NZ506120A - Drug delivery system with a central aperture able to slide over a supporting structure and with fingers extending from the support structure which dispense the drug - Google Patents

Abstract

A substance delivery device 10 suitable for delivery of hormonal and other veterinary treatments intra vaginally is disclosed. The substance delivery device 10 has a substance dispenser 12 releasably attached to a supporting structure 11. The substance dispenser 12 has a central aperture that allows the substance dispenser 12 to slide over a corresponding section of the supporting structure 11. The surface area of the substance dispenser is independent of the supporting structure. The substance dispenser 12 has drug impregnated fingers 13 extending away from the supporting structure 11.

Description

wo 99/40966 DRUG DELIVERY SYSTEM pct/nz99/00016 Technical Field This invention relates to a substance delivery system Reference throughout the specification shall be made to the use of the present 5 invention as a drug delivery system for use m animal body cavities, such as the vagina It should be appreciated however that the present invention can be used to dehver substances other than drugs and can be used in relation to humans and in other body cavities, for example the rumen, ears and so forth.

BACKGROUND ART Drag delivery systems are used extensively in controlled breeding and reproductive management. Although considerable research has been invested m the design of these devices, there are still problems associated with them Firstly, these devices are required to be retained withm the body cavity for the 15 slow release of drugs over a period of time. To facilitate this, various arms and projections have been built into the device which can either engage with the walls of the body cavity, or make the device wide enough such that when in the body cavity it cannot naturally exit the animal through the entrance orifice Major problems with the provision of such arms or projections is that they can 20 irritate or even rupture the lining of the body cavity, causing distress to the animal and providing a site for possible infection.

A major problem with drug delivery devices is that traditionally they have been manufactured with the drug impregnated into the material from which the device is 1 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 made Typically, this material is in many instances a matrix of silicone.

To manufacture devices from drug impregnated silicone is expensive.

A further disadvantage of using a drug impregnated device is that it is very difficult to dispose For example, the hormones used in reproductive management 5 are required to be disposed in accordance with heavily regulated environmental procedures. As it is always possible that the drug within the silicone matrix had not been fully delivered to the animal when the device is removed, the whole device will have to be disposed as the whole device is the drug delivery system It would be desirable if the devices could be reused Another problem with the devices is that they have a specific dose rate which cannot be readily changed Further with these devices, the treatment cannot be changed or customised according to requirements.

In some animals such as cows, the progesterone dose rate for synchronising oestrus is critical to the reproductive cycle. Typically, in the pre-luteal phase the 15 animal will reproduce follicles which are the stage that ovum are produced Follicule maturation then occurs and the follicule develops into the corpus luteum in the ovary Fertilisation can then occur Therefore healthy follicules are a pre-requisite for conception.

Exogenous progesterone is often delivered to cows to inhibit follicle maturation as 20 a means of synchronising oestrus. When the treatment is removed progesterone levels fall and the animals cycle in a controlled manner. If however the progesterone blood levels during treatment fall below critical levels oestrus synchronisation may still occur but follicle integrity may be compromised thereby reducing conception rates and fertility. This condition highlights the necessity to 2 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 maintain adequate progesterone dose using an efficient drug delivery system.

To maintain adequate dose previous drug delivery systems have contained excessively high progresterone dose levels This has resulted in high residual levels of drug remaining in the device after use which has adverse economic and 5 environmental impacts In addition, various applications of a treatment may require different drug delivery periods For instance, one treatment may require six days drug delivery, another treatment may require ten days drug delivery In this situation an ability to offer dose choice would be feasible Also, very large animals of the European breeds 10 may require larger doses than the smaller animals on pastoral systems in countnes like New Zealand What would be desirable then is a drug delivery device that delivers the drug in a sufficient quantity over the treatment period with a minimum of residual drug remaining in the device matrix after treatment to achieve production economies 15 and to avoid adverse environmental impacts caused by disposing used devices in land fills that contain large quantities of hormones. Flexibility in being able to change or customise the treatment would be desirable It is an object of the present invention to address the foregoing problems or at least to provide the public with a useful choice Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only Disclosure of Invention According to one aspect of the present invention there is provided a substance delivery device, 3 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 including a substance dispenser characterised m that the surface area of the substance dispenser is independent of the supporting structure of the substance delivery device The substance delivery device should now be referred to as a drug delivery device 5 such as an intravagmal release device (IRD) It should be appreciated however that a device in accordance with the present invention can be adapted for use in other body cavities such as the rumen, the auditory system, the gum area and other body cavities It should also be appreciated that the present invention can be used in both humans 10 and animals.

In preferred embodiments, the present invention may be used m the treatment of cows.

The applicant has recognised that a dissolution process as a means of drug delivery is very effective provided the drug release process is controlled. The applicant has 15 m his invention concentrated on the principles which aid dissolution, namely the surface area and thinness of the substance dispensers, surface area exposed directly to the body cavity and m some embodiments the holding of drugs in cavities in the dispenser.

It should be appreciated however that other drug delivery methods can be used 20 such as mechanical or electronic.

The present invention can also be used to introduce a biological monitor such as a thermometer.

As a further issue the applicant has also been conscious of providing a ready SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 means by which the drug profile delivered by the substance delivery device can be readily modified For example, different animal weights require different amounts of drugs The substance being delivered may come in a variety of forms For example, these 5 may be liquid, bullets, powder, gel, and other such forms. However, this list should not be seen to be exhaustive.

In one embodiment, the substance dispenser may be a pod with a housing containing vanes. Preferably, the pod may take the form of an obloid The vanes may be positioned so that they are axially directed through the centre of the sphere 10 and are in contact with the inside of the sphere at their outer edges.

Having one embodiment of the substance dispenser as a pod should not be seen to be limiting, as the principles of the present invention may be applied using a substance dispenser of a different configuration.

For example the substance dispenser may be a substantially cylindrical device 15 containing vanes, or containing a grid, honeycomb or mesh arrangement. The grid, honeycomb or mesh arrangement may also be applied to the pod configuration for equal effectiveness In preferred embodiments, the dispenser may be a temporary attachment to a supporting structure, or could be applied as a permanent attachment to a 20 supporting structure. In a further preferred one embodiment the dispenser may be a free-standmg delivery pod within the body cavity.

Preferably the dispenser may be used as a temporary attachment to a supporting structure, such as can be found in New Zealand Patent Application No. 328967. Reference to the device in New Zealand Patent No. 328967 should not be seen to 25 be limiting, as the supporting structure may constitute another form of device SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 while still maintaining the advantages of the dispenser. pct/nz99/00016 In some embodiments in the present invention the dispenser may be used m conjunction with existing structures on the market such as those described in New Zealand Patent No. 207341. The substance delivery device disclosed m that patent 5 application has substance to be delivered contained in the matrix of the supporting structure with all of the inherent problems described earlier m this patent specification However, the present invention could be used to provide add-on substance delivery devices to its supporting structure which may either supplement or substitute for the substance contained within that supporting structure.

One advantage of configunng the dispenser as a pod containing vanes is that the pod has a large surface area, provides increased durability, and provides increased comfort to the animal to which the device is applied.

In further preferred embodiments, the dispenser may have the capability of having supplementary dispensers attached to an existing dispenser. These supplementary 15 dispensers may be of any suitable shape, such as a cylindrical device, a grid arrangement or a honey-comb or mesh arrangement.

However preferably, the supplementary dispenser may be a substantially cylindrical device containing vanes extending towards the centre of the cylinder.

The above configuration of the supplementary dispenser is that this device may be 20 co-operatively attached to the mam dispenser, with greater co-operation between the two structures, due to the facing edges of the two dispensers being substantially the same configuration.

The advantage of a supplementary dispenser as discussed above will be discussed further on. 6 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 In preferred embodiments the support structure may be any device that maintains the structural rigidity of the substance delivery device For example the support structure may be a frame, a system of struts, a cantilever support, an air cushion support, a hydraulically supported device, or some other means of support.

In preferred embodiments, the substance being delivered may be drugs such as hormone treatment substances, for example, progesterone. Reference to the substance being delivered shall hereafter be referred to as drugs, however this should not be seen to be limiting the scope of the present invention's manufacture or use, as other substances may be delivered by the present invention without 10 departing from the present invention's scope of manufacture or use.

This should not be seen to be limiting as other drug delivery devices may be used For example, the drug deliveiy device may be a spine (support structure) with fingers or objects extending from the centre of the spine that carry the drug and such fingers or objects.

Alternatively, there may be a central fixture point with radially extending arms or fingers. The substance to be delivered may be coated or impregnated on these spines or fingers.

Other embodiments of the present invention may be used without departing from the scope of the present invention.

Preferably, the vanes may be coated or impregnated with the substance to be dispensed. This has a number of advantages.

The increased surface area of the IRD means that a greater rate of substance transfer may be achieved Furthermore, the relatively thin nature of the vanes means that a substance that is contained within the material the vanes consist of, 7 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 may diffuse more quickly to the outside surface of the vane and be transferred to the animal This means that a greater proportion of the drugs will be dispensed.

The ability to regulate the device surface area to influence dose levels and to regulate the dose profile through matrix thickness enables specific dose 5 formulations to be delivered through design by varying vane sizes and thickness.

Therefore, the problems associated with residual progesterone in the device may be reduced or overcome. Reduced thickness of the vanes coupled with increased surface area creates more efficient drug transfer resulting in reduced residue. No drugs are associated with the support structure of the IRD.

Therefore, maximum release of drug to specific dose requirements is achieved also providing minimal residue and an ability to modify surface areas and matrix thickness to meet specific treatment needs. With progesterone treatment good synchrony and fertility rates may be achieved using considerably less progesterone and matrix raw material than existing technologies. Drug residue will be 15 considerably less than existing technologies.

In further preferred embodiments, the vanes may be coated with different drugs and different combinations This has an advantage that a multi drug dosing system may be implemented.

In some embodiments, the vanes may be configured so that they form a cavity 20 within the drug delivery device. This has a number of advantages.

The first advantage is that the cavities provide an increased surface area whereby fluid which is body fluid may interact with the increased surface area in the cavity, thereby increasing the capacity for the device to dispense the particular drug desired. 8 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 Secondly the cavities provide a space whereby additional matenals such as further drugs may be stored for release, improving the drug dispensing economy and storage capacity of the drug dispensing device A third advantage of the cavities is that a greater number of cavities provides for 5 multi-dose variability withm specific cavities, for delivery of various drug delivery profiles Thus depending on the dosing required, the amount of drug and particular type of drug may be stored m a particular cavity The vanes or cavity surface may be covered with a biodegradable surface to rate release additional substance By combining various drugs with various vane thicknesses, the consumer may tailor the drug delivery and dosing to match the particular need of the animal. These needs may be in terms of a type of drug required to be dispensed, and the length of time the drug should be dispensed in.

Thus, various drug delivery profiles may be achieved.

In preferred embodiments, the vanes may not be surrounded by an outer wall and project directly into the body cavity - being directly exposed to the body fluids in which the drugs dissolve.

Thus the most appropriate dose may be selected and applied to each specific treatment, independent of the mam earner body. This may be selected on the 20 basis of different dosmg sizes for larger or smaller animals by weight, but other factors such as the age of the animal, and the medical condition of the animal or other conditions may be used.

The present invention may be manufactured from any substance capable of being impregnated or coated with, and then releasing a drug. For example the present 9 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/000i6 invention may be manufactured from plastic, kevlar™, wood, glass, silicone or other substances Preferably however, the present invention may be manufactured from plastics material, polymers or elastomers. The advantages this gives are that the plastic is 5 easily manufactured into the desired shape, is cheap to manufacture, and is malleable so as to prevent irritation to the animal when m use.

In preferred embodiments the material from which the substance dispenser is biomedical silicone elastomer rubber (polydimethylsiloxane). The applicant has found that this material is soft, pliable, does not untate body tissues and can carry 10 release substances embedded in its matrix The feature of the present invention regarding the supplementary dispenser, enables increased control over dose variance. A supplementary dose or a half dose or other dose profiles may be applied by fixing a supplementary dispenser to the main earner body or to the existing dispenser.

Thus, more than one substance may be delivered at a time.

The use of a dispenser provides the ability to replenish treatments or applications, and/or apply them for sustained penods by replacing the dispenser, or adding a supplementary dispenser.

The dispenser design maximises the surface area such that the dose can be 20 enhanced. This is particularly useful when silicone or polymer type materials are used in the construction of the dispenser for delivering the substances via dissolution processes.

The thickness of the vanes can be modified and vaned such that the drug delivery rates can be manipulated to suit the species and dose profiles required SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 An example of the benefits of a dispenser application follows In the intravaginal delivery of progesterone in cattle, whereby progesterone is impregnated into a silicone matrix requiring a sustained dose of approximately two ng/ml of exogenous progesterone in the blood. If dose levels decline below this, 5 the follicule condition is impaired and the desired conception rates from the treatment are not achieved after removal of the device Using the dispenser, various forms of drug delivery can be applied and are not limited to polymer-based dissolution systems. For example, the dispenser cavities could be loaded with substances using a biodegradable coating to regulate the 10 release.

Alternatively an electronically controlled pump may be inserted in the dispenser to release the substance.

In a further preferred embodiment, biological monitor such as an electronic thermometer may be inserted into at least one dispenser to provide real time body 15 temperatures. Alternatively, momtors to detect pH, trace elements, hormones, batena or viruses may be used This has an advantage when determining and monitoring an animal's bodily functions, which may be used to determine the dose variants or drug delivery profile required In preferred embodiments, the substance dispenser is in the form of drug impregnated gills attached to the supporting structure The surface area of the gills can control the amount of drug delivered and the thickness and number of the gills controls the duration of the dose, and the dose profile.

Surface area based on flaps or gills that have no "central spine" component (as in 11 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 CIDR patent) provides a pliable matrix and enables protruding shapes such as gills to be used as these can be compacted for insertion into the body cavity and do not irritate mucosa due to their softness and shape The lack of a rigid spme component also reduces the overall mass of the device Therefore, the size of the gills can be used to modify the drug profile as required. Preferably, the profile has a fast drop off with little residual drugs as a consequence of applying these novel design concepts The gills may also be impregnated with different drugs.

In some embodiments, the gills may be of different types, for example, end gills 10 and middle gills, wherein the end gills ensure the middle gills are secured with respect to the supporting structure.

The gills have a central aperture that allows them to be readily pushed onto (or pulled off) a supporting structure. This allows the number of gills and hence dosage amount to be readily changed Also, only one supporting structure can be 15 used for multiple treatments by removing expended gills and replacing them with fresh gills.

This leads to significantly less wastage than previous devices and less disposal problems In a preferred embodiment of the present invention, the gills are moulded into a 20 sleeve which slides over an arm of the supporting structure. By having the gills moulded into the sleeve, the spacing between the gills can be optimised to ensure that there is no competition between the gills m terms of drug release and that the mucosal absorption is not overloaded.

In this latest embodiment, the dosage or treatments can be changed by removal of 12 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 the whole sleeve in replacement of a further one.

The sleeves may also be made with varymg numbers of gills depending on the type or amount of treatment which is required to be given Preferably, the gills are made of a soft and pliable silicone This aids animal 5 comfort and welfare and in insertion and removal of the IRD with respect to body orifices. This allows certain configurations of IRDs to be compressed to a smaller size than more rigid devices.

Brief Description of Drawings Further aspects of the present invention will become apparent from the following 10 description which is given by way of example only and with reference to the accompanying drawings m which.

Figure 1 shows various views of a vaned pod embodiment, and Figure 2 shows various views of gills used in one embodiments, and Figure 3 shows various views of further variation of the pod m Figure 1, and Figure 4 shows various views of different gill sleeves used in the present invention, and Figure 5 shows a sleeve embodiment, and Figure 6 illustrates a petal shaped variation of the gills. best modes for carrying out the invention In the reference to Figure 1 there is shown a plan view of a substance dispenser in 13 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 the form of a pod generally indicated by arrow 1 The pod includes two half hemispheres (2), supporting vanes (3) and cavities (4) In use, the pod (1) is attached to a support structure (not shown) before being inserted into the vagina of an animal such as a cow The hemispheres (2) and the 5 supporting vanes (3) may be coated with the drug that is required to be dispensed. The pod (1) may be fixed to an insertion device not shown The supporting vanes (3) may be used as a storage location for further drugs or other substances that are required to be released.

Each of the van^ (3) may be coated or impregnated with the same or a different 10 substance simito' , the cavities (4) may hold additional drugs or substances required to be d' pensed.

Figure 2 shows individual plates which in combination form gills generally indicated by arrow (5) which can be inserted into a support structure of an IRD The end gills (6) can be anchored to the support structure ensuring that the middle 15 gills (7) which may sit loosely on the structure do not fall off.

Figure 3 illustrates a vanation of the embodiment m Figure 1, without an outer shell allowing the vanes to have direct contact with body fluid.

Figure 3 illustrates three IRD's, each with the same supporting structure, but with substance dispensers having diffenng number gills.

The dispenser (12) m the form of a sleeve having gills (13) moulded therein. Sleeves (12) can be readily fitted over or removed from the arms (14) of the supporting structure (11) It can be seen that initially different dose amounts can be introduced to the animals 14 SUBSTITUTE SHEET (Rule 26) Printed from Mimosa wo 99/40966 pct/nz99/00016 by usmg different sleeves It should also be seen that after treatment has commenced, there is still flexibility provided through the removal and replacement of the dispensers (12).

Figure 5 shows an alternate sleeve embodiment of an IRD generally indicated by 5 arrow (20) with a gill sleeve (21) that is detachable Consequently, the consumer may design a particular drug delivery profile that is suited to the particular application and needs of the animal. The thickness of the vanes may be varied, to comply with the required dosing rate and drug delivery profile for the particular drug the vanes are impregnated or coated with Similarly, 10 the cavities in Figure 1 may contain an appropriate amount of the substance to be delivered, to comply with the particular drug delivery profile required to suit the particular needs of the animal.

Figure 6 illustrates some possible cross-sections of gills (15) in having petals (16) The applicant has found that petals provide greater flexibility/pliability to the gills 15 (15) providing greater animal comfort and ease of insertion as well as enhancing the dissolution process.

Aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope of the appended claims SUBSTITUTE SHEET (Rule 26) Printed from Mimosa

Claims (10)

CLAIMS:

1. A substance delivery device, including a substance dispenser attached to a supporting structure by a releasable attaching means wherein the substance dispenser has a central aperture allowing the substance dispenser to slide over a corresponding section of the supporting structure and be readily removed from same, characterised in that the surface area of the substance dispenser is independent of the supporting structure and the substance dispenser is m the form of fingers extending from the support structure.

2. A substance delivery device as claimed in claim 1 wherein the said fingers are gills.

3 A substance delivery device as claimed in claim 1 wherein the said fingers are vanes.

4. A substance dispenser as claimed in any one of claims 1 to 3 wherein the fingers are coated or impregnated with the substance to be dispensed.

5. A drug delivery device as claimed in any one of claims 1 to 4 wherein the substance dispenser is made from polydimethylsiloxane.

6. A substance delivery device as claimed in any one of claims 1 to 5 wherein the substance dispenser is highly flexible.

7 A substance delivery device as claimed in any one of claims 1 to 6 in the form of a intravaginal release device. Intellectual Ptopertv Office of N.Z. 2 2 NOV 2001 RECEiwf.O 16 PCT/NZ99/00016 Received 5 April 2000

8. A substance delivery device as claimed in any one of claims 1 to 7 for use with cows.

9. A substance delivery device substantially as herein described with reference to and as illustrated by the accompanying drawings.

10. A method of delivering drugs substantially as herein described with reference to the description within the specification. 17 AMENDED SHEE'f IPEA/AU