Abstract:
There is disclosed a novel device intended to permit the regular and continuous release of chemical substances, including medicaments, and this, over a very long period of time, the release of the active substances following a predetermined kinetic effect from an insoluble polymeric matrix to a liquid medium which can be, particularly, that of an animal or human organism. The device has a specific density to remain in an animal rumen. There is also disclosed a method for treating animals by means of such devices.

Description:
BACKGROUND OF THE INVENTION 
     The present invention relates to a novel device intended to permit the regular and continuous release of chemical substances, meaning also medicaments, and this, over a very long period, the release of the active substances following a predetermined kinetic effect from an insoluble polymeric matrix to a liquid medium which can be, particularly, that of an animal or human organism. 
     Very many systems are known which permit the regulated and programmed release of pharmaceutically-active substances. 
     These are all solid or semi-solid systems, of the type, for example, of tablets or suppositories whose composition is defined so as to result in a slow disintegration of the system, the disintegration itself being produced, either by a purely mechanical effect or by partial solubilization by the liquid medium, for example, body fluids of one or several components forming the system. 
     It is also known to disperse the active principle in a solid support and to produce its programmed release by diffusion through such a support. 
     In this case also, the systems described are numerous: 
     so-called semi-permeable systems are known in which the active agent (dissolved, suspended or emulsified in an inert vehicle) diffuses through a permeable membrane; 
     composite systems are also known in which the active agent diffuses from a more or less porous solid support, constituted by a matrix based on polymers or copolymers. 
     Whatever the system selected, the speeds of release are only maintained over a very short period of time and hence do not lend themselves to prolonged use. 
     In particular, in the veterinary field, the repeated administration of medicinal substances runs up against both economic and technical problems when animals, for example, are very numerous or dispersed in pastures. 
     Also, various devices have been designed so as to permit activity over a prolonged period, and, in particular, as medicinal release systems in ruminants. 
     Thus, there have been described, for example: 
     a medicament with a prolonged delayed reaction characterized in that it is in the form of a parallelepipedic article about 7 to 8 cm long and weighing about 10 to 60 g (Fr. P. 2 461 495). However, the life span of such a device hardly exceeds some days; 
     a device designed for continuous and regulated administration of a chemical substance, characterized in that it is formed from a reservoir of heavy material, for example, a metal cylinder provided at one of its ends with a porous wall (for example a semi-permeable membrane) through which said chemical substance diffuses (cf. French Pat. No. 2 425 242). Such a device, even if it completely fulfils the role of a longterm diffuser (two to three months), has however two important drawbacks: 
     the diffusion surface is very small, resulting in a low and insufficient concentration of active substances on the one hand and frequent clogging on the other hand. 
     GENERAL DESCRIPTION OF THE INVENTION 
     Accordingly, it is an object of the present invention to provide a device enabling the release at a regulated speed into a liquid medium of one or more substances active in veterinary medicine, said device being constituted by a macromolecular thermoplastic solid matrix support (based on insoluble polymers or copolymers associated with adjuvants and additives) enabling the progressive and programmed release of one or more active substances incorporated therein, characterized in that the initial concentration of the one or more active substances, on the one hand, and the surface of the device through which the diffusion is effected, on the other hand, are determined as a function of the period of release and the amount desired to be released daily, the matrix support containing the one or more active substances and totally or almost totally enclosing one or more masses of dense material, conferring to the whole device a density higher than 1.3 g/ml. 
     The devices according to the present invention enable the diffusion of active substances at a constant and uniform speed throughout the life of the device, that is to say until complete or almost complete diffusion of the active substance. 
     The device according to the present invention may be used as a diffuser of medicinal substances in humans or in animals. It may be used for the prevention or treatment of disorders of animal organisms, namely: through individual administration; the device being introduced in the form of a bolus into the animal organism or by collective administration, wherein the device is introduced into a liquid medium used by animals, for example, aquaria, fish ponds, hydroponic installations, water distributing systems for animals, etc. 
     The present invention relates more particularly to devices enabling the diffusion of active substances in a form permitting oral administration to animals and especially to ruminants, these devices being introduced into the rumino-reticular bag where they are retained for a very long period, and this by reason of their specific gravity, higher than that of the liquid in which they are immersed. 
     In an advantageous embodiment of the invention, the device is in cylindrical or oblong form. 
     According to another embodiment of the invention the device is constituted by a plurality of superposed strips surrounded, possibly, by a biodegradable jacket of cylindrical or oblong shape. 
     According to the invention, the dense material is housed inside the matrix support. 
     According to another feature of the invention, the dense material is in the form of rings and/or shapes surrounding the matrix support. Thus, the device according to the invention, whatever the modification produced--dense mass inside the cylinder or ring of small surface area surrounding the matrix support--, enables regular diffusion and in constant proportions throughout the life of the device. 
     In accordance with the invention, the matrix support is produced by extrusion or hot molding of polymers or copolymers of chemical substances taken from the group which comprises vinyl polymers, polyethylenes, polypropylenes, polyacetates, polyurethanes, and vinyl acetates. 
     The matrix support comprises, also, various additives, such as placticizers (selected from the esters: cresyl phthalates, adipates, sebacates or phosphates), stabilizers, and lubricants, permitting molding or extrusion of the devices. 
     According to one embodiment of the present invention, it is advantageous to include in the matrix support, inert substances enabling the precise and continuous regulation of the release of the active principle. Among these soluble substances, may be mentioned, by way of example, sugars (lactose, saccharose, glucose), starches, soluble celluloses, gelatins. 
     In an advantageous embodiment of the invention, the dense materials are selected among minerals and/or metals. Thus all the devices of cylindrical or oblong shape are produced so as to form an internal cavity which can be filled by the dense element, for example, metal. In this manner, the initial shape retained is not affected by the operation of making the device heavier. 
     It is also possible, from solid polymer matrixes, to fix a metal weight, either at one or both ends, or again metal rings positioned at regular intervals. 
     In the case where the matrix is in the form of several strips, the latter are held, for example, at one of their ends by a dense metal tip, the whole being held in a hydrolysable jacket in the animal system (cellulose or gelatin for example). 
     The choice of the one or more active substances incorporated in the polymeric matrix depends upon the desired purpose. 
     It may be therapeutic or prophylactic in the case of human or veterinary medicine. 
     In this respect, the invention also relates to a method of treating ruminants by means of a device, such as described above, said device being in the form of a bolus whose regurgitation is prevented so that all or almost all of the active substance is absorbed according to a predetermined time program. 
     The purpose may be industrial and addressed, in particular, to the agricultural domain for the delivery of pesticidal substances. 
     The active substances can hence include medicinal substances useful in humans and animals or inorganic chemical substances. Thus, recourse may be had to substances with antiparasitic, antihelmintic antibiotic, antifungal, antibacterial, anticoccidial activity, to substances used as a growth factor, to inorganic nutrient agents or vitamin nutrient agents. Substances with pesticidal activity may also be resorted to. 
     The novel systems, with programmed release, as defined in the present invention, can permit the release of chemical substances including medicaments when they are used in media which contain liquids. They are, in particular, well adapted to the release of both very water-soluble and slightly water-soluble chemical substances. 
     The release is constant, continuous, and this, over a very long period. 
     In their design, the devices according to the invention are easy to produce and prove to be of a form particularly well adapted for oral administration in ruminants. 
     The diffusion of the active substances, is effected through the whole surface of the devices, no risk of clogging or of modification of the elimination is to be feared. 
     The method of preparing devices according to the present invention is that of thermoplastic substances which can be worked, either by molding, or by hot extrusion. 
     The choice of technique is conditioned by the form of the devices to be produced. 
     The production of a strip or of a hollow cylinder is done by extrusion. One or more metal parts, serving as a ballast, are added in the course of a second step. 
     The various forms used: cylindrical, ovoid, oblong, are obtained by hot molding. In this case, the matrix support is molded directly around the central metal part, the device being obtained in as single step. 
     In a particularly advantageous modality of the device according to the invention, said device is enveloped in a sheath of biodegradable material, in order to facilitate the oral administration thereof in animals. 
     In a particular embodiment of the devices, it is contemplated the partial covering of the outer surface of the matrix support by an impermeable film, and this for the purpose of reducing the daily amount of active principle and increasing further the effective life of the device. 
     The film deposit may be effected with any impermeable substance, but polymerizable products, such as cross-linkable silicone elastomers and epoxy resins, are preferred for their ease of application. 
     Besides the foregoing features, the invention comprises also other features which will emerge from the description which follows, reference being made to embodiments of the devices according to the present invention shown in the accompanying drawings, to examples of the composition of the matrix supports, including additives and medicaments as well as to reports of experiments on animals. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     In the drawings: 
     FIG. 1 is a diagramatic view of an embodiment of the device according to the present invention, 
     FIG. 2 shows a diagramatic view of another embodiment according to the present invention, 
     FIG. 3 shows a diagramatic view (in longitudinal section) of another embodiment of a device according to the invention, 
     FIG. 3a shows a view similar to that of FIG. 3, but for a modification of this embodiment, 
     FIGS. 4 and 5 show diagramatically, further embodiments of the device according to the invention. 
     It must be well understood, however, that these drawings, examples and reports, as well as the corresponding descriptive portions, are given purely by way of illustration of the invention of which they do not constitute in any way a limitation thereof. 
    
    
     DESCRIPTION OF PREFERRED EMBODIMENTS 
     The device according to the invention shown in FIG. 1 has the shape of a cylinder, composed of two portions: an outer portion 1 formed from the matrix support comprising additives and active substances and an inner portion 2 formed from a metal core, for example, of stainless steel. It is this metal core which confers on the device the desired overall density without affecting in any way the very large surface of contact and of diffusion which characterizes the devices according to the present invention. In the embodiment shown in FIG. 2 the outer portion 3 (matrix support) has an oblong shape, whilst the inner portion is, as previously, constituted by a stainless steel cylinder. 
     In the embodiment of the device shown in FIG. 3, the outer portion 7 (matrix support) has a cylindrical shape having a recessed portion 8 on one end and completely surrounds the inner portion 9 which is, as previously, constituted by a metal cylinder. The same remark applies to the modification shown in FIG. 3a, where P represents a fine film of silicone elastomer cross-linkable at normal temperature of 5/10 mm thickness. 
     In the embodiment shown in FIGS. 4 and 5 the matrix is in the form of five strips 4 held at one of their ends by a tip of stainless steel 5 (FIG. 4) or, for example, three regularly spaced stainless steel rings (FIG. 5). This assembly is held in a rigid, easily hydrolysable cellulose jacket. After dissolution of the jacket, the ballasted strips are deployed inside the rumino-reticular sac of the animal and have for this reason, additional stability. 
     All of these devices as described in the foregoing, are particularly well adapted to be administered orally to an animal, to dwell in the rumino-reticular sac of the animal for a very long period during which they release the active principle--prophylactic or therapeutic--in a continuous, regular, uniform manner. 
     A device according to the present invention is particularly well adapted for combating internal parasites in ruminants (ovine, caprine or bovine cattle) particularly by the fact that the doses of prophylactic or therapeutic agent released can be calculated so as to act on the parasites in their larval stage (hence, with maximum effectiveness of the active principle) progressively according to their ingestion by the animals. 
     As a function of the necessary liberated doses, it is possible to adapt the concentration of the active substance in the polymeric matrix; the latter can vary from 1 to 55 percent by weight of the matrix portion. In addition, the duration of diffusion can be regulated by adjustment of several parameters, including the total diffusion surface, the concentration of active substance, the incorporation of adjuvants or additives, and the nature of the thermoplastic polymer. 
     EXAMPLES OF COMPOSITION 
     EXAMPLE 1 
     
         ______________________________________           Parts by Weight______________________________________Levamisole hydrochloride             23.8Octyl adipate     20Epoxydized soya oil             2Calcium stearate  0.5Lactose           20P.V.C. homopolymer             33.7______________________________________ 
    
     From this composition a hollow cylinder is formed by extrusion. After cutting-up, the dimensions of the extruded parts are as follows: 
     
         ______________________________________length                100    mmtotal diameter        24     mmthickness of the wall 10     mmtotal weight          52.75  g______________________________________ 
    
     This plastic element is ballasted by a solid stainless steel cylinder with the following dimensions: 
     
         ______________________________________  length 100 mm  diameter          4 mm______________________________________ 
    
     which is inserted into the hole of the cylinder. 
     The total weight of the device is about 73 g, corresponding to a density of 1.6 g/ml. It contains 12.55 g of Levamisole hydrochloride. 
     EXAMPLE 2 
     
         ______________________________________           Parts by weight______________________________________Levamisole hydrochloride             45Di-(ethyl 2 hexyl)adipate             20Epoxydized soya oil             4Calcium stearate  2.5P.V.C. homopolymer             28.5______________________________________ 
    
     The homogeneous powder obtained is injected hot into a mold whose dimensions enable a cylindrical system to be produced as described in FIG. 3. The metal cylinder, with the dimensions of 100 mm length and 14 mm diameter, is imprisoned in the polymeric matrix in the course of the molding operation. 
     The final device of 30 mm large diameter, 25 mm small diameter and 110 mm length weighs about 187 g. 
     Its density is 2.6 g/ml and contains 30.15 g of Levamisole hydrochloride. 
     EXAMPLE 3 
     The device as described in Example 2 is covered over half its length with a fine film P of silicone elastomer cross-linkable at normal temperature of 5/10 mm thickness (FIG. 3a). 
     EXAMPLE 4 
     
         ______________________________________         Parts by Weight______________________________________Morantel tartrate           40Di-octyl phthalate           20Calcium stearate           2.5Epoxydized soya oil           4P.V.C. homopolymer           33.5______________________________________ 
    
     The device is produced in accordance with the procedure described in Example 2. It weighs about 195 g and contains 25.5 g of Morantel tartrate. Its density is in the vicinity of 2.6 g/ml. 
     EXAMPLE 5 
     
         ______________________________________         Parts by Weight______________________________________Pyrantel tartrate           40Octyl adipate   25Calcium stearate           2Epoxydized soya oil           0.5P.V.C. homopolymer           32.5______________________________________ 
    
     The powder obtained is heated in a mold whose dimensions enable an oblong system to be obtained 100 mm long and 30 mm maxium diameter. 
     This system has a cylindrical central cavity open at one end enabling the insertion of a stainless steel metal cylinder 80 mm long and 8 mm in diameter. 
     The final device thus forms a bolus administered as such to ruminants. 
     It weighs about 105 g, its density is 2.1 g/ml and it contains 20.5 g of Pyrantel tartrate. 
     EXAMPLE 6 
     
         ______________________________________         Parts by Weight______________________________________Fenbendazole    30Ethyl-2 hexyl adipate           20Lactose         15Calcium stearate           2Epoxidized soya oil           0.5P.V.C. homopolymer           32.5______________________________________ 
    
     The homogeneous powder obtained is heated in a mold identical with that described in Example 2. The device, with identical physical characteristics to those of the device of Example 2, contains 20.1 g of fenbendazole. 
     EXAMPLE 7 
     
         ______________________________________         Parts by Weight______________________________________Ivermectine     3.5Ethyl-2 hexyl adipate           25Lactose         15Calcium stearate           2.5Epoxidized soya oil           15P.V.C. homopolymer           0.5P.V.C homopolymer           38.5______________________________________ 
    
     By extrusion, a hollow cylinder is formed from the homogeneous powder having the composition indicated. 
     After being cut up, the dimensions are as follows: 
     
         ______________________________________Length               30     mmTotal diameter       24     mmWall thickness       5      mmTotal weight         10.7   g______________________________________ 
    
     This plastics elements is weighted by a solid cylinder of stainless steel 14 mm in diameter and 30 mm in length which is inserted into the base of the cylinder. 
     The total weight of the device is about 46.5 g having a density of 3.4 g/ml. It contains 0.375 g of Ivermectine. 
     REPORTS OF TESTS OF RELEASE IN VITRO 
     EXAMPLE 8 
     1. Experimental procedure: 
     The device to be tested is immersed in a liter of drinkable water adjusted to pH 7 and thermostated to 37° C. 
     The container is equipped with a mechanical dipping stirring system (anchor or helix type) driven with a slow rotary motion (100 rpm) ensuring the homogeneity of the solution. 
     The whole of the assembly is placed in darkness. 
     Daily samples of 1 ml of solution are taken and the whole of the volume of liquid is replaced by drinkable water. 
     The concentration of active principle, released daily, is determined by the technique of high-performance liquid chromatography. 
     2. Results 
     The kinetics of elimination in vitro of the active principle is determined on the device described in Example 1. 
     Analysis by high-performance liquid chromatography gives the results indicated in Table I below: 
     
                       TABLE I______________________________________The amounts of Levamisole hydrochloride releasedare expressed in percent of the initial dose andare cumulated       % Leyamisole HydrochlorideDays in vitro       released______________________________________ 3           6.3 5          18.1 7          24.710          38.315          44.918          50.120          60.925          70.130          75.540          87.650          95.9______________________________________ 
    
     After 50 days, the device is taken up from the bath and the amount remaining of Levamisole hydrochloride contained in the plastics weft is analyzed. The results obtained are of the order of 4.1% and confirm the total eliminated values. 
     EXAMPLE 9 
     1. Experimental procedure: 
     It is identical with that of Example 8. 
     2. Results: 
     The kinetics of elimination in vitro of the active principle is determined on the device described in Example 2. 
     Analysis, by high-performance liquid chromatography, gives the results indicated in Table II below: 
     
                       TABLE II______________________________________The amounts of Levamisole hydrochloride releasedare expressed in percent of the initial dose andare cumulatedDays   % Levamisole HCl                  Days   % Levamisole HCl______________________________________ 3      6.8            50     42.4 6      9.4            57     47.510     12.8            65     54.215     17.4            74     61.620     22.2            80     66.627     28.0            92     76.634     33.7            98     81.637     35.5            105    87.443     39.0            110    91.6                  115    95.7______________________________________ 
    
     After 115 days, the device was taken up from the bath and the remaining amount of Levamisole hydrochloride contained in the plastics weft is analyzed. 
     The results obtained were of the order of 3.5% and confirmed the eliminated cumulated values. 
     EXAMPLE 10 
     1. Experimental protocol: 
     It was identical with that of Example 8. 
     2. Results: 
     The kinetics of the elimination in vitro of the active principle was determined on the device described in Example 3. 
     Analysis by high-performance liquid chromatography gave the results indicated in Table III below: 
     
                       TABLE III______________________________________The amounts of Levamisole hydrochloride releasedare expressed in percent of the initial dose andare cumulatedDays   % Levamisole HCl                  Days   % Levamisole HCl______________________________________ 3     4.7              98    45.3 6     5.8             109    50.310     8.3             115    53.015     10.6            125    57.520     14              140    64.727     17.1            165    75.834     19.6            180    82.537     20.5            195    89.343     22.6            210    96.250     23.457     26.665     30.2887     40.3______________________________________ 
    
     After 210 days the device was taken up from the bath and the remaining amount of Levamisole hydrochloride contained in the plastic weft. 
     The results obtained were of the order of 4.5% and confirmed the eliminated cumulated values. 
     In addition, it emerges from a comparison of the values of the Table II and III that the amounts eliminated by the device of Example 3 are a half less than those of the device of Example 2. 
     REPORT OF TESTS OF RELEASE IN VIVO 
     EXAMPLE 11 
     For practicing a process according to the invention, i.e. the treatment of ruminants by means of a device as described above, there was determined the speed of release of the active principle (mg/day) using cylindrical devices whose composition is indicated in the Example 2. 
     These devices were administered to twelve young calves having a ruminal fistula. 
     The devices were withdrawn 15, 30, 45, 60, 75, 95 days after, in order to evaluate the remaining amount of active principle. 
     Each of the results indicated in Table IV is an average of two values: 
     
                       TABLE IV______________________________________                Levamisole HClDays        animal n°                mg/day______________________________________15          1        290       2        26030          3        280       4        26045          5        250       6        24560          7        205       8        24075          9        265       10       25095          11       225       12       258______________________________________ 
    
     Namely an average of 252.33 in 95 days. 
     EXAMPLE 12 
     Experiments carried out under rearing conditions and relating to 40 bovine cattle weighing on the average 400 kg. 
     The animals were divided into four batches of 10: Batch A, Batch B, Batch C and Batch D. 
     The pasture not having undergone any disinfection was divided into four separate equal enclosures, sufficiently large for each to receive 10 animals during the whole pastural system. 
     The experiments started the 1st of May to end on the 24th August. 
     Batch A was constituted by untreated animals. 
     Batch B underwent two treatments in time: 35 days and 56 days with a single oral dose of 10 mg/kg body weight of Levamisole. 
     Batches C and D were constituted by animals receiving the device of Example 2, which corresponds to a daily dose of 220 mg of Levamisole base during 115 days. 
     Coproscopic checks were carried out for all of the four batches at times: D 0, D 34, D 37, D 55 and D 58. 
     The animals of Batches A, B and C were autopsied on day D 116. 
     The animals of Batch D were autopsied at day D 137. 
     The examination consisted of counting adult gastro-intestinal nematodes or those in larval form present in the lumen of the digestive tract. 
     The percentage reduction is calculated by: ##EQU1## 
     The experiment can be summarized in Table V below: 
     
                       TABLE V______________________________________Days Actions    Batch A  Batch B Batch C                                   Batch D______________________________________ 0   Coproscopy Negative Negative                            Negative                                   Negative                            Device 1   Treatment  --       --             Device 3   Putting to Yes      Yes     Yes    YesPastureCoproscopy Positive Positive                            Negative                                   Negative35   Treatment  --       Levamisole                            --     --                    10 mg/kg37   Coproscopy Negative Negative                            Negative                                   Negative55   Coproscopy Very     Positive                            Negative                                   Negative           Positive56   Treatment  --       Levamisole                            --     --                    10 mg/kg58   Coproscopy Negative Negative                            Negative                                   Negative116  Autopsy and           Massive  Average Infesta-                                   --R %        Infesta- Infestation                            tion           tion     R = 60% Nil           R = 0%           R =                            98%137  Autopsy and           --       --      --     Infesta-R %                                tion                                   Practi-                                   cally Nil                                   R =                                   95%______________________________________ 
    
     The results of these experiments show that the use of the device according to the present invention enables animals to be protected from any infestation throughout the pastural season. 
     On the contrary, the animals of Batch B, treated periodically, show a momentary parasite elimination after each treatment, followed by a massive re-infestation some days later. 
     The animals of Batch D, slaughtered three weeks after the arrest of the release of Levamisole by the device had practically nil infestation. 
     This demonstrates the destruction of the helminth&#39;s larvae present initially in the pasture. 
     The device, as described in Example 2, hence permits effective protection for four months against gastro-intestinal parasites for large beef cattle. 
     EXAMPLE 13 
     The experiments were carried out under rearing conditions and related to three batches of six beef cattle weighing on the average 150 kg. 
     The diagram of the test was identical with that described in Example 12. 
     Batch A was constituted by untreated animals. 
     Batch B was constituted by animals undergoing three treatments based on a single oral dose of Levamisole, at 10 mg per kg of body weight. 
     Batch C was constituted by animals receiving the device described in Example 3. 
     All of the actions are summarized in Table VI below: 
     
                       TABLE VI______________________________________DAYS  ACTIONS    BATCH A    BATCH B  BATCH C______________________________________ 0    coproscopy negative   negative negative 1    treatment  0          0 4    putting to yes        yes      yes pasture40    coproscopy positive   positive negative42    treatment  0          Levamisole                                0                       10 mg/kg44    coproscopy positive   negative negative71    coproscopy very positive       negative73    treatment  0          Levamisole                                0                       10 mg/kg75    coproscopy very positive                       negative negative108   coproscopy positive   positive negative110   treatment  0          Levamisole                                0                       10 mg/kg112   coproscopy very positive                       negative negative145   coproscopy massive    average  infestation and R %    infestation                       infestation                                nil            R = 0%     av R = 60%                                R = 98%______________________________________ 
    
     It emerges from this table that the device of Example 3, which corresponds to a daily dose of 120 to 170 mg of Levamisole base during 150 to 200 days, permits very effective protection against helminths. 
     Thus as emerges from the foregoing, the invention is in no way limited to those of its types of its applications and embodiments which have just been described more explicitly; it encompasses, on the contrary, all modifications which may come to the spirit of the technician in the art, without departing from the scope, nor the range of the present invention.