Sustained delivery device and system of an active agent using an implantable system and method for producing of the device; a back-diffusion regulating outlet and a semipermeable plug

Abstract

The invention relates to a liquid-absorbing and body-worn, implantable, active agent delivery device and system, as well as a method for producing the device, as well as a back-diffusion-controlling outlet channel and a semi-permeable plug, which are suitable for the sustained delivery of a biologically active agent in a natural fluid environment in a natural or artificial body cavity. The device comprises a container (12) made of an impermeable material filled with the active agent, into one end of which, at its inner surface, a water-reducing, semi-permeable material is sealedly inserted in such a way that the active agent is located outside the delivery device (10) when the semi-permeable material is swollen with water. It further comprises a back-diffusion regulating outlet channel (22, 40) fitted to the container (12), the active agent flow path (34, 36) being a path defined by the connecting surfaces of the container (12) and the back-diffusion regulating outlet channel (22, 40).Preferably, the active agent and / or the back-diffusion control outlet (22, 40) is inserted into the open end of the container (12) in the form of a plug (24, 26) which can be removed at an internal pressure lower than the maximum osmotic pressure produced by the water-swellable agent. In the process, a container (12) is first formed, then a water-swellable material and an active agent are placed therein, the container (12) is made of an impermeable material, and a semi-permeable plug (24, 26) is formed by injection molding, which is inserted into one of the open ends of the impermeable container (12) in such a way that its wall surrounds the semi-permeable plug (24, 26). ŕ.

Description

The subject of the invention is a liquid absorbing and body-worn, implantable, active agent dosing device and system, as well as a method for the production of the device, as well as a back-diffusion regulating outlet connector, a semi-permeable plug, which are suitable for long-term administration of a biologically active active agent in a natural fluid environment in a natural or artificial body cavity. In the field of drug administration, an old goal is to treat disease through the controlled, sustained administration of an active ingredient. Various solutions have been developed for the dosing of the active ingredient. One solution involves the use of implantable diffusion devices. For example, subcutaneous devices for contraception are described by Philip D. Damey in Current Opinion in Obstetrics and Gynecology, 1991, 3:470-476. Norplant@ requires six silastic capsules filled with levonorgestrel to be implanted under the skin. Contraception for up to five years was achieved with the dosing device. Implantation works by simple diffusion, i.e. the active ingredient diffuses into the body through a polymetric material at a rate controlled by the formula of the active ingredient and the properties of the polymetric material. Damey also describes biodegradable implantable devices, namely Capranor™ and norethindrone pellets. These delivery devices are designed to deliver contraceptives into the body for about a year, after which they are absorbed. The Capranor™ delivery device contains poly(ecaprolactone) capsules filled with levonorgestrel, and the pellets consist of 10% pure cholesterol with 90% norethindrone. There have also been published descriptions of implantable infusion pumps for intravenous, intra-arterial, intrathecal, intra-abdominal, spinal canal and epidural administration of drugs. Pumps are usually surgically implanted in the subcutaneous tissue in the lower abdomen. Dispensing devices for pain management, chemotherapy and insulin delivery are described in BBI Newsletter, Volume 17, Number 12 (December 1994), pp. 209-211. described on page These dosing devices provide more precisely controlled dosing than simple diffusion dosing devices. One particularly promising approach involves osmosis-powered delivery devices, such as those described in US Patent Nos. 3,987,790, 4,865,845, 5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,234,692, and 5,234,693. These dosing devices can be incorporated into an animal in order to administer the active ingredient in a controlled manner during a predetermined treatment period. These dosing devices generally work on the principle that they absorb liquid from their external environment and emit the corresponding amount of active ingredient. Implantable, osmotic dosing devices that administer an active ingredient into an animal body are well known, for example, from patent No. EP 373,867. The implantable dosing device according to EP 373,867 has a breakable plug or tube covering the exit opening so that the active ingredient cannot leak out before the device is implanted. A first wall section surrounds the active active ingredient, and a second wall section surrounds the osmotic active ingredient, and optionally a frictionless, gap-free close-fitting layer is placed between the active active ingredient and the osmotic active ingredient. The device has a straight outlet, so the dosage cannot be controlled with sufficient reliability, and the time from implantation to the start of the dosage cannot be sufficiently reduced. The dosing devices described above could be used for dosing active substances in a liquid environment. Although these dosing devices have been used for both human and veterinary purposes, there is still a need for dosing devices that are suitable for dosing active agents, especially effective, unstable active agents, at a controlled rate over a longer period of time with a reliability suitable for human use. For the purpose of human implantation, the size of the dosing devices must be reduced. The strength of the dispensing devices must be sufficient to provide a robust dispensing device. Accurate and repeatable dosing rates and durations should be ensured, and the time from implantation to initiation of dosing should be minimized. It must be ensured that the active ingredient maintains its purity and activity over a longer period of time, at higher temperatures that are encountered in the body cavities. Accordingly, according to the invention, on the one hand, we have created a liquid-absorbing dosing device suitable for dosing an active agent in a liquid environment, which contains a container filled with an active agent. The essence of the invention is that the container is made of an impermeable material, at one end, at its inner surface, a water-swelling, semi-permeable material is inserted in such a way that the active ingredient HU 221 919 Β1 semi-permeable material in its water-swollen state is located outside the dosing device. In addition, according to the invention, for the purpose of dosing the active ingredient in a liquid environment, we have created an implantable liquid suction dosing device that includes a container and a matching back-diffusion-regulating outlet port, the flow path of the active ingredient is a path defined by the connecting surfaces of the container and the back-diffusion outlet port forms. According to the invention, we have also developed a device suitable for dosing an active active ingredient in a liquid environment over a predetermined period of time, which includes a container containing the active active ingredient, which is at least partially made of a metallic material, the part of the container containing the active active ingredient is non-reactive with the active ingredient. The essence of the new solution according to the invention is that the metal material in contact with the active ingredient is selected from the group containing titanium and its alloys. According to the invention, we have also developed an implantable, liquid-absorbing, active agent dosing system that includes a container and contains a piston, which divides the container into a chamber containing the active agent and a chamber containing the water-swellable active agent, in which the chamber containing the active agent has an exit valve that controls back diffusion provided, and the chamber containing the water-swelling agent is provided with a semi-permeable material. A new solution in the system is that the container is made of a water-impermeable material and has at least one open end, and the semi-permeable material and / or the back-diffusion control outlet is inserted into the open end, in the form of a plug, which can be removed from the container at such an internal pressure , which is lower than the maximum osmotic pressure produced by the water-swelling agent. According to the invention, we have also developed a liquid-absorbing, implantable, active agent dosing system, in which the container has a plug made of a semi-permeable and water-swelling material, which is inserted into the part of the container that forms a linear expansion space for the plug, the dimensions of the dosing device and the active the active ingredient and the water-swelling material are chosen in such a way that the rise time is shorter than 10% of the predetermined treatment time. According to the invention, we have also developed a method for the production of a liquid-absorbing, implantable, active active ingredient for dispensing the active ingredient into a liquid environment for a predetermined treatment period, during which a container is first formed, and then a water-swellable material and an active material is inserted. A new step in the process according to the invention is to make the container from an impermeable material and to form a semi-permeable plug by injection molding, which is fitted into one open end of the impermeable container in such a way that its wall surrounds the semi-permeable plug. According to the invention, we have also developed an implantable, liquid-absorbing, active agent dispensing system that contains a piston that divides the system into a first and second chamber, and also contains a preparation containing a water-swelling substance placed in the first chamber and a second a composition containing an active ingredient placed in a chamber, a semi-permeable material in contact with the first chamber, and an outlet valve for regulating back diffusion in contact with the second chamber. A new solution in the system is that the first and second chambers have one open end each, the semi-permeable material is in the open end of the first chamber, and the outlet for regulating back diffusion is in the open end of the second chamber, and the first chamber containing the active ingredient is airtight is isolated from the environment of use. Furthermore, according to the invention, in a system for dispensing active active ingredient in a liquid environment, we have designed a back-diffusion-regulating exit valve for use by inserting the part of the dosing device containing the active ingredient and the part connecting the active ingredient and the liquid environment, in which the essence of the new solution is that its outlet port forms a flow path with an internal cross-sectional shape and area for the active active ingredient that provides a linear speed higher than the speed of the linear liquid flow inwards from the liquid environment of use. According to the invention, we have also developed a semi-permeable plug for use in a device for dispensing an active ingredient in a liquid environment, with a new solution in which the plug is water-swellable and is arranged in the part of the device that dispenses the active ingredient, which is connected to the liquid environment and forms a space for linear swelling. In addition, according to the invention, an implantable, fluid-absorbing, leuprolide delivery system has been developed, which includes a container, a piston, which divides the system into first and second chambers, and also contains a water-swelling material placed in the first chamber and a water-swelling material placed in the second chamber a composition containing leuprolide, a semi-permeable material in contact with the first chamber, and a back-diffusion control exit valve in contact with the second chamber. A new solution in the system according to the invention is that the tank is made of an impermeable material, and the first and second chambers have one open end, the semi-permeable material is in the open end of the first chamber, and the outlet coupling for regulating back diffusion is in the open end of the second chamber, and the first chamber containing leuprolide is hermetically isolated from the environment of use. Finally, according to the invention, for the administration of leuprolide acetate for one year after subcutaneous implantation, we developed an implantable, continuous dosing system for the active ingredient, which contains a container, a piston, which divides the container into two3 HU 221 919 Β1 divides it into a first chamber and a second chamber, an osmotic engine in the first chamber, an active ingredient in the second chamber, a semi-permeable material in contact with the first chamber, and an exit valve for regulating back diffusion in contact with the second chamber. The essence of the solution according to the invention is that the material of the container is titanium or a titanium alloy, the piston is made of thermoplastic, the first and second chambers both have an open end, the osmotic motor consists of a compressed NaCl-based osmotic motor and PEG additive, the active ingredient is 65 mg , leuprolide in the form of leuprolide acetate dissolved in DMSO, a semi-permeable material placed in the form of a plug in the open end of the first chamber is a 20% water-absorbing polyurethane, the back-diffusion control outlet is made of polyethylene and is installed in the open end of the second chamber, and the back-diffusion control outlet is a screw thread , has a flow path with a transport capacity of 150 pg leuprolide acetate / day. The device, system and method according to the invention are described below in more detail with reference to the attached drawings in connection with an embodiment. The drawings are not to scale and are intended to illustrate various embodiments of the invention. Identical reference numbers indicate identical structural elements. The Figures 1 and 2 show cross-sectional views of two embodiments of the dispensing device according to the invention; the Fig. 3 is an enlarged, cross-sectional view of the back-diffusion regulating outlet of Fig. 1; the Figure 4 is a graph showing the effect of aperture diameter and length on drug diffusion; the Figures 5, 6, 7 and 8 show further embodiments of the semi-permeable plug end portion of the container according to the invention; the Figures 9, 10 and 11 are diagrams showing the delivery rates of delivery devices using leuprolide (Figure 9), blue dye and different membranes (Figures 10 and 11). The invention proposes a dosing device for the purpose of dosing an active agent in a liquid environment of use, in which the active agent must be protected from the liquid environment until it is dosed. We have achieved a long-lasting and controlled dosage. The term "active ingredient" means the active ingredient(s), optionally in combination with pharmaceutically acceptable carriers and optionally with additional components such as antioxidants, stabilizers, permeation enhancers, etc. together. The term "predetermined dosing period" means a period of time greater than 7 days, often 30 days to 2 years, preferably greater than 1 month, and generally 1 month to 12 months. The time leading up to the "run-up" is understood to be the time that elapses from the time of implantation into the liquid environment until the time when the actual dosage of the active ingredient reaches the planned steady rate dosage of approx. 70% or more. The term "impermeable" means that the material is sufficiently impermeable to environmental fluids as well as materials contained in the dispensing device such that the migration of such materials out of the dispensing device or into the dispensing device is so small that no significant adverse effect occurs. to the function of the dosing device during the dosing period. The term "semi-permeable" means that the material is permeable to external fluids but substantially impermeable to other materials contained within the dispensing device and the environment of use. As used herein, the terms "therapeutically effective amount" or "therapeutically effective rate" refer to the amount or rate of active ingredient required to achieve the desired biological or therapeutic effect. The devices for dispensing the active ingredient according to the invention can be used in areas where a sustained and controlled dosage of an active ingredient is desired. In many cases, the active ingredient tends to degrade if it is exposed to the environment of use before dosing, and the dosing devices protect the active ingredient from such effects. Figure 1 shows one embodiment of the dispensing device 10 according to the invention. Figure 1 shows a liquid suction dispensing device 10 that includes an impermeable container 12. The impermeable container 12 is divided into two chambers by means of 16 pistons. A first chamber 18 is designed to store the active ingredient, and a second chamber 20 is designed to store a liquid absorbing material. In the open end of the first chamber 18, an exit valve 22 regulating back diffusion is inserted, and in the open end of the second chamber 20, a water-swelling semi-permeable plug 24 is placed. In Fig. 1, the outlet connection 22 of the back diffusion regulator is represented as a male screw inserted in a manner connected to the smooth inner surface of the impermeable tank 12, which forms a flow path 34 in the shape of a screw thread between the wall of the tank 12 and the male screw. The thread pitch x, thread height y, and cross-sectional area of ​​the screw thread-shaped flow path 34 formed between the outlet port 22 of the back diffusion controller and the connection surfaces of the container 12, as shown in Figure 3, are factors that influence the efficiency of the flow path 34 in the back diffusion of the external liquid. to the material in the first chamber 18, such as the pressure inside the dosing device. The geometry of the outlet coupling 22 controlling the back diffusion prevents the diffusion of water into the tank 12. In general, it is desirable to choose these properties in such a way that the length of the helical flow path 34 and the speed of the active ingredient through it are sufficient to prevent the back diffusion of the external liquid through the flow path 34 HU 221 919 through Β1 without significantly increasing the back pressure, so that after the start-up, the dosage rate of the active ingredient is controlled by the osmotic pumping effect. Figure 2 shows a second embodiment of the dispensing device according to the invention with the container 12, the piston 16 and a plug 26. In this embodiment, a flow path 36 is formed between the outlet port 40 of a back diffusion control thread and a thread 38 on the inner surface of the tank 12. The thread heights of the threaded parts of the back diffusion control outlet 40 and the container 12 are different so that the flow path 36 is formed between the container 12 and the back diffusion control outlet 40. The water-swellable, semi-permeable plugs 24 and 26 shown in Figures 1 and 2 are inserted into the container 12 such that the wall of the container 12 concentrically surrounds and protects the plugs 24 or 26. In Figure 1, the upper part 50 of the plug 24 is exposed to the environment of use, and it can also be designed to form a flanged cap part 56 above the end of the container 12. The semi-permeable plug 24 is flexibly connected to the inner surface of the container 12 and is shown in FIG. 1 as having projections 60 which are intended to frictionally secure the semi-permeable plug 24 to the inner surface of the container 12 . In addition, the protrusions 60 also serve the purpose of providing an additional seal around the circumference of the plug 24 that functions prior to swelling of the semi-permeable plug 24 due to hydration. The tolerance between the protrusions 60 and the inner surface of the container 12 prevents hydration swelling from creating stresses in the container 12 that could lead to failure of the container 12 under tensile stress on the one hand, and to failure of the plug 24 under compressive stresses or shear stresses on the other. Figure 2 shows a second embodiment of the semi-permeable plug 26 where the plug 26 is injection molded into the top of the container 12 and where the top of the semi-permeable plug 26 coincides with the top 62 of the container 12 . In this embodiment, the diameter of the plug 26 is significantly smaller than the diameter of the container 12. Plugs 24 and 26 in both embodiments will swell upon exposure to fluid in the body cavity, providing an even tighter seal for container 12. The novel arrangement of components in the embodiments described above provides implantable delivery devices that are uniquely suitable for implantation into the human body and can provide delivery devices that are suitable for long-term storage of unstable compounds at body temperature, which delivery devices are at 10% of the duration of use they have a shorter start-up time, can be designed to be extremely reliable, with a predictable error-free mode of operation. The container 12 must be sufficiently strong to ensure that it does not leak, crack, collapse, or deform in such a way as to release its active ingredient content under the stresses to which it may be subjected during use when impermeable. Namely, it must be designed to withstand the maximum osmotic pressure that the water-swellable material in the chamber 20 can produce. The container 12 must also be chemically inert and biocompatible, i.e. it must not be reactive with the active ingredient and the human body. Suitable materials usually include non-reactive polymers or a biocompatible metal or alloy. Polymers include acrylonitrile polymers such as acrylonitrile-butadiene-styrene terpolymer and the like; halogenated polymers such as poly(tetrafluoroethylene), poly(chlorotrifluoroethylene), copolymer tetrafluoroethylene and hexafluoropropylene; polyamide; polysulfone; polycarbonate; polyethylene; polypropylene; polyvinyl chloride acrylic copolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene and the like. The rate of water vapor transmission through materials suitable for the formation of the tank is reported in the following literature: J. Pham. Se., volume 29 1634-37. pages, (1970); Ind. Eng. Chem. (Industrial and Technical Chemistry), volume 45, 2296-2306. pages (1953); Materials Engineering, Volume 5, 34-38. pages, (1972); and Ind. and Eng. Chem. (Industrial and Technical Chemistry), volume 49, 1933-1936. pages (1957). Polymers are from Handbook of Common Polymers by Scott and Roff, CRC Press, Cleveland Rubber Co., Cleveland, OH. known from books. Metals useful in the present invention include stainless steel, titanium, platinum, tantalum, gold, and their alloys, as well as gold-plated steel alloys, platinum-plated steel alloys, cobalt-chromium alloys, and titanium nitride-coated stainless steel. For most size-critical applications, high-capacity and long-duration applications, and applications where the composition of the active ingredient is sensitive to compounds in the body at the site of implantation, or where the body is sensitive to the composition of the active ingredient, titanium is preferred at or above 60%, often Tank made of titanium alloys with more than 85% titanium content. Preferred dosage devices contain at least 70% active ingredient after 14 months at 37°C and have a storage stability of at least 9 months, but preferably at least 2 years at 2-8°C. Most preferably, the dispensing devices can be stored at room temperature. In certain embodiments, and for applications other than the liquid suction delivery devices described in detail, where there are unstable compounds in the chamber 18, especially protein and / or peptide compounds, the metal parts of the delivery device that are directly exposed to the compounds should be made of titanium or its alloys. to prepare as described above. The dosing devices of the invention provide a sealed chamber 18 that effectively isolates the active ingredient from the liquid environment. The 12 containers are made of rigid, impermeable and strong material. The water-swelling, semi-permeable 24 plug is a lower hardness material, HU 221 919 Β1 and corresponding to the shape of the container to ensure liquid-free insulation of the interior of the container 12 when exposed to moisture. The flow path 34 isolates the chamber 18 from back-diffusion of the ambient fluid. Piston 16 separates chamber 18 from ambient fluids, which are allowed to enter chamber 20 through plugs 24 or 26 such that, in steady state flow, the active ingredient is forced out through outlet port 22 at the same rate as water exits the chamber 22. flows from the environment into the water-swellable material in the chamber 20 through the semi-permeable plugs 24 or 26. As a result, the plug 24 or 26 and its mixture of active ingredients will be protected against damage and their functionality will not deteriorate even if the container 12 is deformed. In addition, we avoid the use of insulating materials and adhesives, thus solving the additional problems of biocompatibility and ease of manufacture. The materials from which the semi-permeable plugs 24 and 26 can be made are those which are semi-permeable and which can conform to the shape of the container 12 after wetting and adhere to the rigid surface of the container 12. When placed in a liquid environment, the semi-permeable plug 24 or 26 expands upon hydration to create a seal between the mating surfaces of the plug 24 or 26 and the container 12 . The strength of the seal between the container 12 and the outlet channel 22 and between the container 12 and the plugs 24 or 26 can be designed to withstand the maximum osmotic pressure created by the dispensing device 10. In a preferred version, the plugs 24 or 26 can be designed to withstand a pressure 10 times greater than the operating pressure of the osmotic material in the chamber 20. In a further variation, the plugs 24 or 26 can be removed from the tank when the internal pressure is less than the pressure required to release the back diffusion control outlet 22 or 40. In this error-free implementation, the chamber 20 of the water-swelling active ingredient opens and its pressure is removed, thereby preventing the back-diffusion control outlet 22 from being pushed out and, as a result, a large amount of active ingredient escaping from the dosing device 10. In other cases, where the fail-safe dispensing device 10 requires the release of the active ingredient mixture rather than the release of the water-swellable material, the semi-permeable plug 24 or 26 must be removable at a pressure greater than that prevailing in the outlet port 22 . In either case, the semi-permeable plug 24, 26 should be long enough to insulatively connect to the wall of the container 12 under operating conditions, i.e., have a length to diameter aspect ratio between 1:10 and 10:1. , preferably with a length-to-diameter ratio of at least 1:2, and very often with a ratio between 7:10 and 2:1. The plug 24.26 must be able to absorb between 0.1% by weight and 200% by weight of water. The diameter of the plug 24, 26 is such that, prior to hydration, due to the contact of one or more seals in its peripheral zone, it fits into the interior of the container 12 in an insulating manner, and then swells locally due to wetting and forms an even tighter seal with the container 12. The range of materials from which the plugs 24, 26 may be made may vary depending on the pumping rate and layout requirements of the dispensing device 10 and may include, but are not limited to, plasticized cellulosic materials, improved polymethyl methacrylate such as hydroxy -ethyl methacrylate (HEMA) and elastomeric materials such as polyurethanes and polyamides, polyether-polyamide copolymers, thermoplastic copolyesters and the like. The piston 16 isolates the water-swelling active ingredient in the chamber 20 and the active active ingredient in the chamber 18 from each other, and must be able to move under the pressure generated in the container 12 while maintaining the seal. The piston 16 is preferably made of a material that is less hard than the container 12 and which can deform to fill the interior of the container 12 and provide a liquid-tight, pressurized seal of the container 12. The materials from which the piston 16 is made are preferably elastomeric materials that are impermeable and include, but are not limited to, polypropylene, rubbers such as EPDM, silicone rubbers, butyl rubbers, and the like, and can be made from thermoplastic elastomers such as for example, plasticized poly(vinyl chloride), polyurethanes, Santoprene@, C-Flex@ TPE (from Consolidated Polymer Technologies Inc.) and the like. The piston 16 itself can be of a self-loading or pressure-loading structure. The outlet port 22 of the back-diffusion controller forms the dosing path, through which the active active ingredient flows out of the chamber 18 to the place of implantation, where absorption of the active active ingredient takes place. The seal between the outlet port 22 and the container 12 can either be designed to withstand the maximum osmotic pressure created in the dispensing device 10, or it can be designed to be fail-safe, as described above. In a preferred implementation, the pressure to open the outlet valve 22 of the back diffusion controller must be at least ten times the pressure required to move the piston 16, or ten times the pressure prevailing in the chamber 18. The outlet path of the active ingredient is the flow path 34 or 36, which was formed between the outlet port 22 controlling the back diffusion and the connecting surfaces of the container 12. The length, internal cross-sectional shape and area of ​​the flow path 34 or 36 are chosen so that the average linear velocity of the exiting active ingredient is greater than the average velocity of the linear inward flow of materials in the environment of use by diffusion or osmosis, thereby dampening or moderating back-diffusion and its harmful effects in terms of contaminating, destabilizing, dissolving or otherwise changing the active ingredient inside the pump. The dosing rate of the active ingredient is set out in section 6 HU 221 919 Bl can be changed by modifying the geometry of the flow paths 34, 36, the relationship of which is shown below. The convective flow of the active ingredient from the outlet valve 22 controlling the back diffusion is determined by the pumping speed of the dosing device 5 10 and the concentration of the active ingredient in the chamber 20, and can be described by the following formula: Qca=(Q)(Ca) (1) where Qcaaz The convective flow amount of the active ingredient, expressed in mg / day Q is the total convective flow amount of the active substance and its solvents, expressed in cm3 / day Caaz The concentration of the active ingredient in the compound 15 in chamber 20, expressed as mg / cm3. The diffusion flow of the active substance A through the exit valve 22 of the back diffusion regulator is a function of the concentration of the active substance, the cross-sectional shape of the flow path 34 or 36, the diffusivity of the active substance and the length of the flow path 20 34 or 36, and can be expressed as follows: Qda=DTtr2ACa / L (2) where Qdaaz Convective flow amount of the active substance, expressed in 25 mg / day D is the diffusivity through the material of the flow path 34 or 36, expressed in cm2 / day r is the effective internal diameter of the flow path 34 or 36, in cm ACaa The difference between the concentrations of the active substance A in the container 12 and in the body outside the outlet port 22, expressed in mg / cm3 form L is the length of the 34 or 36 flow path in cm. The concentration of the active substance in the container 12 is generally much higher than the concentration of the active substance in the body outside the outlet 22, so the ÁCa difference can be approximated within the container 12 of the active substance. With Ca concentration: Qda=Dnr2CA (3) 40 In general, it is desirable to keep the value of the diffusion flux of the active substance lower than 10% of the convective flow. This is expressed by the following inequality: (4) Equation (4) indicates that the relative diffusion flux decreases with increasing volumetric flow rate and path length, but increases with increasing diffusivity and increasing outlet port diameter 34 or 36, however, it is independent of drug concentration. Equation (4) was also plotted in the diagram of Figure 4, as a function of length L and diameter d, for D=2 x 10~6cm2 / s and Q=0.36 μΐ / day. The diffusion flux of water at the point where the outlet port 34 or 36 opens into the chamber 18 can be approximated using the following equation: Qwd(res)=C0Qe(-QL®wA) (5) where Coa concentration profile of water, expressed in mg / cm3 Q is the total flow rate, expressed in mg / day L is the length of the flow paths 34, 36 in cm Dwa diffusivity of water through the flow path material 34, 36 in cm2 / day The cross-sectional area of ​​the flow path 34, 36, expressed in cm2. The hydrodynamic pressure drop across the orifice can be calculated as follows: AP=8QLp (6) πτ4 The solution of the system of equations consisting of equations (4), (5) and (6) gives the values ​​shown in Table 1, where: Q =0.38 μΐ / day Ca=0.4mg / pl L= 5 cm Da=2.00 E-06 cm2 / s μ =5.00 E+02 cp Cw0=0 mg / μΐ Dw= 6.00 E+06 cm2 / s Table 1 Drug Diffusion & Pumping Water Penetration Pressure Drop Effective Orifice Diameter (mii) Cross Section, Area (mm2) Pumping Rate mg / day Diffusion QDa mg / day Diffusion / Convection QDa / QCa QDw mg / day QDw mg / year delta P Pa 1 0.00051 0.152 0.0001 0.0005 0 0 10 745.92 2 0.00203 0.152 0.0003 0.0018 1.14E-79 4.16E-77 671.63 3 0.00456 0.152 0.0006 0.0041 4.79E-36 l,75E-33 132,63 4 0,00811 0,152 0,0011 0,0074 8,89E-21 3,25E-18 42,00 5 0,01267 0,152 0,0018 0,0115 l,04E-13 3, 79E-11 17.17 6 0.01824 0.152 0.0025 0.0166 7.16E-10 2.61E-07 8.27 0.02483 0.152 0.0034 0.0226 1.48E-07 5.4E-05 4 ,48 HU 221 919 Β1 Table 1 (continued) Drug Diffusion & Pumping Water Penetration Pressure Drop Effective Cross Section. Pumping Diffusion Diffusion / QDW QDW delta P arrow diameter (mii) area (mm2) velocity mg / day QD, mg / day Convection QDa / QCa mg / day mg / year Pa 8 0.03243 0.152 0.0045 0.0295 4.7E- 06 0.001715 2.62 9 0.04105 0.152 0.0057 0.0373 5.04E-05 0.018381 1.65 10 0.05068 0.152 0.0070 0.0461 0.000275 0.100263 1.10 1 0.06132 0.152 0.0085 0.0558 0.000964 0.351771 0.758 12 0.07298 0.152 0.0101 0.0664 0.002504 0.913839 0.5517 13 0.08564 0.0117 0.0152 9 005263 1.921027 0.3448 14 0.09933 0.152 0.0137 0.0903 0.00949 3.463836 0.2758 15 0.11402 0.152 0.0158 0.1037 0.015269 5.569, 107209 5.565 12973 0.152 0.0179 0.1180 0.022535 8.225224 0.1379 17 0.14646 0.152 0.0202 0.1332 0.031114 11.35656 0.1379 18 0.16419 0.0292 0.142 0. 040772 14.88166 0.0689 19 0.18295 0.152 0.0253 0.1664 0.051253 18.70728 0.0689 20 0.20271 0.152 0.0280 0.1844 0.062309 20.7427 22.0628 Calculations show that a flow path 34.36 of about 0.0762-0.2540 mm in diameter and 2 to 7 cm in length is optimal for a dispensing device 10 with the operating conditions described. In a preferred embodiment, the pressure drop along the flow path 34, 36 will be less than 10% of the pressure required to open the back diffusion control outlet port 22. The outlet port 22 of the back diffusion controller is preferably designed as a screw-threaded flow path 34 or 36, which forms a long flow path and also has a dosing device, with the help of which it can be mechanically attached to the container 12 without the use of adhesive or other insulating material. The outlet valve 22 of the back diffusion regulator is made of a chemically neutral and biocompatible material, selected from the group of metallic materials including, but not limited to, titanium, stainless steel, platinum and their alloys, as well as cobalt-chromium alloys and similar metallic materials them to metallic materials, or from a polymer material, which can be, but is not limited to, polyethylene, polypropylene, polycarbonate and polymethyl methacrylate or a similar material. The flow paths 34, 36 are generally between 0.5 and 20 cm long, preferably between 1 and 10 cm, and approx. 0.0254 to 0.0508 mm (0.001 to 0.020 inch) in diameter, preferably approx. 0.0762 to 0.381 mm (0.003 to 0.015 in.) to allow an approx. 0.02 and 50 μΐ / day, usually 0.2-10 μΐ / day. Additionally, a catheter or other delivery device can be attached to the outlet port 22 of the back diffusion controller to deliver the active ingredient to a location outside of the implant. Such dispensing devices are known in the art and are described, for example, in US Patent Nos. 3,732,865 and 4,340,054. In addition, the construction of the flow path 34, 36 may be useful in systems other than the liquid suction dispensing devices 10 described in detail herein. The structure of the novel dosing device 10 described above also enables the time from start-up to the formation of a steady-state flow to be kept to a minimum value. This was achieved in part as a result of the construction of the semi-permeable plugs 24, 26. As the semi-permeable 24 or 26 plug absorbs water, it swells. Its radial expansion is limited by the rigid container 12, so its expansion is only possible in the longitudinal direction, thus it presses against the active agent swelling on the water in the chamber 18, which in turn presses against the lower piston. This allows pumping to begin before the water reaches the water-swelling agent, which would otherwise be required before pumping begins. In order to facilitate a reliable start-up, the flow path 34, 36 can be pre-filled with the active ingredient in the chamber 18. Furthermore, the geometry of the back diffusion control outlet port 22 allows for an initial dose that is influenced by the gradient of drug concentration along the length of the outlet port 22. The ramp-up time is less than 25% of the predetermined dosing time, often less than 10% of the predetermined dosing time, and usually less than 5% of the predetermined dosing time. A one-year 10-doser is one of the preferred ones In the case of the implementation of HU 221 919 Bl, we reach at least 70% of the steady state flow rate in 14 days. The water-swelling active ingredient preparation in the chamber 20 is preferably a tissue-tolerant compound whose high osmotic pressure and high degree of solubility drive the active ingredient out for a long time, while remaining in a saturated solution state in the water that the semi-permeable plug 24 or 26 (membrane) passed through. The water-swelling active ingredient is preferably selected according to the tolerance of the subcutaneous tissue, so that the substance flowing out of the implanted dosing device 10 in an unexpected manner at the pumping speeds and assumed concentrations does not cause problems if the dosing device 10 is used for longer than the planned period of time we would leave it in the patient. In preferred embodiments, the water-swelling agent cannot diffuse out or penetrate through the semi-permeable plugs 24 or 26 to a noticeable extent (for example, in an amount less than 8%) under normal operating conditions. Osmotic agents such as NaCl together with suitable tableting agents (lubricants and binders) and viscosity modifying agents such as sodium carboxymethyl cellulose or sodium polyacrylate are preferred water-swelling agents. Other osmotic agents that can be used as water-swelling agents include osmopolymers and osmagents, which are described in, for example, US Pat. No. 5,413,572. The water-swellable active compound may be a thick suspension, a tablet, a molded or extruded material, or any other form of material known in the art. A liquid or gel-like additive or filler may be added to the chamber 20 to exclude air from the space around the osmotic motor. The exclusion of air from the dispensing means 10 should mean that the dispensing rate is little affected by changes in nominal external pressure (eg ±48279 Pa). The dosing devices 10 according to the invention are suitable for dosing a wide range of active ingredients. These active agents include, but are not limited to, medicinally active peptides and proteins, genes and gene products, other gene therapy agents and other small molecules. Polypeptides include, but are not limited to, growth hormones, somatropin analogs such as somatomedin-C, gonadotropin-releasing hormones, follicle-stimulating hormone, luteinizing hormone, LHRH, LHRH analogs such as leuprolide, nafarelin, and goserelin. , LHRH agonist and LHRH antagonist substances, growth hormone-releasing factor, calcitonin, colchicine, gonadotropins such as chorionic gonadotropin, oxytocin, octreotide, somatropin plus some amino acid, vasopressin, adrenocorticotropic hormone, epidermal -growth factor, prolactin, somatostatin, somatropin plus one protein, cosyntropin, lypressin, polypeptides such as thyrotropin-releasing hormone, thyroid-stimulating hormone, secretin, pancreozymin, enkephalin, glucagon, internally secreted and blood-borne endocrine agents and the like. Active substances suitable for administration include, for example, aj-antitrypsin, factor VIII, factor IX and other coagulation factors, insulin and other peptide hormones, adrenal cortex-stimulating hormone, thyroid-stimulating hormone and other pituitary hormones, interferon-α, interferon-b and interferon-δ, erythropoietin, growth factors such as GCSF, GMCSF, insulin-like growth factor 1, tissue plasminogen activator, CD4, dDAVP, interleukin-1 receptor antagonist, tumor necrosis factor, pancreatic enzymes, lactase, cytokines, interleukin-2, tumor necrosis factor receptor, tumor suppressor proteins, cytotoxic proteins and recombinant antibodies and antibody fragments and the like. The above active ingredients can be used to treat a variety of conditions including, but not limited to, hemophilia and other blood disorders, growth disorders, diabetes, leukemia, hepatitis, kidney failure, HIV infection, hereditary diseases such as cerebrosidase deficiency and adenosine deaminase insufficiency, hypertension, infectious shock, autoimmune diseases such as multiple sclerosis, Grave's disease, systemic and rheumatic arthritis, shock and wasting disorders, cystic fibrosis, lactase intolerance, Chron's diseases, inflammatory bowel diseases, gastrointestinal and other cancers. The active ingredients can be anhydrous or aqueous solutions, suspensions or complexes formed with pharmaceutically acceptable carriers or carriers, which are flowable and thus can be stored for a long time in a warehouse or refrigerated space, and can be stored in an implanted dosing device. The preparations may contain pharmaceutically acceptable carriers and additional neutral components. The active ingredients can occur in different forms, for example as uncharged molecules, as components of molecular complexes or as pharmaceutically acceptable salts. Simple derivatives of the active substances (for example, their prodrugs, ethers, esters, amides, etc.) can also be used, which are sensitive to the pH of the body, enzymes, etc. can be easily hydrolyzed by It should be noted that more than one active ingredient can be included in the active ingredient compositions used in the dosing device 10 according to the invention, and the term "active ingredient" in no way excludes the use of two or more such ingredients. The dosing device 10 according to the invention can be used, for example, in human and veterinary medical environments. The environment of use is a fluid environment, which may include any subcutaneous position or body cavity, such as the peritoneum or the uterus, and may be the same or different from the final destination of the preparation containing the active ingredient. A single delivery device of 10 or more may be implanted in a subject during a treatment program. The dosing devices 10 are intended to be implanted HU 221,919 Bl remain during a predetermined dosing period. If the dosing devices 10 are not removed after the dosing period, they can be designed to withstand the maximum osmotic pressure of the water-swelling agent, but they can also be designed with a bypass line to relieve the pressure created within the dosing device 10. The dosing device 10 according to the invention is preferably sterilized before use, especially if the use is an implantation. This is achieved by sterilizing each component separately, for example by gamma irradiation, steam sterilization or sterile filtration, and then aseptically assembling the final delivery device. Alternatively, the dosing device 10 can be assembled first, and then subjected to a final sterilization using a suitable method. Production of the dispensing device 10 according to the invention The container 12 can preferably be made by machining a metal rod or by extruding or injection molding a polymer. The upper part of the container 12 can be open, as shown in Figure 1, or it can contain a cavity, as shown in Figure 2. When the container 12 is open as shown in Figure 1, the water-swellable semi-permeable plug 24 is mechanically inserted from the outside of the container 12 without using any adhesive before or after inserting the plug 16 or the water-swellable active ingredient composition. The container 12 may be provided with indentations or threads that engage with ribs or threads on the plug 24. In cases where the container 12 includes a cavity, as shown in Figure 2, the shape of the cavity can be cylindrical, as shown in Figure 5, stepped, as shown in Figure 6, or threaded, as shown in It can be seen in Figure 7, or it can be divided into separate spaces, as shown in Figure 8. The semi-permeable plug 26 is then injected, inserted or otherwise installed in the cavity to form a sealed connection with the wall of the container 12. After the plug 26 has been inserted, either mechanically, by welding or injection, the water-swelling agent is placed in the tank 12, followed by the insertion of the lower piston, with appropriate steps taken to remove the trapped air. The active ingredient is introduced into the dosing device 10 with an injection syringe or with the help of a precision dosing pump. The diffusion moderator is generally inserted into the dispensing device 10 by a twisting or screwing operation or by axial pressing. The following examples serve to illustrate the invention. They should not be construed as limiting the scope of the invention. Variations of the presented examples and equivalent implementations will be obvious to those skilled in the art in the light of the description of the invention as well as the accompanying drawings and claims. Examples Example 1 Production of the dispensing device 10 with an HDPE container A delivery device 10 containing leuprolide acetate for the treatment of prostate cancer was assembled from the following components: container (HDPE) (5 mm outer diameter, 3 mm inner diameter) piston (Santoprene®) Lubricant (medical silicone fluid) Compressed osmotic engine (60% NaCl, 40% sodium carboxymethyl cellulose) Membrane plug 26 (Hytrel polyether-ester block copolymer, injection molded to the desired shape) 22 outlet ports regulating back diffusion (polycarbonate) Active ingredient (0.78 g 60% propylene glycol and 40% leuprolide acetate) Assembling The inner jacket surface of the piston 16 and the container 12 was slightly moistened with silicone medical liquid. The piston 16 was pressed into the open end of the chamber 20. The osmotic engine tablets (weighing 40 mg each) were then placed on top of the 16 pistons. The diaphragm plug 24 was fitted in place by aligning the plug 24 with the tank 12 and pushing slightly inwards until the plug 24 was fully engaged with the tank 12. The active ingredient was filled into a syringe, and then the chamber 18 was filled from its open end by injecting the substance into the open tube until the mixture reached approx. It was no more than 3 mm from the end of the tube. The filled 12 containers were subjected to centrifugation in order to completely remove the air bubbles trapped in the material during filling. The outlet clamps 22 were screwed into the open end of the container 12 until they were fully engaged. As the outlet clamp 22 was screwed into place, the excess active agent escaped through the opening, thereby ensuring even filling. Example 2 Implantation of the 10 dosing devices in Example 1 The delivery device 10 of Example 1 was implanted under aseptic conditions using a trocar similar to the implants used in the Norplant® contraceptive delivery device for subcutaneous positioning of the delivery device 10. The implantation is typically done on the inner side of the upper arm, at a distance of 8-10 cm from the elbow. The area was anesthetized and an incision was made through the skin. The incision is approx. It was 4 mm long. The trocar was pushed into the incision until the tip of the trocar was approx. It was 4-6 cm from the incision. The plug was then removed from the writing arm and the delivery device 10 of Example 1 was inserted into the trocar. HU 221 919 Β1 The delivery device 10 was then advanced using the plug to the open end of the trocar. The delivery device 10 of Example 1 was then immobilized by holding the plug in place while the trocar was retracted over both the delivery device 10 and the plug. The plug was then removed, leaving the dispensing device 10 in a well-defined position. The edges of the incision were then secured with a skin closure. The skin surface was covered and kept dry for 2-3 days. Example 3 Removal of the dispensing device 10 in Example 1 The 10 dosing devices in example 1 are removed as follows: The 10 dosing devices are felt with a finger in the area of ​​the upper arm. The area is anesthetized at one end of the implant, and a perpendicular incision about 4 mm long is made through the skin and fibrous capsule surrounding the implant site. The end of the dosing device 10 opposite to the incision is pushed in such a way that the end adjacent to the incision is pushed out through the incision. Any additional fibrous tissue is cut away with a scalpel. After removal, the procedure in Example 2 is repeated to implant another 10 dosing device. Example 4 The dosing rate of the 10 dosing devices in Example 1 Glass test tubes were filled with 35 ml of distilled water and then placed in a water bath at a temperature of 37 °C. One of the 10 dosing devices described in Example 1 was placed in each test tube, and the test tubes were changed periodically. The profile of the dosing rate of the dosing device 10 is shown in Figure 9. The 10 delivery devices had no ramp-up time, given that the 10 delivery devices exhibited a high initial delivery period followed by a lower steady-state delivery period of approximately 200 days. Example 5 Feed rate profiles Glass test tubes were filled with 35 ml of distilled water and then placed in a water bath at a temperature of 37 °C. After the test tubes had reached the temperature of the bath, a single 10 dispensing device as described in Example 1 was placed in each test tube, but this time with 24 stoppers made of the membrane material described below and with 1% FD&C blue dye dissolved in water as the drug substance. The water in the test tube penetrated through the membrane plug 24 and caused the dosing device 10 to pump, forcing the blue dye into the ambient water in the test tube. At regular intervals, the 10 dosing devices were transferred to fresh test tubes. The amount of dye released was determined by measuring the concentration of the blue dye in each test tube using a spectrometer. The pumping rate was calculated from the amount of total dye released, the volume of water in the test tube, the initial concentration of the dye, and the interval that the dispensing device 10 was in the test tube. Figures 10 and 11 show the results for two different tests. Figure 10 shows three different dispensing devices 10 with different stopper materials 24, 26 (Hytrel® 2, 3 and 12 month dispensing devices), all. and Fig. 2 shows the results of four dosing devices 10 with plugs 24, 26 made of different materials. These materials were: Membrane Material 1 month Pebax 25 (Polyamide) 2 months Pebax 22 (Polyamide) 3 months Polyurethane (HP60D) 12 months Pebax 24 (Polyamide) Depending on the membrane used, the dispensing devices 10 could dispense over a period of 2-12 months. Example 6 Production of 10 dosing devices with titanium 12 containers A 10-dosing device containing leuprolide acetate for the treatment of prostate cancer was assembled from the following parts: reservoir (titanium, TÍ6AI4V alloy) (with 4 mm outer diameter, 3 mm inner diameter) piston (C-Flex®) Lubricant (medical silicone fluid) Compressed osmotic engine (76.4% NaCl, 15.5% sodium carboxymethyl cellulose, 6% povidone, 0.5% Mg stearate, 1.6% water) PEG 400 (8 mg added to the osmotic engine to fill the air part) Plug 26 with membrane (polyurethane polymer, injection molded to the desired shape) 22 outlet couplings regulating back diffusion (polyethylene) Pharmaceutical composition (0.150 g 60% water and 40% leuprolide acetate). Assembling The inner jacket surface of the piston 16 and the container 12 was slightly moistened with silicone medical liquid. The plunger 16 was then pushed approximately 0.5 cm deep into the reservoir 12 against the end of the diaphragm 24 with the plug. PEG 400 was added to the 12 containers. Two osmotic engine tablets (40 mg each) were then placed in the container 12, from the end of the membrane 24 with the plug. After insertion, the osmotic motor was level with the end of the reservoir 12 . Diaphragm plug 24 was fitted into place by aligning plug 24 with tank 12 and pushing slightly inward until the fasteners of plug 24 were fully engaged with tank 12. The active ingredient was filled into a syringe, and with its help, the chamber 18 was filled from its outlet end by HU 221 919 Β1 that the substance was injected into the open tube until the mixture was approx. It was not 3 mm from the end of the tube. The filled 12 containers (standing with the outlet end upwards) were subjected to centrifugation in order to completely remove the air bubbles trapped in the material during filling. The outlet clamps 22 were screwed into the open end of the container 12 until they were fully engaged. As the outlet clamp 22 was screwed into place, the excess active agent escaped through the opening, thereby ensuring even filling. Example 7 Production of a leuprolide acetate dosing device with a titanium 12 container A 10-dosing device containing leuprolide acetate for the treatment of prostate cancer was assembled from the following parts: reservoir (titanium, TÍ6AI4V alloy) (4 mm outer diameter, 3 mm inner diameter, 4.5 cm long) piston (C-Flex® TPE elastomer available from Consolidated Polymer Technologies Inc.) Lubricant (silicone medical fluid 360) Compressed osmotic engine (76.4% NaCl, 15.5% sodium carboxymethyl cellulose, 6% povidone, 0.5% Mg stearate, 1.6% water, total 50 mg) PEG 400 (8 mg added to the osmotic engine to fill the air part) Membrane plug 26 (polyurethane polymer, injection molded to desired shape, 3 mm diameter and 4 mm long) Back Diffusion Control Outlet 22 (Polyethylene with 0.006 in. x 5 cm Channel) Pharmaceutical composition (leuprolide acetate dissolved in DMSO, with a measured leuprolide content of 65 mg). Assembling The dispensing devices 10 were assembled in the same manner as in Example 6, using aseptic procedures to assemble the γ-irradiated subassemblies, and then the dispensing devices 10 were aseptically filled with a sterile, filtered leuprolide DMSO preparation. Dosing rate These 10 dosing devices are approx. A leuprolide formulation of 0.35 μΐ / day was delivered, containing an average of 150 pg of leuprolide per day delivered. The delivery devices 10 deliver leuprolide at this rate for approximately one year. The dosing devices 10 reached steady state dosing on day 14. Implantation and exclusion The delivery devices 10 are implanted under local anesthesia, through an incision and a trocar, as seen in Example 2, in patients suffering from advanced prostate cancer. After one year, the delivery devices 10 are removed under local anesthesia as described in Example 3. New dosing devices 10 can then be implanted. Example 8 Prostate cancer treatment Leuprolide acetate, an LHRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of steroid production by the testis. The effect can be reversed by stopping the medication. Administration of leuprolide acetate resulted in growth inhibition and genital atrophy of certain hormone-dependent tumors (prostate tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats). Administration of leuprolide acetate in humans results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which produces a transient increase in gonadal steroids (testosterone and dihydrotestosterone in males). However, continuous administration of leuprolide acetate results in decreasing LH and FSH levels. In men, testosterone drops to the castration level. These decreases occur within two to six weeks of starting treatment, and castration levels of testosterone have been demonstrated in prostate cancer patients over a period of several years. Leuprolide acetate is not active when administered orally. The dosing devices 10 are prepared as shown in example 7 and then implanted as described. Continuous dosing of leuprolide with these 10 delivery devices for a year will reduce testosterone to castration levels. The above description is provided for ease of understanding only. No limitation should be inferred from this description, as various modifications will be apparent to those skilled in the art.

Claims

PATENT CLAIMS 1. A liquid-absorbing dosing device for dosing an active agent in a liquid environment, comprising a container filled with an active agent, characterized in that the container (12) is made of a liquid-impermeable material, a semi-permeable material that swells in water is inserted in a sealed manner at one end of the container (12) at its inner surface in such a way that the active agent is located outside the dosing device (10) when the semi-permeable material is swollen in water.

2. A dispensing device according to claim 1, characterized in that the semipermeable material is inserted therein in the form of a plug (24, 26) having a length-to-diameter ratio of between 1:10 and 10:

1.

3. A dispensing device according to claim 1, characterized in that the semipermeable material is disposed in the open end of the container (12).

4. A dispensing device according to claim 1, characterized in that the semipermeable material is disposed in a cavity at the end of the container (12). HU 221 919 Β1 5. A dispensing device according to claim 4, characterized in that the shape of the cavity is selected from the group consisting of cylindrical, stepped, helical or segmented arrangements.

6. The dispensing device of claim 1, wherein the semipermeable material is selected from the group consisting of plasticized cellulose-based plastics, polyurethanes, and polyamides.

7. The delivery device of claim 1, wherein the active ingredient is selected from the group consisting of a protein, a peptide, or a gene therapy agent.

8. The delivery device of claim 7, wherein the active ingredient is an LHRH agonist or antagonist.

9. The delivery device of claim 7, wherein the active ingredient is leuprolide.

10. The dosing device according to claim 7, characterized in that the active ingredient is selected from the group of substances containing factor VIII or factor IX.

11. A delivery device according to claim 1, characterized in that it is designed as a means for delivering the active ingredient to a point remote from the implantation site of the delivery device (10).

12. An implantable liquid-absorbing delivery device for delivering an active agent in a liquid environment, characterized in that it comprises a reservoir (12) and a back-diffusion-controlling outlet port (22, 40) fitted thereto, the active agent flow path (34, 36) being a path defined by the connecting surfaces of the reservoir (12) and the back-diffusion-controlling outlet port (22, 40).

13. The dosing device according to claim 12, characterized in that the length of the flow path of the active ingredient is between 0.5 and 20 cm and its diameter is between 0.0025 and 0.051 cm.

14. The delivery device of claim 12, wherein the active ingredient is selected from the group consisting of a protein, a peptide, or a gene therapy agent.

15. The delivery device of claim 14, wherein the active ingredient is an LHRH agonist or antagonist.

16. The delivery device of claim 14, wherein the active ingredient is leuprolide.

17. The delivery device of claim 14, wherein the active ingredients are materials containing factor VIII or factor IX.

18. A delivery device according to claim 12, characterized in that it is designed as a means for delivering the active ingredient to a point remote from the implantation site of the delivery device (10).

19. A device for delivering an active agent in a liquid environment over a predetermined period of time, the device comprising a container (12) containing the active agent, which is at least partially formed of a metallic material, the part of the container (12) containing the active agent being non-reactive with the active agent, characterized in that the material of the metal in contact with the active agent is selected from the group consisting of titanium and alloys thereof.

20. The dispensing device of claim 19, wherein the titanium alloy contains at least 60% titanium.

21. The delivery device of claim 19, wherein the active ingredient is selected from the group consisting of a protein, a peptide, or a gene therapy agent.

22. The delivery device of claim 21, wherein the active ingredient is an LHRH agonist or antagonist.

23. The delivery device of claim 21, wherein the active ingredient is leuprolide.

24. The delivery device of claim 21, wherein the active ingredients are materials containing factor VIII or factor IX.

25. A delivery device according to claim 19, characterized in that it is designed as a means for delivering the active ingredient to a point remote from the implantation site of the delivery device (10).

26. An implantable, liquid-absorbing, active agent delivery system comprising a reservoir and a piston dividing the reservoir into an active agent-containing chamber and a water-swellable agent-containing chamber, wherein the active agent-containing chamber is provided with an outlet port for controlling back diffusion, and the water-swellable agent-containing chamber is provided with a semipermeable material, characterized in that the reservoir (12) is formed of an impermeable material and has at least one open end, and the semipermeable material is inserted into the open end in the form of a plug (24, 26), which plug (24, 26) is removable from the reservoir (12) at an internal pressure lower than the maximum osmotic pressure produced by the water-swellable agent.

27. An implantable, liquid-absorbing, active agent delivery system comprising a reservoir and a piston dividing the reservoir into an active agent chamber and a water-swellable agent chamber, wherein the active agent chamber is provided with a back-diffusion-controlling outlet channel and the water-swellable agent chamber is provided with a semipermeable material, characterized in that the reservoir (12) is formed of a water-impermeable material and has at least one open end, and the back-diffusion-controlling outlet channel (22, 40) is inserted into the open end in the form of a plug that can be removed from the reservoir (12) at an internal pressure lower than the maximum osmotic pressure produced by the water-swellable agent.

28. An implantable, liquid-absorbing, active agent delivery system for delivering an active agent to a liquid environment for a predetermined treatment period, comprising a container containing the active agent, characterized in that the container (12) has a plug (24, 26) made of a semipermeable and water-swellable material, which is inserted into a portion of the container (12) forming a linear expansion space for the plug (24, 26), the dimensions of which and the active agent and water-swellable material are selected such that the rise time is shorter than 10% of the predetermined treatment period.

29. A method for producing a liquid-absorbing, implantable, active agent delivery device for delivering an active agent to a liquid environment for a predetermined treatment period, comprising first forming a container, then inserting therein a water-swellable material and an active agent, characterized in that the container (12) is made of an impermeable material and a semipermeable plug (24, 26) is formed by injection molding, which is inserted into one open end of the impermeable container (12) in such a way that its wall surrounds the semipermeable plug (24, 26).

30. The method of claim 29, wherein the semipermeable material is selected from the group consisting of plasticized cellulose-based plastics, polyurethanes, and polyamides.

31. An implantable, liquid-absorbing, active agent delivery system comprising a piston dividing the system into first and second chambers, further comprising a composition containing a water-swellable material placed in the first chamber and a composition containing an active agent placed in the second chamber, a semipermeable material in contact with the first chamber and a back-diffusion control outlet in contact with the second chamber, characterized in that the first and second chambers (18,20) each have an open end, the semipermeable material is in the open end of the first chamber (18), and the back-diffusion control outlet (22) is in the open end of the second chamber (20), and the first chamber (18) containing the active agent is hermetically sealed from the environment of use.

32. The system according to claim 31, characterized in that the active agent is selected from the group consisting of a protein, a peptide or a gene therapy agent.

33. The system of claim 31, wherein the active ingredient is an LHRH agonist or antagonist.

34. The system of claim 31, wherein the active ingredient is leuprolide. 3 5. The system according to claim 31, characterized in that the active ingredients are materials containing factor VIII or factor IX.

36. A back-diffusion-controlling outlet channel for use in a system for delivering an active agent to a liquid environment of use, for insertion into a portion of a delivery device containing the active agent and connecting the active agent to the liquid environment of use, characterized in that the outlet channel (22) forms a flow path of internal cross-sectional shape and area providing a linear velocity for the active agent greater than the linear fluid flow velocity inward from the liquid environment of use.

37. An outlet port according to claim 36, characterized in that the flow path (34, 36) is helical in shape.

38. A semipermeable plug for use in a device for dispensing an active agent into a liquid environment of use, said plug containing the active agent, characterised in that the plug (24, 26) is arranged in a part of the active agent dispensing device (10) which swells upon water and forms a linear swelling space and is connected to the liquid environment of use.

39. An implantable, fluid-absorbing, leuprolide delivery system comprising a reservoir, a piston dividing the system into first and second chambers, further comprising a water-swellable material disposed in the first chamber and a leuprolide-containing composition disposed in the second chamber, a semipermeable material in contact with the first chamber, and a back-diffusion-controlling outlet port in contact with the second chamber, characterized in that the reservoir (12) is formed of an impermeable material, and the first and second chambers (18,20) each have an open end, the semipermeable material is in the open end of the first chamber (18), and the back-diffusion-controlling outlet port (22) is in the open end of the second chamber (20), and the first chamber (18) containing leuprolide is hermetically sealed from the from the usage environment.

40. The system according to claim 39, characterized in that the material of the container (12) is titanium or a titanium alloy.

41. The system of claim 39, wherein the piston (16) is made of C-Flex® TPE.

42. The system of claim 39, wherein the water-swellable active ingredient composition contains at least 64 mg of NaCl.

43. The system according to claim 39, characterized in that the water-swellable active ingredient composition comprises NaCl, a gelling osmopolymer and granules, and processing aids.

44. The system of claim 39, wherein the water-swellable active ingredient composition comprises additives selected from the group consisting of lubricants, viscosity-modifying agents, and air-displacing additives.

45. The system of claim 44, wherein the air-displacing additive is polyethylene glycol 400.

46. ​​The delivery device of claim 39, wherein the leuprolide composition is leuprolide acetate dissolved in DMSO with a substituted leuprolide content of 37%.

47. The delivery device of claim 39, wherein the delivery device contains 65 mg of leuprolide.

48. The dispensing device of claim 24, wherein the semipermeable plug (24, 26) is made of a polyurethane material with a water absorption of 20%.

49. The dispensing device of claim 39, wherein the back-diffusion control outlet channel (22, 40) is formed of polyethylene and has a helical flow path (34, 36) having a diameter of between 0.003 and 0.020 inches (0.0662 and 0.508 mm) and a length of between 2 and 7 cm.

50. The delivery device of claim 24, characterized in that it is configured to deliver 0.35 μΐ / day of leuprolide composition.

51. An implantable, active agent continuous delivery system for the delivery of leuprolide acetate for one year following subcutaneous implantation, comprising a reservoir, a piston dividing the reservoir into a first chamber and a second chamber, an osmotic motor in the first chamber, an active agent in the second chamber, a semipermeable material in contact with the first chamber, and an outlet port controlling back diffusion in contact with the second chamber, characterized in that the reservoir (12) is made of titanium or a titanium alloy, the piston (16) is made of thermoplastic plastic, the first and second chambers (18, 20) both have open ends, the osmotic motor consists of a compressed NaCl5-based osmotic motor and a PEG additive, the active agent is in the form of 65 mg of leuprolide acetate dissolved in DMSO leuprolide, a semipermeable material in the form of a plug (24) placed in the open end of the first chamber (18) is polyurethane with a water absorption of 20%,the back-diffusion control outlet channel (22) is made of polyethylene and is installed in the open end of the second chamber (20), and the back-diffusion control outlet channel (22) has a helical flow path (34,36), a flow path (34,36) with a delivery capacity of 150 pg of leuprolide acetate / day.,