NZ521404A - Method for maintaining progesterone plasma levels - Google Patents

Abstract

A method for delivering progesterone to a non-human target species is described. The method includes inserting into the mammal an intra-vaginal device capable after insertion of releasing or being caused to release the progesterone. The device allows over an insertion period a release of: - A dose rate of about 70mg/day of progesterone - A delivery rate of about 1.6 mL/day of a progesterone composition - A pump rate of about 0.07 mL/hour of a progesterone composition.

Description

52 K 0 4 Intellectual Property Office of 13 SEP 2002 rfceive^ i / NEW ZEALAND PATENTS ACT, 1953 Divided from NZ520515 itself divided from NZ509689 itself divided from NZ337350 itself divided from NZ314175/314572 Dated: 03 February 1997/10 April 1997/30 January 1998/19 August 1999/2 February 2001/31 July 2002 COMPLETE SPECIFICATION "Active Delivery Device and Related Procedures" We, INTERAG, a duly incorporated New Zealand company of 558 Te Rapa Road, Hamilton, New Zealand,, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to active delivery device and related procedures.

In one aspect the invention relates to active delivery devices locatable in a body cavity of an animal to actively release a substance (eg. useful by intra-vagina insertion of synchronising the oestrus of animals or useful by intra-ruminal insertion of releasing desired agents into a ruminant).

The related procedures include the prospect of optimising a delivery profile for an animal or species of animal utilising the flexibility in active delivery arising from the use of such an active delivery device and thereafter profiling a less active or passive delivery device to delivery to that optimised profile.

When one considers the mating of animals, 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.

The traditional method of mating dairy cows with bulls is now largely superseded by the use of artificial insemination procedures which offers 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 should they comes into oestrus within a designated time.

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 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 livestock improvement publication of this company (1995 edition) made available to interested parties by this company trading as INTERAG™ in respect of its intra vaginal Eazi-Breed™ CIDR® product line.

The disclosures in the aforementioned publication, the full contents of which are here included by way of reference, ensures to date the best procedure applicable at least to New Zealand herds of cattle beasts to ensure a timely conception of a herd without a significant downgrading of the fecundity of the herd.

As used herein the term "synchronise" or the derivatives thereof in respect of the onset of oestrus of an animal is not restricted to exact synchrony but rather relates to a period of time usually measured in days over which the synchrony occurs.

Initial attempts using intra vaginal devices from which progesterone could be leached simply had the effect of preventing oestrus until after they were withdrawn thereby deriving some synchrony in the onset of oestrus thereafter during a period when a heifer or lactating cow is able to cycle this lead to a three day spread in the synchrony after a 12 to 15 day insertion of the intra vaginal progesterone containing device.

Subsequent efforts to confine the period of the synchrony lead to such a progesterone containing intra vaginal device being inserted shortly after, simultaneously with or shortly before the administration (usually intra vaginally) of an oestradiol. For instance the use of a CIDR® intra vaginal device as referred to the aforementioned publication simultaneously with a capsule containing ten milligrams of oestradiol and the retention of the CIDR® intra vaginal device in the animal for ten days led shortly thereafter to a three day synchrony onset of oestrus period.

More recently that last mentioned procedure has been refined for heifers to provide a two day period of synchrony with an 80% of the herd onset of oestrus within the first day. In this refined procedure at about day 6 of the 10 day insertion period a prostaglandin is injected.

The aforementioned procedures are now described in the art as are insemination procedures and the use of substantial repeats of the procedure within the available cycling period referred to so that there is at least one additional prospect of conception by artificial breeding within an appropriate economic window.

With all such procedures however the longer the period of the presence of the progesterone containing intra vaginal device in an animal (where about 15 days is the optimum for tightness of the synchronisation) there is a corresponding diminishment in the fertility of individual animals in the herd owing to the effect over time on the follicle development to the fertilisable egg stage. The use of the oestradiol changes follicle growth pattern. Hence with its use an optimisation of the fecundity prospects for the herd can be achieved by better balancing the tightness of the synchronisation (with longer insertion) against the loss of fertility (with longer insertion).

A cost factor arises in the adoption of such procedures as a farmer is faced with the costs of the intra vaginal progesterone containing device as well as the use of the oestradiol and/or prostaglandin materials additionally used. This ignores also the economic cost of the artificial breeding materials themselves.

The intra vaginal progesterone containing devices hitherto used in New Zealand and to a large extent elsewhere are typified by the CIDR® product of this company depicted hereinafter in Figures 1 and 2 being a variable geometry device for vaginal insertion and retention which comprises a structural frame of a metal or appropriate plastics material (eg. nylon) encased in a progesterone impregnated plastics material (eg. silicone) from which the material can leach in the vaginal environment and from which it can be timely withdrawn by appropriate means (eg; a string, tail or a tool) to allow the animal to progress into oestrous shortly after the removal. Reference should be made to New Zealand Patent Specification No. 207341. Hereinafter the aforementioned device will be referred to by its registered trademark CIDR®.

The prior art CIDR™ devices of this company are intra vaginal passive delivery systems to be used in cattle for the control of oestrus. Two major uses are in the treatment of anoestrus and synchrony. Other uses include its role in embryo transfer and treatment of cystic ovaries.

Another product available in the market place of this kind is another variable geometry device and such a device is depicted hereinafter in Figure 3. Such a device is a helical coil capable of being helically tightened and which is retainable its helical form in the animals vagina. The device includes a withdrawal cord and carries a gelatine capsule which includes oestradiol so that there can be co-administration of the progesterone to be released over a protracted period and the oestradiol 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, WD2 4QE, England under its registered trademark PRID®.

Species specific enhancements to better ensure retention of devices abound. See for instance New Zealand Patent Specification No. 299060 that is relevant to pigs.

The aforementioned CIDR® and PRID® devices are manufactured in large volumes with the most expensive material being the progesterone active ingredient. Thus small reductions in the progesterone inclusion in such the devices will provide an economic advantage to a producer and to a farmer.

The CIDR® prior art device of this company has been marketed with a silicone plastics matrix about its spine which contains about 1.9 grams of progesterone (USP) which drops to 1.25 grams still retained in the silicone matrix if the device is withdrawn after only seven days in order to maximise fertility. The same device drops to 1.00 grams of progesterone if it is not withdrawn until after 15 days which is the optimum time for ensuring maximum synchrony.

The PRID® coil intra vaginal device contains at the outset 1.55 grams of progesterone which reduces down to 0.55 grams after 7 days and down to 0.86 grams after 15 days. The leach rate from the PRID® product may be affected in part by the inclusion of inorganic materials in the silicone plastics material such as calcium carbonate. The CIDR® silicone matrix for the progesterone is largely free of any such inclusions.

Our New Zealand Patent Specification No. 286492 discloses a passive delivery device of the CIDR™ type having advantages insofar as reducing the progesterone content is concerned but without any diminution of the delivery. In this respect please see Figure 4 which is a plot of the plasma progesterone levels for individual ovariectomised cows with this particular intra vaginal passive delivery device (CIDR-B™) against time. While the individual profiles of individual animals varies having regard to the nature of the animal, eg; its vaginal liquids etc. a general trend is evident, viz, a rapid release upon device insertion to rapidly elevate progesterone plasma levels above 2 ng/mL and to maintain a progesterone plasma level above 2 ng/mL until device removal whereupon the progesterone plasma level rapidly drops.

Therefore a programme of passive delivery utilising the CIDR-B™ with a silicone elastomer containing progesterone moulded over a T shape nylon spine and a CIDIROL™ capsule which contains oestradiol benzoate and is administered attached to the CIDR-B™ can act to ensure that a fresh follicle is present from the onset of progesterone delivery by the CIDR-B™ device. The length of insertion of the CIDR-B™ device varies but a period as short as five days can now be used. Within 24 - 48 hours after removal of the device the animal will enter oestrus thereby allowing the predetermined timing of insemination.

Active delivery devices have been used for the delivery of active ingredients into the bodies of mammals (whether for therapeutic purposes with a human or in order to achieve a therapeutic or some other advantageous effect in a non human mammal).

For example, PCT/US89/03705 (published as WO 90/02580) to Brown University Research Foundation discloses an implantable delivery system for biological factors. The disclosure envisages in some instances the use of a preprogrammed micro-processor to control a pumping system responsible, when activated, of actively delivering a desired therapeutic, biologically-active factor, (such as a drug) into the target region into which the implantable device has been inserted.

In September 1996 Plade Holdings Limited launched an active delivery device into the New Zealand market for delivery of active ingredients via the vaginal tract. The device was launched as the SMARTT1™ Intelligent Breeding Device. It included a micro-processor chip programmed to deliver three different active ingredients -progesterone, oestradiol benzoate and clonprostenol sodium at various times and durations during a 12 day treatment program. Reference should be made to PCT/NZ96/00024 (published as WO 96/29025) of Advanced Animal Technology Limited which relates to the SMARTT1™ product at least in part.

In column 2 lines 52 to 26 W090/02580 indicates, as an object, the provision of a compact infusion unit which is controlled by electric current supplied by batteries and regulated by means such as an electronic timer, biomedical control means or microprocessor control.

In the SMARTT1™ device each active ingredient is in a liquid form (dissolved in a suitable organic solvent) and is held in a drug reservoir. Each such reservoir is under positive pressure resulting from a spring acting on a plunger or piston. When a solenoid is activated a closure within the solenoid can be opened allowing the liquid to pass from the pressurised reservoir and through a channel running the length of the overall device to be released from its head. By far the bulk of the device (ignoring the variable geometry retention device aspects) are the controller and the pumping mechanisms which occupy greater than 50% of the volume of the device (circuit board, 2AAA batteries, wire, spring, seal, plunger and solid metal components) thus leaving (owing to vaginal tract insertion and retention considerations) the volume of the drug reservoir being limited to about 5 mL.

The present invention in one aspect recognises the desirability, as an alternative to the passive devices, of an active delivery device and in particular a device useful by way of intra-vaginal insertion of controlling the oestrus of animals. Such a device has the prospect of totally delivering its progesterone content.

US Patent 5,318,557 (Elan Medical Technologies Ltd) discloses "smart" pill constructions for insertion into a body cavity and having gas generating means to expand one chamber whilst by contraction of another expressing a substance via an outlet thereof. An electrolytic cell is disclosed as a preferred gas generator. Its New Zealand equivalent is No. 253782.

US Patent 5,354,264 of Insutech, Inc. discloses a drug delivery device which utilises gas pressure from free oxygen and hydrogen derived from the electrolysis of water at the electrodes in negatively charged polymeric hydogels (E-Gel) in the presence of electro-osmosis. The gas pressure forces the infusion of the drugs through appropriate means into the body with the pressure being dependent on the rate of electrolysis which in turn is controlled by an electric current. This means that the rate of drug delivery can be predetermined and precisely controlled under the action of an electronic timer or a biomedical control system.

The full content of US Patent 5,354,264 is hereby included herein by way of reference.

US Patent 5,354,264 indicates that the system is made possible through the use of a solid water swollen polymeric hydrogel network having negative charges along the polymer back bone or fixed within the polymer network. The system allows electro-conductivity to occur even when using pure water as the electrolyte. Pure water itself does not have electric conductivity compared to the saline solution taught in Gross et al. European Patent Application 03 85915. With the negatively charged polymeric hydrogels of Insutech, Inc. electrical current can be conducted along the negative charges of the polymer backbone. The simple phenomena allows water electrolysis around the electrodes to generate hydrogen and oxygen gas only, free of chlorine or other gases which might be present in the case of saline or other solutions containing electrolyte ions.

Two principals governing the flow of water within the solid hydrogel network and the production of gases at the electrodes are discussed. Example 1 of US Patent 5,354,264 discloses a method of preparation of such a hydrogel.

Reference is also drawn to such transdermal and infusion devices as are disclosed in US Patent 4,969,874 (Disetronic Ag), US Patent 5,090,963 (Product Development (ZGS) Ltd), US 5,527,288 (Elan Medical Technologies Ltd), US 5,062,834 (Product Development (ZGS) Ltd), and US 5,156,591 (S.I. Scientific Innovations Ltd).

In a first aspect the present invention consists in a method of delivering progesterone to a non-human target species mammal, said method comprising or including inserting into the mammal an intravaginal device capable after intravaginal insertion of releasing, or being caused to release, the progesterone and allowing or causing over at least an insertion period a release of one or more of: P/C?gX i) a dose rate of about 70 mg/day of progesterone, -if) a delivery rate of about 1.6 mL/day of a progesterone composition, and p) tfi| a pump note of about 0.07 mL/hour of a progesterone composition.

/Preferably the dose rate is as in (i).

^/Preferably the delivery rate is as in (ii).

/ - X Preferably the pump rate is as in (iii).

The present invention will now be described with reference to the accompanying drawings in which; Figure 1 shows a series of drawings (a) through (e) of a prior art EaziBreed™ CIDR™ product of this company having a progesterone impregnated silicone matrix of an average depth of about 1.5mm but having the depth thereof varying greatly, Figure 1A is an elevation of the "T" 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 "T" form so as to be retained within the vagina of an appropriate animal such as a cattle beast, Figure IB is a section at "FF" of the top arms of the "T" form, Figure 1C is a section at "DD" of the body, Figure ID is a view "CC" of the end of the body showing a slot formed therein from a hole through the body so as to allow the lying therein of a retained withdrawal string or other device, Figure IE is a section of the body at "EE", Intellectual Property Office of NZ 11 MAR 2004 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 l'A shows an elevation of the spine, Figure l'B showing a side elevation of the spine, Figure l'C showing the plan view of the top arms of the device, Figure I'D shows the section at "AA", Figure l'E shows the section at "BB", Figure 2 shows the prior art PRID™ device previously referred to, Figure 2A shows the helical or coil form of the device having an optional capsule affixed thereto as previously stated, the device also showing a withdrawal string, and Figure 2B shows an applicator tool for the device of Figure 3 A, Figure 3 shows a CIDR-B™ form of passive device of this company (NZ Patent Specification No. 286492) having an average progesterone impregnated matrix of about 1mm thick over a spine of a kind shown in Figure 2, Figure 3A shows an elevation of the device of Figure 3.

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 3 A and 3B, Figure 3D shows a section at "JJ", Figure 3E shows a section at "II", Figure 3F shows a section at "KK", Figure 3G shows a section at "GG", and Figure 3H shows a section at "HH" being the hinging region of the arms from the body, Figure 31 is the section "LL" of Figure 3 A, Figure 4 is the plot for the SMARTTi™ IBD, Figure 5 is the plot for the CIDR-B™ device, Figure 6 is a device of the present invention substantially of the CIDR™ configuration having a large single reservoir dischargeable under the movement of a piston (less preferred) and variable geometry means to allow retention (eg; as an intra vaginal device), Figure 7 shows in simple form a device for the release of an eroding matrix prior to the release of a drug or a matrix containing drug, Figure 8 is a device for timed release after delay by the controller, Figure 9 shows a device as in Figure 7 having a large single reservoir embodied in the stem of its general T form on one side and also having if desired an arrangement as depicted in Figure 7 in another part of the stem, Figure 10 as in Figure 9 shows a multiple delivery system version of the device of Figure 7, Figure 10 having the arrangement of Figure 9 on the left hand side but substituting as a secondary delivery system that depicted in Figure 8, its being realised that a device that embodies the delivery system of Figure 6, Figure 7 and Figure 8 can be embodied in a single retention device for a body cavity as can other hybrid versions thereof, Figure 11 is a preferred form of device (albeit not showing any intra-vaginal retention features) which uses a flexible membrane or bladder, Figure 12 is the Figure 11 device in an intra-vaginal device form, Figure 13 shows a device for insertion into the vagina the drug reservoir defined by a bladder in the internal cavity and upon which bladder the gas acts, Figure 14 shows a device for insertion into the vagina similar to that of Figure 13 except that a conduit or tube from or which defines the outlet orifice extends back into the drug reservoir, Figure 15 shows a device for insertion into the vagina, a rapid release mechanism being located within the arm of a retention wing preferably a breakable seal, Figure 16 is a similar device to that of Figure 6 except it embodies the preferred use of a bladder as the means by which the drug reservoir is to be reduced in volume under the action of the generated gas, Figure 17 shows the dip tube arrangement (e.g. as in Figure 14) but in a device as in Figure 16 Figure 18 is a preferred form of a device for single drug delivery also having a dip tube arrangement, the sequence of Figures 18A to 18D showing the mode of dispensing via the dip tube under the gas induced collapse of a latex bladder, Figure 19 is a plot for the device of Figure 18A showing in vitro release rate of the device for two different currents to the gas generating hydrogel, Figure 20 shows for a device of Figure 18A plasma progesterone levels (one with and one without a gas and control production unit) against the performance of a CIDR-B™ device of applicant, Figure 21 shows the effect of the dip tube arrangement in a device such as in Figure 18A when there is no gas production and control unit thereby demonstrating vehicle retention/leakage in vivo, Figures 22A and 22B show a resistor controlled circuits for providing current to the hydrogel electrodes, Figure 23 is a plot showing for a hydrogel (E-gel) [upper plot] and aqueous NaCl [lower plot] plots of percent initial current as a function of time, and Figures 24A and 24B show two forms of sealing arrangement for the outlet of a device as in Figure 18.

PRIOR ART The prior art SMARTT7™ IBD is supplied packaged within a two part application container. Each part is manufactured from polypropylene plastic. The inner part is 89 mm in length, 39 mm (o.d.), 37 mm (i.d.) In diameter, and 1 mm in thickness. It has a hole in its base 26 mm in diameter through which the device and tail can protrude. The outer part is 120 mm in length, 1 mm in thickness and 41 mm (o.d.), 39 mm (i.d.) In diameter. It tapers to a rounded shape at its top end. Groves are cut into the tapered round end allowing this part to flex open allowing the device to pass through it upon administration. Also attached to the outer part of the applicator container are hinged wings which rest against the device in the folded position. These wings are each 30 mm in length and designed to be opened, and rest upon the lips of the vulva, upon administration of the device. The SMARTT7™ IBD device fits snugly into the inner part of the application container which in turn fits snugly into the outer sheath of the device. Thus the application container affords protection of the SMARTT7™ IBD device on storage and handling and also holds the retention wings in a folded position during storage.

The SMARTT7™ IBD device itself comprises (i) an outer plastic sheath designed to protect the inner compartment and delicate electronics and (ii) the inner compartment which contains an electronic chip and board, has four drug reservoirs (one at the base of the device and three sited at the head of the device), engages a retention mechanism and has a tail.

The outer sheath is made of plastic (high density polyethylene) and is 131 mm in length and has a diameter of 25 mm at its upper opening. The outer sheath tapers about midway along its longitudinal length to a diameter of 20 mm. The bottom of the sheath has 5 mm diameter hole to allow the tail to pass through. The tail of plastic (high density polyethylene) and extends 226 mm behind the device and is 2 mm in diameter and appears relatively inflexible. At the terminal end of the tail is a flattened portion 22 mm in length, 5 mm wide and 2 mm deep. Integrated into the moulding of the tail at its top end is a round plug containing grips. This plus is designed to fit tightly into the base of the device and the grips are designed to prevent it falling out. This mechanism fixes the tail to the device and prevents it from loss during storage, when activated and during removal from the animal.

The retention mechanism comprises eight fixed prongs made from Hytrel evolving from a central circle each at an angle of 40°. Each prong is 51 mm in length and 2mm deep by 3.5 mm wide. At the terminal end of each prong is a circular protective ball 6 mm in diameter. This ball affords protection to the delicate vaginal mucosa during the insertion and retention of the device during the treatment period. The retention mechanism is located at the head of the device.

The inner compartment contains a "large" drug reservoir that runs approximately half the length of the device. At the top end of the reservoir is a small orifice which is opened and closed by a switch mechanism which is operated by a solenoid. In the closed position the switch is designed to prevent drug solution from leaving the drug reservoir. In the open position drug solution is allowed to freely flow through a small orifice which leads to a small bore stainless steel opening (absolute diameter unknown but <0.45 mm i.d.). To the exterior at the flat face of the head of the device. This large drug reservoir is circular in shape, 18 mm in diameter and 22 mm in length. It has a capacity to hold a total volume of 5 mL of distilled water. The solution is prevented from escaping from the bottom of the device by a tight fitting SANTOPRENE rubber seal. Between the rubber seal and the bottom of the device is a movable plunger and spring which is 80 mm in length when uncoiled and of unknown tension. The device has been designed to allow the organic solution to be released from this large drug reservoir over a 10 day period.

Three other drug reservoirs are in the device (the "small reservoirs"). The reservoirs are located at the head of the device. They are sited equidistant around the flat face of the head of the device and are each of equivalent shape and size being ovoid in shape, 7.5 mm wide and 5 mm across and 16 mm in depth (with the rubber seal in place; 19 mm with the seal removed). Each of these drug reservoirs has the capacity to hold a total volume of 0.45 mL of distilled water (with the rubber seal in place). Drug solutions are prevented from leaking from the small reservoirs during storage and while in the animal by tight fitting rubber SANTOPRENE rubber) seals located at the head of the device (Figure 8). Only two of the small drug reservoirs are utilised and contain drug solutions in the SMARTTi™ IBD device.

The remainder of the device comprises a circuit board and 2 batteries (Type AAA) lying parallel with and under to the left and right of the circuit board. The circuit board contains components primarily consisting of a controlling chip, a power-on indicating LED and a quartz timer.

A plastic tag of variable length and 8 mm width is inserted between the positive end of the left AAA battery and the battery terminal of the device. It is of sufficient length to protrude beyond the head of the device. Removal of this tag activates the device. The circuit board and the battery terminals are coated in a generous layer of silicone grease to prevent moisture coming into contact with the electronic componentry of the device.

To operate the device in the field the device must first be removed from the applicator container in order to turn it on. In addition, to achieve activation of the device, the device itself must be dismantled. This entails partial removal of the outer sheath to enable removal of the plastic strip. After re-assembly of the outer plastic sheath onto the inner compartment and locking it over the retaining clamps, the device is then re-inserted into the applicator container and loaded onto the applicator gun. The rounded end of the applicator container is then lightly lubricated and pushed approximately 30 mm inside the vagina until the wings of the application container lie flush with the lips of the vulva. Pressure is then applied to the device by pushing the applicator gun. This results in the device being inserted into the anterior vaginal close to the cervix. To remove the device at the end of the treatment period the protruding tail is pulled gently but firmly until the device is removed.

Table 3. Summary of the three drug reservoir vehicles Reservoir Vehicle odour Vehicle colour Active agent as stated by Plade Holdings Large Benzaldehyde Straw Progesterone Small reservoir 1 Alcoholic Clear Oestradiol benzoate Small reservoir 2 Aniseed Clear Cloprostenoi sodium Small reservoir 3 Empty Empty Empty Mechanism of oestradiol benzoate and cloprostenoi sodium release from the SMARTTi™ IBD The contents of the small reservoirs are found to be released by the following mechanism. The reservoirs contain a spring loaded plunger which is pulled back and held in the loaded position. This is achieved by locking it in place by a retaining cord which rests over a resistor located on the electronic board. The resistor located under the cord retaining the plunger is activated at a pre-programmed time under the control of the circuit board chip. Upon activation the resistor heats up and the cord burns through and severs. The plunger is therefore no longer under tension and the contents of the reservoir are violently expelled by the sudden relaxing of the spring pushing against the plunger.

Mechanism of progesterone release from the SMARTT7™ IBD The mechanism of release of the progesterone containing vehicle relies upon (i) a large spring located at the base of the device which forces a moveable plunger through the reservoir, (ii) a small orifice and (iii) a solenoid. Progesterone containing vehicle is released through a small orifice which leads to a length of small bore tubing which opens at the head of the device. The opening and closing of the orifice controls how much vehicle is released and this in turn is controlled by a solenoid which opens and closes the small orifice. When the solenoid is activated the closure pulls back against the force of a small spring and opens the orifice that leads to the small bore tubing. The frequency of opening and closing of the orifice follows a pre-defined program which is controlled by the micro chip. When the solenoid is activated the orifice opens during which time the progesterone containing vehicle is allowed to travel through the orifice, up the small bore tubing and out of the opening at the head of the device. When the solenoid is turned off a small spring pushes forward and seals the opening and no progesterone release occurs.

Plasma levels of progesterone following 12 day insertion of the SMARTT7™ IBD device The plasma progesterone levels for six ovariectomised cows with SMARTT7™ IBD inserted for 12 days are shown in Figure 5. The profiles for each device typically show an initial rise in plasma progesterone levels immediately following insertion (the magnitude of which shows considerable variation between animals), decreasing to concentrations close to basal levels on about day 4. Plasma levels then remain at this low level until device removal.

Deliveries from Small Reservoirs of the SMARTT7™ IBD device In vitro trialing showed reliable release at preprogrammed times. Reliability in vivo inconclusive owing to unreliability of the progesterone deliveries and their effects on the recipient animals.

THE PRESENT INVENTION The pump system of the present invention occupying less space could replace much of the pumping mechanism of the SMARTT7™ eg. plunger, spring and solenoid, and thereby can increase the drug reservoir to 60 mL or more.

The following table (Table 4) outlines parameters in respect of the progesterone delivery aspects, a preferred device of the present invention preferably operates at: TABLE 4 Parameter Value dose rate (mg/day) 70 period (days) total volume (mL) 8 delivery rate (mL/day) 1.6 pump rate (mL/hr) 0.07 The CIDR-B™ delivers progesterone at a rate of approximately 70 mg/day. A device of the present invention is believed to achieve the following delivery rates (Table 5).

TABLE 5 Infusion (70 mg/day) Delivery rate (mL/hr) i.v. emulsion (0.67 mg/mL) ~5 i.vag. Emulsion (0.67 mg/mL) ~5 i.vag alcoholic solution (0.1 mg/mL) -30 i.vag aqueous solution (0.01 mg/mL) -300 It has been suggested that the device could be provided with reservoirs used for the pulsile delivery of drugs, immediately on and/or a number of days after administration.

The present invention is depicted in a number of different embodiments in Figures 6 through 16.

In these drawings the reference numerals denote the following; (1) drug reservoir chamber, (2) outlet (preferably simply a small opening or alternatively a one way valved opening or an opening from which a cover has been removed prior to initiation) (3) stopper, plunger, piston or the like (could be a membrane in some forms), (4) a gel of the kind previously described, (5) a controller device embodying the appropriate logic circuit (analogue or microprocessor) preferably having source of power, (eg; one or more batteries) and providing appropriate energisation as required to the electrodes, (6) the electrodes, (7) a switch preferably capable of being activated simply to initiate the device prior to insertion, (8) is a matrix containing drug (preferably liquid but not necessarily so), (9) a matrix not containing the drug, (10) a seal capable of being disrupted by movement of the piston, plunger or the like 4 under the action of the gel 5, (11) drug reservoir bladder.

Figure 6 shows a device for insertion into the vagina with an outlet orifice 2 for the expulsion of vehicle from a reservoir 1 formed by an internal cavity in the body of the device, with a plunger 3 positioned in the reservoir, behind which is an electrolytic cell 4 for the production of gas to activate the plunger, with electrodes 5 inserted into the electrolytic cell, the production of gas being controlled and powered by the electronic control and power supply unit 6 which is activated by a switch 7.

Figure 7 shows a device for the rapid release of a pharmaceutical formulation retained behind a breakable seal 16.

Figure 9 shows the positioning of a rapid release device of Figure 7 within a device for insertion into the vagina, the other release device/devices being (e.g.) as in Figure 6.

Figure 11 shows a simple bladder or membrane (broken line) 11 capable without any jamming prospect of dispensing a liquid through outlet 12 under the action of the E-Gel and electrode generated gases within the housing 13. The E-Gel 14 electrodes are powered and controlled from sealed control chamber 15.

The Figure 11 design responds to very low rates of gas production. Piston including devices have required greater pressures to function.

Figure 12 is a device of Figure 11 in an intra-vaginal device form.

Figure 13 shows a device for insertion into the vagina with the drug reservoir defined by a bladder in the internal cavity and upon which bladder 11 gas activates.

Figure 14 shows a device for insertion into the vagina with the outlet orifice being defined by or being at the upper end of a dip tube (conduit or the like) 17. This tube will have some effect on feed out rate as the gas is generated and, if sufficiently strong, will favour radial collapse of the bladder 11 about the tube 17.

Figure 15 shows a device for insertion into the vagina with a rapid release mechanism located within the arm of the wing of retention means preferably behind a breakable seal 18.

Figure 16 is the preferred bladder form of the device of Figure 6, the bladder being 11.

Figure 17 is the dip tube (17) variant of the device of Figure 16.

Figure 18 shows a preferred form of the device where a single vehicle is to be released via a dip tube 17 whilst being retained in the vagina by variable geometry wing or the equivalent 18, the device being of a kind having a collapsible latex bladder 19.

Preferred dimensions of the Figure 18 device are: • length of body - from 50 to 250 mm, preferably 150 mm. • length of wings - from 40 to 250 mm, preferably 150 mm. • diameter of body - from 5 to 60 mm, preferably 25 mm. • material of body - a rigid material such as rigid PVC tubing. • materials of wings - a rigid material such as PVC, or a material with a degree of softness such as silicone rubber.

Preferred hydrogel material and volume for a device of Figure 18 are: • volume - from 0.1 to 50 mL, preferably 1 mL. • material - a polymer or combination of polymers possessing gelling abilities and negatively charged groups, preferably agarose (obtainable from Sigma Chemical Co, USA - Product code A-6013) and dextran sulfate (obtainable from Sigma Chemical Co. USA - Product code D-4911).

Figures 18A through 18D shows the collapse sequence customarily expected from a device of this kind.

Figure 19 shows the in vitro release rate of a liquid vehicle from a device as shown in Figure 18 using two different currents and thus rates of gas production. In the plot of cumulative volume released (millilitres) against time (days) a lower current of 250 mA is shown below an upper line for a current of 500 mA.

The rate of gas produced during electrolysis in an electrolytic cell is proportional to the applied current. Therefore a constant current is required to achieve a constant and controlled rate of gas production. Figure 23 displays the current observed through two types of electrolytic cell (using a circuit as per Figure 22A) over a period of 7 days. The current through an electrolytic cell containing the hydrogel was observed to be constant, varying by less than 6% of the initial (t=0) current, suggesting a controlled rate of gas production. However current through an electrolytic cell containing saline (NaCl) was observed to steadily decline over the observation period by 14% of the initial (t=0) current, suggesting a decreasing and thus uncontrolled rate of gas production.

Figure 20 shows on a plot of progesterone plasma levels (mg/mL) against time after insertion of the device in days. The line "A" is of a device as shown in Figure 18 without a gas production and control unit. The lines "B" and "C" are two plots of the performance of a device as shown in Figure 18 each with a gas production and control unit. By way of comparison the line "D" shows the performance of a conventional CIDR-B™ device of this company.

Intra vaginal delivery devices of the type shown in Figure 18 that do not possess a dip tube passively release vehicle contained in the bladder at such a rate that after a 7 day insertion period in the vagina of cattle approximately 80% of the initial volume of vehicle is released. This has implications on the ability to control the release of vehicle by controlling the rate of gas production (ie; current) and therefore the flow rate of vehicle. Devices that do not possess a dip tube can not delivery vehicle in vivo at the same rate observed in vitro (see Table 6). Therefore passive leakage should be kept to a minimum in order to differentiate between selected currents and therefore flow rate of vehicle. Acceptable minimum passive release is less than 20% of the initial volume of vehicle over any insertion period.

TABLE 6 In vitro release rate (mL) Current (mA) In vivo release of vehicle after a 7 day insertion period (mL) Initial Final Initial Final Release 1 2.1 11.7 ± 1.6 2 0.0 14.7 ±0.7 0.25 0.24 ±0.01 13.5 ±0.7 1.8± 0.50 0.53 ±0.02 14.8 ±0.8 0.1± Figure 21 shows the effect of a dip tube arrangement upon the in vivo retention of vehicle when there is no gas production and control unit. If no dip tube arrangement is present as depicted by the lower end approximately 80% of the vehicle is lost in vivo due to passive leaking from the delivery orifice. This is to be compared with the upper line which shows the same apparatus but with a dip tube arrangement as shown in Figure 18A present. In this instance only about 30 - 40% of the vehicle is lost owing to passive leaking.

Figures 22 A and 22B show a simple circuit to the electrodes of the hydrogel H, the circuits have in each instance a battery B (of any suitable kind) and a fixed resistor R or a variable resistor VR.

Figures 24A and 24B show preferred methods of sealing the delivery outlet of devices of the type shown in Figure 18. Figure 24A shows a plug "P" that is inserted into the delivery outlet and is designed such that a closed fitting seal is created. A tag or suitable means can also incorporated for removal of the plug. Figure 24B shows a tag or film T that is placed over the delivery outlet, the film may be retained by means of a suitable adhesive. Removal of the tag is achieved when the overlapping edges of the tag are pulled away from the delivery outlet immediately prior to intra vaginal insertion.

A feature of the present invention is the simplicity of each delivery aspect within the retention body and the prospect to improve the volume available from which active ingredient can be expressed. With the preferred embodiments the simplicity of the arrangements within the retention device ensures the prospect of locating the liquid sensitive components at an end of the device away from the liquids to be dispensed unlike the prior art devices discussed.

The active substances are released from the syringe type variable volume reservoir under the action of the gases generated from the gel under the energisation from the controller. The overall arrangement is such that the pump aspect itself (the gel and its energising controller) contains no moving parts.

The pump aspect is able to act upon the piston plunger or the like of the syringe type dispenser in a continuous manner thereby ensuring constant non pulsile release of drug from the outlet of the device. As a consequence it is possible to achieve a constant plasma concentration of drug. If the action of the pump where non constant, (ie; on and off periods of action and inactivity) the on/off nature would result in a non constant plasma concentration profile.

By using an inert matrix that sloughs off under the normal mechanical actions (see Figure 7) the drug matrix would not be available to exert an effect until the inert matrix slug has been expelled.

Also the variant of Figure 8 includes a delay timing mechanism reliant on the controller ie; would force seal 10 open as required.

The present invention therefore by avoiding an on/off dispensing can in preferred embodiments provide the optimum plasma profiling and much greater reliability owing to less likelihood of plunger or piston jamming. As a result of the simplicity of the layout within the device which allows a better isolation of the sensitive controller components from the environment.

The continuous uninterrupted pumping ability of the devices of the present invention and the simplicity of construction is believed will find favour with farmers.

The devices of the present invention can also be programmed to investigate optimum blood serum levels (eg; progesterone et al) relevant (eg; to synchronisation) and that data then be used either to program devices for general sale or to be used with a view to matching passive devices to that desired outcome.

We make no claim to matter that is claimed in claims as are granted on our New Zealand Patent Application 314175/314572.

Claims (4)

WHAT WE CLAIM IS:

1. A method of delivering progesterone to a non-human target species mammal, said method comprising or including inserting into the mammal an intravaginal device capable after intravaginal insertion of releasing, or being caused to release, the progesterone and allowing or causing over at least an insertion period a release of: i) a dose rate of about 70 mg/day of progesterone, ii) a delivery rate of about 1.6 mL/day of a progesterone composition, and/or iii) a pump rate of about 0.07 mL/hour of a progesterone composition.

2. A method of claim 1 wherein the dose rate is as in (i).

3. A method as claimed in claim 1 or 2 wherein the delivery rate is as in (ii).

4. A method as claimed in any one of the preceding claims wherein the pump rate is as in (iii). DATED THIS / ^ DAJT OF June 2-C?oq AJ PARK n n , PER AGENTS FOR THE APPLICANT END OF CLAIMS ""SWar' ^ s JUN 2004 RECEIVED