Sustained release medicating device for livestock

Abstract

Indwelling sustained release reservoirs for dispensing bloat-controlling agents to the rumens of grazing livestock. A plurality of osmotic dispensing devices with varying release patterns generate by bioerodible deposits on their osmotic membranes. The devices are linked together by bioerodible means so that they may be released and pass from the rumen when their contents are exhausted.

Description

This invention relates to devices for providing sustained release of therapeutically active substances into the body. In particular, it relates to such devices which release medication as a result of osmotic pressure generated within the devices themselves.

BACKGROUND OF THE INVENTION

The great desirability of grazing livestock upon alfalfa has long been known. The high protein content of that legume leads to enhanced weight gain in calves permitted to feed upon it. However, a great disadvantage exists. That is the tendency of alfalfa to cause bloat in ruminant stock, particularly cattle and sheep. The bloat is caused by the production and retention of an excess of frothy gas in the rumen, due to the microorganisms of the rumen and the high protein content of the alfalfa. (J. Quin, 1943, Onderstepoort J. Vet. Sci. 18:113 and Weiss, K. 1953, Onderstepoort J. Vet. Res. 26:241) If untreated, the pressure from the gas may accumulate in sufficient quantities to cause discomfort, and even death, by its interference with cardiovascular functions.

A number of chemicals have been tried in order to prevent and treat the frothy bloat. For example, emulsified oils were applied directly to the pasture by Johns and coworkers in New Zealand (A. Johns, N.Z.J. Sc. Tec. A. 36:289). This proved a semi-effective means of treating bloat but was not completely successful in that the oils were rapidly passed through the rumen and the reliability of the method was thus unsatisfactory.

In a seminal paper, Oxford (A. Oxford, N.Z.J. Agri. Res. 2:365) investigated the possible control of certain protozoa (Epidium ecaudatum) which were thought to contribute to bloat. It was further noted that the bloat retarding agent must not be lethal to friendly bacteria which are in the gut. In his paper Oxford points out that a particular class of neutral nonionic surface active agents consisting of straight chain polymers are interesting in this regard. In particular, he advocated the use of polyoxypropylene-polyoxyethylene block polymers at 80% polyoxypropylene and 20% polyoxyethylene.

In a later paper Reid, et al. (C. Reid, et al. N.Z.J. Agri. Res. 4:476 (1962)) carried out field tests using this compound and concluded that whereas such chemicals were useful in a gullet drench, they were not useful as an addition to the drinking water since due to "their bitter taste they are not suitable via drinking water".

Another important paper, Phillips (D. Phillips, N.Z.J. Agri. Res. 11:85 (1968)) concluded in his studies that a polyoxypropylene - polyoxyethylene polymer at 60% polyoxypropylene and 40% polyoxyethylene with a molecular weight of 2,900 was effective when mixed in the drinking water provided the cows were given time to become accustomed to the taste.

Along these lines, Bartley and Scott in their 1969 U.S. Pat. No. 3,465,083 argued that polyoxypropylene-polyoxyethylene block polymers at 67% polyoxypropylene and 33% polyoxyethylene with a total molecular weight of around 3,000, was both effective in controlling bloat and more palatable to the animal. They called this compound "poloxalene". In particular, in claims 6 and 7 of their patent they suggest the addition of the polymer to a molasses salt block ("Bloat Block") on the one hand and as a top dressing administered in granular form on the other. Other pertinent patents are U.S. Pat. Nos. 4,005,192 and 4,061,728, describing a block of reaction products of molasses, magnesium oxide and polyoxypropylene surface active compounds.

While the effectiveness of poloxalene has been demonstrated in many tests, substantial death losses have been associated with its use. In particular, many animals are not as interested in the "Bloat Block" or the poloxalene crumble, as are others, and they do not consume enough of the bloat retardant in order to enable them to safely graze the alfalfa foliage. Furthermore, the cost per animal is substantially higher than it should be since animals which do appreciate the molasses block may consume many times more per day than is required to control the bloat. This has the bad side effect of administering more of the chemical than one would like and, furthermore, it is a substantial economic disadvantage.

For these reasons it would be desirable to achieve a more uniform dosage in order to cut these substantial death losses, and provide a more economic administration of the bloat retardant.

Adding the poloxalene to drinking water would be an attractive solution to these problems. This would ensure a uniform and adequate consumption of the chemical by each animal since each animal drinks a consistent one gallon of water for one hundred pounds of body weight per day. However, the straight application of poloxalene to drinking water has several problems. The palatability of the material is a problem, as has been noted previously, and poloxalene is not easy to bring into solution. When added directly to the water it tends to gell and settle to the bottom of the water tank. In this latter context, Oakes, et al. (U.S. Pat. No. 4,407,780, Oct. 4, 1983) have pointed to previously used compositions as suffering from various disadvantages of gell formation, and lack of solubility which thus leads to difficulty when used under actual farming conditions. Furthermore, in the application of the bloat retarding chemical to drinking water, it is essential that the animals do not have access to other forms of drinking water since this would negate the benefits of the treated water. This is difficult to achieve in a farming operation of considerable size. For all these reasons, a carefully managed program is necessary in order to insure that the animals consume a proper quantity of the bloat retardant per day.

It would appear desirable to administer the bloat retardant by an indwelling reservoir which dispenses a controlled amount of the substance over a continuing period of time. Such devices are well-known in the medical, experimental and veterinary arts. See, for example, the book, Sustained Release Medications, J. C. Johnson, editor, Chemical Technology Review No. 177, Noyes Data Corporation, Park Ridge, N. J., 1980. That book describes patents issued between 1974 and 1980 related to the art under discussion. One such patent, U.S. Pat. No. 3,844,285, discloses an expanding indwelling dispenser for bloat control (page 401).

The present invention belongs to the class known as osmotic dispensing devices. Many such devices are discussed in the chapter "Osmotic Dispensing Devices" pp. 114-151, of the Johnson book described supra.

In an osmotic dispensing device, a dissolved substance is contained in a device carried within the animal to be treated with the situation. At least a portion of a wall of the device is a material such as a membrane permeable to an external fluid in the environment of use. The fluid diffuses through the membrane, and the resulting increase in pressure causes the dissolved substance to be expelled to the exterior of the device. Depending upon the mechanism used, zero order (constant) release rates can be achieved (see Johnson, pp. 114-115; U.S. Letters Pat. No. 3,845,770).

Hitherto such osmotic dispensing devices have not been appropriate for use in bloat control of livestock, for two primary reasons. The first is that the medication for bloat control is required to be dispersed for a much longer period of time and in greater amounts than in the usual application in order to be practical. The spent dispensing devices will thus need to be removed from the rumen. The second reason is that as the animal grows the bloat retardant must be released at a faster rate.

There is thus a need for osmotic dispensing devices which are large enough to be used for an extended period of time in livestock without needing frequent replacement, but can be removed at the end of that time, and which will dispense an increasing amount of medication as time passes.

SUMMARY OF THE INVENTION

According to the present invention, bioerodible substances are employed with osmotic dispensing devices to meet the above described needs. The use of such substances is not unknown in the art; see for example U.S. Pat. Nos. 4,036,277; 4,093,708; 4,096,238 and 4,135,514, in which the osmotic membrane has a bioerodible outer layer.

In my invention, however, a series of simple boluses, on a strand, are adapted to be retained in the rumen. Each bolus is an osmotic dispensing device which in the preferred embodiment is adapted to release bloat retardant at a greater rate or in a greater concentration than the one before it. The osmotic membrane of each is protected by a bioerodible layer, and the thicknesses of the layers are graded so that each bolus releases its contents in turn as the animal grows. The connecting strand comprises a series of strings at least a portion of each of which is also bioerodible according to the same approximate gradient. As a result each string separates its bolus from the strand when that bolus has been emptied of its dose; the bolus can then be eliminated either by passing through the digestive tract, or by being regurgitated with the cud, while the next bolus in turn releases its greater quantity of bloat retardant. Such a device may be simply constructed of known, inexpensive and readily available materials.

Accordingly, it is an object of my invention to provide a device for long-term implantation into ruminant livestock, which device will release a substance at a rate generally proportional to the increasing size of the animal.

A further object of the invention is to provide such a device which is simple and economical to manufacture.

Yet a further object of the invention is to provide a means of bloat control for ruminant animals, which control is economical, easily administered, and requires little continued supervision of the animals.

Further objects of the invention will appear from the claims herein and from the description to follow of a preferred embodiment, taken together with the Figures amended hereto, in which

FIG. 1 is a schematic view of a preferred embodiment of the invention, taken in cross-section, and

FIG. 2 is a schematic view of an alternate embodiment of the invention, taken in cross-section.

DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION

FIG. 1 shows in schematic form the dispensing device of the present invention. Osmotic dispensing devices 10 and 20 are linked physically by a strand 30 having a portion 31 which is bioerodible, or biodegradable. That is, bioerodible portion 31 is constructed of a material which is attacked and degraded by substances naturally occurring in the (human or other animal) body environment in which it is used.

Such substances are well-known in the prior art. For example, the use of waxes and fatty acids such as stearic acid has long been known; see, for example, U.S. Pat. Nos. 2,773,502 (column 3, lines 18-42) and 2,738,303 (column 3, lines 31-51). More recently, various polymers and other materials are described in U.S. Pat. Nos. 3,960,152; 3,978,203; 4,036,227, and 4,326,522. For the bioerodible portion 31 of strand 30, I prefer to use surgical suture material (or a complex of "braided" sutures), covered with a thickness of bioerodible substance such as a mixture of waxes 32.

The osmotic dispensing devices 10 and 20 are ordinarily only two in a larger series of such devices; two are shown for convenience but as many are employed as needed, all connected through bioerodible strand portions. Connected to the series, through another bioerodible strand portion 40, is a weight 50 which serves to retain the devices in the animal's rumen as long as they remain connected together. The use of weights in devices used to medicate parts of the intestinal tract is common in veterinary medicine, and has even been proposed in humans; see for example U.S. Pat. No. 2,773,502. The retention of such weights by the animal is not considered to cause any long-term problems. Iron weights have been used, or it may be preferred to use a weight which is eventually bioeroded, such as that to be described.

The osmotic dispensing devices 10 and 20, in their simplest form, have a reservoir 11 which contains the substance desired to be dispensed, and an osmogent (osmoticall active agent). The osmogent may be a different substance or the same as the one to be dispensed. If it is a different substance, the reservoir may be provided with a piston or dividing membrane 12 (shown in phantom) between two solutions, one containing the dispensed substance and one the osmogent.

The reservoir 11 is separated from the external environment by a wall having an orifice 13, through which the dispensed substance is expelled, and a semi-permeable osmotic membrane 14. In use, a liquid (aqueous rumen liquor) enters reservoir 11 through membrane 14 in osmotic response to the concentration in the reservoir of the osmogent, which may conveniently be a substance of limited solubility present in excess so that a saturated solution continues to be maintained. As a result of the entrance of water, pressure is generated which expels the contents of the reservoir containing the substance desired to be dispensed, through orifice 13.

As noted hereinabove, the technology of osmotic dispensing devices is well-developed. Such devices are in use in many pharmaceutical applications, particularly in experimental therapeutics, and their use is known to those skilled in the art.

The thickness of the bioerodible strand portion 31 is designed, either by calculation or empirically, so that when dispensing device 10 has effectively exhausted its contents, the strand 30 separates. The size of each dispensing device is made small enough to be expelled by the animal, preferably through the normal regurgitation process. The osmotic membrane 14 on dispensing device 20 is coated during manufacture with bioerodible material 15, of such thickness as to postpone the exposure of the osmotic membrane until device 10 is spent. Each successive device in the series may have thus a thicker coat 15 of bioerodible material, as well as a greater thickness of bioerodible strand coat 32, so that as the previous dispensing device is spent and expelled, that device begins to dispense the bloat retardant.

In yet another embodiment of the present invention, shown schematically in FIG. 2, it is envisioned to use a different type of material than a simple iron weight 50 to anchor the bolus assembly. Instead the weight 60 is made of a material that will itself bioerode. This material, which is similar to that used in sustained release bolus formations (U.S. Pat. No. 4,166,167 to Muller et al.) would consist of for example 4 to 17 parts monostearin, about 4 to 10 parts carnauba wax, and about 70 to 75 parts barium sulfate. The different strings holding each of the capsules in place would not be connected in linear sequence as above, but would be affixed to the weight by ends penetrating it to various levels, which ends would be exposed and released over the passage of time. Thus, as the weight was eroded each capsule would be freed in its turn.

The utility of providing a plurality of dispensing devices is seen when it is recalled that for bloat control, large and increasing amounts of bloat retardant should be administered to the animal. There are various ways of providing for this. One way is to increase the size of each dispensing device in turn, or at least the effective size of its membrane. Another way would be to increase the bioerodible membrane coat thickness 15 stepwise in groups so that a greater number of devices would be dispensing at any one time as time passed. Yet another way would be to increase the concentration of bloat retardant in each successive device. A combination of such means might be used.

If the membrane coat 15 is non-uniform in thickness, as shown in FIG. 1, the thinnest part will be eroded first, exposing the osmotic membrane over only a portion of its area. Then the passage of time will allow an ever increasing portion to be exposed, with the result that the rate of release of bloat retardant will increase with time even during the operation of a single dispensing device. The particular release profile with time will depend upon shape of the non-uniform bioerodible coat 15 in a manner easily calculated or determined empirically by those skilled in the art; for a discussion of this phenomenon refer to U.S. Pat. No. 4,036,227 (column 12, lines 49-64).

The invention has been described in detail with particular emphasis on the preferred embodiments thereof, but it should be understood that variations and modifications within the spirit and scope of the invention may occur to those skilled in the art to which the invention pertains.

Claims

1. In an osmotic dispensing device for the dispensing of a substance into the body, the improvement comprising a second osmotic dispensing device linked to said osmotic dispensing device through a bioerodible connecting strand, said connecting strand comprising a material which will be degraded by said body to cause the separation of said osmotic dispensing device from said second osmotic dispensing device after said substance has been dispensed into said body.

2. In an osmotic dispensing device for the dispensing of a substance into the body, the improvement comprising a nonbioerodible strand having a first end affixed to said osmotic dispensing device and having a second end affixed to a bioerodible weight, and further comprising a second osmotic device and a second nonbioerodible strand, said second strand having a third end affixed to said second osmotic dispensing device and a fourth end affixed to said bioerodible weight, and said bioerodible weight having the property that it will be degraded by said body to cause the separation of said second and fourth ends from it at points substantially different in time.

3. The improvement of claim 2 and in which said second osmotic dispensing device has an osmotic membrane at least a portion of which is covered with a bioerodible substance, said bioerodible substance having the property that it will be degraded by said body to cause the exposure of said portion of said osmotic membrane to said body after said osmotic dispensing device is separated from said second osmotic dispensing device and said bioerodible substance being of sufficiently varying thickness over said at least portion of said osmotic membrane to cause the area of said portion which is exposed to said body to increase with time.