CS236761B2 - Agent for controlled,continuous and long-lasting introducing of active compound into environment containing liquid on water base - Google Patents

Abstract

Delivery systems and devices for the controlled release of chemicals, including drugs, comprise a wall, formed in part at least, of a porous material, including a porous fabric material, pores of which contain a hydrogel, said porous wall being in contact with at least a portion of a reservoir comprised of a chemical and, if desired, a water-soluble liquid excipient and/or a detergent. Emphasis is given to said systems and devices in which the hydrogel is gelled cellulose triacetate, and to their use for controlled release of drugs to animals, especially to ruminants over prolonged periods of time.

Description

The invention relates to a composition for the controlled, continuous and prolonged introduction of an active ingredient into an aqueous liquid medium. For example, the composition is in the form of a roller or tablet and is formed by a reservoir containing only the active ingredient or the active ingredient in admixture with a liquid water-soluble excipient which is closed by a shaped wall formed at least partially by a porous material. it is insoluble in that environment and retains its integrity throughout the introduction of the active substance. The composition according to the invention comprises an active substance, such as a medicament or other chemical, which is released into an environment containing an aqueous liquid, in particular into an environment in the animal body. The composition according to the invention is particularly useful in the form of tablets containing a medicament for the release of the medicament into the body of ruminants, which composition is trapped in a rumen and capped animal bag.

Systems and means for controlled release of drugs, i.e., controlled release, retention or sustained release, are well known in the art. Many methods have been described in the literature, including physiological modification of absorption or excretion, solvent modification, chemical modification of drug, absorption of drug on insoluble carrier, use of suspensions and implant tablets and pills (see: Edkins J .: Pharmacol., 11, 54 T (66 T, 1959). In other methods, the medicament is mixed with a carrier that disintegrates gradually in the environment into which it has been introduced, for example in body fluids, resulting in drug release. Waxes, oils, fats and soluble polymers were used as carriers.

Methods of the prior art also include dispersing the drug in a solid base material from which the drug is released by diffusion, or encapsulating the drug in a housing having a wall of polymeric material or polymeric materials through which the drug can pass through diffusion (see U.S. Pat. No. 3,279,996).

U.S. Patent No. 3,975,350 discloses hydrogel carrier systems containing polyurethane polymers used for medical and algae control applications, and for pesticide, insecticide and the like.

U.S. Patent No. 1,693,890 describes the preparation of porous membranes of acetate cellulose in the form of gels used in dialysis. According to this procedure, acetate cellulose is precipitated from its solution in acetic acid by the addition of a false solvent such as water. If necessary, the membrane can be formed on a substrate. The membranes so produced are impregnated with water, which water can be removed by washing in alcohol, acetone or any liquid mixed with water.

The use of liquid cellulose polymer materials, including cellulose esters such as cellulose triacetate or cellulose nitrate or molecular mixtures thereof, in the form of films, fibers or microspheres as carriers for the controlled release of various substances has been described in U.S. Pat. The substance to be released is impregnated into the liquid cellulosic polymer as part of the liquid phase, or as all of the liquid phase (alcohol or water or mixtures thereof) and is contained in the microscopic pores of the cellulosic material.

U.S. Pat. No. 3,846,404 discloses the use of semipermeable membranes of gelled cellulose triacetate, useful as a carrier material for other materials, for example, fluids with medicinal properties.

This patent also describes impregnating a smooth surface nonwoven polyethylene fabric and ordinary cotton fabric with gelled cellulose triacetate to provide reinforced cellulose triacetate-containing hydrogel materials. Also disclosed in this patent is the use of a drug-impregnated gelled triacetate cellulose product as a sustained release implantable animal drug, such as those obtained by depositing a gelled cellulose triacetate on a woven or non-woven carrier sheet.

Means for dispensing controlled-release medicaments comprising a reservoir containing the medicament and a solid or liquid carrier for said medicament and a wall in contact with or surrounding said reservoir the wall is made of any variety of materials, including microporous materials in which microscopic pores store a diffuse environment, such as a liquid phase containing a solution, colloidal solution, suspension or sol through which the active substance permeates diffusion, are described in several U.S. patents, such as 3,993,072, 3,993,073, 3,896,819, 3,948,254, 3,448,262,

828 777, 3,797,494, 4,060,084 and 3,995,634.

U.S. Patent No. 3,993,073 discloses that hydrophilic hydrogels of acrylic and methacrylic acid esters and cross-linked polyvinyl alcohol can also be used as suitable wall preparation materials in the compositions. The main feature of the compositions described in the aforementioned patents is the use of a wall formed at least partially of microporous material whose pores contain a drug release rate controlling environment permeable to the drug substance and a container containing the drug substance and a carrier through which permeation of the drug substance at a rate greater than that of the release rate controlling environment deposited in the pores of the microporous wall.

UK Patent No. 1,318,259 discloses a composition suitable for administering to a ruminant an active substance or a nutrient. The substance to be administered is encapsulated in a water-insoluble permeable material having a capillary structure or interconnected pores passing through the composition and a paper or fabric that is partially impregnated with water-insoluble polymers such as cellulose acetate.

U.S. Pat. No. 3,594,464 discloses tablets containing. magnesium and iron intended for ruminants, the administration of which releases these metals on a long-term basis and is thus delivered to the; ruminant bodies in a long time interval. In one embodiment, the tablets are a magnesium alloy cylindrical tube filled with beads and a biologically active agent that is sealed at both ends with porous plates.

According to U.S. Pat. No. 3,938,515, a sustained, long-term drug delivery device is comprised of a reservoir containing the medicament and a solid or liquid carrier through which the medicament can permeate and is further surrounded by a polymeric material through which said drug substance permeates at a slower rate than said carrier.

U.S. Patent No. 3,946,734 discloses a diffusion cell, particularly for use as an implant. It is essentially a capillary whose one end is sealed with an impermeable material while the rest of the tube and its other end are closed with a neutral porous hydrogel. The biologically active agent is placed in a capillary against insoluble material, and the capillary is then filled with hydrogel [agarose, polyacrylamide j, through which the biologically active drug substance diffuses.

Many of the known controlled-release agents of the prior art are referred to as zero order release agents. However, these devices can only maintain the zero order release rate in relatively short fractions of their expected life, but are not suitable in practice for long-term use, for example in ruminants.

The prior art means, including those comprising a reservoir containing a drug substance, surrounded by a shaped wall made up of at least partially microporous material, in which pores are located an environment allowing release of the drug substance at a controlled rate at which the drug substance can permeate clogging or physical damage in certain cases of application, for example in the rumen bag formed by rumen and ruminant cap. Clogging reduces and even stops the release of the drug substance, and the compositions become ineffective for the intended purpose.

For the prior art compositions disclosed in U.S. Patent Nos. 3,993,073, and 3,993,072, and further 3,967,618, 3,948,262, 3,948,254 and 3,896,819, used for the controlled release of high water solubility drugs. Preferably, the wall and / or container is formed of a substantially water impermeable material to prevent dilution of the medicament in the container by absorbing body fluids into the storage space of the device, reducing the rate of drug release. Therefore, these compositions are not suitable for the administration of water-soluble active substances, especially in relatively large amounts. The compositions described in most of these patents require, in addition, that the permeability of the environment through which the drug substance permeates at a controlled release rate and which is embedded in the pores of the porous wall surrounding the container is less than that of the liquid carrier in the drug container. The passage of the drug substance through the wall of the composition becomes this step of controlling the rate of drug release.

The use of a small amount of morantel tartrate as an anthelmintic agent in drinking water of calves which has constant access to such treated water as a method of endoparasitic control has been described by Downing et al. In Irish Vet. J., 221, November 1974, a. In United Kingdom Patent No. 1,530,161. It has been found that the continuous daily anthelmintic treatment of calves from early April to mid June suppressed the production of worm eggs in calves, avoiding or · the development of · severe larval infections that occur on pasture has been reduced to a minimum.

Daily small ration of morantel tartrate administered to calves · from the moment of expulsion to grazing until mid-June has shown successful control of parasitic gastroenteritis and infection caused by lung parasites of the metastrongilidae family, due to a reduction in grazing infections in which the calves graze. et al., see Brit. Vet. J., 134, 166, 1978.

The essence of the composition for the controlled, continuous and long-term introduction of the active substance into an aqueous liquid medium, for example in the form of a roller or a tablet, constituted by a reservoir containing only the active substance or the active substance in admixture with a liquid excipient soluble in water. enclosed by a shaped wall formed at least in part by a porous material, said part being at least partially in contact with the storage space and insoluble in said environment and retaining its integrity throughout the introduction of the active ingredient, The pores of the porous material are impregnated with a hydrogel permeable to the active ingredient used and an aqueous liquid, said roller or tablet having a density of at least 2 g / cm @ ³ , which is achieved by using a high density material in this section.

In a preferred embodiment of the present invention, the porous material whose pores are impregnated with hydrogel is selected from the group consisting of sintered polyethylene, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride and sintered polystyrene.

It is also preferred that the porous material is a porous fabric selected from the group consisting of polyethylene, polypropylene, polytetrafluoroethylene, glass fiber fabric or modaralkyl fiber.

Preferably, the hydrogel is gelatinized cellulose triacetate.

The high density material may preferably be steel, wherein the shaped wall is formed by a steel roller and the end portions are sintered polyethylene whose pores comprise gelatinized cellulose triacetate.

In a preferred embodiment of the present invention, the high density material comprises a perforated steel or iron sheath located between the storage space and the porous material.

An advantage of the composition of the present invention is that it allows the controlled, continuous and long-term introduction of the active ingredient, such as a drug or any other chemical, from a storage space into an aqueous fluid containing environment, especially into the animal's environment. For example, the composition of the present invention may be in the form of a pill or tablet that can be injected into ruminant bodies and, by weight of the composition, may be contained in a rumen and capped animal bag.

Compared to the prior art, a controlled and predetermined rate of introduction of the active ingredient of the zero order for the active ingredient is achieved and maintained over a long period of time.

In the composition of the present invention, the pores of the hydrogel-containing porous material that are in contact with the storage space in which the drug substance is placed do not clog or cause physical damage, which composition can also be used for long-term administration of the drug substance. released at a controlled and predetermined rate into an aqueous fluid containing environment.

As already mentioned, in the prior art compositions used for the controlled release of high water solubility drugs, the wall and / or storage space are preferably made of a material which is substantially impermeable to water to prevent the drug substance from being diluted in the water. storage space by absorbing body fluids into the device, thereby reducing the rate of drug release into the body. Therefore, these compositions are not suitable for the administration of water-soluble drugs, especially in relatively large amounts. In addition, as discussed in the prior art, prior art compositions require that the permeability of the environment through which the drug substance passes at a controlled release rate and which is embedded in the pores of the porous material surrounding the storage space is less than is the permeability of the liquid carrier in the drug container. In this way, in the prior art compositions, the permeation of the drug substance becomes a wall step that controls the rate of drug release. The composition of the present invention is without such limitations. A significant difference between the composition of the present invention and the prior art compositions lies precisely in the presence of a highly water-soluble hydrogel embedded in the pores of the porous material in contact with the storage space. The function of the device depends on the diffusion of water from the medium containing the aqueous liquid into which the device is deposited, through pores or channels in the hydrogel filled with liquid, into the storage space, and on the diffusion of the drug substance out of the reservoir into the environment. Unexpectedly, according to the present invention, it has been found that the concentration of dissolved drug substance in the storage space does not decrease. As a result, the composition of the present invention achieves a substantially constant release rate over a long period of time. The amount of drug substance dissolved in the storage space varies continuously over the life of the device.

The composition of the present invention releasing chemical agents including drug substances (both terms used interchangeably) is useful for the controlled administration of drug substances and other chemical agents to an environment containing an aqueous liquid. These compositions are of particular importance for the oral dosing of various active substances to animals and humans. Furthermore, the composition of the present invention well suited for administration of substances with high water solubility, which are released at high speed, which was not possible do236761 ^one touch by means of the prior art. In this case, · those substances is highly soluble possible to quickly process the hydrogel and thus the administration of chemical agent ¹ at high speeds. The composition of the invention allows long-term controlled release of chemicals. It is easy to make, reliable and easy to use. In addition, the composition of the invention maintains its physical and chemical integrity, does not clog in the environment used, and is particularly valuable for oral use in ruminants when in the form of large pills. The composition according to the invention is the first product which is suitable without problems for the controlled and continuous release of chemicals, including medicaments, into an environment containing an aqueous liquid, thereby fulfilling this long-standing need, especially in animal husbandry.

The controlled release chemical composition of the present invention is provided with a partition or wall in contact with at least a portion of the storage space containing the chemical agent, the wall being formed of at least partially or completely porous material, including a porous textile fabric whose pores contain a hydrogel. wherein environmental fluids permeate the pores of said hydrogel and the chemical is released from the storage space by diffusion. When using the composition of the present invention, the hydrogel comprises liquid from the environment, the liquid being contained in spaces or channels (pores) in the hydrogel itself, and serves as a diffusion pathway for the liquid from the environment and for transporting the drug substance.

The shapes and dimensions of the composition of the present invention may vary widely depending upon the intended use. For example, the composition may be in the form of a capsule for oral and human and animal use, or a cylindrical shape for implantation, or a tablet or pill for use in ruminants.

A preferred form of the composition according to the invention is in its most general embodiment provided with a porous material whose pores comprise a hydrogel, in particular a gelled cellulose triacetate, which permits liquid from the environment in which the composition is present and the drug substance by diffusion through the pores in the hydrogel and porous the material is in contact with at least a portion of the storage compartment containing the chemical, including the drug substance, and, if necessary, further comprising a suitable water-soluble liquid excipient as well as a detergent if necessary. The preferred form of the composition of the present invention is in the form of a tablet or pill for the controlled, long-term release of the drug substance in ruminant bodies, especially cattle and sheep, which means release over a long period of time. Such pills are of particular use in the prophylactic and therapeutic control of parasitological, in particular helminthic, livestock and sheep conditions in gastroenterological and pulmonary parasites of the metastrongylidae family and in pasture-derived helminthic diseases.

The term "pill" is used herein to mean devices that are generally cylindrical, spherical, spheroid, elliptical, or otherwise shaped without sharp edges and protrusions.

Similar prior art devices require different factors to be taken into account in use, and a compromise must be made between them. These factors include the carrier used in the storage space, the solubility and / or permeability of the carrier relative to the drug contained in the container, the nature of the microporous wall surrounding the storage space, the diffusion environment contained within the pores of the microporous wall, relative to the drug substance, the relative solubility of the drug in diffuse. and in the carrier and the need to maintain a substantially constant amount of dissolved drug in the reservoir.

In contrast to these prior art compositions, the composition of the present invention has a simpler design and function. In the composition of the invention, the rate of chemical release can be varied within wide limits simply by varying the area or thickness of the porous material, including the porous fabric whose pores are filled with a hydrogel in contact with the storage space. · Manipulation of only two parameters allows to control the amount of released chemical.

1 is a cross-sectional view of an embodiment of the device of the present invention; FIG. 2 is a cross-sectional view of another embodiment of the device of the present invention; FIG. 3 is an enlarged view of a porous wall in the device; In accordance with the invention, FIG. 4 is a sleeve-shaped composition of the invention, FIG. 5 is another possible solution of the composition of the present invention, and FIGS. 6 to 8 show test results relating to Example 16 below. .

Fig. 1 is a cross-sectional perspective view of an exemplary embodiment of the device of the invention. This means 10 for the controlled release of the chemical during a long interval is formed by a cylindrical wall 11 which is in contact with the container 12 containing the chemical. The wall 11 is formed from a porous material whose pores 14 contain a hydrogel (not shown) through which the fluid from the medium containing the aqueous fluid diffuses into the container 12 and the chemical diffuses from the container 12 into the environment through channels or pores in the hydrogel itself. A chemical substance 15 is stored in the reservoir, preferably the chemical substance 2336761 is a drug, and the liquid excipient 16 is water-soluble. The ends 17 are impermeable caps or closures.

Fig. 2 is a schematic view of another embodiment of the device of the present invention. The chemical release agent over a long period of time in this embodiment is the same as the one of FIG. 1, and additionally comprises a perforated sleeve in the form of a sheath 18, for example of stainless steel, iron or plastic, inserted in the device according to the invention. to control the surface area of the porous wall 11 with the hydrogel impregnated pores 14. If the sleeve is in the form of a sheath 18 of metal, it serves to increase the weight of the device.

FIG. 3 is an enlarged view of the porous wall 11 of the device 10 of the present invention. The pores 14 comprise a hydrogel 19 which is in contact with a container containing a chemical 15 and a water-soluble liquid excipient 16.

FIG. 4 shows a means for releasing a chemical substance according to the invention in the form of a housing with a single closure 17.

FIG. 5 shows another possible embodiment of the device according to the invention, in which a porous material in which pores (14 not shown) form the end walls of the device 10. The cylindrical shell 18 with the bottom closure is formed of an impermeable non-porous material In this case a stainless steel which, in combination with the hydrogel-impregnated end walls, closes the container 12 containing the chemical 15. and excipient 16.

.Giant. 6 to 8 relate to a graph depicting the values obtained when testing a control group of animals and animals treated with the composition of the invention according to Example 16. The animals tested and control were calves. Figure 6 shows the weight gain in. . during the grazing season, both in treated calves and in calves. control groups of calves.

On the y-axis. Yippee . average weight gain in kilograms and per. The x-axis is the days in the grazing season. The solid line corresponds to the control calves and the dashed line refers to the calves being treated. From the test result. it can be seen that both groups of calves had almost the same weight gain in the first about 3 months, after which time the gains in control calves decreased, corresponding to the increased amount of grazing parasites. Weight gain in calves treated with the composition of the present invention continued in this period almost as much as at the beginning of the grazing season.

Figures 7 and 8 show the development of parasites throughout the grazing season, both in treated calves and control calves. The number of eggs per gram of feces was plotted on the right rank and the number of larvae per

- kilogram of dry grazing grass is plotted on the left rank. The x-axis indicates the individual intervals during which the measurements were carried out. April to October. Empty triangles mean eggs in feces and solid circles mean parasite larvae on pasture.

Giant. 7 refers to control calves, wherein FIG. 8 corresponds to treated calves. At the time of calving for grazing, the number of eggs in the animal droppings and the number of larvae in the pasture were low. In the control group of animals, parasite eggs began to appear in the faeces of the animals early in June, reaching their maximum in late July and slowly declining during August and September. The parasite eggs caused an increased incidence of parasite grazing larvae late in July, reaching a maximum in August.

In the treated animal group, parasite egg production decreased sharply in June and July, and this was reflected in a significant decrease in parasite grazing larvae during July and September.

The results, which are shown graphically in Figures 6-8, thus illustrate the advantages of the composition of the present invention and relate to the practical application of the composition.

As mentioned above, the composition for controlled, continuous and long-term delivery of the active ingredient of the present invention is constituted by a reservoir in which the active ingredient, which may be a chemical, in particular the drug substance, is located. both a chemical and a water-soluble liquid excipient are present. This water-soluble liquid excipient has several important functions, for example, removing air from the storage space, thereby allowing greater dosage of the active ingredient, and further increasing the convective mixing in the storage space by using the excipient, ensuring a constant rate of chemical release. . The liquid water-soluble excipient also serves another purpose of not exhibiting any apparent volume change as the chemical dissolves, since the chemical passes from a solid or crystalline state to a solution state.

Typical water-soluble liquid excipients include monools and polyols, and their ethers such as ethanol, ethylene glycol, propylene glycol, glycerin, polyethylene glycol, sorbitol, diethylene glycol, triethylene glycol, dipropylene glycol, tripropylene glycol,

1,2-dimethoxyethane, monoalkyl ethers having 1 to 4 carbon atoms in the alkyl moiety, ethylene glycol and propylene glycol, N, N-dimethylformamide, dimethylsulfoxide, and the like. However, this excipient must be compatible with the hydrogel used.

When used in animals or humans, or in formulations containing an aqueous liquid that is accepted by animals, such as in aquariums, ponds, animal and poultry water systems, and in hydroponic systems, the composition of the present invention should be a liquid excipient. water soluble physiologically acceptable substance.

The amount of liquid water-soluble excipient used per unit weight of drug substance depends on the characteristics of the drug. Generally, an amount of excipient is used which makes it possible to form a compact mass from the combination of drug and excipient. This amount is readily determined by a simple experiment.

Detergents may be used in the storage space of the composition of the present invention in an amount of up to 20% by weight based on the total weight of the container, i. by weight of the chemical agent including the drug substance, together with an excipient and a detergent, if any. These detergents are used to reduce any clogging of the composition. Representative detergents may be inorganic or organic detergents, and include sodium and potassium hexamethaphosphates and tripolyphosphates, sodium lauryl sulphate, sodium glyceryl monolauryl sulphate, sodium dioctyl sulphosuccinate, sodium bis (1-methylamyl) sulphate, polyoxyethylene sorbitan mono-oleate and other esters of known fatty acids and other esters in this area. When a detergent is used, its amount is not critical, and in any case is kept to a minimum so as not to compromise the amount of chemical that can be placed in the container. The optimum amount is determined by the procedures described below.

Throughout the specification, alternate embodiments of the terms storage space, container, chemical container, drug container are used interchangeably. Since the compositions of the present invention are preferably used for the controlled and sustained release of drug substances, the term drug container is preferably used in the description of the invention.

The term porous material, porous partition, porous wall as used hereinabove also includes porous fabric materials. Representative types of materials of this kind will be described below. The porous materials used may be isotropic, i.e. with a homogeneous pore structure throughout the cross-section of the material, or may be anisotropic, i.e. with a non-homogeneous pore structure. However, they shall be insoluble in the environment in which they are used and shall not react with that environment and the substances contained in the container. In general, porous materials whose pores have dimensions ranging from about 1 micrometer to about 10 micrometers can be used in the composition of the present invention. In the composition according to the invention, it is necessary to use porous materials having a porous structure with continuous pores, i.e. pores having an effective opening on both sides of the connected porous wall.

In order to facilitate the transfer of the drug substance from the reservoir to the environment using the controlled release agent of the invention, the pores of the porous material or a portion thereof are filled with hydrogel. The combination of the porous material and the hydrogel, wherein the pores of the porous material are to a greater or lesser extent filled with the hydrogel, results in a composition capable of withstanding clogging and physical destruction under normal use conditions while maintaining its physical integrity and to be used in compositions and situations where known hydrogel compositions would be destroyed and rendered ineffective for long-term controlled release of the active ingredients. The composition of the invention is of particular importance for use in ruminants, in particular cattle and sheep. The hydrogel-containing pores allow passage of the liquid (water into the reservoir through the pores in the hydrogel itself by diffusion from the liquid medium in which the controlled release agent has been deposited upon application, thereby dissolving the drug, and the drug substance thereafter diffuses through the fluid stored in the pens and in the septum formed by the porous material · containing the hydrogel at a rate dependent on the concentration of the drug in the solution in the reservoir, the resistance of the septum, ie the liquid in the pores of the hydrogel, and the effective surface area porous wall sections.

As the drug substance exits the composition, a depleted area gradually develops and a movable boundary between drug and solution is formed. Diffusion of water into the composition from the environment through the pores in the hydrogel-containing wall into the container causes convective mixing of the incoming aqueous phase with the solution in the container. The driving force for this mixing is the difference in density of the two solutions, caused by large differences in their concentration. As noted above, the function of a water-soluble liquid excipient is to help maintain this large difference in density, thereby increasing the mixing rate. Convective mixing results in a constant concentration of the drug substance in the reservoir, which in turn allows long-term controlled drug release, so that if the drug substance remains undissolved in the formulation, the release of the drug substance is of the zero order. As the drug substance is released from the container and the aqueous fluid from the environment diffuses into the container, the amount of dissolved drug in the container changes continuously over the entire life of the composition, i.e., over a long period of drug release. This drug release mechanism allows any geome236761 to be used in any form of geometry, while the dimensions and shape of the container are not limited. This is quite different from prior art formulations such as those disclosed in U.S. Patent No. 3,993,073, in which function and contraction depend on a substantially constant amount of solute in the reservoir and on diffusion of solute in the reservoir. a reservoir to determine the delivery of the drug substance to the wall of the device. The size and shape of these prior art compositions are therefore severely limited in manufacture.

The term "hydrogel" in the description of the present invention refers to a water-containing gel and is defined, for example, in Hackh's Chemical Dictionary, 4th Edition, Grant, p. 332, 1969, as follows: gel formed by coagulation of colloids and water inclusions. Representative hydrogels that can be used to fill the pores of the porous material are, for example, gelled cellulose triacetate, see U.S. Patent Nos. 1,693,890 and 3,846,404, cellulose acetate hydrogels derived from cellulose acetate with an acetyl moiety ranging from 20% to 40%. %, polymeric hydroxyethyl methacrylate, cross-linked polyvinyl alcohol, agarose, polyacrylamide, partially hydrolyzed cross-linked polyvinyl acetate, hydroxyethyl acrylate, diethylene glycol mono methacrylate, diethylene glycol monoacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl acrylate

3-hydroyypropyl methacrylate, dipropylene glycol mono methacrylate, vinylpyrrolidone, acrylamide, methacrylamide, N-propyl acrylamide, N-isopropylmethacrylamide, N-2-hydroxyethylmethacrylamide, polyurethane hydrogel-containing polyisocyanate-containing polymers which are weakly crosslinked cross-linked water or organic polyamine as disclosed in U.S. Pat.

939,105; the copolymers of the ethylenically unsaturated monomers of hydroxyalkyl acrylate and methacrylates and alkoxyalkylene glycol acrylates and methacrylates, which are disclosed in U.S. Pat.

038 264, further a polyether polyurethane resin formed by the reaction between an organic diisocyanate with a mixture of at least two diols, one of which is a water-soluble polyalkylene glycol having a molecular weight ranging from 3,000 to 30,000, and the other is an oxyalkylated diphenol containing 2 to 20 oxyalkylene groups; hydrogels well known in the art.

In the compositions of the present invention, preference is given to using polyurethane hydrogels, polymeric hydroxy (lower) alkyl acrylates or methacrylates, vinylpyrrolidone, acrylamide, lower N-alkyl acrylamides and methacrylamides, especially those hydrogels which are crosslinked or copolymerized with hydroxyalkyl methacrylate to render the resulting copolymer insoluble in water. Preferred hydrogels are gelled cellulose triacetate, polymeric hydroxyethyl methacrylate and cross-linked polyvinyl alcohol. Particularly preferred is a gelled cellulose triacetate, whereby a smooth and efficient functioning of the controlled-release formulation according to the invention is achieved.

The water present in the hydrogel pores can be readily replaced by water-soluble liquids, for example the aforementioned liquid water-soluble excipients. Water can also be replaced by other water-soluble liquids, including alcohols containing one to two carbon atoms. For practical reasons, in order to stabilize the composition of the present invention, especially when the hydrogel is gelled cellulose triacetate, the hydrogel water is replaced with a suitable water-soluble liquid whose vapor pressure is lower than the water vapor pressure so that the composition can be stored without losing efficiency due to the drying of the hydrogel. When a combination of a water-soluble liquid excipient and a drug substance is used in a reservoir, it is advisable to use the same liquid as a replacement for water in the hydrogels.

Hydrogels per se are porous in the sense that they contain areas or areas, i.e. channels or pores, filled with water or other liquid. For this reason, when referring in this description to the diffusion or transfer of chemicals or active substances through a septum, the term "whose pores contain a hydrogel" or a similar other term means that the transport or diffusion of the chemical or active substance occurs through these regions rather than through the hydrogel itself. The hydrogel itself has pores filled with liquid, which serves as diffusion pathways that are considered to be permeable to the environmental fluid and the chemical from the reservoir.

The porous wall that is in contact with the drug-containing container may be formed from a variety of materials. The porous material may completely surround the container or may form only a portion of the wall surrounding the container. Suitable porous materials are porous metals, porous ceramics, sintered polyethylene, sintered polyvinyl chloride, sintered polypropylene, sintered polstyrene, and sintered polytetrafluoroethylene, porous polymers made from thermoplastic resins by the phase separation technique as set forth in Chem. Eng. News, December 11, 1978, p. 23, and other publications well known in the art.

Suitable porous materials are polypropylene and polyethylene, and in particular products made from such materials, generally known as filtering agents, glass, poles, 2336761 tetrafluoroethylene, nylon, cotton, polyacrylonitrile fibers, i.e. long chain acrylic fibers containing 35 to 85 % acrylonitrile units, acrylic fibers, ie synthetic polymers containing at least 85% by weight, acrylonitrile, and polyesters, ie long-chain synthetic polymers of at least 85% by weight. an ester of a divalent alcohol and terephthalic acid, as well as polyvinylacetate, polyvinyl chloride, polyvinyl acetate, vinyl chloride, polyvinyl alcohol, polyvinyl alcohol and vinyl acetate. polyvinyl alkyl ethers, polymers of vinylidene cyanide, vinylidene chloride, vinylidene fluoride, urea polymers and other materials well known in the art, see Encyclopedia of Polymer Science and Technology, Vol. 1, 342 (1964), Vol. 8, 812 (1968), Vol. 9, 403 (1968), Vol. 10, 347, 206 (1969), Vol. 6, 275 (1967), Vol. 11, 62, 445 and 506 (1969), Vol. 14, 305, 575 (1971), Interscience Publishers, New York.

In addition, metal sieves or grids and filter media are suitable, including those made of stainless steel, carbon steel, brass, copper, aluminum, various alloys such as nickel and copper, etc.

However, the porous substance chosen in the present case must be compatible with the hydrogel to be impregnated and must correspond to the end use of the composition. For example, in a composition used as a pill or, a tablet for long-term administration of medicaments to ruminants, it is not possible to use cotton as a porous material as it would degrade in the ruminant's body. In a composition used for the controlled release of a chemical into the. on the other hand, cotton can be used.

Nylon would not be a suitable porous material when used as a hydrogel of gelled cellulose triacetate because it would be degraded by the formic or acetic acid used in the impregnation process.

However, the hydrogel-impregnated porous materials must have sufficient strength, durability and inertness to the drug substance and the environment to be used so as to provide a means for the continuous, controlled, long-term introduction of the active ingredient made from this drug. The material retains its physical and chemical integrity throughout the life of the composition.

The porous material is impregnated with a suitable hydrogel using procedures well known in the art. A frequently used and relatively simple process for impregnating a porous material with gelatinised cellulose triacetate, which is a preferred hydrogel, is to press a solution of cellulose triacetate in formic acid or acetic acid, which is This can be accomplished by immersing the material in a solution of cellulose triacetate placed in a container that is evacuated. After impregnation, the cellulose triacetate-containing plastic mass is coagulated by contact with a large volume of water and equilibrated to obtain a hydrogel-impregnated material. If the porous material is sintered polyethylene and the hydrogel is gelled cellulose triacetate, then the preferred solvent for cellulose triacetate is acetic acid rather than formic acid, since acetic acid wets polyethylene better than formic acid, thereby facilitating the preparation of the hydrogel-impregnated porous material.

If the hydrogel is derived from 2-hydroxyethyl methacrylate cross-linked with ethylene glycol dimethacrylate as disclosed in U.S. Pat. No. 3,520,949, the porous material is impregnated by filling its pores with a mixture of 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate and the latter. the mixture is then polymerized in the pores by the addition of a free radical catalyst such as t-butyl peroctoate. In the same way, other hydrogels can be impregnated into the porous wall material in situ from suitable reactants. If the hydrogel is cross-linked polyvinyl alcohol, the pores are filled with a mixture of polyvinyl alcohol (in the form of a 10% aqueous solution) and resorcinol (2- to 3% solution) by the above procedures and crosslinking is carried out in situ. However, it is also possible to use other crosslinking agents which are well known in the art.

In preparing compositions of the present invention that are intended to retain their storage stability until use, the hydrogel-filled pores are dehydrated by bringing the hydrogel to equilibrium in a suitable water-soluble liquid, e.g. to equilibrium with the above-mentioned water-soluble liquid excipients. As mentioned above, it is desirable to replace the water in the pores of the porous wall material with the same water-soluble liquid, which is used as an excipient, in the reservoir, when the reservoir contains a combination of a chemical and an excipient. If the reservoir contains only a chemical in the said compositions, the choice of the water-soluble liquid used as a substitute for the water in the hydrogel in the pores of the porous wall filled with the hydrogel is determined only by the end use of the composition. an acceptable water-soluble liquid. Such a liquid is suitably introduced into the hydrogel at the same time as the preparation of the porous wall, the pores of which contain the hydrogel, prior to filling the reservoir of the composition as mentioned.

The prior art means, which are closest to their solution in the prior art, of the present invention, i. compositions according to United States Patent Nos. 3,993,073 and 3,993,072 - are based on - different rates - permeability - of the drug through the environment - contained in the pores of the porous wall - in comparison - to the rate of - drug transport in the a phase consisting of the drug substance and the carrier substance in the reservoir. In order to achieve the zero-order release rate envisaged for the compositions described in said patents, it is critical that the environment in the walls of the composition have a lower permeability to the drug substance than the drug carrier has in the reservoir. The environment contained in the porous wall of the composition thus becomes part of the composition controlling the rate of drug release.

The dissolved drug diffuses through the more permeable carrier to the inner wall fairly quickly so that the wall becomes part of the drug controlling the rate of drug release. In this way, a zero-order release rate is achieved for a period of time until the disappearing drug-drug interface in the formulation has increased to the extent that the difference between the permeability in the carrier and the environment is equalized. Therefore, the zero order speed is no longer reached. Therefore, the practical use of these means is limited and the dosages of large quantities of the active substances at zero order are not suitable in cases where they are applied by virtually applicable dosage forms.

The composition according to the present invention has at. - use - as opposed to - means - according to the prior art - aqueous - environmental - contained - in - the porous wall and - also in - the - container. Even if the permeability for the drug substance is the same in the liquid - in the wall - and in the container, the zero order speed is achieved over a large part of the life of the composition according to the invention. In addition, the maintenance of the release rate of the zero order chemical substance does not depend on its diffusion in the carrier substance in the reservoir, so there are no geometric limitations or limitations on the dosages of the compositions of the invention. and it is only in the formulations of the present invention that it has been achieved for the first time that a large number of active substances can be dosed by means of these formulations at a zero-order design with practical dimensions and shapes.

In view of the most effective function of the composition according to the invention for the controlled, continuous and long-term dosing of the active compound according to the invention, it is important to prevent the porous material from being impregnated with the hydrogel as completely as possible. By changing the characteristics of the membrane wall, especially? Its thickness, pore size and porosity, and by varying the size of the reservoir can be achieved with compositions having the same surface area of different dispensers, rates and release times for a given drug substance.

As mentioned above, the composition according ^to the invention is preferably in the form of a pill or tablets intended for long-term, controlled-dosing of the active substance in ruminants. in particular - cattle and - livestock. Tablet with ruminants -. administered - preferably - orally in such a manner that it remains - in the long term - in the stomach formed; bag, rumen - a. cap and - at this time - drug - is continuously released - animal - controlled - release rate. The compositions of the invention thus allow for prophylactic and therapeutic control of the various pharmacological and physiological conditions to which the animals are subject by simple oral administration of these compositions to the animals.

In order to stay in the long-term after being introduced into the rumen-formed bag and the cap in the cattle-molrla at this point, it is necessary to have a density of at least 2.0 g / tonne. In practice, this - density - can range from - 2.0 - to - 7.0 g. Cm ^-3 , or even higher. - Density is, however, the most important factor affecting the maintenance of the pill in the rumen-and-cap bag The overall size of the tablet depends on the required dose to be administered and the size which may be practically In view of the above, additional weight can be added to achieve the desired tablet size; average density. If possible, it is desirable to select a maximum permissible tablet size, since larger pills of a given density are better retained than pills of a smaller size.

If - but average - the density - of the pill increases - to a value greater than - about 5.0 g. Cm 3, then, increasing the pill size no longer - does not improve - more significantly the retention factor. ranging from about 2.5 to about 5 grams. cm3.

The size of the tablet depends, of course, on the animal to which it is intended to be treated. In ruminants, such as sheep and goats, the pill size and weight will be less than that of cattle. The maximum size of the pill used in animals is determined by the practical difficulties in introducing the composition into the animal.

In sheep, the minimum weight of a tablet with a density of 4 g. Cm ³ , which is still retained in the animal, is about 1 gram. - The size - the pill - will vary according to the density of the pill. In cattle, the minimum weight of the pill of an average density of 5- g, cm ^{3 is} about 5 grams. As mentioned above, the upper size limits are determined by the practical suitability of the dosage for the animal, and by the minimum density of the pill.

For example, a pill having an approximate length of 7.5 centimeters, a diameter of 2.5 centimeters, and a density of 2.2 g. cm ³ will have a weight of about 90 grams.

The density of pills containing only the above ingredients is generally below the lower level mentioned above. It is therefore necessary to increase the average density of the pill by adding a suitable high density material such as metal (iron powder, iron spheres, steel spheres) or other density enhancers to minerals such as calcium sulfate to increase the density to the required value. Alternatively, to increase the average density in a suitable manner by inserting a perforated high density material into the tablet as an inner ^one jacket, whereby this material is a metal (such as stainless steel, steel, in particular steel, with a low "carbon or iron ·) and this the perforated shell is in turn surrounded by a porous wall impregnated with a hydrogel. The punch in the sheath should be large enough to allow the drug substance and liquid from the environment to pass freely through the porous wall filled with the hydrogel. The main purpose of the solution is to increase the average density of the tablet to a value sufficient to retain the tablet in a rumen-cap bag, and also to control the size and surface area of the hydrogel-impregnated porous material in contact with the tablet. a reservoir containing the active substance.

In addition, such a sheath may also improve the 'physical stability' of the tablet by ensuring that its physical shape is substantially maintained under the conditions of use. In another alternative embodiment, which is also preferred, a tablet comprising a roller of metal, steel or iron is used, one end or both ends of which are closed by a porous membrane, the pores of which are impregnated with a hydrogel. Tablets of this type are advantageous because they are inexpensive, economical to manufacture and easy to adjust. A low carbon steel is a highly preferred construction material for preparing these rollers. Other alternative solutions customary in the art are also possible.

The controlled, sustained and sustained delivery of the active ingredient of the present invention can be used for a variety of purposes and in various situations where controlled release of a drug substance or other chemical substance is required. The composition of the invention may be introduced into the body near or away from the site of infection, such as antibiotics that are dispersed throughout the body by the circulation of blood or other body fluids. These compositions may be introduced by suitable methods at appropriate locations within the body of the animal, in which they are in contact with body fluids, for example in the stomach of livestock, in particular in a rumen and ruminant pouch. Compositions for controlled dosing of an active ingredient of the invention also include those which can be used as reservoirs of implants for the purpose of administering the drug directly to the host at a controlled rate.

Implants differ from the formulations according to the invention intended for other purposes only in their shape, which, however, is adapted for the implantation purpose. They can also be used as 'sublingual tablets, buccal tablets, pessaries or suppositories, bandages and transplanted' skin. Other uses of the 'controlled, continuous and long-term dosing' of the active ingredient of the present invention are possible in agriculture for 'fertilizer and pesticide formulation', 'fish farming' including aquariums and ponds, 'drainage ditches, canals and tanks for to control the occurrence of algae, and in water supplies, especially for animals and 'poultry, which need to be' administered 'for' therapeutic and prophylactic treatment.

The criterion which must be met by suitable substances, drugs and chemicals contained in the composition of the invention is that they must be sufficiently soluble in water to achieve the required release rate of the drug or chemical in the environment used. give the desired result. For this reason, 'drugs' and 'chemicals which are acids' or 'bases in the form' of their physiologically and pharmacologically acceptable salts are used. The release rate of the drug or chemical from the composition herein depends on several factors, such as wall thickness, available surface area, effective pore diameter, nature of the hydrogel, concentration of the substance in the reservoir and its solubility in the liquid in the environment. The suitability of a given substance is determined in a manner which will be described hereinafter.

Representative drugs useful in the compositions of the present invention are: anthelmintics including morantel, pyrantel, oxantel, piperazine, diethylcarbazine, levamisole, tetramisole, and hygromycin B salts, as well as bactericides including tetracycline salts such as 5-oxylethracin chlortetracycline, doaycycline and their Mannich bases, further penicillin such as ampicillin, penicillin G, aminoglycosides such as neomycin, streptomycin, apramycin, bacitracin and its zinc or methylenedlsalicylic acid derivatives, such as macrolides, for example erythromycin, oleandomycin and 'tylosin, furthermore antibacterial growth promoters such as salts of avoparicin, polymiaine, lincomycin, bambermycin and efrotomycin, further hormonal growth promoters including diethylstlbestrol, zearanol, antiparasitic agents such as ampropolic agents how o for example, soluble salts of magnesium, selenium, copper236761 di and vitamins such as thiamine hydrochloride, sulfonamides such as sulfamethazine, medicines against skin tumors (molluscicides) such as N-tritylmorphine, and anti-swelling products such as alcohol ethoxylates and polyoxyethylene polyoxypropylene-polyoxyethylene polymers, for example poloxalene.

As mentioned above, in addition to the drug, a water-soluble excipient is present in the drug-containing container, preferably a water-soluble excipient. The composition thus formed has the advantage that a larger amount of drug substance can be used in one composition and thus extend the life of the composition. However, the container may contain only the selected drug.

The compositions of the present invention are particularly useful as long-acting tablets for the therapeutic and prophylactic control of helminthic infections in ruminants, especially cattle. In this way, an appropriate control or treatment can then be achieved in animals whose movement is not restricted to a certain area of pasture but can freely graze over large areas.

In areas with mild climates, the residual population of grazing larvae in early spring, which is the remainder of the previous season's infection, is multiplying, and cycling through the animals grazing on them and in summer will cause a sharp increase in infectious resources on pastures. This condition creates clinical parasitism during the summer grazing season and a decrease in the performance of animals grazing on these pastures.

Smooth and controlled release of anthelmintic agent, ie morantel in rumen and bonnet bag, in grazing animals at the beginning of the season, when pasture infection is low, suppresses helminthic egg formation and later larval development, interrupting the above cycle and keeping low worm levels on pastures and animals. This minimizes parasitic infections of ruminants grazing on the same pasture during the summer season. This method of controlling helminthic disease is particularly suitable and valuable in calves which are very sensitive to infection by the helminthic disease when they are first released for grazing. Adequate use of pills reduces the incidence and sources of infectious forms at the site. The use of tablets containing anthelmintic agents according to the present invention prevents or at least minimizes the seasonal increase in the amount of grazing larvae causing parasitic gastroentritis and a decrease in the performance of grazing animals later in the season. In this method of control, the release period of the medicament is set according to the spring reproductive phase and not according to the period of severe pasture infection, lag infested and worm infections that cause clinical diseases and a decrease in performance.

For this reason, this kind of use is called "indirect control". In other words, in the pasture of ruminants having in their rumen stomach bag and cap one or more agents of the present invention which allow controlled and sustained release of anthelmintic agents, such as morantel, into the bag during the early grazing season, i.e. when the larval infection still at a minimal level, or at a nearly minimal level, the composition according to the invention minimizes the usual seasonal increase in larval infestation in the pasture, which serves to protect grazing animals on the pasture throughout the grazing season.

For indirect control of helminthic infections, the compositions of the present invention are preferably administered to a ruminant at the time of the epidemiological cycle of said helminthic worms, at a time when the grazing infections caused by them, their eggs and / or larval stages are still at or near minimal levels. .

In temperate areas, this corresponds to a period of spring expulsion to grazing, ie the period when calves are first grazing. To achieve maximum efficacy, the tablet is administered to calves about two to seven days before the pasture. In those regions of the world where there is no mild climate, ie in semi-tropic and tropical parts, the period of the lowest level of infection in grazing areas usually occurs before the rainy season. The pills are given in such cases to ruminants in these parts of the world preferably two to fourteen days before the start of the rainy season. However, due to the unpredictability of the beginning of the rainy season, helminthic control is carried out in areas where the mild climate is not best 'direct control'.

Tablets formulated as compositions of the invention eliminate helminthic infection in ruminants and prevent severe helminthic infections during the summer. This type of use is called "direct control". The direct control method protects ruminants only during the period of release of the anthelminthic agent. The indirect way of helminthic control protects ruminants grazing on a given pasture throughout the season as it achieves a significant overall reduction in pasture infection. As mentioned above, sustained release of drugs at a controlled rate, including anthelmintic agents, can be achieved by the composition of the present invention.

Particularly suitable for such purposes are the water-soluble salts of (E) -1,4,5,6-tetrahydro-1-methyl-2- [2- (3-methyl-2-thienyl) ethenyl] -pyramidine, called morantel, hereinafter (E). ) 236761

-1, -4,15,6-tetrahydro-1-methyl-2- [2- (thienyl) ethenyl] pyramidine, called pyranthel and (+) -2,3,5,6-tetrahydro-5-phenyl imidazo [2,1-b] thiazole, called tetramisole, and its L- (-) -forms, called levamisole. In a preferred embodiment, the water-soluble salts of pyrantel and morantel are tartrates and citrates, and in the case of tetramisole and levamisole, the selected salts are hydrochlorides.

The tablets according to the invention are administered orally to the animals, for example by means of a delivery device. In calves, an average morantel release rate is appropriate for indirect control of helminths ranging from 60 to 200 milligrams of morantel (i.e. as such) per day of about 60 days, covering the normal maximum life expectancy of the spring larvae population. Additional release intervals ranging from 60 to 120 days are suitable for direct control, as the period of severe grazing infection normally lasts from mid-summer to autumn. At a release rate ranging from about 65 to 150 milligrams, based on morantel, per day, helminthic infection is effectively controlled during said release periods.

More than one tablet may be administered for dosing larger animals. In indirect control of helminths, using pyrantel and levamisole salts, suitable release rates for each of these compounds (taken as free base) range from 100 to 400 milligrams, or from 100 to 500 milligrams per day for about 60 days. . In direct control, the release rate of pyrantel (as free base) ranges from about 100 to 300 milligrams per day, and in the case of levamisole (as free base), the release rate ranges from about 100 to 400 milligrams per day, effective control of the helminthic disease is achieved for a period ranging from 60 to 120 days when the infection is greatest.

Smooth dosing of m-orantel in small amounts with the aforementioned helminthic disease control composition of the invention gives a surprisingly different efficacy profile from that observed with conventional therapeutical dosages of morantel that could not be predicted, which effect is superior to that achieved with conventional means. For example, the long-term maintenance of a certain amount of tartrate and citrate of morantel or other salt in the gastrointestinal tract of ruminants prevents an effective method of infecting metastro-ngilidae lung parasites in said animals at a drug release interval. In addition, while cattle and sheep grazing on contagious pastures are subject to immediate re-infection with nematodes, or nematodes, after routine therapeutic treatment, animals that have received the tablet of the invention are substantially free of new infection and protected from reinfection for 60 days or longer.

The use of the tablets according to the invention for the control of grazing disease, i.e. the indirect control method, is a unique, practical and not yet performed method of controlling helminthic disease, which protects ruminants, in particular grazing ruminants treated in this way, throughout the grazing season. With this method, greater advantages can be achieved than with previously used control methods. The increased daily weight gain of the cattle is significantly greater than that of the conventional therapies compared to untreated control animals during the grazing season.

The release rate of the drug or other chemical passing from the drug containing container through the porous walls of the sustained, sustained and controlled release composition of the present invention, and the effectiveness of combining the drug and / or the water-soluble and / or detergent-free excipient the composition can be readily determined by methods known in the art, for example, by permeability measurement methods, or by sorption and desorption methods. A suitable method for selecting porous materials and hydrogels is to use selected porous material whose pores are filled with the selected hydrogel as a partition between intensively stirred spaces, one containing a saturated solution of the drug or other chemical whose controlled the release is desired and analyzed in the present case, and the other comprises a mixed solvent, wherein the composition stimulates the environment containing the aqueous liquid in which the controlled release formulation is to be used. The temperature of each solution is kept constant, preferably close to the average temperature of the environment in which the composition is to be used. Samples are taken at specified intervals from the solvent bath, which are then analyzed to determine drug concentration. Standardized procedures may also be used to determine the permeability of a drug or other chemical through the pores of a material that is filled with a hydrogel. For this purpose, the standardized procedures described in the Encyclopedia of Polymer Science and Technology, Vol. 5 and 9, pp. 65-82 and 794-807, 1968, and references cited in this publication, as well as the Chcmical Engineers Handbook, pp. 17-45, 1963, Mc Graw-Hill, Inc.

A particularly suitable method for determining the rate of release of an active ingredient in a composition of the invention, and to determine the relative suitability of use of the excipient or detergent used in the composition, especially when the drug is morantel, is the following.

2367B1

The "in vitro" procedure, i.e. outside the living body, is based on the release of a water-soluble salt of morantel, such as tartrate, from the composition of the present invention as a function of time. The composition of the present invention containing morantel tartrate is placed in a one-liter conical flask protected from light because the morantel tartrate is photosensitive, 500 milliliters of pH 7 buffered phosphate buffer is added, and the temperature of the flask and its contents is adjusted and maintained at 37 ° C.

Shake the flask containing the formulation for about 70 cycles (7.62 cm) per minute and collect 5 milliliters periodically. Replace the sample volume with an equivalent volume of fresh pH 7 phosphate buffer and continue to shake the flask. The morantel concentrations in the samples are determined spectrophotometrically by measuring the absorbance of the sample at 318 nm, compared to fresh phosphate buffer at pH 7. The sample analysis procedure is continued until 5 grams of morantel tartrate is released, then transferred to another flask containing 500 milliliters of fresh phosphate buffer solution at pH 7 and the process is continued as before.

The release of morantel tartrate "in vivo", i.e. in a living organism, from a composition of the present invention is determined by introducing the composition into, for example, normal bulls or rumen-fed animals. After a period of time, for example 30, 60, 90 or 120 days, the composition is removed through a fistula or the animals are slaughtered to remove the composition and determine the residual amount of morantel tartrate in the composition. Experiments of this kind have shown that the release of morantel tartrate "in vitro", or the rate of release, respectively, is approximately four times higher than "in vivo".

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The composition of the present invention for the controlled, continuous and long-term introduction of the active ingredient, the process for preparing the composition, and the effect of the composition in comparison with the compositions used so far are illustrated. methods. The scope of the invention is not limited to these examples, and various alternative modifications and changes are possible within the scope of the invention.

He did

The tablet formulation was formed from sintered polyethylene, the pores being filled with gelled cellulose triacetate and the storage space contained morantel tartrate blended with polyethylene glycol 400 [which is a viscous, slightly hygroscopic fluid of the formula HfOCbúCHaJnOH, where n is 8.2 to 9.1, having a molecular weight in the range of 380 to 420] and sodium hexamethaphosphate. The formed wall had a perforated stainless steel sleeve, and the composition was prepared as follows.

One end, designated the first end, of a sintered polyethylene tube with an average feather size of 10 µm, an outside diameter of 25.4 millimeters, an inside diameter of 22.225 millimeters, and a length of 7.938 centimeters was immersed in a 10% solution of cellulose acetate butyrate in methylene chloride. depth of 4.763 millimeters. The tube was air dried and the other end of the tube, referred to as the other end, was immersed in a solution of cellulose acetate butyrate to a depth of 9.525 millimeters, and the tube was then dried again. This procedure was repeated. The first end was again immersed in a cellulose acetate butyrate solution for 30 seconds, allowed to air dry for б0 seconds and a cellulose acetate butyrate disk of 22.225 millimeter in diameter and 3.175 in thickness. millimeter was inserted into the end of the tube to be in the same plane as the first end of the tube being processed. The cellulose acetate butyrate disk floated at the methylene chloride level for 60 seconds before inserting it into the first end of the tube. The tube was then rolled on a workbench and finger pressed on its end containing the disk to ensure complete connection between the disk and the tube.

A rubber stopper number 3 was then inserted into the tube with one hole provided with a glass tube long enough to protrude from the single-hole rubber stopper and from the vacuum cell when the tube was placed on the bottom of the flask. The protruding end of the tube was then connected to a flask containing a 6% solution of cellulose triacetate in formic acid, creating a vacuum of about 20 kPa. After the cellulose triacetate solution covered the outer walls of the tube which were not immersed in cellulose acetate butyrate, the tube was removed from the vacuum flask and the remaining cellulose triacetate was then wiped off.

The tube was then inverted to empty the interior of the cellulose triacetate. The inner and outer open ends of the tube were then wiped completely with a towel. The tube was then immersed in distilled water and boiled overnight. Then the tube was removed from the water, the outer part was dried with a towel and the excess water was shaken from the inside of the tube. The procedure of impregnating the pores of the tube with cellulose triacetate and equilibrating in distilled water was then repeated. Then the tube was boiled in running water for 4 hours.

At this stage, the tube was leak tested by connecting it to a nitrogen source, immersing the tube in water and subjecting it to a pressure of 0.028 MPa of nitrogen for 10 seconds. If a leak is detected in this condition, a procedure is required

236781 impregnation and equilibration repeat.

The tube was equilibrated overnight in polyethylene glycol 400 (specification above), then withdrawn and dried in the inverted position for 4 hours. Excess polyethylene glycol 400 was wiped off the outside of the tube with a towel and an inner perforated stainless steel tubing in the form of a perforated inner cylinder having an outer diameter of 22.225 millimeters, an inner diameter of 18.923 millimeters, a length of 6.985 centimeters and 16 round holes was inserted. A diameter of 7,114 millimeters, evenly distributed over the circumferential surface, the perforated tube being inserted into the polyethylene tube until it is level with the sealed end. The cellulose triacetate scrapers resulting from the insertion of the tightly fitting perforated tube into the tube itself were removed. The cellulose acetate butyrate disk (3.175 mm) was then inserted into the open end of the tube at the level of the perforated stainless steel inner tube and the tube was cut so that its end was flush with the disk. The disc was then removed and the tube was filled with a homogeneous mixture containing 63.31 why, morantel tartrate, 26.61% polyethylene glycol 400 and 10.08% sodium hexamethaphosphate, the insert being level with the end of the inner perforated stainless steel tube. The open end of the tube was filled with a 10% cellulose acetate butyrate solution, which was then immediately cast, and the open end of the tube was immersed in the cellulose acetate butyrate solution to a depth of 6.35 mm and allowed to dry.

A cellulose acetate butyrate disk was then pushed into the open end of the tube and floated for 60 seconds at the methylene chloride surface immediately prior to use, with sufficient force to press the disk onto the inner perforated stainless steel tube. The tube was then rolled over the workbench and finger pressed with sufficient force to ensure sufficient connection between the disk and the tube. The tube was then dried for 1 hour, and each end of the tube was then immersed in 10% cellulose acetate butyrate to a depth of 6.35 millimeters and allowed to dry. The tablet weight was approximately 90 grams, of which it was

24.8 grams of drug mixture. Its density was 22 g. This formulation exhibited a release rate of about 250 milligrams of morantel tartrate per day "in vivo" in cattle for about 60 days.

Example 2

Three formulations of the present invention were prepared in the same manner as in Example 1 and tested in vitro, with an approximately constant release rate over a period of time. 4 to 17 days. The mean dose released for all three formulations was 0.927 grams of morantel per day.

The results obtained from the analyzes performed in this way are shown in the following table.

In vivo tests with three other tablets prepared according to Example 1 and placed in the rumen bag formed by the rumen and bovine cap showed a release amount of 0.224 grams of morantel tartrate per day at an interval of 30 days. This represents a 4: 1 ratio for in vitro / in vivo results.

In vitro days Accumulated morantel tartrate (g)

Pill 1 Pill 2 Pill 3

1 0.357 0.295 0.284 2 0,804 0,723 0.66 4 1.63 1.63 1.38 5 2.12 2.24 1.86 6 2.61 2.96 2.4 8 4.05 6.31 3.7 11 6.55 9.0 5.76 13 8.24 11.34 7.57 15 Dec 11.38 13.4 9.74 19 Dec 14.52 16.2 13.2 25 17.99 17.4 15.4 29 17.13 17.3 15.9

deny below. The average release rate achieved (dose released) was 0.96 grams of morantel tartrate per day and this rate was kept constant for 0-14 days.

Example 3

In vitro tests were performed with two additional pills prepared according to Example 1, the results of which are shown in

235781 31 32 Days in vitro Accumulated morantel tartrate (g) Pill 4 Pill 5

1 0.51 0.59 2 1.5 2.16 3 2.4 2.2 5 4.9 5.4 6 5.1 5.9 7 6.5 6.1 10 9.7 9.7 12 11.00 11.7 14 13.5 12.6 17 14.8 13.6 19 Dec 16.4 14.6 21 17.1 14.7 24 16.8 14.7 26 16.9 14.8

In vivo tests with the same pills placed in the rumen bag of the rumen and cap for 30 to days gave the following results:

Pill no. Days in vivo Average amount of morantel tartrate per day (g) 6 30 0.222 7 30 0.228 8 45 0.238 9 45 0.335 10 49 0.174 11 60 0.198 12 60 0.178

The total average in vivo dose released is 0.224 grams per day and the in vitro / in vivo ratio is approximately 4: 1.

Example 4

According to this example, the pills were prepared from stainless steel tubes with the following dimensions: outside diameter 22.225 millimeter, inside diameter 21.336 millimeter, wall thickness 0.889 millimeter, length 3 centimeters. The ends of the tubes were threaded for a ring holding the disc of a porous substance impregnated with a hydrogel in the correct position. The disc with an outside diameter of 22.225 millimeters and a thickness of 3.175 millimeters was made of polypropylene filter material with an average pore size of 50 μϊΐ, impregnated with gelatinised cellulose triacetate. These disks were prepared by immersing in a container containing a 6% solution of cellulose triacetate in formic acid and evacuating the container to 3.32 kPa or less. The flask containing the contents was held under vacuum for about 10 minutes, the disks removed and the excess cellulose triacetate solution was wiped off. Then, the discs were immersed in distilled water and equilibrated in this environment, which lasted overnight.

The discs were then removed from the water, dried with a towel and then equilibrated with polyethylene glycol, which lasted again overnight. The discs were then removed and wiped with a towel.

The impregnated disks were then inserted into each end of the tube by being placed between two washers having a thickness of 0.254 millimeters with the same diameter as the steel tubes. The steel tube washer was made of cellulose acetate butyrate and the other was made of dental rubber. Stainless steel rings with a bore of 21.336 millimeters were swabbed at the ends. The tubes were then filled with morantel tartrate at 63.3%, polyethylene glycol 400 (specification above) at 26.6% and sodium hexamethaphosphate at 10.1%. The other end of each tube was sealed as described above.

The pills contained 21.4 grams of morantel tartrate, having a weight of 97 grams and a density of 3.30 g.cm ^-3 .

The pills were then administered to rumen fist bulls while the delivery device was swollen, and the pills were removed through the fistula at intervals of 30, 45, 60, 75 and 90 days to determine the amount of drug remaining in the pill. From this, the average daily release rate, or dose released, of morantel tartrate was calculated.

Pill Days v

The results are shown in the following table.

Bovine release dose (mg / day)

108

136

106

The average dose released was 85 milligrams per day with a standard deviation of 25 milligrams.

Significant reductions in parasite eggs in the faeces were found in each bull.

Example 5

Four sintered polyethylene tablets having an average pore size of 10 µm were prepared in the same manner as in Example 1, the pens of which were filled with gelled cellulose triacetate. These tablets contained stainless steel inner rollers only in part of the total length of the tablets, so that part of the tablet did not contain an inner roller. Morantel citrate (63.3%) mixed with polyethylene glycol 400 as specified above (26.6%) and sodium hexamethaphosphate (10.1%) were contained in the storage space.

Instead of the perforated stainless steel inner roller used in Example 1, non-perforated rollers of 5.08 centimeters, 4.455 centimeters, 3.175 centimeters and 1.905 centimeters were used herein. The walls of the rollers were 0.165 centimeters thick. The drug mixture was then introduced into each tablet to form a drug layer of 6, 35; 12, 70; 25, 4; and 38.1 millimeters above the sleeve. Each tablet was then provided with a stainless steel stopper with a diameter of 22.225 millimeters and a height of 12.7 millimeters, closing the ends of the tablets above the drug. The ends of the tablets containing the steel stopper were cut so that the disc of cellulose acetate butyrate at the level of the ends of the tablets could be slipped onto the stoppers. The total weight of the individual pills was 120.0; 115.4; 106.2 and 97.0 grams. The weight of the drug mixture ranged from about 25.5 grams to 27.4 grams for each tablet. Tablet densities were 3.1; 2.98; 2.75 and 2.51 g. cm ~ ³ ,

Example 6

Morantel citrate release rate tests were performed using the tablets prepared according to Example 5. Each was found to exhibit a constant drug release rate over an interval of 3 to 21 days. The lightest of the tablets of Example 5, i.e., the 1.905 centimeter sleeve tablet, had an average release rate of 774.8 milligrams of morantel citrate per day for 3 to 21 days at which a sustained continuous drug dose was achieved.

Example 7

Fourteen tablets prepared according to the method of Example 1 were tested in vivo in cattle, and the average release rate of morantel tartrate in cattle was found to be 238 milligrams per day for 60 days. The standard deviation was 67 milligrams, ie 28%.

Example 8

Tablets were prepared in the same manner as in Example 1, using instead of the drug mixture of Example 1 in the storage space of the tablets: pyrantel tartrate (63.3%), polyethylene glycol 400, whose specification has already been mentioned above, in an amount of 26.6%, sodium hexamethaphosphate in an amount of 10.1%; morantel tartrate in an amount of 100%; tetramisole hydrochloride at 100%; levamisole hydrochloride at 85.0%, glycerol at 15.0%; diethylcarbamazine citrate in an amount of 100%; hydromycin B at 100%; alkoxycycline hemihydrate in an amount of 100%; bacitracin methylenedisalicylic acid at 66%, sorbitan at 22%, sodium lauryl sulfate at 12.0%; ampicillin in the form of sodium salt at 63.5%, polyethylene glycol at 26.5%, sodium hexamethaphosphate at 10.0%; penicillin G in the form of the sodium salt in an amount of 67,3%, Ν, Ν-dimethylforamide in an amount of

22.2%, sodium glyceryl monolaurylsulphate at 10.5%; neomycin complex at 68.5%, dimethyl sulfoxide at 22.5%, sodium lauryl sulfate at 10.0%; streptomycin trihydrochloride in an amount of 100%; 80% oleandomycin hydrochloride, polyethylene glycol 400 as specified above, at 20%; tylosin hydrochloride in an amount of 100%; polymysine hydrochloride at 79.5%, glycerol at 15.0%, sodium lauryl sulfate at 5.5%; Linkomychi Hydrochloride Hemihydrate at 100 why; magnesium acetate tetrahydrate 77%, sorbitan 15%, disodium sulfosuccinate 8%.

Example 9

A sintered polyethylene tablet was prepared in which an average pore size of 100 gin was filled with hydrogel cross-linked polyvinyl alcohol. The storage space contained morantel citrate at 63.3%, polyethylene glycol 400 as specified above at 26.6% and sodium hexamethaphosphate at 10.1%.

The tablet contained a stainless steel inner roller (perforated), the procedure for preparing the tablets being the same as in the example

1. Instead of the cellulose triacetate solution and formic acid solution, the hydrogel solution contained an aqueous solution of 10% polyvinyl alcohol (88 why, hydrolyzed polyvinyl acetate) containing 3% resorcinol. After vacuum treatment to fill the pores, the tube was wiped clean and held at a temperature of 0 to -10 degrees Celsius for 5 hours to gel the polymer. Equilibrating the tube in water is not necessary in this embodiment. The tube was then leak tested, equilibrated in polyethylene glycol 400, and then not filled and sealed as in Example 1.

In vitro testing showed a controlled, sustained release of morantel citrate.

Example 10

The preparation of the composition according to the invention was carried out as in Example 1 except that a sintered polyethylene tube of half length and half the diameter of the tube was used in comparison with Example 1.

The resulting tablet is intended for sheep, where a controlled, sustained release of the enthelmintic agent in vivo has also been achieved.

Example 11

In this example, the preparation and testing procedures of Examples 1 and 5 were repeated except that the following microporous materials were used in place of sintered polyethylene: porous ceramic, porous steel, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride, sintered polystyrene . The average pore size for each material is 100 gm.

A controlled, long-term release of the chemical agent in in vivo tests was found for each of the tablets so produced.

Example 12

Stainless steel tube tablets having the following dimensions were prepared: outside diameter 22.225 millimeter, inside diameter 21.336 millimeter, wall thickness 0.889 millimeter, length 7.62 centimeter. The ends of the tubes were threaded with a length of 0.5 millimeter at each end onto which a ring was fitted to hold the hydrogel impregnated disk in the correct position. Discs of 22.225 mm in diameter and 3.175 mm in thickness were prepared from sintered polyethylene impregnated with cellulose triacetate eluting by immersing them in a container containing a 6% solution of cellulose triacetate in acetic acid. which are capable of being vacuum operated at or below 3 bar. The flask containing the contents was kept under vacuum for about 10 minutes, the discs were then removed and wiped clean to remove excess cellulose triacetate solution. Then, the discs were immersed in distilled water and allowed to equilibrate overnight. The disks were then removed from the water, dried with a towel and then immersed overnight in polyethylene glycol 400 (as specified above) to equilibrate. The discs were then removed and wiped with a towel.

The impregnated disks were then mounted on one end of each tube by placing them between pads of 0.254 millimeter thick and with the same diameters as the steel tubes. The steel tube was made of cellulose acetate butyrate and the other was dental rubber. The ends were then provided with stainless steel rings with a bore of 21.336 millimeters in diameter. The tubes were then filled with the required chemicals and the other end of each tube sealed as described above.

Tubes were prepared in this way

3 6 7 6 1 in the form of tablets containing the following chemicals in the storage compartment: morantel citrate at 63.3%, polyethylene glycol 400 at 26.6%, hexamethaphosphate at 10.1%; oxytetracycline hydrochloride at 100%; pyrantel citrate at 88%, glycerin at 12%; pyrantel tartrate at 63.3%, polyethylene glycol 400 at 26.6%, sodium lauryl sulfate at 10.1%; tetramisole hydrochloride at 100%; polyoxaline. in an amount of 100%; erythromycin hydrochloride in an amount of 100 why; thiamine hydrochloride in an amount of 100 why.

Example 13

The preparation of the composition of Example 1 was repeated except that the tablet was filled with morantel tartrate instead of a mixture of morantel tartrate, polyethylene glycol 400 and sodium hexamethaphosphate used in Example 1. The tablet thus prepared weighed 84, 0 grams, of which 18.6 grams was morantel tartrate.

An in vitro tablet according to the procedure described in this example was found to have a controlled and almost constant release rate for morantel tartrate over an 8-20 day interval, with an average release dose of 1.36 grams per day.

In vitro days Accumulated amount of morantel tartrate (g)

1.7 0.04 5.7 1.03 8.7 2.74 12.7 7.63 15.7 12.3 19.7 17.5 23.7 18.3 26.7 18.6

Example 14

A low carbon steel tube having the following dimensions was used: length 8.77 centimeters, internal diameter 2.16 centimeters, external diameter 2.54 centimeters. This tube had a groove of 0.3 centimeters deep and 0.6 centimeters wide, located at a distance of 0.1 centimeters from each of its ends to attach an aluminum flange completely surrounding the tube. The tube was sealed at one end with a very high molecular weight sintered polyethylene disk (average 2 million to 4 million), with an average pore size of 10 µΐη in this material, which was filled with gelled cellulose triacetate as shown in Example 15.

A blade of 2.54 centime.ru diameter and 0.16 centimeter thickness was sealed in the tube with aluminum trim. Then the tube was inverted and filled with a homogeneous mixture containing 54.4% morantel tartrate, 35.6% polyethylene glycol 400 (specification above) and 10% sodium hexamethaphosphate. The flange seal was repeated at the other end to give the final tablet. The total weight of the tablet was 145.1 grams, of which 41.4 grams was a drug mixture. The density was 2.8 g. . cm ~ ³ .

In this way, the aluminum flanges delimit a free central area of 3.25 cm ² at each end of the tube, providing a total area of 6.5 cm ² for drug release. This tablet releases morantel tartrate in cattle in a controlled manner for about 90 days.

Example 1 5

In this example, an aluminum cylinder of 6 centimeters long with an outside diameter of 2.1 centimeters and a wall thickness of 0.1 centimeter with a groove at the open end for sealing, in the form of an aluminum trim, was filled with a mixture of 70% levamisole hydrochloride and 30% polyethylene glycol 400 as specified above and sealed with a high density sintered polyethylene disk (ranging from 0.95 to 0.97 c.cm ^-3 ) impregnated with cellulose gelled cellulose acetate in the same manner as in the example. The tablet thus prepared had a density of 2.8 g / cm ³ .

The reservoir contained 23.46 grams of the active ingredient in the form of the above mixture, corresponding to 16.42 grams of levamisole hydrochloride.

The aluminum skirt used delimited an open circular area of 1.1 centimeters in diameter, providing a drug delivery area of 0.95 cm ² .

In vitro tests at 37 ° C have shown that the pill releases levamisole hydrochloride at a controlled rate.

Days in vitro

Levamisole chloride released (g)

0,815

1,572

1,805

2.33

2.64

2.79

2.83

2.87

4.66

5.10

6.67

Example 16

In this exemplary embodiment, a field test is illustrated with 40 test calves of the same breed and sex and of approximately the same weight (average 150 kilograms) that have not yet been grazed to which the compositions of the present invention have been applied. The calves were divided into four groups of 10 pieces according to their body weight. Two groups of animals were treated with drug substances and the two remaining groups were control. At the beginning of the field trial and every four weeks, control worm-free calves were attached to each of the four test groups. Each control calf was kept in its enclosure for two weeks, then it was taken out and housed three weeks prior to slaughter, after which the number of worms was counted.

Test and control calves were expelled to the infected pasture, which had been saved by infected cattle the previous summer and autumn. The pasture was large enough for 44 animals to be grazed throughout the grazing season, divided into four identical and separate pens.

The two treated groups of animals were orally administered a 60-day pill prepared according to the procedure of Example 1. The pills continuously released 250 mg of morantel tartrate for one animal per day for 60 days, corresponding to 150 mg of morantel. Treated groups of animals received the pills orally two days prior to their sprout in the spring. The presence of the pill in each treated animal was determined by a metal detector 24 hours after drug administration. Pill retention controls were then performed at two-week intervals. All animals treated, control and comparative were weighed before the grazing shoot and then at four-week intervals.

Grass samples were collected according to the method described by Taylor in Parasitilogy, 31, 473, 1939, at two-week intervals, starting four weeks prior to the start of the field test until the end of the test.

Fecal samples for the number of eggs by the Mc Master method and the number of larvae of the lung parasites of the Metastrongilidae family were collected at the start of the experiment and then at biweekly intervals. The rectum samples (one from each animal) were used in the first eight weeks. Then rectal samples were taken every four weeks when weighing the animals. In the meantime, 10 samples of each pasture were taken from pastures (see: Gibson, Veterinary Bulletin No. 7, 403-410, 1965).

The total number of worms was measured for the spleen, including mucosal digestion residues, the small intestine and the lungs of slaughtered animals.

Group of animals

Method of treatment

Space, Number of animals in which the animals are morantel tartrate

250 mg / day morantel tartrate

250 mg / day control control

Ά 10 4-1 comparative (every four weeks)

В 10 + 1 comparative (every four weeks)

C 10 + 1 comparative (every four weeks)

D 10 + 1 comparative (every four weeks)

The results obtained are shown graphically in Figures 6, 7 and 8.

Figure 6 shows the weight gain during the grazing season in both the treated and control groups. It turned out that both groups gained weight almost equally in the first about 3 months. After this time, the gains in the control groups decreased, while the decrease in weight gain coincided with an increase in the number of grazing parasites. In the treated animals, weight gain was found to be almost the same as observed at the beginning of the season.

Figures 7 and 8 show the development of parasites throughout the grazing season in both treated and control animals. The number of eggs per gram of feces was plotted on the right rank and the number of larvae per kilogram of dry grazing grass was plotted on the left rank. The calves were driven to pasture in mid-May. The treated calves received 60-day pills orally two days prior to expulsion, which guaranteed effective treatment until mid-July.

At the time of grazing, the number of parasite eggs in faeces and larvae in the pasture was low. In the control group, see Fig. 7, the parasite eggs began to appear in the faeces of the animals early in June, peaking late in July and slowly declining during August and September. The eggs of the parasites increased the incidence of grazing larvae late in June 23761 ci, reaching their peak in August.

In the treated animal group, see Figure 8, parasite egg production decreased sharply in June and July, and this was reflected in a significant decrease in pasture larvae during July and September.

Example 17

In this example, similar field experiments were performed as in Example 16, using only one treatment group and one control group per experiment. The results are shown in the following table.

Try Number of animals per group Increase in mean weight gain in treated animals relative to control (kg The sum of the number of parasite eggs in animals Reduced number (° / o) treatment kontr. 1 12 17.0 0 79 100 ALIGN! 2 13 9.0 33 146 77 3 12 32.5 67 408 84 4 11 9.5 145 436 67 5 17 18.2 135 886 85 6 18 13.4 23 62 63 7 24 17.1 34 150 77 8 31 36.5 14 28 50 Example 18 Porous material Average size In this embodiment, it was the opposite pores in um the procedure according to example 4 that the filter substance made of polypropylene polyethylene 75 nu, impregnated gelled · triacetate polytetrafluoroethylene 100 ALIGN! cellulose, was used below listed glass 60 gelled fabric triacetátem ce- filter substance of stainless steel lulosis. steel 80 copper sieve 30 modacrylic substancea) 10 nickel-copper alloy sieve 50 n copolymer acrylonitrile [40 %] and vinyl-

chloride [60 ° / o), ^(b) current commercial product.

Claims (6)

A composition for: the controlled, continuous and long-term introduction of an active ingredient into an aqueous medium containing, for example, a cylinder or tablet, comprising a storage space containing only the active ingredient or the active ingredient in admixture with a water-soluble liquid excipient; enclosed by a shaped wall formed at least in part by a porous material, said part being at least partially in contact with the storage space and insoluble in said environment and retaining its integrity throughout the introduction of the active substance, characterized in that the pores of the porous material are impregnated with a hydrogel permeable to the active ingredient used and an aqueous liquid, said roller or tablet having a density of at least 2 g / cm ³ , which is achieved by using a high density p material in this section. 2. A composition according to claim 1, wherein the porous material whose pores are impregnated with a hydrogel is selected from the group consisting of sintered polyethylene, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride and sintered polystyrene. 3. The composition of claim 1 wherein the porous material is a porous tissue selected from the group consisting of polyethylene, polypropylene, polytetrafluoroethylene, glass fiber or modacrylic fiber. 4. The composition of claims 1 to 3 wherein said hydrogel is gelatinized cellulose triacetate. 5. A composition according to any one of claims 1 to 4, wherein said high density material is steel, wherein the shaped wall is formed by a steel roller and the end portions are sintered polyethylene having pores containing gelatinised cellulose triacetate. 6. The composition of items 1 to 4, wherein said high density material comprises an apertured steel or iron sheath located between the storage space and the porous material.