said frame is of nylon.

In a further aspect an intra vaginal device for insertion into a vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, retainable therein over a period of time within a range of from 7 to 12 days and then to be withdrawable therefrom to allow the onset ofoestrus, said device comprising or including: a frame having a matrix of a cured silicone rubber material including greater than and less than 20% by weight progesterone to a weight of the matrix, the matrix defining an exterior surface of at least 100 cm 2 contactable upon insertion in the vagina of an animal by biological fluids of the animal, a total progesterone load being from 1 to 1.5 grams within said matrix, said exterior surface being at least substantially all available for progesterone release and said exterior surface having said progesterone load having a thickness of less than 1 millimeter, and said matrix, upon vaginal insertion into an animal, achieving and then maintaining, for at least seven days, a minimum progesterone blood plasma level of 2 nanograms per millilitre of plasma of the animal and after seven days from insertion having a residual load in the matrix of less than 60% by weight of the total progesterone load at insertion.

In still a further aspect an intra vaginal device for insertion in a vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, and retainable therein over a period of time and then to be withdrawable therefrom to allow the onset of oestrus, said device comprising or including: a matrix of cured silicone rubber material including greater than 5% by weight of 15 progesterone to a weight of the matrix, said matrix having at least one progesterone release surface, said at least one release surface having a total area of at least 75 cm 2 contactable, once inserted in the vagina of an animal, by the biological fluids of the animal, *•ooo substantially all of the progesterone within the matrix being within about 1 millimeter of said at least one release surface, a total progesterone load being at least 1 gram within said matrix, said matrix, upon vaginal insertion into an animal, achieving and then maintaining in the animal, for at least seven days, a minimum progesterone blood plasma level of 2 nanograms per milliliter of plasma of the animal and if removed after seven days from insertion having a residual progesterone load in the silicone rubber matrix of less than 1 25 gram and also less than 65 by weight of the total progesterone load at insertion.

i Preferably the at least one progesterone release surface is greater than 100 cm 2 In still a further aspect an intra vaginal device for insertion into a vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, and retainable therein over a period of time and then to be withdrawable therefrom to allow the onset of oestrus, said device comprising or including: a matrix of cured silicone rubber material including greater than 5% by weight of progesterone to weight of the matrix, said matrix having at least one progesterone release surface, said at least one release surface having a total area of at least 75 cm 2 contactable, once inserted in the vagina of an animal, by the biological fluid of the animal, the progesterone, the cured silicone rubber material and said at least one progesterone release surface producing a zero-order intra vaginal release rate of progesterone from the matrix, substantially all of the progesterone within the matrix being less than 1 millimeter from said at least one progesterone release surface, a total progesterone load being at least 1 gram within said matrix, and said matrix, upon vaginal insertion into an animal, achieving and then maintaining in the animal, for at least seven days, a minimum progesterone blood plasma level of 2 nanograms per milliliter of plasma of the animal and if removed after seven days from insertion having a residual load or progesterone in the silicone rubber matrix of less than 1 gram and also less than 65% by weight of the progesterone load at insertion.

BRIEF DESCRIPTION OF DRAWINGS The present invention will now be described with reference to the accompanying drawings in which: 15 Figure 1 shows a series of drawings through of a prior art EaziBreed

M

CIDRTM product of this company having a progesterone impregnated silicone matrix of an average depth of about 1.5 mm but having the depth thereof varying greatly, o"Figure 1A is an elevation of the shaped device capable of having the top arms thereof resiliently bent to alongside the upstanding body during insertion with an appropriate applicator pull and capable of assuming some return to the form so as to be retained within the vagina of an appropriate animal such as a cattle beast, Figure 1B is a section at "FF" of the top arms of the form, Figure 1C is a section at "DD" of the body, Figure 1D is a view "CC" of the end of the body showing a slot formed therein 25 from a hole through the body so as to allow the lying therein of a retained withdrawal string or other device, S .Figure 1E is a section of the body at "EE".

Figure 1' shows the preferred spine of the prior art device, a spine which with no or little modification is useful in a device in accordance with the present invention, Figure 1 'A shows an elevation of the spine, Figure 1 'B showing a side elevation of the spine, Figure 1 'C showing the plan view of the top arms of the device, Figure 1 'D shows the section at "AA", Figure 1 'E shows the section at "BB", Figure 2 shows the PRID T M device previously referred to, Figure 3 shows a preferred device in accordance with the present invention having -8an average progesterone impregnated matrix of about or less than 1 mm thick over a spine of a kind shown in Figure 1', Figure 3A shows an elevation of the (CIDR-B T M device in accordance with the present invention, Figure 3B shows the side elevation of the device of Figure 3A, Figure 3C shows a plan view of the top of the device as shown in Figures 3A and 3B, Figure 3D shows a section at "DD" of Figure 3A, Figure 3E shows a section at of Figure 3A, Figure 3F shows a section at "BB" of Figure 3A, Figure 3G shows a section at "AA' of Figure 3A, Figure 3H shows a section at "PP" of Figure 3A, being the hinging region of the arms from the body, and ~Figure 31 is the section "HH" of Figure 3A, and Figures 4 through 15 show results, plots, models and concepts hereinafter described Sin greater detail.

DETAILED DESCRIPTION The device of the present invention will now be described with reference to both in vitro and in vivo studies. In the following description the reference to the CIDR M device is by reference to the device of the form depicted in Figures 1A to 1E. The reference hereafter to the device of the present invention (to be known as the CIDR-B T M device) is preferably that substantially as depicted in Figures 3A through 31 and described hereinafter in more detail.

In vitro studies SThe in vitro release assessment method for the existing CIDR T M device was based on the equipment and general procedures documented in the US Pharmacopoeia, XXIII pp 1791-1975 (1995). In vitro release of progesterone from the device followed a declining profile with time (Figure 4).

0 Mechanism of Release Release data was plotted as cumulative amount of progesterone released per unit area versus square-root-of-time. the release profile over greater than 75% of total release from the existing CIDR TM device followed a square-root-of-time model (Figure 5; linear dependence of progesterone release as a function of the square root of time).

-9- S Effect of drug load Release rate was observed to be affected by initial drug load as expected from the square-root-of-time model (Figure linear dependence ofprogesterone release rate as a function of the square root of twice the amount of initial drug load).

0 Determination of the depletion zone within silicone Depletion zone determinations clearly showed the formation of a depletion zone in the silicone skin (Figure 7) which is consistent with the square-root-of-time theory (Figure 8).

the results of all in vitro experiments conducted on the CIDR T M device suggested that progesterone was being released from the silicone matrix according to the squareroot-of-time model of release.

*i .15 In vivo studies The following in vivo studies which led to our discoveries were conducted on the existing CIDR T M device and on devices of the present invention devices referred to ""as the CIDR-BTM devices).

0 Blood level parameter (steady-state blood level) Following insertion of the existing CIDRTM device into ovariectomized cattle a characteristic plasma profile was observed (Figure There was a rapid absorption phase. blood levels peaked within a few hours. The peak level was sustained for 48 hours before it fell over the following 24 to 48 hours to levels which were constant or diminished only very slightly over the remaining 4 days of the 7 day insertion period 25 (apparent steady-state levels). Following removal of the device, plasma levels fell rapidly to basal levels. Based on Figure 9 we selected average progesterone steady-state plasma levels over the last four days of a 7 day insertion period as the performance indicator of the device.

Effect of initial progesterone concentration The effect of initial progesterone concentration in the device on the average progesterone steady-state plasma levels over the last four days of a 7 day insertion period is shown in Figure 10. Figure 10 shows that the devices containing above a 5% w/w initial progesterone concentration produce average progesterone steady-state plasma levels over the last four days of a 7 day insertion period above 2 ng/mL.

S Effect of surface area The effect of surface area upon the average progesterone steady-state plasma levels over the last four days of a 7 day insertion period is shown in Figure 11. An increase in surface area produced an increase in average progesterone steady-state plasma levels over the last four days ofa 7 day insertion period (Figure 11). A surface area of greater than cm 2 is required to ensure that average progesterone steady-state plasma levels over the last four days of a 7 day insertion period are above 2ng/mL.

S Determination of the depletion zone within silicone of used devices Progesterone concentration at various depths of a spent existing device that had been inserted for 7 days in cattle is shown in Figure 12. Figure 12 shows clearly that no distinct depletion zone was apparent following removal of the device after a 7 day insertion period in the vagina of cattle (cf. the clear depletion zone which was observed in the in vitro experiments; Figure Indeed following in vivo insertion the 0-0.5 mm outermost layer of silicone rubber skin still contained drug but at a concentration less than that originally Sincorporated into the device, the 0.5-1.0 mm layer also still contained drug but at a concentration less than that originally incorporated into the device. Beyond 1 mm the ooo original amount of progesterone incorporated into the device was detected (Figure 12).

These results (Figure 12) clearly demonstrate that progesterone was only eluted out of the first 1 mm of silicone rubber skin. The results also suggest that no distinct depletion zone forms as the drug is being released while the device is inside the animal but instead as release occurs a gradation of solid particles forms within the first 1 mm of skin. Possible reasons why such observations were detected are shown in Figure 13. These observations o are not consistent with the square-root-of-time model. Indeed, the in vivo release of 25 progesterone from the device was observed to be constant with time (figure 14) and follow i a zero-order release mechanism (cf the declining profile when the amount of progesterone released from the CIDR-B in vitro was plotted against time; Figure 4).

S Investigations on a device of the present invention From these studies a device was manufactured which had a uniform silicone rubber skin thickness of <1 mm, surface area of 120 cm 2 and initially contained 1.25 g w/w) of progesterone. Figure 15 shows the average progesterone steady-state plasma levels over the last four days of a 7 day insertion period determined for the existing CIDR device and a device in accordance with the present invention (CIDR-B device). Figure clearly shows that the CIDR-B device is able to effectively sustain progesterone steadystate plasma levels over the last four days of a 7 day insertion period above 2 ng/mL. In -11addition, the final:initial content ratio for the CIDR-B device is less than 60% following a 7 day insertion period (Table 1).

Table 1: Comparison of the initial amount of progesterone, residual progesterone in spent devices and amount of progesterone released from existing CIDRTM device and device (CIDR-B TM device) which has characteristics described in this patent application following removal after 7 days.

Intra vaginal Initial Initial amount Residual Amount of Final:initial progesterone progesterone of amount of progesterone ratio release device concentration progesterone progesterone released over in device In device remaining in 7 days device (g) (g) Existing CIDR T M 10 1.92 1.36 0.56 0.71 device Device of the 10 1.25 1.36 M0.56 0.59 present invention

(CIDR-B

T M The following table of in vivo comparative data compares a device in accordance with the present invention (CIDR-B

T

with a CIDR

T

device and a PRID'device.

boo* In vivo Comparisons Parameter Existing CIDRT New CIDR.BT M device PRID T M

DEVICE

device (Present invention) At least 10% Yes Yes No (Approx. Progesterone in skin Progesterone bloods>2 Yes Yes Yes ng/mL for at least 7 days Initial Progesterone 1.9 1.35 1.55 Final Progesterone (7 days) 1.3 0.8 1.18 Final Progesterone (10 days) 1.18 0.63 0.94 Final/Initial (7 days) 0.68 0.59 0.76 Final/Initial (10 days) 0.62 0.47 0.61 Skin thickness (mm) Variable 1.0 Surface area (cm 2 120 120 220 The device of the present invention (CIDR-B

TM

-12- The device (CIDR-B T M consists of a progesterone impregnated silicone elastomer skin moulded over an inert nylon spine. The active ingredient of the device is micronised USP natural progesterone. Device potency is determined by the percentage of active ingredient present in the inactive silicone elastomer.

The progesterone is mixed into each of two liquid silicone parts prior to the silicone being introduced to the machine for moulding. The progesterone is preferably mixed in at by total weight.

At the moulding stage the two parts of the liquid silicone are pumped under pressure of approximately 100 bar from pails into the injection chambers of an injection moulding machine. Upon injection, the two parts of silicone are simultaneously forced through a static mixer before flowing into an electrically heated mould.

The nylon spine is inserted into the mould prior to the silicone being injected. The mould has a die surface temperature of typically 190' 1950 C, but preferably never exceeding 2000 C. The mould is kept clamped shut under approximately 30 tonnes of 15 static pressure while the silicone cures. At the indicated temperature and pressure, the liquid silicone takes approximately 50 seconds to cure into a rubber.

Following curing, the finished product is removed from the mould and cooled before packaging.

The surface area of the silicone skin is approximately 120 125 cm 2 with the typical formulation for the device being: Outer Skin Nominal Weight Percentage of Percentage of (Impregnated Matrix) (gm) Skin Device Active progesterone USP 1.35 10% 5.1% Inactive silicone elastomer 12.15 90% 45.9%

Claims (11)

1. An intra vaginal device for insertion into a vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, retainable therein over a period of time within a range of from 7 to 12 days and then to be withdrawable therefrom to allow the onset of oestrus, said device comprising or including: a matrix of a cured silicone rubber material including greater than 5% by weight progesterone to a weight of the matrix and defining an exterior surface of at least 75cm 2 contactable upon insertion in the vagina of an animal by biological fluids of the animal, a total progesterone load being from 1 to 1.5 grams within said matrix, said exterior surface being at least substantially all available for progesterone release and said exterior surface having said progesterone load having a thickness of less than 1 millimeter, and said matrix, upon vaginal insertion in an animal, achieving and then maintaining, for at least seven days, a minimum progesterone blood plasma level of 2 nanograms per millilitre of plasma of the animal and after seven days from insertion having a residual load in the matrix of less than 65% by weight of the total progesterone load at insertion.

2. The device of claim 1, wherein said exterior surface is from 100 to 1500 cm 2 oo

3. The device of claim 1, wherein said matrix has about 10% by weight progesterone to the weight of the matrix.

4. The device of claim 1, wherein said matrix, at least in part, encases a deformable frame.

The device of claim 4, wherein said frame is resilient.

6. The device of claim 5, wherein said frame is substantially in a form ofa with the arms of the form being defined by a resilient spine about which at least in part, there S 25 is moulded said matrix.

7. The device of claim 4, wherein said frame is of nylon.

S"8. An intra vaginal device for insertion into a vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, retainable therein over a period of time within a range of from 7 to 12 days and then to be withdrawable therefrom to allow the onset of oestrus, said device comprising or including: a frame having a matrix of a cured silicone rubber material including greater than and less than 20% by weight progesterone to a weight of the matrix, the matrix defining an exterior surface of at least 100 cm 2 contactable upon insertion in the vagina of an animal by biological fluids of the animal, a total progesterone load being from 1 to 1.5 grams within said matrix, said exterior surface being at least substantially all available for progesterone release -14- and said exterior surface having said progesterone load having a thickness of less than 1 millimeter, and said matrix, upon vaginal insertion into an animal, achieving and then maintaining, for at least seven days, a minimum progesterone blood plasma level of 2 nanograms per millilitre of plasma of the animal and after seven days from insertion having a residual load in the matrix of less than 60% by weight of the total progesterone load at insertion.

9. An intra vaginal device for insertion in a vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, and retainable therein over a period of time and then to be withdrawable therefrom to allow the onset of oestrus, said device comprising or including: a matrix of cured silicone rubber material including greater than 5% by weight of progesterone to a weight of the matrix, said matrix having at least one progesterone release surface, said at least one release surface having a total area of at least 75 cm 2 contactable, once inserted in the vagina of an animal, by the biological fluids of the animal, substantially all of the progesterone within the matrix being within about 1 millimeter of said at least one release surface, a total progesterone load being at least 1 gram within said matrix, said matrix, upon vaginal insertion into an animal, achieving and then maintaining in the animal, for at least seven days, a minimum progesterone blood plasma level of 2 nanograms per milliliter of plasma of the animal and if removed after seven days from insertion having a residual progesterone load in the silicone rubber matrix of less than 1 .000.. gram and also less than 65 by weight of the total progesterone load at insertion.

The device of claim 9, wherein the at least one progesterone release surface is greater 25 than 100 cm 2 00o0

11. An intra vaginal device for insertion into a vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, and retainable therein over a period of time and then to be withdrawable therefrom to allow the onset of oestrus, said device comprising or including: a matrix of cured silicone rubber material including greater than 5% by weight of progesterone to weight of the matrix, said matrix having at least one progesterone release surface, said at least one release surface having a total area of at least 75 cm 2 contactable, once inserted in the vagina of an animal, by the biological fluid of the animal, the progesterone, the cured silicone rubber material and said at least one R4 Zgesterone release surface producing a zero-order intra vaginal release rate of progesterone from the matrix, substantially all of the progesterone within the matrix being less than I millimeter from said at least one progesterone release surface, a total progesterone load being at least I gram within said matrix, and said matrix, upon vaginal insertion into an animal, achieving and then maintaining in the animal, for at least seven days, a minimum progesterone blood plasma level of 2 nanograms per milliliter of plasma of the animal and if removed after seven days from insertion having a residual load or progesterone in the silicone rubber matrix of less than I gram and also less than 65% by weight of the progesterone load at insertion. *eve