GB2191400A

GB2191400A - Intraruminal delivery device

Info

Publication number: GB2191400A
Application number: GB08713086A
Authority: GB
Inventors: Guy Derrieu; Frederic-Michel Ascher; Jacques Cuvelier
Original assignee: Virbac SA
Current assignee: Virbac SA
Priority date: 1986-06-09
Filing date: 1987-06-04
Publication date: 1987-12-16
Anticipated expiration: 2007-06-04
Also published as: NL192818B; DE3719185A1; IE871458L; FR2599624A2; FR2599624B2; IE61860B1; NZ220594A; GB2191400B; NL192818C; NL8701317A; GB8713086D0

Description

GB2191400A 1

SPECIFICATION

Intrarurninal delivery device The invention relates to an intraruminal delivery device as disclosed in the French Patent Applica- 5 tion 84 03520, i.e. a device enabling the release into a liquid medium, at a controlled speed, of one or more active principles formed by a solid macromolecular and thermoplastic matrix support of insoluble polymers or copolymers associated with adjuvants and additives enabling the pro gressive and programmed release of the active principle(s) contained therein, in which the initial concentration of the active principle(s), on the one hand, and the surface of the device through 10 which diffusion takes place, on the other hand, are determined as a function of the desired duration of release and daily quantity to be released, the matrix support completely or almost completely enclosing one or more masses of dense materials which provide the assembly with a specific weight of more than 1.3 g/m].

A device of this type may be used to diffuse drugs in humans or animals and, in the latter 15 case, is administered orally to introduce it into the ruminoreticular sac of ruminants where it is retained for a long period of time.

Although such devices provide satisfactory results for the release of antiparasitic and/or anthelmintic substances, in particular in the case of bovine livestock, the fact that the diffusion of the active principle(s) takes place through the whole of the surface of the device may lead, 20 firstly, to a release of the principle(s) which may not be uniform, whereas a device which can release the same daily dosage over a long period of time, at least three months, is what is actually needed in practice, and, secondly, to the fact that the release of active principle(s) may take the form of an asymptotic curve, as a function of time, which may be a drawback in the use of the device. 25 When these known devices are administered to young animals the various factors which control the release of the active principle(s) are calculated and combined so that the release of active principle(s) is compatible during the initial days of treatment with the weight of the animal being treated in accordance with the conventional rules of posology. If, however, the release of active principle(s) also increases as the animal grows and its weight increases, this increase is 30 asymptotic, as mentioned above, because the elimination of the active principle(s) via the juices or fluids of the diestive tract takes place progressively from the exterior to the interior of the device, i.e., in the case of a body of general elongate shape, along progressively decreasing surfaces (and therefore also with decreasing quantities) whereas normal posology would require the quantities of substance(s) released to increase in a non-asymptotic manner as a function of 35 the increasing weight of the animal being treated.

In addition, the manufacture of these known devices in accordance with the French Patent Application 84 03520 may, in some cases, pose technical problems as regards the positioning of the mass(es) of dense material with respect to the remainder of the polymer matrix.

It is for this reason that the Applicants, starting from the prior art set out above, have 40 attempted to provide a device which satisfies practical requirements in an improved way with respect to known devices, in particulr as regards the quantity of active principle(s) released over time, the uniformity of the dosages released daily and the progression over time of these dosages so as to achieve the optimum posology as far as possible, particularly in the case of growing animals. 45 An object of the invention is, in this respect, to provide a device of this type in which the daily release of active principle(s) evolves over time in linear steps, i. e. by providing a uniform daily quantity of active principle(s) at the beginning of use and during an initial stage, and then, during a second stage, a further uniform daily quantity and, during a third stage, a new uniform daily quantity which is preferably, but not necessarily, different from the first and/or the second, 50 etc., so that the quantities released, which are suitably matched to the size and weight of the animals to which the devices are administered, enable the achievement of the best possible results.

The Applicants have now discovered, in a surprising manner, that it was possible to obtain this result from a device of the type set out above, by providing a through duct in the solid 55 matrix support, through which duct the active principle(s) is(are) diffused, diffusion being pre vented, in contrast to the devices of the prior art, on the outer surface of the matrix support which is covered, for this purpose, with a film which cannot be permeated by the active principle(s).

In a device of the invention, the density, which is preferably kept fairly high, is obtained by 60 distributing a material of high density throughout the whole of the support, for example metal powder, filings or grit, which provides the assembly of the device with the desired density.

In an advantageous embodiment, the device is oblong in shape and somewhat ogival with a rounded end with a longitudinal axis along which the through duct is disposed, this duct having a cross-section which is constant or which increases slightly from one end of the device to the 65 2 GB2191400A 2 other.

Given that the whole of the outer surface of the device is covered by a polymerisable impermeable film, for example of a material such as a cross-linkable silicone elastomer, an epoxy resin, a polyurethane varnish and/or an acrylic varnish or a like material, the progressive release of the active principle(s) takes place through the wall of the cavity bounded by the duct with the 5 result that the active principle(s) is(are) released in constant daily dosage steps.

By incorporating a high density product in the solid thermoplastic and macromolecular matrix of insoluble polymers or copolymers in order to achieve the desired final density, a very homogeneous product is simultaneously obtained which therefore has no damaging side effects on the animal to which it is administered. 10 By means of an appropriate selection of the concentration of the active principle(s) in the polymer matrix, the shape and dimensions of the through duct and the addition, if necessary, of adjuvants or additives to the polymers or copolymers of the matrix as a function of the nature of these polymers or copolymers, the duration of the diffusion stages and the daily dosages of active principle(s) released by the device within, for example, an animal organism, may be 15 regulated.

The active principle(s) may be selected for their prophylactic or therapeutic effects from amongst antiparasitics, antibiotics, antibacterial agents, antifungals, vitamins or nutritional preparations.

In the case of substances with anthelmintic properties, the active principles are advantageously 20 selected from the group including levamisole, tetramisole, morantel, pyrantel, or their soluble salts, nitroxynil, albendazole, oxibendazole, oxfendazole, mebendazole and ivermectin.

A particularly advantageous embodiment involves the use of levamisole hydrochloride as the active principle.

Mineral chemical substances may also be selected to provide micronutrient supplements. 25 The concentration of the active principle in the polymer matrix may vary from 1 to 60% by weight of the matrix portion, as a function of the desired steps and daily dosages to be released.

The specific weight of the device is determined by the quantity of metal introduced in the form of powder, filings or grit, the amount of this product being between 10 and 75% of the 30 matrix portion.

Among the insoluble polymer or copolymer-based macromolecular thermoplastic materials, a preferred embodiment of the invention uses a copolymer of ethylene and vinyl acetate (EVA).

To produce a device of the invention, the polymer(s) or copolymer(s), the active principle(s) and the powder of dense material are mixed homogeneously and the mixture obtained is hot- 35 moulded to obtain a product which contains the desired through duct directly on demoulding or, as a variant, to obtain an intermediate component which is then shaped, for example by machining, to form the desired through duct.

In both cases, the outer surface of the device is then covered under cold conditions by an impermeable film, for example a cross-linkable silicone elastomer, an epoxy resin, a polyurethane 40 varnish or an acrylic varnish.

This production technique, which is much simpler than that of known devices, enables a substantial reduction of the production cost of such devices, in particular for their use in veterinary medicine.

The invention is illustrated in the following description, given by way of example, with refer- 45 ence to the attached drawings, in which:

Figure 1 is a diagrammatic perspective view of a device of the invention; Figure 2 is a view in longitudinal section.

The device 10 shown in Figs. 1 and 2, which is described here by way of non-limiting example, has a general oblong shape, substantially of revolution about an axis 11, with one 50 rounded end or apex 12 and another, distal, end 13 which is planar and substantially perpendi cular to the axis 11. The body 14 of the device is formed by the solid macromolecular matrix support of insoluble polymers or copolymers, one or more active principles and one or more materials of high density, for example powdered metal filings or grit shown here by reference numeral 15 for the purposes of illustration, whereas the assembly is in fact completely homoge- 55 neous.

According to the invention, the device 10 has a through duct 16 passing through it along its axis 11, which duct may have a constant circular cross-section, i.e. may form a cylindrical surface 17 with an axis 11 or, as an alternative and as shown in the drawings, may form a duct with a circular cross-section which increases progressively from the base 13 to the apex 12, i.e. 60 a slightly frustoconical surface 17 which opens out at the face 13 through an aperture 18 and at the apex 12 through an aperture 19. When the device is positioned, for example in the rumino reticular sac of an animal, its inner surface 17 is in contact with the ruminal fluid which psses through the device via the apertures 18 and 19.

In accordance with the invention, the outer surface of the device 10 is covered by a film 20 65 3 GB2191400A 3 of impermeable, polymerisable material, such as a cross linkable silicone elastomer, an epoxy resin, a polyurethane varnish or an acrylic varnish, this film extending over the whole of the outer surface of the device, i.e. between the periphery of the aperture 18 and the -periphery of the aperture 19 with the exception of the inner surface or wall 17 of the through duct 16.

As a result of this, at the beginning of use, the solvation fluid, such as bovine ruminal fluid or 5 any other like fluid, comes into contact with the wall 17 and the active principle is released through this wall. Over time the solvation fluid progresses from the wall 17 in the direction of the outer surface of the body 14 and, bearing in mind the geometry of the device, the solvent contacts and dissolves increasing quantities of active principle(s); the speed of penetration of the solvent into the matrix simultaneously decreases, bearing in mind the increase in the distance to 10 be travelled by the solvation fluid to reach the active principle, while the elimination of the substance (which is a function of the quantity conveyed across the regions of the matrix which have already been dissolved) is regulated by the matrix which acts to some extent as an intermediate membrane.

This behaviour of the device is particularly advantageous when a drug is to be released in 15 young, growing animals.

When appropriate parameters, such as the volume and the shape of the through duct, the concentration of active principle(s), the nature of the matrix and that of the material incorporated to achieve an appropriate density, are selected for the device, this behaviour also makes it possible to define time stages or steps during each of which a constant daily dosage is released 20 by the device.

If a daily dosage which is greater than that selected at the beginning of use is selected at the end of the life of the device, the dosage of active principle(s) is increased in correlation with the increase in the weight and size of the animal being treated in accordance with the conventional rules of posology. 25 Examples

Example 1

The following composition, in parts by weight, was initially prepared:

30 Levamisole hydrochloride 15 Powdered iron 66 Ethylene/vinyl acetate copolymer with 28% vinyl acetate (EVANTANE 28-05 produced by the company ATOCHEM) 19 35 The three constituents were mixed homogeneously and the mixture obtained was injected, at a temperature of 105'C, into a mould with a core which thus provided, after demoulding, a device as shown in Figs. 1 and 2.

This device, which was approximately 105 mm long with a greater diameter at the apex of its 40 front, rounded end 12 of approximately 30 mm and a plane circular base with an external diameter of approximately 27 mm, weighed approximately 150 g and had a density of approxi mately 2.6 g/mi. The through duct 16 had a circular cross-section of approximately 8 mm at the base 13 and a diameter of approximately 10 mm at the front, rounded portion 12.

After the device had been cooled, its entire outer surface was covered with a thin film of 45 polyurethane varnish to a thickness of 1/10 mm, which therefore covered the whole of the surface of the device with the exception of the wall 17 of the through duct 16.

The device was then subjected to in vivo and in vitro release tests.

In vitro release tests The test device was immersed in a litre of drinking water adjusted to a pH of 7 and kept at 50 37'C by a thermostat.

The container was fitted with a mechanical plunger agitation system (of the anchor or propeller type) which was rotated slowly (approximately 100 rpm) ensuring that the solution was homoge neous.

The entire assembly was placed in darkness and daily samples of 1 mi of solution were taken, 55 the fluid volume being topped up with drinking water.

The active principle concentration, released daily, was calculated by the high performance liquid chromatography technique and the release kinetics are shown in Table 1 below which shows the amounts of levamisole hydrochloride released, expressed as cumulative percentages of the initial dosage. 60 4 GB2191400A 4 Table 1

Days in vitro % levamisole hydrochloride released 5 1 2.9 2 3.2 4 4.6 7 6.5 14 10.1 10 21 12.9 28 15 16.9 42 18.5 49 19.4 15 56 20.1 63 22.05 27.2 84 35.1 105 49 20 126 58.7 147 72.4 168 82.8 After 169 days, the device was removed from the container and the residual quantity of 25 levamisole hydrochloride in the matrix was calculated by analysis.

This showed a residual quantity of approximately 16% which confirmed the cumulative values eliminated.

It would seem from the above Table that the elimination of the active principle in vitro corresponds in effect to three successive stages with different kinetics. 30 in the first stage, or kinetic stage 1, lasting 21 days, the daily amount released was substan- tially 152 mg. In a second stage, or kinetic stage 11, between day 21 and day 73, the daily amount released was approximately 54 mg per day, while during the third stage, or kinetic stage Ill, i.e. from day 73 to day 168, the daily amount released was substantially 143 mg.

It can therefore be seen that after a first stage of constant daily release, the release decreased 35 and then increased again in contrast to known devices in which release is asymptotic, i.e.

decreases towards the end of the service life of the device.

The above tests were supplemented by in vivo tests conducted as follows.

In vivo tests The speed of release of the active principle (mg per day) was calculated using devices as 40 described above administered to 12 young cattle with a ruminal fistula.

The devices were removed after 5, 21, 42, 70, 98 and 126 days to evaluate the residual quantity of active principle.

The quantities of levamisole hydrochloride released were expressed as percentages of the initial dose, and are shown in Table 11 below as a mean for two animals per test. 45 Table 11

Days Animals % levamisole hydrochloride released 50 A and B 7.1 21 C and D 19.8 42 E and F 33.5 G and H 55 98 1 and J 75.2 55 126 K and L 94.9 The amount released per day was approximately 186 mg for the entire duration of the tests, with kinetics which differed somewhat from those of the in vitro tests.

It can be seen that the speed of release is greater than that of the in vitro tests and also that 60 -it is not possible to discern steps of the type discussed above. Despite the difference in behaviour, due, undoubtedly, to the nature of the solvent liquid and to complex factors predominating in the animals' rumens, the non-asymptotic release of the active principle provided major advantages with respect to known devices.

Similar results were obtained using a device with a matrix formed by an ethylene/vinyl acetate 65 GB2191400A 5 copolymer of the type sold under the trademark ESCORENE ULTRA by the company ESSO CHIMIE.

Example 11

The following composition, in parts by weight, was initially prepared: 5 Copper carbonate 19.30 Cobalt carbonate 0.73 Sodium selenite 0.47 Powdered iron 59.50 10 EVATANE 28-05 20.00 The constituents were mixed homogeneously and the mixture obtained was injected at a temperature of approximately 1 10C into a mould comprising a core, which thus provided, after demoulding, a device as shown in Figs. 1 and 2. 15 This device, which was approximately 50 mm long with a greater diameter at the apex of its front, rounded end 12 of approximately 19 mm and a plane circular base with an external diameter of approximately 17 mm, had a weight of approximately 35 g and a density of 3.5 9/mi. The through duct 17 had a circular section of approximately 5 mm at the base 13 and a diameter of approxiately 6 mm at the front, rounded portion. 20 After the device had been cooled, its entire outer surface was covered with a thin film of silicone, cross-linkable under cooling, to a thickness of 1/10 mm, which therefore covered the - whole of the surface of the device with the exception of the wall 17 of the through duct 16.

A device of this type may be used, in particular, for the administration of micronutrients to sheep in predetermined metered quantities. 25

Claims

1. A device enabling the release into a liquid medium, at a controlled speed, of one or more active principles formed by a macromolecular and thermoplastic solid matrix support (10) formed by insoluble polymers or copolymers associated with adjuvants and additives enabling the progressive and programmed release of the active principle(s) incorporated therein, in which the initial concentration of the active principle(s), on the one hand, and the surface of the device through which diffusion takes place, on the other hand, are determined as a function of the desired duration of release and daily quantity to be released, this matrix support completely or almost completely enclosing one or more masses of dense material (15) which provide the 35 assembly with a specific weight of more than 1.3 g/mi, characterised in that the surface (17) of the device through which diffusion takes place is solely that of a through duct (16), the outer surface of the matrix support (14) being covered with a film (20) which cannot be permeated by the active principle(s).

2. A device as claimed in claim 1, characterised in that the device is provided with a specific 40 weight of more than 1.3 9/m] by the incorporation in the matrix of metal powder, filings or grit distributed homogeneotisly throughout the matrix support.

3. A device as claimed in claims 1 or 2, characterised in that it has an oblong shape with a longitudinal axis (11) along which the through duct (16) is provided, this duct having a cross section which is constant or which increases slightly from one end of the device to the other. 45

4. A device as claimed in any one of claims 1 to 3, characterised in that the impermeable film (20) is a material of the type of cross-linkable silicone elastomers, epoxy resins, polyure thane varnishes and/or acrylic varnishes.

5. A device as claimed in any one of claims 1 to 4, characterised in that it is produced by moulding a homogeneous mixture of polymers or copolymers, approximately 1 to 60% by 50 weight of the matrix of one or more active principles and 10 to 75% by weight of metal powder, filings or grit.

6. A device as claimed in claim 5, characterised in that the matrix has an ethylene/vinyl acetate copolymer base.

7. A device as claimed in claim 5, characterised in that the metal powder is powdered iron. 55

8. A device as claimed in any one of the preceding claims, characterised in that the active principle(s) has(have) prophylactic or therapeutic effects and are selected from antiparasitics, antibiotics, antibacterial agents, antifungals, vitamins or nutritional preparations.

9. A device as claimed in claim 8, characterised in that the active principle(s) has(have) anthelmintic activity and are selected from the group including levamisole, tetramisole, morantel, 60 pyrantel, or their soluble salts, nitroxynil, albendazole, oxibendazole, oxfendazole, mebendazole or ivermectin.

10. A device as claimed in claim 8, characterised in that the active principle(s) comprise(s) nutritional supplements such as micronutrients or the like.

11. A device as claimed in any one of the preceding claims, characterised in that it releases 65 6 GB2191400A 6 the active principle(s) which it contains in substantially constant daily dosages over a period of time of approximately three months at least.

12. A device as claimed in claim 11, characterised in that the active principle(s) is(are) released in substantially constant daily dosages during a discrete number of separate stages of its service life. 5 Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd, Dd 899 1685, 1987. Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.

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