NL8401470A - OSMOTIC DEVICE WITH DUAL THERMODYNAMIC ACTIVITY. - Google Patents

Description

. - * '' N.0. 32,214 1

Osmotic device with dual thermodynamic activity.

The invention relates to both a new and unique delivery system. In particular, the invention relates to an osmotic device comprising a wall formed at least in part of a semipermeable material surrounding a compartment 5, said compartment comprising: (1) a first osmotic composition, which comprises an advantageous agent and preferably an osmotic agent and / or an osmotic polymer, which composition is in contact with (2) a second osmotic composition, which contains an osmotic agent and an osmotic polymer. A passage through the wall connects the outside of the osmotic device to the first osmotic composition containing the beneficial agent for delivering the first composition from the osmotic device. The osmotic device is useful for delivering beneficial agents, which because of their solubilities are difficult to deliver from an osmotic delivery system at a known rate at a controlled rate.

Since the beginning of ancient times, a delivery system for administering an advantageous drug has been sought in the field of pharmacy and medicine. The first dosage-form writing is the Eber Papyrus, written in about 1552 BC. Dosage forms are mentioned in the Eber Papyrus, such as anal suppositories, vaginal pessaries, ointments, pill formulations intended for oral administration, and other dosage forms. About 2500 years passed without any progress in the development of the dosage forms until the Arab physician Ehazes (865-925 A.D.) invented the coated pill. About a century later, Avicenna (980-1037 A.D.) coated pills with gold or silver to enhance patient acceptability and increase drug efficacy. Also about this time, the first tablet was described in Arabic manuscripts written by al-Zahrawi (936-1009 A.D.). The manuscripts described a tablet formed from the cavities of two opposing tablet forms. Pharmacy and medicine have waited about 800 years for the next development of dosage forms, when Mothes invented the cap-35 sule for drug delivery in 1883. The next major development in dosage forms came in 1972 with the invention of the osmotic delivery device by the inventors Theeuwes and Higuchi, as described in U.S. Patent 8401470

* V 'V

2 scriptures 3,845,770 and 3,916,899. The osmotic devices described in these patents include a semipermeable wall surrounding a beneficial agent containing compartment. The wall is permeable to the passage of an external fluid and is substantially impermeable to the passage of beneficial agent. There is a passage through the wall for the delivery of the beneficial agent from the osmotic device. These devices deliver beneficial agent by incorporating liquid at a rate determined by the permeability of the semipermeable wall and the osmotic pressure gradient through the semipermeable wall into the compartment through the semipermeable wall, producing an aqueous solution, which is beneficial agent which solution is delivered from the device through the passage. These devices are extremely effective in delivering a beneficial agent, which is soluble in the liquid, and exhibits an osmotic pressure gradient through the semipermeable wall to the external liquid.

A groundbreaking development in the field of osmotic delivery devices is described in U.S. Patent 4,111,202. In this patent, the release kinetics of the osmotic device for improving the delivery of beneficial agents, which are insoluble to very soluble in the liquid, are improved by the production of an osmotic device having a beneficial agent compartment and a compartment for osmotic agent, which are separated by a film. The film is movable from a quiescent state to an expanded state. The osmotic device delivers agent in that fluid, which is absorbed through the semipermeable wall into the osmotic agent compartment, thereby forming a solution, increasing the volume of the compartment, which acts as a driving force against the film exerted. This force 30 forces the film to expand against the beneficial agent compartment and correspondingly reduces the volume of the beneficial agent compartment, delivering beneficial agent through the passage from the osmotic device. While this device works successfully for its intended application and while it may release numerous beneficial agents of various solubilities, its use may be limited due to the manufacturing steps and costs required to produce and place the movable film in the compartment of the osmotic institution.

U.S. Pat. No. 4,327,725 provides an osmotic dispenser for the delivery of beneficial agents, 8401470-a * 3, which, due to their solubilities in aqueous and biological fluids, are difficult to make in meaningful amounts at controlled rates over time. be issued. The osmotic devices of this patent include a semipermeable wall surrounding a compartment 5 which is an advantageous agent, which is insoluble to very soluble in aqueous and biological fluids, and an expandable hydrogel. During operation, the hydrogel expands in the presence of external liquid entering the device, causing the release of the beneficial agent through the passage of the device. This device operates successfully for its intended use and it delivers many difficult to deliver beneficial agents for its intended purpose. However, it has now been observed that its use may be limited because the hydrogel lacks the ability to absorb sufficient liquid for the maximum self-expansion required for the expulsion of beneficial agent from the device.

It will be appreciated by those skilled in the art that when an osmotic device can be provided that exhibits a high degree of osmotic activity with respect to the delivery of an advantageous agent by generating an expansion force in situ sufficient to be supplied with a delivering the maximum amount of agent from an osmotic device at a controlled rate, such an osmotic device would have a positive value and represents an advance in the delivery devices. It will also be readily apparent to one skilled in the art that when an osmotic device is made available that has a dual thermodynamic osmotic activity for delivering increased amounts of a beneficial agent, this osmotic device could find practical application in the art Therefore, according to the present invention, an osmotic system is provided, which means further improvement and advancement in the delivery devices.

Next, according to the invention, there is provided an osmotic system, which is manufactured in the form of an osmotic device 35 for delivering a beneficial agent in vivo, which is difficult to deliver and can now be delivered in therapeutically effective amounts over time by the osmotic device provided according to the present invention.

Furthermore, according to the invention, an osmotic system is provided, which has dual osmotic activity, which system comprises an 8401470 1 1 1 1 4 compartment containing a first osmotic composition comprising a medicament and preferably an osmotic agent and / or an osmotic polymer, and a second osmotic composition, comprising an osmotic agent and an osmotic polymer, the compositions cooperating for drug delivery from the osmotic device.

Furthermore, according to the invention there is provided an osmotic device, which has means for loading to a considerable degree with a water-insoluble or a slightly water-soluble medicine and means for in all cases at a controlled speed and continuously for time to release the medicine.

Next, according to the invention, there is provided an osmotic device which can deliver a pH-dependent beneficial agent by providing a neutral medium for delivering the beneficial agent in a finely dispersed form for increasing its surface area and for maximizing the dissolution rate of the beneficial agent.

Furthermore, according to the invention, there is provided an osmotic system for the delivery of a drug with a very low dissolution rate, ie the rate-limiting step for the delivery of drug from the system, which however can now be delivered using a osmotic composition, which serves in situ as a wetting agent and solubilizing agent to increase the dissolution rate and solubility of the drug, promoting its release from the osmotic system.

Furthermore, according to the invention there is provided an osmotic system comprising means for maintaining a high degree of osmotic activity of a polymer which is used to deliver a beneficial agent from the osmotic system.

Furthermore, according to the invention there is provided an osmotic therapeutic device, which can administer a complete pharmaceutical dosage regimen, comprising sparingly soluble to very soluble agents, at a controlled rate and continuously for a certain period of time, the application requiring only intervention for the start and possible termination of the regimen.

Other objects, aspects and advantages of the invention will become apparent from the following detailed description in combination with the accompanying drawings and claims.

In the drawings, not drawn to scale, but those illustrating various embodiments of the invention, the figures are as follows: Figure 1 shows an isometric view of an osmotic device , which is for oral administration of an active substance to the gastrointestinal tract; Fig. 2 shows an exploded view of the osmotic device of fig. 1, illustrating the structure of the osmotic device of fig. 1; FIG. 3 shows an exploded view of the osmotic device of FIG. 1, wherein the osmotic device is in operation and a beneficial agent is delivered from the osmotic device; FIG. 4 shows an exploded view of the osmotic device of FIG. 1, taking into account FIG. 3, wherein the osmotic device is in operation and a substantial amount of a beneficial agent is delivered from the osmotic device; Fig. 5 shows an osmotic device for therapeutic ends, the wall of which has been partially removed, which device is intended for the delivery of an advantageous agent in a body cavity, such as the anal (rectal) and vaginal cavities; Fig. 6 shows the osmotic device of Fig. 5 with a different structure of the wall; FIG. 7 shows the osmotic device of FIG. 5 showing another structure of the wall of FIG. 6; FIG. 8 shows weight gain as a function of time for a polymer in a semipermeable membrane enclosure when the encapsulated polymer is introduced into water; Figure 9 shows the cumulative amount of drug delivered from a device comprising an osmotic polymer of two different molecular weights; Figure 10 shows the cumulative amount of drug delivered from a device using a different set of osmotic polymers; Fig. 11 shows the osmotic pressure curves for a number of osmotic agents and a number of compositions of osmotic polymer and osmotic agent; Fig. 12 shows the cumulative release profile for an osmotic system using two different osmotic polymers; FIG. 13 shows the hourly release rate for an osmotic system, which is different from FIG. 9 and which contains an osmotic polymer of 40 having two different molecular weights; 8401470

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Fig. 14 shows the cumulative amount released from a single composition-containing device comprising only one layer. Fig. 15 shows the cumulative release in vivo and in vitro for a drug delivered by the osmotic device; Figure 16 shows cumulative in vivo and in vitro release for another drug delivered by an osmotic device.

In the drawings and in the description, like parts in related figures are indicated with like reference numerals. The terms mentioned earlier in this description and in the description of the drawings as well as the embodiments thereof are further elucidated elsewhere in the description.

As for the drawings, which are examples of various osmotic devices according to the invention, and which examples should not be construed as limiting, an embodiment of an osmotic device is shown in Fig. 1. In Fig. 1, the Osmotic device 10 is shown. shown with a body 11 having a wall 12 and a passage 13 for delivering a beneficial agent from osmotic device 10.

In Figure 2, the osmotic device 10 of Figure 1 is shown cut away. In Fig. 2, osmotic device 10 comprises a body 11, a semipermeable wall 12, which surrounds and forms an internal compartment 14, which compartment communicates via a passage 13 with the outside of the osmotic device 10. Compartment 14 contains a first osmotic composition comprising an advantageous agent 15, indicated by dots, which may be insoluble to very soluble in the liquid contained in compartment 14, an osmotic agent 16, indicated by wavy lines, which is soluble in the liquid contained in compartment 14, and an osmotic pressure gradient through the semipermeable wall 12 to an external liquid, and an osmotic polymer 17, indicated by horizontal dashes, which accepts liquid in compartment 14 and exhibits an osmotic pressure gradient through the semipermeable wall 12 to an in-use external liquid. Wall 12 is formed of a semipermeable composition, which is substantially permeable to the passage of the external fluid, and which is substantially impervious to the passage of the external fluid, and is substantially impermeable to the passage of agent 15, osmotic agent 16 and osmotic polymer 17. The semipermeable wall 40 is nontoxic and maintains its chemical cohesion during the 84 0 1 4 7 0 * 7 release period of device 10.

Compartment 14 also contains a second osmotic composition spaced from passage 13 and in contact with the first composition. The second composition provides an expandable driving force which interacts with the first osmotic composition to deliver the maximum amount of beneficial agent 15 from osmotic device 10. The second osmotic composition comprises an osmotic agent 18 which is soluble in the compartment 14 «absorbed liquid and exhibits an osmotic pressure gradient through wall 12 to an external liquid, mixed with an osmotic polymer 19, which incorporates liquid into compartment 14 and exhibits an osmotic pressure gradient through wall 12 to the external liquid. The osmotic polymers 17 and 19 are hydrophilic, water-soluble or slightly cross-linked, water-insoluble polymers and they have osmotic properties, such as the ability to absorb external liquid, they exhibit an osmotic pressure gradient through the semipermeable wall to the external fluid and swell or expand (expand) in the presence of the fluid. The osmotic polymers 17 and 19 are mixed with osmotic agent 16 and 18 to receive the maximum volume of external liquid in compartment 14. This liquid is available for the osmotic polymers 17 and 19 to optimize the volumetric value and for the total expansion of the osmotic polymers 17 and 19. That is, the osmotic polymers 17 and 19 absorb liquid, which is contained in compartment 14 by the osmotic aspirating effect of the osmotic polymers 17 and 19, supplemented by the osmotic aspirating effect of the osmotic means 16 and 18 for causing the maximum expansion of the osmotic polymers 17 and 19 to an enlarged state.

In operation, the delivery of the beneficial agent 15 from the osmotic device 10 in a preferred embodiment is performed by (1) uptake of liquid by the first composition to form a suspension in situ, and delivery of the suspension through the passage; and at the same time by (2) incorporation of liquid by the second composition, causing the second composition to swell and interact with the first composition in driving the suspension of the agent through the passage. According to the above-described process, the osmotic device can be considered as a cylinder, the second composition expanding like the movement of a piston to contribute to the release of the suspension of the agent from the osmotic device. r ting. Although the shape of the osmotic device as shown in Figures 1 and 2 is not a true cylinder, this shape is approximated sufficiently for the following physical analysis. In this analysis, the volume value Ft delivered by the osmotic device is composed of two sources 5: the water absorption value by the first composition F and the water absorption value by the second composition Q, wherein:

Ft = F + Q (1)

Since the interface between the first composition and the second composition hydrates very little during the operation of the osmotic device, there is insignificant migration of water between the compositions. Therefore, the water uptake value of the second composition, Q, is equal to the expansion of its volume, dvp at * -Q <2>. The total release value from the osmotic device is then: dm -JE "- Ft - C - (F + Q) C (3) where C is the concentration of beneficial agent in the delivered suspension Maintaining the volume of the osmotic device V and the area A gives equations 4 and 5: 20 V - Vd + Vp (4) A - Ad + Vp (5) where V <j and Vp are the volume of the first composition and the second composition, respectively, and where A <j and Ap are the contact surface with the wall through the first composition, respectively. Second composition During operation, both Vp and Ap increase over time, while V <j and A ^ decrease over time as the device delivers beneficial agent.

The volume of the second composition, which expands over time when liquid is incorporated into the compartment, is given by equation 7: -fe ·) where Wh is the weight of the liquid absorbed by the second composition, Wp the weight of the second composition initially present in 84 0 1 4 7 0 m λ * r 9 is the device, Wg / Wp is the ratio of liquid to initially solid material of the second composition, Vp is 5 where e is the density of the second composition, corresponding to Wg / tfp. Therefore, based on the geometry of a cylinder, where r is the radius of the cylinder, the recording area is related to the volume of the swollen second composition in the following manner:, 2 wp% / 10 Ap * r1 + - -1 + / W „(8) re *

Ad - A - Ap (9)

The liquid uptake values in each compartment are: »- (4 ·) id ^ Q '(^) (^ Δ! ΓΡ) (U> 15 where k is the osmotic permeability of the wall, h is the thickness of the wall, and Δϋρ are the osmotic gradient for the first composition and the second composition, respectively, so the total release value is: dm k _ - 2 wp% --- C A-TTr1 --- 1 + - dt h Y p Wp Δ d 8401470

«P wH

20 + ^ 2 + - 1 + - (12) r p Wp Δ p

Figures 3 and 4 illustrate the in-operation osmotic device as described for Figures 1 and 2. In Figures 3 and 4, with respect to osmotic device 10, liquid is taken up by the first composition having a value which is determined by the permeability of the wall and the osmotic pressure gradient through the wall. The absorbed liquid continuously forms a solution containing beneficial agent or a solution or gel of osmotic agent and osmotic polymer containing beneficial agent in suspension which is released during each operation. by the combined actions of device 10. These actions mean that the solution or suspension is osmotically released through the passage due to the continuous formation of a solution or suspension and by swelling and increasing the volume of the second composition, indicated by the increase in the height of the vertical lines in Figs. 3 and 4. This later swelling and increase in volume exerts pressure against the solution or suspension, supporting the first composition and simultaneously delivering the beneficial agent. the exterior of the device is brought about.

The first composition and the second composition work together by two methods to substantially ensure that the release of the beneficial agent from the compartment is constant over an extended period of time. First, the first composition absorbs external fluid through the wall, forming a solution or a suspension, the final fraction of which would not be substantially delivered ("non-zero order") to a significant degree (without the second composition is present), because the driving force decreases with time. Second, the second composition 20 operates according to two simultaneous actions: first, the second composition acts to continuously concentrate beneficial agent by incorporating some liquid from the first composition to drop below saturation of the beneficial concentration. and secondly, the second composition continuously increases in volume by absorbing external liquid through the shore, exerting a force against the first composition and decreasing the volume of the beneficial agent, thereby reducing beneficial agent is led to the passage in the compartment. In addition, since the additional amount of solution or suspension formed in the first compartment is squeezed out, the osmotic composition comes into intimate contact with the interior wall and produces a constant osmotic pressure and therefore a constant release value along with the second composition. The swelling and expansion of the second composition with its associated volume increase together with the simultaneous corresponding volume reduction of the first composition ensures the release of beneficial agent at a time controlled rate.

The device 10 of Figures 1-4 can be manufactured in many embodiments, including the present preferred embodiments for oral use, for the delivery of some local or regional systemic therapeutic agent in the gastrointestinal tract. The oral system 10 can have various conventional shapes and sizes, such as a round shape with a diameter of about 0.48-1.3 cm. In these forms, system 10 can be adapted for the administration of beneficial agent to humans and numerous animals, including warm-blooded animals, birds, reptiles and fish.

In Figs. 5, 6 and 7, another embodiment is shown, namely an osmotic device 10, which is intended to be placed in a body cavity, such as the vagina or the anal (rectal) cavity. The device 10 has an elongated, cylindrical, self-supporting shape with a rounded front end 20, a rear end 21, and is provided with manually operated strings 22 for easy removal of the device 10 from a biological cavity. The device 10 is identical in structure to the above-described device 10, and 15 functions in a similar manner. In FIG. 5, device 10 is shown with a semipermeable wall 23, in FIG. 6 with a laminated wall 24, comprising an internal semipermeable wall 25 adjacent to compartment 14, and an outer microporous layer 26 spaced from compartment 14. . In Fig. 7, device 10 comprises a laminated wall 28 formed of a microporous layer 29 defining compartment 14 and a semipermeable wall 30 on the side of the operating environment and in laminar application with the microporous layer 29. Device 10 a beneficial agent for absorption through the vaginal mucosa or the anal (rectal) mucosa, producing a local or systemic effect in vivo over a prolonged period of time.

The osmotic devices of FIGS. 1-7 can be used for the delivery of very many agents, including drugs, at a controlled rate, independent of the drug's dependence on pH, or when the dissolution value of it can range from low to high in liquid environments, such as gastric juice and visceral fluid. The osmotic devices also provide for the large amount of low solubility agents and their delivery in meaningful therapeutic amounts. And although FIGS. 1-7 are illustrative of the various osmotic devices that can be manufactured according to the invention, these devices should not be construed as limiting the variety of shapes, sizes and construction for the devices. delivery of resources to the environment of use. For example, the use of the osmotic devices extends to the mouth, 8401470 * * I * 12 the ear, nose, skin, implantation, artificial glands, cervical, intrauterine, subcutaneous and delivery devices. the blood. The devices may also have a shape, size and structure such that they are suitable for the release of an active agent into open water, aquariums, fields, factories, reservoirs, laboratory equipment, greenhouses, transport equipment, ship equipment, military equipment, hospitals , veterinary clinics, nursing homes, farms, zoos, infirmaries, in chemical reactions and in other environments of use.

It has now been found according to the invention that the osmotic delivery device 10 can be manufactured with a first osmotic composition and a second osmotic composition, which are co-housed together in the device compartment. The compartment is formed by a wall which comprises a material which does not adversely affect the beneficial agent, osmotic agent, osmotic polymer and the like. The wall is permeable to the passage of an external liquid, such as water and biological liquids, and is substantially impermeable to the passage of agents, osmotic agents, osmotic polymer and the like. The wall 20 is formed from a material which does not adversely affect a host or an animal, and the selectively semipermeable materials used to form the wall cannot be eroded and are insoluble in liquids. Typical materials for forming the wall in one embodiment are cellulose esters, cellulose ethers, and cellulose ester ethers. These cellulose polymers have a degree of substitution, D.S., on the anhydroglucose unit of 0-3.

By "degree of substitution" is meant the average number of hydroxyl groups originally present on the anhydroglucose unit comprising the cellulose polymer, which are replaced by a substituent group. Representative examples of such materials are cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono, dien tricellulose alkanylates, mono, di and tricellulose arylates, and the like. Examples of polymers are cellulose acetate with a D.S.

35 of maximum 1 and an acetyl content of at most 21% by weight, cellulose acetate with an acetyl content of 32 - 39.8% by weight, cellulose diacetate with a DS of 1 - 2 and an acetyl content of 21 - 35% by weight, cellulose acetate with a DS of 2 - 3 and an acetyl content of 35 - 44.8 wt% and the like. More specific cellulose polymers are cellulose 40 propionate with a DS of 1.8 and a propionyl content of 39.2 - 45 8401470 * 13% by weight and a hydroxyl content of 2.8 - 5.4% by weight, cellulose acetate butyrate with a DS of 1.8, an acetyl content of 13 - 15 wt% and a butyryl content of 34 - 39 wt%, cellulose acetate butyrate with an acetyl content of 2-29 wt%, a butyryl content of 17 - 53 wt% and 5 a hydroxyl content of 0.5-4.7% by weight, cellulose trclacates with a DS of 2.9-3, such as cellulose trivalerate, cellulose trellaurate, cellulose tripalmitate, cellulose trisuccinate and cellulose trioctanoate; cellulose diacylates with a D.S. of 2.2 - 2.6, such as cellulose disuccinate, cellulose dl palmitate, cellulose dloctanoate, cellulose dlpental, cellulose coesters such as cellulose acetate butyrate and cellulose acetate propionate and the like.

Other semipermeable polymers include ethyl cellulose, cellulose nitrate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose acetate dimethyl amino acetate, poly permeable polyamides, semipermeable polypropylene, semipermeable polyphenylene sulfonated sulfonated sulfonate U.S. Patents 3,173,876, 3,276,586, 3,541,005, 3,541,006, and 3,546,142; semi-permeable polymers as disclosed in U.S. Patent 3,133,132, Slightly cross-linked polystyrene derivatives, cross-linked poly (sodium styrene sulfonate), cross-linked poly (vinyl benzyl trimethyl ammonium chloride), semipermeable polymers, which have a liquid permeability of 2.5 x 10 ”® to 2.5 x 10" ^ (cm®.cm / cm ^ .hr.bar), expressed per bar 10 "® hydrostatic or osmotic pressure difference through the semi-permeable wall. The polymers are known per se from U.S. Pat. Nos. 3,845,770, 3,916,899, and 4,160,020 and from the Handbook of Common Polymers, J.R. Scott and W.J. Roff, 1971, published by CRC Press, Cleveland, Ohio.

The laminated wall, which comprises a semipermeable layer and a microporous layer, is a laminar structure and the layers cooperate to form a continuous laminated wall, which maintains its physical and chemical cohesion and is not separated during the entire operating period for dispensing the agent from an osmotic device. The semipermeable layer is made from the above semipermeable polymeric materials, the semipermeable hamo polymers, the semipermeable copolymers and the like.

Microporous layers suitable for manufacturing an osmotic device generally include pre-formed microporous polymeric materials and polymeric materials which can form a micro-porous layer in the environment of use. The microporous materials are laminated in both embodiments to form the laminated wall. The preformed materials suitable for forming the microporous layer are substantially inert, they retain their physical and chemical coherence during the agent release period, and they can generally be described as materials having a spongy appearance, which provides a support structure for a semipermeable layer and also provides a support structure for very fine interconnected pores or voids. The materials can be isotropic with the structure homogeneous over the entire cross-sectional area, or they can be anisotropic with the structure non-homogeneous across the entire cross-sectional area. The pores can be continuous pores, which have an opening on both sides of a microporous layer, pores interconnected via serpentine paths of regular or irregular shape, such as curved, curved-straight, randomly oriented continuous pores, not freely connected pores and other porous paths, which can be detected by microscopic examination. Generally, microporous layers are defined by the pore size, the number of pores, the tortuosity of the microporous path, and the porosity associated with the size and number of the pores. The pore size of a microporous layer is easily determined by measuring the observed pore diameter on the surface of the material using an electron microscope. Generally, materials containing from 5 to 95% pores and having a pore size from 1 mm to 100 µm can be used to make a microporous layer. The pore size and other parameters, which characterize the microporous structure, can also be obtained from flow measurements, in which a liquid flow J is brought about by a pressure difference ΔΡ through the layer. The flow of liquid through a layer with a uniform radius of pores, which extends through the membrane and is perpendicular to its surface with a surface A, is given by the relationship 13: j * ν7γ4 ^ · ... (13) 8 ^ Δχ 35 where J is the volume that is transported per unit time and the surface of the laminate contains a number of pores N with a radius r, is the viscosity of the liquid and ΔΡ is the pressure difference through the layer with thickness Δχ. For a layer of this type, the number of 8401470 15 pores N can be calculated from the relationship 14, where £ represents the porosity, which is defined as the ratio of the void volume to the total volume of the layer; and A is the cross-sectional area of the layer containing N pores.

5 N * A- (14)

Ttr2

The radius of the pores is then calculated from the relation 15: r = 8 * 1 —--- (15) Δ p £ where J is the volume of the flow through the layer per unit time, caused by the pressure difference ΔΡ through the layer , represents, "%, 10 £ and Δχ have the above defined meaning and is the tortuosity, which is defined as the ratio of the serpentine path length in the layer to the thickness of the layer. Relations of the above type are discussed in Transport Phenomena In Membranes, by N. Lakshimatayanaiah, Chapter 6, 1969, published by Academy 15 Press, Inc., New York.

As discussed in this reference on page 336, table 6.13, the porosity of the pore-ray layers r can be expressed with respect to the size of the transported molecule with a radius a, and when the ratio of the molecular radius 20 to the pore radius a / r decreases, the layer becomes porous to this molecule. That is, when the a / r ratio is less than 0.3, the layer becomes substantially porous, as represented by the osmotic reflection coefficient 0 ", which decreases to a value of less than 0.5. Microporous layers with a reflection coefficient 0 * in the range below 1, usually from 0-0.5 and preferably from less than 0.1 relative to the active agent, are suitable for making the system The reflectance is determined by forming the material in the form of a layer and conducting water flow measurements as a function of the hydrostatic pressure difference and as a function of the osmotic pressure difference caused by the active agent. The osmotic pressure difference creates a hydrostatic volume flow and reflects the reflection coefficient expressed by relation 16: 0- * osmotic volume flow hydrostatic volume flow 35 Properties of microporous materials are described in

Science, vol. 170, pages 1302-1305, 1970; Nature, Vol. 214, 8401470 16, page 285, 1967, Polymer Engineering and Science, Vol. 11, pages 284-288, 1971; U.S. patents 3,567,809 and 3,751,536; and in Industrial Processing With Membranes by R.E. Lacey and Sidney Loeb, pages 131-134, 1972, edited by Wiley, In-5 terscience, New York.

Microporous materials with a preformed structure are commercially available and can be prepared by methods known per se. The microporous materials can be prepared by etching, "nuclear tracking", by cooling a solution of a flowable polymer below the solidification point, the solvent leaving the solution in the form of crystals, dispersed in the polymer, then curing the polymer, followed by removal of the solvent crystals by cold or hot stretching at high or low temperatures until pores are formed, by leaching a soluble component with a suitable solvent from a polymer, by ion-exchange reaction and by polyelectrolyte processes. Methods for manufacturing microporous materials are described in Synthetic Polymer Membranes by R.E. Resting, Chapters 4 and 5, 20 1971, published by McGraw Hill, Inc .; Chemical Reviews, Ultrafiltration, Vol. 18, pages 373-455, 1934; Polymer Eng. and Sci., Vol. 11, No. 4, Pages 284-288, 1971; J. Appl. Poly. Sci., Vol. 15, pages 811-829, 1971; and in U.S. Patents 3,565,259, 3,615,024, 3,751,536, 3,801,692, 3,852,224 and 3,849,528.

Microporous materials that can be used to make the layers include microporous polycarbonates consisting of linear polyesters of carbonic acid in which carbonate groups repeat in the polymer chain, microporous materials prepared by phosgenation of an aromatic dihydroxy compound such as bisphene -30 nol A, microporous polyvinyl chloride, microporous polyamides such as polyhexamethylene adipamide, microporous modacrylic copolymers, including the materials formed from polyvinyl chloride 60% and acrylonitrile, styrene acrylic and copolymers thereof, porous polysulfones, characterized by a linear vinyl sulfone groups chain thereof, halogenated polyvinylidene, polychloroethers, acetal polymers, polyesters, prepared by esterification of a dicarboxylic acid or anhydride with an alkylene glycol, polyalkylene sulfides, phenolic polyesters, microporous polysaccharides, microporous polysaccharides with substituted and unsubstituted substituted anhydroglucose units, which preferably have a higher permeability to water and biological fluids than the semipermeable layers, asymmetric porous polymers, cross-linked alkylene polymers, hydrophobic or hydrophilic microporous homopolymers, copolymers or interpolymers reduced bulk density and materials described in U.S. Patents 3,597,752, 3,643,178, 3,654,066, 3,709,774, 3,718,532, 3,803,061, 3,852,224, 3,853,601 and 3,852,388 , in British Patent 1,126,849 and in Chem. Abst., Vol. 71 4274F, 22572F, 22573F, 1969.

Other microporous materials include polyurethanes, cross-linked, elongated chain polyurethanes, microporous polyurethanes of U.S. Pat. No. 3,524,753, polyimides, polybenzimidazoles, collodion (cellulose nitrate with 11% w / w nitrogen), regenerated proteins, semi-cross-linked polyvinylpyrrolidone, microporous materials prepared by dispersing polyvalent cations in polyelectrolyte sols, such as according to U.S. Pat. No. 3,565,259, anisotropic permeable microporous materials of ionically associated polyelectrolytes, porous polymers formed by the coprecipitation of a polycation and a polyanion as described in U.S. Pat. Nos. 3,276,589, 3,541,055, 3,541,066 and 3,546,142, derivatives of polystyrene such as poly sodium styrene sulfonate and polyvinyl benzyl trimethyl ammonium chloride, the microporous materials disclosed in U.S. Pat. Nos. 3,615,024, 3,646. 178 and 3,852,224.

Furthermore, the microporous material used for the purposes of the invention includes the embodiment wherein the microporous layer is formed in situ by a pore-forming agent, which is removed by dissolving or leaching to form the microporous layer during the operation of the system. The pore-forming agent can be a solid or a liquid. According to this description, the term liquid also includes semi-solid and viscous liquids. The pore-forming agents can be inorganic or organic. The pore-forming agents suitable for the invention include pore-forming agents which can be extracted into the polymer without any chemical change. The pore-forming solids are about 0.1-200 µm in size and include alkali metal salts such as sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium benzoate, sodium acetate, sodium citrate, potassium nitrate and the like. Alkaline earth metal salts include calcium phosphate, calcium nitrate and the like. The transition metal salts include iron (III), iron (II) sulfate, zinc sulfate, copper (II) chloride, manganese fluoride, manganese fluorosilicate and the like. Pore-forming agents include organic compounds such as polysaccharides. The polysaccharides include the sugars sucrose, glucose, fructose, mannitol, mannose, galactose, aldohexose, altrose, talose, sorbitol, lactose, monosaccharides and di-saccharides. Also organic aliphatic and aromatic oils, including diols and polyols, such as, for example, polyhydric alcohols, polyalkylene glycols, polyglycols, alkylene glycols, polyctyl alkylene diol esters or alkylene glycols and the like; water-soluble cellulose polymers, such as hydroxyalkyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, methyl ethyl cellulose, hydroxyethyl cellulose and the like; water-soluble polymers such as polyvinylpyrrolidone, sodium carboxymethyl cellulose and the like. The pore-forming agents are non-toxic and when removed from the layer, channels are formed through the layer. In a preferred embodiment, the non-toxic pore-forming agents are selected from the group consisting of inorganic and organic salts, carbohydrates, polyalkylene glycols, poly-α, alkylene diols, esters of alkylene glycols, glycols and water-soluble cellulose polymers. used to form a microporous layer in a biological environment. In general, for the purposes of the invention, when the polymer forming the layer contains more than 25% by weight of a pore-forming agent, the polymer is a microporous precursor layer which, upon removal of the pore-forming agent yields a layer 25 which is substantially microporous; at lower concentrations than the aforementioned, the layer behaves as a semipermeable layer or membrane.

The term "passage" used in this description includes agents and methods suitable for the delivery of drug or other agent from the osmotic system. The term includes openings, nozzles, holes or bores through the semipermeable wall or the laminated wall. The passageway can be formed by mechanical drilling, making an opening with the aid of a laser or by eroding an erodible element, such as a gelatin barrier, in the environment of use. An extensive description of osmotic passageways and maximum and minimum passage dimensions are described in U.S. Pat. Nos. 3,845,770 and 3,916,899.

The osmotically effective compounds that can be used for the purposes of the invention include inorganic and organic compounds which have osmotic pressure gradient to an external liquid through the semipermeable wall or through a semipermeable microporous laminated wall. Osmotically effective compounds (together with the osmotic polymers) incorporate liquid into the osmotic device, whereby in situ liquid is made available for uptake by an osmotic polymer to promote its expansion and / or to form a solution or suspension containing an beneficial agent for its delivery from the osmotic device. The osmotically effective compounds are also known as osmotically effective solvents or osmotic agents. The osmotically effective compounds are used by mixing them with a beneficial agent and an osmotic polymer to form a solution or suspension containing the beneficial agent which is osmotically released from the device. The term "limited solubility" used in this specification means that the agent has a solubility of less than about 5% by weight in the surrounding aqueous medium. The osmotic solvents are used by homogeneously or heterogeneously mixing the solvent with the agent or osmotic polymer and then introducing them into the reservoir.

The solvents and osmotic polymers draw liquid into the reservoir, thereby forming a solution of the solvent in a gel which is released from the system, simultaneously transporting dissolved or undissolved beneficial agent to the outside of the system. Osmotically effective solvents used for the above-described purpose include, for example, magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium hydrogen phosphate, d-mannitol, urea , magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, ar-d-lactose monohydrate and mixtures thereof. The amount of the osmotic agent in the compartment will generally contain 0.01 - 30 wt.% Or more in the first composition and usually 0.01 - 40 wt.% Or more in the second compartment.

The osmotic solvent is initially present in excess and can be in any physical form compatible with the beneficial agent and the osmotic agent. The osmotic pressure of saturated solutions of various osmotically effective compounds and for mixtures of compounds at 37 ° C in water is listed in the table below. In this table, the osmotic pressure is indicated in bar. The osmotic pressure is measured in a commercially available 40 osmometer, in which the difference in vapor pressure between pure water and the solution to be analyzed is measured and according to standard thermodynamic principles, the vapor pressure ratio is converted into osmotic pressure difference. The table lists osmotic pressures from 20 bar to 500 bar; of course, the invention also includes the use of substances with a lower osmotic pressure from zero bar and a higher osmotic pressure than indicated by way of example in the table below. The osmometer used for these measurements is referred to as Model 320B, Vapor Pressure Osmometer, manufactured by Hewlett Packard Co., Avonadale, Pennsylvania.

i 8401470 • 21

TABLE

Compound or mixture Osmotic pressure, bar lactose fructose 500 5 dextrose fructose 450 sucrose fructose 430 mannitol fructose 415 sodium chloride 356 fructose 355 10 latose sucrose 250 potassium chloride 245 lactose dextrose 225 mannitol dextrose 225 dextrose sucrose 190 15 mannitol sucrose 170 dextrose 82 potassium sulfate 39 mannitol 38 sodium phosphate tribasic. 12H20 36 20 sodium phosphate diphasic. 7H20 31 sodium phosphate dibasic. also suitable for forming the second osmotic composition are osmotic polymers which have liquid uptake properties. The osmotic polymers are swellable, hydrophilic polymers that interact with water and aqueous biological fluids and swell or expand to an equilibrium state. The osmotic polymers have the ability to swell in water and retain a significant portion of the absorbed water within the polymer structure. The osmotic polymers swell or expand to a very great extent, usually a 2 to 50 fold volume increase takes place. In a preferred embodiment, the swellable, hydrophilic polymers are slightly cross-linked polymers, the cross-links being formed by covalent or ionic bonds. The osmotic polymers can be of vegetable, animal or synthetic origin. The osmotic

S4a; f4T (T

I * «* 22 polymers are hydrophilic polymers. Hydrophilic polymers suitable for the purposes of the invention include polyhydroxyalkyl methacrylate having a molecular weight of 30,000-5,000,000; polyvinylpyrrolidone with a molecular weight of 10,000-360,000; anionic and cationic hydrogels; polyelectrolyte complexes; polyvinyl alcohol with a low acetate residual content, cross-linked with glyoxal, formaldehyde or glutaraldehyde and with a degree of polymerization of 200-30,000; a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; a water-insoluble, water-swellable copolymer prepared by molding a dispersion of finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butene or isobutylene, cross-linked with about 0.001 - 0.5 mole polyunsaturated crosslinker per mole of maleic anhydride in the copolymer; water-swellable polymers of N-vinyl lactars and the like.

Other osmotic polymers include polymers that form hydrogels, such as Carbopol® acidic carboxy polymers with a molecular weight of 450,000-4,000,000; Cyanamer® polyacrylamides, cross-linked water-swellable indene-maleic anhydride polymers, Good-rite® polyacrylic acid with a molecular weight of 80,000-200,000, 20 Polyox® epoxyethane polymers with a molecular weight of 100,000-5,000,000; starch graft copolymers; Aqua-Keeps® acrylic polymer; polyglucan cross-linked with diester; and such. Representative polymers that form hydrogels are known from U.S. Patent Nos. 3,865,108, 4,002,173, and 4,207,893 and from the Handbook of Com-mon Polymers, by Scott and Roff, published by the Chemical Rubber Company, Cleveland , Ohio. The amount of osmotic polymer in the first osmotic composition is about 0.01 - 90 wt% and the amount of osmotic polymer in the two osmotic composition is 15 - 95 wt%. In a preferred embodiment, the molecular weight of the osmotic polymer in the second osmotic composition is greater than the molecular weight of the osmotic polymer in the first osmotic composition.

The determination of the liquid uptake by osmotic polymer can be performed for a particular polymer according to the procedure below. A round disc of about 1.3 cm in diameter, provided with a stainless steel plug of about 1.3 cm in diameter, is filled with a known amount of polymer with the plugs extending over each end. The plugs and the mold were placed in a Carver press with plates at a temperature of about 93-149 ° C. The plugs were subjected to a pressure of about 70,000 - 840 1 470 l »» 105 105 105,000 kPa. After heating for 10-20 minutes and holding under pressure, the electrical heating of the plates was turned off and tap water was circulated through the plates. The resulting discs of about 1.3 cm were placed in an air-suspension coater, in which 1.8 kg of saccharide nuclei had been introduced, and coated with cellulose acetate with an acetyl content of 39.8% by weight, dissolved in CH2CI2 / CH3OH in a weight ratio of 94: 6 to obtain a 3 wt% solution. The coated systems were dried at 50 ° C overnight. The coated disks were immersed in water at 37 ° C and removed intermittently for a gravimetric determination of incorporated water. The initial recording pressure was calculated using the water transmission constant for the cellulose acetate, after normalizing the recording values for the surface of the membrane and the thickness. The polymer used in this assay was the sodium derivative of Carbopol 934® polymer prepared according to the procedure of B.F. Goodrich Service Bulletin GC-36, "Carbopol® Water-Soluble Resins," page 5, issued by B.F. Goodrich, Akron, Ohio.

The cumulative weight gain values y as a function of the time t for the water-soluble polymer disc coated with cellulose acetate were used to determine the equation of the line y®c + bt + at ^, which is determined by the method of the least squares goes certain points.

The weight gain for the Na-Carbopol-934 is determined by equation 17: weight gain * 0.359 + 0.665t - 0.00106t ^ (17) where t is the elapsed time in minutes. The value of the water flow at any time will be equal to the slope of the line, which is determined by the following equations 18 and 19: 30 dy, d (0.359 + 0.665t - O.OOlOót2) (18) dt dt ii » 0.656 - 0.00212t (19) dt

To determine the initial value of the water flow, the derivative is determined at t = 0, and dy / dt = * 0.665 μΐ / minute, which is equal to the coefficient b. When normalizing the recording value 35 to the time, the thickness and the surface of the membrane and the water transmittance constant of the membrane K, T can be determined according to the following equation 20: 84 0 1 4 70 1 · » 24 τ, τ * _ η ^, - r ·, /. / 60 minN, 1 ml Ν, 0.008 αηλ, ηΛν Κ it a 0.665 μΐ / min χ (-) χ (-) (-2-s ·) (20) hours 1000 μΐ 2.86 sp with Κ = 1.13 χ 10 “^ cm2 / hour. The IT value for NaCl was determined with a Hewlett-Packard vapor pressure osmometer at 345 bar + 10%, and the K value for cellulose acetate used in this experiment, calculated from 5 NaCl uptake values, was determined to be 1.9 x 10 ^ Cm ^ / hour bar.

Substitution of these values in the calculated expression for K (1.9 χ 10 ”^ / cm ^ / hr.bar) ('7 | -) 1.13 x 10” ^ cm ^ / hr gives' ft' = 600 bar at t = 0. As a method of determining a polymer's efficiency in terms of the "zero-order" impeller duration, the percentage of water uptake was chosen before the values of the water flow decreased to 90% of its initial values. The slope value for a straight line equation coming from the axis with the percentage of weight gain will be equal to the initial value of dy / dt determined at t * 0.1 where the y intercept c defines the linear swelling time, where (dy / dt) 0 * 0.665 and the y intercept = 0, yielding y - 0.665t + 0.359 · To determine, when the cumulative water absorption value is 90% below the initial value, the solved the following equation for t; 0.9? T2- + bt + c M- 0.9 (21) bt + c w -0.00106 t2_ + 0.665 t + 0.359. gn 0.665t + 0.359 it follows: -0.00106t ^ + 0.0665t + 0.0359 = 0 1/2 (23) -0.0665 + [(0.0665) 2 - 4 (-0.00106) ( 0.0359)] t = - = - 2 (-0.00106) 25 t 62 minutes and the weight gain is -0.00106 (62) 2 + (0.665) (62) + 0.359 = 38 μΐ, with an initial weight of the 100 mg sample so that (Aw / w) 0.9 x 100 * 38%. The results are shown in Figure 8 as a graphical representation of the values. Other methods available for examining the hydrogel solution interface include rheological analysis, viscosimetric analysis, ellipse geometry, contact angle measurements, electrokinetic assays, infrared spectroscopy, optical microscopy, interface morphology and microscopic examination of an operating device.

8401470 25

The term "active agent" used in this description broadly encompasses any beneficial agent or compound that may be released by the system, thereby obtaining an advantageous and useful result. The agent can be insoluble to very soluble in the external liquid entering the device and can be mixed with an osmotically effective compound and an osmotic polymer. The term "active agent" includes pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, disinfectants, sterilizers, catalysts , chemical reagents, fermentation agents, sex sterilizers, fertility suppressants, fertility promoting agents, air purifying agents, growth of microorganism suppressants and other agents which are beneficial to the environment of use.

The term "beneficial agent" as used in this specification and accompanying claims includes medicaments and the term "medicament" includes any physiologically or pharmacologically active substance which produces a local or systemic effect in humans and animals, such as warm-blooded mammals and primates , birds, pets, animals used for sports or farm animals, laboratory animals, fish, reptiles and zoo animals The term "physiological" 25 used in this description refers to the administration of medicament to achieve normal levels and Functions The term "pharmacologically" refers to variations in the response to amounts of drug administered to the host (compare Stedman's Medical Dictionary, 1966, published by Williams and Wilkins, Baltimore, Md.). The term used herein "drug formulation" means that the drug is in the that the drug is mixed in the compartment with an osmotic solvent and / or an osmotic polymer and, if applicable, with a binder and a lubricant. The active drug, which can be released, includes, without limitation, inorganic and organic compounds, including drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the nervous system, skeletal muscles, the cardiovascular system. , smooth muscles, circulatory system, synoptic sites, sites located near neuro-effectors, endocrine system, 40 hormonal systems, immunological system, organ systems, productive system, skeletal system, autocoid systems, nutrition and secretion systems, inhibition of autocoids and histamine systems. Active drugs that can be delivered to these systems of humans and animals to produce an effect include tranquilizers, hypnotic agents, sedatives, psychic stimulants, tranquilizers, anti-convulsants, muscle relaxants, antiparkinson agents. , analgesics, anti-inflammatory drugs, local anesthetics, muscle astringents, anti-microbial agents, anti-malarial agents, hormonal agents, anti-conceptives, sympathomimetics, diuretics, anti-parasitic agents, neoplastic agents, hypoglycemic agents, ophthalmic agents, electrolytes, diagnostics and cardiovascular drugs.

Examples of drugs which are very soluble in water and can be delivered by the devices according to the invention are prochlorperazine edisylate, iron (II) sulfate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procainamide hydrochloride chloride, amphetamine sulfate, benzphetamine hydrochloride, isoproternol sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanecol chloride, methacholine chloride, pilocarpine hydrochloride, 20 atropine sulfate, methascopolamine bromide, isopropamide iodide, tridiinide-hydrochloride, phenol -de, oxprenolol hydrochloride, metoprolol tartrate, cimetidine hydrochloride, theophyllinecholinate, cephalexin hydrochloride and the like.

Examples of drugs which are poorly soluble in water and which can be released by the devices according to the invention are diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate, anisindone, diphenadione erythylate, dazoxin, isofurazurin, isofurin methazole amide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, fenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, progestins, oestero-estol estol-tetramethiol ester, methyl esterone, hydrocortisone, hydrocortisone, hydrocortisone prazosin hydrochloride, ethynyloestradiol-3-methyl-35 ether, prednisolone, 170-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindone, norethiderone, progesterone, norgesterone, nor-ethynodrel and the like.

Examples of other drugs that may be released by the osmotic device are aspirin, indomethacin, na-40 proxen, fenoprofen, sulidac, diclofenac, indoprofen, nitroglycerin, 8401470 • t, Λ. * 27 propanolol, metoprolol, valproate, oxprenolol, timolol, atenolol, al-prenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, reserpine, methyl-dopa, dihydroxyphenylalanine, pivaloyloxyethyl, ester of α-methyldofyl-hydrochloride-hydrochloride-hydroxy ketopro-5 fen, ibuprofen, cephalexin, erythromycin, proszin, haloperidol, summer pyracar, iron (II) lactate, vincamine, diazepam, phenoxybenzamine, α-blocking agents, calcium channel blocking agents, such as nifedipine, diliazen, verapamil , beta blockers and the like. The beneficial drugs are known, for example, from Remington's Pharmaceutical Scien-10 ces, 14th ed., Published by Mack Publishing Co., Easton, Pennsylvania, The Drug, The Nurse, The Patient, Including Current Drug Handbook, 1974 - 1976 by Falconer et al., Published. by Saunder Company, Philadelphia, Pennsylvania, and Medicinal Chemistry, 3rd ed., volumes 1 and 2 by Burger, published by Wiley-Interscience, New York.

The drug may be in various forms, such as uncharged molecules, molecular complexes, pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, borate, acetate, maleate, tartrate, oleate and salicylate. For acidic drugs, salts of metals, amines or organic cations, for example quaternary ammonium, can be used. Derivatives of drugs, such as esters, ethers and amides, can also be used. Also, a water-insoluble drug may be used in a form which is a water-soluble derivative thereof and serves effectively as a solubilizing agent and is converted upon release from the device by enzymes hydrolyzed under the influence of the pH in the body or other metabolic processes to form the original biologically active form. The medicament comprising agent may be contained in the compartment with a binder, dispersant, wetting agent, suspending agent, lubricant and / or colorant. Examples of these are suspending agents such as acacia, agar, calcium carrageenan, alginic acid, algin, agarose powder, collagen, colloidal magnesium silicate, colloidal silicon dioxide, hydroxyethyl cellulose, pectin, gelatin and calcium silicate; binders such as polyvinylpyrrolidone, lubricants such as magnesium stearate, wetting agents such as fatty amines, quaternary ammonium salts of fats and the like. The term "drug formulation" indicates that the drug is contained in the compartment together with an osmotic agent, osmotic polymer, a binder and the like. The amount of beneficial agent in a device is generally about 0.05 ng - 5 g or more, with individual devices, for example, 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.5 g and the like. The devices can be administered once, twice or three times a day.

The solubility of an advantageous agent in the liquid can be determined by known techniques. For example, according to one method, a saturated solution containing the liquid and the agent is prepared, as determined by analyzing the amount of agent present in a given amount of the liquid. A simple device for this purpose consists of a medium-sized test tube, which is arranged vertically in a water bath, which is kept at a constant temperature and pressure, into which the liquid and the medium are introduced and stirred with a rotating glass spiral. After a certain stirring time, an amount by weight of the liquid is analyzed and stirring is continued for a further period. If the analysis shows no increase in solute after successive stirring periods in the presence of excess solid in the liquid, the solution is saturated and the results are taken as the solubility of the product in the liquid. If the agent is soluble, an added osmotic ef-20 effective agent may not be necessary; if the agent has limited solubility in the liquid, an osmotically effective agent can be incorporated into the device. Numerous other methods are available for determining the solubility of an agent in a liquid. In particular, chemical and electrical conductivity methods are used to measure solubility. Details of various methods for determining solubilities are described in United States Public Health Service Bulletin, No. 67 of the "Hygenic Laboratory," Encyclopedia of Science and Technology, Vol. 12, pages 542 - 556, 1971, published by McGraw-Hill, Inc .; and Ency-30 clopedia Dictionary of Physics, Vol. 6, pages 547 - 557, 1962, published by Pergamon Press, Ine.

The osmotic device according to the invention is manufactured according to conventional techniques. In one embodiment, the beneficial agent is mixed with an osmotic agent and osmotic polymer and pressed into a solid article having dimensions corresponding to the internal dimensions of the compartment adjacent the passage; or the beneficial agent and other ingredients of the formulation and a solvent are mixed into a solid or a semisolid using conventional methods such as ball milling, calendering, stirring or milling with a roller 8401470 29 and material is then pressed into a preselected shape. Then, a layer of a composition consisting of an osmotic agent and an osmotic polymer is contacted with the layer of the beneficial agent formulation and the two layers are surrounded by a semipermeable wall. Layering the composition of the beneficial agent and the osmotic agent / osmotic polymer can be carried out according to conventional techniques for pressing two-layer tablets. The wall can be applied by molding, spraying or dipping the pressed shapes into wall-forming materials. Another and preferred technique that can be used for wall mounting is the air-suspension process. This process consists of suspending and tumbling the pressed compositions into a wall-forming composition and air-containing stream until the wall surrounds and coats the two compressed compositions. The process is repeated with another layer-forming composition to form a laminated wall. The air suspension process is described in U.S. Patent 2,799,241; J. Am. Pharm. Assoc., Vol. 48, pages 451 - 459, 1979 and ibid, vol. 49, pages 20 - 82 - 84, 1960. Other conventional manufacturing methods are described in Modern Plastics Encyclopedia, vol. 46, pages 62 - 70, 1969 and in Remington's Pharmaceutical Sciences, 14th ed., Pages 1626-1678, 1970, published by Mack Publising Co., Easton, Pennsylvania.

Examples of solvents suitable for forming the laminates and layers include inert inorganic and organic solvents that do not adversely affect the materials and the finished laminated wall. The solvents broadly include aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof. Typical solvents are, for example, acetone, diacetone alcohol, methanol, ethanol, isopropanol, butanol, methyl acetate, ethyl acetate, iso-propyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, 35 n-hexane, π-heptane, ethylene glycol monoethyl ethyl ether, ethylene glycol, ethylene glycol , dichloropropane, carbon tetrachloride, chloroform, nitroethane, nitropropane, tetrachloroethane, diethyl ether, diisopropylether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglym, water and 40 mixtures thereof, such as acetone , acetone and methanol, acetone and 8401470 ethanol, dichloromethane and methanol and dichloroethane and methanol.

The following examples further illustrate the invention. Example I.

An osmotic delivery device, also in shape and size suitable as an osmotic tablet for oral administration in the gastrointestinal tract, is prepared in the following manner: a first osmotic drug composition is prepared by sieving 355 g of polyepoxyethane having an average molecular weight of about 200,000 through a 0.42mm aperture stainless steel screen, then 100g of nifedipine is passed through the 0.42mm aperture screen and 25g of hydroxypropylmethylcellulose is also passed through the 0.42mm aperture screen, and finally, 10 g of potassium chloride are passed through the 0.42 mm orifice screen. Then all the sieved ingredients are placed in a laboratory mixer bowl and the ingredients are ground dry for 15-20 minutes to obtain a homogeneous mixture. Then a 250 ml ethanol and 250 ml isopropanol-containing granulation liquid is prepared and this liquid is added to the mixing bowl; first 50 ml are sprayed into the bowl under constant mixing and then 350 ml of the granulation liquid are slowly added to the contents of the bowl and the wet mass is mixed for a further period of 15-20 minutes. Then, the wet granules are passed through a 1.19 mm aperture screen and dried at room temperature for 24 hours, and the dry granules are passed through a 1.19 mm aperture screen. Then, 10 g of magnesium stearate are added to the dry granules and the ingredients are mixed with two rolls for 20-30 minutes using a conventional roller.

Then, a second osmotic composition is prepared as follows: first, 170 g of 5,000,000 molecular weight polyepoxyethane are passed through a 0.42 mm aperture sieve, then 72.5 g of sodium chloride are passed through the aperture sieve 0.42 mm driven and the ingredients are placed in a mixing bowl and mixed for 10-15 minutes. Then, a granulation liquid is prepared by mixing 350 ml of methanol and 150 ml of isopropanol and the granulation liquid is added to the contents of the mixing bowl in two steps. First, 50 ml of the granulation liquid are sprayed into the bowl under constant mixing and then 350 ml of the granulation liquid are slowly added to the contents of the bowl and the wet mixture is mixed for 15-20 minutes, mixing a homogeneous 8401470. .

31 no mixture is formed. The wet mixture is then passed through a 1.19 µm aperture sieve, spread on a stainless steel tray and dried at 22.5 ° C for 24 hours. The dry mixture is passed through a 1.19 mm aperture sieve and then mixed with 5 g of magnesium tearate for 20-30 minutes using a two-roller mill.

A number of drug nuclei are made by pressing the two compositions using a Manesty Layer press. The drug-containing composition is placed in the press die and pressed into a solid layer. Then, the second osmotic composition is applied to the compressed layer in the mold and pressed into a solid layer, forming a two-layered drug core.

The drug cores are then coated with a semipermeable wall-forming composition consisting of 95 g of cellulose acetate with an acetyl content of 39.8 wt% and 5 g of polyethylene glycol 4000 in a solvent consisting of 1960 ml of dichloromethane and 820 ml of methanol . The drug cores are coated with the semipermeable wall-forming composition until the wall surrounds the drug core. An air suspension coating machine from Wurster is used to form the semi-permeable wall. The coated cores are then spread on a tray and the solvent is evaporated in a circulating air oven at 50 ° C for 65 hours.

After cooling to room temperature, a passage with a diameter of 0.26 mm is laser drilled through the semipermeable wall, thereby connecting the outside of the osmotic device to the drug-containing composition. The osmotic device weighs 262 mg, with 30 mg of drug in the first composition weighing 150 mg, the second composition weighing 75 mg, and the semipermeable wall weighing 37 mg. The first osmotic composition of the osmotic device contains 30 mg of nifedipine, 106 mg of polyepoxyethane, 3 mg of potassium chloride, 7.5 mg of hydroxypropylmethylcellulose and 3 mg of magnesium stearate. The second osmotic composition contains 51 mg of polyepoxyethane, 22 mg of sodium chloride and 1.5 mg of magnesium stearate. The device has a diameter of 8 mm, a surface of 1.8 cm and the semipermeable wall has a thickness of 0.17 mm. The cumulative amount of drug delivered is shown in Figure 9.

Example 1A.

40 Osmotic delivery systems are prepared with a first 8401470 32 composition containing 25-100 mg nifedipine, 100-325 mg polyepoxyethane of molecular weight 200,000, 2-10 mg potassium chloride, 5-30 mg hydroxypropylmethylcellulose and 2-10 mg magnesium stearate contains; and a second composition containing 30-175 mg of polyepoxyethane of 5,000,000 molecular weight, 20-75 mg of sodium chloride and 1-5 mg of magnesium stearate. The procedure of Example I is repeated for the manufacture of osmotic devices having the following compositions: (a) an osmotic device with a first composition consisting of 60 mg nifedipine, 212 mg polyepoxyethane, 6 mg potassium chloride, 15 mg hydroxypropyl methyl cellulose and 6 mg of magnesium stearate; and a second composition consisting of 102 mg of polyepoxyethane, 44 mg of sodium chloride and 3 mg of magnesium stearate; and (b) an osmotic device with a first composition consisting of 90 mg nifedipine, 318 mg polyepoxyethane, 9 mg potassium chloride, 22.5 mg hydroxypropylmethylcellulose and 9 mg magnesium stearate, and a second composition consisting of 102 mg polyepoxyethane, 66 mg of sodium chloride and 4.5 mg of magnesium stearate. In one embodiment, the osmotic device described in (a) and (b) further comprises a drug-inducing coating on the exterior semipermeable wall. The drug-inducing coating contains 30 mg of nifedipine and hydroxypropylmethylcellulose. During use in the liquid use environment, the drug impact coat provides immediate drug availability for immediate therapy.

Example II.

The procedure of Example I is repeated, all conditions being the same, except that the drug in the compartment is replaced by a beta-blocker, an anti-inflammatory, analgesic, sympathomimetic, antiparkinson or diuretic agent.

Example III.

An osmotic therapeutic device for the controlled and continuous oral delivery of the beneficial calcium channel blocking drug verapamil is manufactured as follows: 90 mg verapamil, 50 mg mg sodium carboxyvinyl polymer of molecular weight 200,000 and marketed under the tradename Carbopol (E) polymer, 3 mg sodium chloride, 7.5 mg hydroxypropylmethylcellulose and 3 mg magnesium stearate are thoroughly mixed as described in Example I and pressed into a Manesty press with a 0.8 cm punch using a pressure of 1 1/2 ton to form a layer of the drug composition. Then, 51 mg of the carboxyvinylpolymer with a molecular weight of 3,000,000, sold under the brand name Carbopol® polymer, 22 mg of sodium chloride and 2 mg of magnesium stearate are thoroughly mixed and placed in the Manesty press and compressed to form a layer of an expandable, osmotic composition, in contact with the layer of the osmotic drug composition.

Then, a semipermeable wall is formed by mixing 170 mg of cellulose acetate with an acetyl content of 39.8 wt% with 900 ml of dichloromethane and 400 ml of methanol and coating by spraying the two-layer composition constituting the compartment in a air suspension device until a semipermeable wall with a thickness of 0.13 mm surrounds the compartment. The coated device is then dried at 50 ° C for 72 hours and then a laser passage of about 2 mm is drilled through the semipermeable wall, the drug-containing layer being bonded to the outside of the delivery device of medicine for a long time.

Example IV.

The procedure of Example III is repeated, all conditions being the same, except that the drug in the osmotic device is fendiline, diazoxide, prenylamine or diltiazenes. Example V.

An osmotic therapeutic device for the delivery of the drug sodium diclofenac for use as an anti-inflammatory agent is manufactured by first compressing an osmotic drug composition containing 75 mg of sodium diclofenac in a Manesty press. 300 mg sorbitol, 30 mg sodium hydrogen carbonate, 26 mg pectin, 10 mg polyvinylpyrrolidone and 5 mg stearic acid, and compress the composition in a mold until a solid layer is formed. A second, more vigorous effect composition is then introduced into the cavity, which consists of 122 mg of pectin with a molecular weight of 90,000-130,000, 32 mg of mannitol, 20 mg of polyvinylpyrrolidone and 2 mg of magnesium stearate and compressed to form a second layer, in contact with the first layer. The second layer has a density of 1.28 g / cm 2 and a hardness value of more than 12 kg. Then, the two-layer core is surrounded by a semipermeable wall, consisting of 85 g of cellulose acetate with an acetyl content of 39.8 wt% and 15 g of polyethylene glycol 4000, using 40 wt% solid in a wall-forming solvent 8401470 Iβ '34 consisting of 1960 ml dichloromethane and 819 ml methanol. The coated device is dried at 50 ° C for 72 hours and then a 0.26 mm diameter passage is laser drilled through the wall. The semipermeable wall has a thickness of 0.1 mm, the device has a surface of 3.3 cm and an average drug release rate of 5.6 mg per hour over a period of 12 hours. The cumulative quantity dispensed is shown in fig.

10. The small vertical bars represent the minimum and maximum drug delivery for five systems currently being measured.

Example VA.

The procedure of Example V is followed to provide an osmotic device in which the compartment contains a mixture of osmotic polymers. The compartment contains a first composition weighing 312 mg and consists of 48 wt% diclofenac as drug, 38 wt% polyepoxyethane as osmotic polymer with a molecular weight of 200,000, 10 wt% polyethylene glycol ("osma polymer ') having a molecular weight of 20,000, 2 wt% sodium chloride and 2 wt% magnesium stearate; and a second composition weighing 150 mg and consisting of 93 wt% polyepoxyethane with a molecular weight of 5,000,000.5 wt % sodium chloride and 2% by weight magnesium stearate.

Example VI.

In this example, the increase in osmotic pressure for a number of compositions comprising an osmotic agent and an osmotic polymer is determined to demonstrate the benefit provided in accordance with the invention during operation. The measurements were made by measuring the amount of water absorbed by the semipermeable wall of a bag containing an osmotic agent or an osmotic polymer or an osmotic agent and an osmotic polymer containing composition. The semipermeable wall of the bag is formed from cellulose acetate with an acetyl content of 39.8%. The measurements are made by weighing the dry components of the semipermeable bag, followed by weighing the soaked bag, after the bag 35 has been kept in a water bath at 37 ° G for various times. The weight gain is due to the water uptake through the semipermeable wall, which is brought about by the osmotic pressure gradient through the wall. The osmotic pressure curves are shown in Fig. 11. In Fig. 11, the triangle with the triangles represents the osmotic pressure for poly-40-epoxyethane with a molecular weight of 5,000,000; the curve with 84 0 1 4 70 <* »35 the circles represents the osmotic pressure of a composition consisting of polyepoxyethane with a molecular weight of 5,000,000 and sodium chloride, the components being present in the composition in a ratio of 9, 5 parts by weight of osmotic polymer to 0.5 parts by weight of 5 parts by weight of osmotic agent; the square curve represents a composition consisting of the same osmotic polymer and osmotic agent in the ratio of 9 parts by weight osmotic polymer to 1 part by weight osmotic agent, the curves with the hexagons represents the same composition from the osmotic polymer and the osmotic agent 10 in a ratio of 8 parts to 2 parts; and the dotted line represents the osmotic agent sodium chloride. The mathematical calculations were performed using the formula dw / dt "A (ΚΔ? T) / hour, where dw / dt is the rate of water uptake over time, A is the area of the semipermeable wall and K is the permeability coefficient. 15. In Figure 11,% / Wp is the amount of water taken up, divided by the weight of the osmotic polymer plus the osmotic agent.

Example VII.

An osmotic therapeutic device for the release of sodium tri-diclofenac is prepared by sieving a composition of 49 weight percent sodium diclofenac, 44 weight percent polyepoxyethane with a molecular weight of 100.00, 2 weight percent sodium chloride and 3 weight percent hydroxypropyl methyl cellulose by mixing a 0.42 mm orifice screen and then the sieved composition with an alcohol as a solvent, which is used in an amount of 75 ml of solvent per 100 g of granulate. The wet granulate is sieved through a 1.19 mm orifice screen, dried under reduced pressure at room temperature for 48 hours, passed through a 1.19 mm orifice screen and mixed with 2 wt.% Magnesium stearate which has been driven through a sieve with 30 openings of 0.177 mm. The composition is compressed as described above.

Then, a composition of 73.9 wt.% Pectin having a molecular weight of 90,000-130,000, 5.8 wt.% Microcrystalline cellulose, 5.8 wt.% Polyvinylpyrrolidone, 14.3 wt.% Sodium chloride, and 2 wt. Sucrose passed through a 0.42 mm aperture sieve, mixed for 25 minutes with an organic solvent, used in an amount of 100 ml solvent per 100 g of granulate, passed through a 1.19 mm aperture sieve, for 48 hours dried at room temperature under reduced pressure, again passed through a 1.19 mm aperture sieve, mixed with 2 wt.% magnesium stearate 84 0 1 4 7 0 4 * * ψ * 36 and then compressed onto the compressed layer, which In the previous paragraph has been described. The bilayer drug core is coated by dipping into a wall-forming composition consisting of 80 wt% cellulose acetate with an acetyl content of 39.8 wt%, 10 wt% polyethylene glycol 4000, and 10 wt% hydroxypropyl methyl cellulose. A passage is drilled through the wall, which is in communication with the drug-containing composition. The diameter of the passage is 0.38 mm. The theoretical cumulative release profile for the device is shown in FIG. 12. FIG. 13 depicts the theo-10 retic release rate in mg per hour for the osmotic device.

Example VIII.

The procedure of Example VII is repeated, the conditions being the same, except that the osmotic polymer in the drug composition is polyepoxyethane-polyepoxypropane block copolymer having a molecular weight of about 12,500.

Example IX.

An osmotic device is prepared by the methods described above, the device of this example contains a separate composition of 50 wt% sodium diclofenac, 46 wt% polyepoxyethane having a molecular weight of 100,000, 2 wt% sodium chloride and 2 wt% magnesium stearate. The device has a semipermeable wall consisting of 90 wt% cellulose acetate with an acetyl content of 39.8 wt% and 10 wt% polyethylene glycol 4000. The cumulative amount released for this device, which includes the separate composition, is 40% of the device, which includes two compositions. The cumulative quantity dispensed is shown in fig.

14.

Example X.

The in vivo and in vitro determined average cumulative seals of sodium diclofenac from an osmotic device, comprising a first osmotic composition consisting of 75 mg sodium diclofenac, 67 mg polyepoxyethane with a molecular weight of 100,000, 3.0 mg sodium chloride, 4.5 mg of hydroxypropyl methyl cellulose and 3.0 mg of magnesium stearate; a second osmotic composition, spaced from the delivery passageway, consisting of 51 mg of polyepoxyethane with a molecular weight of 5,000,000, 22.5 mg of sodium chloride and 1.5 mg of magnesium stearate, and surrounded by a semipermeable wall consisting of 90 wt. % cellulose acetate with an acetyl content of 39.8% by weight and 40% by weight polyethylene glycol 4000 was measured in vivo and in vitro in dogs as 840 1 4 70 37 animals. The amounts of drug delivered at various times were determined in vivo by administration of a number of devices to the animal and measuring the amount released from the corresponding device at the appropriate residence time. The results are shown in Figure 15, where the circles with the bars are the mean cumulative amounts in vitro and the triangles with the bars are the mean cumulative releases in vivo.

The mean cumulative release in vivo and in vitro for a device containing nifedipine was measured in the manner described above. The osmotic device included a passageway contiguous composition consisting of 30mg nifedipine, 106.5mg polyepoxyethane of molecular weight 200,000, 3mg potassium chloride, 7.5mg hydroxypropylmethylcellulose and 3mg magnesium stearate spaced from the passageway Lying composition, consisting of 52 mg of epoxyethane 15 with a molecular weight of 5,000,000, 22 mg of sodium chloride and 1.5 mg of magnesium stearate and a semipermeable wall, consisting of 95 wt% cellulose acetate with an acetyl content of 39.8 wt% and 5 wt% hydroxypropylmethylcellulose. Figure 16 shows delivery from the system. In Figure 16, the circles represent the cumulative release in vivo and the triangles represent the average cumulative release in vitro.

Example XI.

The procedure of Example X is followed to prepare an osmotic therapeutic delivery system, comprising: a first drug composition weighing 638 mg consisting of 96 wt% cefalexin hydrochloride, 2 wt% Povidone (polyvinylpyrrolidone) and 2 wt.% magnesium stearate, a second, osmotic composition weighing 200mg, consisting of 68.5 wt.% polyepoxyethane with a molecular weight of 5 x 106, 29.5 wt.% sodium chloride and 2 wt.% magnesium stearate, a semi-permeable wall with a weight of 55.8 mg, consisting of 80 wt.% cellulose acetate with an acetyl content of 39.8 wt.%, 14 wt.% polyethylene glycol 4000 and 14 wt.% hydroxypropylmethylcellulose, and an osmotic opening with a diameter of 0.039 mm. The device has an average release rate of about 54 mg per hour over a 9 hour period.

In the novel osmotic system of the invention, a dual agent is used to achieve an accurate release rate of drugs, which are difficult to deliver in the environment of use, while maintaining the cohesion and character of the system. It will be understood that di-AIIM470-t-38, fc. -.

fresh modifications, changes, additions and deletions are possible in the system according to the invention.

84 0 1 4 7 0

Claims (12)

A device for delivering a beneficial agent at a controlled rate to a use environment, characterized in that it comprises: a) a basket, which is formed at least in part from a composition which is permeable to the passage of an external liquid, which is present in the environment of use, which is surrounded and formed by the wall, b) a compartment, c) a first composition in the compartment, the first composition being an advantageous agent, an osmotic agent and a osmotic polymer, d) a co-composition in the compartment, the second composition comprising an osmotic agent and an osmotic polymer, and e) a passage in the wall communicating with the first composition and the exterior of the device for delivering the beneficial agent from the device. A controlled rate delivery device for a beneficial agent according to claim 1, characterized in that the wall-forming composition is cellulose acetate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, ethyl cellulose, cellulose acetate butyrate, cellulose acetate propionate. hydroxypropylmethyl cellulose, hydroxyalkyl cellulose, methyl cellulose, methyl ethyl cellulose or mixtures thereof. The controlled rate delivery device of the beneficial agent according to claim 1 or 2, characterized in that both the first composition and the second composition are layered in the compartment. A controlled rate delivery device of a beneficial agent according to claim 1, characterized in that the first composition incorporates external liquid through the wall into the compartment and the second composition also receives external liquid through the wall into the compartment. . 5. A controlled rate delivery device for a beneficial agent according to claims 1 to 4, characterized in that the osmotic polymer of the second composition has a higher molecular weight than the osmotic polymer of the first composition. A controlled rate delivery device of a beneficial agent according to claims 1 to 5, characterized in that the beneficial agent is a medicament. 84 0 1 4 7 0 Η τΛ ». - »“ Controlled release device of a beneficial agent to a use environment according to claims 1-6, characterized in that the wall comprises a laminate, consisting of a semipermeable layer and a microporous layer. Controlled release device of a beneficial agent to an environment of use according to claims 1-7, characterized in that the wall-forming composition contains polyethylene glycol. 9. Device for the controlled release of a beneficial agent to a use environment according to claims 1-8, characterized in that the osmotic polymer in the first composition is polyepoxyethane. Controlled release device of a beneficial agent to an environment of use according to claims 1-9, characterized in that the osmotic polymer in the second composition is polyepoxyethane. 11. Device for the controlled release of a beneficial agent 15 to an environment of use according to claims 1-10, characterized in that the beneficial agent is the drug nifedipine, verapamel, diltiazenes, diclofenae, propanolol, proszin, ibuprofen, ketoprofen, haloperio -dol, indomethacin or cephalexin. ******** 8401470 * 7 fU- * ^ ··! 1_j Improvement of errata in the description associated with the patent application 8401470 proposed by the applicant, under date 19 June 1984 Page. 8, line 21: change formula (5) to: "A = + Ap" Page 9, line 10: change formula (8) to: v * r2 + _Lj (1 + Vp) Page. 9, lines 19/20: change formula (12) to r Gr, pj + Tf r2 + (1 +) Λ / Τ'ρ ’Γ p Γ Λ P. 39, line 11: Delete "an osmotic agent". 40, add after line 18: "12. Device for the controlled release of a beneficial agent to a use environment according to claims 1-11, characterized in that the first composition contains an osmotic agent." 8401470