FR2545721A1 - OSMOTIC DEVICE FOR THE DELIVERY OF MATERIALS IN A MEDIUM OF USE - Google Patents

Abstract

THE INVENTION RELATES TO A DEVICE ALLOWING THE RELEASE, AT A REGULATED SPEED, OF AN ACTIVE AGENT IN A ENVIRONMENT OF USE. THIS DEVICE 10 INCLUDES: A. A WALL 12 FORMED, IN PART AT LEAST, OF A COMPOSITION PERMEABLE TO THE PASSAGE OF AN EXTERNAL FLUID, THE SURROUNDING WALL FORMING: B. A COMPARTMENT 14 CONTAINING: C. A FIRST COMPOSITION CONTAINING A ACTIVE AGENT 15, AN OSMOTIC AGENT 16 AND AN OSMOTIC POLYMER 17, AND D. A SECOND COMPOSITION CONTAINING AN OSMOTIC AGENT 18 AND AN OSMOTIC POLYMER 19; AND E. A PASSAGE 13 IN WALL 12 COMMUNICATING THE FIRST COMPOSITION AND THE OUTSIDE OF THE DEVICE TO ALLOW THE RELEASE OF THE ACTIVE AGENT 15. APPLICATION TO THE PHARMACEUTICAL FIELD.

Description

The present invention relates to a new system

  and remarkable for the supply of materials

  The invention relates to an osmotic device comprising

  a wall formed, at least in part, of a semi-permeable material which surrounds a compartment comprising: (1) a first osmotic composition including an active agent,

  and preferably an osmotic agent and / or an osmotic polymer

  wherein said composition is in contact with (2) a second osmotic composition including an osmotic agent and an osmotic polymer. A passage in the wall connects the exterior of the osmotic device to the first osmotic composition containing the active agent, to release

  the first composition of the osmotic device

  The osmotic agent is useful for releasing active agents which, because of their solubility, are difficult to release in a known amount at a set speed of a device.

with osmotic release.

  Since the beginning of antiquity, the pharmacy and

  medicine sought a system of liberation for

  administering an active drug The first written reference regarding a form of administration is in the Papyrus

  d'Eber, written around 1552 BC This book

  forms of administration such as

  for the anal way, vaginal pessaries, on-

  guents, oral formulations in pills, and other preparations for administration About 2500 years have passed without progress in the development of forms

  when the Arab physicist Rhazes, 865-

  925, invented the coated pill About a century later, the Persian Avicenna, 980-1037, coated gold or silver pills to increase patient acceptability and improve the effectiveness of the drug at that time

  approximately, the first tablet was described in

  Written by al-Zahrawi, 936-1009 Manuscripts describe a tablet formed from hollow impressions in two compression molds facing each other Pharmacy and medicine have waited about 800 years for a new innovation in the forms to appear of administration, when in 1883 Mothes invented the capsule to administer the drug The next leap in this area came

  in 1972 with the invention of the osmo-

  by the inventors Theeuwes and Higuchi as described

  in US Pat. Nos. 3,845,770 and 3,916,899.

  Osmotic positives described in these patents include

  a semi-permeable wall that surrounds a compartment

  holding a useful agent The wall is permeable to the passage of an external fluid and is substantially impermeable

  at the passage of the useful agent There is a passage through

  the wall to release the beneficial agent from the

  These devices release the agent through the ab-

  fluid sorption through the semipermeable wall into the compartment at a rate determined by permeability

  of the semi-permeable wall and the osmo- pressure gradient

  in the crossing of the semipermeable wall, to produce an aqueous solution containing the beneficial agent that is released from the device through the passage These devices are very effective in releasing a useful agent that is soluble in the fluid and has a gradient of osmotic pressure, with respect to the external fluid, in the crossing

of the semi-permeable wall.

  A pioneering breakthrough in liberation

  osmotic ration was introduced to the art of distribution

  by the inventor Felix Theeuwes in US Patent No. 4,111,202.

  In this patent, the kinetics of the release of the osmotic device is improved so as to release useful agents

  which are insoluble to very soluble in the fluid, in

  reading the osmotic device with a compartment for the beneficial agent and a compartment of osmotic agent separated by a film The film is movable between a state of rest and an expanded state The osmotic device releases the agent by the imbibition effect fluid through the semipermeable wall in the osmotic agent compartment producing a solution which causes an increase in volume of the compartment and acts as an active force which is applied against the film This force forces the film to expand against the compartment of the beneficial agent and correspondingly reduces the volume of this compartment, so that the beneficial agent is released from the osmotic device through the passageway Although this device works successfully for the application for which it is intended and well it can release many useful agents of varying solubilities, its use can be limited because of the steps and costs required areas for its manufacture and implementation of the mobile film

  in the compartment of the osmotic device.

  In US Patent No. 4,327,725, filed by Richard Cortese and Felix Theeuwes, there is provided an osmotic delivery device for the delivery of active agents which, by

  because of their solubility in aqueous and biological fluids

  The osmotic devices of this patent include a semipermeable wall surrounding a compartment containing an active agent that is insoluble to very soluble in aqueous and biological fluids and an expandable hydrogel. hydrogel expands in the presence of the external fluid that enters the device

  thus causing the release of the active agent of the dis-

  Positive through the passage This device works successfully

  for its intended use, and it releases many active agents difficult to release for the purpose for which it is intended It has now been observed that its use may be limited because the hydrogel does not have the possibility of absorb sufficient fluid for the maximum self-expansion necessary for the expulsion of

the active agent of the device.

  It is obvious to the specialists versed in

  the art of preparation that if one could obtain a dissertation

  osmotic positive with a high degree of osmotic activity

  to release an active agent by generating in situ a

2545721.

  sufficient expansion force to release the quantity

  agent at a set speed of an osmotic device.

  tick, such an osmotic device could have a value

  certain and represent a progress in the art of liberation.

  Similarly, those skilled in the art of liberation will immediately realize that if an osmotic device having a dual thermodynamic osmotic activity were to be used to release larger amounts of active agent, said osmotic device would find application. practice in the fields of

pharmacy and medicine.

  Therefore, in view of the foregoing, it is an immediate object of the present invention to provide an osmotic system which represents further development and advancement in the art of liberation. Another object of the invention is to provide an osmotic system manufactured in the form of an osmotic device to release in vivo an active drug that is

  difficult to release and can now be

  osmotic positive provided by the present invention in

  quantities with therapeutic action.

  Another object of the invention is to provide an osmotic system having a dual osmotic activity,

  which system comprises a compartment containing a first

  first osmotic composition including a drug, and preferably an osmotic agent and / or an osmotic polymer, and a second composition including an osmotic agent and

  an osmotic polymer, the compositions acting as

  cert to release the drug from the device.

  Still another object of the invention is to provide an osmotic device comprising means for containing a high charge of a drug insolubled in water or slightly soluble in water, and a means for releasing the drug

  in both cases at a set speed and continuously.

  Yet another object of the invention is to provide an osmotic device which can release a p H-dependent active agent by providing a neutral medium for the

  release of the active agent in a finely

  to increase its contact surface and to maximize

bet his dissolution rate.

  Yet another object of the invention is to provide an osmotic system for releasing a drug having a

  very low resolution which is the step limiting the

  release of the drug from the system but

  what can now be achieved by using a

  osmotic solution which acts in situ as a wetting agent and as a solubilizing agent to increase the dissolution rate and solubility of the drug, so as to

  improve its release by the osmotic device.

  Yet another object of the invention is to provide an osmotic system comprising a means for maintaining a high degree of osmotic activity of a polymer used for

  release an active agent from the osmotic system.

  Yet another object of the invention is to provide an osmotic therapeutic device which can administer a complete dose administration cycle comprising poorly soluble to highly soluble agents at a controlled rate and continuously over a particular period of time. whose use requires intervention only for the

  start and possibly the end of the administration.

  Other goals, characteristics, aspects and advantages

  of the invention will be obvious to the specialists

  versed in the art of liberation in relation to the

  detailed description which will follow with regard to

in which:

  FIG. 1 is a perspective view of a FIG.

  osmotic positive designed for oral administration of an active agent to the gastrointestinal tract; FIG. 2 is an exploded view of the device

  osmotic of Figure 1, illustrating the structure of the dis-

  osmotic positive of Figure 1; FIG. 3 is an exploded view of the device

2545721.

  osmotic of FIG. 1, representing the osmotic device

  In operation and releasing an active agent, FIG. 4 is an exploded view of the osmotic device of FIG. 1, in consideration of FIG. 3, showing the device in operation and releasing a dominant amount of an active agent;

  FIG. 5 represents a therapeutic device

  osmotic tick whose wall is partially broken away, designed to release an active agent into a body canal, for example the anorectal and vaginal channels, FIG. 6 represents the osmotic device of FIG. 5 but with a different wall structure; Figure 7 shows the osmotic device of Figure 5 with a wall structure different from that shown in Figure 6; Figure 8 shows the increase in weight

  as a function of time of a polymer encapsulated in a mem-

  semi-permeable brane when the encapsulated polymer is placed in water; FIG. 9 represents the cumulative amount of drug released by a device comprising an osmotic polymer having two different molecular weights; FIG. 10 represents the cumulative amount of

  drug released from a device using a different group

osmotic polymers;

  Figure 11 shows the osmo- pressure curves

  for a number of osmotic agent compositions.

  and a number of osmo-

  tick / osmotic agent; Figure 12 shows the cumulative release curve of an osmotic system using two different osmotic polymers; Figure 13 shows the release rate per hour of an osmotic system different from that of Figure 9, containing an osmotic polymer having two different molecular weights;

  FIG. 14 represents the cumulative quantity

  a single-composition device having only one layer; Figure 15 shows the cumulative release in vivo and in vitro for a drug released by the osmotic device; and Figure 16 shows the cumulative in vivo and in vitro release of a different drug released by

an osmotic device.

  In the drawings and in the specification, like parts are designated by like references.

  Now going back in more detail to the

  are examples of various osmotic systems provided by the invention, which examples should not be considered limiting, a first embodiment of an osmotic system is shown in FIG. 1. In FIG. 1, the osmotic device 10 is shown

  having a body 11 having a wall 12 and a step

  13 for the release of an active agent from the

osmotic agent 10.

  In FIG. 2, the osmotic device 10 of

  FIG. 1 is shown in open section on FIG.

  2, the osmotic device 10 comprises a body 11,

  a semi-permeable wall 12 surrounding and forming a

  internal part 14, which communicates through a passage 13

  with the outside of the osmotic device 10 The compartment

  14 contains a first osmotic composition

  holding an active agent 15, represented by dots, and being insoluble to very soluble in the fluid absorbed in the compartment 14, an osmotic agent 16, represented by wavy lines, which is soluble in the

  absorbed fluid in the compartment 14 and presents a

  osmotic pressure, with respect to the external fluid, in the passage of the semi-permeable wall 12, and an osmotic polymer 17 represented by horizontal dashes, which absorbs the fluid in the compartment 14 and has an osmotic pressure gradient, in crossing the semipermeable wall 12, with respect to an external fluid

  present in the environment of use The wall 12 is

  A semi-permeable composition which is substantially permeable to the passage of the external fluid and substantially impermeable to the passage of the agent 15, the osmotic agent 16 and the osmotic polymer 17 The semi-permeable wall 12 is non-toxic and keeps his physical integrity and

  during the service life of the device 10.

  The compartment 14 also houses a second osmotic composition which is remote from the passage 13 and

  contact with the first composition The second

  It has a push for expansion and acts in cooperation

  with the first osmotic composition to release the quantity

  maximum active agent content 15 of the osmotic device 10.

  The second osmotic composition comprises an osmotic agent

  tick 18, which is soluble in the fluid absorbed in the

  14 and presents an osmotic pressure gradient

  in the passage of the wall 12 with respect to an external fluid, mixed with an osmotic polymer 19 which imbibes fluid into the compartment 14 and presents a

  osmotic pressure gradient in the crossing of the

  king 12 with respect to the external fluid The osmo- polymers

  ticks 17 and 19 are hydrophilic water-soluble or water-insoluble and slightly crosslinked polymers and have osmotic properties that imbibe external fluid imbibition, they exhibit a gradient

  of osmotic pressure in the crossing of the semi-

  permeable to the external fluid, and they swell

  or dilate in the presence of the fluid The osmo-

  ticks 17 and 19 are mixed with an osmotic agent 16 and 18 to absorb the maximum volume of external fluid in the compartment 14 This fluid is available for osmotic polymers 17 and 19 to optimize the volumetric flow rate and for the total expansion of the polymers

  In other words, the osmotic polymers

  17 and 19 imbibe the fluid absorbed in the

  14 by the osmotic absorption action of the osmotic polymers 17 and 19 reinforced by the osmotic absorption action of the osmotic agents 16 and 18, to achieve the

  maximum expansion of the osmotic polymers 17 and 19

than to an enlarged state.

  In operation, the release of the active agent from the osmotic device 10 is effected in a

  currently preferred embodiment, by (1) absorp-

  fluid by the first composition to form a suspension in situ and release the suspension through the passage

  and, simultaneously, by (2) fluid absorption by the se-

  conde composition so that it swells and cooperates with the first composition to cause the suspension of the agent through the passage According to the process described,

  the osmotic device can be considered as a cylinder

  The second composition expands as the movement of a piston to promote release of the agent suspension from the osmotic device. Although the shape of the osmotic device shown in FIGS.

  and 2 is not a real cylinder, it is close enough

  for the following physical analysis In this

  lysis, the volume flow released by the osmotic device Ft consists of two sources; the speed of absorption of

  water by the first composition F and the absorption rate

  water by the second composition Q o Ft = F + Q (1)

  Since the borderline between the first composi-

  tion and the second composition only hydrates very little during the operation of the osmotic device, it exists

  an insignificant migration of water between the compositions.

  Thus, the rate of absorption of water by the second com-

  position, Q, is equal to the expansion of its volume dv

R = Q (2)

dt

  The total rate of release by the osmotic device

what is then:

= F C = (F + Q) C (3)

  o C is the concentration of active agent in the released suspension The constant volume of the osmotic device, V, and the contact area, A, gives equations 4 and V = Vd + Vp (4) A = Ad + Ap (5)

  o V and V represent the volumes of the first component

  composition and the second composition respectively; and Ad and Ap represent the contact surface with the wall for

  the first composition and the second composition

  In operation, both V and Ap increase with time while Vd and Ad decrease with time.

  as the device releases the active agent.

  The volume of the second composition, which increases

  with time when the fluid is absorbed in the

  ment, is given by equation 7

V (7)

  where WH is the weight of fluid absorbed by the se-

  composition, Wp is the weight of the second composition

  initially present in the device, WH / Wp is the

  port of the fluid to the initial solid of the second composition, V is equal to (1 +) P oe is the density of the second composition corresponding to WH / Wp Thus, on the basis of the geometric shape of a cylinder, gold represents the radius of the cylinder, the absorption surface is associated with the volume of the second inflated composition, as follows: Ap = r 2 W p 1 (8) pre W 19) Ad = A Ap

  The absorption rates of the fluid in each compartment

  are: k (h) P () (O (h) 7d P) (11) ok represents the osmotic permeability of the wall, h represents the thickness of the wall, Aed and Aitp are the osmotic gradients for the first composition and the second composition respectively The total rate of release is therefore: ## EQU1 ## where ## EQU1 ##

  Figures 3 and 4 illustrate the osmo-

  in operation, as described with reference to the figures

  1 and 2 in FIGS. 3 and 4, for the osmo-

  10, the fluid is absorbed by the first composition at a rate determined by the permeability of the wall

  and the osmotic pressure gradient across the wall.

  The absorbed fluid continually forms a con-

  holding the active agent, or a solution or gel of osmotic agent and osmotic polymer containing the suspended active agent, which solution or suspension is released

  in each case of operation by the processes

  These processes include the release of

  solution or osmotic suspension by

  the passage because of the continuous training of the solu-

  tion or suspension, and because of the swelling and

  the increase in volume of the second composition,

  felt by the height increase of the vertical lines in Figures 3 and 4 This swelling and this increase

  of volume apply a pressure on the solution or sus-

  to support the first composition by simultaneously causing the release of the active agent

towards the outside of the device.

  The first composition and the second composition

  act together to ensure that the release

  The active agent of the compartment is constant over a prolonged period of time by two processes. Firstly, the first composition imbibes external fluid through the wall, so as to form either a solution or a suspension, of which the last-fraction could be substantially released at a non-zero order rate (in the absence of the second composition), because the driving force decreases with time Second, the second composition acts by two simultaneous means: all of first, the second composition acts to continuously concentrate the agent

  active by absorption of a certain amount of fluid

  coming from the first composition in order to pocket the

  concentration in active agent to fall below the saturation

  ration, and second, the second composition by absorp-

  external fluid through the wall increases continuously

  volume, thus exerting a force against the first composition and decreasing the volume of the active agent, thereby directing the active agent towards the passage of the compartment In addition, since the solution or

  additional suspension formed in the first compartment

  is expressed, the osmotic composition comes into con-

  intimate touch with the inner wall and generates pressure

  constant osmosis and, consequently, a speed of liberation

  constant ration, together with the second composition.

  The swelling and dilation of the second composition, with the concomitant increase in its volume, as well as

  the corresponding simultaneous reduction in volume of the first

  composition, ensure the release of active agent

a set speed.

  The device 10 of FIGS. 1 to 4 can be

  in many embodiments, including currently preferred embodiments for the oral route, to release a therapeutically active agent.

  localized or systemic in the gastrointestinal tract.

  The system for the oral route may take a variety of conventional shapes and sizes, for example a round shape with a diameter of 4.76mm to 12.7mm. In these forms, the system 10 may be for administering an active agent to many animals, including warm-blooded animals, humans, birds, reptiles and fish. FIGS. 5, 6 and 7 show another embodiment of a device 10 designed to be placed in a body canal, for example the vagina, or the anorectal canal. The device 10 has an elongate, cylindrical shape, holding itself, with a rounded front end 20, a lower end 21, and it is provided with cords 22 to control

  manually to easily remove the device 10 from the

  biological wise The device 10 is by its structure

  identical to the device 10 described above and it functions

  In Figure 5, the provision of

  10 is shown with a semi-permeable wall 23, in FIG. 6 with a laminated wall 24 comprising

  a semipermeable inner layer 25 adjacent to the compartment

  14 and an outer microporous layer 26 spaced

  of the compartment 14 In FIG. 7, the device 10 com-

  carries a laminated wall 28 formed of a micro-layer

  porous 29 adjacent to the compartment 14, and a semi-permeable layer 30 facing the medium of use and

  in a laminar arrangement with the microporous layer 29.

  The device releases an active agent to be absorbed by the vaginal mucosa, or the ano-rectal mucosa, to produce a local or systemic effect in vivo during a period of time.

extended period of time.

  The osmotic devices of FIGS. 1 to 7

  can be used to free many

  taking medication at a speed that escapes

  When the rate of dissolution of the agent can vary between low and high values in the fluid medium, for example the fluid, the dosage of the drug can be varied.

  gastric and intestinal fluid Osmo-

  ticks also provide a high load of

  low solubility and their release in therapeutic amounts.

* important figures Although Figures 1 to 7 are

  of various osmotic devices that can be

  According to the invention, it is obvious that these devices should not be considered as limiting because they can take on a wide variety of configurations, sizes and shapes to release active agents in

  the environment of use For example, these devices

  take those intended for release in oral, implant, artificial gland, cervical,

  intrauterine, auricular, nasal, dermal, subcutaneous

  The devices may also be dimensioned, shaped, structured and designed to release an active agent into streams, aquariums, fields, factories, reservoirs, laboratory facilities, greenhouses, means

  transport, maritime installations, military installations,

  hospitals, veterinary clinics, nursing homes,

  farms, zoos, infirmaries,

  chemical and other use environments.

  In accordance with the present invention, it has now been

  having discovered that an osmotic-release device

  could be made with a first bone composition and a second osmotic composition mutually arranged in

  cooperative relationship in the compartment

  of the device The compartment is formed by a wall

  taking a material that does not deleteriously affect the active agent, the osmotic agent, the osmotic polymer, etc. The wall is permeable to the passage of an external fluid such as water and biological fluids, and is substantially impermeable the passage of agents, osmotic agents, osmotic polymers, etc. The wall consists of a material that does not adversely affect an animal or a recipient, and the selectively semi-permeable materials used to form the wall are not not erodible and they are insoluble in fluids Examples of

  materials which may constitute the wall are, in a first

  Embodiments of the present invention are cellulose esters, cellulose ethers and cellulose ether-esters. These cellulosic polymers have a degree of substitution, DS, on the anhydroglucose unit of between more than 0 and 3 inclusive. substitution "means the average number of hydroxyl groups initially present in the

  the anhydroglucose unit comprising the cellulose polymer

  Examples of materials include a member selected from the group consisting of cellulose acylates, di-acylates, and the like.

  of cellulose, cellulose triacylates, cellulose acetates,

  lulose, cellulose diacetates, cellulose triacetates,

  cellulose, mono-, di- and tri-alkanylates, cellulose mono-, di-, and tri-aroylates, etc. Examples of polymers include cellulose acetate having a

  D.sup.S reaching 1 and a content of -acetyl groups

  21%; cellulose acetate having an acetyl group content of 32 to 39.8%; cellulose acetate having a D S of 1 to 2 and an acetyl content of 21 to 35%; cellulose acetate having a D S of 2 to 3 and an acetyl group content of 35 to 44.8%; More specific cellulosic polymers include cellulose propionate having a D S of 1.8 and a propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a D S of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylates having a D S of 2.9 to 3 such

  that cellulose trivalerate, cellulose trilaurate

  cellulose triphalitate, cellulose trisuccinate, and cellulose acetate; the diacylates

  cellulose having a D S of 2.2 to 2.6 such as the disulfide

  cellulose cinate, cellulose dipalmitate, diocatholic

  cellulose tanoate, cellulose dipentalate, co-polymers

  cellulose esters such as cellulose acetate butyrate and cellulose acetate propionate, etc. Other semi-permeable polymers include

  ethyl cellulose, cellulose nitrate, dimethyl

  acetaldehyde acetate, 11 acetate ethylcarbamate

  lulose, cellulose acetate methyl carbamate, di-

  cellulose acetate methyl-aminoacetate, semipermeable polyamides, semi-permeable polyurethanes,

  semi-permeable sulphonated polystyrenes, polymers

  selectively semi-permeate forms formed by coprecipitation

  polyanion and polycation as described in U.S. Patent Nos. 3,173,876; No. 3,276,586; No. 3,541,005;

  N 3 541 006; and 3,546,142; semi-permeate polymers

  described by Loeb and Sourirajan in the US Pat.

  No. 3,133,132; polystyrene derivatives slightly

  culés; cross-linked poly (sodium styrenesulfonate); cross-linked poly (vinylbenzyltrimethylammonium chloride); semi-permeable polymers having a permeability to

-51 3 2

  fluids of 10-5 to 10-1 (cm 3 25> m / cm 2 bar) expressed by O 8 bar of hydrostatic or osmotic pressure difference across the semipermeable wall. The polymers are known in the art from US Pat. 3,845,770; N 3,916,899; and N 4,160,020; and Handbook of Common Polymers by JR Scott

  and W J Roff, 1971, published by CRC Press, Cleveland, Ohio.

  The laminated wall comprising a semi-layer

  permeable and a microporous layer has a laminar arrangement and the layers act in concert to form a single-piece laminate wall, which retains its physical and chemical integrity and does not separate in layers during release of the agent by the device The semi-permeable layer is made of the semipermeable polymeric materials presented above, semi-permeable homopolymers, semipermeable copolymers, etc. A couchemicroporous suitable for the manufacture of an osmotic device generally consists of preformed microporous polymeric materials. and polymeric materials which can form a microporous layer in the medium of use The microporous materials of the two embodiments are laminated to form the laminated wall The preformed materials suitable for producing the microporous layer are essentially inert, they retain their integrity physiqu and chemically during the agent release period and may be generically described as having a spongy appearance which provides a support structure for a semipermeable layer and also a support structure for interconnected microscopic pores or voids The materials can be isotropic, in which case the structure is homogeneous throughout the surface

  cross-section, or they may be ani-

  in which case the structure is inhomogeneous over the entire cross-sectional area. The pores may be continuous pores having an opening on the

  two faces of a microporous layer, intercon-

  nected along sinuous paths of regular and irregular shapes including curved, curved-linear pores with continuous statistical orientation, hindered pores and other pore paths,

  be detected by microscopic examination. In general,

  The microporous path is defined by the pore size, the number of pores, the sinuosity of the microporous path and

  the porosity associated with the size and number of pores.

  The pore size of a microporous layer is easily

  established by measuring the diameter of the pores observed

  on the surface of the material under the electron microscope.

  In general, materials having from 5 to 95% pores and having a pore size of between 1.0 nanometer

  and 100 micrometers can be used for the manufacture

  The size of the pores and other parameters characterizing the microporous structure can also be obtained by measuring the flow rate or

  a liquid flow, J, is produced by a difference of pres-

  The flow of liquid through a layer having pores of uniform radius crossing the membrane and perpendicular to its surface, surface A, is given by the relation 13 313) in which J is the transported volume. per unit of time and surface of the layer containing a number N of pores of radius r, n% is the viscosity of the liquid, and AP is the

  pressure difference across the layer of a thickness MX.

  For this type of layer, the number of pores N can be cal-

  based on the relationship 14, where ú is the porosity defined by 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.

  SAX gzz (14> The pore radius is then calculated from the relation 15: zr 83 AX T (15) Ap e where J is the volume of flux passing through the layer per unit area produced by the pressure difference AP through the layer, ft, ú and Ax have the meaning

  given above and <is the sinuosity defined by the

  Length of the diffusion path in the layer at the thickness of the layer Relations of the above type are described in Transport Phenomena In Membranes, Lakshminatayanaiah, N, Chapter 6, 1969, published by Academic

Press, Inc., New York.

  As described in this reference on page 336, in Table 6-13, the porosity of the layer having pore rays can be expressed in relation to the size of the molecule transported having a radius, and as the ratio of molecular radius to pore radius a / r

  decreases, the layer becomes porous for this molecule.

  That is, when the ratio a / r is less than 0.3, the layer becomes substantially microporous, as expressed by the osmotic reflection coefficient, which falls below 0.5. microporous having a reflection coefficient in the range of less than 1, generally from 0 to 0.5, and preferably less than 0.1,

  active agent, is suitable for the manufacture of

  The reflection coefficient is determined by shaping the material into one layer and taking measurements of the water flow as a function of the hydrostatic pressure difference and as a function of the difference in temperature.

  osmotic pressure caused by the active agent The difference

  osmotic pressure creates a fluid volume flow

  static and the reflection coefficient is expressed by the relationship 16 Volume of the osmotic flow (16) Volume of the hydrostatic flow The properties of the microporous materials are described in Science, vol 170, pages 1302 to 1305, 1970; Nature, Vol. 214, p. 285, 1967; Polymer Engineering and Science, Vol 11, pp. 284-288, 1971; U.S. Patent Nos. 3,567,809 and 3,751,536; and in Industrial Processinq With Membranes, by R. Lacey and Sidney Loeb, pp. 131-134, 1972, published

by Wiley, Interscience, New York.

  Microporous materials having a structure

  preformed are commercially available and can be

  can be performed by methods known in the art.

  The microporous materials can be made by etching, electric discharge, cooling of a fluid polymer solution below the point of contact.

  freeze so that the solvent evaporates from the solution.

  in the form of dispersed crystals in the polymer and then curing the polymer and then removing the solvent crystals by cold or hot drawing at low or elevated temperatures until the pores form, by leaching A Soluble Component from a Polymer Using an Appropriate Solvent, an Ion Exchange Reaction and Electrolytic Processes Processes for the preparation of microporous materials are described in Synthetic Polymer Membranes, from RE Kesting, Chapters 4 and 5, 1971, published by McGraw Hill, Inc .; Chemical Reviews, Ultrafiltration, Vol 18, pp. 373-455, 1934; Polymer Eng and Scio, vol 11, No. 4, pages 284-288, 1971; J Appl_Poly Sci, Vol 15, pp. 811-829, 1971; and in US Pat. Nos. 3,565,259, 3,615,024, 3,751,536, 3,801,692, and 3,852,224.

No. 3,849,528.

  Microporous materials useful in the manufacture of

  cation of the layer include micro-carbon polycarbonates

  porous polyesters consisting of linear polyesters of carbon

  in which the carbonate groups repeat in the polymer chain, microporous materials prepared by phosgenation of a dihydroxyl aromatic hydrocarbon

  such as bisphenol A, polyvinyl chloride

  porous, microporous polyamides such as polyhexane

  methylene adipamide, micro-modacrylic copolymers

  porous including those formed from 60% polyvinyl chloride and acrylonitrile, styrene-acrylic and its copolymers, porous polysulfones characterized by diphenylene sulfone groups in the linear chain, poly (vinylidene) halogenated , polychloroethers,

  acetal polymers, polyesters prepared by esterifi-

  of a dicarboxylic acid or anhydride with an alkylene

  polyol, the poly (alkylene sulphides), the polyesters

  microporous poly (saccharides), poly (saccharides),

  microporous ripples having substituted and unsubstituted anhydroglucose motifs and preferably having a higher

  high permeability to the passage of water and bio-fluids

  such as semi-permeable layer, asymmetric porous polymers, crosslinked olefinic polymers, hydrophobic or hydrophilic microporous homopolymers, copolymers or interpolymers having a reduced bulk density and the materials disclosed in US Patents

  N 3,597,752, N 3,643,178, N 3,654,066, N 3,709,774,

  Nos. 3,718,532, 3,803,061, 3,852,224, 3,853,601 and 3,852,388, GB No. 1,126,849 and Chem.

  Abst, vol 71 4274 F, 22572 F, 22573 F, 1969.

  Other microporous materials include

  polyurethanes, cross-linked polyurethanes, polyurethanes

  thannes with chain extension, micro-polyurethanes

  US Pat. No. 3,524,753, the polyimides, the polyamides and

  (benzimidazoles), collodion (cellulose nitrate with

  11% nitrogen), regenerated proteins, polyvinylpyrrolidine

  semi-solid crosslinked lidone, microporous materials prepared by diffusion of polyvalent cations in polyelectrolyte sols as described in US Pat.

  No. 3,565,259, permeable microporous materials

  tropics of ionically associated polyelectrolytes,

  porous polymers formed by the coprecipitation of a poly-

  cation and a polyanion as described in US Pat. Nos. 3,276,589, 3,541,055, 3,541,066 and 3,554,142.

  polystyrene derivatives such as poly (styrene sulpho)

  sodium nate) and poly (vinyl benzyl chloride

  methylammonium), the microporous materials described in

  U.S. Patent Nos. 3,615,024, 3,646,178 and 3,852,224.

  In addition, the microporous material used

  for purposes of the invention include those of the mode of

  wherein the microporous layer is formed in situ by a blowing agent which is removed by dissolution or leaching to form the microporous layer during operation of the system. The blowing agent may be a solid or a liquid. The term "liquid" of

  the invention covers semi-solids and

  Porogenic agents may be inorganic or organic. Porogenic agents suitable for the invention.

  include those that can be extracted without modification

  The solid porogens have a size of about 0.1 to 200 micrometers

  include alkali metal salts such as chlorine

  sodium chloride, sodium bromide, potassium chloride

  sium, potassium sulphate, potassium phosphate, sodium benzoate, sodium acetate, sodium citrate, potassium nitrate, etc. The alkaline earth metal salts include calcium phosphate, nitrate Calcium, etc. Transition metal salts include ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride, manganese fluoride, manganese fluorosilicate, etc. Pore forming agents include organic compounds such as polysaccharides. polysaccharides include sugars such as sucrose, glucose, fructose, mannitol, mannose, galactose, aldohexose, altrose, talose, sorbitol, lactose,

  monosaccharides and disaccharides are also acceptable.

  Aliphatic and aromatic oils and solids comprising diols and polyols, examples of which are polyalcohols, poly (alkylene glycols), polyglycols, alkylene glycols, poly (C) alkylenediols, esters, and the like.

  alkylene glycols, etc .; cellulose cellulosic polymers

  soluble such as hydroxy (lower alkyl) cellulose, hydroxypropylmethylcellulose, methylcellulose, methylethylcellulose, hydroxyethylcellulose, etc .; water-soluble polymers such as polyvinylpyrrolidone, sodium salt of carboxymethylcellulose, etc. Agents

  porogens shall be non-toxic and, where

  In one preferred embodiment, non-toxic blowing agents are selected from the group consisting of inorganic and organic salts, carbohydrates, polyalkylene glycols, polyalkylenediols, alkylene glycol esters, glycols and water-soluble cellulosic polymers, applicable to the formation

  a microporous layer in a biological medium.

  In general, for the purpose of the present invention, when the polymer forming the layer contains more than 25% by weight of blowing agent, the polymer is a precursor of a layer

  microporous which, during the removal of the porous agent,

  gene, gives a layer that is substantially microporous at concentrations below this value, the layer

  behaves like a layer or semi-permeable membrane.

  The term "passage" as used herein expresses a means and methods suitable for releasing the agent or drug from the osmotic system.

  includes an opening, a hole, a light or an

  wise in the semi-permeable wall or the struc-

  The passage may be formed by mechanical drilling, laser drilling, or erosion of an erodible element,

  for example a mass of gelatin, in the medium of

  A detailed description of the osmotic passages,

  and the maximum and minimum dimensions of the passages are

  data in U.S. Patents Nos. 3,845,770 and 3,916,899.

  The osmotically active compounds which can be used for the purposes of the present invention include those

  inorganic and organic compounds with

  osmotic pressure in the crossing of a semi-permeable wall, or in the crossing of a stratified wall

  microporous semi-permeable, with respect to an external fluid.

  Compounds with osmotic action (as well as polymers

  osmotic) imbibe fluid in the osmotic device

  by making this fluid available to be ab-

  sorbed by the osmotic polymer to carry out its expan-

  and / or to form a solution or suspension containing 545721

  an active agent to be released by the osmo-

  The compounds with osmotic action are also known

  as osmotic-acting solutes or osmotic agents.

  The osmotically active compounds are used in mixtures

  with an active agent and an osmotic polymer to form a solution or suspension containing the agent

  active which is released from the device by osmotic effect.

  The term "limited solubility" as used

  As used herein, the agent has a solubility of less than about 5% by weight in the aqueous fluid present in the medium. Osmotic solutes are used by homogeneously or heterogeneously mixing the solute with the osmotic agent or polymer. , then introduced into the reserve Solutes and polymers

  osmotics draw the fluid into the Ga reservoir

  A solution of solute in a gel that is released from the system while carrying the undissolved and dissolved active agent to the outside of the system. The osmotic solutes used for the first purpose include magnesium sulfate, magnesium chloride, sodium chloride,

  potassium chloride, lithium chloride, sulphate

  potassium fate, sodium sulphate, lithium sulphate, potassium acid phosphate, d-mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, "-d-lactose monohydrate, and mixtures thereof. The amount of osmotic agent in the

  compartment is generally from 0.01% to 30% or more

  first composition and in general 0.01%

  40% or more in the second compartment.

  The osmotic solute is initially present in excess and may be in any compatible physical form

  with the active agent and the osmotic agent The osmotic pressure

  saturated solutions of the various osmotic compounds and for mixtures of 37

  water, is shown in Table 1 In this table, the pressure

  The osmotic pressure IX is expressed in M Pa. The osmotic pressure

  This is measured in a commercially available osmometer, which measures the difference in vapor pressure between the pure water and the solution to be analyzed, and, according to conventional thermodynamic principles, the ratio of the vapor pressures is transformed into a difference. osmotic pressures In Table 1, the osmotic pressures of 2.0 to 50 M Pa are indicated; naturally, the invention includes the use of lower osmotic pressures from zero and osmotic pressures greater than

  those given as examples in Table 1.

  The osmometer used in the measurements in question is

  Model 320 B, Vapor Pressure Osmometer, manufactured by

  Hewlett Packard Co, Avonadale, Pennsylvania.

  Table 1 Compound or mixture Osmotic pressure (M Pa) Lactose-fructose 50.0 Dextrose-fructose 45.0 Sucrose-fructose 43.0 Mannitol-fructose 41.5 Sodium chloride 35.6 Fructose 35.5 Lactose-sucrose 25, 0 Potassium chloride 24.5 Lactose-dextrose 22.5 Mannitol-dextrose 22.5 Dextrose Sucrose 19.0 Mannitol-sucrose 17.0 Dextrose 8.2 Potassium sulfate 3.9 Mannitol 3.8 Tribasic sodium phosphate 12 H 20 3.6 Sodium phosphate dibasic 7 H 20 3.1 Sodium phosphate dibasic 12 H 20 3.1 Sodium phosphate dibasic anhydrous 2.9 Sodium phosphate monobasic H 20 O 2.8 The osmotic polymers-suitable for forming the first osmotic composition and also suitable

  to form the second osmotic composition are poly-

  osmotic mothers that have absorptive properties

  fluid flow Osmotic polymers are expandable hydrophilic polymers that interact with water and

  aqueous fluids and swell or dilate

  at a state of equilibrium The osmotic polymers present

  The ability to swell in water and to retain a large portion of imbibition water in the polymer structure are inhibited. The osmotic polymers swell or dilate to a very high degree, usually from 2 to 50 times their volume. The hydrophilic expandable polymers are, in a

  first embodiment currently preferred, lightly

  These crosslinks are formed by covalent or ionic bonds. The osmotic polymers

  may be of plant, animal or synthetic origin.

  The osmotic polymers are hydrophilic polymers.

  Suitable hydrophilic polymers for this purpose include

  poly (hydroxyalkyl methacrylate) having a molecular weight of

  from 30,000 to 5,000,000; poly (vinylpyrrolidone)

  having a molecular weight of 10,000 to 360,000; hydro-

  anionic and cationic gels; poly complexes

  electrolytes; a polyvinyl alcohol having a low residual acetate content, cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of

  polymerization of 200 to 30,000; a mixture of methylcellulose

  lulose, cross-linked agar and carboxymethylcellulose; a copolymer insoluble in water and expandable in water

  obtained by forming a dispersion of a fine

  divided maleic anhydride with styrene, ethyl

  lene, propylene, butylene or crosslinked isobutylene

  with 0.001 to about 0.5 moles of polymeric crosslinking agent

  unsaturated per mole of maleic anhydride of the copolymer; expandable polymers in water of N-vinyl lactams; etc. Other osmotic polymers include polymers forming hydrogels such as polymers

  carboxylic acids of the Carbopoi type having a molecular weight of

  from 450,000 to 4,000,000; polyacrylamides of the Cyanamei O type; crosslinked and dilatable maleic anhydride polymers in water; Good-rite polyacrylic acid having a molecular weight of 80,000 to 200,000; polyethylene oxide polymers of the Polyoi type having

  a molecular weight of 100,000 to 5,000,000; copoly-

  mothers grafted with starch; the acrylic polymer Aqua-Keepâ; polyglucanereticulated with a diester; Examples of hydrogel-forming polymers are known in the prior art from US Pat. No. 3,865,108; U.S. Patent No. 4,002,173; U.S. Patent No. 4,207,893 and Handbook of Common Polymers, Scott and Roff, published by Chemical Rubber Company, Cleveland, Ohio The amount of polymer

  osmotic in the first osmotic composition is to

  0.01 to 90% and the amount of osmotic polymer in the second osmotic composition is 15 to 95%.

  presently preferred embodiment, the molecular weight

  of the osmotic polymer in the second osmotic composition is greater than the molecular weight of the polymer

  osmotic of the first osmotic composition.

  The determination of the fluid absorption by the osmotic polymer for a selected polymer can be

  carried out in accordance with the process described below.

  than 12.7 mm, fitted with a 12.7 mm diameter stainless steel plug, is loaded with a known quantity

  of polymer, the plugs coming out of each end.

  The plugs and the matrix are placed in a Carver press whose plates are at 93 and 149 C. A pressure of 70 to 105 M Pa is applied on the plugs.

  20 minutes of heating and pressurizing, the heater

  electrical fogging of the plates is stopped and d @ water the

  valve is circulated on the plates

  The resulting 12.7 mm were placed in an air suspension coating machine with 1.8 kg saccharide cores and coated with cellulose acetate having an acetyl content of 39.8% dissolved. in

  a 94: 6 mixture by weight / weight of CH 2 C 12 / CH 3 OH to give

  3% w / w solution The coated systems are dried for about 16 hours at 50 ° C.

  coated are immersed in water at 370 C and removed periodically

  The initial imbibition pressure is calculated using the water transmission constant for cellulose acetate, after correcting values to account for the surface and 1 thickness of the membrane The polymer used in this determination is the sodium derivative of the polymer Carbopol 93 w * prepared in accordance with the process

  B Goodrich Service Bulletin GC-36, c'Carbopo'o Water-

  Soluble Resins ", page 5, published by B o Fo Goodrich, Ak: ron,

Ohio.

  The values of cumulative weight gain,

  y, as a function of time, t, for the hydrogen polymer disk

  soluble cellulose acetate coated, are used to

  determine the equation of the curve y = c + bt + at 2 pas-

  these points by a method of adjusting the

square.

  The weight increase for the sodium derivative of Carbopol-934 is given by the following Equation 17: Increase Weight equal to 0.359 + 0.665 t 0200106 t 2

  o t is the elapsed time in minutes.

  at any time is equal to the slope of the curve, which is given by the following equations 18 and 19: dd (0.359 + 0.665 t 0.00106 t 2) 218) dy) (18) dt dt Y = 0.665 0, 00212 t (19) dt To determine the initial rate of water flow, the derivative is evaluated at t = 0, and dy / dt = 0.665 pl / min, which is equal

  at the coefficient b Then, encorrecting the speed of ab-

  sorption for time, surface and

The thickness of the membrane, and the water permeability constant of the membrane, K, X can be determined from the following equation: K = 0.665 pl / min × (G 60 min) × 1 ml 0.008 cm) (20) h 1000) 11 2.86 cm 2 with K = 1.13 x 10 4 cm 2 / h The value (0) for NaCl is determined with a steam pressure osmometer

  Hewlett-Packard as 34.5 M Pa 10%, and the

  their K for the cellulose acetate used in this experiment.

  calculated from the absorption values of NaCl is

  determined to be 1.9 x 10-7 cm 2 / hr bar.

  Substituting these values in the calculated KX expression (1.9 x 10 7 cm 2 / h bar) () = 1.13 x 10-4 cm 2 / h, we obtain 9 = 600 bar at t = 0. to evaluate the effectiveness of a polymer with respect to the duration of the non-zero order driving force, the percentage of water absorption is chosen before the water flow values decrease to 90% of their initial values The value of the slope for the equation of a

  straight line emanating from the percentage axis of increase

  weighted is equal to the initial value of dy / dt evaluated at t = 0, with y intercepting c defining the time

  linear dilatation, with (dy / dt) 0 = 0.665 and the intersec-

  y = 0, which gives y = 0.665 t + 0.359 To determine when the value of water absorption

  accumulated is 90% below the initial rate, the expression

  following resolution is solved for t, at 2 + bt + c AW 09 + bt + c = O 9 (21) (22) -0.00106 t 2 + 0.665 t + 0.359 0.665 t + O j 359 = 019 'and solving to find t, -0.00106 t 2 + 0.0665 t + 0.0359 = O t = -OQ 665 l (O, 0665) 2 4 (0.0 Q 106) (0.0359) J (23 )

2 (-0.00106)

  t = 62 min and the weighted increment is -0.00106 (62) 2 + (0.665) (62) + 0.359 = 38 μl with the initial sample weight = 100 mg; so, (Apoids / weight) x

  0.9 x 100 = 38% The results are present on the

  Figure 8 is a graphical representation of values.

  Other methods applicable to the study of the interface of a hydrogel solution include theological analysis, viscometric analysis, ellipsometry, contact angle measurements, electrokinetic determinations, infrared microscopy, optical microscopy, an interface morphology and a microscopic examination of a

operational device.

  The term "active agent" as used herein includes any active agent or active compound that can be released from the device producing an interesting and useful effect. The agent can be insoluble to very soluble in the external fluid. which enters the device and may be mixed with an osmotic compound and an osmotic polymer. The term "active agent" covers pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, antioxidants, plant growth, plant growth inhibitors, preservatives, disinfectants, sterilization agents, catalysts, body

  chemical reactants, fermentation agents, anti-

  conceptions, fertility inhibitors,

  fecundity, air purifiers, attenuators

  microorganisms and other agents exerting an

taggy on the middle of use.

  In this memo and the claims

  the term "active agent" includes a drug, t 2545721 and the term "drug" includes any physiologically or pharmacologically active substance that produces a local or systemic effect in animals, including warm-blooded mammals, humans and primates, birds, domestic animals, sport and farm animals, laboratory animals, fish, reptiles and zoo animals The term "physiological" as it

  is used here refers to the administration of a drug

  The term "pharmacological" as used herein refers to variations in response to the amounts of drug administered to the recipient. See Stedm'an's Medical Dictionary;

  1966, published by Williams & Wilkins, Baltimore, Maryland.

  The term "drug formulation" as used herein means that the drug is in the compartment mixed with an osmotic solute and / or an osmotic polymer, and where appropriate with a binder and lubricant. The active drug that can be released is an inorganic or organic compound without limitation, including drugs acting on peripheral nerves, adrenergic receptors, cholinergic receptors, the nervous system, skeletal muscle, cardiovascular system, muscles

  smooth, blood circulatory system, synoptic sites,

  neuroeffector junction sites, systems for

  endocrine and hormonal systems, the immunological system,

  the organic systems, the reproductive system, the

  skeletal system, autocold systems, food and excretory systems, steroid inhibition and histamine systems Among the active drugs that can be released to act on these animal systems are depressants, hypnotics, sedatives,

  psychic stimulants, tranquillizers, anti-inflammatory

  convulsions, muscle relaxants, anti-inflammatory agents,

  Parkinson's, analgesics, anti-inflammatories, local anesthetics, muscle contracters,

  antimicrobials, antimalarials, hormone

  monkeys, contraceptives, sympathomimetics, diuretics, anti-parasitics, neoplastics, hypoglycemics, ophthalmics, electrolytes, diagnostic agents and cardiovascular drugs.

  Examples of drugs that are highly soluble

  in water and can be released by the devices

  of the present invention include the edisylate of

  chlorperazine, ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, benzophetamine hydrochloride, isoproternol sulfate, methamphetamine hydrochloride, hydrochloride phenmetrazine, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, sulfate

  of atropine, methascopolamine bromide, isopropyl iodide,

  propamide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, metoprolol tartrate, cimetidine hydrochloride, theophylline cholinate, cephalexin hydrochloride, and the like. Examples of drugs which are poorly soluble in water and which can be released by the devices of the present invention include diphenidol, meclizine hydrochloride, prochlorperazine maleate,

  phenoxybenzamine, thiethylperazine maleate, animal

  sindione, diphenadione erythrityl-tetranitrate, the di-

  Zoxin, Isofurophate, Reserpine, Acetazolamide, Methazolamide, Bendroflumethiazide, Chlorpropamide, Tolazamide, Chlormadinonele Phenaglycodol Acetate, Allopurinol, Aluminum Aspirin, Methotrexate, Acetyl Sulfisaxazole , erythromycin, progestins, an estrogen agent of progestation, corticosteroids,

  hydrocortisone, hydrocorticosterone acetate, acetic acid,

  cortisone, triamcinolone, methyltesterone, 17-estradiol, ethinyl estradiol, prazosin hydrochloride, ethinyl estradiol 3-methyl ether,

  prednisolone, 173-hydroxyprogesterone acetate, 19-

  nor-progesterone, norgestrel, norethindone, nor-

  thiderone, progesterone, norgestone, norethy-

  nodrel, etc. Examples of other drugs that can

  to be released by the osmotic device include the

  pirin, indomethacin, naproxen, fenoprofen, sulidac, diclofenac, indaprofen, nitroglycerin, propranolol, metoprolol, valproate, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chloropropazine, reserpine, methyldopa, dihydroxypenylalanine,

  pivaloyloxyethyl ester of (methyl) -hydrochloride

  dopa, theophylline, calcium gluconate, ketone

  profen, ibuprofen, cephalexin, erythromycin, proszine, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, alpha-blocking agents, calcium metabolism blockers such as lanifedipine , diliazene, levapamil, beta-blockers, etc. Active drugs are known in practice from Pharmaceutical Sciences, edited by Remington, 14th Edition, 1979, published by Mack Publishing Co., Easton, Pennsylvania; The Drug, The Nurse, The Falconer Patient Including Current Drug Handbook, 1974-1976, and

  Coll., published by Saunder Company, Philadelphia, Pennsylvania

  vanie; and Medicinal Chemistry, 3rd edition, volumes 1

  and 2, Burger, published by Wiley-Interscience, New York.

  The drug can take various forms, for example

  uncharged molecules, molecular complexes

  pharmaceutically acceptable salts such as hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, borate, acetate, maleate, tartrate, oleate and salicylate.

  use metal salts, amines and organic cations.

  For example, a drug which is insoluble in water can be used in a form which is a water-soluble derivative to serve as a dietary supplement, for example as a quaternary ammonium compound. solute, and when released from the device, it is transformed by the enzymes, hydrolysed by the body p H or other metabolic processes into the original biologically active form The agent comprising the drug may be present in the compartment with a binder, a dispersant, a wetting agent, a

  suspension, a lubricant and a dye.

  Many of these include suspending agents.

  such as gum arabic, agar, calcium carrageenan, alginic acid, algin, agarose powder, collagen, colloidal magnesium silicate, colloidal silicon dioxide, hydroxyethylcellulose, pectin gelatin and calcium silicate; binders like

  polyvinylpyrrolidone; lubricants such as stearate

  magnesium spleen; wetting agents such as fatty amines, quaternary ammonium fatty salts, etc. The term "drug formulation" indicates that the drug present in the compartment is accompanied by an osmotic agent, an osmotic polymer, a binder, etc. The amount of active agent in a device is generally about 0.05 to 5 g or more, the individual devices containing for example 25 ng, 1 mg, 5 mg, 125 mg, 500 mg,

  750 mg, 1.5 g, etc. Devices can be administrated

  very once, twice or three times a day.

  The solutility of an active agent in the fluid

  can be determined by known techniques.

  The process involves preparing a saturated solution comprising the fluid plus the agent, as indicated by analyzing the amount of agent present in a defined amount of fluid. A simple apparatus suitable for this purpose consists of

  into a medium-sized test tube kept vertically

  in a water bath maintained at

  in which the fluid and the agent are placed

  by shaking them with a rotating glass spiral.

  After a given period of agitation, we analyze a number of

  some fluid weight and continues agitation for a

  If the analysis does not reveal any increase in

  the amount of dissolved agent after successive stirring periods, in the presence of an excess of solid agent in the fluid, the solution is saturated and the results are interpreted as the solubility of the product in the fluid If the agent is soluble, the addition of an osmotically active compound may not be necessary if the agent has limited solubility in the fluid, an osmotically active compound may then be incorporated into

  the device Many other methods are

  to determine the solubility of an agent in a fluid.

  Examples of methods used to measure solubility

  are based on chemical and electrical conductivities.

  The details of various methods for determining solubility

  These are described in United States Public Health Service Bulletin, No. 67, Hygien Laboratory; Encyclopedia of Science and Technology 2, vol 12, pp 542-556, 1971, published by McGraw-Hill, Inc. -and Encyclopedia Dictionary of Physics, vol 16, pp 547-557, 1962, published by Pergamon Press, Inc.

  The osmotic device of the invention is manufactured

  For example, in one embodiment, the active agent is mixed with an osmotic agent and an osmotic polymer, and compressed into a solid having dimensions corresponding to the interior dimensions of the compartment adjacent to the passageway; or

  the active agent and other ingredients constituting the

  and a solvent are mixed into a solid or semi-solid

  solid by conventional methods such as ball milling, calendering, stirring, or grinding with

  roll, then tablets to the previously chosen form.

  Next, a composition layer comprising an osmotic agent and an osmotic polymer is placed in contact

  of the active agent formulation layer, and both

  They are surrounded by a semi-permeable wall. Layers of active agent and osmotic agent / osmotic polymer compositions can be made by conventional two-tablet compression techniques.

  The wall can be applied by molding, atomizing

  sation or immersion of the compressed forms in a wall-forming material Another currently preferred technique that can be used to apply the wall

  is the air-suspended coating process

  The process involves suspending and shaking the compressed compositions in an air stream and a wall-forming composition until the wall

  surrounds and coats the two compressed compositions.

  The process is repeated with a different layer forming composition to form a laminated wall. The air suspension process is described in US Pat. No. 2,799,241; J Am Pharm Assoc, Vol 48, pp. 451-459, 1979; and ibid., Vol. 49, pp. 82-84, 1960 Other conventional methods of manufacture are described in Modern Plastics Enc Yopedia, Vol 46, pp. 62-70, 1969; and in Pharmaceutical Sciences, of Remington, 14th Edition, pages 1626 to 1678, 1970, published by Mack Publishing Co,

Easton, Pennsylvania.

  Examples of suitable solvents for the manufacture of

  laminates and layers include solvents

  inert inorganic and organic substances which do not adversely

  The solvents generally comprise elements selected from the group consisting of aqueous solvents,

  alcohols, ketones, esters, ethers, hydro-

  aliphatic carbons, halogenated solvents, hydro-

  cycloaliphatic carbides, aromatic hydrocarbons,

  heterocyclic solvents, and their mixtures

  Many solvents include acetone, diacetone alcohol and

  methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate,

  isopropyl acetate, n-butyl acetate, methyl-

  isobutyl ketone, methylpropyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride , carbon tetrachloride, chloroform, nitroethane, nitropropane, tetrachloroethane, ether

  ethyl ether, isopropyl ether, cyclohexane, cyclohexane,

  octane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and

  ethylene dichloride and methanol.

  The following examples have the sole purpose of

  to polish the present invention and should not be

  considered as limiting the scope of said invention.

EXAMPLE 1

  An osmotic release device made in the form of a shaped osmotic tablet, dimensioned and designed

  for oral administration in the gastrointestinal tract.

  Tinal is manufactured in the following manner: A first osmotic drug composition is prepared by sieving 355 g of poly (ethylene oxide) having a molecular weight

  approximately 200 000 through a stainless steel sieve

  0.42 mm mesh, then 100 g of nifedipine is passed through the 0.42 mm mesh sieve, 25 g of hydroxypropyl methylcellulose through the 0.42 mm mesh sieve and finally 10 g of Potassium chloride through the 0.42 mm mesh screen Then, all the sieved ingredients are introduced into the bowl of a laboratory blender and blended dry for 15-20 minutes to obtain a homogeneous mixture. then a granulation fluid comprising 250 ml of ethanol and 250 ml

  isopropyl alcohol, and the granular fluid is added.

  in the mixer bowl; firstly, ml is atomized in the bowl by constantly mixing, then 350 ml of the granulation fluid is slowly added to the bowl and

  the wet mass is mixed for another 15 to 20 minutes.

  The wet granules are then passed through a 1.19 mm mesh screen and dried at room temperature for 24 hours, and the dried granules are passed through a 1.19 mm mesh screen. 10 g of magnesium stearate are added to the dry granules, and the ingredients are mixed with the rolls for 20 to 30 minutes.

  minutes on a conventional two-roll mill.

  A second osmotic composition is then prepared.

  As follows: first, poly (ethylene oxide) having a molecular weight of 5,000,000 is passed through a 0.42 mm mesh sieve followed by 72.5 g of chloride. Sodium through the 0.42 mm mesh screen, and the ingredients are added to a mixing bowl and mixed for 10 to 15 minutes. A granulation fluid is then prepared by mixing 350 ml of methanol and 150 ml of water. isopropyl alcohol, and the

  granulation fluid at the mixing bowl in two stages.

  First, 50 ml of the granulation fluid is atomized

  in the bowl, stirring constantly, then add

  350 ml of the granulation fluid in the mixing bowl.

  Mix and mix the wet mixture for 15-20 minutes to obtain a homogeneous mixture. The wet mixture is then passed through a sieve of 1.19 mm mesh, spread on a stainless steel tray and dried at room temperature. the ambient temperature of 22.50 C for 24 hours. The dried mixture is passed through a mesh screen.

  1.19 mm, then crush the rolls with 5 g of

  magnesium spleen on a two-roll mill during

-30 minutes.

  A number of drug nuclei are prepared

  compress the two compositions on a press "Manesty Layert" The composition containing the drug is introduced into the cavity of a mold of the press and

  compressed into a solid layer The second osmotic composition

  The tick is then introduced into the cavity by covering the compressed layer and is compressed into a layer.

  solid to obtain a two-layer drug core.

  The drug nuclei are then coated with a semipermeable wall-forming composition comprising 95 g of cellulose acetate having an acetyl group content of 39.8% and 5 g of poly (ethylene glycol) 4000 in a solvent comprising 1960 ml of methylene chloride and 820 ml of methanol The drug nuclei

  are coated with the composition forming the semi-per-

  until the wall surrounds the drug core.

  Wurster, an air suspension coating apparatus, is used to form the semi-permeable wall. The coated cores are then spread on a tray and the

  The solvent is evaporated off in a circulating oven.

  50 WC for 65 hours after cooling.

  until it reaches room temperature, a laser drill

  orifice with a diameter of 0.26 mm through the semi-

  permeable to connect the exterior of the osmotic device with the composition containing the drug The osmotic device weighs 262 mg and contains 30 mg of medicament

  in the first composition weighing 150 mg, the second composition

  position weighs 75 mg and the semipermeable wall weighs 37 mg.

  The first osmotic composition of the osmotic device

  contains 30 mg of nifedipine, 106 mg of poly (ethylene oxide)

  lene), 3 mg of potassium chloride, 7.5 mg of hydroxypro-

  pylmethylcellulose and 3 mg of magnesium stearate.

  The second osmotic composition contains 51 mg of poly-

  (ethylene oxide), 22 mg of sodium chloride and 1.5 mg of magnesium stearate The device has a diameter of

  8 mm, a contact area of 1.8 cm 2 and the semi-circular wall

  permeable to a thickness of 0.17 mm The cumulative amount

  released drug is shown in Figure 9.

EXAMPLE 1

  Osmotic delivery systems having a first composition comprising 25 to 100 mg of nifedipine, 100 to 325 mg of poly (ethylene oxide) having a molecular weight of 200,000, 2 to 10 mg of potassium chloride, 5 to 25 30 mg of hydroxypropyl methylcellulose, and 2

  10 mg magnesium stearate; and a second

  comprising from 30 to 175 mg of poly (ethylene oxide) having a molecular weight of 5,000,000, 20 to 75 mg of sodium chloride and 1 to 5 mg of magnesium stearate is repeated

  the procedure of Example 1 to prepare

  osmotic substances having the following composition: (a) an osmotic device the first composition of which contains nifedipine mg, 212 mg of poly (ethylene oxide), 6 mg

  potassium chloride, 15 mg hydroxypropyl methylcellulose

  lose and 6 mg of magnesium stearate; and whose second composition contains 102 mg of poly (ethylene oxide),

  44 mg of sodium chloride and 3 mg of magnesium stearate

  sium; and (b) an osmotic device whose first

  position contains 90 mg of nifedipine, 318 mg of poly (oxide

  ethylene), 9 mg of potassium chloride, 22.5 mg of hydro-

  xylpropyl methylcellulose and 9 mg of magnesium stearate,

  whose second composition contains 102 mg of poly-

  (ethylene oxide), 66 mg of sodium chloride, and 4.5 mg of magnesium stearate In one embodiment, the osmotic device described in (a) and (b) comprises

  in addition to a quick-release layer applied to the

  outdoor semi-permeable king The fast-acting layer

  30 mg of nifedipine and hydroxypropylmethyl-

  cellulose In operation in the fluid medium of use

  the fast-acting layer makes it possible to

  immediate release of the drug for the purpose of

by the drug.

EXAMPLE 2

  The operations of Example 1 are repeated, all the conditions being the same as previously described, at

  the difference that the medicine contained in the

  is replaced by a member selected from the group consisting of a beta-blocking agent, an anti-inflammatory, an analgesic, a sympathomimetic, an antiparkinsonian,

S or a diuretic.

EXAMPLE 3

  An osmotic therapeutic device is prepared for the controlled and continuous oral release of verapamil which is a calcium metabolism blocking drug as follows: Blend intimately as described in

  Example 1, 90 mg verapamil, 50 mg carboxy polymer,

  sodium vinyl having a molecular weight of 200,000 and R

  sold under the trade name Carbopol, 3 mg of chlorine

  sodium hydroxide, 7.5 mg of hydroxypropyl methylcellulose and 3 mg of magnesium stearate, and

  Manesty press with a punch of 7.93 mm using

  At a head pressure of 1.5 tons to obtain a layer of the drug composition 51 mg of the carboxyvinyl polymer having a molecular weight of 3,000,000 and sold under the tradename Carbopol, 22 mg of chloride, are intimately mixed. of sodium and 2 mg of magnesium stearate and introduces them into a press Manesty, and

  compresses them to obtain a layer of osmo-

  expandable tick in contact with the composition layer

osmotic drug. A semipermeable wall is then formed into

  containing 170 g of cellulose acetate having a content of

  acetyl groups of 39.8% with 900 ml of methyl chloride

  and 400 ml of methanol, and by spraying the element constituting the two-layer compartment in a machine suspended in the air until a wall

  semi-permeable material with a thickness of 129.5 ym surrounds

  The coated device is dried for 72 hours

  at 500 ° C., then a hole of 203 μm is pierced by laser.

  towards the semi-permeable wall to connect the

  the medicine outside the device for releasing

  the medication over a prolonged period of time.

EXAMPLE 4

  The procedure of Example 3 is repeated, all conditions being as described except that the drug contained in the osmotic device is fendiline, diazoxide, prenylamine or diltiazen.

EXAMPLE 5

  An osmotic therapeutic device for the release of diclofenac sodium, for use as an anti-inflammatory, is prepared by first compressing in an Manesty press an osmotic drug composition containing 75 mg of diclofenac sodium, 300 mg of sorbitol, mg of bicarbonate of sodium, 26 mg of pectin, 10 mg of

  polyvinylpyrrolidone, and 5 mg of stearic acid, and in

  priming the composition in a cavity until a solid layer is formed is then introduced into the cavity a second composition generating a greater force and which comprises 122 mg of pectin having a molecular weight

  from 90,000 to 130,000, 32 mg of mannitol, 20 mg of polyvinyl

  pyrrolidone and 2 mg of magnesium stearate, and

  to form a second layer in contact with the first

  The second layer has a density of 1.28 g / cm 3 and a hardness greater than 12 kg. Next, the two-layer core is surrounded by a semi-permeable wall comprising 85 g of cellulose acetate having acetyl group content of 39.8%, and 15 g of polyethylene glycol 4000, 3% w / w of solid material in a wall-forming solvent comprising 1960 ml of methylene chloride and 819 ml of methanol. device coated for 72 hours at 50 ° C, then a hole with a diameter of 0.26 mm is laser drilled in the wall. The semi-permeable wall has a thickness of 0.1 mm, the device has a surface of 3 , 3 cm 2 and has an average drug release rate of 5.6 mg per hour on a

  period of 12 hours The cumulative amount released is

  shown in Figure 10 The small vertical bars represent the maximum release drug amounts

  and minimal on five systems measured at this time.

EXAMPLE 5 A

  The procedure of Example 5 is followed to

  prepare an osmotic device in which the compartment

  contains a mixture of osmotic polymers.

  partment contains a first composition weighing 312 mg

  and consisting of 48% diclofenac sodium as a medicinal

  38% osmotic polymer of the poly (ethylene oxide) type

  lene) having a molecular weight of 200 000, 10% poly-

  poly (ethylene glycol) type osmotic mother having a molecular weight of 20,000, 2% sodium chloride and 2% magnesium stearate; and a second composition weighing mg and consisting of 93% poly (ethylene oxide) having a molecular weight of 5,000,000, 5% chloride.

  of sodium and 2% of magnesium stearate.

EXAMPLE 6

  In this example, the increase in osmotic pressure for a number of compositions comprising an osmotic agent and an osmotic polymer is measured to demonstrate the advantages offered by the invention.

  measurements are made by measuring the amount of water

  sorbed through the semi-permeable wall of a bag containing

an osmotic agent or an osmotic polymer, or a compound

  comprising an osmotic agent and an osmotic polymer

  tick The semi-permeable wall of the bag is formed of acetate

  cellulose having an acetyl content of 39.8%.

  Measurements are made by weighing the dry ingredients of the semipermeable bag, then weighing the semi-permeable bag

  soaked after placing it in a 370 C water bath

  during various periods of time The increase in weight

  is due to the absorption of water through the semi-per-

  The osmotic pressure curves are shown in Figure 11 In this figure, the curved line provided with triangles represents the osmotic pressure for the poly (ethylene oxide) having a molecular weight. 5,000,000; the curved line provided with circles represents the osmotic pressure for a composition comprising poly (ethylene oxide) having a molecular weight of 000 000 and sodium chloride with the ingredients present in the composition in a ratio of 9.5 parts of osmotic polymer for 0.5 part of osmotic agent

  the curve with squares concerns a composition containing

  the same osmotic polymer and osmotic agent at a ratio of 9 parts of osmotic polymer to one part of osmotic agent; the hexagonal curve relates to the same composition comprising the osmotic polymer and the osmotic agent in a ratio of 8 parts to 2 parts; and the dashed curve refers to the sodium chloride used as the osmotic agent. The mathematical calculations are made using the formula dw / dt = A (KAX) / h, where dw / dt is the absorption rate of the water, A is the surface of the semi-permeable wall and K is the coefficient

  Likewise, in FIG. 11, D H / Wp represents

  the amount of water absorbed divided by the weight of osmotic polymer plus the osmotic agent,

EXAMPLE 7

  an osmotic therapeutic device is prepared

  intended to release diclofenac sodium by sieving through

  to a sieve of 0.42 mm mesh of a composition

  taking 49% diclofenac sodium, 44% poly (4% ethylene) having a molecular weight of 100,000, 2% sodium chloride and 3% hydroxypropyl methylcellulose, then mixing the sieved composition with an alcoholic solvent The wet granules were sieved at a rate of 1.19 mm, dried at room temperature for 48 hours under vacuum, and sieved at 1.19 mm mesh. mixed with 2% magnesium stearate passed through the 0.177 mm mesh screen The composition is compressed

as described above.

  A composition comprising 73.9% of pectin having a molecular weight of 90,000 to 5,000, 5.8% of microcrystalline cellulose, 5.8% of polyvinylpyrrolidone, 14.3% of sodium chloride and 2% of 0.42 mm sieve sucrose, mixed with an organic solvent at a ratio of 100 ml of solvent per 100 g of granules for 25 minutes, sieved to 1.19 mm mesh, dried for 48 hours at room temperature under vacuum, it is again passed through the sieve of 1.19 mm, mixed with 2% magnesium stearate, and then compressed on the compressed layer

  described in the paragraph above The Medicine Core

  double layer is dip-coated in a wall-forming composition comprising 80% cellulose acetate having an acetyl content of 39.8%,

  % polyethylene glycol 4000 and 10% hydroxypropyl-

  Methylcellulose An orifice is drilled through the wall

  to establish a communication with the composition

  The diameter of the orifice is 0.38 mm.

  The theoretical cumulative release curve for the device is shown in FIG. 12. FIG. 13 represents the theoretical release rate in mg per hour for the

osmotic device.

EXAMPLE 8

  The procedure of Example 7 is repeated, always

  the conditions being as described with the difference that the osmotic polymer of the drug composition

  is a block polymer of polyoxyethylene and polyoxyethylene

  propylene having a molecular weight of about 5000.

EXAMPLE 9

  An osmotic device is prepared by the modes

  above The device of this example

  takes a single composition containing 50% diclofenac

  sodium, 46% of poly (ethylene oxide) having a molecular weight

  100,000, 2% of sodium chloride and 2% of

  magnesium stearate The device has a semi-circular wall

  permeability comprising 90% cellulose acetate having a

  acetyl group content of 39.8%, and 10% polyethylene-

  glycol 4000 The cumulative amount released in the case of this device with a single composition is 40% of that of the two-composition device The cumulative amount

  released is shown in Figure 14.

EXAMPLE 10

  In vivo and in vitro laboratory dogs are measured for the average cumulative in vivo and in vitro diclofenac sodium release from an osmotic device comprising a first osmotic composition.

  consisting of 75 mg diclofenac sodium, 67 mg poly-

  (ethylene oxide) having a molecular weight of 100,000,

  3.0 mg of sodium chloride, 4.5 mg of hydroxypropylmethyl-

  cellulose and 3.0 mg magnesium stearate; a second osmotic composition spaced from the delivery port comprising 51 mg of poly (ethylene oxide) having a molecular weight of 5,000,000, 22.5 mg of sodium chloride, and 1.5 mg of magnesium stearate; all surrounded by a

  semi-permeable wall comprising 90% of cellulose acetate

  with an acetyl group content of 39.8% and 10% -20% of polyethylene glycol 4000.

  drug released in vivo at various times by admi-

  administering a series of devices to the animal and measuring the released amount of the corresponding device

  at the appropriate time of stay The results are

  Figure 15 shows the circles with bars representing the average cumulative in vitro releases and the triangles with bars representing the

  average cumulative release in vivo.

  Mean cumulative release in vivo and in vivo

  in the case of a device containing nifedi-

  pine are measured as described immediately above.

  The osmotic device comprises a composition close to the orifice containing 30 mg of nifedipine, 106.5 mg of poly (ethylene oxide) having a molecular weight of

  200,000, 3 mg of potassium chloride, 7.5 mg of hydroxy-

  propyl methylcellulose, and 3 mg of magnesium stearate; a composition spaced from the orifice containing 52 mg of polyethylene oxide having a molecular weight of 000 000, 22 mg of sodium chloride and 1.5 mg of magnesium stearate; and a semipermeable wall comprising 95% cellulose acetate having a content in groups

  acetylated 39.8%, and 5% hydroxypropyl methylcellulose.

  Figure 16 shows the release of the system In Figure 16, the circles represent the cumulative release

  in vivo and the triangles represent the cumulative

average in vitro.

EXAMPLE 11

  The procedure of Example 10 is followed to prepare an osmotic release therapeutic system comprising: a first composition, or Qn composition of

  drug, weighing 638 mg and consisting of 96% chlorine

  cephalexin hydrate, 2 R of Poviclone (polyvinylpyrrolidine)

  lidone) and 2% magnesium stearate; a second

  position, or osmotic release composition, weighing mg and consisting of 68.5% poly (ethylene oxide) having a molecular weight of 5 x 106, 29.5% chloride

  sodium and 2% magnesium stearate; a semi-circular wall

  permeate weighing 55.8 mg consisting of 80% cellulose acetate having an acetyl content of 39.8%,

  14% polyethylene glycol 4000 and 14% hydroxypropyl-

  methylcellulose; and an osmotic port with a diameter of 0.039 mm The device has an average release rate of about 54 mg per hour over a period of

9 hours.

  The new osmotic system of the present

  vention uses a dual means to obtain a precise release rate of drugs that are difficult to release into the use environment, while retaining

  simultaneously the integrity and character of the system.

Claims (10)

  1 Device for the release, at a set speed, of an active agent in a medium of use, characterized in that it comprises: a) a wall (12) formed, at least in part,   of a composition permeable to the passage of an external fluid.   the surrounding wall and forming: b) a compartment (14) c) a first composition in the compartment (14), said first composition comprising an active agent (15), an osmotic agent (16), ) and an osmotic polymer (17); d) a second composition in the compartment   (14), said second composition comprising an osmotic agent   tick (18) and an osmotic polymer (19); and   e) a passage (13) in the wall (12) communicating   as for the first composition and the exterior of the   positive to release the active agent (15) of the device (10).   2 Device for the release, at a speed   an active agent according to claim 1, characterized   in that the wall-forming composition comprises a member selected from the group consisting of   cellulose, cellulose diacylate, triacylate of   lulose, cellulose acetate, cellulose diacetate   cellulose triacetate, ethylcellulose, cellulose acetate butyrate, aceto-propionate   cellulose, hydroxypropyl methylcellulose, a hydroxypropyl   (lower alkyl) cellulose, methylcellulose,   methylethylcellulose, and mixtures thereof.   3 Device for the release, at a speed   of an active agent according to claim 1,   in that the first composition is in the   compartment in the form of a layer, and the second   is in the compartment as a layer.   4 Device for the release, at a speed   an active agent according to claim 1, characterized   in that the first composition imbibes external fluid through the wall into the compartment, and the second composition is imbibed with external fluid through the wall in the compartment.   5 Device for release, at a speed   an active agent according to claim 1, characterized   in that the osmotic polymer included in the second   composition has a molecular weight greater than the   of the osmotic polymer included in the first position.   6 Device for release, at a speed   an active agent according to claim 1, characterized   in that the active agent is a medicament.   Device for the controlled release of active agent in a use medium according to claim 1, characterized in that the wall is a laminate comprising   a semi-permeable layer and a microporous layer.   8 Device for the controlled release of an active agent in a use medium according to claim 1,   characterized in that the composition forming the wall holds polyethylene glycol.   Device for the regulated release of an active agent in a use medium according to claim 1, characterized in that the osmotic polymer of the first   composition is poly (ethylene oxide).   Device for the controlled release of an active agent in a use medium according to claim 1, characterized in that the osmotic polymer of the second   composition is poly (ethylene oxide).   Device for the regulated release of an active agent in a use medium according to claim 1, characterized in that the agent is the drug nifedipine, verapamel, dilthazen, diclofenac, propanolol, proszine, ibuprofen, ketoprofen, haloperiodol, indomethacin or cephalexin.