Our PCT/NZ97/00052 (published as WO 97/40776) discloses a variety of different forms of intra vaginal devices of a variable geometry type for retention within the intra vaginal cavity of an animal. Such devices hitherto have primarily involved the use of a silicone rubber composition which as a matrix has been impregnated with an active pharmaceutical agent (eg progesterone). In the variable geometry type devices typified by the CIDRTM devices of this company the impregnated matrix has primarily been supported on a spine of a resilient material such as nylon, the resilience of which is utilised for the variable geometry retention characteristics notwithstanding that such spine is usually fully overlaid with the impregnated matrix.

BACKGROUND ART Various polymers have been used to deliver pharmaceutical agents, one such class of polymers extensively utilised for the delivery of pharmaceutical agents are the polyesters. Examples of these polymers include poly lactic acid, poly glycolic acid, poly (e-caprolactone) and various co-polymers of lactide, glycolide and e-caprolactone.

Pharmaceutical products utilising these polymers are typically formulated as microspheres, microcapsules, films, rods or blocks. Retention within a body cavity has been achieved by a number of methods, eg: the addition of dense fillers, injection or surgical implantation into muscle or subcutaneous areas.

Various agents may be employed to enhance the absorption of agents across mucosal membranes and into the blood circulatory system. One such class of agents extensively utilised for the enhanced absorption of agents are the cyclodextrins.

Examples of the cyclodextrins include a-cyclodextrin, p-cyclodextrin, y-cyclodextrin and hydroxypropyl P-cyclodextrin.

Devices utilising these absorption enhancing agents are typically formulated as microspheres, microcapsules, tablets or liquids.

It is an object of the present invention to provide intra vaginal devices having the

prospect of allowing for a given device size or loading an enhanced systemic uptake of an active ingredient or at least provide the public with a useful choice.

DISCLOSURE OF THE INVENTION The present invention preferably relates to a device designed to deliver progesterone over an extended period of time (2 to 20 days) upon insertion into the vagina of mammals, eg: cattle, sheep, horses, pigs, goats, buffalo or deer. The device is preferably retained within the vagina preferably by means of a flexible geometric arrangement of arms with respect to a body portion.

Accordingly in a first aspect the present invention consists in a device for insertion into the vagina of a mammal, said device consisting of a matrix (preferably mouldable, eg: a polymer) containing both a cyclodextrin and an intra vaginally effective active ingredient.

As used herein, the term"intra vaginally effective active agent"means any compound or composition or complex that by means of delivery into the vaginal cavity of a mammal can be absorbed systemically by the mammal therefrom so as to achieve or suppress some physiological effect. Examples include progesterone (eg: for oestrus synchronisation and other purposes), and oxytocin (eg: for milk let down).

As used herein, the term"cyclodextrin"includes any suitable cyclodextrin or mixtures thereof.

As used herein, the term"polymer"in respect of carrying matrix of the cyclodextrin and intra vaginally effective active agent includes any suitable polymer and need not be restricted to the preferred polymers hereinafter discussed.

In a second aspect the invention consists in an intra vaginal device having at least for a target species of appropriate size a form insertable and retainable in the vaginal tract, said device at least in part having a moulded matrix which includes both a cyclodextrin and an intra vaginally effective active agent.

Preferably said matrix is at least in part (and preferably primarily) of a polymer or a mixture thereof.

Preferably the polymer is poly (e-caprolactone).

As an alternative the polymer is a starch-like polysaccharide.

In other forms the polymer may be a blend of the options and/or a blend with

another polymer.

Preferably the cyclodextrin (s) comprise from 5 to 70% W/w Preferably the active agent (s) comprise from 5 to 70% W/w Preferably the agent is progesterone in the concentration of 5 to 70% W/w Preferably the absorption enhancing agent is hydroxypropyl P-cyclodextrin in the concentration of 5 to 70%"'/W.

Preferably the device is of such geometry (eg; preferably of variable geometry) to facilitate retention in the vagina.

Preferably the agent does not appear as a fine powder or crystals upon the surface of the device.

In another aspect the present invention is an intra vaginal device or insert for a target mammal species comprising or including an intra vaginally insertable, retainable and removable mass of at least primarily one or both of poly (e-caprolactone) and a mouldable biodegradable starch-like polysaccharide, the mass by virtue of its resilience being of variable geometry which allows the intra vaginal insertion, retention and removal, wherein said mass includes therein sufficient progesterone therein such that for a target species a blood serum level of progesterone of greater than 2"g/m, for a period of at least 5 days can follow intra vaginal insertion thereof and wherein after removal the mass is biodegradable after removal from the animal.

Preferably said target species is selected from cattle, sheep, horses, pigs, goats, buffalo and deer.

Preferably said device or insert includes no supporting spine (eg; nylon or polyester).

Preferably the progesterone inclusion is sufficient to deliver progesterone for a period from 2 to 20 days.

Optionally said mass may include cyclodextrin.

In a further aspect the present invention consists in the use or methods of use of such a device or any device of the present invention.

The present invention also consists in a method of manufacture of an intra vaginal device which results in any device in accordance with the present invention.

In a further aspect the invention consists in a method of manufacture of an intra vaginal device which comprises the step of including in a mouldable matrix forming material or polymer composition both a cyclodextrin and an intra vaginally effective agent.

Preferably said active agent is a particulate solid.

Preferably the cyclodextrin (s) comprise from 5 to 70% W/w Preferably the active agent (s) comprise from 5 to 70% W/wv Preferably said cyclodextrin is a particulate solid.

Preferably said active agent and cyclodextrin are pre-mixed prior to association with the mouldable material or polymer composition.

Preferably any one or more of the material/polymer, active agent and cyclodextrin (and preferably the form and/or proportions thereof) are as herein defined.

In another aspect the invention consists in the use inter alia for animal group oestrus synchrony purposes of devices of the present invention.

Preferably said use is intra vaginal use for a period of from 2 to 20 days and said device has a capability in the target species mammal of providing for at least 5 days (if intra vaginally inserted for at least about 5 days) a blood serum level of progesterone of greater than 2ng/m,.

Preferably all polymer (s) of the said mass (if all, as is preferred, is to be moulded) can be moulded without use of conditions prejudicial to the pharmaceutical agent and any cyclodextrin (or for that matter, any other absorption enhancing agent) present.

The addition of particulate material such as progesterone to silicone in amounts <BR> <BR> <BR> <BR> greater than 20%"/,. has been found to be detrimental to the structural integrity of the intra vaginal inserts. Silicone based intra vaginal inserts must include a spine of a material such as Nylon or stainless steel, over which the silicone is moulded, to maintain a configuration conducive to vaginal retention. The addition of large amounts of particulate material has been found to reduce the strength of the silicone such that the spine may rupture and protrude through the other silicone laminate.

The invention also consists in a method of achieving with an animal (or group of animals) a blood serum level of greater than 2"g/m, for a period of at least 5 days

of progesterone, said method comprising inserting and retaining in the vagina of each animal for at least the 5 day period a device of any of the kinds of the present invention.

Preferably said device has a loading of from 0.1 to 4 gms of progesterone for the target animals such as cattle, sheep, goats, deer, etc.

Preferably said device has an impregnated matrix surface of from 15 to 200 cm2.

The present invention also consists in a method of manufacture of an intra vaginal device which results in a device in accordance with the present invention, and/or vice versa.

DETAILED DESCRIPTION OF THE INVENTION Preferred forms of the present invention will now be described with reference to Figures 1 to 13 in which; Figure 1 shows a device of variable geometry (the geometry being variable much in the way as discussed in WO 97/40776) but without a need for a spine of a dissimilar material although if desired that can optionally be present, Figure 2 shows in vitro progesterone release, Figure 3 shows plasma progesterone concentration against time, Figure 4 shows mass lost, Figure 5 shows tensile performance, Figure 6 shows for silicone plasma progesterone concentration against time, Figure 7 shows mass loss for poly (e-caprolactone) formulations, Figure 8 shows plasma progesterone concentration against time, Figure 9 shows plasma progesterone concentration against time, Figure 10 shows plasma progesterone concentration against time, Figure 11 shows plasma progesterone concentration against time, Figure 12 shows plasma progesterone concentration against time, and Figure 13 shows plasma progesterone concentration against time.

The present invention relates to the discovery that polymers typified by poly (e- caprolactone) or a starch like saccharide can be appropriately impregnated with an intra vaginally effective active agent such as progesterone (eg: in concentration of from 5% to 70% w/w) and an absorption enhancing agent such as hydroxypropyl ß-cyclodextrin (eg: in concentrations of from 5% to 70% w/w) so as to provide appropriate release

characteristics for the active agent over the period of intra vaginal retention.

Whilst conventional silicone type polymers may be used they are not normally considered biodegradable in a pasture environment as is, eg; poly (£-caprolactone).

Nevertheless, for the reasons mentioned previously, (ie; including the structural integrity of the silicone where high levels of particulate material are included) other polymers including poly (e-caprolactone) and starch-like polysaccharides are preferred.

In the device of Figure 1 the preferred device is wholly of the impregnated matrix which is poly (g-caprolactone) impregnated with hydroxypropyl p-cyclodextrin in the concentration of 5 to 70% w/w.

In Figure 1 the wings 1 are resilient with respect to the body 2 and in an injection mode can be reduced to a form or assume a position in an applicator in a known manner which facilitates insertion after which the resilience deploys the wings 1 to such condition as is required for retention. The resilience can be subsequently utilised to withdraw the device from within the vagina.

A suitable source of poly (e-caprolactone) is that product TONE P-767TM available from Union Carbide Specialty Polymers and Products, Danbury, Ct, USA.

Starch-like polysaccharides that can likewise be impregnated and can be used for some or all of the device include MATER-Bi available from Novamont, Italy.

A suitable source of hydroxypropyl p-cyclodextrin is that product BETA W7 HP available from Wacker Chemicals Australia, Victoria, Australia.

A preferred method of manufacture of the device is as follows: Polymer (poly (£-caprolactone), starch-like polysaccharide or a blend of the two) are mixed with active and absorption agent into a mixing vat. The polymer/active/absorption agent mixture is then loaded into the hopper of an injection moulding machine; and processed as a conventional thermoplastic, with machine set point parameters as per technical recommendations of the polymers suppliers literature, and as per injection moulding standard practice. Key processing points are: barrel temperatures ranging from 60- 250°C with an injection pressure of 1600 bar. Total cycle time due and allowed to cool to equilibrium prior to packaging.

Figure 2 shows an in vitro cumulative progesterone release against the square- root-of-time (inserts manufactured from poly (e-caprolactone) (thin line) or silicone

(thick line)).

Figure 3 shows an average plasma progesterone concentration against time following two rounds of vaginal treatment with a silicone insert of 134 cm1 surface area (#) or a poly (e-caprolactone) insert of 105 cm2 surface area (E), both of which contain 10%'/w progesterone (error bars are standard error means (n-12 for silicone inserts, n=9 for poly (E-caprolactone) inserts)), Figure 4 shows a percentage of initial mass lost for drug-loaded (N) and blank (#) poly (£-caprolactone) inserts stored in compost over time (the solid line is the suggested mass loss as per promotional literature supplied by the poly (£-caprolactone) manufacturer (error bars are ranges (n=2)), Figure 5 shows a percentage of tensile performance lost for drug-loaded (M) and blank (Q) poly (£-caprolactone) inserts buried in compost over time (the solid line is the suggested tensile performance loss as per promotional literature supplied by the manufacturer. (Error bars are ranges (n=2)), Figure 6 shows plasma progesterone concentration against time following <BR> <BR> <BR> <BR> vaginal treatment for 7 days with a silicone insert of 134 cm2 surface area (N), poly (e- caprolactone) insert of 115 cm2 surface area (#) or poly (£-caprolactone) with lactose insert of 115 cm2 surface area (o) (A final plasma sample was collected 6 hours after removal on day 7. (Error bars are standard error means (n=3)), Figure 7 shows the percentage of initial mass lost for various poly (£- caprolactone) formulations stored in compost over time [Poly (E-caprolactone) (+), poly (£-caprolactone) with 10% W/W progesterone (w), poly (E-caprolactone) with 12.1% W/W lactose and 10. 47% w/w progesterone (A), poly (£-caprolactone) with 37. 2% w/w ß- cyclodextrin and 10.3% W/W progesterone (x), poly (£-caprolactone) with 43. 8% w/w hydroxypropyl (3-cyclodextrin and 10% W/W progesterone (*) or poly (£-caprolactone) with 39. 9% w/w y-cyclodextrin and 9. 7% w/w progesterone (#). (Error bars are ranges (n=2))], Figure 8 shows plasma progesterone concentration against time following vaginal treatment for 7 days with a Mater-Bi insert of 58 cm2 surface area with (N) or without (w) the addition of 20% w/w NaCl. (Error bars are ranges (n=2)), Figure 9 shows plasma progesterone concentration against time following

vaginal treatment for 7 days with various inserts; CIDR cattle insert (), poly (s- caprolactone) with 10 %w/w progesterone (+), poly (E-caprolactone) with 12.1 %w/w lactose and 10.47 %w/w progesterone (w), poly (s-caprolactone) with 37.2 %w/w ß- cyclodextrin and 10.3 %w/w progesterone (A), poly (s-caprolactone) with 43.8 %w/w hydroxypropyl ß-cyclodextrin and 10 %w/w progesterone (O) or poly (E-caprolactone) with 39.9 %w/w y-cyclodextrin and 9.7 % W/w progesterone (x), Figure 10 shows plasma progesterone concentration against time following vaginal treatment for 7 days with various inserts; poly (E-caprolactone) with 44 %w/w hydroxypropyl P-cyclodextrin and 10 %w/w progesterone (D), poly (E-caprolactone) with <BR> <BR> <BR> <BR> <BR> 22 %w/w hydroxypropyl ß-cyclodextrin and 10 %w/w progesterone (A), poly (s- caprolactone) with 22 %w/w hydroxypropyl ß-cyclodextrin and 10 %w/w progesterone and 22 % W/W lactose (+), poly (#-caprolactone) with 11 % w/,, hydroxypropyl ß- cyclodextrin and 10 and33%w/wlactose(#),progesterone Figure 11 shows plasma progesterone concentration against time following vaginal treatment for 7 days with various inserts; poly (s-caprolactone) with 5 %w/w hydroxypropyl P-cyclodextrin and 5 %w/w progesterone and 30 %w/w lactose (R), poly (s-caprolactone) with 20 %w/w hydroxypropyl ß-cyclodextrin and 10 %"'/W progesterone and 30 %w/w lactose (A), poly (s-caprolactone) with 10 %w/w hydroxypropyl ß- cyclodextrin and 10 %w/w progesterone and 40 %w/w lactose (), poly (s-caprolactone) with 10 ß-cyclodextrinand5%w/wprogesteroneand35%w/whydroxypropyl lactose(#), Figure 12 shows plasma progesterone concentration against time following <BR> <BR> <BR> <BR> <BR> vaginal treatment for 7 days with various inserts; CIDR cattle insert (w), poly (s- caprolactone) with 10 %w/w hydroxypropyl ß-cyclodextrin and 10 % w/w progesterone and 50 % @ poly ethylene oxide (#), Mater-Bi with 40 %w/w y-cyclodextrin and 10 %w/w progesterone (1), and Figure 13 shows plasma progesterone concentration against time following vaginal treatment for 15 days with a poly (E-caprolactone) with 20 %w/w hydroxypropyl P-cyclodextrin and 10 %w/w progesterone and 30 % lactose (A).

The choice of a resilient mouldable or shapable"polymer"which is biodegradable is such that degradation of the impregnated matrix (but with a low residual active ingredient loading) will occur over time after removal from the animal after having served its purpose during an intra vaginal insertion of preferably from 2 to 20 days (eg; about 7 days). Minimal degradation (if any) occurs during the period of insertion.

In the device of Figure 1 the device is wholly of the impregnated matrix which is poly (e-caprolactone) impregnated with progesterone in the concentration of 5 to 70% w/w without any solid active pharmaceutical agent appearing as a fine powder or crystals on the surface of the device.

Preferably the performance of the device while inserted and its effect upon withdrawal is substantially as discussed in WO 97/40776 but with the advantages of (i) biodegradability after removal from the animal and (ii) the preferred omission of a spine of resilient material.

The preferred biodegradable polymers (typified by poly (e-caprolactone) or a starch like saccharide) can be appropriately impregnated with an intra vaginally effective active agent such as progesterone (eg: in concentration of from 5% to 70% w/w) and an absorption enhancing agent such as hydroxypropyl P-cyclodextrin (eg: in concentrations of from 5% to 70% w/w) so as to provide appropriate release characteristics for the active agent over the period of intra vaginal retention.

The preferred device is wholly of the impregnated matrix which is poly (E ;- caprolactone) impregnated with hydroxypropyl ß-cyclodextrin in the concentration of 5 to 70% w/w.