BR112018000479B1 - DELIVERY DEVICE CAPABLE OF INSERTION, RETENTION AND WITHDRAWAL OF A BODY CAVITY OF A NON-HUMAN TARGET MAMMAL AND METHOD FOR MANUFACTURING A DELIVERY DEVICE FOR INSERTION INTO A BODY CAVITY OF A NON-HUMAN TARGET MAMMAL - Google Patents

Abstract

The present invention relates to described delivery devices for insertion into a body cavity of a target mammal, the delivery device comprising a resilient frame adapted to receive one or more molded impregnated masses. The frame, together with the impregnated mass, can be inserted, retained and withdrawn from the intended body cavity. The masses or impregnated masses are attached to the frame to present substantially all of each face of the masses to exposure to a body cavity fluid when held therein.

Description

FIELD OF THE INVENTION

[001] The present invention relates to a drug delivery device for delivering a drug into a body cavity or passageway of a mammal, the fabrication of the drug delivery device, and its use.

BACKGROUND OF THE INVENTION

[002] Various devices are known to deliver drugs into cavities, such as the vaginal cavity. For example, New Zealand Patent Document No. 200564 reports an intravaginal device that has multiple lobes that form a "Y" shaped device. The document device in NZ 200564 includes the use of silicone rubber or ethylene vinyl acetate (EVA) which has been formed to a heat curable liquid form and which, prior to curing to form the solid form, has a chemical dispersed or dissolved in it. This chemically impregnated solid portion can form the device or be applied as a layer of skin over the device.

[003] New Zealand Patent Document No. 207341 also reports an intravaginal device formed from a "T"-shaped spine coated in a chemically impregnated material. Document No. NZ 207341 reports that the spine is formed of a flexible thermoplastic such as nylon or polypropylene with the drug-bearing coating formed of silicone.

[004] New Zealand Patent Document No. 230023 further reports an intravaginal device formed from a multiconfigurable spine impregnated or coated with a drug.

[005] New Zealand Patent Document No. 286492 further reports an intravaginal device formed from a pimple covered with a matrix of progesterone-containing silicone rubber material formed by injecting the uncured progesterone-containing matrix as a liquid into a mold .

[006] The PCT patent application published as WO 1998/053758 reports an intravaginal device for pigs that contains a matrix impregnated with progesterone on a nylon spine.

[007] The PCT patent application published as WO 1999/040966 (Duirs) reports the use of blocks impregnated with a drug, or containing gills or fins.

[008] The PCT patent application published as WO 2002/062415 reports a "T" or "Y" shaped device impregnated with progesterone for insertion into the vagina of a target species.

[009] Cost of manufacture is an important consideration with regard to drug delivery devices. Typically the active agent represents a high percentage of the total device cost, followed by the cost of the material (eg, silicone) used to form the device. Ease of manufacture also contributes significantly to lower device cost. All the devices mentioned above have disadvantages, be it the amount of active agent residue left in the device after use, or the complexity of manufacturing, such as the Duirs device.

[0010] It is an object of the present invention to provide a drug delivery device, or at least to provide the public with a useful choice.

SUMMARY OF THE INVENTION

[0011] In a first aspect the invention relates to a delivery device for insertion into a body cavity of a target mammal comprising

[0012] a resilient frame adapted to receive one or more impregnated masses, the frame together with the impregnated mass being able to be inserted, retained and removed from the intended body cavity, and

[0013] at least one of the impregnated masses is at least substantially laminar and secured to the frame to present substantially the whole of each face of the masses to exposure to a body cavity fluid when retained therein.

[0014] In a further aspect, the invention relates to a delivery device capable of insertion, retention and removal from a body cavity of a target mammal, the delivery device comprising

[0015] ¦ a resilient frame, and

[0016] - one or more impregnated masses that have a thickness of less than about 0.95 mm, and more preferably about 0.1 to about 0.8 mm, which are impregnated with one or more active agents to delivery to a target mammal upon insertion and retention in the target mammal, and

[0017] each of one or more impregnated masses are supported by the resilient frame at at least two or more separate attachment points.

[0018] In a further embodiment, the invention relates to a method for manufacturing a delivery device for insertion into a body cavity of a target mammal comprising

[0019] provide a resilient frame,

[0020] molding an impregnated mass that has a thickness of less than 0.95 mm, and more preferably about 0.1 to about 0.8 mm, and

[0021] attaching the molded impregnated mass to the resilient frame such that the molded impregnated mass is supported by the resilient frame at at least two or more separate attachment points.

[0022] In some embodiments, the frame is formed from a polymer, natural or synthetic, such as a polycarbonate, a polyethylene, a polypropylene, a nylon or a combination thereof.

[0023] In some embodiments, the shape of the frame is in the form of a "T"', "t", "Y", "V", "C", "X" or "M" format, or in a wishbone, kite or diamond.

[0024] In one embodiment, at least one of said impregnated masses is present in or on the frame in a plane in which the insertion direction of said delivery device is parallel to or in the plane.

[0025] In an alternative embodiment, at least one of said impregnated masses is present in or on the frame in a plane that is orthogonal to the insertion direction of said delivery device.

[0026] In one embodiment, all impregnated masses are retained in or on the frame in a plane in which the insertion direction of said delivery device is parallel to or in the plane.

[0027] In one embodiment, at least one of the impregnated mass or masses is retained in or on the frame at an angle relative to the direction of insertion of the delivery device into the animal.

[0028] In some embodiments, the frame has an implanted and non-implanted condition. Preferably, when in said implanted condition, it retains the delivery device in the body cavity.

[0029] In some embodiments, the frame includes one or more projections from the main body of the device.

[0030] In some embodiments, the frame includes seats or projections on which part of a face on which the one or more impregnated masses is held.

[0031] In one embodiment, the impregnated mass includes openings, curved cutouts or protrusions for engaging protrusions, protrusions or seats.

[0032] In some embodiments, the frame is in the form of a skeletal frame for supporting one or more impregnated masses.

[0033] In some embodiments, the one or more impregnated masses are at least substantially laminar.

[0034] In some embodiments, the one or more impregnated masses are flat.

[0035] In one embodiment, the impregnated masses are formed from a polymer.

[0036] In one embodiment, the delivery device comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 g of polymer, and useful ranges can be selected from any of these values.

[0037] In one embodiment, the delivery device comprises 1, 2, 3, 4, 5, 6, 7 or 8 cm 3 of polymer, and useful ranges can be selected from any of these values.

[0038] In one embodiment, the surface area ratio of the mass or masses impregnated in the polymer is from 12:1 (surface area: polymer mass) to 60:1 cm2.g-1, and useful ranges can be selected from any of these values.

[0039] In one embodiment, the polymer is selected from a non-degradable thermostable polymer, a non-degradable thermoplastic polymer, a biodegradable polymer, or a combination thereof. For example, the polymer can be formed from silicone, ethylene vinyl acetate, polycaprolactone, natural rubber (latex), styrene butadiene rubber, polyurethane, polyamide (nylon), low density polyethylene (LDPE), high density polyethylene (HDPE), polypropylene, polycarbonate, polyester, polyacrylonitrile, polyolefin, acrylic such as polymethyl methacrylate, polyvinyl chloride, polyvinyl fluoride, polymethacrylate, high impact polystyrene, polystyrene, polysulfone, polybutadiene, poly(aryl ether ketone), terephthalate polyethylene (PET), polyglycolic acid, polylactic acid, polylactic-co-glycolic acid, starches, polybutylene succinate, poly p-dioxane, poly-3-hydroxybutyrate, or a combination thereof.

[0040] In one embodiment, the one or more impregnated masses contain one or more active agents.

[0041] In one embodiment, the one or more active agents are distributed throughout the polymer.

[0042] In a modality, the active agent is selected among

[0043] a) a natural or synthetic hormone,

[0044] b) an antibiotic, antifungal or antiviral,

[0045] c) a peptide or a protein,

[0046] d) an antiparasitic,

[0047] e) an anti-inflammatory,

[0048] f) a mineral,

[0049] g) a vitamin,

[0050] h) trace elements,

[0051] i) growth promoters, and

[0052] j) any combination of (a) to (i) above.

[0053] In one embodiment, the active agent is a hormone selected from progesterone, estradiol, GnRH, prostaglandins, and melatonin.

[0054] In one embodiment, the active agent is an antibiotic selected from penicillins, cephalosporins, macrolides, fluoroquinolones, sulfonamides, tetracyclines, glycylcyclines, aminoglycosides, carbapenems, or a combination thereof.

[0055] In one embodiment, the active agent is an anti-inflammatory selected from, for example, non-steroidal anti-inflammatory drugs (NSAIDs), such as, for example, aspirin, ibuprofen, naproxen, aceclofenac, diclofenac, acetmetacin, dexibuprofen , ketoprofen, dexketoprofen, fenoprofen, flurbiprofen, etodolac, sulindac, indomethacin, nebumetone, tiaprofenic acid, meloxicam, selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib, rofecoxib, etoricoxib or a combination thereof.

[0056] In one embodiment, the one or more impregnated masses have a thickness of less than 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0, 6, 0.55, 0.5 or 0.45 mm, and useful ranges can be selected from any of these values.

[0057] In one embodiment, the one or more impregnated masses have a thickness of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8 mm, and useful ranges can be selected from any of these values.

[0058] In one embodiment, the impregnated mass, or each, contains 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 or 75% by weight of the active agent , and useful ranges can be selected from any of these values.

[0059] In one embodiment, in the case of multiple impregnated masses, each impregnated mass contains a different active agent.

[0060] In one embodiment, in the case of multiple impregnated masses, at least two of the impregnated masses contain the same active agent and the same wt% of that active agent.

[0061] In one embodiment, in the case of multiple impregnated masses, at least two of the impregnated masses contain the same active agent, and wherein said same active agents are present in different % by weight in each of the impregnated masses.

[0062] In one embodiment, in the case of multiple impregnated masses, at least two of the impregnated masses have the same thickness.

[0063] In one embodiment, in the case of multiple impregnated masses, at least two of the impregnated masses have a different thickness.

[0064] In one embodiment, the impregnated masses have at least two surfaces of substantially the same surface area, both of which surface areas are substantially exposed to body cavity fluid upon insertion into the mammal. Preferably at least 70, 75, 80, 85, 90 or 95% of the surface area of both surfaces are exposed to body cavity fluid upon insertion into the mammal.

[0065] In some embodiments, the delivery device comprises two or more separate impregnated masses, whereby the surface areas (whether exposed or confined) of the two or more impregnated masses are exposed to body cavity fluid. Preferably at least 70, 75, 80, 85, 90 or 95% of the surface area (whether exposed or confined) of the two or more impregnated masses is exposed to body cavity fluid upon insertion into the mammal.

[0066] In one embodiment, the delivery device achieves an active agent release rate of at least about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0, 4, 0.45, 0.5, 0.55 or 0.6 mg.cm-2.day-1, and useful ranges can be selected from any of these values.

[0067] In one embodiment, each of the one or more impregnated masses is at least generally laminar and has substantially parallel faces.

[0068] In one embodiment, the impregnated mass includes a release rate modifier. In some embodiments, the release rate modifier is selected from inert fillers such as calcium carbonate, salts such as sodium chloride, pore-forming substances such as water-soluble salts, oils such as arachis and liquid paraffin, and agents surface actives such as sodium lauryl sulfate.

[0069] In one embodiment, the one or more impregnated mass is manufactured by compression molding, extrusion, casting or injection molding.

[0070] In one embodiment, the one or more impregnated masses include at least two or more slots, openings or passages to facilitate attachment to the frame. Preferably such fastening passages are molded into the impregnated masses.

[0071] In one embodiment, the impregnated masses are molded in situ with the frame, the frame including two or more slots, openings or passages. In such an embodiment, the silica of the impregnated mass penetrates the two or more cracks, openings or passages, and upon hardening the penetration secures the impregnated mass in the frame.

[0072] In one embodiment, the one or more molded impregnated masses are each attached to the frame.

[0073] In one embodiment, the one or more molded impregnated masses are attached to the frame, but are spaced from the frame.

[0074] In some embodiments, the one or more impregnated masses are retained by the frame with or without any settlement of any face region of the one or more masses in the frame.

[0075] In some embodiments, the one or more impregnated masses are retained externally on the frame.

[0076] In an alternative embodiment, the one or more impregnated masses are retained in the frame.

[0077] In some embodiments, the impregnated mass, once attached to the frame, is held in a non-planar orientation.

[0078] In alternative embodiments, the impregnated mass, once attached to the frame, is held in a flat orientation.

[0079] In one embodiment, multiple impregnated masses are attached to the frame.

[0080] In one embodiment, the one or more masses are spontaneously expressible from the body cavity if detached from the frame.

[0081] In some embodiments, each of the impregnated masses has a different surface area.

[0082] In some embodiments, the delivery device is of a shape and size so as to be suitable for use with fully grown cattle, steers, sheep, pigs or camels.

[0083] In some embodiments, the frame includes a projection to aid in device removal. In some embodiments, the projection is a cable, wire or some other flexible material.

[0084] In some embodiments, upon removal of the mammalian delivery device, the one or more impregnated masses contain less than 40, 35, 30, 25, 20, 15, 10, 5 or 1% by weight of the loading of original active agent, and useful ranges can be selected from any of these values.

[0085] In one embodiment, at least 70, 75, 80, 85, 90, 95, 96 or 98% of the total notional surface area (i.e., including surface area that can touch the frame) of the impregnated mass is exposed to a body cavity fluid.

[0086] In some modalities, the frame provides

[0087] ¦ a configuration that can be inserted,

[0088] ¦ a configuration capable of retaining a body cavity, and

[0089] ¦ a withdrawal configuration.

[0090] In one embodiment, the delivery device is used to control estrous in an animal.

[0091] In one embodiment, the invention relates to a method for regulating the estrous cycle of an animal comprising inserting the delivery as described into a body cavity of the animal and then, after a period of time, withdrawing the device. Preferably the delivery device is inserted into the animal's vaginal cavity to control estrus, wherein the device releases progesterone upon insertion.

[0092] In one embodiment, use of the delivery device maintains or achieves a blood plasma progesterone concentration of at least 2 ng/ml.

[0093] In the present document, a reference to a "frame" can include either a unitary member (eg, as molded or cut from an extrusion) or an assembled member. The frame is preferably resilient so that it can be conformed to a condition from which it can relax or at least partially relax if compressed (e.g., as in a body cavity).

[0094] Reference to a range of numbers disclosed herein (e.g., 1 to 10) is intended to also incorporate reference to all rational numbers within that range (e.g., 1, 1, 1, 2, 3 , 3,9, 4, 5, 6, 6,5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3 .1 to 4.7).

[0095] This invention may also be considered to consist largely of the parts, elements and features cited or indicated in the application specification, individually or collectively, and any or all combinations of any two or more of said parts, elements or resources, and wherein specific integers are mentioned herein, which have equivalents known in the art to which this invention pertains, wherein such known equivalents are intended to be incorporated herein as if individually presented.

[0096] In this specification, where reference has been made to external sources of information, including patent specifications and other documents, this is generally for the purpose of providing a context for discussing the features of the present invention. Unless otherwise stated, reference to such sources of information should not be construed, in any jurisdiction, as an admission that such sources of information are prior art or form part of common general knowledge in the art.

[0097] The term "comprising" as used in this specification means "consisting at least in part of". When interpreting statements in this specification that include that term, the features introduced by that term in each statement all need to be present, but other features may also be present. Related terms such as "understand" and "understood" are to be interpreted in the same way. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Additional aspects of the present invention will become apparent from the following description which is given by way of example only and in reference to the attached drawings in which:

[0099] Figure 1A is a side perspective view of a device of the present invention comprising a frame supporting multiple impregnated masses.

[00100] Figure 1B is a bottom perspective view of a device of the present invention comprising a frame that supports multiple impregnated masses.

[00101] Figure 1C is a schematic perspective view of an alternative device shown in an implanted condition.

[00102] Figure 1D is a schematic perspective view of the device of Figure 1C shown in an unimplanted condition.

[00103] Figures 2A and 2B are an alternative design of a device of the present invention.

[00104] Figure 3 shows plots of plasma progesterone concentration versus time (days) for each of the different intravaginal delivery devices investigated in the study.

[00105] Figure 4 is a graph of the amount of progesterone released versus time (days) for each of the different intravaginal delivery devices investigated in the study.

DETAILED DESCRIPTION OF THE INVENTION

[00106] The invention generally relates to a delivery device that is capable of being inserted, retained and withdrawn from a body cavity of a target mammal. The delivery device comprises a resilient frame that supports one or more impregnated masses, the impregnated masses having a thickness of less than 0.95 mm, or more preferably about 0.1 to about 0.8 mm, and are impregnated with one or more active agents for delivery to a target mammal upon insertion and retention in the target mammal. each of the impregnated masses is supported by the resilient frame at at least two or more separate attachment points.

[00107] The delivery device can be inserted into a body cavity of a target mammal and comprises a resilient frame that is adapted to receive one or more impregnated masses, the frame together with the impregnated mass being insertable, retention and withdrawal from the intended body cavity. at least one of the impregnated masses is at least substantially laminar and attaches to the frame to present substantially the whole of each face of the masses to exposure to a body cavity fluid when retained therein.

[00108] It should be appreciated that, upon use, the delivery device delivers the one or more active agent at an effective concentration or amount to ensure a desired biological response.

[00109] Previous devices require relatively large amounts of silicone and progesterone to be used which leads to a high residual loading of the active agent in the device after use. In contrast, the present device has a much lower residual charge after use. For example, the residual active agent loading in the after-use delivery device is less than 40, 35, 30, 25, 20, 15, 10, 5% of the original drug loading. 1. FRAME

[00110] The frame provides the structure on which one or more impregnated masses are carried. The frame can be supplied in a number of different shapes, such as a “T”, “t”, “Y”, “V”, “C”, “X" or “M”, or wishbone shape , kite or diamond.

[00111] The delivery device comprises a frame on which or in which the impregnated mass or masses are attached. The delivery device can be configured in a number of ways. In a first embodiment, the frame or the projections of said frame are arranged in the same plane. In an alternative embodiment, the frame comprises multiple projections wherein at least one projection is oriented in a different plane from another projection of said frame. For example, a projection of the frame can be arranged in a plane, the plane being parallel to or coincident with the direction of insertion of the delivery device into the animal. In an alternative embodiment, the frame projections may be orthogonal or at some other angle to the direction of insertion of the delivery device into the animal.

[00112] As shown in Figure 1, a device is arranged in a “T” shape. The top of the “T" is a projection of the frame in which it is in a plane (that is, the insertion direction is “ normal" to the plane of the top of the "T") orthogonal to the direction of insertion of the delivery device into the animal. The plane of the "T" stem is also parallel to the direction of insertion of the delivery device. As shown in Figure 1, the top of the "T" is in a plane perpendicular to the plane of the delivery device stem.

[00113] In an alternative embodiment, the frame (shown in Figure 1C), is a "T" shape, in which the top of the "T" and the stem of the "T" are in the same plane (or at least planes parallel) and the direction of insertion of the delivery device into the animal as parallel. As shown in Figure 1C, the impregnated mass or masses can be attached to the frame so that they are in the same plane as the plane of the device frame Of delivery.

[00114] The frame can form for an implanted and non-implanted condition. The non-implanted condition is one in which the frame is limited to a particular shape. Upon release, the frame then forms in the implanted condition. For example, the delivery device is manufactured in the implanted condition and is then forced into the non-implanted condition, for example, through the use of degradable tape, or insertion into a tube. Once delivered into the mammalian body cavity, the frame installs in the implanted state due to its inclination towards that state.

[00115] The frame can be made of any material, but is preferably made of plastic. Plastic can be degradable or non-degradable. The plastic may be a thermoplastic. For example, the frame can be formed from a polymer such as polyethylene, polypropylene, starch-like polysaccharides such as Mater-Bi, polycaprolactone, polyglycolide, polylactide, polyurethane, rubber, silicone, ethylene and vinyl acetate, nylon, or combinations thereof. Specific examples of suitable polymers include polyamide (nylon), low density polyethylene, high density polyethylene, polypropylene, polycarbonate, polyester, polyacrylonitrile, polyolefin, acrylate (such as polymethyl methacrylate), polyvinyl chloride, polyvinyl fluoride, polymethacrylate, high impact polystyrene, polystyrene, polysulfone, polybutadiene, poly aryl ether ketone, polyethylene terephthalate (PET), polyglycolic acid, polylactic acid, polylactic-co-glycolic acid, polycaprolactone, starches, polybutylene succinate, poly p-dioxanone, poly -3-hydroxybutyrate, or a combination thereof.

[00116] The frame may include one or more projections from the main body of the device. For example, the frame can include seats or projections on which part of a face of the one or more impregnated masses is held. The impregnated mass may include openings, curved cutouts or protrusions for engaging with protrusions, ridges or seats.

[00117] The frame can be formed in different formats, as long as it can support one or more impregnated masses.

[00118] For example, the frame can be formed as a skeletal framework to form the basic shape of the device. The one or more impregnated masses are then attached to this scaffold.

[00119] The frame can act to frame one or more impregnated masses in such a way that the one or more impregnated masses are kept within the confines of the frame. Alternatively, one or more impregnated masses can be placed on the frame and kept spaced from the frame by the projections or seats mentioned above as shown in Figures 1 and 2. 2. IMPREGNATED MATTER

[00120] The one or more impregnated masses contain one or more active agents for delivery to a mammal through the body cavity in which the delivery device is located.

[00121] One or more impregnated masses is formed from a polymer. The impregnated masses may be formed from a polymer such as a non-degradable thermostable polymer, a non-degradable thermoplastic polymer, a biodegradable polymer or a combination thereof. For example, the polymer can be formed from silicone, ethylene vinyl acetate, polycaprolactone, natural rubber (latex), styrene butadiene rubber, polyurethane, polyamide (nylon), low density polyethylene (LDPE), high density polyethylene (HDPE), polypropylene, polycarbonate, polyester, polyacrylonitrile, polyolefin, acrylic such as polymethyl methacrylate, polyvinyl chloride, polyvinyl fluoride, polymethacrylate, high impact polystyrene, polystyrene, polysulfone, polybutadiene, poly(aryl ether ketone), terephthalate polyethylene (PET), polyglycolic acid, polylactic acid, polylactic-co-glycolic acid, starches, polybutylene succinate, poly p-dioxane, poly-3-hydroxybutyrate, or a combination thereof.

[00122] The polymer forms a matrix in which the active agent is retained. Upon delivery and retention in the body cavity, the active agent is released from the matrix. Delivery in this manner allows release of the active agent over a period of time, which can be controlled by manipulating the amount, active agent concentration and size of the impregnated mass.

[00123] The delivery device comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 g of polymer, and useful ranges can be selected from any of these values (for example, about 2 to about 10, about 2 to about 8, about 2 to about 6, about 3 to about 10, about 3 to about 8, about 3 to about 7, about 4 to about 10, about about 4 to about 9, about 4 to about 7, about 5 to about 10, about 5 to about 7, about 6 to about 10, about 6 to about 8 or about 7 to about 10g). In comparison, alternative devices contain a higher amount of silica as shown in Table 1 below. TABLE 1. THE APPROXIMATE WEIGHT OF SILICONE AND RATIO OF SURFACE AREAS TO SILICONE OF VARIOUS INTRAVAGINAL DEVICES

[00124] The volume of polymer used in the alternative devices as listed in TABLE 1 in Table 1 is greater than in the comparable devices of the present invention. In one embodiment, the delivery device comprises 1, 2, 3, 4, 5, 6, 7, or 8 cm 3 of polymer, and useful ranges can be selected from any of these values (e.g., about 1 to about 8 , about 1 to about 6, about 1 to about 5, about 2 to about 8, about 2 to about 7, about 2 to about 5, about 3 to about 8, about from 3 to about 7, about 3 to about 6, about 4 to about 8, about 4 to about 6, about 5 to about 8, about 6 to about 8 cm 3 of polymer) .

[00125] The particular design characteristics of the devices of the present invention lead to a high ratio of surface area (from mass or impregnated masses) to polymer. That is, for each unit of polymer, the devices of the present invention have a greater surface area from the impregnated mass or masses compared to other devices, such as those shown above TABLE 1 in Table 1. In one embodiment, the ratio The surface area of the putty or putties impregnated into the polymer is from 12:1 (surface area:polymer) to 60:1 cm-1, and useful ranges can be selected between any of these values, (for example, about 12:1 to about 60:1, about 12:1 to about 50:1, about 12:1 to about 40:1, about 12:1 to about 30:1, about 12: 1 to about 20:1, about 15:1 to about 60:1, about 15:1 to about 50:1, about 15:1 to about 40:1, about 15:1 to about 30:1, about 15:1 to about 20:1, about 25:1 to about 60:1, about 25:1 to about 50:1, about 25:1 to about 40:1, about 25:1 to about 30:1, about 25:1 to about 20:1, about 35:1 to about 60:1, about 35:1 to about 50: 1, about 35:1 to about 40:1, about 35:1 to about 30:1, about 35:1 to about 20:1, about 45:1 to about 60:1, about 45:1 to about 50:1, about 45:1 to about 40:1, about 45:1 to about 30:1, about 45:1 to about 20:1 surface of the polymer weight impregnated mass or masses).

[00126] The one or more impregnated masses are at least substantially laminar. That is, they are molded into a substantially flat shape to form a sheet-like shape. In some embodiments, the one or more impregnated masses can be molded into a non-flat shape, but will still retain its sheet-like shape. For example, such as a curved sheet.

[00127] The one or more impregnated masses have a thickness of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 0.95 mm, and useful ranges can be selected from any of these values, (e.g., about 0.1 to about 0.95, about 0.1 to about 0.9, about 0, 1 to about 0.8, about 0.1 to about 0.7, about 0.1 to about 0.5, about 0.1 to about 0.4, about 0.1 to about 0.2, about 0.2 to about 0.95, about 0.2 to about 0.9, about 0.2 to about 0.8, about 0.2 to about 0.9 0.6, about 0.2 to about 0.5, about 0.3 to about 0.95, about 0.3 to about 0.9, about 0.3 to about 0, 8, about 0.3 to about 0.7, about 0.3 to about 0.5, about 0.4 to about 0.95, about 0.4 to about 0.9, about 0.4 to about 0.8, about 0.4 to about 0.6, about 0.4 to about 0.5, about 0.5 to about 0.8, about 0.5 to about 0.7 or 0.6 to about 0.8 mm)

[00128] Each impregnated mass can contain a single active agent or multiple active agents. The one or more active agents are distributed throughout the impregnated mass.

[00129] When multiple impregnated masses are attached to a single frame, the impregnated masses may all be the same, or there may be a range of impregnated masses with different characteristics, such as different sizes, thicknesses and carrying different active agents.

[00130] In this way, a delivery device can be customized to deliver multiple active agents that each have their own release profile that is suitable for that active agent.

[00131] For example, when there are multiple impregnated masses, a mass can have a first thickness, and other masses can have different thicknesses, either thicker or thinner.

[00132] When there are multiple impregnated masses, one impregnated mass may contain multiple active agents, and other impregnated masses may contain an active agent, or a combination of different active agents.

[00133] The impregnated masses may contain a different concentration of active agents. For example, a first active agent may contain a first concentration of an active agent, and other slurries may contain the same active agents or different active agents at a different concentration (i.e., higher or lower).

[00134] A range of active agents can be used. For example, the active agent can be selected from a natural or synthetic hormone, an antibiotic, antifungal or antiviral, a peptide or protein, an antiparasitic, an anti-inflammatory, minerals, vitamins, trace elements, growth promoters, and any combination of the same.

[00135] As specific examples, when the active agent is a hormone, the hormone can be selected from progesterone, estradiol and testosterone.

[00136] When the active agent is an antibiotic, it can be selected penicillins, cephalosporins, macrolides, fluoroquinolones, sulfonamides, tetracyclines, glycylcyclines, aminoglycosides, carbapenems, or a combination thereof. When the active agent is an anti-inflammatory, it may be selected from, for example, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, aceclofenac, diclofenac, acetmetacin, dexibuprofen, ketoprofen, dexketoprofen, fenoprofen, flurbiprofen, etodolac, sulindac, indomethacin, nebumetone, tiaprofen acid, meloxicam, selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib, rofecoxib, etoricoxib or a combination thereof.

[00137] In one embodiment, the impregnated mass, or each, contains 1, 5, 10, 15, 20, 25, 30, 35, 40 45, 50, 55, 60, 65 or 75% by weight of the active agent , and useful ranges can be selected from any of these values (e.g., about 1 to about 75, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 5 to about 75, about 5 to about 70, about 5 to about 65, about 5 to about 55, about 5 to about 40, about 5 to about 20, about 10 to about 75, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 15 to about 75, about 15 to about 65, about 15 to about 55, about 15 to about 25, about 20 to about 75, about 20 to about 60, about 20 to about 40, about 25 to about 75, about 25 to about 65, about 25 to about 60, about 25 to about 35, about 30 to about 75, about 30 to about 60, about 30 to about 40, about 35 to about 75, about 35 to about 65, about 35 to about 40, about 40 to about 75, about 40 to about 60, about 40 to about 50, about 45 to about 75, about 45 to about 60, about 50 to about 75, about 50 to about 70, or about 60 to about 75% by weight of the active agent) .

[00138] Given the molding of the impregnated mass, it contains at least two surfaces with substantially the same surface area, both surface areas being substantially exposed to body cavity fluid upon insertion into the mammal.

[00139] In comparison, prior art devices such as those discussed in the background section are formed as a coating of the active agent-impregnated material coated onto a spine. In this way, such a device has a single outer layer and consequently a much smaller surface area per volume of material impregnated by active agent.

[00140] In one embodiment, each of the one or more impregnated masses is at least generally laminar and has substantially parallel faces.

[00141] Regarding the present device, at least 70, 75, 80, 85, 90 or 95% of the surface area of both surfaces are exposed to body cavity fluid upon insertion into the mammal, and useful ranges can be selected between any of these values (for example, about 70 to about 95, about 70 to about 85, about 70 to about 80, about 75 to about 95, about 75 to about 85, about from 80 to about 95, about 80 to about 90, about 85 to about 95, or about 85 to about 90% of the surface area of both surfaces).

[00142] In some embodiments, the delivery device comprises two or more separate impregnated masses, whereby the surface areas (whether exposed or confined) of the two or more impregnated masses are exposed to body cavity fluid. Preferably at least 70, 75, 80, 85, 90 or 95% of the surface area (whether exposed or confined) of the two or more impregnated masses is exposed to body cavity fluid upon insertion into the mammal.

[00143] The impregnated mass may also include a release rate modifier that facilitates dissolution or delays diffusion of the active agent from the polymer. Examples of suitable release rate modifiers include inert fillers such as calcium carbonate, salts such as sodium chloride, pore-forming substances such as water-soluble salts, oils such as arachis and liquid paraffin, and surface active agents such as as sodium lauryl sulfate. 3. MANUFACTURING

[00144] In additional preferred embodiments, the substance delivery device can be imbued with an active substance using processing methods such as compression molding, extrusion, casting or injection molding. An advantage of this method is that the manufacturing steps are less than the amount required for injection molding a traditional device as shown in New Zealand Patent Document No 207341 discussed above.

[00145] The impregnated mass is preferably manufactured using compression, extrusion or injection molding.

[00146] When compression molding is used, the active agent is first mixed with the polymer. For example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60% by weight of active agent is fixed with the polymer, and useful ranges can be selected from any of these values ( for example, about 1 to about 60, about 1 to about 45, about 1 to about 25, about 1 to about 20, about 5 to about 60, about 5 to about 40 , about 5 to about 30, about 5 to about 20, about 5 to about 15, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 25, about 10 to about 20, about 15 to about 60, about 15 to about 35, about 15 to about 25, about 20 to about 60, about 20 about 50, about 20 to about 40, about 25 to about 60, about 25 to about 45, about 25 to about 35, about 30 to about 60, about 30 to about about 50, about 30 to about 40, about 35 to about 60, about 35 to about 45, about 40 to about 60, about 40 to about 50, about 45 to about 60 , about 45 to about 50 or about 50 to about 60% by weight).

[00147] The mixture of active and polymer is then mixed. Preferably the active and the polymer are mixed by laminators.

[00148] An amount of active/polymer mixture is placed over the mold cavity. It will be appreciated that the size and shape of the mold cavity is designed to produce the impregnated mass having the desired dimensions.

[00149] The active/polymer mixture placed in the mold is heated to about 50, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280 or 300 °C, and useful ranges may be selected from any of these values under pressure of about 1.034 (150), 2.068 (300), 3.102 (450), 4.136 (600), 5.171 (750), 6.205 (900), 7.239 (1,050), 8.273 (1,200 ), 9.307 (1,350), 10,342 (1,500), 11,376 (1,650), 12,410 (1,800), 13,444 (1,950), 14,478 (2,100), 15,513 (2,250), 16,547 (2,400), 17,581 (2 .550), 18,615 (2,700 ), 19,650 (2,850) or 20,684 (3,000) MPa (psi) until the active/polymer mixture has polymerized and cured into a solidified impregnated mass. Once cooled, the impregnated mass can be attached to the frame.

[00150] When extrusion molding is used, the active agent is first mixed with the polymer. For example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60% by weight of active agent is fixed with the polymer, and useful ranges can be selected from any of these values ( for example, about 1 to about 60, about 1 to about 45, about 1 to about 25, about 1 to about 20, about 5 to about 60, about 5 to about 40 , about 5 to about 30, about 5 to about 20, about 5 to about 15, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 25, about 10 to about 20, about 15 to about 60, about 15 to about 35, about 15 to about 25, about 20 to about 60, about 20 about 50, about 20 to about 40, about 25 to about 60, about 25 to about 45, about 25 to about 35, about 30 to about 60, about 30 to about about 50, about 30 to about 40, about 35 to about 60, about 35 to about 45, about 40 to about 60, about 40 to about 50, about 45 to about 60 , about 45 to about 50 or about 50 to about 60% by weight).

[00151] The mixture of active and polymer is then mixed. Preferably the active and polymer are mixed by use of a blade stirrer.

[00152] The active/polymer mixture is then extruded using an extruder with a die having a cross-sectional shape that is contiguous with the cross-section of the desired impregnated mass.

[00153] The extruded impregnated mass can also be cut to a particular dimension before clamping onto the frame.

[00154] When injection molding is used, the active agent is first mixed with the polymer. For example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60% by weight of active agent is fixed with the polymer, and useful ranges can be selected from any of these values ( for example, about 1 to about 60, about 1 to about 45, about 1 to about 25, about 1 to about 20, about 5 to about 60, about 5 to about 40 , about 5 to about 30, about 5 to about 20, about 5 to about 15, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 25, about 10 to about 20, about 15 to about 60, about 15 to about 35, about 15 to about 25, about 20 to about 60, about 20 about 50, about 20 to about 40, about 25 to about 60, about 25 to about 45, about 25 to about 35, about 30 to about 60, about 30 to about about 50, about 30 to about 40, about 35 to about 60, about 35 to about 45, about 40 to about 60, about 40 to about 50, about 45 to about 60 , about 45 to about 50 or about 50 to about 60% by weight).

[00155] The mixture of active and polymer is then blended. Preferably the active and polymer are mixed by use of a blade stirrer.

[00156] A mold is selected that is of a size and shape so that the internal chamber is in contiguity with the desired dimensions of the impregnated mass. The two halves of the mold are clamped together and the active/polymer mixture is injected into the mold. The mold is heated to cure the active/polymer mixture into the impregnated mass.

[00157] Once removed from the mold, the impregnated sheet is allowed to cool before gripping the frame. 4. USE

[00158] The device of the present invention can be used to administer an active agent to mammals, which include domesticated animals such as cattle, calves, sheep, camels, pigs and goats.

[00159] In one embodiment, the delivery device is used to control estrous in an animal. Estrus control typically requires the device to achieve a sufficient blood plasma concentration of progesterone. For example, in bovine animals, it is desired that a blood plasma concentration of at least 2 ng/ml be maintained to effectively control estrous. In pigs, a blood plasma concentration of at least 8 to 10 ng/ml is desired to control estrous.

[00160] One aspect of the invention relates to a method for regulating the estrous cycle of an animal comprising inserting the delivery as described into a body cavity of the animal and then, after a period of time, withdrawing the device. Preferably the delivery device is inserted into the animal's vaginal cavity to control estrus, wherein the device releases progesterone upon insertion.

[00161] The benefits of the present invention include at least a cheaper manufacturing process compared to traditional devices as described in New Zealand Patent Document No. 200564 and WO 1999/040966, and also a more effective use of the given active agent that the use of the device of the present invention leads to less residual active agent remaining in the device after use.

[00162] For example, an advantage of the present invention is that the one or more impregnated mass exhibit high drug utilization of the substance upon removal from the animal. This means that minimal amounts of the one or more active agent or agents are delivered into the environment.

[00163] For example, after use, the spent impregnated mass contains less than 40, 35, 30, 25, 23, 21, 19, 17, 15, 13, 11, 9, 7, 5, 3, 1% in weight of active agent, and useful ranges can be selected from any of these values (e.g., about 1 to about 40, about 1 to about 35, about 1 to about 30, about 1 to about 25, about 1 to about 21, about 1 to about 15, about 1 to about 9, about 3 to about 40, about 3 to about 35, about 3 to about 30, about 3 to about 30, about about 3 to about 25, about 3 to about 21, about 3 to about 17, about 3 to about 13, about 3 to about 7, about 5 to about 25, about 5 to about 21, about 5 to about 17, about 5 to about 13, about 5 to about 9, about 7 to about 25, about 7 to about 21, about 7 to about 17, about 7 to about 15, about 7 to about 11, about 9 to about 25, about 9 to about 21, about 9 to about 17, about 9 to about 25, about 9 to about 21 11, about 11 to about 25, about 11 to about 21, about 11 to about 17, about 11 to about 15, about 13 to about 25, about 13 to about 21, about 13 to about 19, about 15 to about 25, about 15 to about 19, about 17 to about 25, about 17 to about 21, about 19 to about 25, about 19 to about 21, about 21 to about 25% by weight active agent).

[00164] Put another way, after use, the impregnated mass contains less than 35, 30, 25, 23, 21, 19, 17, 15, 13, 11, 9, 7, 5, 3, 1% of the amount of active agent, and useful ranges can be selected from any of these values (e.g., about e.g., about 1 to about 25, about 1 to about 21, about 1 to about 15, about 1 to about 9, about 3 to about 25, about 3 to about 21, about 3 to about 17, about 3 to about 13, about 3 to about 7, about 5 about 25, about 5 to about 21, about 5 to about 17, about 5 to about 13, about 5 to about 9, about 7 to about 25, about 7 to about about 21, about 7 to about 17, about 7 to about 15, about 7 to about 11, about 9 to about 25, about 9 to about 21, about 9 to about 17 , about 9 to about 11, about 11 to about 25, about 11 to about 21, about 11 to about 17, about 11 to about 15, about 13 to about 25, about 13 to about 21, about 13 to about 19, about 15 to about 25, about 15 to about 19, about 17 to about 25, about 17 to about 21, about 19 to about 25, about 19 to about 21, about 21 to about 25% of the original amount of active agent).

[00165] In one embodiment, the delivery device achieves an active agent release rate of at least about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0, 4, 0.45, 0.5, 0.55 or 0.6 mg.cm-2.day-1, and useful ranges can be selected from any of these values, (for example, 0.1 to about 0 .6, about 0.55 intraruminal, about 0.1 to about 0.4, about 0.1 to about 0.3, about 0.15 to about 0.6, about 0 .15 to about 0.5, about 0.15 to about 0.4, about 0.2 to about 0.6, about 0.2 to about 0.5, about 0.2 about 0.4, about 0.2 to about 0.35, about 0.25 to about 0.6, about 0.25 to about 0.55, about 0.25 to about from 0.4, 0.3 to about 0.6, about 0.3 to about 0.5, about 0.35 to about 6, about 0.35 to about 0.45, about from 0.4 to about 0.6, about 0.4 to about 0.55, about 0.45 to about 0.6 mg.cm -2 .day -1).

[00166] An additional advantage of the present invention is the ease with which the active release profile can be altered and/or customized in order to optimize the drug delivery device for use in a mammal. Modifying the imbued active agent release can be achieved, for example, by controlling the surface area of the impregnated mass, the amount of active agent, the active agent concentration, the type of polymer used, or a combination thereof.

[00167] The substance delivery device can be secured to an appropriately designed plastic form that is configured to be an intravaginally administered drug delivery device. The intravaginally administered substance delivery device may be configured to be retained in the vagina of a cow, sheep, camel, pig, deer, goat or any other animal (such as a cat or dog) or human.

[00168] The drug delivery device of the present invention can be administered into a range of cavities such as the rumen, rectum or vagina of a mammal.

[00169] Examples of body cavities in which the invention can be applied include, but are not limited to, the vagina, the rumen of a ruminant animal, the stomach of a monogastric animal, the colon, the rectum, the subcutaneous tissue, the tissue muscle, the urethra, the uterus or the eye.

[00170] For example, in some embodiments the drug delivery device is an intraruminal delivery device for delivering an active agent to a ruminant such as a cow, sheep, deer or goat. For example, to ensure retention (given the possibility of removing the device from the rumen during regurgitation), the device may include a retention mechanism. One such example is that the device has a shape that inhibits removal, such as a "T" or "Y" shape. The frame of the drug delivery device can provide

[00171] ¦ a configuration that can be inserted,

[00172] ¦ a configuration capable of retaining a body cavity, and

[00173] ¦ a withdrawal configuration.

[00174] For example, the drug delivery device may have an origin that allows administration through the esophagus such that, upon delivery, the device "pops open" into a retentive shape that prevents removal.

[00175] In an alternative embodiment, the drug delivery device may be an intravaginal device. For example, the shape of the drug delivery device is one that fits easily and comfortably within an animal's vagina. The impregnated mass of the drug delivery device is imbued with sufficient active agent (such as progesterone) to provide sufficient exogenous active agent (i.e., progesterone) to have a biological effect (e.g., to control the estrous cycle in the case of progesterone). The drug delivery device may also have a handle to facilitate removal after the desired period of administration.

[00176] The active agent delivered may include natural or synthetic hormones, an antibiotic, antifungal or antiviral, a peptide or a protein, an antiparasitic, an anti-inflammatory, minerals, vitamins, trace elements, growth promoters, and any combination thereof .

[00177] Examples of substances that can be incorporated into the substance delivery device include, but are not limited to, drugs used in estrous control such as natural or synthetic hormones that include progesterone, estradiol, GnRH, prostaglandins, melatonin, drugs used to control infections such as antibiotics, antifungals or antivirals, drugs such as proteins and peptides, drugs used to control parasitic infections including anthelmintics such as ivermectin, abermectin, oxfendazole, macrolytic lactones, oxfendazole or levamisole, nutrients such as minerals, vitamins, trace elements , growth promoters.

[00178] For intravaginal devices the preferred active agent includes natural or synthetic hormones.

[00179] For intraruminal devices the preferred active agent includes an antiparasitic such as anthelmintics, anti-swelling, minerals and/or vitamins.

[00180] With reference to Figures 1A and 1B there is shown a drug delivery device in a "T" shape that has multiple impregnated masses 1 located in a frame 2. Such a device may be suitable for intravaginal or intraruminal administration of the drug delivery agent.

[00181] With reference to Figure 2A and 2B there is shown a view of a drug delivery device that has an alternative design. Such a design may be suitable for intravaginal administration from the drug delivery device. As shown in Figures 2A and 2B the device can include multiple impregnated masses, some of which are of a different size. For example, the device of Figures 2A and 2B includes three impregnated masses of unequal size: two thin sheets of the invention which are of equal size and the remaining sheet of a different size, all imbued with an active agent.

[00182] It can be appreciated that different dose amounts of the active substance can be loaded into the substance delivery device and thereby provide the opportunity to modify doses delivered to the body cavity of the animal or human. Consequently, the substance delivery device allows for a particular drug delivery profile that is suited to the particular application and needs of the animal.

[00183] Drug release from the substance delivery device is influenced by surface area, silicone thickness or drug loading. Thus, rate (amount per day), extent (total amount delivered or drug use), and duration (length of treatment) can be predetermined. In addition, the substance delivery device can be made with different polymers, each different polymer being attached to the same plastic format of appropriate design and thereby allowing different release rates of different drugs, either simultaneously or sequentially. from the same device.

[00184] Figures 1 and 2 illustrate some possible non-limiting designs that incorporate the substance delivery device secured over a plastic format of appropriate design that is suitable for insertion into various animal or human body cavities. It is obvious that different shapes are required for different body cavities, and also that different sizes of the same shape are required for the same body cavity of different species. The different sizes and shapes allow ease of insertion, ease of removal, comfort, security and shape retention in different body cavities of different species.

[00185] Aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions can be made thereto without departing from the scope of the patent claims. EXAMPLE 1 - PROGESTERONE DELIVERY DEVICE

[00186] The use of a delivery device of the present invention provides the ability to regulate the surface area, thickness and drug load of the substance delivery device, which allows the formulator to influence dose levels and regulate the profile of release of active agent through various means.

[00187] For example, optimizing amount of progesterone, % w/w of progesterone load, silicone thickness, and/or surface area, problems associated with residual progesterone in intravaginally administered drug delivery devices that contain progesterone for estrous control in fully grown cattle can be reduced or superseded. Enhancing progesterone utilization through optimal loading or silicone thickness modification creates more efficient drug delivery that results in reduced waste. Therefore, release of progesterone according to specific dose requirements is achieved while providing minimal residue while meeting specific treatment needs.

[00188] A series of experiments were designed to demonstrate that the intravaginal delivery device can be manufactured, inserted into the vagina of cattle, remain in place for the duration of treatment, be removed from the vagina at the end of treatment, and produce biological effects similar to commercially available intravaginal inserts that are currently on the market. 1. STUDIES ON INTACT ANIMALS

[00189] This study examines the effect of various delivery device characteristics, such as surface area, impregnated mass thickness, formulation loading (% w/w), on plasma progesterone profiles in intact animals. 1.1 METHODOLOGY

[00190] In this study, 24 beef Brangus cattle with intact ovaries weighing 300 to 450 kg received intravaginal delivery devices as shown in Table 2.

[00191] Figure 1 shows the devices used in the in vivo studies. Essentially the devices used in the in vivo tests comprised a nylon spine with an end-to-end distance of 14.5 cm and body length of 12.0 cm covered in blocks comprising silicone of various thicknesses (0.3 or 0.5 mm) that contain progesterone in % w/w loads of 15.8 or 21% w/w. The surface area of the devices was varied between 115 and 450 cm2, and initial loads varied between 400 and 2570 mg. The weight of the silicone-impregnated masses ranged from 1,800 to 12,500 mg with volumes ranging from 35 to 225 cm3. The impregnated masses were oriented in the same plane as the joint, but could just as well have been perpendicular to the joint.

[00192] All enrolled cows underwent blood sampling prior to insertion of the intravaginal delivery device. From this group, 12 cows that exhibited zero progesterone levels at the start of the test were selected for inclusion in the data analysis. Such animals may have their endogenous progesterone suppressed by the exogenous progesterone arising from the intravaginal delivery device, and thus the progesterone levels measured in the blood of these cows would arise only from the intravaginal delivery device. Intravaginal delivery devices were administered into the vagina using a plastic applicator. Delivery devices were left in place for seven days before removal.

[00193] Animal health, mucus production and retention rate were recorded during the test. Blood samples were collected in heparinized tubes on a daily basis immediately preceding insertion, each day of the treatment period, as well as the three days after removal of the insert. Plasma was separated by centrifugation and stored at -20°C for subsequent progesterone analysis. Plasma progesterone concentrations were determined using a Progesterone RIA kit (Beckman Coulter). Plasma progesterone concentration versus time (days) were plotted. TABLE 2. DESIGN OF THE DEVICES USED IN THE TEST.

[00194] Intravaginal delivery devices that were removed on day seven were rinsed in clean water, air dried, and stored until residual progesterone levels were determined. Residual progesterone content was determined using an alcoholic extraction method that involved placing impregnated masses from the intravaginal delivery device into a 250 ml plastic bottle. To this was added 200 ml of SDA (denatured ethanol containing 50 ml/l of methanol). The bottle was left for more than 17 hours with occasional hand shaking until complete extraction of the progesterone. Drug content was quantified by UV at 239 nm after appropriate dilution.

[00195] At the end of the study the amount of intravaginal delivery devices that still remained in the vagina was recorded. Retention rates were determined from knowledge of the initial amount that is administered and the amount that is still left in the animal's vagina at the end of the insertion period.

[00196] Vaginal reaction to the insert was determined on the day of removal by observing the appearance of mucus production at the end of the treatment period.

1.2 RESULTS

[00197] All inserts were retained for the seven day insertion period and provided the 100% retention rate in this study. This retention rate is comparable to commercially available intravaginal inserts.

[00198] Amounts of mucus observed upon removal varied between intravaginal inserts. The smaller the intravaginal insert, the less copious were the vaginal secretions. The smallest intravaginal surface area delivery device has been observed to produce amounts similar to the amounts observed, or slightly more than the same, with the commercially available CIDR cattle inserts. The larger intravaginal surface area delivery devices have been observed to produce copious amounts of clear mucus secretions reminiscent of the volumes seen when the previously commercially available PRID spring insert was used.

[00199] The blood levels in the cows are shown in Figure 3.

[00200] All intravaginal delivery devices tested produced a plasma progesterone profile similar to commercially available intravaginal inserts. All intravaginal delivery devices produced an increase in plasma progesterone levels which were then maintained until the delivery device was removed. After removal of the intravaginal delivery device, plasma progesterone levels dropped to baseline levels.

[00201] Intravaginal delivery devices 1 (115 cm2, 21% w/w, 0.5 mm) and 2 (115 cm2, 21% w/w, 0.3 mm) compared the effect of impregnated mass thickness on plasma progesterone levels when the impregnated mass surface area (115 cm 2 ) and drug loading (21% w/w) were held constant. Intravaginal delivery devices of impregnated mass of different thickness showed similar elevations and maintenance of plasma progesterone levels. Intravaginal delivery devices 4 (450 cm2, 21% w/w, 0.5 mm) and 5 (450 cm2, 21% w/w, 0.3 mm) also compared the effect of impregnated mass thickness on levels of plasma progesterone when a larger impregnated mass with a surface area (450 cm 2 ) and the same drug loading (21% w/w) were held constant.

[00202] Intravaginal delivery device 5 (450 cm2, 21% w/w, 0.3 mm) and 6 (450 cm2, 15.8% w/w, 0.3 mm) compared the effect of concentration of progesterone (% w/w) in different impregnated masses whose surface area (450 cm2) and thickness (0.3 mm) were kept constant. Different % w/w of intravaginal delivery devices showed similar elevations and maintenance of plasma progesterone levels.

[00203] Larger intravaginal delivery devices (devices 4, 5 and 6 - 450 cm2) showed higher plasma levels compared to medium-sized (device 3 - 195 cm2) and small-sized devices (device 1 and 2 - 115 cm2).

[00204] This result means that the surface area can be varied, for example, to customize the device for different delivery profiles, as would be required for use in tropical zone cattle (milk emissions <25 l) or, for example in high lactation Holstein cattle (>45 l).

[00205] Table 3 shows the initial progesterone load, % w/w and residual progesterone content in each of the different intravaginal delivery devices investigated in the study after a 7-day insertion period. TABLE 3. INITIAL PROGESTERONE LOAD AND RESIDUAL PROGESTERONE CONTENT IN EACH OF THE DIFFERENT INTRAVAGINAL DELIVERY DEVICES INVESTIGATED IN THE STUDY AFTER A 7-DAY INSERTION PERIOD

[00206] Both the initial progesterone load before insertion and an amount of progesterone released from the insert over 7 days varied with the thickness and surface area of the impregnated mass. For any given surface area, residual progesterone loads and residual % initial load were lowest in the thinnest intravaginal inserts. The amount of progesterone released per day was the same for inserts of the same surface area regardless of impregnated mass thickness or initial progesterone load. The amount of progesterone released per day increased with increasing insert surface area. The amount of progesterone released per unit area per day was similar for all inserts studied.

2. STUDIES ON INTACT ANIMALS - RELEASE RATE OF IN VIVO DRUG 2.1 METHODOLOGY

[00207] In this study, 72 beef Brangus cattle with intact ovaries weighing 300 to 450 kg were given intravaginal delivery devices of various surface areas and skin thicknesses that were formulated with various w/w% drug loadings (see to Table 1). The in vivo drug release profile of an intravaginal delivery device was determined by administering the intravaginal delivery device into the vagina of cattle using a plastic applicator and leaving them in place for varying periods of time (3 , 4, 5, 6, and 7 days), the intravaginal delivery devices were removed (n >2 per time period). After removal, the amount of progesterone remaining in each intravaginal delivery device was determined in each device using an alcoholic extraction method that involved placing the impregnated masses of the intravaginal delivery device into a 250 ml plastic bottle. To it was added 200 ml of SDA (denatured ethanol containing 50 ml/l of methanol). The bottle was left for more than 17 hours with occasional hand shaking until complete extraction of the progesterone. Drug content was quantified by UV at 239 nm after appropriate dilution. Plots of amount of progesterone released from the intravaginal delivery device versus time (days) were plotted.

2.2 RESULTS

[00208] For the entire duration of insertion, each of the intravaginal delivery devices released more progesterone, in a similar fashion as commercially available intravaginal devices.

[00209] Figure 4 shows a plot of amount of progesterone released versus time (days) for each of the different intravaginal delivery devices investigated in the study.

[00210] When comparing intravaginal delivery device 1 (115 cm2, 21% w/w, 0.5 mm) with 2 (115 cm2, 21% w/w, 0.3 mm) and the delivery device delivery 4 (450 cm2, 21% w/w, 0.5 mm) with 5 (450 cm2, 21% w/w, 0.3 mm) it can be seen that if the surface area and progesterone concentration (% w/w) are held constant, and only the thickness of the impregnated mass is varied, these similar in vivo progesterone release profiles result.

[00211] This result allows the thinner impregnated mass or masses to achieve equivalent progesterone release profiles.

[00212] The intravaginal delivery device 3 (195 cm2, 15.8% w/w, 0.3 mm) and 6 (450 cm2, 15.8% w/w, 0.3 mm) show that increasing the surface area of the intravaginal delivery device results in an increased amount of drug delivered. This observation is supported when comparing delivery devices 1 (115 cm2, 21% w/w, 0.5 mm) and 4 (450 cm2, 21% w/w, 0.5 mm) and delivery devices 2 (115 cm 2 , 21% w/w, 0.3 mm) and 5 (450 cm 2 , 21% w/w, 0.3 mm).

[00213] This result means that the surface area can be varied, for example, to customize the device for different delivery profiles, as would be required for use in tropical zone cattle (milk emissions <25 l) or, for example in high lactation Holstein cattle (>45 l).

[00214] Drug release rates were estimated for each different intravaginal delivery device and are shown in Table 4. TABLE 4. DRUG RELEASE RATES FOR EACH INTRAVAGINAL DELIVERY DEVICE.

[00215] Table 4 shows that all inserts of the same surface area released drug at the same release rate regardless of the drug load and the thickness of the impregnated mass on each surface area studied due to the fact that each insert in the study was designed to ensure the % w/w loading was above 10% w/w as required. This information can be used to design an intravaginal delivery device with the appropriate release rates, which leads to the minimal amounts of silicone and progesterone required for the purpose, resulting in a low-cost intravaginal insert to manufacture that delivers sufficient progesterone. at the right release rate for the insertion period to completely control the estrous cycle of cattle.

[00216] Table 5 shows the initial progesterone load, % w/p and residual progesterone content in each of the different intravaginal delivery devices investigated in the study after a 7-day insertion period. TABLE 5. INITIAL PROGESTERONE LOAD AND RESIDUAL PROGESTERONE CONTENT IN EACH OF THE DIFFERENT INTRAVAGINAL DELIVERY DEVICES INVESTIGATED IN THE STUDY AFTER A 7-DAY INSERTION PERIOD.

[00217] The initial progesterone load before insertion and the amount of progesterone released from the insert over 7 days varied with the thickness and surface area of the impregnated mass. For any given surface area the residual progesterone loads and % initial residual load were the lowest in the thinnest intravaginal delivery devices. The amount of progesterone released per day was the same for intravaginal delivery devices of the same surface area regardless of impregnated mass thickness or initial progesterone load. The amount of progesterone released per day increased with increasing insert surface area. The amount of progesterone released per unit area per day was similar for all intravaginal delivery devices studied.

[00218] The residual observations underscore an advantage of intravaginal delivery devices over commercially available inserts. The use of thinner impregnated masses (0.3 mm) results in the residual amount of progesterone remaining in an intravaginal delivery device to be less (less than 90 mg) compared to commercially available inserts (e.g., the Cattle Insert CIDR 1900 and CIDR 1380 cattle inserts which exhibit residual progesterone content after 7 days of inserts of 1250 mg and 730 mg, respectively).

EXAMPLE 3 - MANUFACTURING FLAT SHEETS USING EXTRUSION MOLDING

[00219] Progesterone (21% by weight) is accurately weighed and added to a sufficient amount of silicone material accurately weighed and homogeneously mixed by a blade stirrer.

[00220] The silicone/progesterone mixture is delivered in a barrel. The plastic is then forced through a hole in a steel die custom shaped to the cross-sectional shape of the intended part, and forms a flat sheet continuous workpiece.

[00221] The workpiece is cooled and then cut into the desired shape using predefined shaped cutters before clamping onto a preformed spine manufactured by injection molding.

EXAMPLE 4 - MANUFACTURE OF FLAT SHEETS USING INJECTION MOLDING

[00222] Progesterone (21% by weight) is accurately weighed and added to a sufficient amount of silicone material accurately weighed and homogeneously mixed by a blade stirrer.

[00223] The two halves of the mold are securely closed and the hydraulically powered clamping unit exerts sufficient force to keep the mold securely closed while the material is injected.

[00224] Then, the mixture is fed into the injection molding machinery, and advanced towards the mold through the injection unit. A precisely measured amount of silicone/progesterone mixture is then injected into the mold (dose). The silicone inside the mold is then heated in order to cure the mold.

[00225] After sufficient time has passed, the heated silicone/progesterone flat sheet is removed from the mold. Once the part has been ejected, the mold is squeezed tight for the next dose to be injected.

[00226] The cured silicone/progesterone flat sheet part is then allowed to cool. The cooled cured flat sheets are then secured over a preformed spine fabricated by injection molding.

Claims (14)

1. Delivery device insertable, retainable and withdrawn from a body cavity of a non-human target mammal, characterized in that it comprises a resilient frame (2), and one or more impregnated masses (1) formed from a polymer, which have a thickness of about 0.1 to about 0.8 mm, which are impregnated with one or more active agents, and each of the one or more impregnated masses (1) being supported by the frame resilient (2) at at least two or more separate attachment points, and in which the ratio of the mass surface area of the impregnated masses (1) to the mass of the polymer is 12:1 (surface area: polymer mass) at 60:1 cm2.g-1. 2. Delivery device, according to claim 1, characterized in that the impregnated mass or masses (1): a) are substantially laminar to thereby comprise two opposite faces, or b) are flat, or c) include openings, cuts in curves or protrusions for engaging protrusions, bosses or seats of the frame (2), or d) are formed of a polymer, or e) contain one or more active agents, or f) any combination of (a) through (It is). 3. Delivery device, according to claim 1 or 2, characterized in that the frame (2) a) substantially presents the whole of each face of the impregnated mass or masses (1) to exposure to a cavity fluid of body when retained therein, or b) is in the shape of a "T"', "t", "Y", "V", "C", "X" or "M", or in the shape of a wishbone, kite or diamond, or c) has an implanted and non-implanted condition, or d) includes one or more projections from the main body of the device, or e) includes seats or projections on which part of a face on which the one or more masses (1) is retained in the frame (2), or f) is in the form of a skeletal frame (2) for supporting one or more impregnated masses (1), or g) is formed of a polymer, or h) any combination of (a) through (g). 4. Delivery device according to claim 3, characterized in that the polymer is selected from polycarbonate, a polyethylene, a polypropylene, a nylon and a combination thereof. 5. Delivery device according to claim 3 or 4, characterized in that the delivery device comprises a) about 2 to about 10 g of polymer, or b) about 1 to about 8 cm3 of polymer. 6. Delivery device according to any one of claims 3 to 5, characterized in that the polymer is selected from a non-degradable thermostable polymer, a non-degradable thermoplastic polymer, a biodegradable polymer or a combination thereof. 7. Delivery device according to any one of claims 1 to 6, characterized in that at least one of the one or more impregnated masses has a thickness of about 0.1 to about 0.95 mm. 8. Delivery device according to any one of claims 1 to 7, characterized in that the impregnated mass (1), or each, contains about 1 to about 75% by weight of the active agent. 9. Delivery device according to any one of claims 1 to 8, characterized in that the impregnated masses (1) have at least two surfaces with substantially the same surface area, both surface areas being substantially exposed to body cavity fluid upon insertion into the mammal, wherein at least 70 to about 95% of the surface of both surfaces are exposed to body cavity fluid upon insertion into the mammal. 10. Method for manufacturing a delivery device for insertion into a body cavity of a non-human target mammal, characterized in that it comprises providing a resilient frame (2), molding an impregnated mass (1) having a thickness of less than 0.95 mm, and attaching the molded impregnated mass (1) to the resilient frame (2) such that the molded impregnated mass (1) is supported by the resilient frame (2) at at least two or more separate attachment points , and in which the ratio of the surface area of the mass of the impregnated masses (1) to the mass of the polymer is from 12:1 (surface area: mass of polymer) to 60:1 cm2.g-1. 11. Method, according to claim 10, characterized in that the one or more impregnated masses (1) molded: a) are manufactured by compression molding, extrusion, casting or injection molding, or b) include at least two or more slots, openings or passages to facilitate attachment to the frame (2), or c) are each attached to the frame (2), or d) are retained by the frame (2), with or without seat from any region of a or more masses (1) in the frame (2), or e) are held outside on the frame (2), or f) are held within the frame (2), or g) any combination of (a) to (f ). 12. Method according to claims 10 or 11, characterized in that the fixing passages are molded in the impregnated masses (1). 13. Method according to any one of claims 10 to 12, characterized in that the one or more molded impregnated masses (1) are attached to the frame (2), but are spaced from the frame (2). 14. Method according to any one of claims 10 to 13, characterized in that, after removal from the mammalian delivery device, the one or more impregnated masses (1) contain less than about 40% by weight from the original active agent load, and useful ranges can be selected from any of these values.