DE2201533A1 - Osmotic device for the application of active agents - Google Patents

Description

Hamburg 50 - Königstrasse 28
W.25113 / 72 12 / Sch "January 1972

ALZA Corporation
Palo Alto, Calif. (V.St.A.)

Osmotic device for the delivery of active

Means.

The invention relates to osmotic delivery devices and in particular to an osmotic delivery device which is of simple construction and which Concentrations of active agent for an extended period of time at an osmotically controlled level or can release to their external environment in an osmotically controlled amount.

The term "active agent" as used herein is, includes any drugs, compositions, which in any way affect any biological ensemble, substances, nutritional or stimulatory Have effect, growth-inhibiting substances that inhibit plant growth or in some way control substances produced by any organism, for example a human organism, an animal Organism or a lower organism are assimilated for nutrition or control of growth, substances, that produce any of the above effects and directly at the seat, the narrow of the anterior ones Environment of any of the above organisms or has been applied, and substances that have any other effect on any aaderö-n 3belle or

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Environment, especially in an aqueous environment.

Thus, without limitation, suitable active agents for use with the delivery device according to FIG the invention those means that are able to

1. non-normal and pathological conditions of the living body to prevent, mitigate, treat or to cure by destroying a parasitic organism or by limiting it the effect of the disease or abnormality by chemically changing the physiology of the parasite, and

2. To maintain, improve, and enlarge a physiological body or a plant function or to increase, decrease or decrease, limit or destroy, 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 an environment or a living body or protect by attracting, disabling, inhibiting, killing, modifying, pushing back or retarding an animal or a microorganism »like Food bait or non-food bait, attractants, biocides, pesticides, algicides, parasiticides, Rodenticide, 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 catalyst or metered addition of a reactant into a reactive chemical system, or by evoking any chemical

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Process in it such as fermentation, including Spread and / or weakening of a microorganism Headquarters, etc., as used here, refer to any promising or prospective position or arrangement for the osmotic delivery device according to the invention, or at least fib: the water-permeable Membrane of the dispensing device that contains or contains enough water for absorption into the device supplies enough such water to build up the osmotic pressure required, from which its driving force depends. These terms are implicit in the above definition of active agent, one Means, which its effect in the presence of such a near or further environment or such Sitzes developed, odor a means, we3.chcs its effect evolved in a remote and / or other environment that need not be watery, such as ec below is described and illustrated.

Many and varied compositions, products, conditions, depositors, ablators, dispensing devices. Injectors and other devices are known in the art in which the timed or spaced Administration or absorption of an active agent by structure or physical arrangement or design of elements is regulated in such a way that a single administration is gradual but continuous or provides prolonged delivery of the active agent to a system through slow or differential release. All however, such known devices and the like are characterized by at least one feature, which controlling the rate of the extended or differential release is detrimental affects or diminishes the practical benefits, long-term continuous administration accompanied by various active agents in humans, animals and in other environments.

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An osmotic delivery device is also proposed which can deliver the drug solution at a relatively constant rate. This is done referred au.? Rose and Nelson, Austral. J exp. Biol * » 53, pages 415 to 420 (1955) · The one described there Injector consists of three compartments or compartments or subdivisions and a clamp to a semi-permeable ode: o to hold semi-permeable membrane. The driving force of the injector depends on the osrnotic Pressure built up or developed by a saturated aqueous congo red lion against water. These Solution is contained in a partially collapsed rubber compartment or chamber, and they is separated from a second water chamber by the semi-permeable cellophane membrane · The partially collapsed The pouch is placed in a glass ampoule and the drug compartment of the device is across the compartment between the congo red sachet and the glass ampoule. The ampoule is also provided with a drug release device, and if so, the drug chamber is filled with a drug solution, water moves into the Congo red solution by means of osmosis, causing the rubber chamber expanded and the mechanical force is created to expel or deliver the drug from the device.

However, there are considerable drawbacks with this known device, one of which is major Have prevented use in the medical field. First, allows the use of a solution as a drug carrier does not indicate the use of a high concentration drug, and such solutions show the adverse or detrimental tendency to be released from the device by simple leaching. In addition, many chemical substances undergo chemical deterioration upon prolonged storage in a dissolved state. The well-known injector is still cumbersome and unwieldy because it is used for development; his drive

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Iat relying on a separate water chamber and not on its surroundings · In addition, the known injector is essentially only a research and development Examination device, which is of complex design and, at least according to the description, on a Congo ^ ot solution is limited to the generation of the osraotiachen propulsive force, as well as one made of oellophane; osmoticche Membrane. For this purpose, reference is made in particular to pages 4-11 to 414 of the literature cited above.

Accordingly, one of the main purposes of the invention is to to provide an osmotic delivery device made by simple execution and which shows all the practical advantages that result from long-term continuous Administration of various active agents, People and other environments *

Another purpose of the invention is to provide an osmotic delivery device in which the Problems have been overcome which are present in the upcoming devices described so far ”.

Another purpose of the invention is to provide an osmotic delivery device which incorporates the receptacle allows a high concentration of active agent, while at the same time high concentrations of active Agents never show an eagerness to be leached out of the device, nor show an eagerness regarding their potency odex 'their ticisiunigovei-niogeiiB by chemical deterioration to be worsened ",

Another purpose of the present invention is to provide an osmotic device for active delivery To create means that depend on their environment in terms of their driving force.

Yet another purpose of the invention is to provide an osmotic delivery device, the The osmotic membrane can be made from many and varied suitable materials, with a variety of solutions of osmotically active dissolved substances can be used to generate the osmotic driving force.

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Yet another purpose of the invention is to an osmotic delivery device of simple design to create that during longer periods of time and in controlled speed or in controlled quantity delivers a solution or gel of active agent or a semi-solid composition of the active agent cd ei 'releases.

To achieve the stated purposes of the invention, there is a feature which is shown in FIGS is, in an osnotic delivery device, the one water-permeable housing part, which is advantageously rigid or otherwise maintains its shape and which defines a first flexible pouch made of relatively impermeable material and contains the active agent, advantageously a drug, preferably in a stinging state, paste state or another semi-solid state (although sometimes a solution or concentrated solution of the active agent is sufficient), the housing part delimiting a second bag which is controlled against moisture Has permeability and contains a solution of an osmotically active solute which is opposite to water shows an osmotic pressure gradient. The two bags are in the water-permeable housing part or in the porous jacket arranged so that water from the environment through the porous jacket or the housing part passes through and migrates into the solution contained in the second bag by means of osmosis. The solution in that The second pouch increases in volume and exerts a mechanical force on the first pouch containing the active agent and this mechanical force in turn leads to the expulsion or expression of the active agent from the Contraption. In order for the active agent to be squeezed or squeezed out of the first flexible pouch this bag is provided with any suitable active agent releasing device or dispensing device.

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head to the outside of the device provided ^ for example with a long plastic tube that extends extends through the porous scantling, or with channel-like small tubes or tube connections through the outer dumbbell.

An on-terea feature of the invention according to FIGS Pig '. 4 to 9 consists of an osmotic delivery device, which have a rigid housing part or a chamber includes the water controlled permeability and contains a solution of an osmotically active dissolved substance which is oesiiiotic to V.'acser Pressure gradient shows * In part of the volume of the rigid housing part and part of the volume engaging there is a flexible pouch from proportion. , ": Ig impermeable material that is the active Contains agent, advantageously a pharmaceutical agent, preferably in gel state, paste state or other semi-solid Condition (although a solution or concentrated solution of the active agent is sometimes sufficient). The flexible one The bag is arranged in the rigid housing part of controlled permeability to water in such a way that, if water from the environment diffuses into the solution contained in the housing part by osmosis, this solution their volume increases, thereby exerting a mechanical force on the flexible pouch containing the active agent will. The mechanical force in turn pushes the active agent out of the device. So that active agent can be pressed or squeezed out of the flexible bag, this is with any suitable active agent releasing device or delivery head to the exterior of the Device provided, for example with a long plastic hose that extends through the housing part, or with channel-like small pipe connections or tube connections or Eapillarkanälcn through the housing part.

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Further purposes, features and advantages of the invention will become apparent from the description below in which the invention is explained, for example, with reference to the drawing.

Figure 1 is a cross-sectional view of an osmotic delivery device according to the invention.

Fig. 2 is a partially cross-sectional view

Partial diagrammatic view of an intravaginal device embodying the principles of Osraotic Dispensing device according to Fig. 1 are embodied.

Figure 2 is a cross-sectional view of another osmotic delivery device in accordance with the invention.

Fig. 4 is a cross-sectional view of a basic one Osraotic dispensing device according to the Invention.

Figure 4a is a top view of the osmotic delivery device according to Fig. 4-,

Fig. 5 is a cross-sectional view of another osmotic delivery device according to the invention.

Fig. 6 is a cross-sectional view of a still

another osmotic delivery device according to the invention.

Fig. 7 is a cross-sectional view of a still

another osmotic delivery device according to the invention.

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

Fig. 9 is a schematic view of the embodiment

and making yet another osmotic delivery device according to the invention referred to as a mini-pump type.

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According to one embodiment of the invention, as shown in Fig. 1, comprises an osmotic delivery device 10 a water-permeable housing part or a porous jacket 12, which is advantageously rigid otherwise maintains its shape, and which has a first substantially parallel configuration flexible bag 14 made of relatively impermeable material, and a second bag 16 with opposite Moisture controlled permeability circumscribes. The first flexible bag 14 contains the vote or Formulation 18 of the active agent, preferably in a gel, paste or other semi-solid state. 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 a saturated one aqueous solute solution and excess solid 22. An active agent releasing device 24 provides communication from the inside of the pouch 14 to the outside of the device 10, and at In this example, the device 24 comprises a narrowing neck in the porous shell 12 and one Outlet in the pouch 14 which is concentrically attached to the narrowing neck in the jacket 12. Of the The bag 16 is of a closed design and it is initially partially collapsed in the jacket 12, when fully expanded it substantially fills the shell.

To the osmotic delivery device for active agents shown in Fig. 1, in which the various bags Arranged in parallel configuration, the device will use when the active agent is a drug or some other means of treating, etc., a living organism, either physically employed or surgically implanted, typically a breast, in the body of the organism, or it is over administered to the gastrointestinal tract. When they meet once

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± i \ its position, the second bag 16 expands by absorption of water either from the body or body fluid through the porous jacket 12 and through the wall portions of the bag in an effort to achieve osmotic equilibrium, ie a transition from kypertonicity to isotonicity. When the lined pouch 16 expands, it exerts pressure against the likewise delimited medicament contained in the first flexible pouch 14. The pressure is used to force the drug contents 18 of the bag 14 out through the line. There is thus provided gradual and controlled release of the drug or similar agent directly to the body or affected organ of the body and over a prolonged period of time. Since about one half of the pouch is exposed to moisture, relatively fast drug release rates can be obtained. In addition, the use of a semi-solid excipient reduces the tendency to release the drug or any other effective or active agent by leaching and enables high concentrations of the drug or the like to be in the device.

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

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direction in an aqueous reaction process

If desired, the long bendable one can be used Polyethylene hose or the like to the outside of the Device from the interior of the bag 14 through the Means extending from the narrowing neck of the mantle 12 and the outlet of the pouch 14 (see Fig., 3) are formed. In this way can the device at a »location away from the desired one Application;; place arranged v / earth and its content of active agent can still be through the hose can be released directly to the desired location · This enables the dispenser to be arranged in a watery environment and release of the active Mitbals to another environment that needs to be very watery.

In Fig. 2 is an intravciginalc device 30, which is ring-shaped, and this device dispenses a drug formulation or formulation at a substantially constant rate, based on the principle of osmotic Active agent delivery device according to FIG. 1. This intravaginal device 30 has an annular shape water-permeable housing part or a porous jacket 12, which in turn is advantageously rigid or otherwise maintains its shape, and the v.'ieaerum in an essentially parallel configuration a first flexible bag 14 made of relatively impermeable Material and a second bag 16 with moisture controlled permeability circumscribed. The bag 14 contains the medicine 18, • preferably in a gel, in a paste or in another semi-solid state, and the bag 16 contains the solution 20 of the osmotically active dissolved substance, which has an osmotic pressure gradient with respect to water shows. The bag 16 advantageously contains a saturated solution of the dissolved substance and

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excess solid fabric 22 to ensure that the solution remains saturated. The bag 14 is at a distance from one another channel-like linen tubular or tubular connections provided through the outer dumbbell 12 to To enable release of the drug 18, and this Connections are in the drawing as release openings shown. For example, these fine tube connections can take the form of a plurality of hard capillary nipples have on the bag 14, which is through the Coat 12 extend.

The embodiment of FIG. 2 is used by it is placed around the cervix using standard techniques for placing a cervical ring, and, once in place, the device will deliver the drug or geroic Drugs in a tightly or precisely directed constant amount or rate. Accordingly, it can be seen that the mechanism of the embodiment of FIG. The osmotic delivery device of FIG. 1 is functional is equivalent.

It can also be seen that while an intravaginal delivery device is shown in FIG. which is based on the principle of the osmotic delivery device according to FIG. 1, the said principle of the invention glcienf & lls applied, for example, to a device which is of such size, weight, and shape as to be contained in the first stomach of several Stomach animals can be kept to take medicines or similar means in carefully to deliver a controlled amount. An apparatus according to Fig. 1 is admirable for continuous Administration of antibiotic oxytetracycline to cattle from the stomach. Other variations of the basic principle are readily apparent to those skilled in the art. Although special configurations be designed for special body applications

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each of these configurations is in others Environments applicable.

In Pig. FIG. 3 ifcj-fc shows another osmotic delivery device 40 for delivering active agents _s that of the device according to Pig. 1 is similar with the exception that instead of the more or less parallel arrangement of two separate bags there is a concentric design. Such a concentric design is more efficient and easier to manufacture. In the embodiment according to Pig. 1 there is an inner first flexible pouch 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 orenie, with the active agent therein suspended or dissolved. The bag IA- 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 in order to achieve the required osmotic pressure gradient or the pressure differential to accomplish. This material, which must be non-toxic when used for pharmaceuticals or similar agents, is preferably present partly as an aqueous solution and partly as a pesticide 22. It can be seen that in use, as water from the external aqueous environment is absorbed through the porous jacket and into the annulus, the contents of the pouch 14 are forced to the outside of the device via a long plastic tube 24, which is Length is directly proportional to the reduction in the above-mentioned leaching effect.

In certain cases the device does not have sufficient specific gravity to hold the assembly to maintain the desired location. In these In cases, a weight or ballast can be arranged in the device. For this purpose, iron parts, Iron ore parts, brass buckets or Kci / aiailcteLle verv.'or.'ic; (,

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will. When used in the bovine stomach, the weight should be sufficient _such% that an effective specific gravity of higher than 1 _t 5 is provided.

Optionally, a separator made of porous paper, fabric or the like can be placed between the porous outer housing and your representing the semi-permeable membrane Bags are arranged. This prevents the membrane from being perforated or into tight contact is pulled with the housing, thereby ensuring that the entire membrane is exposed to the aqueous environment is.

The impermeable bag 14- of the osmotic delivery device according to the figures, which contains the composition of the active agent, should essentially be impermeable to both water and other elements of the environment, in one Device of this type is to be arranged. Furthermore, the bag should be osmotically effective against the dissolved matter and the components of the composition of the active agent must be impermeable. Typical materials for use for the impervious pouch 14 include Polyethylene, polyethylene terephthalate ("Mylar") »plasticized polyvinyl chloride, layer structure made of metal foil and polyethylene, neoprene rubber, natural rubber and rubber hydrochloride (Pliofilm). These Materials are also flexible, insoluble and chemically compatible with the active agent to be incorporated into them, and in the case of creating a drug depot or the like in the body of a living organism they are biologically inert, do not disturb the body tissues and do not cause allergies.

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 (} j _{ern a} ut'f; t: Lör.ten substance, ie , e. ^c ; can the mater; r.ialien be used for the Au;.; Führuu;.? ^; ner o ;;: uoticH

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Cell are suitable * For best potency should the membrane is substantially impermeable to the passage of the osmotically active solute to prevent loss of solute · Typical membranes are isotropic i-icmbranen like Horibranen made from non-softened) Zollulcjeacotatj v / eichgen: n.chteni cellulose acetate, fortified cellulose acetate, cellulose acetate, Cellulose triacotate, A * th; j> l55ellu3.orje, furthermore anisotropic Reverse Os: Nose, typically made from cellulose acetate, silicone rubber, polyurethane, natural rubber and vascer-free ethylene-vinyl-acetate-Kischpolymeriijaten are formed. Isotropic membranes have lower water permeability than anisotropic membranes. It also leads to both types of LiGHiOranen the increase of the AcetatRehs.ltes des Cellulose acetate polymer leads to a reduction in water permeability. In a particular embodiment, the membrane used consisted of an isotropic one Cellulose acetate without plasticizer with an acetate substitution of 2.4 with a thickness of 5 mils, where against a saturated solution of magnesium sulfate at a temperature of 59 ° 0 water in an amount of 70 mg / cm ^ per day passed through · These membranes are also insoluble and with the salt solution and the excess material there? “Nit den FUrh ^ rinl in the Ein ^ ausi chemically compatible between the two bags (Fig. 3).

For drug depot applications as described above, these membranes are also biological inert, they do not disturb the tissues of the body and they do not cause allergies. For devices that are intended are able to deliver active agents relatively quickly over a limited period of time, membranes become indicated with controlled ei 'large water permeability. Membranes with low water permeability are also used

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used more slowly and for longer periods of time submit. At least according to the execution form Fig. 1, in which mechanical force is applied by expansion of the bag 16, should be the one used Membrane must be flexible at least to such an extent that such expansion and transmission such ir.shanifjjforces is made possible. This is not necessary for the Dform design according to FIG. 3, however acceptable. For example, the bag 16 can at least partially with the porous shell 12 as Be executed 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 Sheet metal (for example, made of aluminum, copper, steel, etc.), perforated galvanized pipe, perforated reinforced epoxy resin, metal sieve, sintered brass tube, porous styrene / acrylonitrile copolymer, porous sintered polyethylene od. Like. Be formed. It is not intended that the porous housing or the pump body acts as a barrier for the transport of water. For drug depot applications is the coat, in turn, is biologically inert, does not disturb body tissues and does not cause allergies. When executing Gicrm according to FIG. 2, there is an annular scantling advantageously made of porous hard plastic material, preferably with a smooth outer finish to reduce irritation. It can be seen that the porous housing or the jacket only needs to be rigid to the extent or otherwise maintain its shape, by creating enough boundary for the two bags is such that as the volume of a bag increases, the required corresponding pressure or pressure the corresponding force required to expel or force the active agent out onto the other pouch

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is transmitted or generated at this. In this way it can still be seen that it is in the frame The invention is to provide an osmotic delivery device that does not open the housing part as long as how the bags are designed and physically arranged relative to one another that the aforementioned pressure generation and pressure transmission is enabled, for example a shape-retaining balloon being present which is divided into two bags or spaces by means of a flexible membrane «In this embodiment the active agent-containing half of the balloon would be provided with a suitable dispensing head and the other half would contain the osmotic agent solution and at least it would partially made of 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. While the different parts of the device are according to the invention described above so that they under the conditions and in the environment of intended use are insoluble, it is further within the scope of the invention that such materials only are insoluble during the period of intended use, after which they become in the environment dex · device dissolve. Accordingly, the invention encompasses a dispensing device that is unaffected by its environment remains, i.e. is not solvable at the point of its use, or that during the period of the intended Use is only marginally solvable such that once the active agent content is released, the Device dissolves or erodes, leaving no objectionable residue or empty container on the Use parts remain.

It is also within the scope of the invention, optionally the dispensing device with a closed

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Water supply or to be provided with a separate water space, as it is in the publication mentioned in the introduction is described, in addition.

The relative thickness of the various membranes which comprise the various bags according to the invention, and also the relative thickness of the porous shell can vary widely and does not constitute any However, typically the flexible pouch containing the active agent has one Wall thickness of 0.5 to 50 mils, and the water-permeable membrane bag has a wall thickness of 1 to 10 mils, i.e. 0.0127 to 1.27 mm or 0.025 * 1 to 0.254 ir.n.

A special embodiment of a dispensing device, which is made according to the design according to Pig * I, and which is with a flexible pouch 14 · for the active agent having a wall thickness of 2 mils and a semipermeable membrane bag 16 having a wall thickness of 3 mils is provided, both of which are enclosed in a porous copper jacket 12 having a density of at least 2.77, had the following dimensions and properties:

Outside diameter of the device 2.7 cm

Wall thickness of the porous jacket 0.2 cm

Internal 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 44.1 cm

Active agent volume 20.2 ^

Active agent density 1,2 active agent: about 60 % tetracycline hydrochloride

dispersed in 40 # cocoa butter medium,

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oemotic solution: saturated aqueous solution from

KgSOy ,, which contained sufficient excess solvent in solid form to keep the solution saturated for at least three days,

water-permeable

Membrane: cellulose diacetate with one grade

of acetyl substitution of 2,4-,

Bag for that

active agent: polyethylene "

Such a device is capable of 5 rag of the active drug $ e dispense day, namely übex * a period of three days, when administered to the stomach of a heavy calf about 230 kg wove the device through the gastrointestinal tract is held back; -

In another embodiment of the invention as described in Pig. 4, an osmotic delivery device 10 includes a rigid canister 12 in which at least a portion of the wall portions exhibit the same controlled permeability to water as will be fully described below. A flexible bag 14 made of relatively impermeable material is received in the canister 12. The flexible bag 14 includes a SOrniulierung or vote 16 of an active agent, preferably einas medicament, preferably in fine gel ₅ of a paste or in other semi-solid state (although a solution or concentrated solution of the active agent is sometimes sufficient), and the active agent is when it is a medicament, preferably usually carried an oil phase, for example in cocoa butter. The volume of the canister 12, which is not occupied by the bag and its contents 16 of active agent, is occupied by a solution 18 of an osmotically active solvent which exhibits an osmotic pressure gradient in relation to water. The open end of the

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Canister 12 is tightly closed with a rigid, impermeable dispensing head, dispensing stopper or dispensing cap 20, with the open end of the flexible pouch 14 being fastened concentrically therebetween (see also FIG. 4a). In this way, a tight barrier between and under the active agent phase 16 in the flexible pouch 1%, the osmotic medium 18 in the canister 12 and the external environment of the device 10 is maintained. Without this tight i-lock, undesirable contamination could result. The dispensing head 20 is preferably snap-fit or press-fit in place with the flexible pouch 14 either already circumferentially fixed thereto or to the upper inner circumference of the canister 12. Alternatively, these three elements may conveniently be heat-sealed together and, as To aid in maintaining the tight or tight barrier, a chamfered or tapered polycarbonate retaining ring 22 can optionally be press fit around the top of the device Device 10, and in this example device 24 is a capillary channel or orifice drilled into the dispensing head. The channel advantageously has a diameter of approximately 1.59 mm
(0.0625 inch).

To use the osmotic delivery device for active Using means according to Fig. 4, the device will when the active agent is a drug or another Means for treating, etc., a living organism is, in the body of the organism, typically a breast, physical inserted or surgically implanted, or administered through the gastrointestinal tract. here refer to the description of the use of the execution

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~ 21 -

referenced form according to FIG. Once the device is in place, body tissue or fluids are absorbed into the device through the surface of the canister 12 showing the controlled permeability to water in an attempt to achieve osmotic equilibrium achieve, ie a transition from hypertonicity to isotonicity. As the water flows into the canister 12 by osmosis, the volume of the solution 18 is increased and appropriate pressure is applied against the circumscribed flexible pouch 14 containing the drug composition 16. This pressure serves to push the medicament contents 16 of the bag 14 through the line 24 in an osmotically controlled and constant amount into the external environment. Accordingly, there is provided gradual and controlled constant delivery of the drug or the like directly to the body or affected body organ over an extended period of time. Furthermore, the use of any semi-solid excipient reduces the tendency to release the drug or any other active agent therefor, by leaching, and enables high concentrations of the agent to be present in the device. The design of the canister 12 is such that a given area of the wall parts forming the canister exhibits permeability to water in an osmotically controlled amount from the outer surfaces to its interior. The canister 12 is therefore either a unitary or a composite construction and advantageously comprises a semi-permeable membrane which is either a unitary wall portion of the canister or a liner of the canister or which is formed in some way as a layer on the canister or otherwise in is arranged in the desired functional position or in the desired functional relationship.

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5 shows, for example, a csinotic dispensing device 10 for active agents, in which the canister 12 has a rigid, impermeable, cylindrical plastic side / and part 30 and a base αν / and part 32 that is uniformly connected to it. A plurality of openings or channels 34 are drilled into the body wall 32, each of which preferably has a lux diameter of about 1 »58 mm (1/16 inch). It can thus be seen that only the bottom wall 32 of the canister 12, which is largely porous, is capable of admitting water into the device, and the cylindrical side wall portion 30 remains impervious to water. It is not intended that the highly porous floor portion 32 act as a barrier or limit the transport of water in any way. Above or at the upper end of the perforated bottom wall part 32, a flat membrane disk 36 is securely fastened and supported, which shows permeability controlled by water. The membrane 36 can, for example, be glued in place or it can be formed as a lining or attached as a layer or it can be cast from solution at the top or over the side wall part 32. The aforementioned casting of the porous wall is advantageously completed by attaching the film or disk from a solution of membrane-forming material in a solvent, for example a 20 # solution of cellulose acetate in a mixed solvent of acetone, ethanol-ethyl and lactate in a ratio of 65 #, 20 # and 15 %, respectively, When casting the film, care should be taken to ensure that the pores of the wall part 32 are not clogged. It is of course intended that the seal between the membrane 36 and the porous wall 32 be watertight such that water can only enter the interior of the device by

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that it diffuses through by means of osrcosis through the herbalism 36. As can also be seen, it is also possible for the down rop 36 to be attached to the bottom rope «of the bottom wall part 32. The design according to Piß. 5 is also ineoi'crn novel that here relative to the Gcsantebacsiraugen dos canisters a membrane r.dt mr I c- _: 'ror, /. Tor area ο ei orders ,, Dior: results from the boquotfon availability of in large extent Water-permeable cellulose acetate membranes, which are bent on it, are used in reverse osmosis processes for water desalination.These burners, which are typically and preferably anisotropic membranes, are permeable to water (allow water to pass through at relatively high velocities ), but eic are relatively impermeable to sais so that their Bc use in devices with relatively small exposed surfaces allows ict · water migrates into the dispenser only the site of exposure thereof s of the membrane 36 to the Außenurcgebung via the channels ~ ^J J v a.

Optionally, in a modified embodiment of the invention, a separator formed from porous paper, fabric or the like can expediently be arranged between the bottom wall part 32 and the membrane 36. This prevents major ehlöchei-n G.eir I-ieubran CDER pulling the membrane in to close contact with the canister 12, thereby ensuring that the entire membrane is exposed to the aqueous environment. The modification indicated immediately above can also be applied to a device according to Pig · 6 . Furthermore, the use of the porous separator in the aforementioned embodiment, in which the membrane is poured from solution , supports the pouring of the membrane because it forms a ready- to-receive molding or pouring surface, with no risk of the openings 34 being clogged or become clogged.

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Referring to Fig. 6, there is shown an osmotic active agent delivery device 10 which has a greater available exposed area of membrane 36 creates, which design takes advantage of the fact that a much larger number of membranes is available as the semipermeable anisotropic cellulose acetate membranes of the kind shown in used in water desalination using reverse osmosis will. In this embodiment it is the rigid impermeable plastic cylindrical sidewall portion JO, the one with the plurality of openings or channels 34 is provided, which in turn each preferably have a diameter of about 1.58 mm

(1/16 inch). It is also this perforated wall 30 which, as in FIG. 5, is tightly connected to the membrane 36, and in this example the diaphragm is cylindrical in shape. Many modified designs in the execution lie between the embodiments according to FIG. 5 and according to FIG. 6, as far as the available exposed Concerning membrane surface, are of course within the scope of the invention.

Again, in some cases, the dispensers have According to FIGS. 4 to 6, the specific gravity is not sufficient to give the device the desired Place to hold. For example, when used in the stomach of multiple stomachs, the weight should be large enough to have a specific gravity of littleetens 1.5 to create. In cases of insufficient specific weight, a weight or ballast can be used be arranged in the device, for example a steel ball 38, as shown in FIG. Other suitable weights include iron parts, iron ore parts, Meeaing parts, ceramic parts or the like.

When the active agent is not a drug or the like, or when it is not for a living Organism is to be used, the device according to FIGS. 4-6 is also in the desired aqueous Environment introduced to create the desired effect,

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just as it would be with any of the known means of achieving the same result " This is generally just a physical insertion, for example a device containing a pesticide placed in a river or stream, or a device containing a catalyst in a aqueous reaction medium is used.

If so desired, the long flexible hose made of polyethylene or the like can also be made of the Dispensing head of the device according to FIGS. 4-, 5 and 6 be extended. In this way, the device can be removed from one of the desired application sites lying position, and it can still be active agent through the delivery head and then through the hose can be delivered directly to the application site. This enables the dispensing device to be arranged in an aqueous environment and releasing the active agent into another environment that is not aqueous too needs to be. The dispensing head can also be provided with a check valve, for example a one-way ball valve, to reflux active agent or other material from the external environment into the device to prevent.

Furthermore, an apparatus according to FIG. 4, 5 or FIG. 5 is admirably suitable for continuous Administration of antibiotic oxytetracycline Cattle from the beef stomach. This is because these devices have a size, a weight and a Shapes can be made such that they are retained in the stomach of multiple stomachs of animals can be used to deliver a drug or similar agent in a carefully controlled amount. Other modifications of the basic principle are readily apparent to those skilled in the art. Though special Designs made for special body applications any of these designs is for use

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suitable in other environments.

The membrane 36 according to FIGS. 5 and 6, and FIG Part of the canister 12 according to FIG. 4 forming V / and parts, dor opposite? \ 7asser controlled permeability, like the bag 16 according to FIG A large variety of materials are formed that are permeable or semi-permeable to solvents (water / water) aind, the o'edoch against dissolved matter or solvents are not permeable. That is, the materials used for the Execution of an osmotic cell are suitable. For best results, the membrane should be opposite the Passage of the osmotically active solute will be essentially impermeable to loss to prevent this substance. Typical membranes are isotropic membranes such as membranes made of non-plasticized Cellulose acetate, plasticized cellulose acetate, fortified cellulose acetate, cellulose diacetate, cellulose triacetate, Ethyl cellulose, anisotropic membranes for reverse osmosis, which are typically formed from Cellulose acetate, silicone rubber, polyurethane, natural rubber and anhydrous ethylene / vinyl acetate copolymers. Isotropic membranes have lower water permeability than anisotropic membranes. Farther in both types of membrane, when the acetate content of the cellulose acetate polymer is increased, the Reduced water permeability. Since, as described above, in a device according to FIG Area of the membrane is relatively limited, it is preferred in this general category of dispensers to use semi-permeable © membranes that allow relatively rapid water passage enable. Accordingly, anisotropic membranes are preferred in such embodiments. A cellulose acetate membrane The one suitable for this limited area is an "Eastman Chemical Products" membrane Type RO 97 "» cLLe a nominal capacity of 1.5 to 2 cnr / cm * and day at atmospheric pressure in terms of permeability to

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has a saturated solution of KgS (X at 39 ° C. A special example of the design according to FIG. 5 rait a dispensing head made of polymethyl methacrylate and with an inner diameter of 1.9 cm can be 4 to 6 cnr per day an active agent, advantageously a medicament; In a particular embodiment one Dispensing device of the type shown in Figure 6 was the isotropic cellulose acetate membrane used formed without plasticizers and with an acetate substitution of 2.4 and a thickness of 0.0762 mm (3 mils), with 70 mg per cm of water per day against a saturated magnesium sulfate solution of 39 ° C was passed through. The membranes are also insoluble and Chemically compatible with the saline solution and any excess solvent it contains. For Drug depot applications as described above, the membranes are also biologically inert, irritating the body tissues do not and do not generate allergies. Active means for devices designed for this purpose To dispense relatively quickly over a limited period of time, controlled high permeability membranes become specified for water. Membranes with low water permeability are used during to dispense more slowly for longer periods of time.

The impermeable pouch 14 of the osmotic delivery devices of FIGS. 4-6, which contains the composition of the active agent should also be used against water and the other elements of the environment, in which a device of this type is to be arranged, opposite the osmotically active solvent and components of the composition of the active agent be impermeable. Typical materials for use as an impervious bag include polyethylene, Polyethylene terephthalate ("Mylar") »plasticized polyvinyl chloride, Laminate made of metal foil and polyethylene, neoprene rubber, natural rubber rubber,

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and rubber hydrochloride (Pliofilm) · These materials are additionally flexible, insoluble and chemically compatible with the active agent contained therein, and in the case of the creation of a drug depot or of a similar depot in the body of a living organism, they are biologically inert and irritate the body tissues do not and do not generate allergies.

The impermeable plastic canister 12 according to FIGS Pig. 5 and 6 and the impermeable parts of the canister 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. made of aluminum, copper, steel etc.), galvanized pipe, or made of styrene / acrylonitrile mixed polymer. It is of course intended that such a housing or jacket acts as a barrier for the transport of water with the exception of the perforated surfaces. Again, these are materials beneficial for drug depot applications, biologically inert, non-irritating and generating body tissues no allergies. The dispensing head 20 and the retaining ring 22 may be formed from materials that the Materials are identical to those used to manufacture the canisters 12, being polycarbonate is also well suited for the ring 22. Of the aforementioned materials are impermeable or heat-resistant plastics are particularly preferred.

Many other materials, including those that are biologically acceptable, are suitable for manufacture of the various parts of the devices according to FIGS. 4 to 6 are suitable. While the various Parts of the device according to the invention previously than under the conditions and in the vicinity of the intended Use are described as insoluble, it is also within the scope of the invention that such materials only during the period of intended use

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are insoluble, so that they are then in the exercise the device can dissolve. Accordingly, a dispensing device is also encompassed by the invention which regarding solvability at the point of use its surroundings are unaffected, or only slightly during the period of intended use is solvable such that once the content of active agent is released, it dissolves or eroded and leaves no objectionable residue or an empty container at the point of use.

It is also within the scope of the invention, optionally the dispensing device according to the ffig. 4, 5 and 6 to create with a closed water supply or a separate water space, as in the introductory part mentioned parts of the literature is described.

The relative thickness of the various membranes of the devices according to FIGS. 4 to 6 and the relative The thickness of the various canisters can vary widely and they do not pose any limitations Invention. Typically, however, each canister has one Wall thickness of about 0.0127 to 1.27 mm (0.5 to 50 mils), preferably from 0.127 to 1.27 mm (5 to 50 mils), and the water permeable membranes have a wall thickness of about 0.0254 to about 0.254 mm (1 to 10 mils).

A special embodiment of a dispensing device, which is made according to the invention and is made in Figs. 7 and 8, and with a semipermeable membrane 36 0.0762 mm (3 mils) thick and with a flexible pouch 14 for active Material approximately 0.0508 mm (2 mils) thick has the following dimensions and properties:

Outer diameter of the dispenser?

Wall thickness of the canister 12 3ji?

(012

3j? 5 (0.125 inch)

Dispenser inner diameter 22.22 mm

(0.875 inch)

209837 / 1Q30

.3

Total length 63 »5 mm

(2.5 inch)

External volume * », on cm

(2.45 zoJl ⁵ )

Inneiivo lumen 2.0! cm

(1.24 zoIlO

Overall device density 1.5,

available Mornbran area 2.8 cm _p

(0.44 inch)

Active agent volume 15.5 cnr

(0.94

Active agent density 1.2

active agent: about 60 % tetracycline hydrochloride

dispersed in 40 % polyethylene glycol medium,

osmotic solution: saturated aqueous solution from

^ SO ^ that have enough excess of solvent in solid form contains to the solution for a period of at least three days to keep saturated, water-permeable membrane: ZeHulose diacetate with

a degree of acetyl substitution of 2.4,

Canister 12: soft polyethylene, threaded end cap 32: soft polyethylene, Dispenser cap 20: soft polyethylene, bag 14 for the active agent: polyethylene, beveled ring 22: polycarbonate, membrane support 40: polystyrene

Dispensing opening 24 diameter: about 1.59 mm

(0.0625 inch)

Diameter of the openings in the

Cap 32: about 1.59 mm

(0.625 inch)

Diameter of the openings in

Beam 40: 3.175 mm

(0.125 inch).

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Such a device is capable of delivering 5 ^ g of the active drug daily for a period of three days when it is placed in the stomach of a PCaIbe weighing about 2JO kg (500 lbs) where it is via the stomach -This tract is being held back. 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. 5, v / whether the most pronounced differences between them in the device according to FIGS. 7 and 8 in FIG Execution of the perforated end cap 32, which is screwed onto the canister 12 and provided with an O-ring 4-2 made of rubber, in order to prevent leakage at the location of the threaded seat BU. The cap 32 receives the diaphragm 36 and a diaphragm support 40. Of course, the larger the free space or the total open area of the plurality of channels drilled in the end cap 32, the greater the portion or extent of the diaphragm 56 which is or , which is exposed to the aqueous environment. In the same way, water diffuses more easily into the space 24, the larger the open area of the plurality of channels drilled in the membrane support 40. As in the embodiment according to FIGS Optionally, a separator made of porous paper, fabric or the like between the membrane support 40 and the end cap 32 and / or the permanent construction. 3G or between the two. The membrane is thereby, as mentioned above, protected against perforation or against being pulled into too tight contact with its housing, which additionally ensures that the entire membrane is exposed to the aqueous environment.

In yet another embodiment according to FIG The invention, hereinafter referred to as the mini-pump and shown schematically in Fig. 9, is one modular or modular osmotic active agent delivery device implemented which conceptually the Devices according to FIGS. 4 to 6 is similar. For

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the manufacture of the drug sachet for the Mini-pump corresponding to the bag 14 according to FIG First the raw materials selected, consisting of thin-walled polyethylene tubing of a size in Coincide with the required volume of the drug, two identical dispensing and filling hoses 20 made of polyethylene (each for example an outside diameter of about 1.09 mm (0.04-3 inches) and has an inside diameter of about 0.381 mm (0.015 inches) and made of, for example, a nail cleaner or Wire cleaners measuring about 0.254mm (0.010 inches) exist. Reference is made here to step I according to FIG. 9. Next, as shown in Fig. 9 as As shown in step II, the wire is arranged in the tubes made of polyethylene 20 and the resulting The embodiment is arranged in the medicament pouch as shown. The dispensing and filling hoses are then (on Vertod) at each end of the polyethylene tubing of the larger medicine pouch attached by heat sealing, and the medicine pouch is filled with the drug composition, and either in solution form or in another form. An added overflow hose catches the displaced Work equipment composition and hold it back, when the lower end of the device is closed. The overflow hose is then removed and the dispensing hose is closed at its end. The final manufacture of the drug sachet is in step IV shown, 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 covered with sandpaper is roughened. At this point in the operations, the one containing the drug composition becomes Medicinal pouches suitably pressure-tested by simply pressing or squeezing.

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The mini-pump design is finally completed by the work steps according to steps V to VII according to FIG (meaning effective solvent as described below), after which the previously prepared Aranei center bag is placed in the mold and this is compressed by any convenient means not shown, for example by means of a typical C-clamp. Then the mold, the bag and the gelatin-sals matrix are frozen. Half of the mold is then removed and the half containing the pump is dried in an oven overnight. Please refer to step V for the appearance of the mini-pump after containment. Optionally, see step VI, the drug sachet enclosed with salt can be coated with a thin layer of gelatin by simply dipping the sachet in a gelatin solution and drying the coating until it hardens to form a smooth surface that is suitable for the patient Membrane coating process of step VII is more susceptible. In step VII, the execution of the mini pump is completed by covering the structure according to step V or step VI with a layer of membrane material of the type described above is allowed to pass, after which the membrane-coated design is allowed to dry for about 4-8 hours. The membrane coating is sufficiently rigid and is such that when water from an external aqueous environment passes through the permeable membrane coating and by osmosis into the salt

209837/1030

immigrates, so that an osmotically effective solution is formed with it, which causes the appearance of osmosis as a result of the effort towards osmotic equilibrium with the environment initiates the membrane coating is able to withstand this increase in volume in the minipurape, so that concurrently with it a © mechanical evacuation force is generated which acts on the flexible drug sachet and in turn takes the active agent from the delivery device pushes or expels in an osmotically controlled amount for an extended period of time.

The device of FIG. 9 is used / ended in the same way like the dispensing devices described above, with the additional advantages of small size, (The representations according to FIG. 9 are approximately twice as large as the actual size). For example, this can The free end of the delivery tube can be conveniently cut off with a scalpel and placed in the delivery area brought, planted or administered. The pump will then dispense all of its contents. The different The materials that make up the mini-pump essentially correspond to the materials including equivalent and corresponding components used in the osmotic Dispensing devices are used.

Any of the medicines that are used to treat the body, both topical and systemic © drug, can be used as an active agent in any of the osmotic delivery devices according to of the invention can be used. The term "medicament" is used here in the broadest sense and they includes any composition or substance that causes a pharmacological or biological response.

Suitable medicaments for use in therapy with the delivery device according to the invention include without limitation:

209837/1030

1. Proteinraedikanieirfce, v; ie insulin}

2. OeBC-nsibiiiaatoren, v.ie /uibrosiapi'lari.r'or^ollenanLigene. HeufiberpolleiiantiüeiiG, dust antigen and 1.IiIcIiantigeii;

3. Vaccines, such as smallpox, yellow fever, distemper, swine fever, poultry pocizen, anti-poison, scarlet fever, Diphtheria toxoid, ffetanus toxoid, pigeon pox, I pouch cough, Flu, xoliwut, jiuiiips, iiasern, polio ::: yelitis-yaccine, Vaccine against the i4e \; castle ~ SraiiIch.eit etc .;

4 · Anti-infectives, including antibiotics. Penicillin, tetracycline, chiortcuracycline, sacixraciri., Nystatin, streptonycin, neomycin, polymyxin, gramicidin, Oxy tetracycline, chloramphenicol and erythromycin; Suliona: .iio including Sulfacetaaid, Sulfauethi ^ ol, Sulfaiuethaniii, Sulfadiasin, sulfamerazine and sulfisoxasol; Antivirus ^ tcffe including ΙαοχιαΊαΙη, and andsro ilntiiniei: i; 3tci'ie including llitrofurazon and liatrius propionate;

5 antiallergenic substances, v / ie ilnxasolin, llethapyrilen, Chlorpheniraiüin, Pj'rilanin and Prophenpyridarain;

209837/1030 ORIGINAL BATHROOM

6. Anti-inflammatory agents such as hydrocortisone, cortisone, Hydrocortisone acetate, dexamethasone, dexaniethasone-21-phosphate, Pluocinolone, Triaucinolone, Lie dry son, Prednisolone. PredniGOlon-21-phosphate and prednisolone acetate}

7. Deodorants such as phenyl epiir in, naphazoline and Tetrahydrozolinj

8. Lliotica and anticholine ester drugs, v / ie pilocarpine, Eserine salicylate, carbachol, diisopropyl fluorophosphate, Phospholine iodide and demecariuin bromide}

9. Iiydriatica, such as atropine sulfate, cyclopentolate ,. Homatropin, scopolamine, tropic acid, eucatropin and hydroxyamphetainine;

10. SympathoEiinietica, such as Epineohrinj

11. Sedatives and hypnotics, such as pentobarbital sodium, phenobarbital, secobarbital sodium, codeine, alphabromisovaleryl urea, Carbronalj

12. Psychological stimulants, such as 3- (2-aminopropyl) indole acetate and 3- (2-aminobutyl) indolactatej

13 * Tranquilizers, such as reserpine, ChlcrproLiasin and Thiopropazatj

14 · Androgen steroids, such as methylteetosterone and pluoxj mesteronj

15 · Estrogen, such as oestrone, 17- ß -estradiol, ethinylestradiol and diethylstilbesterolj

16. Progestatives, such as progesterone, Liegastrol, Helengestrol, Chlorruadinone, ethisterone, ilorethynodrel ,. 19-llorprogeateron, Korethindron, Iledroxyprogesterone and 17-cC-

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hydroxyprogesterone;

17 · Kimoral agents, such as prostaglandin, κ.Β. PGE, and PGl ₂ J

18. Antipyretics such as aspirin, ITatriuiasalicylat and Salicylamide;

19 · Antispasinodica such as atropine, hethantelin, papaverine and methscopolaniine bromide;

20. Antimalarial agents such as 4-aniinoquinolines, 8-aminoquinolines, Chloroquinine and pyrimethamine j

21. Antihistamines such as diphenhydramine, dimehydrinate j Tripelennamine, perphenazine and carpenazine;

22 Cardiac drugs, such as hydrochlorothiazide, plumethiazide, Chlorothiazide and Trolnitratej

23. Food such as vitamins, essential amino acids and essential fats;

24. Anti-Parkinson's disease agents, such as L-dopa (L-3,4-dihydroxyphenylalanine) j

25 · antihypertensive measures intended for examination purposes! like Dopäniiii, 4— (2 — Aiäiij.Oö.bliyi ^ pyrücä'iieciiOis

Other drugs that have the same or different physiological effects as the drugs listed above can be used in osmotic delivery devices within the scope of the present invention. Suitable drug mixtures can of course be dispensed just as easily as with individual component systems. The drugs can have different forms, ie, for example, as uncharged molecules, components of molecular ones

209837/1030

ie

Complex, or non-irritating, pharmacologically acceptable salts, such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, haleate, tartrate, salcylate, etc. are present. For acidic drugs, metal salts, amines or organic cations (2nd B, quaternary ammonium) can be used. Furthermore, simple derivatives of the drugs can also be used _; (such as ether, ester, amide, etc.) _; which have desirable retention and sample properties but are readily hydrolyzable by body pH, enzymes, etc. can be used.

The one included in the osraotic delivery device Amount of drug changes largely depending on the particular drug desired therapeutic Effect and the amount of time it takes for the drug to be released. As a variety of dispensers come in a variety of sizes and shapes complete dosage schedules to treat a wide variety of disease, there is no critical upper limit on that in the delivery device enclosed amount of medication. The lower limit is also dependent on the effectiveness of the drug and the time it takes to release it from the delivery device. Therefore, it is not practical to have a range for the therapeutically effective amount of that to be released from the delivery device Determine drug.

209837/1030

S9

The driving force of the dispensing device according to the invention depends on the osmotic pressure generated by the solution of the osmotically active solvent contained in it, this solution exhibiting an osmotic pressure gradient with respect to water. Most preferably, the solution is an aqueous saturated saline solution. In order to keep the solution saturated and therefore achieve constant osmotic pressure while the dispensing device is operating, the membrane, bag or canister containing the solution also contain excess solvent in solid form. Various osmotically active solvents can be used v /earth. These include magnesium chloride, magnesium sulfate, sodium chloride, potassium sulfate, sodium carbonate, Hatriumsulfid, sodium sulfate, Hatriumbicarbonat, Kaliumphthalatsäure, calcium bicarbonate, potassium acid phosphate, raffinose, ^We i ⁿ acid, succinic acid, Kalziumsuccinat, calcium lactate and Magnesiuinsuccinat. The excess solid solvent may be in the form of dispersed particles or, preferably, in the form of a pellet. The solution can initially be a solution of the same or a different osmotically effective solvent than the solid excess solvent *

The osmotic delivery device can be made in any convenient shape for either physical introduction or implantation in the body, or for administration via the gastrointestinal tract, or for introduction into any desired environment. The dimensions of any device can accordingly vary widely and are of no controlling importance. The lower limit of the size of the device is determined by the amount of the particular active agent that is to be delivered to the environment in order to produce the desired response and also by the shape of the device

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Dosage unit, for example in cases of special body applications in the form of an implantation! one Spherical body, for intrauterine applications, intravaginal applications a vaginal ring, a uterine capsule for fertility suppression, an artificial bar or an artificial bridge, a prosthesis, a pessary, a suppository, and the like. The same applies in with respect to the upper limit of the size of the device.

In a particular embodiment, the dispensing device can be of a size such that 1 to 2 centimeters of the drug composition are dispensed per day and that a total of 5 to 10 centimeters of the drug composition are dispensed over a period of 5 to 10 days. Alternately, choosing lower permeability membranes will allow the pump to deliver drug more slowly over a period of up to a year and beyond a year. It is preferred that the design of the delivery device and the active agent releasing device be such that the osmotic drive pressure developed is 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 to obtain effective concentrations of active agent or active agent contained in it, to release to the body of a living organism, or to release to any other environment, and although to an osmotically controlled extent and for a prolonged period of time. In addition, there are primary Advantages of any dispensing device according to the invention in that it is of simple construction is and all the practical advantages of long-term continuous administration of various active Agent to humans, animals and other environments shows and that the active agent contained therein

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does not show the tendency to be leached out of the device to become·

209837/1030

Claims (17)

Patent claims 1. Osmotic device for the delivery of active agent, characterized ^ a _a ß first barely is provided, which has controlled permeability to water and contains an osmotically active solvent which, when it is in solution, shows an osmotic pressure gradient to water, a space formed from a flexible bag made of relatively impermeable material and containing an active agent and provided with means for releasing the active agent to the outside of the dispenser, the first space and the space formed from the flexible bag from one Execution are and are physically arranged relative to each other such that the flexible bag can collapse in response to the increase in volume of the first space via absorption of water in these, so that when water migrates into the dispenser by means of osmosis in an effort to achieve osmotic equilibrium with the Vice exercise and a mechanical emptying force exerts on the flexible bag, the fictitious agent is continuously pressed out of the device for a prolonged period of time and in an osmotically controlled amount 2. Device according to claim 1, characterized in that that a first flexible bag of relatively impermeable material is provided which is an active Contains means and provided with means for releasing the active agent to the outside of the dispensing device is, and a second bag with water-controlled permeability is provided, dor one Contains a solution of an osmotically effective solvent, 2098 37/1030 which has an osmotic pressure gradient compared to water. en shows that the bags are of one embodiment and are physically arranged relative to one another such that the first bag may collapse in response to an increase in volume in the second bag via absorption of water ir Dispensing device, in an effort to achieve osiaotiechcs equilibrium with the environment, the active gown is continuously squeezed out of the device for an extended period of time and in an osmotically controlled amount. 5. Apparatus according to claim 1, characterized in that that a water-permeable housing part is provided which comprises a first flexible bag relatively impermeable material containing an active agent and having a means for releasing it of the active agent is provided to the outside of the device, and a second bag of controlled Permeability to water, which is a solution of an osmotically active reading substance, which an osmotic pressure gradient tone compared to water shows, contains, and that the bags are arranged in the housing part in such a way that the containing the active agent Pouch on volume increase of the osmotically effective solvent-containing pouch on absorption of water in them by collapsing responds so that when water flows into the device in an effort to maintain osmotic equilibrium with the environment to achieve active agent for a prolonged period of time in an osmotically controlled Amount is pressed out continuously. 209837/1030 4. Device according to one of claims 1 to 3 »characterized in that the active agent is a drug or is a biologically active composition. 5 · Device according to one of claims 1 to 4-, characterized in that the active smock in the form a semi-fixed vote or composition is available. 6. Device according to one of claims 1 to 5 »characterized in that the solution, the opposite Water shows an osmotic pressure gradient when it is a saturated aqueous saline solution. 7. Device according to claim 6, characterized in that the saturated salt solution is in excess Contains solvent in solid form. 8. Device according to one of claims 1 to 7 »characterized in that the containing the active agent flexible bag a part made of polyethylene, polyethylene terephthalate, polyvinyl chloride, a laminated body ens metal foil and polyethylene, keoprcn rubber, 209837/1030 natural gourami rubber and rubber hydrochloride having. 9 · Device according to one of claims 1 to 8, characterized in that the solution consists of a Bags containing osmotically active solvent a part made of cellulose acetate, silicone rubber, Polyurethane, natural rubber or hydrolyzed or anhydrous ethylene / vinyl acetate copolymer having. 10. Device according to one of claims 1 to 9f characterized in that it has the configuration of a intravaginal device. 11. Device according to one of claims 1 to 9 »characterized in that it has the shape of a Has a veterinary bullet or bolus, 12. Device according to one of claims 1 to 11, characterized in that the two spaces or bags are arranged in a substantially parallel configuration. 15 · Device according to one of claims 1 to 11, characterized in that the spaces or bags in im are arranged in a substantially concentric configuration. 14. Device according to one of claims 1 to 13, characterized in that the osmotically effective solvent consists of magnesium chloride, magnesium sulfate, Sodium chloride, potassium sulfate, sodium carbonate, sodium sulfate, sodium bicarbonate, potassium phthalic acid, calcium bicarbonate, Potassium phosphate acid, raffinose, tartaric acid, succinic acid, calcium succinate, calcium lactate or magnesium succinate is selected. 15. Device according to claim 1, characterized in that that a shape-retaining chamber is provided, the water-controlled permeability has and a solution of an osmotically active solvent that has a osmotic pressure gradient shows, contains, and in the 209837/1030 a flexible pouch of relatively impermeable material is received and contains an active agent and having means for releasing the active agent to the exterior of the delivery device is provided, and that the flexible bag is arranged in the receiving chamber such that, if Water from the external environment enters through the permeable walls of the chamber and enters the chamber by osmosis The solution contained therein migrates in an effort to achieve osmotic equilibrium with the environment, the volume of the chamber is increased, creating a mechanical evacuation force on the flexible bag generated and exerted, which osmotically engenders the active agent for a prolonged period of time controlled amount pushes out of the device. 16 · Device according to claim 15 »characterized in that that the chamber is formed from a membrane made of cellulose acetate, silicone rubber, polyurethane, Natural rubber or ethylene-vinyl-acetate copolymer made anhydrous is formed. 17. The device according to claim 16, characterized in that the membrane is anisotropic. 209837/1030 Blank page