• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    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.
    公开号:SU1222186A3
    申请号:SU792761214
    申请日:1979-05-07
    公开日:1986-03-30
    发明作者:Самуэл Дресбак Дэвид
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to devices for the controlled introduction of drugs into the body.
    A capsule of known drug substance is known, having at least one wall of polymeric material through which the drug passes through diffusion.
    The closest in technical essence to the present invention is a capsule for oral administration of medicinal substances to animals, comprising a housing for accommodating a medicinal substance in it with at least one end wall of porous material selected from a group including polyethylene, polypropylene, porous ceramics, polyvinyl chloride, polystyrene, polytetrafluoroethylene and porous metals, dp ensure the release of the drug at a controlled rate into the aqueous medium.
    However, the known device does not provide a sufficient duration of drug release, which reduces the effectiveness of its use.
    The purpose of the invention is to increase the duration of the drug release.
    This goal is achieved in that in a capsule for oral administration of medicinal substances to animals containing a housing for placing a medicinal substance in it with at least one end wall of a porous material selected from the group including polyethylene, polypropylene, porous ceramics, polyvinyl chloride, polystyrene , polytetrafluoroethylene and porous metals, to ensure the release of the drug at a controlled rate into the aqueous medium, the pores of the said porous material are filled with hydrogel triacet ata cellulose or polyvinyl alcohol with resorcinol.
    Figure 1 shows the capsule, a longitudinal section; Figure 2 shows the same, with a perforated metal spacer; on fig.Z - porous wall; 4 shows a capsule with one impermeable wall; Fig. 5 is a capsule in which the wall is made of porous metal.
    Capsule pd oral administration of medicinal substances (Fig. 1) consists of 1222186
    it is from a cylindrical wall I made of a porous material, the pores 2 of which contain a hydrogel through which the liquid
    from the aqueous medium (where the capsule is) diffuses into the capsule and through which the chemical substance from the capsule diffuses into the liquid medium. In apsup, there is a chemical substance 3, which is a drug and a water-soluble inert carrier 4. The ends of the capsule are impermeable caps, or overlapped 5.
    The capsule may contain, (FIG. 2) a perforated metal gasket .6 of stainless steel, cast iron or plastic, serving as a means of adjusting the area
    the surface of the porous wall 1 impregnated with hydrogel and the increasing weight of the capsule.
    Porous wall 1 contains hydrogel 7 in pores 2 and is in contact with chemical substance 3 and an inert liquid carrier 4 that is soluble in water. .
    The capsule can have only one impermeable overlap S (figure 4). The capsule can be made in such a way (Fig. 3) that its end walls contain pores 2 with a hydrogel, and the cylindrical ones are made in the form of an impermeable overlap 5 of stainless steel, which together with the end walls forms a capsule containing chemical substance and inert carrier four.
    The water soluble liquid carrier performs several very important functions, such as de-airing 3 capsules, which provides a higher degree of filling during its preparation. Furthermore, said water-soluble liquid inert carrier performs a useful function, manifested in the fact that when a chemical dissolves, there is no volume change as this chemical changes from a solid or crystalline state to a solution state.
    Typical water-soluble liquid inert carriers include mono-OLES and polyols, as well as their ethers, such as ethanol, ethylene glycol, propylene glycol, glycerin, polyethylene glycols, sorbitol, di- and tri
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    thylene glycol, di- and tripropylene glyol, 1,2-dimethoxyethane, monoalkyl (S.) ethers of ethylene and direct glycol; N, y-dimethylformamide, imethylsulfoxy; c5, and so on. These. Non-swab carriers must be compatible with hydrogel.
    The amount of water-soluble liquid carrier, the arrival of the drug per unit weight of the drug, depends on the d characteristics of this medicine. Usually the amount of such a carrier should be sufficient for the mixture of the drug with this carrier to have the form of a KOMnaKTkoft mass, and this quantity is easily determined experimentally,
    Capsules may be used in an amount of up to 20% by weight of the total weight of the capsule (chemical substance, including medicine, plus carrier and detergent if desired) in order to minimize possible clogging of the device during their use. The most typical detergents are inorganic or organic in nature substances, including sodium and potassium hexametaphosphates and tripolyphosphates, sodium lauryl sulfate, sodium glyceryl monouryl sulfate, dioctyl sodium sulfosuccinate, bis- (1-methyl-amyl) sodium sulfosucrosucers, sodium sulfosucrosucers, sodium bisulfosuccinate, bis (1-methyl amyl) sodium sulfosucrosucers, sodium bisulfosuccinic succinic succinic succinic succinic sulfates, sodium bisulfonic sulfates, sodium bisuric sulfates, sodium bisuric sulfates. other fatty acid esters.35
    Porous materials used may be isotropic, i.e. have a uniform porous structure throughout the cross section of the material, or may be anisotropic, i.e. have a heterogeneous porous structure. They can be insoluble and chemically inactive in relation to the environment and the contents of the capsule.
    Porous materials with a pore size of about 1-100 microns can usually be used. Porous materials with a porous structure containing continuous pores, i.e. pores having open exits on both surfaces of the porous wall, which consists of these materials. In order to facilitate the transfer of the drug from the capsule to the environment, the pores or part of the pores of the porous material 55 are filled with hydrogel. This combination of porous material with hydrogel leads to the fact that
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    the capsule is insensitive to ingress and withstands physical damage under normal use. The capsule has been used successfully in ruminants, and especially in cattle and sheep. Hydrogel-containing pores allow fluids (water) to pass through the pores in the hydrogel itself due to diffusion from the medium in which the controlled release device is placed into a capsule in which the drug is dissolved. The drug then diffuses through the fluid in the pores of the hydrogel containing the barrier (or wall) of the porous material in the pores at a rate dependent on the concentration of the drug in the solution in the capsule, on the resistance exerted by the barrier, i.e. from the fluid in the pores of the hydrogel, and from the effective surface area of the porous part of the wall.
    The most typical hydrogels that can be used to fill the pores of a porous material are as follows: cellulose triacetate in the form of a gel; cellulose acetate hydrogels derived from cellulose acetate with an acetyl content of 20-40%; hydroxyethyl methacrylate polymer; crosslinked polyvinyl alcohol; agarose; polyacrylamide; cross stitched at acrylamide, methacrylamide, N-propylacrylamide, N-isopropylmethacrylamide, N-methyl acrylamide, N-2-hydroxyethyl methacrylamide; polyurethane hydrogels including poorly crosslinked polymers with isocyanate terminal groups. which are the reaction product of a poly (alkyleneoxy) polyol with an organic diisocyanate slightly cross-linked with water or an organic polyamine; copolymers of hydroxyalkyl acrylates with unsaturated ethylene bonds with methacrylates and alkoxyalkylene glycol acrylates with methacrylates; polyester polyurethane resins obtained by chemically reacting an organic diisocyanate with a mixture of at least two diols, one of which is a water soluble polyalkylene glycol with a molecular weight of 3000-30000 and the other is an oxyalkylated diphenol containing 2-20 oxyalkylene groups.
    The trouble present in the pores of the hydrogel can be easily replaced with water-soluble liquids, such as the water-soluble liquid inert carriers described above. Other water-soluble VH fluids, including alcohols containing 1-4 carbon atoms, may also be used to replace water. In the practical implementation of the process in order to stabilize the devices according to the invention, especially in cases where the hydrogel is a gel-like cellulose triacetate, the water of the hydrogel is replaced with a suitable water-soluble liquid whose vapor pressure is lower than the pressure of water vapor. the capsules can be preserved without loss of effectiveness as a result of drying the hydrogel. In the case where a combination of a water-soluble liquid carrier with the drug is used in the capsule, it is desirable to use the same liquid to replace the water in the hydrogel.
    The porous wall in contact with the drug-containing capsule can be made from any of a variety of materials. This porous material may completely surround the capsule or it may form only a part of the wall surrounding the capsule. Suitable porous materials used for this purpose include porous metals, porous ceramics, agglomerated polyethylene, agglomerated poly (vinyl chloride), agglomerated polypropylene, agglomerated polystyrene and agglomerated polytetrafluoroethylene, porous polymers.
    Appropriate porous fabric materials used for this purpose are polypropylene and polyethylene, and especially such fabric materials that are commonly referred to as filter fabrics, namely glass, polytetrafluoroethylene, nylon, cotton, modified
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    acrylic fibers, i.e. acrylic fibers consisting of long chains of a synthetic polymer containing 35-85% acrylonitrile units; acrylic fibers, i.e. synthetic polymers containing a minimum of 85 NOC. of acrylonitrile; polyesters, i.e. long molecular chains of a synthetic polymer containing at least 85 wt. 7, dihydric alcohol ester with tereftao: oic acid; polyvinyl acetate, polyvinyl chloride, polyvinyl acetate vinyl chloride, polyvinyl alcohol, vinyl acetate, polyvinyl alkyl ethers; polymers of vinylidene cyanide, vinylidene chloride, vinylidene fluoride; polyurea. Along with the above, metal nets or filter cloths can be used, including those made from stainless steel, carbon steel, brass, copper, various alloys such as nickel-copper alloys and others.
    The selected tissue material must be compatible with the hydrogel, with which it must be impregnated, and must meet the requirements in accordance with the intended purpose of the capsule. For example, if a capsule is intended to introduce medicine into the body of ruminants for an extended period of time, then cotton should not be used as a fabric material, since it will decompose in the body of ruminants. Cotton can be used in devices that serve for the controlled release of a chemical into the aquatic environment, such as aquariums or ponds. Nylon cannot be used as a fabric material when gel-like cellulose triacetate is used as a hydrogel, since it will decompose with formic or acetic acid 5 applied to the fabric during impregnation.
    Porous tissue materials impregnated with hydrogel should certainly have a sufficiently high strength, durability and inertness with respect to the drug and to the medium in which the device is used, so that the device of controlled release of the preparation made of this material keeps
    its physical and chemical integrity throughout its life.
    The porous material is impregnated with the appropriate hydrogel in a manner already known to those skilled in the art. The most successful and relatively simple way to propica a porous material with cellulose triacetate in the form of a gel, which is the most preferred gel, is to introduce a solution of cellulose triacetate in formic or acetic acid into the pores of the porous material by immersing the tissue material in a solution of cellulose triacetate, which is in the vessel in which the vacuum is created. After impregnation, the cellulose triacetate-filled plastic coagulates by contacting with a large volume of water and maintaining balance with this volume of water, resulting in a hydrogel-impregnated material. In the case when the porous material is agglomerated polyethylene and the hydrogel is cellulose triacetate in the form of a gel, acetic acid rather than formic acid is preferred as the solvent of cellulose triacetate, because it wets polyethylene better, than formic acid, and thus it facilitates the preparation of porous material soaked in hydrogel.
    In the case where the hydrogel is derived from 2-hydroxyethyl methacrylate crosslinked with ethylene glycol dimethacrylate, the porous material is impregnated by filling it with a pore mixture of 2-hydroxyethyl methacrylate ethylene glycol dimethacrylate and then polymerizing the mixture directly into the pores of the mat. with the introduction of a catalyst with free radicals such as gret-butyl alcohol. In the same way, the porous materials of the walls are impregnated with other hydrogels and the process of obtaining hydrogels is carried out directly in the pores using appropriate reagents. In the case where the hydrogel is polyvinyl alcohol, which is crosslinked by crosslinking, the pores are filled with a mixture of polyvinyl alcohol.
    JQ 5 20 25 o
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    d ", (
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    alcohol (10% aqueous solution) and resorcinol (2-3%) ..
    . Dp manufacturing capsules that are stable during storage prior to their practical use, hydrogel-filled pores are free from water: by filling them with an equilibrium amount of a suitable water-soluble liquid, for example, water-soluble liquid inert carriers listed above. It has been found that it is advisable to replace the water in the hydrogel-filled pores of the porous material with the same water-soluble liquid that is used as an inert carrier in the capsule when the capsule consists of a mixture of a chemical substance with an inert carrier. If the capsule consists of only one chemical substance, then the choice of a water-soluble liquid displacing water from the hydrogel in the porous wall containing hydrogel pores is determined solely by the final destination of the capsule, but in any case, the use of a physiologically acceptable water-soluble liquid is required. It is desirable to introduce such liquid into the hydrogel. the preparation time of the porous wall, the pores of which contain a hydrogel, before filling the capsule of the device.
    The most preferred form of the capsule is the shape of the rounded body. The rounded (spherical) body is introduced into the organism of ruminants, preferably through the mouth, so that it remains in the reticular sac of the stomach for an extended period of time, during which it continuously releases the drug at a controlled rate.
    In order for this rounded body to enter the reticular sac of the stomach of cattle and stay there for an extended period of time, it is necessary that this body have a density of at least 2.0 g / ml. In practice, this density can vary from a minimum of 2.0 up to 7 or even more.
    The overall size of this rounded body depends on the dose that must be injected into the body and on the size that can be practical. ki is acceptable. Once the desired size is determined, the weight of the tribute
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    The rounded body can be further increased to achieve the desired average density.
    When sheep are introduced into the body, the minimum weight of the rounded body with a density of 4 g / ml, which should be maintained in the body, is about 1 g. When administered to cattle, the minimum weight of the rounded body with an average density of 4 g / ml is about 5g.
    Capsules can be used as implants in order to administer the drug at a controlled rate into the host's body. Other forms of use include oral, oral or oral tablets, pessaries, suppositories, dressings and skin patches. Another area of capsule use is the introduction of fertilizers and pesticides into fish culture media, including aquariums and fish; into drainage channels, channels and tanks in order to prevent algae development; as well as to water sources, especially those that serve for animal feed and domestic poultry, if necessary, for their treatment or prophylactic treatment.
    Typical drugs that can be used in capsules according to the invention are as follows: clayey agents, including Morantel, Pyrantel, Oxantel, Piperazine, Diethylcarramazine, Levamisole, Tetramisole and Hydromycin B; antibacterial agents, including tetracyclone salts, such as 5-cetra-tetracycline, chlortetracycline, dixi-cyclin, and their Mannich bases; penicillins, such as ampicillin, penicillin; aminoglycosides, such as neomycin, streptomycin, apramycin, bacitracin, in the form of zinc compounds or a derivative of methylenedisalicylic acid; macrolides (substances with a macrocyclic lactone ring), such as spectrometry, oleandomycin and tylosin; antibacterial growth stimulants such as salts of avoparicin, polymyxin, lincomycin, bambermycin and efromycin; hormone growth stimulants, including diethylstilbestrol, zearalanol; antiparasitic agents such as ampromitis;
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    nutrients, such as soluble salts of magnesium, selenium, copper ;, vitamins, such as thiamine hydrochloride; sulfa drug presses, such as sulfamethazine; molluscicides, such as N-trityl-morpholine; antiblocking agents, such as ethoxylates of alcohol (poly (oxyethylene polySok Q, propylene)) - poly (oxyethylene) polymers, for example, poloxalen.
    Continuous and regular introduction of an antihelminthic, for example, morantel, into the reticular bag
    5 Puddles Ruminants in the spring pasture when the pastbish infestation rate is low results in the destruction of invasive helminth eggs and, consequently, in the suppression of the formation of larvae, which maintains a low content of parasitic worms (worms) in animals. Thus, the infection of ruminant animals grazing on the same pasture
    25 in the summer time, minimized. This way of dealing with helminths is especially desirable and has a great value for the body, since the body is very susceptible to the worms when they are first released into the pasture. Consistent use of rounded bodies reduces the amount of helminth infection at a given location of these bodies. In implementing the method of dealing with
     with parasites, drug administration occurs during the period of spring reproduction, and not during the period of severe infection of the pasture, removal of larvae and infection with parasitic worms (worms),
     which leads to sickness and reduced productivity. Grazing of ruminant animals, in the reticulum of the gastric sac which contains one or more capsules offered,
    5 that provide an adjustable and continuous release of an anthelminthic (or anthelmintic) agent, for example, morantel, into a specified reticular bag of the stomach, on a pasture in a century period, i.e. when the larval contamination is minimal or close to minimal, it reduces to a minimum the seasonal increase in the larval contamination of the pasture soil and
    55 provides the animals that are grazing on this pasture, for the entire pasture season. Particularly desirable antihelmintic drugs used for these purposes are (E) -1,4,5, 6-tetrahydro-1-methyl-2-.2- (3-methyl-2-thienyl) ethenyl pyrimidine salts that are dissolved in water (moran. tel). (E) -1,4,5,6-tetrahydro-l-methyl-C2-2- (2-thienyl) ethenyl pyrimidine (pyrantel) and (+) - 2,3,5,6-tetrahydro -6-phenylimidazo C2,1-b3 thiazol (tetramisole), as well as levamisol N / -form of this salt (levogyrate). Typical of these preferred water soluble pyrantel and morantel salts are tartaric and citric acid salts, as well as tetramisole and levamisole, hydrochloric acid salts.
    The rounded capsules are introduced into the body of animals through the mouth, for example, with a dispenser. When using these devices in the body of a body, the desired average release rate of a morantel (calculated on the basis) in the case of an indirect effect on helminths is about 60-200 mg (of a morantel base) per day for about 60 days, which covers the usual maximum lifespan the larvae of the spring period, with the direct method of acting on helminths, longer periods of drug release are desirable within 60-120 days, since the time during which the pasture is heavily infected lasts for a long time. mid summer to autumn. The drug release rates of 60–150 mg per day (based on the base of the morantel) ensure the effective elimination of the helminth infection during the entire specified release period. When using capsules for larger animals, more than one capsule can be administered to these animals. In the case of an indirect effect on helminths using the pyrantel or levamisole salts, the desired average release rates of each of these drugs (based on the free base) are about 100-400 mg per day and 100-500 mg per day, respectively, for about 60 days. . In the case of a direct effect, the rate of release of pyrantel (based on the free base) is approximately lOOr 300 mg per day and the rate of release is gone. zamizol (based on free base) is about 100-JOO mg per day and the release rate of levamisole (calculated on free base) is about 100-400 mg per day to ensure effective elimination of helminth infections for 60-120 days.
    Example 1. A rounded capsule consisting of agglomerated polyethylene, the pores of which are filled with gel triacetate in the form of a gel,
    Q and from a capsule containing Morantel tartrate mixed with polyethylene glycol 400 and sodium hexametaphosphate, and also including a perforated stainless steel pipe, prepared by i
    are as follows.
    One end of a tube of agglomerated polyethylene with a medium section; a measure of pores 10 microns, outer rum 25.4 mm and inner diameter
    d 22,235 mm and a length of 7.938 cm is immersed in a 10% solution of cellulose acetate-butyrate in methylene chloride to a depth of 4.763 mm. It is then air dried and the other end
    5 tubes are immersed in a solution of cellulose acetatebutyrate to a depth of 9.525 mm and dried. This step is repeated. The end of the tube is again immersed in a solution of cellulose acetatebutyrate for 30 s, air-dried. for 60 s, a disk of cellulose acetate acetate butyrate with a diameter of 22.225 mm, a thickness of 3.175 mm is inserted into the end of the tube in such a way as to ensure a tight fit with the end of the tube. Before being inserted into the end of the tube, a disk of cellulose acetatebutyrate is immersed for 60 seconds in methylene chloride, on the surface of which it floats. Then this tube
    rolled on the laboratory table, pressing his fingers on its end, where the disk is located, in order to ensure that the disk is completely secured with the tube. This tube is inserted
    5 rubber stopper, with one hole in which glass n- is inserted. on the tube, such a distance that it passes through a rubber pro & ku (-with one hole) vacuumized flask,
    0 when this tube remains at the bottom of the flask. The protruding end of the tube is then connected to a flask containing
    A 6% solution of triacetate telpulo-ee in formic acid, and in this flask a vacuum of approximately 150 mm Hg is created. When a solution of cellulose triacetate covers the outer walls of the tube that are not
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    immersed in cellulose acetate butyrate, the tube is removed from the vacuumized flask, and cellulose triacetate is removed (wiped) from it. Then the tube is inverted so that its internal part has been removed cellulose triacetate. The outer and inner open ends of this tube are wiped dry with a towel. The tube is then immersed in distilled water, where it is in equilibrium overnight. It is then removed from the water, the outside is wiped dry with a towel, and the excess water is removed from the inside by shaking. The steps of impregnating the pores of this tube with cellulose triacetate and maintaining it in equilibrium in distilled water are repeated. The tube is then kept at equilibrium for 4 hours in tap water.
    After that, the tube is subjected to a leak test, connected to a source of nitrogen, immersing it in water and creating it; there is nitrogen dashtetion 0.28 kg / cm for 10 s. If such a test detects a leak, then the steps of soaking and soaking in water in an equilibrium state are repeated. The tube is then equilibrated overnight in polyethylene glycol, removed from polyethylene glycol and dried in an inverted position for 4 hours. Excess polyethylene glycol is removed from the outer surface of the tube, wiped with a towel, and a perforated stainless steel tube with an outer diameter of 22.225 mm, an internal diameter of 18.923 mm, a length of 6.985 cm, having 16 round holes located at the same distance from each other, with a diameter of 7.114 mm, fit into this tube until it fits close Besides bloom fitment tube. An excess of cellulose triacetate, which is the result of inserting a nozzle tightly seated in this tube, is removed. Then, a disk made of cellulose acetate butyrate (3.175 mm thick) is inserted into the open end of a tube filled with a stainless steel pipe, and this tube is prepared in such a way that its end is filled with a disk.
    The disk is then removed, and into a tube filled with a homogeneous mixture,
    one
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    Morantel tartrate additive (63.31%), polyethylene glycol (26.61%) and sodium hexametaphosphate (10.08%), insert the end of the stainless steel tube. The open end of the tube is filled with a 10% -11M solution of cellulose acetate acetate, which is then quickly drained, and the open end of the tube is immersed in a solution of cellulose acetate acetate butyrate to a depth of 6.35 mm and dried. Then, a disk of cellulose acetate-butyrate (which was previously immersed for 60 seconds in methylene chloride, before it was directly used), was inserted into the open end of the tube, while pressing the disk with such force that it directly adjoined the branch pipe from of stainless steel. Then the tube is rolled on the laboratory table, pressing it with your fingers in such a way as to guarantee the complete fixation of the disk with the tube. This tube is dried for 1 hour, after which each end is immersed in a 10% solution of cellulose acetate butyrate to a depth of 6.35 mm and dried. The weight of this rounded capsule is approximately 90 grams, of which 24.8 grams is the drug mixture. The density of such a rounded body is 2.2 g / ml. When tested on cattle under vivo conditions, such a device releases about 250 mg per day of Morantel tartrate for about 60 days.
    EXAMPLE 2. Three capsules prepared in the same manner as described in Example 1 were subjected to a vitro test; they show a constant drug release rate for 4-17 days, with an average Morantel tartrate injection rate for all three rounded bodies being 0.927 grams per day.
    When tested in vivo conditions of these three capsules prepared in the same manner as described in Example I, and ruminant animals placed in the reticular sac of the stomach of the stomach, when these bodies were removed after 30 days, it was found that the release rate of Morantel tartrate was 0.224 g / day. This ratio of the release rate of the drug when tested in vitro to release when tested in vivo conditions is 4: 1.
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    EXAMPLE 3: The in vivo test of two capsules prepared as described in example 1 and subjected to the test as described in this example show an average constant rate of release of morantel tartrate for 0-14 days, 0 96 g / day.
    Tests in vivo identical rounded capsules placed in a reticular sac of the stomach for 30-60 days showed an average drug release rate when tested in vivo conditions of 0.224 g / day and the ratio of drug release to vitro Vivo speeds are approximately 4: 1.
    PRI me R 4. Prepare rounded ampoules from stainless steel tubes having the following dimensions: outer diameter 22.225 mm, inner diameter 21.336 mm, wall thickness 0.889 mm and length 3 cm. At the ends of these tubes, thread is made (0.5 mm at each end) to receive a sleeve that serves to maintain at a given position a disk of porous tissue material impregnated with hydrogel. Disks with an outer diameter of 22.225 mm and a thickness of 3.175 mm made of polypropylene filter paper with an average pore size of 40 µm and impregnated with cellulose triacetate in the form of a gel are prepared by immersing them in a 6% solution of cellulose triacetate in formic acid contained in a vessel that can be subjected vacuum up to 25 mm Hg or less. This flask and its contents are kept in a vacuum for 10 minutes, discs are removed from the flask and washed, with an excess of cellulose triacetate solution. They are then immersed in distilled water, where they are in equilibrium overnight. These discs are then removed from the water, dried with a towel, and then they are held in polyethylene glycol in equilibrium overnight. After that, the discs are removed and wiped with a towel. The impregnated discs are fixed at the end of each tube by inserting them in the middle between gaskets with a thickness of 0.254 mm and the same diameter as the steel tube. Gasket directly beside the steel
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    the tubes are made of cellulose acetate butarate, and the other gasket is made of a thin dental rubber pl. Then on the ends of the tube dress, g bushings out. stainless steel with a hole diameter of 21.336 mm. These tubes are then filled with morantel tartrate (63.3% solution), polyethylene glycol (26.6% solution) Q sodium hexametaphosphate (10.1% solution), and the other end of each tube is blocked as described above. . Rounded capsules containing 21.4 E, Morantel tartrate, weighs 97 g, JJ and have an average density of 3.30 g / ml. The rounded capsules are introduced into the body of bulls that have a fistula in the first section of the stomach using a spray gun, and the removal of these bodies through the fistula is carried out at intervals of 30.45, 60.75 and 90 days in order to determine the amount of drug left in these rounded bodies, and based on this number, calculate the average daily rate of release of tartrate of Morantel.
    A decrease in the number of fecal invasive eggs of parasitic worms was found in each bullhead.
    Example 5: According to the procedure described in Example 1, four rounded capsules are prepared consisting of agglomerated polyethylene with an average pore size of 10 µm, the pores of which are filled.
    35 cellulose triacetate in the form of a gel,
    and including stainless steel nozzles, occupying only a part of the total capsule length, so that a part of the capsule remains free of a nozzle with a content of citrate morantel (63.3%) mixed with polyethylene glycol (26.6% growth p) and hexametaphosphate. sodium (10.1% solution). However, in this.
    In 5 cases, instead of a perforated stainless steel pipe (as in Example 1), use a non-disconnected pipe of 5,08 amperes; 4,445, 3,175 cm - 1,905 cm respectively. The walls of this socket have a thickness of 0.165 cm. Then, in each capsule, the injection of drug mixture is entered in such a way that the width of the drug zone above the branch pipes is 6.35, 12.70,
    5 25.4 and 38.1 mm respectively. A stainless steel cap, 12.7 microns thick and 22.225 mm in diameter, is inserted into each of the capsules;
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    over the drug mixture. The ends of the capsules containing the steel plug are prepared in such a way that it is possible to place a disk of cellulose acetate butyrate on top of the plugs and overlap the ends of the capsules. The total weight of the individual capsules is 120; 115.4; 106.2 and 97.0 g, respectively. The weight of the drug mixture is in the range of 25.2-27.4 grams per capsule. The densities of these capsules are 3.1, 2.98, 2.75, and 2.51 g / ml, respectively. PRI me R 6. Testing, provo) 0 polymyxin hydrate (79.5%); glycerol (15.0% solution); sodium lauryl sulfate (5.5% solution) j lincomycin hydrochloride hemihydrate; magnesium acetate tetrahydrate (77% solution
    vitrified; on definite, j sorbitol. (15% solution); dioctyldinasulfosuccinate (8% solution).
    the rate of citrate release of the moranel from the capsules described in example-. Re 5 show that each of these capsules provides a constant release rate for 3–21 days. The lightest of the four capsules described in Example 5, i.e. having a nozzle of 1,905 cm in size, show an average rate of release of citrate of Morantel 774.8 mg per day at a constant rate of its release for 3-21 days.
    Example 7. A test of fourteen capsules prepared according to Example 1, carried out on bodies in vivo conditions, shows an average release rate of Morantel tartrate 238 mg per day for 60 days. The standard deviation is 67 mg (28%).
    Example 8. Capsules are prepared in accordance with the procedure described in Example 1, but using the following chemical substances contained in the capsule instead of the mixture mixture described in Example 1: pyrantel tartrate (BZ, 3% solution)} Morantel tartrate; pyrantel chlorohydrate; tetramizole hydrochloride; Levamisole hydrochloride (85.0% disodium sulfosuccinate (8% solution).
    EXAMPLE 9 In the same manner as described in Example 1, rounded capsules are prepared consisting of agglomerated polyethylene, the pores of which with an average size of 100 µm are filled with crosslinked polyvinyl alcohol.
    25 form of a hydrogel and citrate-containing morantel (63.3% solution), polyethylene glycol (26.6% solution), and sodium hexametophosphate (10.1% solution), as well as including perforated
    2- stainless steel pipe. However, instead of a solution of triacetate of celloshoye in formic acid, the hydrogel solution is an aqueous solution of 10% polyvinyl alcohol (88% hydrolyzed polyvinyl acetate) containing 3% resorcin. The capsule after its processing in vacuum with the purpose of filling the pores is wiped off and kept at a temperature of 0 - (- 10) С
    40
    within 5 hours in order to convert the polymer to gel. Keeping the tube in water in equilibrium is not necessary. Then this tube is tested for leakage, kept in polyethylene glycol in
    niy solution); glycerol (15.0%); cyt-5 equilibrium, filled and injected with diethylcarbamazine; hydromycin B; doxycycline hemihydrate hemihydrate; Bacitracinmethylenedisalicylic acid (66.0% solution), sorbitol (22.0% solution); sodium lauryl sulfate 50 (12.0% solution); ampicillin, sodium salt (63.5% solution), polyethylene glycol (26.5% solution); sodium hexametaphosphate
    stop one as described in example 1.
    The test carried out in vitro shows that the controlled release of citrate of Morantel.
    Example 10. The procedure described in Example 1 is repeated, but using tubes made of agglomerated polyethylene with a length of half and a diameter of
    (10.0% solution); penicillin sodium 55 is half the tube size when used (penicillin sodium) (67.3% used in Example 1. Obtained in a real solution); N N-dimethylformamide resulting rounded capsules serve (22.2% solution); glyceryl mono- for entry into the body of sheep and provided sodium sulfate (10.5% solution); complex neomycin compound (68.5% solution); dimethyl sulfoxide (22.5% solution);
    sodium lauryl sulfate (10.0%
    solution); streptomycin trichlorohydrate; oleandomycin hydrochloride (80% solution); polyethylene glycol (20% solution); tylosin hydrochloride; polymyxin hydrochloride (79.5%); glycerin (15.0% solution); sodium lauryl sulfate (5.5% solution) j lincomycin hydrochloride hemihydrate; magnesium acetate tetrahydrate (77% solution);
    sorbitol. (15% solution); dioctyl sorbitol. (15% solution); dioctyldinasulfosuccinate (8% solution).
    EXAMPLE 9 In the same manner as described in Example 1, rounded capsules were prepared, consisting of agglomerated polyethylene, the pores of which with an average size of 100 µm were filled with crosslinked polyvinyl alcohol.
    form of a hydrogel and citrate-containing morantel (63.3% solution), polyethylene glycol (26.6% solution) and sodium hexametophosphate (10.1% solution), as well as including perforated
    stainless steel pipe. However, instead of a solution of triacetate of celcsoic in formic acid, the hydrogel solution is an aqueous solution of 10% polyvinyl alcohol (88% hydrolyzed polyvinyl acetate) containing 3% resorcin. The capsule after its processing in vacuum with the purpose of filling the pores is wiped off and kept at a temperature of 0 - (- 10) С
    40
    within 5 hours in order to convert the polymer to gel. Keeping the tube in water in equilibrium is not necessary. Then this tube is tested for leakage, kept in polyethylene glycol in
    equilibrium state is filled and
    stop one as described in example 1.
    The test carried out in vitro shows that the controlled release of citrate of Morantel.
    Example 10. The procedure described in Example 1 is repeated, but using tubes made of agglomerated polyethylene with a length of half and a diameter of
    191
    have a controlled release of an anti-irrigating agent for an extended period of time when tested in vivo conditions,
    Example 11. The procedure described in examples 1 and 5 is repeated, but using instead of agglomerated polyethylene the following microporous materials: porous ceramics, porous steel, agglomerated polypropylene, agglomerated polytetrafluoroethylene, agglomerated polyvinyl chloride, agglomerated polystyrene (average size for each material em 100 microns).
    Each of the rounded capsules prepared in this way provides a controlled release of the chemical over an extended period of time when tested in vitro.
    Example 12. Prepare rounded capsules made of stainless steel tubes having the following dimensions: outer diameter 22.225 mm, inner diameter 21.336 mm, wall thickness 0.889 mm and length 7.62 cm. At the ends of the tubes there is a thread for. take a sleeve that serves to maintain the porous disc soaked with hydrogel in a predetermined position. The disk with an outer diameter of 22.225 mm and a thickness of 3.175 mm, made of agglomerated polyethylene, is impregnated with cellulose triacetate in the form of a gel by immersing them in. A 6% solution of celksoza triacetate in acetic acid contained in a vessel that can be evacuated to a residual pressure of 25 mm Hg. Art. or less. The flask and its contents are evaporated under vacuum for about 10 minutes, discs are removed and wiped to remove excess cellulose triacetate solution. They are then immersed in distilled water, where they are kept in equilibrium overnight. After this, the disks are removed from the water, wiped with a towel and kept in equilibrium state in polyethylene glycol overnight. Next, the discs are removed and wiped with a towel.
    The impregnated discs are fixed at one end of each of the tubes by placing them in the middle between two shims 0.254 km thick and the same diameter as the steel tube. The gasket is directly
    s
    2
    ..
    5 0 5 0
    five
    0
    18620
    but near a steel tube, consists of cellulose acetate acetate, and the other consists of a thin dental rubber plate. Then, stainless steel sleeves with a hole diameter of 21.236 mm are worn on the ends of the tube. These tubes are then filled with the desired chemicals, the other end of each tube is plugged as described above.
    In this way, capsules containing morantel citrate (63.3% solution) are obtained; polyethylene glycol (-26.6% solution), hexamet-, sodium phosphate (10.1% solution), oxytetracycline hydrochloride, cytrate tarentel (88%), glycerin (12%), pigrant tarragrate; 63.3% solution), the role of ethylene glycol (26.6%) sodium lauryl sulfate (10.1% solution), tetramisole chlorohydrate, poloxalen, erythromycin chlorohydrate, thiamine hydrochloride. Example 13: The procedures of ru described in example 1 are repeated, except that the rounded capsules are filled with morantel tartrate. These rounded ampoules weigh 84.4 grams, of which 18.6 grams per morantel tar waste.
    By testing these rounded capsules under vitro conditions according to the procedure described, adjustable and almost constant release rate of Morantel tartrate is obtained during the test period of 8-20 days, the average release rate of Morantel tartrate is 1.36 g / day.
    Example 14. A mild steel pipe of the following dimensions: length 8.77 cm, internal diameter 2.16 cm, outer diameter 2.54 cm, and having a groove 0.15 cm deep and a width of 0.6 cm located at distance 0 1 cm from each end to insert an aluminum bead, and the tube that passes through the entire circumference is overlapped with a disk of ultramolecular
     /
    agglomerated polyethylene (average molecular weight 2-4 ppm).
    The average pore size of the material is 10 µm, which is impregnated with cellulose triacetate in the form of a gel, as described in Example 12. This disk is 2.54 cm in diameter and 0.16 cm thick and inserted into a tube with an aluminum collar. The tube is then inverted and filled with a homogeneous mixture containing 21
    “Left 5h, 4% morantel tartrate, 35.6% polyethylene glycol and 10% sodium hexametaphosphate. The compaction process using the disc and the shoulder is repeated until the final production of the rounded body. The total weight of this rounded body is 145.1 g. 41.4 g is the drug mixture. The density of this rounded capsule is 2.8 g / ml.
    The aluminum shoulders located at each end of the tube have a central hole area of 3.25 cm, so that the total area is up to. Step for the passage of the Drug, is 6.5 cm-h. These rounded tepas provide an adjustable release of morantel tartrate in cattle for about 90 days.
    Example 15. An aluminum cylinder with a length of 6 cm, an outer diameter of 2 cm, and a wall thickness of 0.1 cm, having a groove at the open end for inserting the seal in the form of an aluminum bead, is filled with a mixture containing 70% levamisole hydrochloride and 30% polyethylene. ethylene glycol, and sealed with a disk of agglomerated high density (0.95-0.97 g / ml) polyethylene impregnated with cellulose triacetate as a gel according to the method described in example 12. This rounded body has a density of 2.8 g / ml. The capsule contains 23.46 g of drug.
    122218622
    the calf was at the very beginning of the practical and torture and every four weeks the calf turned on the indicator, in which no parasitic traces were found
    , wei. Each calf indicator was kept on the pasture for two weeks and then taken away from the pasture and driven into the room for three weeks, after which they were killed for the purpose of detecting them.
    JQ number of parasitic worms.
    The bodies to be treated and those of the indicators allowed to graze on infected parasitic pasture, on which in the previous summer and autumn, 5 cattle infected with parasitic hearts. This pasture for livestock pasture was of sufficient size so that 44 animals of the same individual could graze on it during the entire grazing period, and this pasture was divided into four separate equal sized zones.
    20
    A rounded capsule, prepared according to the procedure described in Example 1, was introduced through the mouth into the bodies of the calves belonging to the two 2J indicated groups subjected to repeated 60-day experiments through the mouth of the device described in Example 1. These rounded capsules Moran bodies at a rate of 250 mg per animal per day (equivalent to 150 mg of Morantel in base form)
    thirty
    a mixture equivalent to 16.42 g of chlorohydrate-W for 60 days These are subject
    rata levamisole. The aluminum flange used has a diameter of a round hole located in the center, so that the area available for the passage of the drug is 0.95 cm.
    vitro
    Tests conducted under conditions
    When it is shown that a rounded body releases levamisole hydrochloride at a controlled rate.
    Example 16. This example describes a practical test conducted on 40 experimental bodies of the same breed, weight (150 kg in average), which were not allowed to graze for pasture before the test .. These bodies were divided into 4 groups of 10 bodies t, in each group based on their weight (Table 1). On two groups, repeated experiments were carried out with the introduction of the proposed capsule and the other two groups were control. In each of the four groups tested
    . 2218622
    The calves at the very beginning of practical testing and every four weeks included a calf indicator in which no parasitic trays were found, wei. Each calf indicator was kept on the pasture for two weeks, and then taken away from the pasture and driven into the room for three weeks, after which they were killed for the purpose of revealing them
    JQ number of parasitic worms.
    The tel under treatment and the tel t of the indicators were allowed to graze on infected parasitic pasture, on which in the previous summer and autumn, cattle were infected with parasitic worms. This pasture for cattle pasture was of sufficient size so that 44 animals of the same individual could graze on it during the entire grazing period, and this pasture was divided into four separate zones of equal size.
    20
    A rounded capsule, prepared according to the procedure described in Example 1, was introduced through the mouth into the bodies of calves belonging to the two 2J specified groups subjected to repeated 60-day experiments to detect the effect of the proposed device. These rounded capsules provide continuous release of Morantel tartrate at a rate of 250 mg per animal per day (equivalent to 150 mg of morantel in base form)
    thirty
    The test group of animals received data: rounded capsules, entered by che, cutting mouth two days before pasturing them in pasture in spring.
    40 The presence of a rounded capsule in each experimental animal is confirmed with a metal detector 24 hours after the introduction of the capsule. After that,
    5 check the preservation of capsules in the body at intervals of two weeks. All animals undergoing experimentation with a capsule inserted into them, control animals and animals were weighed before the pasture on the pasture and during the pasture at intervals of 4 weeks,
    I ::
    After the animals were killed, the total number of parasitic worms, including those on the mucous membrane of the stomach, on the small intestine and lungs, was calculated.
    231
    Table 1
    Morantel Tartrate
    250 mg / day A
    Also
    Control test
    Also
    AT
    10 and 1 indicator every 4 weeks
    Also
    As established, the studied groups have almost the same weight gain rate for about the first three months. After this period of time, the weight gain of control groups of animals slows down and even decreases with time as the number of parasites on the pasture increases. At the same time, the weight gain is treated
    five
    one(
    2218624
    animals continues and is almost equal to the weight gain observed in the early period of pasture in the field.
    In the control group of animals, invasive eggs began to appear in the feces at the beginning of June, their number reached a maximum at the end of July, after which it slowly decreased during August and September. These invasive eggs caused as a result of an increase in the number of larvae on the grass cover of the pasture, which reached a maximum in August,
    In the treated groups, the observed number of deposited invasive eggs during June and July was extremely intensively reduced, which was reflected in a significant decrease in the number of larvae on the pasture cover during July and Selt Br.
    Example 17. Has A. been carried out practical practical tests in this way & as described in example 16, but using only one 25 treatment group (the group with the input of the proposed capsule and one control group in each trial). The data obtained are given in table 2.
    Table 2
    15
    20
    25
    Example 18. The procedure described in Example 4 was repeated, but using instead of polypropylene filter cloth impregnated with cellulose triacetate in gel form, the following porous cloth materials impregnated with cellulose triacetate in gel form:
    Porous tissue - Medium nevy material size realpor., Micron
    Polyethylene. 75
    0
    26
    Polytetrafluoroethylene 100 Glass60
    Filtronal-ng fabric from stainless steel 80 Copper mesh 30 Modified acrylic fiber 10 Netting from nickel-copper alloy 50
    Phi .2
    /
    .
      . . . "
    t-g. "
    l /
    4jKMMMMifc VM m

    Fig l
     Phil..5
    Compiled by E.Arska Editor N.Kishtulinets Tehred G.Gerber Proofreader V.Sinick
    Order 1622/61 Circulation 660 g. Subsidiary VNISHSh USSR State Committee
    for inventions and discoveries 1 13035, Moscow, Zh-35, Raushsk nab., 4/5
    Branch PPP Pateit, Uzhgorod, st. Projects, 4
    权利要求:
    Claims (1)
    [1]
    CAPSULE FOR ORAL ADMINISTRATION, ANIMAL DRUGS, containing a housing for containing a medicinal substance with at least one end wall of a porous material selected from the group consisting of polyethylene, polypropylene, porous ceramics, polyvinyl chloride, polystyrene, polytetrafluoroethylene and providing release of the drug substance at a controlled rate into the aquatic environment, characterized in that, in order to increase the duration of the release of the drug substance, pores are indicated This porous material is filled with hydrogel of cellulose triacetate or polyvinyl alcohol with resorcinol. $
    SU a ,, 1222186
    Fs / g /
    1, ι2
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    同族专利:
    公开号 | 公开日
    IT7922426D0|1979-05-07|
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    DE2918522C2|1986-06-19|
    FR2425242A1|1979-12-07|
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    KE3367A|1984-02-10|
    NO147902B|1983-03-28|
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    NL179703B|1986-06-02|
    PH17566A|1984-10-01|
    ATA339379A|1989-05-15|
    FI75735C|1988-08-08|
    FI791452A|1979-11-09|
    BE876074A|1979-11-07|
    DK122779A|1979-11-09|
    CH643140A5|1984-05-30|
    AR219795A1|1980-09-15|
    DD143504A5|1980-08-27|
    GR73637B|1984-03-26|
    GB2020181A|1979-11-14|
    HU186995B|1985-10-28|
    ES480320A0|1983-04-16|
    YU106679A|1984-10-31|
    PL126835B1|1983-09-30|
    DK153917B|1988-09-26|
    DD152482A5|1981-12-02|
    IE790891L|1979-11-08|
    IL57227D0|1979-09-30|
    PL215452A1|1980-03-10|
    HK13384A|1984-02-24|
    EG15524A|1987-05-30|
    MX5953E|1984-09-06|
    FR2425242B1|1984-12-14|
    JPS6118525B2|1986-05-13|
    LU81233A1|1979-12-07|
    CS236761B2|1985-05-15|
    NL7903549A|1979-11-12|
    NO147902C|1983-07-06|
    SG65583G|1985-03-29|
    CA1113395A|1981-12-01|
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    ZA792129B|1980-05-28|
    ES8305583A1|1983-04-16|
    FI75735B|1988-04-29|
    DK153917C|1989-02-06|
    引用文献:
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    US3279996A|1962-08-28|1966-10-18|Jr David M Long|Polysiloxane carrier for controlled release of drugs and other agents|
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    US3975350A|1972-08-02|1976-08-17|Princeton Polymer Laboratories, Incorporated|Hydrophilic or hydrogel carrier systems such as coatings, body implants and other articles|
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    US3961628A|1974-04-10|1976-06-08|Alza Corporation|Ocular drug dispensing system|GB8305797D0|1983-03-02|1983-04-07|Graham N B|Hydrogel-containing envelopes|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US90407878A| true| 1978-05-08|1978-05-08|
    US90404978A| true| 1978-05-08|1978-05-08|
    US06/014,387|US4220152A|1978-05-08|1979-02-22|Delivery system|
    US06/014,388|US4220153A|1978-05-08|1979-02-22|Controlled release delivery system|
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