JPS6210205B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for manufacturing a device that operates by an osmotic bursting mechanism to continuously release an active agent, such as a drug, over an extended period of time into an aqueous environment, such as a body fluid.

Continuous or scheduled active agent release dosage forms primarily employ one of two release mechanisms: diffuse release or erosive release. In a diffusive release mechanism, the active agent is dispersed in a matrix or surrounded by a membrane, through which the active agent diffuses at a controlled rate. This allows for longer release times. In the corrosion release mechanism, the active agent is coated with or trapped within a material that is gradually and continuously corroded over time. As the coating or surrounding material erodes, the active agent is released.

Sustained release dosage forms that use a diffuse release mechanism have the disadvantage that they are often difficult to manufacture and often require substantial experimentation in selecting the correct material of construction. Erosive release dosage forms often do not provide the desired constant rate of release and generally present the problem of initially administering large amounts of active agent when introduced into an aqueous environment.

The delivery device of the present invention uses a different release mechanism: an osmotic bursting mechanism. Osmotic pressure is used in prior art delivery devices. For example, U.S. Pat. No. 3,732,865 to Higuchi and Leeper, issued May 15, 1973, discloses a device that uses osmotic pressure to drive a moving septum that continuously expels active agent from a container. There is. The extended release form of the present invention uses osmotic pressure in a different manner and has no moving parts.

The present invention provides a method for manufacturing a device that continuously and sustainably releases an active agent into an aqueous environment.
The method comprises: (a) adding one part by weight of an osmotically active agent reservoir-forming material comprising a water-soluble active agent or a mixture of a water-insoluble active agent and an osmotically active material to a vinyl polymer or Copolymer, 14-700
Tensile strength of Kg/ ^cm2 , maximum elongation of 10-2000%,
Water permeability of 2.5×10 ^-6 to 2.5 cc・micron/cm ²・hr・atm of water and 2.5×10 ⁻⁹ g・micron/cm ²・hr・atm of storage body forming substance or less permeable, substantially impermeable to the reservoir-forming substance, insoluble in the aqueous environment, at least while the osmotically effective active agent is released, permeable to water and the individual osmotically effective active agent; 0.25 to 5 parts by weight of a matrix polymer having a cohesive strength inferior to the osmotic pressure generating capacity of the reservoir, thereby dispersing the reservoir-forming material in the polymer to form a matrix polymer having a diameter of 0.1 to 100 microns. (b) molding or casting the mixture; (c) forming a molded article; is cut to form a unit of size and shape suitable for introduction into an aqueous environment.

Vinyl polymers and copolymers of matrix polymers include hydroxylated and non-hydroxylated ethylene-vinyl acetate copolymers, highly plasticized polyvinyl chloride, polyesters of acrylic and methacrylic acid, polyvinyl alkyl ethers and polyvinyl acetate. Made of vinyl fluoride. Ethylene-vinyl acetate copolymers, alone or in admixture with other materials, are particularly effective in forming rupturable matrix materials. Among the ethylene-vinyl acetate copolymers, those having a melt index of about 20 g/min or more and a vinyl acetate content of about 20% or more, for example 20-45%, are preferred.

The matrix polymer is water insoluble and 2.5×
Water permeability of 10 ^-6 to 2.5 cc microns/cm ² hr atm of water, tensile strength of 14 to 700 Kg/cm ² (preferably 35 to 210 Kg/cm ² ) and 10 to 2000% (preferably 200-1700%) and a high degree of impermeability to the reservoir contents (2.5 × 10 ^-9 g microns of reservoir contents/cm ²
・Has a reservoir contents permeability of less than hr.atm). Water permeability regulates the rate at which water enters the device. If this value is lower than the lower limit (2.5 × 10 ^-6 ), the device takes too long to release the contents of the reservoir, and if it is higher than the upper limit (2.5), the device is too fast. The release is pulsed instead of controlled continuous release.

The device, when placed in an aqueous environment, allows water to be ossically absorbed into the reservoir closest to the external surface of the device, thereby creating a pressure sufficient to rupture the surrounding polymer and causing the activator to rupture. is released,
Characterized by the access of the aqueous environment to the next nearest reservoir and so on.

Referring to FIG. 1, in one of its more basic embodiments, the present invention provides a controlled release device configuration 10 having a plurality of separate osmotically effective active agent reservoirs 11 dispersed in a matrix 12. include. The material of matrix 12 surrounds and encloses the active agent reservoirs, confining the plurality of reservoirs within unitary device 10. The material of matrix 12 is a polymeric material that is insoluble in the aqueous environment in which it is used, at least during the active agent release period. Preferably, and necessarily in devices for delivering drugs to patients, the materials of matrix 12 are non-toxic. The matrix 12 is initially substantially porous so that the active agent is not lost by mere dissolution (leaching). Matrix 1
The material of 2 is semi-permeable, ie it allows water to pass through, but not actually the contents of the reservoir 11. The contents of the reservoir 11 contain osmotically active substances, i.e. compounds which, when dissolved in water, form a solution exhibiting an osmotic pressure above a barrier that is permeable to the aqueous environment in which it is used, but which is impermeable to this substance, such as a salt. contains. The active agent in the reservoir 11 can itself be a permeatingly effective substance, or an additive substance mixed with the active agent can produce a permeating effect. When the device 10 is placed in a working aqueous environment, the device absorbs water from the environment.
FIG. 2 shows the device 10 shortly after it has been placed in an aqueous environment. As shown in FIG. 2, initially only the outermost reservoir 11A absorbs the absorbed water, instead of all reservoirs absorbing water equally. As water passes through matrix 12 and enters outermost reservoir 11A, hydrostatic pressure is generated by the percolation drive mechanism. When this pressure exceeds the cohesive strength of the material of matrix 12 surrounding these outermost reservoirs, this material ruptures and the contents of the reservoir become aqueous, as shown by ruptured reservoir 11B. released into the environment. This rupture not only releases the contents of the reservoir, but also creates a path for the aqueous environment to travel, reach the internal active agent reservoir, be osmotically absorbed, and rupture the reservoir.
Finally, a lattice of polymeric material is formed, as shown in FIG. 3, and the aqueous environment reaches the innermost reservoir.

In practice it is essential to use multiple reservoirs if continuous release is to be achieved. For example, if there is only one reservoir, its rupture causes the entire contents of the reservoir to be released instantaneously. The number of reservoirs is a function of the active agent loading of the device and the reservoir dimensions. In this regard, the diameter of the reservoir is usually about 0.1-100
Microns, usually 5 to 50 microns.

The reservoir loading, ie the proportion of reservoir in the device, is also important as it determines, in part, the release characteristics of the device or dosage form. The storage loading rate is usually 15 to 90% by weight storage, more commonly 20 to 70% by weight storage. If the device contains more than about 85% by weight of matrix polymer (and therefore less than 15% by weight of the permeable reservoir), the thickness and cohesive strength of the polymer coating are probably too great to achieve the desired permeability rupture. It will not be possible to achieve it. If the device contains less than 10% by weight of polymer, sufficient polymer to sufficiently surround the active agent particles and separate them into separate and separate reservoirs as required by the method of the present invention. would not exist. Also, the resulting device would be so weak that it would not be able to retain its unitary shape after being substantially expelled by rupture of the reservoir. Retention of the unitary shape is desirable in order to be able to more precisely control the position of the device and the rate and position of active agent release.

The critical internal structure of the device according to the invention is further illustrated in FIGS. 4 and 5 by electron micrograph scanning of the microstructure. Figure 4 shows the structure before use.
Figure 5 shows the structure after seepage rupture has occurred. Fifth
In the figure, region A still contains active agent. Region B is devoid of active agent. As FIG. 5 shows, region B contains no active agent particles. However, the unit structure is maintained.

The permeately effective reservoir of the present invention consists of a minimally water-soluble active agent (drug) or an intimate mixture of a water-insoluble active agent and permeately effective material. In the present invention, the term "active agent" refers to a compound, or a mixture of compounds, or a composition of mixed substances that produces a certain beneficial and effective result when applied. Active agents include pesticides, fungicides, biocides, algaecides, rodenticides, antifouling agents, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, surfactants, and disinfectants. agents, sterilizers, catalysts, chemical reagents, fermentation agents, cosmetics, foods, nutrients, food supplements, drugs,
These include vitamins, contraceptives, fertility suppressants, fertility promoters, air fresheners, microbial detoxifiers, and other agents of benefit to humans, animals, plants, or the environment.
"Drug" means an active agent of the preferred class, a chemical compound or biological compound that can be administered to a patient to aid in the diagnosis, treatment or prevention of a disease or to control or ameliorate a pathological or physiological condition. shall include reagents. "Drugs" are not limited to hypnotics, sedatives, psychostimulants,
Tranquilizers, antispasmodics, muscle relaxants, analgesics, anti-inflammatory agents, anesthetics, antispasmodics, antiulcer agents,
These include bactericidal agents, standard reagents, cardiovascular agents, diuretics, and antitumor agents. Drugs can be present in various forms such as uncharged molecules, components of molecular complexes, pharmaceutically acceptable salts such as hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates. , and salicylates. In the case of acidic chemicals, metal salts, amines, or organic cations, such as quaternary
Ammonium can be used. Additionally, simple derivatives of drugs such as esters, ethers and amides are suitable for use in the present invention.

As mentioned above, the active agent can be "water soluble" or can have "limited solubility." A "water-soluble" active agent is one that has a solubility in water of 1% by weight or greater. A "limited solubility" active agent has a water solubility of 1% by weight or less. A water-soluble active agent (drug) is created by a water activity gradient (activity gradient) between the interior of the reservoir and the aqueous environment outside the device.
It is itself a potentially penetratingly effective substance because it can produce a gradient. Common water-soluble active agents include, without limitation, organic and inorganic compounds. Common water-soluble drugs include, but are not limited to, efuedrine hydrochloride, efuedrine sulfate, hydroxy-amphetamine, isoprotanol hydrochloride, carbachol, procarpine hydrochloride, pilocarpine nitrate, demecarium bromide, ecothiophate. Iodide, physostigmine salicylate, propranolol hydrochloride,
homatropine hydrochloride, homatropine methyl bromide, methscopolamine nitrate, alverine citrate, chlorphenoxamine hydrochloride, calcium pantotheate, epinfurin bitartrate, chloramphenicol sodium succinate, hydrocortisone phosphate, Hydrocortisone sodium succinate, gentamicin sulfate, neomycin sulfate, prednisolone sodium phosphate, tetracycline hydrochloride and polymyxin sulfate, all of which can be added with the osmotically active agent in the device of the invention, if desired. It has solubility properties that make it suitable for use without water.

Active agents (drugs) that are water-insoluble can be used with osmotically effective substances to act as osmotically effective active agents. Once released from the device, the active agent is converted by enzymes, hydrolyzed by the body's PH, or otherwise converted to its original active form.

A "limited solubility" active agent (and optionally a "soluble" active agent), the osmotic active substance is intimately mixed with the active agent. In the case of "limited solubility" active agents, this allows an appropriate permeation pressure to be generated. With "water-soluble" active agents, the amount of osmotic pressure generated is thereby more precisely controlled, and as a result, the rate of active agent release is more precisely controlled.
As these added penetrantly effective substances,
Water-soluble inorganic and organic salts and compounds such as magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium sulfate,
Potassium acid phosphate, calcium lactate, magnesium succinate, tartaric acid, urea, acetamide, choline chloride, soluble carbohydrates such as sorbitol, mannite, raffinose, glucose, sutucarose, lactose and mixtures thereof. If a percutaneously effective substance is added to the active agent, it is necessary that it be well mixed with the active agent.
In the device of the invention the active agent reservoir is very small.
If an osmotically active substance is required, each reservoir needs to be osmotically active and therefore need to contain an active agent and an osmotically active substance. Common "limited solubility" drugs that can be delivered through the use of such percutaneously active substances include hormones such as estrous hormone and progestin; steroids such as hydrocortisone alcohol or acetate and prednisolone acetate; and other drugs. Examples are bacitolicin, iodotuxuridine and catapres.

Other materials such as binders can be included in the permeable reservoir. The reservoir material can take a variety of forms, including solutions, dispersions, pastes, creams, particles, granules, tablets, emulsions, suspensions, and powders. However, solid or semi-solid forms are generally preferred for ease of manufacture and handling.

A simple "continuous permeable" delivery device (device 10), embodied and described as a drug delivery device, may offer many advantages over conventional drug dosage forms.
A single device, requiring only one application, provides enough drug for a complete treatment regimen. This large amount of drug can be safely administered at one time without the risk of accidental release of the entire amount due to puncture of the device. The device can be of simple and inexpensive construction. Importantly, in drug delivery embodiments, the device can be used in a patient's physical environment containing water despite erratic rates of change in environmental PH, enzyme activity, and other characteristics. Prior art corrosion and diffusion devices are susceptible to environmental changes, such as environmental PH, such as those that occur when passing the device through the gastrointestinal system.
changes have a significant impact on the drug release characteristics of the device.

The device according to the invention also makes it possible to continue drug release over a long period of time. The feed rate can be easily adjusted by varying the strength and water permeability of the matrix or membrane polymer or by varying the seepage effect of the contents of the drug reservoir.

The present invention can be used to release any drug into any aqueous physical environment of a patient.
As explicitly defined above, an aqueous bodily environment can be any bodily tissue or bodily cavity that contains an aqueous medium. Common aqueous bodily environments include the eye sac, gastrointestinal tract, vagina or uterus, muscle tissue or circulatory system. The devices of the present invention can take a variety of shapes, sizes and configurations for insertion, placement and injection or administration into these different aqueous body environments as is known in the art.

In one preferred embodiment, the method of the invention is applied to the manufacture of drug-delivering eye inserts. A typical ocular insert is shown in FIG. 6 as device 60. The device 60 is illustrated as an oval and enlarged. In fact, the device 60 has dimensions suitable for insertion and retention in the upper or lower cul-de-sac of the eye, i.e., a length of 6-
25 mm, 4-10 mm wide, and 100-750 microns thick, and can take any shape conducive to such insertion and retention. Such an arrangement is shown in FIG.

In FIG. 7, an osmoruptible oval ophthalmic device 60 according to the method of the present invention is shown positioned to administer medication to a second eye 70. Eye 70 is upper eyelid 7
1. The lower eyelid 72 and most of the posterior part are sclera 74
It also consists of an eyeball 73 whose central portion is covered by a cornea 75. The eyelids 71 and 72 have an epithelial membrane or palpebral conjunctiva (not shown) on the back side,
On the back side of the sclera 74, there is a bulbous conjunctiva that covers the exposed surface of the eyeball 73. The cornea 75 is covered with a transparent epithelial membrane (not shown). The part of the palpebral conjunctiva behind the upper eyelid 71 and the lower part of the bulbar conjunctiva constitutes the upper cul-de-sac as shown by the dotted line 76, and the part of the palpebral conjunctiva behind the lower eyelid 72 and the lower part of the bulbar conjunctiva constitutes the upper cul-de-sac as shown by the dotted line 76. The lower cul-de-sac is constructed as indicated by dotted line 77. The osmotic drug delivery device 60 is designed to be inserted into the conjunctival cul-de-sac 76 between the sclera 74 and the upper eyelid 71 of the eyeball 73 or into the conjunctival cul-de-sac 77 between the sclera 74 and the lower eyelid 72 of the eyeball 73; It is generally held in place by the natural pressure of each eyelid. Device 60 consists of a semi-permeable matrix 12 having a plurality of discrete osmotic reservoirs 11 containing drugs dispersed therethrough. The drug in the osmotic reservoir may itself be an osmotically active water-soluble ophthalmic drug such as pilocarpine salts (e.g., nitrates and hydrochloride) or a limited solubility drug such as the relatively osmotically inert hydrocortisone acetate and an osmotic agent such as those described above. It can be an intimate mixture with a chemically effective substance. The eye capsule provides a suitable aqueous environment for device 60 to operate. The lachrymal fluid present in the eye sac contains water which is absorbed through the semi-permeable polymeric matrix 12 by an osmotic drive mechanism, creating pressure within the outermost drug reservoir. This pressure sequentially ruptures the outer reservoir coating, liberating the drug within the reservoir and allowing the lachrymal fluid to access the underlying reservoir. The external result of this continuous osmotic rupture is a sustained continuous supply of drug to the eye, which continues over an extended period of time.

The shape and dimensions of the delivery device are factors that play a role in the rate at which the active agent is released from the device. As previously mentioned, the osmotic rupture release mechanism involves release of the active agent from an inwardly moving osmotic rupture surface or front surface. The rate of release is a function of the area of this surface or front surface. A drug delivery device in the form of device 60 is relatively thin and thus is essentially a two-dimensional device. Thus, the device provides a substantially constant surface area for drug release. Assuming a constant distribution of drug reservoirs 11 within matrix 12, this constant surface area will result in a relatively constant drug release rate.

The situation is different with spherical delivery devices embodying the invention for use in the delivery of fertilizers or other bioactive agents or drugs to the gastrointestinal tract or as inserts. When using a spherical device,
The exudative rupture front always moves inward. The radius of the spherical front surface decreases at a constant rate, i.e., according to the formula radius = radius first - [K·time] (K is a constant). In this case 4π・
The seepage rupture surface area, which is (radius) ² , decreases in proportion to the square of the usage time. The active agent release rate coupled to the rupturable surface area therefore decreases rapidly over time. If a constant release rate is desired (i.e., a rate of release of the active agent that does not vary as a function of time...a rate with zero-order time dependence, rate=Kt°), it is possible to provide a constant drug release surface area. (unless, of course, an activator concentration gradient is created within the device to compensate for rupture area changes). As illustrated by device 60, one way to achieve a constant surface area device is to make the device substantially two-dimensional, i.e., by subtracting one dimension (thickness) from the other dimensions (length and width). 1/
It should be 10 or less. Such a shape is approximately 1
It is effective to release the drug at a constant rate for a period of time up to several days or weeks, such as 20 days.

During use of a device such as device 60, the distance (thickness) that the osmotically rupturable front surface moves is small, so the speed of movement of the front surface must be very small, especially if the delivery is substantially prolonged. Such a slowly moving front is unduly susceptible to interference. A device configuration according to the method of the present invention that provides a uniform area for osmotic rupture without the potential disadvantages of the device of FIG. 6 is device 80 of FIG. Device 80 includes an externalized core 81 , a core with a portion of its surface exposed to the exterior of the device and the remaining surface covered by a membrane or coating 82 . Core 81 is constructed from a plurality of permeable active agent reservoirs 11 dispersed and surrounded by matrix 12. Storage body 1
1 and matrix 12 cooperate to cause the core 81 to rupture through the "seepage rupture" mechanism described in FIGS. 1, 2, and 3.
It acts to supply the active agent from the exposed area of the body. Membrane or coating 82 is a material that is substantially impermeable to the contents of reservoir 11, but also impermeable to the aqueous environment in which it is used. In device 80, when the device is in use, the active aqueous environment substantially enters the core through the two open ends of the device, and osmotic rupture occurs at the two front faces moving inward from the open ends. The area of the front surface of seepage rupture is 80
remains substantially constant as it moves through the area. Device 80 is simple to manufacture. A long tubular membrane or coating filled with core 81 can be extruded and cut into appropriate lengths. A simple and inexpensive device such as device 80 can be used to deliver a wide variety of low cost non-pharmaceutical active agents.

The osmoruptible active agent delivery device according to the method of the invention further has an embodiment as an intrauterine drug delivery device. Figures 9 and 11 illustrate the device of the present invention as two of the many art-recognized forms that a uterine retention device can take. Device 90 of FIG. 9 is a loop-like device of a shape and size suitable for insertion into the uterus through the cervical canal. Device 110 of FIG. 11 is a "T" shaped device of suitable shape and dimensions for placement in the uterus. The device 90 is the device 80
It has the same structure as . As shown in FIG. 10 (view of one end of device 90), device 90 includes outer covering 82
It consists of 81 cores that are combined. Core 81 is comprised of a permeatively rupturable matrix containing a permeately effective drug reservoir according to the present invention. These details are in the first
Not shown in Figure 0. The coating 82 is impermeable to the aqueous uterine fluid that enters the device 90 from the two open ends of the drug reservoir and causes osmotic drug release. Each open end exposes the inner core to an aqueous environment. It goes without saying that it is not necessary that both ends of such a device be open to expose the heart, as illustrated by device 10 of FIG. 11.
In the device 110, the coated device 80 is connected to the crosspiece 11
1 to form a "T". A drug reservoir is present within device 80. The contents of these reservoirs are continuously released by uterine fluid entering the lower end of the axial arm of device 110 and causing osmotic rupture. Device 90 or 110 provides continuous, prolonged drug release. This release is also at a substantially constant rate. Since the path through which the corrosion front must travel is relatively long (e.g., device 90
(length of time), fairly rapid (and therefore less sensitive) frontal movement speeds can be used even over very long periods of time, such as a year or more. Thus, although intrauterine devices according to embodiments of the present invention can be used for relatively short term uterine administration of drugs, such as administration of antibiotics or counterstimulants for 0.5 to 7 days,
It can also be used to deliver drugs to the uterus over long periods of time, such as a year or more. In this latter application, it is preferably used to provide progestin, estrous hormone and contraceptive hormones, preferably over a period of about two months to two years. Since these hormones are not water soluble, it is generally necessary to intimately add the osmotic active substance to the hormone reservoir of the device, as described above.

Devices 90 and 110 are just two of the many possible forms that devices according to the methods of the invention can take in utero. Other suitable forms of intrauterine contraceptive devices are shown in the text of Shubetsk et al., published in 1971 by the Massachusetts Institute of Technology, and this text is cited here.

In describing devices 80, 90, and 110, reference was made to their outer walls or barrier membranes that are impermeable to aqueous environments. Precisely, a good barrier membrane exhibits a water permeability from the atmosphere of 2.5×10 ^-9 cc·microns/cm ² ·hr. Materials that meet this criterion include polyethylene, polyvinylidene chloride, polyvinyl chloride, natural rubber, silicone rubber, polyisoprene, polybutadiene, styrene/butadiene copolymers, ethylene/propylene rubber, and tetrafluoroethylene polymers. These membranes or walls need to be imperforate and thick enough so that they do not become punctured by osmotic expansion or rupture that occurs within the device core.

In the apparatus shown in Figures 1-3 and 6-11,
A reduction or constant rate of reagent release is achieved.
One embodiment of such a device is shown as device 120 in FIGS. 12 and 13. FIG. 12 is a front view of the device 110, and FIG. 13 is a cross-sectional view of the device.

Device 120 includes an active agent reservoir containing a permeable rupturable core 81 of substantially trapezoidal cross section. Device 1
20 contains an active agent and an outer wall 121 that is impermeable to an aqueous environment surrounding all but one side of the top, bottom, and core 81. Core 81 is exposed at opening 122.

In use, fluid from an aqueous environment is first introduced into opening 1.
22 core 81 is contacted. With this opening (at t°)
A seepage rupture occurs first. The rupturable front moves inward in time at successive times t ₁ , t ₂ , t ₃ and t _{4 ,} respectively, until it reaches each point of the heart indicated by the dotted line in FIG. The width of the rupture front increases with inward movement. Since the front surface moves at a relatively constant speed, this means that the amount of active agent released increases gradually and the rate of release increases.

A number of other techniques can be used to alter the temporal pattern of active agent release in devices according to the method of the invention. For example, instead of uniformly distributing constant active agent content reservoirs in a rupturable matrix, the number of reservoirs or active agent content can be varied within a single matrix, increasing and/or decreasing the release rate over time. let Also, more than one active agent can be included in different locations of the device to allow for administration of multiple different active agents at different times.

Examples of the present invention will be described below.

EXAMPLE 1 A "seep-rupture" delivery device for the prolonged release of drug (pilocarpine nitrate) into the eye is constructed and tested as follows.

(a) Manufacture of seepage-rupturing substance 7 g of finely powdered pilocarpine nitrate was
% vinyl acetate and melt index
Mix with 3 g of ethylene-vinyl acetate copolymer (DuPont Elvax 40) having a rate of 45-70 g/min (ASTMD 1238-modified test). This copolymer has a tensile strength of about 42-49 Kg/cm ² and an elongation at break of 1400-1500%. This copolymer is semipermeable, impermeable to pilocarpine nitrate, but water-permeable. Pilocarpine nitrate is a "water-soluble" substance (water solubility approximately 25%) and acts as an osmotically active substance. Pilocarpine nitrate particles have an average diameter of ~40 microns. The mixture is heated to 120°C and cast into a 580 micron thick film.

(b) Manufacture for ocular insertion A number of 6 mm disks of suitable dimensions for placement in the eye capsule are cut from a 580 micron thick film.
The surface area of these discs is 66mm ² .

(c) Testing the Insert The insert is placed in the aqueous environment of the eye. The outermost drug reservoir absorbs water and swells, rupturing the surrounding membrane, releasing the drug and exposing the inner reservoir. The amount of drug released is monitored by a UV spectrometer set at 215+1 meter wavelength. Relatively rapid pilocarpine nitrate release begins to be observed. Release continues at a gradually decreasing rate for about 22 hours, from an initial 400 micrograms/hour to about 250 micrograms/hour after 22 hours. After 22 hours the release rate decreases rapidly. Microscopic and macroscopic comparisons of the device before and after use show that the device retains its unitary shape, yet releases the drug by osmotically rupturing the membrane surrounding the drug reservoir. Fourth
Figures 5 and 5 are microscopic photographs taken of this drug-containing matrix material before and after drug release, respectively.
This shows the effect of osmotic burst release.

Example 2 A partially enclosed "permeable" eye drug delivery device is created.

First, a strip having a width of 2500 microns and a length of about 20 cm was cut from the 580 micron thick pilocarpine nitrate-ethylene-vinyl acetate copolymer permeable matrix prepared in Example 1. This strip is made of two transparent polymeric materials that are impermeable to water and chemicals.
Sandwiched between 75 micron sheets of air. An oval ocular insert is punched out of the laminate enclosing the enclosed matrix. This insert has a shaft of 6mm x 13mm.
There is a central strip of matrix 13 mm long, 2500 microns wide and 580 microns thick.
Only the 580 x 2500 micron edges of the matrix are exposed. 14 and 15 are front and cross-sectional views of such a device, in which device 140 shows an inner matrix 142 and an outer laminated partial cover 141.

Place one of these inserts in a fancy ocular environment. Pilocarpine nitrate is released continuously at a controlled rate by seep-rupture. Visual inspection of the device shows that rupture occurs as the rupture front gradually moves, since the area where the drug is present is opaque white and the matrix area used is translucent.

The first two days the release rate decreases from about 75 micrograms/hour to about 50 micrograms/hour. Over a further 6 days, the drug release rate is about 50 to about 40 micrograms/hour. After about 200 hours of total testing, the chemical content is virtually gone. The drug release rate decreases to 0 micrograms/hour.

Examples 3-6 To demonstrate the insensitivity of controlled release devices according to the method of the invention to environmental conditions, one device made in Example 2 was placed in an acidic aqueous environment (PH4) and the other in an alkaline environment. One is placed in an aqueous environment (PH9), one is placed in a 3°C aqueous environment, and one is placed in a sample of laboratory wastewater. Even under these conditions, all devices continue to release active agent in substantially the same manner as in Example 2.

Example 7 A tubular continuous release system is made as follows.

80 parts monobasic ammonium phosphate fertilizer is pulverized to an average particle size of 40 microns.

10 parts of polyvinyl chloride (Geon 103), 10 parts of plasticizer (Santisizer 334) and 162 parts of tetrahydrofuran are mixed with fertilizer and this mixture is
It is extruded through a cm die to form a continuous rod, and is flash dried to remove tetrahydrofuran. The rods are spray coated with a water and fertilizer impermeable coating to a thickness of 25 microns and then cut into 11/4 cm long coupons.

These coupons were then tested in an aqueous environment, which showed that the open (cut) ends of the coupons were able to osmotically absorb water and gradually release the enclosed fertilizer over several hours. I understand.

When applied to artificially irrigated soil, these specimens osmotically absorb water with any irrigation and release water and fertilizer during the irrigation period.

Examples 8 and 9 40g of progesterone (10μ particles) are mixed with 40g of sodium bicarbonate (10μ particles). Mix progesterone and NaHCO ₃ in a V-type dry blender for 24 hours. Add this drug/bicarbonate mixture to 20 g Erbax 40 in a small enclosed mixer and heat mix for approximately 30 minutes. After mixing in a mixer, the intimately mixed molten mass is extruded into 1.8 mm ID polyethylene tubing. Seal one end of this 6 cm long tube, heat it, and bend it into a loop shape as shown in Figure 9. A 3.5 cm long piece is used as the center bar of a "T" shaped device and is joined to a solid polyethylene arm bar to yield the device shown in FIG. When placed in the human uterus, each of these devices releases progesterone at a rate of ~50 micrograms/day. A 6 cm long loop device maintains this release rate for approximately 2 years, resulting in a "T"
The equipment will be retained for one year. After these periods the release rate decreases.

Example 10 3 g of Elvax 40 are mixed with 27 g of tetrahydrofuran to obtain a homogeneous solution. Add 7g of triethylenethiophosphoramide (40μ) to this polymer solution.
particles). The drug/polymer/solvent mixture is cast and the solvent is driven off to yield a 750 micron thick dry sheet. Polymer/chemical sheet 2.4mm wide
This strip is then coated with a 100 micron thick layer of drug and water impermeable polymeric material.
Place it between two sheets. Punch an elliptical device out of the stack that encloses the enclosed matrix. In this device with a length of 13 mm and a width of 6 mm,
A matrix strip 2.4 mm wide and 750 microns thick runs down the center of the large axis. Only the ends of the matrix are exposed.

The device is surgically injected directly into the location of the cancerous growth. As body fluids are absorbed by the exposed matrix, the device begins to release triethylene phosphoramide at a constant rate of about 2 mg/day. After 10 days, the chemicals are gone and the device can be removed.

Example 11 The experiment of Example 1 is repeated using an intimate 50/50 mixture of hydrocortisone acetate and sodium chloride as the drug instead of 7 g of micronized pilocarpine nitrate.

Substantially insoluble hydrocortisone acetate alone does not promote exudative rupture. However, when combined with soluble salts, osmotic burst release occurs.

Example 12 (a) Preparation of seepage rupture material 37.5 parts of the copolymer of Example 1 and 150 parts were dissolved in methylene chloride. 12.5 parts of tetracycline hydrochloride were ultrasonically mixed with 25 parts of methylene chloride. The two resulting mixtures were then combined, the container containing them rinsed with 10 parts of methylene chloride, and the rinse solution added to the mixture. The entire mixture was mixed so that the slurry had a smooth texture.

This slurry was cast into a 250-300 micron film.

(b) Manufacture of eye inserts A number of crescent moon inserts (13.3 mm x 3.6 mm) each containing 3.33 mg of tetracycline hydrochloride were punched out from the above film using a punch.

A number of oval inserts (5 mm x 8 mm) each containing 2.40 mg of tetracycline hydrochloride were punched out of the film.

(c) Testing of Inserts The crescent and oval inserts of (b) were tested in the manner of Example 1, (c) with a UV monitor set at 356+1 meter wavelength.

The initial tetracycline hydrochloride release rate from the crescent insert was approximately 25 μg/hour. After 40 hours, the rate decreased to 8-9 μg/hr and then generally leveled off with a gradually decreasing curve. After 160 hours, the release rate was 4 μ
g/hour.

The initial release rate from the oval insert is approximately 17μ
g/hour. This speed is approximately 8μ after 15 hours.
It showed a curve that decreased in g/hour, then leveled out and gradually decreased. After 160 hours the release rate was approximately 21/2 μg/hour.

The release mechanism was the same as that observed with the insert of Example 1.

Example 13 (a) Production of seepage-rupturable material Six parts of the polymer of Example 1 were kneaded in a roll mill to form a film. 4 parts of diethyl carbamazine citrate (<5 micron particle size) were slowly added to the film with further martication. This mixture is passed through the mill again to obtain a smooth dispersion of diethyl carbamazine citrate dispersed in the polymer.
The resulting sheet was placed in a liner and hot pressed at 55°C for 5 minutes to form a 500 micron film.

(b) Manufacture of eye inserts A number of oval inserts were punched out from the above film using a punch. The insert is 5.8mm x 13.5mm,
The surface area was 1.2 cm ² .

(c) Testing of Inserts The inserts of (b) were tested with a UV monitor set at 213.5+1 meter wavelength according to the method of Example 1, (c).

The initial release rate of diethyl carbamazine citrate was approximately 30 μg/hour. This rate was approximately 25 μg/hour after 1 day, and this rate was maintained with a slight decrease over approximately 5 days. After 5 days the release rate decreased rapidly.

The release mechanism was the same as that observed with the insert of Example 1.

Example 14 Example 13 was repeated, except that the seepage rupture material was made from 7 parts polymer and 3 parts diethylcarbamazine citrate.

The initial release rate was about 17-18 μg/hour.
After 1 day the release rate was approximately 10 μg/hr and this rate continued for approximately 8 days and then rapidly decreased.

The release mechanism was the same as that observed with the insert of Example 1.

Example 15 (a) Preparation of percolation-rupturable material A mixture of 8 parts of the polymer of Example 1 and epinephrine bitartrate (particle size 5-50 microns) was solvent cast to obtain a film. This film was placed in a liner and melt pressed at 50°C to obtain a 425 micron film.

(b) Manufacture of eye inserts A large number of circular inserts (6mm
D) was punched out with a punch.

(c) Testing of the Insert The insert of (b) was tested using the method of Example 1, (c) with a UV monitor set at 279+1 meter wavelength. The initial release rate of epinephrine bittertrate was 32 μg/hour. This rate decreased rapidly to approximately 5 μg/hr on the first day of testing and then leveled out. After 120 hours, the rate was 2 μg/hour.

The release mechanism was the same as that observed for the insert of Example 1.

Example 16 (a) Preparation of a seepage rupture material A mixture of 85 parts of the polymer of Example 1 and 15 parts of isoproterenol hydrochloride (particle size 5-100 microns) was prepared by the method of Example 15, (a). difference
Created 150 micron film.

From a mixture of 70 parts of the polymer of Example 1 and 30 parts of isoproterenol hydrochloride (particle size 5-100 microns), the thickness was prepared by the method of Example 15, (a).
Created 150 micron film.

(b) Manufacture of eye insert A number of 6 mm D disks were punched out from the above film using a punch. Sandwich a 70/30 polymer/isoproterenol hydrochloride disc between two 85/15 polymer/isoproterenol hydrochloride discs and heat press the three discs together at 50°C to a thickness of 450 microns. I made a laminate board.

(c) Testing of the Insert The insert of (b) was tested using the method of Example 1, (c) with a UV monitor set at 279+1 meter wavelength.

The initial release rate of isoproterenol hydrochloride was 30 μg/hour. This rate decreased by approximately 7 μg/hour during the first day of testing;
It became uniform at this speed. After 120 hours, the release rate was still approximately 7 μg/hour.

The release mechanism was the same as that observed for the insert of Example 1.

[Brief explanation of the drawing]

FIG. 1 is an enlarged cross-sectional view of a dispensing device according to the method of the invention; FIGS. 2 and 3 are enlarged cross-sectional views of FIG. 1 after two different periods of use; and FIGS. 4 and 5 are before and after drug dispensing. Scanning electron micrographs of the internal structure of the drug supply device according to the method of the present invention, respectively;
FIG. 6 is a partially cutaway enlarged perspective view of an oval embodiment according to the method of the invention for delivering drugs into the eye; FIG. 7 is a front view of the eye illustrating the use of the device of FIG. 6; FIG. 9 and 11 are enlarged front views of two devices according to the method of the invention for delivering drugs into the uterus, FIG. FIG. 10 is an end view of the exposed end of the device of FIGS. 9 and 11;
Figures 2 and 13 are front and cross-sectional views of a substantially enclosed embodiment according to the method of the present invention, and Figures 14 and 15 are front and cross-sectional views of another ocular delivery embodiment according to the method of the present invention. . 10...Release device form, 11...Active storage, 12...Matrix, 60...Ocular insert,
70...Eye, 73...Eyeball, 81...Heart, 82...
... Covering, 90 ... Loop-shaped device, 110 ... T-shaped device, 111 ... Arm bar, 120 ... Trapezoidal cross-section device, 121 ... Outer wall, 122 ... Opening, 141
...Coating, 142...Matrix.

Claims (1)

Claims: 1 (a) 1 part by weight of an osmotically effective active agent reservoir-forming material comprising a water-soluble active agent or a mixture of a water-insoluble active agent and an osmotically active material;
A vinyl polymer or copolymer, from 14 to
Tensile strength of 700Kg/ ^cm2 , maximum elongation of 10-2000%, water permeability of 2.5× ^10-6 to 2.5 cc・micron/ ^cm2・hr・atm of water and 2.5× ^10-9 storage body forming material g microns/cm ² hr atm or less, substantially impermeable to the reservoir forming material, at least during the release of the osmotically effective active agent in an aqueous environment. 0.25 to 5 parts by weight of a matrix polymer that is insoluble in water, permeable to water, and has a cohesive strength inferior to the osmotic pressure generating capacity of the individual osmotically effective active agent reservoir, thereby forming a reservoir-forming material. is dispersed in a matrix polymer, and the diameter is 0.1~
(b) forming or casting the mixture; characterized in that the molded article is cut to form a unit of size and shape suitable for introduction into an aqueous environment, such that when placed in an aqueous environment, water will flow into the reservoir closest to the external surface of the device. osmotically adsorbed, thereby generating sufficient pressure to rupture the surrounding polymer, releasing the active agent and allowing access of the aqueous environment to the next nearest reservoir, followed by similar 1. A method for producing a device for continuous and sustained release of an active agent into an aqueous environment, characterized in that: