FR2599624A2 - PROGRAMMED RELEASE DEVICE - Google Patents

Abstract

THE PRESENT INVENTION RELATES TO A PROGRAMMED RELEASE DEVICE. DEVICE ALLOWING THE RELEASE AT A REGULATED SPEED IN A LIQUID MEDIUM OF ONE OR OF ACTIVE SUBSTANCE (S) CONSISTING OF A SOLID MACROMOLECULAR AND THERMOPLASTIC MATRIX SUPPORT, BASED ON INSOLUBTIVE POLYMERS OR COPOLYMERS AND ADDITIVES ASSOCIATED WITH ADDITIVES ALLOWING THE PROGRESSIVE AND SCHEDULED RELEASE OF THE INCORPORATED ACTIVE SUBSTANCE (S). THE SURFACE 17 OF THE DEVICE 10 THROUGH WHICH THE DIFFUSION IS EFFECTED IS ONLY THAT OF A THROUGH CHANNEL 16, THE EXTERNAL SURFACE OF THE MATRIX SUPPORT 14 BEING COATED WITH A FILM 20 IMPERMEABLE TO THE SAID ACTIVE SUBSTANCE (S) . APPLICATION: TREATMENT OF LIVESTOCK, IN PARTICULAR WITH ANTHELMINTIC PRODUCTS OR PRODUCTS ADDED TO OLIGO-ELEMENTS.

Description

The subject of the invention is a device with programmed release according to the

  Principal patent application, ie a device for the controlled rate release in a liquid medium of one or more active substance (s) consisting of a macromolecular and thermoplastic solid matrix support based on polymers or insoluble copolymers associated with adjuvants and additives allowing the gradual and programmed release of the active substance (s) incorporated (s), wherein the initial concentration of the active substance (s) (s) ), on the one hand, and the surface of the device by which the diffusion is carried out on the other hand, are determined as a function of the duration of the release and the desired daily release quantity, said matrix support enclosing totally or almost totally one or more nasses of dense materials giving the whole a weight

  volume greater than 1.3 gram / ml.

  Such a device can be used for the diffusion of drug substances in humans or animals and, in the latter case, it is administered orally for its introduction into the rumino-reticulate bag of ruminants where it is retained for a long time. period of time. Although such devices are satisfactory for the release of substances with pest control and / or anthelmintic activity, particularly in the case of bovine herds, the fact that the diffusion of the active substance (s) occurs the entire surface of the device may have as a first consequence a sometimes non-regular release of the substance or substances, while the practice seeks to have a device to release the same daily dose for a long period of time, on the order of at least three months, and secondly the fact that the release of active substance (s) can be represented by an asymptotic curve, as a function of time, this may be a disadvantage of 'use

of the device.

  Indeed, when such known devices are administered to young animals the various factors that control the release of the active substance (s) are calculated and combined for the release of substance (s) active (s) is compatible in the first days of treatment with the weight of the animal treated, and this in accordance with the usual dosing rules. However, as the animal grows and its weight increases, if the release of active substance (s) also increases, this increase is asymptotic, as indicated above, and this because the elimination of substance (s) active (s) by the juices or liquids of the digestive system takes place progressively from the outside to the inside of the device that is to say, for a body of elongated general shape, following gradually decreasing surfaces (and therefore quantities

  also decreasing) while the normal dosage would require that the amounts of released substance (s) go up but non-asymptotically as the growing weight of the treated animal increases.

  In addition, the manufacture of such known devices according to the main patent can sometimes present technical difficulties for the positioning of the one or more

  masses of dense material with respect to the rest of the polymer matrix.

  Therefore, from the state of the art as defined above, the Applicant has sought to provide a device that satisfies better than the known devices to the desiderata of the practice, particularly with regard to quantities of substance. (s) active (s) released over time, both with regard to the regularity of doses released daily than with respect to the progression over time of said doses and that to adapt as well as

  possible at the best dosage, especially in the case of ani35 malnutrition during growth.

25996Z4

  It is, in this respect, an object of the invention to provide such a device in which the daily release of active substance (s) evolves over time in linear increments, that is to say by providing at the beginning of its use and during a first phase, a regular daily quantity of substance (s) active (s) then, during a second phase, another regular daily quantity and, during a third phase a a new regular daily amount preferably but not necessarily different from the first and / or second, etc., so that the released amounts, well adapted to the size and weight of the animals to which the devices are administered,

  make it possible to obtain the best possible results.

  The Applicant has now surprisingly found that it was possible to obtain this result from a device of the type defined above, by providing in the solid matrix support a through channel through which performs the diffusion of the substance (s) active (s), diffusion which, unlike that implemented in the device of the prior art, is prohibited on the outer surface of the matrix support, which is

  coated for this purpose with a film impermeable to the active substance (s).

  In a device according to the invention, the volume mass which it is desired to maintain relatively high is obtained by distributing a material of high density in the assembly of said support, for example a powder, filings or metallized shot which gives the whole

device the desired density.

  In an advantageous embodiment the device is of oblong shape, somewhat ogival with rounded end, with a longitudinal axis along which is disposed the

  through channel, the latter having a constant cross section or slightly increasing from one end to the other of the dispo35 sitif.

  Since the entire outer surface of the device is coated with a polymerizable impermeable film, for example a material such as a crosslinkable silicone elastomer, an epoxy resin, a polyurethane varnish and / or an acrylic varnish or the like, it As a result, the progressive release of the substance (s) active (s) is effected by the wall of the cavity defined by said channel with the result of a release of the or

  active substance (s) at constant daily dose levels.

  By incorporating into the macromolecular and thermoplastic solid matrix based on insoluble polymers or copolymers of a high density product, in order to obtain the desired final density, a product is simul¬ taneously obtained. very homogeneous and so without counter effects

  harmful to the animal to whom it has been administered.

  An appropriate choice of the concentration of the active substance (s) in the polymer matrix, the shape and dimensions of the through-channel and the addition, if necessary, of adjuvants or additives polymers or copolymers of the matrix depending on the nature of said polymers or copolymers, makes it possible to adjust the duration

  diffusion levels and daily doses of active substance (s) released by the device, for example within an animal organism.

  The active substance (s) may be chosen for their prophylactic or therapeutic action in the field of antiparasitic, antibiotic, antibacterial, antifungal, vitamin or nutritional.

  In the case of substance (s) anthelmintic action said substances are advantageously chosen from

  the group which comprises Levamisole, Tetramisole, Morantel, Pyrantel, or their soluble salts, Nitroxynil, Albendazole, Oxybendazole, Oxfendazole, Mebendazole and Ivermectin.

  A particularly advantageous embodiment thus provides for the application, as an active substance,

levamisole hydrochloride.

  Mineral chemical substances may also be selected to provide micronutrient intakes.

  The concentration of the active substance in the polymer matrix may vary from 1 to 60% by weight of the matrix part, depending on the desired levels and

  daily doses that one seeks to release.

  As regards the density of the device, this is determined by the quantity of the metal mass introduced in the form of powder, metal filings or shot, the quantity of this product being between

  and 75% by weight of the matrix portion.

  Among the macromolecular thermoplastics based on insoluble polymers or copolymers, the invention provides, in a preferred embodiment, the application of an ethylene vinyl acetate copolymer (EVA).

  For the manufacture of a device according to the invention, the polymer (s) or copolymer (s), the active substance (s) and the powder of the dense material are homogeneously mixed together and The mixture obtained is hot-molded to obtain a product which directly demoulding the desired through channel or, alternatively, to obtain an intermediate part which is then shaped, for example by

  usinaae, for the formation of the wanted through channel.

  In either case, the outer surface of the device is then covered with an impermeable film such as a crosslinkable silicone elastomer, an epoxy resin, a polyurethane varnish, or a cold acrylic varnish.

  The manufacturing technique, thus simpler than that of known prior art devices, makes it possible to lower the manufacturing cost of said devices appreciably, in particular for their use in veterinary medicine. The invention will be well understood by the description

  which follows, given by way of example and with reference to the appended drawing in which: - Figure 1 is a schematic perspective view of a device according to the invention; - Figure 2 is a longitudinal sectional view. The device 10 shown on 1 and 2, and which is described here by way of non-limiting example, is of form

  generally oblong, substantially of revolution about an axis 11 11 with a rounded end or apex 12 and another distal end 13, flat and substantially orthogonal to the axis 11.

  The body 14 of the device consists of the macromolecular solid matrix support based on polymer (s) - or insoluble copolymer (s), one or more active substance (s) and one or more mass-based materials. high volume,

  for example the metal filings or powdered shot shown here for purely illustrative reference 15, while the assembly is in fact completely homogeneous.

  According to the invention, the device 10 is pierced along its axis 11 along a through channel 16 which may be of constant circular cross section, that is to say form a cylindrical surface 17 of axis 11 or, in variant and as shown in the drawing, form a gradually increasing circular cross sectional channel from the base 13 25 to the top 12, that is to say a somewhat frustoconical surface 17 which opens on the face 13 through an opening 18 and at the top 12 by an opening 19. When the device is in place, for example in the rumino-reticulated bag of a

  animal, its inner surface 17 is in contact with the rumen juice 30 which passes through the device through the openings 18 and 19.

  According to the invention, also, the outer surface of the device 10 is covered with a film or film 20 in an impermeable, polymerizable substance, such as

  a crosslinkable silicone elastomer, an epoxy resin, a polyurethane varnish, or an acrylic varnish and said film or film;

  It extends over the entire external surface of the device, that is to say between the periphery of the opening.

  and the periphery of the opening 19 with the exception of the inner surface or wall 17 of the through channel 16.

  As a result, at the beginning of use, the solvating liquid, such as rumen juice in a bovine or other similar liquid, comes into contact with the wall 17 and that it is by said wall that released the active substance. Over time, the progress of the solvation liquid proceeds from the wall 17 towards the external surface of the body 14 and, taking into account the geometry of the device, the solvent encounters and solvates increasing amounts of active substance (s). (s); concomitantly, the rate of penetration of the solvent into the matrix is decreasing, taking into account the increase in the distance to be traveled by the solvating liquid to reach the active substance while the elimination of said substance (which is function of the quantity conveyed through the already solvated regions of the matrix) is regulated by said

  matrix that plays somewhat the role of an intermediate membrane.

  Such behavior of the device is particularly interesting in the case of the release of a drug substance to young animals during growth. It allows, in fact, by an appropriate choice of the parameters of the device such as the volume and the shape of the through channel, the concentration of substance (s) active (s), the

  The nature of the matrix and that of the material introduced to assist in obtaining an appropriate density, to determine phases or stages of time during which a constant daily dose is released by the device.

  If we choose a daily dose at the end of

  the life of the device greater than that of the beginning of use, the dose of active substance (s)

  increase the weight and size of the treated animal, in accordance with the usual rules of posology.

EXAMPLES

Example 1

  The following composition is first prepared in parts by weight: Levamisole hydrochloride ........ 15 Iron powder ..................... 66 Copolymer of ethylene / vinyl acetate with 28% vinyl acetate (EVATANE 28-05 from Soiété ATOCHEM) The three constituents are mixed homogeneously and the mixture obtained is injected under heat at a temperature of about 105 C in a mold having a core 15 and which thus provides, on demolding, a device as shown

in Figures 1 and 2.

  Such a device, having a length of about 105 mm, a larger diameter at the top of its rounded front face 12 of about 30 mm and having a circular flat base 20 with an external diameter of about 27 mm has a weight of about gr and a density of about 2.6 gr / ml. The through channel 16 has a circular section of about 8 mm at the base 13 and a diameter of about 10 mm at the front.

curved 12.

  After cooling the device it is covered on its outer surface with a thin film of polyurethane varnish 1/10 mm thick, which reigns

  thus on the entire surface of the device with the exception of the wall 17 of the through channel 16.

  The device is then subjected to tests of

in vitro and in vivo release.

In vitro release assays.

  -The test device is immersed in a liter

  drinking water adjusted to PH 7 and thermostated at 37 C.

  The container is equipped with a plunging mechanical stirring system (anchor or propeller type) driven by a slow rotation movement (approximately 100 revolutions / minute) ensuring

the homogeneity of the solution.

  The entire assembly is placed in the dark and daily samples of 1 ml of solution are made, the entire volume of liquid being replaced by

Of drinking water.

  The concentration of active ingredient, released per day, is determined by the high performance liquid chromatography technique and the kinetics of release is given in Table I below in which are indicated the amounts of levamisole hydrochloride released expressed

in% cumulative of the initial dose.

TABLE I

  Days in vitro Levamisole Hydrochloride% released

1 2,9

2 3.2

4,6

7 6.5

14 10.1

21 12.9

28 15

16.9

42 18.5

49 19.4

56 20.1

63 22.05

27.2

84 35.1

49

126 58.7

147 72.4

168.88

  After 169 days, the device is removed from the bath and the remaining amount of levamisole hydrochloride in the matrix

is determined by analysis.

  This shows a remaining amount of the order

  16%, which confirms the cumulative values eliminated. 35 It appears from the table above that the elimination of

  the active ingredient in vitro corresponds, in fact, to three

  different and successive stages of kinetics.

  In a first phase, or kinetic phase I, lasting 21 days, the daily quantity released is substantially of the order of 152 mg. In a second phase or phase of kinetics II, between the 21st day and the 73rd day, the daily quantity released is of the order of 54 mg per day, whereas during the third phase, or phase of kinetics III , ie, from the 73rd day to the 168th day, the daily quantity released is approximately

the order of 143 mg.

  It is thus found that after a first phase of constant daily release it is slowed down and then resumed again with a constant daily release 15 and this in contrast to the devices of the prior art in which the release is asymptotic, that is, to say decreases as we get closer to the

  end of the life of the device.

  The previous tests are supplemented by in vivo tests conducted in the following manner.

  In vivo tests The release rate of the active ingredient (milligrams per day) is determined using

  as described above which are administered to 12 young cattle with ruminal fistula.

  The devices are removed after 5, 21, 42, 98, and 126 days to assess the remaining amount of

active ingredient.

  The amounts of levamisole hydrochloride released are expressed as a% of the initial dose, and are given

  in Table II below, and for the average of two animals in each test.

TABLE II

  Days Animals N Levamisole hydrochloride released A and B 7.1 21 C and D 19.8 42 E and F 33.5 Get H 55 98 I and J 75.2 126 K and L 94.9 The amount released per day is of the order of 10 186 mg for the duration of the tests, with kinetics

  somewhat different from in vitro tests.

  It is found, in fact, that the release rate is higher than that of the in vitro tests, on the one hand, and it does not detect, on the other hand, steps of the type of those reported above. Notwithstanding the difference in behavior, no doubt due to the nature of the solvent liquid and to the complex factors that prevail in the rumen of animals, the non-asymptotic release of the active principle provides

  important advantages over known devices.

  Similar results were obtained using a device whose matrix is an ethylene / vinyl acetate copolymer of the type sold under the name

  commercial ESCORENE ULTRA by ESSO CHIMIE.

Example II

  The following composition is first prepared in parts by weight: copper carbonate ....... 19.30 - cobalt carbonate ....... 0.73 Sodium selenite ...... .. 0,47 - Iron powder ............. 59,50

- EVATANE 28-05 ............. 20,00

  The constituents are homogeneously mixed and the mixture obtained is injected at a temperature of about 110.degree. C. into a mold having a core and which thus furnishes the mold, a device as shown in FIG.

Figures 1 and 2.

  Such a device, with a length of about 50 mm, a larger diameter at the top of its rounded front face 12 of about 19 mm and having a circular flat base with an outside diameter of about 17 mm, at a weight of about 35 g, and a density of 2.5 g / ml. The through channel 17 has a circular section of about 5 mm at the base 13 and

  a diameter of about 6 mm on the convex front part 12.

  After cooling the device it is covered on its entire outer surface with a thin film of silicone crosslinkable cold to 1/10 mm thick, which thus reigns over the entire surface of the device to

  the exception of the wall 17 of the through channel 16.

  Such a device can be used, in particular, for the administration in metered, predetermined amounts of trace elements to sheep.

Claims (12)

  1. Device for the controlled rate release in a liquid medium of one or more active substance (s) consisting of a macro-molecular and thermoplastic solid matrix support (10) based on associated insoluble polymers or copolymers adjuvants and additives allowing the gradual and programmed release of the active substance (s) incorporated, in which the initial concentration of the active substance (s) on the one hand, and the surface of the device by which the diffusion is carried out, on the other hand, are determined according to the duration of the release and the desired daily release quantity, said matrix support enclosing totally or almost totally one or more mass (s) of dense material 15 (15) conferring on the assembly a density greater than 1.3 g / ml, characterized in that the surface (17) of the device by which the diffusion takes place is only that of a through channel ( 1 6), the outer surface of the support   matrix (14) being coated with a film (20) impermeable to the active substance (s).   2. Device according to claim 1, characterized in that the density greater than 1.3 g / ml of the   This device is imparted by the incorporation into the matrix of a powder, filings, or metal shot homogeneously distributed in the matrix support.   3. Device according to claim 1 or claim 2, characterized in that it is of oblong shape with a longitudinal axis (11) along which is formed the through channel (16), the latter having a constant cross section 30 or slightly increasing from one end to the other of the device.   4. Device according to any one of claims 1 to 3, characterized in that the impermeable film   (20) is a material of the type of crosslinkable silicone elastomers, epoxy resins, polyurethane varnishes and / or acrylic varnishes.   5. Device according to any one of claims 1 to 4, characterized in that it is produced by molding a homogeneous mixture of polymers or copolymers, from about 1 to 60% by weight of the matrix of one or of substance (s)   active (s) and from 10 to 75% by weight of a powder, filings or metal shot. 6. Device according to claim 5, characterized in that the matrix is based on ethylene copolymer / vinyl acetate.   7. Device according to claim 5, characterized in that the metal powder is an iron powder.   8. Device according to any one of the preceding claims, characterized in that the active substance (s) has (have) a prophylactic activity or   therapeutic in the field of pest control, antibiotics,   -antibacterial, antifungal, vitamin or nutritional.   9. Device according to claim 8, characterized in that the active substance (s) has (have) an anthelmintic activity and is selected from the group which includes levamisole, tetramisole, morantel,   Pyrantel, or their soluble salts, Nytroxinil, Albendazole, Oxybendazole, Oxfendazole, Mebendazole or Ivermectin.   10. Device according to claim 8, characterized in that the active substance (s) comprises (include) nutritional additive elements such as trace elements or the like.   11. Device according to any one of the preceding claims, characterized in that it releases the active substance (s) it encloses in substantially constant daily doses for a period of time on the order of at least three months.   12. Device according to claim 11, characterized in that the substance (s) active (s) is (are) bfered in substantially constant daily doses during the course of   distinct phases and in discrete number of its lifetime.