DE2201533C3 - Osmotic device for the delivery of active agent - Google Patents

Description

65

The invention relates to an osmotic device according to the preamble of the patent

Spruchs The term "active agent" as used here is, includes any drugs, compositions, which in some way affect any biological ensemble. Substances that have nutritional effects or have a stimulating effect, growth-inhibiting substances that inhibit plant growth or control in any way. Substances produced by any organism, for example a human Organism, an animal organism or a lower organism can be assimilated for Nutrition or control of growth, substances that produce any of the above effects and directly on the seat, the close or wider environment of any of the above mentioned organisms applied or applied, and substances that have any other effect on any other place or environment, especially in an aqueous environment.

Therefore, include suitable active agents for use with the delivery device according to the invention those means that are able to

1. not prevent normal and pathological conditions of the living body, mitigate, too treat or cure by destroying a parasitic organism or by limiting the effect of the disease or abnormality by chemically changing the Physiology of the Parasite, and

2. a physiological body or a plant function maintain, improve, enlarge or increase, decrease or increase degrading, limiting or destroying, for example vitamin compositions, sex sterilants, Fertility inhibitors, fertility aids or aids, growth aids and the like, and

3. diagnose a physiological condition or condition, and

4. to control or protect an environment or a living body by attracting it, disabling it, Inhibiting, killing, modifying, repelling or retarding an animal or a microorganism such as food bait or non-food baits, attractants, organic silk, pesticides, algicides, parasiticides, rodenticides, Insecticide, Fungicide and the like, and

5. Maintain or preserve disinfection or sterilization, and

6. To control or influence an environment in general, for example by introducing a Catalysts or metered addition of a reactant to a reacting chemical System, or by causing some chemical process in it such as fermentation, including spread and / or weakening of a microorganism.

The terms nearer surroundings, further surroundings, seat, etc., as used here, denote any promising or prospective location or arrangement for the osmotic Dispensing device according to the invention, or at least for the water-permeable membrane of the dispensing device, which includes enough water for absorption into the device, or enough such water supplies to build up the required osmotic pressure on which their driving force depends. These Designations are implicit in the aforementioned

Definition of the active agent included, an agent which determines its effect in the presence of such closer or further environment or such a seat developed, or a means which his Effect on a distant and / or other Environment developed that need not be watery, as described and illustrated below.

In a known osmotic device of the type mentioned in the introduction ("Rose and Nelson", Australia, I. exp. Biol, 33, pages 415-419, 1955) is the first Space through a partially collapsed flexible one containing the osmotically active solvent Bag formed, whose open Er.de for the passage of water with a disc-shaped permeable cellophane membrane is closed. This structure is inserted in the second room, the is formed by a glass ampoule, the protruding end of the den to form a tight seal The first space-forming bag is folded over the open end of the glass ampoule in such a way that dij is disc-shaped In this way, the membrane is arranged in the open end of the glass ampoule Glass ampoule with the disc-shaped membrane has a water-permeable rigid housing. Furthermore is a Water-containing pouch attached to the glass ampoule so that its open end with the membrane in Connection is so that water penetrate into the bag containing the osmotically active solvent can. The known device has a comparatively complicated structure. In addition, there is in the known device the disadvantage that a device of a different size for each dosage is required

The object of the invention is to implement a device of the type mentioned in the introduction so that at simpler design greater flexibility of the device is obtained.

This object is achieved with the invention as it is protected in claim 1.

In a device according to the invention can within a rigid housing of the same size through Use of bags of different sizes containing the active agent in the first and second spaces be made different sizes, if the containing the osmotically active solvent Space is enlarged, there is an enlarged contact area between the water-permeable housing and the space containing the osmotically active solvent, because an arbitrarily large space Surface of the rigid housing can be made water-permeable. This allows you to choose one water-permeable material from a larger number of such materials of different permeability thereby greater setting options for the osmoic effect and thus for the displacement or delivery of the active agent are given. It can thus with a single device Size different dosages of the active agent can be obtained.

Further features of the invention are protected in further claims.

The invention is explained below with reference to the drawing, for example.

F i g. 1 is a cross-sectional view of an osmotic delivery device according to the invention;

F i g. 2 is a fragmentary perspective view, in partial cross-section, of an intravaginal device; on which the principles of the osmotic delivery device of FIG. 1 are embodied,

Fig.3 is a cross-sectional view of another osmotic delivery device according to the invention,

F i g. 4 is a cross-sectional view of a basic osmotic delivery device according to the invention;

Figure 4a is a top view of the osmotic delivery device of Figure 4. 4,

F i g. 5 is a cross-sectional view of another osmotic delivery device according to the invention;

FIG. 6 is a cross-sectional view of yet another osmotic delivery device according to FIG Invention,

F i g. 7 is a cross-sectional view of yet another osmotic delivery device according to FIG Invention,

Figure 8 is an exploded view of the dispenser of Figure 8. 7,

F i g. Figure 9 is a schematic view of the design and manufacture of yet another osmotic Dispensing device according to the invention, which is referred to as a mini-pump version

According to one embodiment of the invention as shown in FIG. 1 includes an osmotic Dispensing device 10 has a water-permeable housing part or a porous jacket 12, which is advantageous is rigid and comprises a first flexible bag 14 in a substantially parallel configuration relatively impermeable material, and a second bag 16 with moisture controlled Limits permeability. The first flexible pouch 14 contains the vote or formulation 18 of the active agent, preferably in the gel state, paste state or other semi-solid state. Of the second bag 16 contains a solution 20 of an osmotically active solute, the opposite Water shows an osmotic pressure gradient. Initially, the bag 16 advantageously contains one saturated aqueous solution of the solute and excess solid 22. An active agent Release device 24 provides communication from the interior of the pouch 14 to the exterior of the device 10, and in this example the device 24 comprises a narrowing neck in the porous shell 12 and an outlet in the pouch 14 which is concentric at the narrowing neck in the jacket 12 is attached. The bag 16 is of a closed design and is initially in the jacket 12 partially collapsed, and when fully expanded it substantially defines the jacket 12 fills out.

In order to provide the osmotic active agent delivery device of FIG. 1, in which the various pouches in parallel configuration, the device will use when the active agent is on Is a drug or other means of treating, etc., a living organism, either physically used or surgically implanted in the body of the organism, or it is via the Gastrointestinal tract administered. Once in place, the second pouch will stretch 16 due to absorption of water either from body tissue or from body fluid of the porous shell 12 in an effort to achieve osmC'sches equilibrium. If the circumscribed pouch 16 expands, it exerts pressure against the medicament which is circumscribed in the same way, which is contained in the first flexible bag 14.

This pressure is used to read the drug content 18 of the Bag 14 through the line 24 to push out. It is accordingly a gradual and controlled release of the drug or similar agent created directly to the body or the affected organ of the body and for a prolonged period of time. Since about half of the bag) 6 exposure to moisture can obtain relatively fast drug release rates will. In addition, the use of a semi-solid excipient increases the tendency to Release of the drug or any other effective or active agent by leaching and it is made possible to high concentrations of the drug or the like in the device to have.

When the active agent is other than a drug or the like, or when it is for any use other than that intended in a living organism, the device is incorporated into the desired aqueous environment introduced to produce the desired effect, just like that, as would any of the known devices for achieving the same result. And this is generally purely physical, e.g., by placing a pesticide containing device in a river or stream or placing a containing a catalyst Device in an aqueous reaction medium.

If desired, the long flexible polyethylene hose or the like. To the outside of the Device can be extended from the interior of the bag 14 by the means provided by the constricting The neck of the jacket 12 and the outlet of the bag 14 (see FIG. 3) are formed Device can be arranged at a location away from the desired application site and her Content of active agents can nevertheless be released directly to the desired location through the hose will. This enables the dispenser to be placed in an aqueous environment and released active agent in another environment that need not be watery.

In Fig. Fig. 2 is an intravaginal device 30 which is ring-shaped, shown, which in its structure essentially corresponds to the device according to FIG. 1 corresponds

The bag 14 (FIG. 2) is provided with channel-like fine points at a distance from one another tubular or tubular connections provided through the outer jacket 12 to release the Medicament 18, and these connections are in the drawing as release openings 24 shown. For example, these fine tube connections may take the form of a plurality of hard ones Have capillary nipples on the bag 14 which extend through the jacket 12.

The embodiment according to FIG. 2 is used by placing it around the cervix under Using conventional techniques to place a cervical ring and, once the device is in her position is, she gives the drug or a mixture of drugs in close or precise terms directed constant amount or speed. Accordingly, it can be seen that, in terms of the mechanism, the Embodiment according to Figure 2 of the osmotic Dispensing device according to FIG. 1 is functionally equivalent.

It can also be seen that. while in FIG. FIG. 2 shows an inteavaginal delivery device based on FIG the principle of the osmotic delivery device according to FIG. 1 is based on the aforementioned principle of The invention can also be applied, for example, to a device which is of such a size Its weight and shape meant that it was held in the first stomach of animals with multiple stomachs can be used to deliver drugs or the like in a carefully controlled amount. One

The device of Figure 1 is admirably suited for the continuous administration of antibiotic oxytetracycline to cattle from the stomach. Other variations on the principle will be readily apparent to those skilled in the art. Although particular configurations can be designed for particular body applications, each of these configurations is applicable in different environments.
In Fig. 3, there is shown another osmotic delivery device 40 for the delivery of active agents similar to the device of FIG. 1 is similar with the exception that instead of the more or less parallel arrangement of two separate bags there is a concentric configuration. Such a concentric configuration is more efficient and easier to manufacture. In the embodiment according to FIG. 3 is an inner first flexible pouch 14 of relatively impermeable material containing the active agent 18 (or active agent) either as a solution, concentrated solution or, preferably, as a semi-solid gel, semi-solid paste or semi-solid cream, the active agent being suspended therein or The bag 14 is arranged in a second bag 16, which has moisture-controlled permeability, and the annular space between the bags 14, 16 is filled with the solution 20 of the osmotically active dissolved substance around the required osmotic pressure gradient or the pressure differential to accomplish. This material, which must be non-toxic when used for drugs or similar agents, is preferably present partly as an aqueous solution and partly as a solid 22. It can be seen that in use, as water is absorbed from the external aqueous environment through the porous jacket and into the annulus, the contents of the pouch 14 will be forced to the outside of the device via a long plastic tube 24 which increases in length is directly proportional to the reduction in the above-mentioned leaching effect

so in certain cases the device does not have sufficient specific gravity to hold the arrangement maintain in the desired place. In these cases, a weight or Ballast can be arranged. For this purpose you can use iron parts, iron ore parts, brass parts or ceramic parts be used. When used in beef stomachs, the weight should be sufficient such that one effective specific gravity of more than 13 is created

Optionally, a separator made of porous paper, fabric or the like can be placed between the porous outer housing and the bag constituting the semipermeable membrane. This prevents the The membrane is perforated or drawn into too tight contact with the housing, whereby it is ensured that the entire membrane is exposed to the aqueous environment

The impermeable bag 14 of the osmotic

Dispensing device according to the figures containing the composition of the active agent should be in essentially impermeable to both water and other elements of the environment in which a device of this type should be arranged. Furthermore, the pouch should be exposed to the osmotically active solute and impermeable to the components of the composition of the active agent. Typical materials for use for the impermeable pouch 14 include polyethylene, polyethylene terephthalate, plasticized polyvinyl chloride, laminates of metal foil and polyethylene, neoprene rubber, more natural Rubber and rubber hydrochloride. These materials are also flexible, insoluble and with the 1 ■ -, chemically compatible active agent to be included, and in the case of the creation of a medicinal product deput or the like. In the body of a living organism, they are biologically inert and do not interfere with the body tissues and not allergenic.

The membrane or the second bag 16 can be formed from a wide variety of materials which are permeable or semi-permeable to solvents (water), but are not permeable to the solute, that is, the materials can be used which are suitable for the Execution of an osmotic cell are suitable. For best results, the membrane should be substantially impermeable to the passage of the osmotically active solute to prevent loss of solute. Typical membranes are isotropic membranes such as membranes made of non-plasticized cellulose acetate, plasticized cellulose acetate, reinforced cellulose acetate, cellulose diacetate, cellulose triacetate, ethyl cellulose, and anisotropic membranes for reverse osmosis, which are typically made of cellulose acetate, silicone rubber, polyurethane, polyurethane Acetate copolymers are formed. Isotropic membranes have lower water permeability than anisotropic membranes. Furthermore, in both types of membrane, the increase in the acetate content of the cellulose acetate polymer leads to a reduction in the water permeability. In a particular embodiment, the membrane used consisted of an isotropic cellulose acetate without plasticizer with an acetate substitution of 2.4 with a thickness of 76 μΐη, against a saturated solution of magnesium sulfate at a temperature of 39 ° C water in an amount of 70 mg / cm ² each Day passed. These membranes are also insoluble and chemically compatible with the saline solution and the excess material in it and with the material in the annular space between the two bags (FIG. 3).

For drug depot applications as described above, these membranes are also biological inert, they do not interfere with the tissues of the body and they do not cause allergies. For devices that do this are intended to dispense active funds relatively quickly during a limited period of time, membranes with controlled high water permeability are specified. Membranes with low Water permeabilities are used to deliver more slowly and for longer periods of time. 6s At least in the embodiment according to FIG. 1, at which mechanical force due to expansion of the Bag 16 should be used Membrane at least to such an extent be pliable to allow for such expansion and transmission of such mechanical forces is. This is the case in the embodiment according to FIG. 3 not necessary, but acceptable. For example, the Bag 16 can be designed at least partially with the porous jacket 12 as a layer structure.

The porous housing is also insoluble and can be made of perforated polystyrene, perforated polyethylene, perforated polypropylene, perforated polyvinylchloride, perforated polymethyl methacrylate, etc., perforated metal sheet, for example made of aluminum, Copper, steel, etc.), perforated galvanized tube, perforated reinforced epoxy resin, metal sieve, sintered measuring tube, porous styrene / acrylonitrile copolymer, porous sintered polyethylene or the like. be educated. It is not intended that the porous housing or pump body act as a barrier to the Transport of water works. For drug depot applications, the jacket is again biologically inert, does not disturb the tissues of the body and does not cause allergies. In the embodiment according to FIG. 2 the annular jacket 12 is advantageously made of porous hard plastic material, preferably with smooth exterior finish to reduce irritation. It can be seen that the porous housing or the jacket need only be rigid to such an extent or otherwise maintain its shape by sufficient containment is created for the two bags, such that when the volume of a bag increases, the required corresponding pressure or the required corresponding force for ejection or forcing out the active agent is transferred to or generated on the other bag. It can further be seen in this way that it is within the scope of the invention to provide an osmotic delivery device that does not include the housing portion has, as long as the bags are designed and physically arranged relative to one another that the the aforementioned pressure generation and pressure transmission is enabled, for example, its shape holding balloon can be present, which by means of a flexible membrane into two bags or spaces is divided. In this embodiment, the active agent-containing half of the balloon would with a suitable dispensing head, and the other half would be the osmotically effective solution Of fabric and it would be made at least in part from semi-permeable materials.

Many other materials including those that are biologically acceptable are suitable for manufacture of the various parts of the device according to the invention suitable While the various parts the device according to the invention are described above so that they under the conditions and in the environment of the intended use are insoluble, it is further within the scope of the invention that such materials are insoluble only during the period of intended use after which they become dissolve in the vicinity of the device. Accordingly, the invention provides a dispensing device includes those who remain unaffected by their environment d. H. is not solvable at the point of use or those during the period of intended use is only slightly solvable such that when the content is on Once the active agent has been released, the device dissolves or erodes so that there is no objectionable residue or empty container at the point of use

remains.

It is also within the scope of the invention, optionally, the dispensing device with a closed Water supply or to be provided with a separate water space, as described in the introductory part mentioned publication is described, in addition.

The relative thickness of the various membranes which make up the various bags according to the invention include, and also the relative thickness of the porous shell can vary widely and they does not constitute a limitation of the invention. Typically, however, the one containing the active agent has a flexible one Bag has a wall thickness of 0.0127 to 1.27 mm, and the water-permeable membrane bag has a wall thickness from 0.0254 to 0.254 mm.

A special embodiment of a dispenser, according to the design according to FIG. 1, and the one with a flexible pouch 14 for the active agent having a wall thickness of 2 mils and a semipermeable membrane bag 16 one Wall thickness of 0.0762 mm is provided, both in a porous copper jacket 12 with a density of at least 2.77 have the following dimensions and properties:

outer diameter

of the device 2.7 cm

Wall thickness

of the porous jacket 0.2 cm

Inside diameter

of the porous jacket 2.3 cm

Total length 6.5 cm

External volume 37.2 cm

Internal volume 25.3 cm

Overall device density 1.75

Available membrane area 44.1cm ²

Active agent volume 20.2 cm ³

Active agent density 1 2

Active agent:

about 60% tetracycline hydrochloride dispersed in 40% cocoa butter medium,

Osmotic solution:

Saturated aqueous solution of K ₂ SO *, which contained sufficient excess solvent in solid form to keep the solution saturated for at least three days.

Water-permeable membrane:

Cellulose diacetate with a degree of acetyl substitution of 2.4,

Bag for the active agent:
Polyethylene.

Such a device is capable of delivering 5 mg of the active drug per day over and above a period of three days when administered to the stomach of a calf weighing approximately 230 kg, the The device has aged back through the gastrointestinal tract

In another embodiment of the invention, as shown in FIG. 4, includes an osmotic Dispensing device 10 comprises a rigid canister 12 in which at least some of the wall parts are the same Controlled permeability to water shows as fully described below. In the Canister 12 is housed in a flexible pouch 14 of relatively impermeable material. The flexible one Bag 14 contains a formulation or formulation 18 of an active agent, preferably a drug, preferably in a gel, paste, or other semi-solid state (although a solution or concentrated solution of the active agent is sometimes sufficient), and the active agent will if there is one Medicinal product is preferably usually carried in an oil phase, for example in cocoa butter. That Volume of the canister 12, which of the bag 14 and its contents 18 of active agent is not

ίο is taken, of a solution 20 is one osmotically active solvent taken, which compared to water an osmotic pressure gradient shows. The open end of the canister 12 is sealed with a rigid impermeable Dispensing head, dispensing plug or with a dispensing cap 26, the open end of the flexible pouch 14 is fastened concentrically in between (see also Fig. 4a). This way there is a tight barrier between and below the active agent phase 18 in the flexible pouch 14, the osmotic medium 18 in the canister 12 and the external environment of the device 10. Without this density Lockdown could result in undesirable contamination. The dispensing head 26 is preferably with Snap fit or press fit in place with the flexible pouch 14 either already on the periphery is fixedly attached thereto or to the upper inner periphery of the canister 12. Alternatively, can these three elements are conveniently heat sealed together and, as a support to maintain the fixed or tight barrier, a retaining ring 28 provided with a chamfer or bevel can be used made of polycarbonate, optionally with a press fit around the top of the device 10. the Device 24 for releasing the active agent provides communication from the interior of the flexible pouch 14 to the Outside of the device 10, and in this example the device 24 is a capillary channel or a Capillary opening drilled into the dispensing head 26

• »o The channel advantageously has a diameter of approximately 1.59 mm.

To use the osmotic active agent delivery device of FIG. 4, the device will when the active agent is a drug or other agent for treating, etc., a living Is surgically implanted in the body of the organism or it is via the organism Gastrointestinal tract administered Here will be the description of the usage of the embodiment according to FIG. 1 referenced. Once the device is in position, the Body tissue or from body fluids absorbed water into the device being the volume of the Solution 20 is enlarged and corresponding pressure is exerted against the delimited flexible bag 14, the the drug composition 18 contains This pressure is used to display the drug content 18 of the sachet 14 to press through the line 24 in an osmotically controlled and constant amount into the external environment.

Accordingly, there is gradual and controlled constant delivery of the drug or similar agent directly to the body or the affected body organ gan created over an extended period of time. Furthermore, through the use of any semi-solid excipient the attempt to release the drug or any other active agent for this, reduced by leaching and it is made possible that high concentrations of the

22 Ol 533

Means can be present in the device.

The design of the canister 12 is such that a given area of the wall parts forming the canister Permeability to water in an osmotically controlled amount from the outer surfaces to his Interior shows. The canister 12 is therefore either a unit or an assembled version, and it advantageously comprises a semi-permeable membrane which is either a unitary wall portion of the canister or a liner of the canister or which in some way as a layer on the canister is formed or otherwise in the desired functional position or in the desired functional Ratio is arranged.

5, an osmotic active agent delivery device 10 is shown in which the canister 12 a rigid, impermeable, cylindrical one. Plastic sidewall part 30 and a bottom wall part 32 integrally connected therewith. In the bottom wall 32 A plurality of openings or channels 34 are drilled, each preferably of a diameter of about 1.58 mm. It can thus be seen that only the bottom wall 32 of the canister 12, which in large Extent is porous, is able to admit water into the device, and the cylindrical side wall portion 30 remains impenetrable for water. Above or at the top of the perforated bottom wall part 32 a flat membrane disk 36 is securely attached and supported, the water-controlled permeability The membrane 36 can for example be glued in place or it can be used as a Liner can be formed or attached as a layer or it can be made from solution at the top or over the side wall part 32 be cast. The aforesaid casting of the porous wall 32 is thereby made advantageous perfect that the film or the disk is made of a solution of membrane-forming material in one Solvent is deposited, for example a 20% solution of cellulose acetate in a mixed Solvent from acetone, ethanol ethyl and lactate in proportions 65%, 20% and 15% respectively. When pouring the Care should be taken to ensure that the pores of the wall portion 32 are not clogged with the foil. It is of course intended that the seal between membrane 36 and the porous wall 32 is waterproof. such that water gets into the interior of the The device can only occur in that it diffuses through the membrane 36 by means of osmosis. As furthermore, it is also possible that the membrane 36 is on the underside of the bottom wall part 32 is attached The design according to FIG. 5 is also novel in that it is relative to the overall dimensions of the canister requires a membrane with limited area. This results from the convenience Availability of large-scale water-permeable cellulose acetate membranes designed to do so are to be used in reverse osmosis processes for water desalination. These membranes, which are typically and preferably anisotropic membranes are highly permeable to water (allow water to pass through at relatively high velocities) but they are opposite Salt relatively impermeable, so that their use in devices with relatively small exposed surfaces allows water to migrate into the dispenser only at the point of exposure the membrane 36 to the outside environment via the channels 34.

Optionally, in a modified embodiment of the invention, a porous paper, fabric or the like. The separator formed is expediently arranged between the bottom wall part 32 and the membrane 36 will. This prevents perforating the membrane or pulling the membrane too tight Contact with canister 12, thereby ensuring that the entire membrane is in an aqueous environment is exposed. The one specified immediately before

ίο Modification can also be made in accordance with a device Fig. 6 can be applied. The Use of the porous separator in the aforementioned embodiment, in which the membrane from Solution is poured, the casting of the membrane, because it forms a receptive mold or pouring surface, there is no risk of the openings 34 becoming clogged or clogged.

In Figure 6, an osmotic device 10 for the delivery of active agents is shown, which has a larger provides the available exposed area of the membrane 36, being taken advantage of in this design it becomes apparent that a much larger number of membranes are available than the semi-permeable anisotropic ones Cellulose acetate membranes of the kind used in

.'5 of water desalination by means of reverse osmosis can be used. In this embodiment it is the rigid impermeable cylindrical plastic side wall part! 30, which is provided with the plurality of openings or channels 34, which in turn each preferably have a diameter of about 1.58 mm. It is also this perforated wall 30 which, as shown in FIG. 5 is sealed to the membrane 36, and in this example the membrane is cylindrical in shape. Many modified designs, which in the embodiment lie between the embodiments according to FIG. 5 and according to FIG. 6, as far as the available exposed membrane surface is concerned, are of course within the scope of the invention.
Again, in some cases, the dispensing devices shown in FIGS. 4 to 6 insufficient specific gravity to hold the device in the desired location. For example, when used in the stomach of animals with multiple stomachs, the weight should be large enough to create a specific weight of at least 1.5. In cases of insufficient specific weight, a weight or ballast can therefore be arranged in the device, for example a steel ball 38, as shown in FIG. 6. Other suitable ones

so weights include iron parts, iron ore parts, brass parts, ceramic parts or the like.

If the active agent is not a drug or similar agent! is or if it is not for one living organism are used so'l, the device according to Figure 4 to 6 is also in the desired aqueous environment introduced to produce the desired effect, just as it was at would be any of the known means of achieving the same result. This is general only a physical insertion, for example a device containing a pesticide in a Flow or stream is arranged, or a device containing a catalyst into an aqueous Reaction medium is used.

If desired, the long bendable one can be used OddgL polyethylene hose also from the dispensing head of the device according to FIGS. 4,5 and 6 be extended. In this way, the device

device can be arranged at a location remote from the desired application position, and it your active agent can nevertheless be delivered through the delivery head and then through the hose directly to the application control. This enables the dispensing device to be arranged in an aqueous one Environment and release of the active agent into another environment that need not be watery Dispensing head can also be provided with a check valve, such as a one-way ball valve, to prevent reflux of active agent or other material from the external environment into the device.

Furthermore, a device according to FIG. 4, 5 or Fig.6 admirably suited for continuous administration of oxytetracycline antibiotic to cattle from the bovine stomach. This gives because these devices are made with a size, a weight, and a shape that they can be retained in the stomach of multiple stomachs having animals, to deliver a drug or similar agent in carefully controlled amounts. Other Modifications to the basic principle are readily apparent to those skilled in the art. Though special Designs for specific body applications can be made, each of these designs is for Suitable for use in other environments

The membrane 36 according to FIGS. 5 and 6, and the part of the wall parts forming the canister 12 according to FIG. 4, which shows permeability controlled by water, can, like the bag 16 according to FIG. 1 can be formed from a wide variety of materials that are permeable or semi-permeable to solvents (water), but which are not permeable to solute or solvent. That is, the materials suitable for making an osmotic cell can be used. For best results, the membrane should be substantially impermeable to the passage of the osmotically active solute to prevent loss of that material. Typical membranes are isotropic membranes such as membranes made of unplasticized cellulose acetate, plasticized cellulose acetate, reinforced cellulose acetate, cellulose diacetate, cellulose triacetate, ethyl cellulose, anisotropic membranes for reverse osmosis, which are typically made of cellulose acetate, natural rubber, natural rubber, silicone-based rubber, polyurethane. Isotropic membranes have lower water permeability than anisotropic membranes. Furthermore, in both types of membrane, when the acetate content of the cellulose acetate polymer is increased, the water permeability is reduced. Since, as previously described, the surface of the membrane is relatively limited in a device according to FIG. Accordingly, anisotropic membranes are preferred in such embodiments. A cellulose acetate membrane that is suitable for this limited area is a membrane that has a nominal capacity of 1.5 to 2 cmVcm ² and day at atmospheric pressure for permeability against a saturated solution of K2SO4 at 39 ° C. A special example of the design according to FIG. 5 with a dispensing head Polymethyl methacrylate and with an internal diameter of 1.9 cm can ^{release 4 to 6 cm 3 of} an active agent, advantageously a drug, per day. In a special embodiment of a dispensing device of the type shown in FIG. 6, the membrane used was formed from isotropic cellulose acetate without plasticizers and with an acetate substitution of 2.4 and a thickness of 0.0762 mm, with 70 mg per cm ^{2 of} water per day a saturated one Magnesium sulfate solution at 39 ° C allowed through became. The membranes are also insoluble and chemically compatible with the saline solution and any excess solvent therein. For drug depot applications as described above, if the membranes are also biologically inert, they do not irritate the body tissues and do not cause allergies. For Devices designed to release active agents relatively quickly for a limited period of time release, membranes are controlled with large size Permeability to water indicated. Membranes with low water permeability are used to dispense more slowly during longer periods of time. The impermeable bag 14 of the osmotic Dispensing devices according to FIGS. 4 to 6 who the Composition of the active agent containing it should also be compared to water and the other elements of the environment in which a device of this type is placed should be arranged opposite the osmotic effective solvent and components of the active agent composition must be impermeable. Typical materials for use as an impermeable bag include polyethylene, polyethylene terephthalate ("Mylar"), plasticized polyvinyl chloride,

3 ^r i Laminate made of metal foil and polyethylene, neoprene rubber, natural rubber rubber, and rubber hydrochloride. Additionally, these materials are pliable, insoluble, and chemically compatible with the active agent therein, and in the case of the Creation of a drug or similar depot in the body of a living organism if they are biologically inert, they do not irritate the body tissues and do not cause allergies. The impermeable plastic canister 12 according to FIGS Fig. 5 and 6 and the impermeable parts of the Canister 12 according to FIG. 4 are also insoluble and can be formed from polystyrene, polyethylene, Polypropylene, polyvinyl chloride, reinforced epoxy resin, polymethyl methacrylate, etc., sheet metal (e.g. se made of aluminum, copper, steel etc.), galvanized Pipe, or made of a styrene / acrylonitrile copolymer, it is of course intended that such a Housing or such a jacket acts as a barrier for the transport of water with the exception of the perforated surfaces. Again, for drug depot applications, these materials are advantageously biologically inert, non-irritating and non-irritating to body tissues do not generate allergies. The dispensing head 26 and retaining ring 28 may be formed from materials that are identical to the materials used to make the canisters 12, Polycarbonai is also well suited for the ring 28 of the aforementioned materials are impermeable or heat-resistant plastics are particularly preferred.

hi Lots of other materials including those that are biologically acceptable, are for the manufacture of the various parts of the devices according to the F i g. 4 to 6 suitable. While the different parts

the device according to the invention above as below the conditions and in the environment of the intended use are described inextricably, it lies furthermore within the scope of the invention that such materials only during the period of the intended Use are insoluble, so that they can then dissolve in the vicinity of the device. Accordingly, a dispensing device is also of the invention includes, which is unaffected with respect to the solvability at the point of use by its environment, or which is only slightly solvable during the period of intended use such that once the Content has been released to active means, it dissolves or erodes and there is no objectionable residue or leaves an empty container at the point of use.

It is also within the scope of the invention to optionally use the dispensing device according to FIGS. 4, 5 and 6 to provide a closed water supply or a separate water space, as in FIG literature mentioned in the introduction is described

The relative thickness of the various membranes of the Devices according to FIGS. 4 to 6 and the relative thickness of the various canisters can be found in They vary widely and are not intended to limit the invention. Typically, however, each has Canisters have a wall thickness of about 0.0127 to 1.27 mm, preferably 0.127 to 1.27 mm, and the water-permeable membranes have a wall thickness of about 0.0254 to about 0.254 mm.

A particular embodiment of a dispensing device made according to the invention and shown in FIG the F i g. 7 and 8 is made, and with a semipermeable membrane 36 a thickness of 0.0762 mm and with a flexible pouch 14 for active material with a thickness of about 0.0508 mm has the following dimensions and properties:

outer diameter 28.575 mm the dispenser 3.175 mm Wall thickness of the canister 12 Inside diameter 22.22 mm the dispenser 63.5 mm overall length 4.04 cm3 External volume 2.04 cm * Internal volume 1.5 Overall device density 2.84 cm * Available membrane area 15.5 cm * Active agent volume 1.2 Density of the active agent

Canister 12: soft Polyethylene Threaded end cap 32: soft Polyethylene

Dispensing cap 26:

Bag 14

for the active agent:

Beveled ring 28: Membrane support 40: diameter

of the delivery opening 24:

Diameter of the openings

in cap 32:

Diameter of the openings

in carrier 40:

Active agent:

about 60% tetracycline hydrochloride dispersed in 40% polyethylene glycol medium,

Osmotic solution:

saturated aqueous solution of K2SO4 containing sufficient excess of solvent in solid form to keep the solution saturated for a period of at least three days,

Water-permeable membrane:

Cellulose diacetate with a degree of acetyl substitution of 2.4,

soft polyethylene,

Polyethylene, Polycarbonate, Polystyrene

about 1.59 mm about 1.59 mm 3.175 mm

Such a device is capable of delivering 5 mg of the active daily for a period of three days To dispense drug when introduced into the stomach of a calf weighing about 230 kg is where it is retained by the gastrointestinal tract. It should be noted that the design of the Device according to FIGS. 7 and 8 is very similar to the design of the device according to FIG most pronounced differences between them in the device according to FIGS. 7 and 8 in execution of the perforated end cap 32 screwed onto the canister 12 and covered with a rubber existing O-ring 42 is provided to prevent leakage at the point of thread fit. The cap 32 accommodates the membrane 36 and a membrane carrier 40. Of course, the larger the free space or the larger the total open area of the plurality of channels drilled in the end cap 32, the greater the The portion or extent of membrane 36 that is exposed to the aqueous environment. In similarly, water diffuses more easily into the space 24, the larger the open area of the plurality of in that Membrane support 40 drilled channels is. As in the case of the embodiment according to FIGS. 5 and 6 can turn Optionally, a separator made of porous paper, fabric or the like. Between the membrane support 40 and the End cap 32 and / or the semi-permeable membrane 36 or between the two. The membrane is thereby, as mentioned above, against perforation or against pulling into too firm contact with her Housing protected, which also ensures that the entire membrane of the aqueous environment is exposed.

In yet another embodiment according to the invention, hereinafter referred to as a mini-pump and shown schematically in Figure 9, a modular or modular osmotic active agent delivery device is embodied in conceptually the devices according to FIGS. 4 to 6 is similar. For the manufacture of the drug pouch for the Minipump according to the bag 14 according to FIG. 4, the raw materials are first selected from thin-walled polyethylene tube of a size in accordance with the required volume of drug, two identical made of polyethylene Dispensing and filling hoses (each of which, for example, have an outside diameter of about 1.09 mm and a Has an inner diameter of about 0.381 mm and consists of, for example, a needle cleaner or wire cleaner a dimension of about 0.254 mm exist. Reference is made here to step I according to FIG. as next, as shown in FIG. 9 shown as step II, the wire is arranged in the tubes made of polyethylene and the resulting embodiment is placed in the medicament pouch as shown. the

Dispensing and filling tubes are then heat-sealed to each end of the polyethylene tube of the larger drug sachet, and the Drug sachet is filled with the drug composition, either in solution form or in another form. An added overflow hose catches the displaced working fluid composition and holds it back when the lower end of the Device is closed. The overflow hose is then removed and the dispensing hose is connected closed to its end. The final manufacture of the drug sachet is shown in step IV, according to which the filling hose is removed by severing, the various seals or Terminations are trimmed to minimize their size and according to which the dispensing tube is roughened with sandpaper. At this point in time during the work process, the medicament pool containing the medicament composition is expediently pressure-tested by simply pressing or To squeeze.

The mini pump design is finally completed by the work steps according to steps V to VII according to Figure 9. The first step is salt containment; H. a form not shown is with filled with a gelatine-salt matrix ("salt" here means any osmotically active solvent according to following description meant), according to which the previously manufactured drug sachet in the form is arranged and these compressed by any convenient means not shown using a typical C-clamp, for example. After that, the mold, the bag and the Frozen gelatin salt matrix. Half of the mold is then removed and the one containing the pump Half is dried in an oven overnight. For this, refer to step V with regard to the appearance referenced the mini pump after the enclosure. Alternatively, see step VI, the one with salt enclosed drug sachets can be coated with a thin layer of gelatin by simply dipping the sachet in a gelatin solution and by drying the coating until it hardens to form a smooth surface for the membrane to cover. Zugsvorgang according to step VII is more susceptible Im Step VII, the execution of the mini-pump is completed by covering the structure according to FIG Step V or step VI with a layer of membrane material of the type described above. For example, such structures can expediently be coated by simply immersing them in, for example, a cellulose acetate solution, with an hour passing between successive immersions is left, after which the membrane-coated version for about 48 hours is dried. The membrane coating is sufficiently rigid and is such that when water from a external aqueous environment passes through the permeable membrane coating and by osmoue in the salt migrates, so that an osmotically effective solution is formed therewith, which the appearance of the Osmosis is the result of an effort towards osmotic equilibrium with the environment that initiates Membrane coating is able to withstand this increase in volume in the mini pump, so that at the same time a mechanical evacuation force is generated which acts on the flexible medicament pouch acts and in turn the active means from the Dispenser, pushes or ejects, namely for a prolonged period of time in an osmotically controlled amount.

The device according to FIG. 9 is exactly the same used like the dispensing devices previously described, with the added benefit of small size can be obtained (the representations according to FIG. 9 are approximately twice as large as the actual size). For example, the free end of the dispensing loop ches appropriately cut off with a scalpel and placed, implanted, or administered in the delivery environment. The pump then gives their contents completely. The different materials that make up the mini pump correspond

is further essentially the materials, including equivalent and corresponding components, the are used in the osmotic delivery devices previously described. To keep the solution saturated and therefore to achieve constant osmotic pressure while the dispenser is operating, contain the The membrane, bag or canister containing the solution also contains excess solvent in solid form. Various osmotically effective Solvents can be used. These include magnesium chloride, magnesium sulfate, sodium, Chloride, potassium sulfate, sodium carbonate, sodium sulfide, sodium sulfate, sodium bicarbonate, potassium phthalic acid, calcium bicarbonate, potassium phosphate acid, raffinate se, tartaric acid, succinic acid, calcium succinate, calcium lactate and magnesium succinate The excess Solid solvent can be in the form of dispersed particles or, preferably, in the form of a pellet be. The solution can initially «.! Ne solution from the the same or a different osmotically effective solvent than the solid excess solvent be.

The osmotic delivery device can be in any convenient shape for either physical For introduction or implantation in the body or for administration via the gastrointestinal tract, or for Introduction to any desired environment. The dimensions of any Device can accordingly be to a large extent change and they are not of controlling importance. The lower limit of the size of the device is determined by the amount of the particular active agent that should be released to the environment in order to evoke the desired response and also through

so the form of the dosage unit, for example in cases special body applications in the form of an implantation, a spherical body, in intrauterus applications, intravaginal applications a vaginal ring, a Uterine capsule for fertility suppression, a artificial footbridge or an artificial bridge, one

Prosthesis, a pessary, a suppository and the like. The same applies to the upper limit of the size

the device.

In a particular embodiment, the

Dispensers are sized to dispense 1 to 2 cm ^{3 of} the drug composition per day and to dispense a total of 5 to 10 cm ^{3 of} the drug composition over a period of 5 to 10 days. at Alternative selection of membranes with lower permeability can pump the drug more slowly in a period of up to a year and over a period Year given out. It is preferred that the

Execution of the delivery device and the device releasing the active agent is such that the osmotic drive pressure that is developed, at least ten times greater than the back pressure created by the active agent composition

The invention thus provides a reliable device in an osmotic delivery device that effective concentration of active agent or active agent contained in it to release the body of a living organism, or to release to i.-gene of another environment

to an osmotically controlled extent and for an extended period of time. Additionally The primary advantages of any dispensing device according to the invention are that they are simpler Execution is various and all the practical advantages of long-term continuous administration active means in humans, animals and in other surroundings shows and that in it active agent contained does not show a tendency to be leached from the device.

For this purpose 4 sheets of drawings

Claims (8)

Patent claims: 1. Osmotic device for the delivery of active agent, a) with a first space, which has a water-controlled permeability and a Contains osmotically active solvent, which, when it is in solution, is opposite Water shows an osmotic pressure gradient, b) with a second space made of relatively impermeable material and a contains active agent and with means for releasing the active agent for The outside of the dispenser is provided, c) wherein the first and second spaces are rigid within a common water-permeable Housing are arranged and d) are arranged physically relative to one another in such a way that when the volume of the first Space through absorption of water, the volume of the second space is reduced with the release of active agents, and so that active agents for a prolonged period of time and in an osmotically controlled manner Amount is continuously pressed out of the device, characterized in that the second space containing the active agent (18) consists of a flexible bag (14) is formed 2. Apparatus according to claim 1, characterized in that the first space has a shape retaining chamber and the flexible bag (14) is disposed within this chamber 3. Apparatus according to claim 1, characterized in that the free space containing a solution (20) contains an osmotically active solvent, a second bag (16) with opposite water controlled permeability is. 4. Apparatus according to claim 3, characterized in that the two spaces or bags (14, 16) are arranged in a parallel configuration. 5. Device according to one of claims 1 to 3, characterized in that the bag (14) which the contains active means (18), is arranged within the bag (16). 6. Apparatus according to claim 5, characterized in that the osmotically active solvent (20) is in the form of a layer comprising the flexible one containing the active agent (18) Bag (14) encloses. 7. Apparatus according to claim 6, characterized in that the osmotically active solvent (20) contains gelatin and that the layer formed from it with that containing the active agent (18) flexible bag (14) is in contact. 8. Apparatus according to claim 6 or 7, characterized in that the delimiting the first space Wall closely surrounds said solvent layer on its outside.