BE900817R - Osmotic device for controlled delivery of pharmaceuticals - comprises permeable enclosure contg. active ingredient mixed with osmo:polymer - Google Patents

Abstract

Device consists of a wall, made at least partly of a material which is permeable to the external fluid, which defines a compartment. This contains (1) a compsn. contg. active ingredient (I) and an osmopolymer (II) and (2) a compsn. of (II) only. - The wall has an opening which establishes contact between the exterior and (1). Pref. both compsns. inside the compartment are formulated as layers and both imbibe fluids which permeate in through the walls.

Description

       

  "Osmotic device" "Osmotic device"

  
The present invention relates to a distribution system which is both new and particular. More particularly, the invention relates to an osmotic device comprising a wall formed at least in part of a semipermeable material which surrounds a compartment comprising (1) a first osmotic composition comprising a beneficial agent, and preferably an osmotic agent and / or an osmopolymer, this composition being in contacting arrangement with

  
(2) a second osmotic composition comprising an osmotic agent and an osmopolymer. A passage through the wall connects the exterior of the osmotic device to the first osmotic composition containing the beneficial agent for dispensing the first composition from the osmotic device. The osmotic device is useful for dispensing beneficial agents which, because of their solubilities, are difficult to dispense in a known quantity at a speed set at. from an osmotic distribution system.

  
Since the beginning of antiquity, it has been thought both in pharmacy and in medicine to develop a distribution system for the administration of a beneficial drug. The first written reference to a dosage form is the Eber papyrus, written around 1552 BC. The Eber papyrus mentions dosage forms, such as anal suppositories, vaginal pessaries, ointments, oral pill formulations and other dosage preparations. About 2,500 years passed without any progress being made in the development

  
dosage forms, until the Arab doctor Rhazes, 865-925 AD, invented the coated pill. About a century later, the Persian Avicenna, 980-1037 AD, coated pills with gold or silver to increase patient acceptability and improve the effectiveness of the drug. Around this time, the first tablet was described in Arabic manuscripts written by al-Zahrawi, 936-1009 AD. The manuscripts described a tablet formed from hollow impressions in two facing tablet molds. We waited in pharmacy and medicine about 800

  
years for the next innovation in dosage forms, when Mothes invented in 1883 the capsule for drug administration. The next important step in dosage forms came in

  
1972 with the invention of the osmotic distribution device of Theeuwes and Higuchi, as described in the patents of the United States of America n [deg.] 3,845,770 and
3,916,899. The osmotic devices described in these patents include a semi-permeable wall which surrounds a compartment containing an effective agent. The wall is permeable to the passage of an external fluid, and it is practically impermeable to the passage of the effective agent. There is a passageway through the wall for the delivery of the effective agent from the osmotic device.

   These devices release the effective agent as the fluid soaks through the semi-permeable wall into the compartment, at a rate determined by the permeability of the semi-permeable wall and the osmotic pressure gradient across the wall, producing an aqueous solution containing the effective agent which is discharged through the passageway of the device. These devices are extraordinarily effective in delivering an effective agent which is soluble in the fluid and which manifests an osmotic pressure gradient across the semi-permeable wall vis-à-vis the external fluid.

  
An unexpected progress concerning the osmotic distribution device was made by Felix Theeuwes in the patent of the United States of America

  
n [deg.] 4.111.202. In this patent, the distribution kinetics of the osmotic device is increased for the distribution of effective agents which are insoluble to very soluble in the fluid, by arranging the osmotic device with an effective agent compartment and an osmotic agent compartment separated by a movie. The film can go from a rest state to an expanded state.

  
The osmotic device distributes the agent as the fluid soaks through the semi-permeable wall in the osmotic agent compartment,

  
by producing a solution which causes an increase in volume of the compartment and which acts in the manner of a pushing force which is applied against the film. This force causes the film to expand against the effective agent compartment and, correspondingly, decreases the volume of the effective agent compartment, so that the effective agent is discharged through the passageway of the osmotic device. Although this device works successfully for its intended use, and although it can dispense a large number of effective agents of various solubilities, its use may be limited due to the manufacturing steps and the costs involved in manufacturing and

  
placing the movable film in the compartment of the osmotic device.

  
In the patent of the United States of America

  
n [deg.] 4.327.725 by Richard Cortese and Felix Theeuwes, an osmotic delivery device is provided for the distribution of beneficial agents, which due to

  
their solubilities in aqueous and biological fluids are difficult to distribute in significant quantities at rates regulated as a function of time. The osmotic devices of this patent comprise a semi-permeable wall surrounding a compartment containing a beneficial 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 fluid which enters the device, thus causing the unloading of the beneficial agent through the passageway of the device. This device works successfully for its intended use, and it delivers a large number of beneficial agents which are difficult to deliver for their intended application.

   However, it has been noted that its use could be limited because the hydrogel does not have the intrinsic capacity to soak a sufficient quantity of fluid for the maximum automatic expansion necessary for the unloading of the beneficial agent from the device.

  
It will be noted, as specialists in the distribution technique well know, that if we

  
can develop an osmotic device which exhibits a high degree of osmotic activity to deliver a beneficial agent by the in situ production of an expansion force sufficient to deliver the maximum amount of agent at a rate set from an osmotic device, such an osmotic device would be of great interest and would represent progress in

  
distribution technique. In the same way, it will be noted immediately, as specialists in the distribution technique well know, that if an osmotic device having a double osmotic, thermodynamic activity is produced to distribute increased amounts of beneficial agent, this osmotic device would find practical application in the fields of pharmacy and medicine.

  
Therefore, in view of the above,

  
an immediate object of the present invention is to provide

  
an osmotic system which represents a new improvement and a new progress in the technique of distribution.

  
Another object of the invention is to provide

  
an osmotic system produced in the form of an osmotic device for the in vivo distribution of a beneficial drug, which is difficult to deliver and which can now be delivered by the osmotic device produced according to the present invention in therapeutically effective amounts function of time,

  
Another object of the invention is to provide an osmotic system having a double osmotic activity, which system comprises a compartment containing a first osmotic composition comprising a drug, and preferably an osmotic agent and / or an osmopolymer, and a second osmotic composition comprising an osmotic agent and an osmopolymer, the compositions acting at the same time to discharge the drug from the osmotic device.

  
Yet another object of the invention consists in providing an osmotic device comprising a means for the full loading of a drug insoluble in water or of a drug slightly soluble in water and

  
means for dispensing the drug in each case

  
at a set speed and continuously as a function

  
time.

  
Yet another object of the invention is to provide an osmotic device which can distribute a beneficial agent dependent on pH by providing a neutral medium for distributing the beneficial agent in a finely dispersed form, so as to increase its surface area and to maximize the rate of dissolution of the beneficial agent.

  
Yet another object of the invention is to provide an osmotic system for dispensing a drug having a very low dissolution rate, which is in fact the step limiting the speed for discharging the drug from the system, but which can now be dispensed using an osmotic composition which functions in situ as a wetting agent and a solubilizing agent to increase the speed of dissolution and the solubility of the drug, thereby improving its discharge from the osmotic system.

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

  
Yet another object of the invention is

  
providing a therapeutic, osmotic device which can administer a complete pharmaceutical dosage regimen comprising poorly soluble agents

  
very soluble, at a regulated speed and continuously, for a particular period of time, the use of which requires intervention only during the start and possibly the end of the regime.

  
Other details and particularities of the invention will emerge from the description below, given by way of nonlimiting example and with reference to the appended drawings, in which:
Figure 1 shows an isometric view of an osmotic device designed to orally administer a beneficial agent to the gastrointestinal tract. 2 shows a view, partially broken, of the osmotic device of Figure 1, this view illustrating the structure of the osmotic device. Figure 3 shows a partially broken view of the osmotic device of Figure 1, illustrating the osmotic device in operation and dispensing a beneficial agent.

  
The fignr'- '' is a view: partially broken of the osmotic device of Figure 1, illustrating, just like Figure 3, the osmotic device in operation but distributing a significant amount of beneficial agent.

  
FIG. 5 represents an osmotic therapeutic device, the wall of which has been partially broken, designed to deliver a beneficial agent in a passage of the body, such as the anorectal and vaginal passages. Figure 6 shows the osmotic device of Figure 5, with a different wall structure. FIG. 7 represents the osmotic device of FIG. 5, showing a wall structure different from the wall structure represented by FIG. 6. FIG. 8 represents the weight gain as a function of time of a polymer encapsulated in a semi membrane -permeable, when the encapsulated polymer is placed in water. Figure 9 shows the cumulative amount of drug released from a device comprising an osmopolymer having two different molecular weights.

   Figure 10 shows the cumulative amount of drug released from a device using a different group of osmopolymers. Figure 11 shows the osmotic pressure curves of a number of osmotic agents and a number of osmopolymer / osmotic agent compositions. Figure 12 shows the cumulative release profile of an osmotic system using two different osmopolymers. FIG. 13 represents the rate of release per hour of an osmotic system different from that of FIG. 9, containing an osmopolymer having two different molecular weights. FIG. 14 represents the cumulative quantity released from a device with a simple composition comprising only one layer. Figure 15 shows the cumulative in vivo and in vitro release of a drug delivered by the osmotic device.

   Figure 16 shows the cumulative in vivo and in vitro release of a different drug dispensed by an osmotic device.

  
In the drawings and in the description which follow, identical or similar elements are designated by the same references. The terms which appear previously in the specification and in the description of the drawings, as well as embodiments, are more detailed in the description.

  
If reference is made to the drawings which are examples of various osmotic devices provided by the invention, these examples not being given by way of limitation, an example of an osmotic device can be seen in FIG. 1. In FIG. 1 , it can be seen that the osmotic device 10 comprises a body element
11 comprising a wall 12 and a passageway 13 for the release of a beneficial agent from the osmotic device 10.

  
Figure 2 shows an open form by breaking of the osmotic device 10 of Figure 1. In Figure 2, the osmotic device 10 comprises a body
11, a semi-permeable wall 12 which envelops it and forms a compartment 14, which communicates via a passageway 13 with the exterior of the osmotic device 10. The compartment 14 contains a first osmotic composition comprising a beneficial agent 15, represented by dots, which can be insoluble to very soluble in the fluid soaked in compartment 14, an osmotic agent 16, represented by li- <EMI ID = 1.1>

  
darsle compartment 14 and which manifests an osmotic pressure gradient across the semi-permeable wall

  
12 vis-à-vis an external fluid, as well as an osmopolymer 17, represented by horizontal lines, which imbibes the fluid in the compartment 14 and manifests an osmotic pressure gradient through the semi-permeable wall 12 vis-à-vis an external fluid present in the environment of use. The wall 12 is formed of a semi-permeable composition which is substantially permeable to the passage of the external fluid, and which is substantially impermeable to the passage of the agent
15, osmotic agent 16 and osmopolymer 17. The semi-permeable wall 12 is non-toxic and it maintains its physical and chemical integrity during the release of the beneficial drug by the device 10.

  
The compartment 14 also contains a second osmotic composition which is distant from the passageway 13 and which is in contact with the first composition. The second composition imparts an expandable pushing force which acts in conjunction with the first osmotic composition to release the maximum amount of beneficial agent from the osmotic device

  
10. The second osmotic composition comprises an osmotic agent 18, which is soluble in. fluid which has soaked the compartment 14 and which manifests an osmotic pressure gradient across the wall 12 vis-à-vis an external fluid, mixed with an osmopolymer 19, which is imbibed with the fluid located in the compartment 14 and which manifests an osmotic pressure gradient across the wall 12 vis-à-vis the external fluid. Osmopolymers 17 and 19 are soluble polymers

  
in water, hydrophilic or insoluble in water, slightly crosslinked, and they have osmotic properties, such as the ability to absorb external fluid, manifest an osmotic pressure gradient

  
through the semi-permeable wall vis-à-vis the external fluid, and swell or expand in the presence of the fluid. Osmopolymers 17 and 19 are mixed with osmotic agents 16 and 18 to absorb the maximum volume of external fluid in compartment 14. This fluid is available vis-à-vis osmopolymers 17 and 19 to optimize the volumetric rate and to fully dilate the osmopolymers 17 and 19. This means that osmopolymers 17 and 19 absorb the fluid which has soaked compartment 14 through the osmotic imbibing action of osmopolymers 17 and 19 to which is added the osmotic imbibing action of osmotic agents. 16 and 18 to achieve the maximum expansion of osmopolymers 17 and 19 until an enlarged state is obtained.

  
In operation, the distribution of beneficial agent 15 by the osmotic device 10 is carried out, according to a currently preferred embodiment, by (1) soaking the fluid of the first composition so as to form a suspension in situ and by distribution of the suspension in the passageway, and simultaneously by (2) the imbibition of fluid of the second composition by causing it to swell, in cooperation with the first composition to push the suspension of agent in the route of passage. According to the operation described, the osmotic device can be treated in the manner of a cylinder, the second composition expanding like the movement of a piston to facilitate the release of the agent suspension from the osmotic device.

   Although the shape of the osmotic device shown in Figures 1 and 2 is not a real cylinder, it is close enough to perform the following physical analysis. In this analysis, the volume flow released by the os-

  
  <EMI ID = 2.1>

  
of water imbibition of the first composition F and the rate of water imbibition of the second composition Q where:

  

  <EMI ID = 3.1>


  
Since the bond between the first composition and the second composition becomes very weakly hydrated during the use of the osmotic device, there is an insignificant migration of water between the compositions. This is how the rate of water imbibition of the second composition Q is equal to the expansion of its volume:

  

  <EMI ID = 4.1>


  
The total distribution rate of the osmotic device is then:

  

  <EMI ID = 5.1>


  
where C represents the concentration of beneficial agent in the dough distributed. The conservation of the volume of osmotic device V and of the surface area A give equations 4 and 5:

  

  <EMI ID = 6.1>


  
  <EMI ID = 7.1>

  
surface contact between the wall and the first composition and between the wall and the second composition. In operation, the two values V and A

P P

  
increase as a function of time while the values Vd and Ad decrease as a function of time as the device distributes the beneficial agent.

  
The volume of the second composition which differs

  
  <EMI ID = 8.1>

  
compartment, is given by equation 7:

  

  <EMI ID = 9.1>


  
  <EMI ID = 10.1>

  
the second composition initially present in the device, W H / W p represents the initial fluid / solid matter ratio of the second composition, V being equal to

  

  <EMI ID = 11.1>


  
where e represents the density of the second composition corresponding to WH / Wp. Thus if we base ourselves on the geometry of a cylinder, where r represents the radius of the cylinder, the imbibition area is linked to the volume of the second composition inflated in the following way:

  

  <EMI ID = 12.1>


  
The fluid soak rates in each compartment are as follows:

  

  <EMI ID = 13.1>


  
k representing the osmotic permeability of the wall, h

  
  <EMI ID = 14.1>

  
representing respectively the osmotic gradients of the first composition and of the second composition.

  
The total release rate is therefore equal to:

  

  <EMI ID = 15.1>


  
Figures 3 and 4 show the osmotic device of Figures 1 and 2, in operation. Referring to the osmotic device 10 of Figures 3 and 4, the fluid has soaked the first composition at a rate determined by the permeability of the wall and by the osmotic pressure gradient across the wall. The imbibition fluid continuously forms a solution containing beneficial agent, or alternatively a solution of osmopolymer and osmotic gel-forming agent containing beneficial agent in suspension, which solution or suspension in each operation is released by the combined operations of device 10.

   These operations involve the osmotic distribution of the solution or suspension by the passageway due to the continuous formation of solution or suspension, as well as the swelling and increase in volume of the second composition, represented by the increase of height of the vertical lines in FIGS. 3 and 4. This latter swelling and increase in volume applies pressure against the solution or suspension, thus helping the first composition and, simultaneously, causing the distribution of beneficial agent outside. of the device.

  
The first composition and the second composition act together to:. essentially ensuring that the release of beneficial agent from the compartment is constant over a period of time extended by two processes. First of all, the first composition is soaked with external fluid passing through the wall, thus forming a solution or a suspension, the last fraction of which would be essentially distributed at a non-zero speed (without the second composition present), since the force thrust weakens over time.

   Secondly, the second composition acts according to two simultaneous processes, firstly, the second composition acts by continuously concentrating the beneficial agent by soaking up a certain quantity of fluid originating from the first composition to prevent the concentration of beneficial agent falling below saturation, and secondly, the second composition by soaking external fluid passing through the wall increases in volume continuously, thereby exerting a force against the first composition and decreasing the volume of beneficial agent, and thereby directing the beneficial agent to the pathway through the compa &#65533; timent.

   In addition, since the additional solution or suspension formed in the first compartment is expressed, the osmotic composition comes into intimate contact with the internal wall and produces a constant osmotic pressure, and therefore a constant distribution rate, together with the second composition.

  
The swelling and expansion of the second composition, with its corresponding increase in volume, at the same time as the corresponding reduction in volume, simultaneous of the first composition, ensure the distribution of beneficial agent at a controlled rate as a function of time.

  
The device 10 of Figures 1 and 4 can be brought in various forms, including the presently preferred embodiments for oral use, for the release of a therapeutic agent locally or generally in the gastrointestinal tract. The oral system 10 can have different forms

  
and usual dimensions, such as a round shape with a diameter of 4.8 mm to 12.7 mm. In these forms, the system 10 can be adapted to the administration of beneficial agents to a large number of animals, in particular warm-blooded animals, humans, birds, reptiles and fish.

  
Figures 5, 6 and 7 show another embodiment, namely an osmotic device
10 designed for placement in a body passageway, such as a vagina or anorectal canal. The device 10 has a self-supporting, cylindrical, elongated shape with a rounded front end 20 and a tail end 21, this device being provided with wires 22 adjusted manually for easy separation of the device 10 from a track. of biological passage.

   The device 10 is structurally identical to the device 10 as described above, and it works in the same way, In FIG. 5, the device 10 is shown with a semi-permeable wall 23, and in FIG. 6 with a wall laminate
24 comprising an inner semi-permeable strip 25 adjacent to the compartment 14, and an external microporous strip 26 distant from the compartment 14. In FIG. 7, the device 10 comprises a laminated wall 28 formed of a microporous strip 29 adjacent to the compartment 14, and a semi-permeable strip 31 oriented towards the medium of use and arranged in a layered arrangement with the microporous strip 29.

   The device 10 releases a beneficial agent so that it is absorbed by the vaginal mucosa, or the anorectal mucosa, so as to produce a local or general effect in vivo over an extended period of time.

  
The osmotic devices of FIGS. 1 to 7 can be used to dispense a large number of agents, in particular of medicaments, at a regulated speed, independently of the dependence of the medicament on the pH, or of the fact that the dissolution of the agent can vary between a low value and a high value in fluid environments, such as gastric fluid and intestinal fluid. Osmotic devices are also suitable for
- high support for agents of low solubility and their distribution in therapeutic, effective quantities.

   Although FIGS. 1 to 7 represent various osmotic devices which can be produced according to the invention, it will be noted that these devices are not limiting, the devices being able to present a wide variety of shapes and dimensions adapted to the distribution of agents different environments of use. For example, the devices are oral devices, implants, artificial glands, cervical, intrauterine, atrial, nasal, dermal, subcutaneous devices as well as blood delivery devices. The devices can also be dimensioned, shaped, structured and adapted to distribute an active agent in currents, aquariums, fields, factories, tanks, laboratory installations, heated houses,

  
transport devices, maritime devices, military devices, hospitals, veterinary clinics, maternity hospitals, farms, zoos,

  
patient rooms, chemical reactions and other environments.

  
In accordance with the practice of the present invention, it has now been found that the osmotic distribution device 10 could be produced with a first osmotic composition and a second osmotic composition housed jointly in the compartment of the device. The compartment is formed by a wall comprising a material which does not adversely modify the beneficial agent, the osmotic agent, the osmopolymer, etc. The wall is permeable to the passage of a fluid
-of external, such as water and biological fluids, and it is substantially impermeable to the passage of beneficial agents, osmotic agents, osmopolymers, etc.

   The wall is formed of a material which does not adversely affect an animal or a host, and the selectively semi-permeable materials used to form the wall do not corrode and are insoluble in fluids. Typical materials for forming the wall are, in one embodiment, cellulose esters, cellulose ethers and cellulose ether esters. These cellulosic polymers have a degree of substitution (D.S.) on the anhydroglucose unit, which is greater than 0 and goes up to 3 inclusive. By degree of substitution is meant the average number of hydroxyl groups initially present on <EMI ID = 16.1>

  
lose, which are replaced by a substitution group. Representative materials include a member of the group comprising cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and alkanylates tricellulose, aroylates of mono-, di- and tricellulose, etc. Examples of polymers are cellulose acetate having a DS of up to 1 and an acetyl content of up to 21%, cellulose acetate having an acetyl content of 32 to 39.8%, cellulose acetate having a DS of 1 to 2 and an acetyl content of 21 to 35%, cellulose acetate having a DS of 2 to 3 and an acetyl content of 35 to 44.8%, etc. More specific cellulosic polymers are

  
  <EMI ID = 17.1>

  
propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%, the cellulose acetobutyrate having a DS of 1.8, an acetyl content of 13 to 15% and a content in butyryl from 34 to 39%, acetobutyrate

  
cellulose 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 as cellulose trivalerate, cellulose trilaurate, tripalmitate

  
cellulose, cellulose trisuccinate and cellulose trioclanoate, cellulose diacylates

  
having a D.S. of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, dioclanoate

  
cellulose, cellulose dipentale, cellulose coesters, such as cellulose acetate butyrate and cellulose acetate propionate, etc.

  
Other semi-permeable polymers are ethyl cellulose, cellulose nitrate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, methyl acetate cellulose carbamate, acetate dimethyl amino acetate of cellulose, semi-permeable polyamides, semi-permeable polyurethanes, semi-permeable sulfonated polystyrenes, selectively semi-permeable, crosslinked polymers formed by the coprecipitation of a polyanion and of a polycation, as described in the patents from the United States of America

  
n [deg.] 3,173,876, 3,276,586, 3,541.005, 3,541,006 and
3,546,142, semi-permeable polymers as described by Loeb and Sourirajan in United States patent n [deg.] 3,133,132, polystyrene derivatives
- slightly crosslinked, poly (sodium styrene sulfonate) crosslinked, poly (vinylbenzyltrimethyl ammonium chloride) ^ crosslinked semi-permeable polymers mon- <EMI ID = 18.1>

  
hydrostatic or osmotic pressure difference across the semi-permeable wall. Polymers are described in the art in U.S. Patents 3,845,770, 3,916,899 and 4,160,020, as well as in Scott's Handbook of Common Polymers,

  
J.R. and Roff, W.J., 1971, published by CRC Press, Clevela &#65533; d, Ohio.

  
The laminated wall comprises, a semipermeable lamella and a microporous lamella arranged in a laminated arrangement and these lamellae act jointly to form an integral laminated wall, which maintains its physical and chemical integrity and does not separate into lamellae throughout the operation. releasing the active agent from the osmotic device. The semi-permeable coverslip is made of the aforementioned semi-permeable polymeric materials, homopolymers,

  
semi-permeable res, semi-permeable copolymers, etc.

  
The microporous lamella suitable for the manufacture of an osmotic device generally comprises microporous polymeric materials, pre-formed, as well as the polymeric materials which can form a microporous lamella in the environment of use. The microporous materials in both embodiments are laminated to form the laminated wall.

   The previously shaped materials, which are suitable for the formation of the microporous lamella, are essentially inert, they maintain their physical and chemical integrity during the period of release of the agent and they can be generally described as having the appearance a sponge which provides a support structure for a semipermeable coverslip and also a support structure for pores or microscopic gaps, which are in mutual communication. The materials can be isotropic, their structure being homogeneous

  
over the entire cross-sectional area, or else they can be anisotropic, their structure being non-homogeneous over the entire cross-sectional area. The pores can be continuous pores which have

  
an opening on both sides of a microporous coverslip, pores mutually connected by tortuous passages of regular and irregular shapes containing continuous curved pores, curved-linear, randomly oriented, impeded communication pores and other passages porous that can be discerned on microscopic examination. Generally speaking, microporous lamellae are defined by the dimension

  
of pores, the number of pores, the tortuosity of the microporous path and the porosity which depends on the size

  
and the number of pores. The pore size of a microporous lamella is easily noted by measuring the pore diameter observed on the surface of the material, using an electron microscope. In general, materials with 5% to 95% of pores and

  
  <EMI ID = 19.1>

  
microns can be used for the production of a microporous coverslip. The pore size and other parameters characterizing the microporous structure can also be obtained by flow measurements, where a flow or flow of <EMI ID = 20.1>

  
the coverslip. The flow of liquid through a coverslip having pores of uniform radius which extend through the membrane and are perpendicular to its surface is, for an area A, given by equation 13:

  

  <EMI ID = 21.1>


  
in which J represents the volume transported per unit of time and per lamella area containing a number N of

  
  <EMI ID = 22.1>

  
the number of pores N can be calculated by equation 14, in which [pound] represents the porosity defined as being the ratio between the empty volume and the total volume of the strip, and A represents the cross-sectional area of the strip which contains N pores.,

  

  <EMI ID = 23.1>


  
We then calculate the radius of the pores by equation 15:

  

  <EMI ID = 24.1>
 

  
in which J represents the volume of flow through the lamella per unit area, produced by the

  
  <EMI ID = 25.1>

  
Ax have the meaning given above and &#65533; represents the tortuosity defined as being the ratio between the length of the diffusion path in the coverslip and the thickness of the coverslip. The above equations are discussed in Transport Phenomena In Membranes, by Lakshminatayanaiah N, chapter 6, 1969, published by Academic Press, Inc., New York.

  
As described in this reference, on page
336, Table 6.13, the porosity of the lamella comprising pores of radius r can be expressed relative to the dimension of the transported molecule having a radius a, and, when the ratio between the radius of the molecule and the radius of pore a / r decreases, the coverslip becomes porous with respect to this molecule. So when the a / r ratio is less than 0.3, the coverslip becomes substantially microporous, as expressed by

  
the coefficient of-osmotic reflection C, which drops below 0.5. Microporous coverslips that have a

  
  <EMI ID = 26.1>

  
from 0 to 0.5, and preferably less than 0.1, relative to the active agent, are suitable for the manufacture of the system. The reflection coefficient is determined by the shaping of the material in the form of a strip

  
and by carrying out water flow measurements

  
as a function of hydrostatic pressure difference and retort a function of osmotic pressure difference. caused by the active agent. The difference in osmotic pressure creates a hydrostatic flow volume, and the reflection coefficient is expressed by equation 16:

  

  <EMI ID = 27.1>


  
The properties of microporous materials are described in Science, volume 170, pages 1302 to 1305, 1970, Nature, .volume 214, page 285, 1967, Polymer Engineering and Science, vol. 11, pages 284-288, 1971, United States patents n [deg.] 3,567,809 and 3,751,536, and in Industrial Processing With Membranes by Lacey RE and Loeb Sidney, pages 131 to 134, 1972 , published by Wiley, Interscience, New York.

  
Microporous materials having a preformed structure are commercially available and can be prepared by methods known in the art. The microporous materials can be prepared by chemical attack, by corroded nuclear tracing, by cooling of a solution of flowable polymer below the freezing point, the solvent separating from the solution in the form of crystals dispersed in the polymer, and then by curing the polymer followed by removal of the solvent crystals, by cold or hot drawing at low or high temperatures until pores are formed, by leaching, from a polymer, a soluble component using an appropriate solvent, by ion exchange reaction, and by polyelectrolytic processes.

   Methods for preparing microporous materials are described in Synthetic Polymer Membranes,

  
from R. E. Kesting, chapters 4 and 5, 1971, published by McGraw Hill, Inc., Chemical Reviews, Ultraflltration, volume 18, pages 373-455, 1934, Polymer Eng. and Sci., volume 11, n [deg.] 4, pages 284 to 288, 1971, J. Appl.

  
Poly. Sci., Vol. 15, pages 811 to 829, 1971, as well as in the patents of the United States of America n [deg.] 3,565,259,
3,615,024, 3,751,536, 3,801,692, 3,852,224 and 3,849,528.

  
As microporous materials usable for. making the coverslip, mention may be made of microporous polycarbonates consisting of linear polyesters of carbonic acid in which the carbonate groups are found in the polymer chain, microporous materials prepared by the phosgenation of a dihydroxy aromatic compound, such as bisphenol A , microporous poly (vinyl chloride), microporous polyamides, such as polyhexamethylene-adipamide, microporous modacrylic copolymers containing those formed from 60% poly (vinyl chloride) and acrylonitrile, styrene-acrylic and its copolymers, porous polysulfones characterized by diphenylene sulfone groups in a linear chain, halogenated poly (vinylidene), polychloroethers, acetal polymers,

   polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, poly (alkylene sulfides), phenolic polyesters, microporous poly (saccharides), microporous poly (saccharides) comprising substituted anhydroglucose units and unsubstituted and preferably showing a greater permeability to the passage of water and of biological fluids than the semi-permeable lamella, asymmetric porous polymers, crosslinked olefin polymers, homopolymers, copolymers and microporous hydrophobic or hydrophilic interpolymers , having a reduced apparent density, and the materials described in the patents of the United States of America n [deg.] 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 n [deg.] 1,126,849 and

  
in Chem. Abst., Vol. 71, 4274F, 22572F, 22573F, 1969.

  
There may be mentioned, as additional microporous materials, poly (urethanes), cross-linked poly (urethanes) with long chain, microporous poly (urethanes) of United States of America patent n [deg.] 3,524,753 , poly (imides), poly (benzimidazoles), collodion
(cellulose nitrate containing 11% nitrogen), regenerated proteins, cross-linked semisolid poly (vinylpyrrolidone), microporous materials prepared by diffusion of multivalent cations in polyelectrolytic soils, as in the US patent

  
America n [deg.] 3.565.259, permeable, anisotropic microporous materials of ionically associated polyelectrolytes, porous polymers formed by the co-precipitation of a polycation and a polyanion, as described

  
in United States patents no. [deg.] 3,276,589,
3,541,055, 3,541,066 and 3,546,142, poly derivatives
(styrene), such as poly (sodium styrene sulfonate) and poly (vinyl chloride benzyltrimethyl-ammonium), as well as the microporous materials described in the patents of the United States of America n [deg.] 3,615,024 , 3.646.178 and 3.852.224.

  
In addition, the material forming micropores used in the context of the invention, comprises the embodiment in which the microporous lamella is formed in situ, by a pore-forming agent eliminated by dissolution or leaching to form the lamella. microporous during use of the system. The pore-forming agent can be a solid or a liquid. The term liquid, in the context of the present invention, includes semi-solids and viscous fluids. The pore-forming agents can be inorganic or organic. The pore-forming agents used in the context of the invention are pore-forming agents which can be extracted without any chemical modification in the polymer.

   The pore-forming solids are about 0.1 to 200 microns in size and include the alkali metal salts, such as sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium benzoate, sodium acetate, sodium citrate, sodium nitrate, etc. As alkaline earth metal salts, mention may be made of calcium phosphate, calcium nitrate, etc. As transition metal salts, ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride,

  
manganese fluoride, manganese fluorosilicate, etc. Pore-forming agents include organic compounds, such as polysaccharides. As polysaccharides, there may be mentioned sugars, sucrose, glucose, fructose, mannitol, mannose, galactose, aldohexose, altrose, talose, sorbitol, lactose, monosaccharides and di-

  
  <EMI ID = 28.1>

  
aliphatic and aromatic, especially diols and polyols, such as, for example, polyalcools, poly (alkylene glycols), polyglycols,

  
  <EMI ID = 29.1>

  
or alkylene glycols, etc., water-soluble cellulosic polymers, such as hydroxyalkyl celluloses in which the alkyl group is lower alkyl, hydroxypropyl methylcellulose, methylcellulose, methylethyl cellulose, hydroxyethyl cellulose, etc. water-soluble polymers, such as polyvinylpyrrolidone, sodium carboxymethylcellulose,

  
etc. Pore-forming agents are non-toxic and, upon separation from the coverslip, channels are formed in the coverslip. According to a preferred embodiment, the non-toxic pore-forming agents are chosen from the group comprising inorganic and organic salts, hydrates of

  
  <EMI ID = 30.1>

  
kylenediols, alkylene glycol esters, glycols and water-soluble cellulosic polymers, which can be used for the formation of a microporous lamella in a biological medium. In general, in the context of the present invention, when the polymer forming the lamella contains more than 25% by weight of a pore-forming agent, the polymer is a microporous lamella precursor which, upon separation of the pore-forming agent, gives a lamella which is essentially microporous, the lamella behaving like a lamella or semi-permeable membrane at concentrations below the above-mentioned value.

  
The term "passageway" as used in the context of the present invention includes means and methods suitable for the release of the agent or drug from the osmotic system. The term includes orifice, opening, hole or perforation through the semi-permeable wall or the laminated wall. The passageway can be shaped by mechanical drilling, laser drilling or by corrosion of a corrodable element in the environment of use, such as a plug, of gelatin. A detailed description of the osmotic passageways and the maximum and minimum dimensions for a passageway are given in US Pat. Nos. 3,845,770 and 3,916,899.

  
The osmotically effective compounds, which can be used in the context of the present invention, are inorganic and organic compounds which

  
  <EMI ID = 31.1>

  
towards a semi-permeable wall or a semi-permeable microporous laminate wall, vis-à-vis an external fluid. Osmotically effective compounds (along with osmopolymers) soak the osmotic device with fluid, thereby making available in situ the fluid soaking of an osmopolymer to increase its expansion and / or to form a solution or suspension containing an agent beneficial for its release from the osmotic device. Osmotically effective compounds are also known as osmotically effective solutes or osmotic agents. The osmotically effective compounds are used by mixing them with a beneficial agent and an osmopolymer to form a solution or suspension containing the beneficial agent which is osmotically released from the device.

   The term "limited solubility", as used herein, means that the beneficial or beneficial agent has a solubility of about less than 5% by weight in the aqueous fluid present in the medium. Osmotic solutes are used by homogeneously or heterogeneously mixing the solute with the agent or osmopolymer, and then loading them into the reservoir. The solutes and osmopolymers attract the fluid inside the tank to produce it.

  
  <EMI ID = 32.1>

  
fogging from the system by jointly transporting

  
undissolved beneficial agent dissolved outside the system. As osmotically effective soluble bodies used for this purpose, there may be mentioned magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium acid phosphate, d-mannitol, urea, inositol,

  
magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose,

  
glucose, α-d-lactose monohydrate and mixtures of these compounds. The amount of osmotic agent in the compartment will generally be of the order of 0.01% to

  
30% or more in the first composition, and usually in the range of 0.01% to 40% or more in the second compartment.

  
Osmotic solution is initially present

  
in excess and it can be in any physical form which is compatible with the beneficial agent and the osmopolymer. The osmotic pressure of the saturated solutions of the various osmotically effective compounds and of mixtures of compounds at 37 [deg.] C, in water, is given in the Table below. In this Table, the

  
  <EMI ID = 33.1>

  
osmotic is measured in a commercially available osmometer, which measures the vapor pressure difference between pure water and the solution to be analyzed, and according to standard thermodynamic principles, the vapor pressure ratio is converted into a pressure difference osmotic. In the Table, osmotic pressures from 20 bars to 500 bars are advanced; the invention naturally includes the use of osmotic pressures lower from 0 and osmotic pressures higher than those presented by way of example in the Table. The osmometer used for these measurements is the vapor pressure osmometer, model 320B, manufactured by Hewlett Packard Co., Avonadale, Pennsyvanie.

BOARD

  

  <EMI ID = 34.1>
 

  
The osmopolymers suitable for forming the first osmotic composition, and also for forming the second osmotic composition, are osmopolymers which have fluid-soaking properties. Osmopolymers are hydrophilic, swellable polymers which react with each other with water and aqueous biological fluids and which swell or expand to a state of equilibrium. Osmopolymers have the ability to swell in water and retain a significant portion of the water soaked in the polymer structure. Osmopolymers swell or expand to a very high degree, usually showing an increase in volume from 2 to 50 times.

   The hydrophilic, swellable polymers are, according to a currently preferred embodiment, slightly crosslinked, these transverse bonds being formed by covalent bonds or ionic bonds. The osmopolymers can be of vegetable, animal or synthetic nature. Osmopolymers are hydrophilic polymers. Poly-

  
  <EMI ID = 35.1>

  
sente invention are poly (hydroxyalkyl methacrylates) having a molecular weight of 30,000 to 5,000,000, poly (vinylpyrrolidones) having a molecular weight of
10,000 to 360,000, anionic and cationic hydrogels, polyelectrolytic complexes, polyvinyl alcohols having a low residual acetate content, crosslinked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of 200 iL 30,000 mixtures of methyl cellulose , crosslinked agar and carboxymethyl cellulose, the water-swellable, water-insoluble copolymers obtained by forming a dispersion of finely divided copolymer of maleic anhydride and styrene, ethylene, propylene, butylene or isobutylene, cross-linked with 0.001

  
about 0.5 mole of polyunsatu-

  
re per mole of maleic anhydride in the copolymer, polymers of N-vinyl lactams, swellable in water, etc.

  
Other osmopolymers are the polymers which form hydrogels, such as the carboxyl acid polymers of the Carbopol typa (registered trademark) having a

  
molecular weight from 450,000 to 4,000,000, polyacrylamides of the Cyanamer type (registered trademark), water-swellable, crosslinked maleic anhydride-indene polymers, Good-rite acrylic acid (registered trademark) having a molecular weight from 80,000 to 200,000, polyethylene oxide polymers of the Polyox type (registered trademark) having a molecular weight of 100,000 to
5,000,000, starch graft copolymers, acrylate polymers of the Aqua-Keeps type (registered trademark),

  
diester crosslinked polyglucans, etc. Examples of polymers which form hydrogels are given in United States patent no. [Deg.] 3,865,108

  
of Hartop, the patent of the United States of America n [deg.] 4,002,173 of Manning, the patent of the United States of America

  
n [deg.] 4,207,893 by Michaels and in the Handbook of Common Polymers, by Scott and Roff, published by Chemical Rubber Company, Cleveland, Ohio. The amount of osmopolymer

  
in the first osmotic composition is around

  
from 0.01 to 90%, and the amount of osmopolymer in the second osmotic composition is from 15 to 95%. In a preferred embodiment, the molecular weight of the osmopolymer in the second osmotic composition is greater than the molecular weight of the osmopolymer in the first osmotic composition.

  
Determination of the imbibition of the osmopolymer by fluid for a chosen polymer can be carried out by following the process described below. A 2.54 cm round disc, loaded with a 2.54 cm diameter stainless steel punch, is loaded with a known quantity of polymer, the punches protruding from each end. The punches and the die are placed in a Carver press fitted with heated plates between
93 [deg.] C and 149 [deg.] C. A pressure of 69-103.5 MPa is applied to the punches. After 10 to 20 minutes of heat and pressure, the electric heating is cut off and the circulating water is circulated therein. The 2.54 cm discs obtained are placed in an air suspension coating machine <EMI ID = 36.1>

  
cellulose acetate having an acetyl content of
39.8% dissolved in CH2Cl2 / CH30H (94/6 by weight by weight) so as to obtain a 3% w / w solution. The coated systems are dried overnight at 50 [deg.] C. The coated discs are immersed in

  
water at 37 [deg.] C and removed periodically to determine gravimetrically the amount of water soaked. The initial imbibition pressure is calculated using the water transmission constant for cellulose acetate, after normalizing the imbibition values for the surface area and the thickness of the membrane. The polymer used in this determination is the sodium derivative of the Carbopol-934 polymer (registered trademark), pre-prepared according to the method of B. F. Goodrich Service Bulletin GC-36, "Carbopol Water-Soluble Resins", page

  
5, published by B.F. Goodrich, Akron, Ohio.

  
The cumulative weight gain values y are used as a function of time t of the water-soluble polymer disc coated with cellulose acetate to determine the equation of the line y = c + bt + at <2> passing through these points by a least squares adjustment technique.

  
The weight gain for Carbopol-934 from Na is given by equation 17 which follows; the weight gain is equal to 0.359 + 0.665t - 0.00106t <2>, where t is the elapsed time in minutes. The rate of water flow at any given time will be equal to the slope of the line, which is given by the following equations 18 and 19:

  

  <EMI ID = 37.1>


  
To determine the initial water flow rate, the derivative e is evaluated at t = 0, dy / dt then being equal to 0.665 1 1 / minute, which is equal to the coefficient b. By then normalizing the rate of imbibition as a function of time, the surface area and the thickness of the membrane, as well as the constant of permeability of the membrane with respect to water K, we

  
  <EMI ID = 38.1>

  

  <EMI ID = 39.1>


  
  <EMI ID = 40.1> is determined using a Hewlett-Packard vapor pressure osmometer to be 345 atmospheres

  
+ 10%, and the K value of the cellulose acetate used in this experiment calculated from the NaCl soaking values is determined to be 1.9 x
10 -7 cm <2> / hr atmosphere.

  
The substitution of these values in the expression-

  
  <EMI ID = 41.1>

  
To evaluate the effectiveness of a polymer compared to the duration of a pushing force of order 0, the percentage of water fixation was chosen before the water flow values reached 90% of their initial values. The value of the slope for the equation of a straight line coming from the axis of the percentage of weight gained will be equal to the initial value of dy / dt considered at t = 0, with the segment c of y defining

  
the linear swelling time, (dy / dt) 0 = 0.665 and

  
  <EMI ID = 42.1>

  
In order to determine the moment when the value of the cumulative water fixation is 90% of the initial rate, we solve for t the following expression:

  

  <EMI ID = 43.1>
 

  
t = 62 minutes and the weight gain is -0.00106 (62) <2> +

  
  <EMI ID = 44.1>

  
The results are shown in Figure 8, which gives a graphical representation of the values. Other methods available to study the interface of solu-

  
  <EMI ID = 45.1>

  
viscometric, ellipsometry, measurements of contact angles, electrokinetic determinations, infrared spectroscopy, optical microscopy, interface morphology and microscopic examination of an operating device.

  
The term "active agent" as used in the context of this patent includes any beneficial agent, or beneficial compound, which can be released from the device to produce a beneficial and effective result. The agent can be insoluble to very soluble in the external fluid which enters the device and it can be mixed with an osmotically effective compound and an osmopolymer. As active agents, there may be mentioned pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, antioxidants, agents promoting growth

  
plants, plant growth inhibitors, preservatives, disinfectants, sterilizers, catalysts, chemical reagents, fermentation agents, sterility agents, fertility inhibitors, fertility promoters, air purifiers, attenuators microorganisms and other agents which are beneficial to the environment of use.

  
In the specification, the term "beneficial agent" includes drugs, and the term "drug" includes any physiologically or pharmacologically active substance which produces a local or general effect in animals, including mammals warm-blooded, humans and primates, birds, domestic, sport and farm animals, laboratory animals, fish, reptiles and zoo animals. The term "physiologically" as used here, designates the administration

  
of a drug to produce normal functions and levels. The term "pharmacologically" refers to variations in response to the amount of drug administered to the host. See Stedman's Medical Dictionary,
1966, published by Williams and Wilkins, Baltimore, Md. The term "drug formulation" as used herein means that the drug is in the compartment mixed with an osmotic solute and / or an osmopolymer and, as necessary, with a binder and a lubricant.

   The active drug which can be dispensed includes inorganic and organic compounds, without limitation, including drugs which act on peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles , the blood circulatory system, synoptic sites, neuroeffective junction sites

  
teurs, the endocrinal system, the hormonal systems,

  
the immunological system, organ systems, the reproductive system, the skeletal system, the autocoid systems, the food and excretory systems, the autocoid and histamine inhibitor systems. The active drug which can be dispensed to act on these animal systems includes depressants, hypnotics, sedatives, psychic stimulants, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, pain relievers, anti-inflammatory drugs, local anesthetics, muscle contraction agents, .. antimicrobial agents, antimalarial agents, hormonal agents, contraceptives, sympathomimetic agents, diuretics, antiparasitic agents, hypoglycemic agents, agents ophthalmic, electrolytes,

   diagnostic agents and drugs for the cardiovascular system.

  
Examples of drugs which are very soluble in water and which can be dispensed by the devices of the present invention are prochlorperazine edisylate, ferrous sulfate, aminocapro acid

  
  <EMI ID = 46.1>

  
amphetamine, benzphetamine hydrochloride, isoproternol sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, methascopolamine bromide , isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, metoprolol tartrate, cimetidine hydrochloride, theophylline cholinate, cephalexin hydrochloride, etc. .

  
Examples of drugs which are sparingly soluble in water and which can be dispensed by the devices of the present invention are diphenid ol, meclizine hydrochloride, perchlorperazine maleate, phenoxybenzamine, thiethylperazine maleate, anisindone , diphenadione erythrityl tetranitrate, dizoxin, izofurophate, reserpine, acetazolamide, methazolamide, bendroflume-
-thiazide, chlorpropamide, tolazamide, chlormadinone acetate, pheglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, progestin, progestogens estrogens, corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, triamcinolone, methyltesterone, 17 &#65533;

  estradiol, ethinyl estradiol, prazosin hydrochloride, 3-methyl ether of ethinyl estradiol, pednisolone, 17P-hydroxyprogesterone acetate,
19-nor-progesterone, norgestrel, norethindone, norethiderone, progesterone, norgestone, norethynodrel, etc.

  
Examples of other drugs that can be dispensed through the osmotic device are aspirin, indomethacin, naproxen, fenoprofen, sulidac, diclofenac, indoprofen, nitroglycerin, propranolol, metoprolol, valproate, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, reserpine, methyl-dopa, dihydroxyphenylalanine, pivoloyloxyethyl ester of hydrochloride a-methyl dopa, theophylline, gluco-

  
  <EMI ID = 47.1>

  
lexin, erythromycin, prozine, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, a-blockers, calcium channel blockers, such as nifedipine, diliazene , verapamil, beta-blockers, etc. Beneficial drugs are described in the art in Pharmaceutical Sciences, edited by Remington, 14th edition, 1979, published by Mack Publishing Co., Easton, Pennsylvania, in The Drug, <EMI ID = 48.1>

  
1974-1976, de Falconer et al., Published by Sander Company, Philadelphia, Pennsylvania, and in Medicinal Chemistry, 3rd edition, vol. 1 and 2, by Burger, published

  
by Wiley-Interscience, New York.

  
The medicament can 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, you can use

  
salts of metals, amines or organic cations, for example quaternary ammonium. It is possible to use derivatives of drugs, such as esters, ethers

  
and amides. Likewise, a drug which is insoluble in water in a form which is a derivative of this water-soluble drug can be used to serve as a solute, and when released from the device it is converted by enzymes, hydrolysis: by the body's pH or other metabolic processes in the form of biologically active origin. The agent comprising the medicament may be present in the compartment with a binder, a dispersant, a wetting agent, an agent

  
suspension, lubricant and dye.

  
Examples of these agents are suspending agents, such as carob, agar, carrageenan calcium, alginic acid, algin, agarose powder, collagen, magnesium silicate col-
-lbïdal, colloidal silicon dioxide, hydroxyethyl cellulose, pectin, gelatin and calcium silicate, binders such as polyvinyl pyrrolidone, lubricants, such as magnesium stearate, wetting agents, such as fatty amines, fatty quaternary ammonium salts, etc. The term "drug formulation" means that the drug is present in the compartment along with an osmotic agent, an osmopolymer, a binder, etc.

   The amount of beneficial agent in a device is generally between 0.05 ng and 5 g or more, specific devices containing, for example, 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 700 mg, 1.5 g, etc. The devices can be administered once, twice or three times a day.

  
The solubility of a beneficial agent in the fluid can be determined by known techniques. One method is to prepare a saturated solution comprising the fluid plus the agent as determined by analyzing the amount of agent present in a defined amount of the fluid. For this purpose, a simple apparatus consists of a medium-sized test tube fixed vertically in a water bath maintained at constant temperature and pressure, test tube in which the fluid and the agent are placed and agitated by a serpentine. rotating glass. After a given period of agitation, a weight of the fluid is analyzed and agitation is continued for an additional period of time.

   If the analysis does not show any increase in the dissolved agent after successive periods of agitation, in the presence of the excess of solid agent in the fluid, the solution is saturated and the results are considered to correspond to the solubility of the product in the fluid. If the agent is soluble, it may not be necessary to add an osmotically effective compound; if the agent has limited solubility in the fluid,

  
one can then incorporate an osmotically effective compound into the device. Many other methods are available for determining the solubility of an agent in a fluid. Typical methods used for measuring solubility are chemical and electrical conductivity. Details of various methods for determining solubilities are described in United States Public Health Service Bulletin, No. [deg.] 67 of the Hygenic Laboratory, in Encyclopedia of Science and Technology, vol. 12, pages 542 to

  
556, 1971, published by McGraw-Hill, Inc., and in Encyclopedia Dictionary of Physics, vol. 6, pages 547 to 557,
1962, published by Pergamon Press, Inc ..

  
The osmotic devices of the invention are manufactured by standard techniques. For example, according to one embodiment, the beneficial agent is mixed with an osmotic agent and an osmopolymer, and compressed to dimensions having the appearance of a solid material, which correspond to the interior dimensions of the compartment adjacent to the passageway, or the beneficial agent, the other formulation ingredients and a solvent are brought in a solid or semi-solid form by usual methods, such as passage through a ball mill, rolling, stirring or a passage through a roller mill, and they are then compressed into a previously chosen shape.

   Next, a layer of a composition comprising an osmotic agent and an osmopolymer is placed in contact with the beneficial agent formulation layer, and the two layers are surrounded by a semi-permeable wall. Stratification of the beneficial agent composition and the osmotic agent / osmopolymer can be accomplished by techniques

  
press for standard two-layer tablets. The wall can be applied by molding, spraying

  
or soaking the compressed forms in a wall-forming material. Another currently preferred technique that can be used to apply the wall is the air suspension coating process. This method involves suspending and agitating the compressed compositions in a stream of air and a wall-forming composition until the wall envelops and covers the two compressed compositions. The process is repeated with a different lamella formation composition to form a laminate wall. The process of air suspension is described in the patent of the United States of America

  
n [deg.] 2,799,241, in J. Am. Pharm. Asoc., Vol. 48, pages

  
451 to 459, 1979, and in ibid, vol. 49, pages 82 to 84,
1960. Other standard manufacturing processes are described in Modern Plastics Encyclopedia, vol. 46, pages
62 to 70, 1969, as well as in Pharmaceutical Sciences, by Remignton, 14th edition, pages 1626 to 1678, 1970, published by Mack Publishing Co., Easton, Pennsylvania.

  
Examples of interesting solvents for the preparation of laminates and lamellae are inorganic and organic solvents which do not adversely affect the materials and the final laminated wall. As solvents, mention may be made generally of the elements chosen from the group comprising aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic solvents, heterocyclic solvents

  
and mixtures of these substances. Typical solvents are acetone, diacetonic alcohol,

  
methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane,

  
n-heptane, monoethyl ether of ethylene glycol,

  
ethylene glycol monoethyl acetate, dichloride

  
methylene, ethylene dichloride, propylene dichloride, carbon tetrachloride, chloroform, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water and mixtures, such as acetone and water, acetone and methanol, acetone and alcohol ethylene, methylene dichloride and methanol as well as ethylene dichloride and methanol.

  
The examples given below simply illustrate the present invention and should in no way

  
cases be considered as limiting the scope of the invention; equivalents of these examples will appear to specialists versed in this technical field in the light of the present description, the drawings and the claims which follow.

Example 1

  
An osmotic delivery device made in the form of a shaped osmotic tablet, sized and suitable for oral administration in the gastrointestinal tract is prepared as follows: a first composition of osmotic drug is prepared by sifting 355 g poly (ethylene oxide) having an approximate molecular weight of 200,000 through a stainless steel screen with openings

  
0.42 mm, then pass 100 g of nifedipine through the sieve with openings of 0.42 mm, pass

  
25 g of hydroxypropyl methyl cellulose in the sieve with 0.42 mm openings, and finally 10 g

  
of potassium chloride in the sieve with openings of 0.42 mm. Then all the sieved ingredients are added to the bowl of a laboratory mixer

  
and the ingredients are mixed dry for 15 to 20 minutes so as to obtain a homogeneous mixture. Then, a granulation fluid is prepared comprising

  
250 ml of ethanol and 250 ml of isopropyl alcohol, and the granulation fluid is added to the mixing bowl; first spray 50 ml into the bowl with a constant mixture, and then slowly add 350 ml of granulating fluid to the bowl and mix the wet mass for an additional 15 to 20 minutes. pass the wet granules through a sieve with 0.991 mm openings and dry them at room temperature for 24 hours, and pass the dry granules through a sieve with 0.991 mm openings. Then add 10 g of magnesium stearate to the dry granules, and grind the ingredients for 20

  
30 minutes in a standard two-cylinder mill.

  
Then, a second osmotic composition is prepared in the following way: first, we sift
170 g of poly (ethylene oxide) having a molecular weight of 5,000,000 through an open sieve

  
0.42 mm, then pass 72.5 g of chloride

  
sodium through the sieve with 0.42 mm openings,

  
add the ingredients to a mixing bowl and mix for 10 to 15 minutes. Then, a granulation fluid is prepared by mixing 350 ml

  
methanol and 150 ml isopropyl alcohol, and the granulating fluid is added to the mixing bowl in two stages. First, 50 ml of the granulation fluid is sprayed into the bowl with constant agitation, then 350 ml of the granulation fluid is slowly added to the bowl and the wet mixture is kneaded for 15 to 20 minutes until obtaining a homogeneous mixture. Then, the wet mixture is passed through a sieve with 0.991 mm openings, spread on a stainless steel plate and dried at room temperature of 22.5 [deg.] C for 24 hours. The dried mixture is passed through a sieve with 0.991 mm openings, and is then ground with 5 g of magnesium stearate in a two-cylinder mill for 20 to 30 minutes.

  
A number of drug cores are prepared by compressing the two compositions in a Manesty Layer press. The drug-containing composition is brought into the mold cavity of the press and is compressed as a solid layer. Then, the second osmotic composition is brought into the cavity so as to cover the compressed layer and is compressed as a solid layer to form a two-layer drug core.

  
The drug cores are then coated with a wall-forming, semi-permeable composition comprising 95 g of cellulose acetate having an acetyl content of 39.8% and 5 g of poly (ethylene glycol)
400 in a solvent comprising 1960 ml of methylene chloride and 820 ml of methanol. The drug cores are coated with the semi-permeable wall-forming composition until the wall completely envelops the drug core. A Wurster air suspension coating device is used to form the semi-permeable wall. The coated cores are then placed on a tray and the solvent is evaporated in an air circulation oven at 50 [deg.] C for
65 hours. After cooling to room temperature

  
  <EMI ID = 49.1>

  
created by laser through the semi-permeable wall so as to connect the exterior of the osmotic device to the composition containing the medicament. The osmotic device weighs 262 mg and it contains 30 mg of drug in the first composition weighing 150 mg, the second composition weighs 75 mg and the semi-permeable wall weighs
37 mg. The first osmotic composition of the osmotic device comprises 30 mg of nifedipine, 106 mg of poly (ethylene oxide), 3 mg of potassium chloride, 7.5 mg of hydroxypropylmethylcellulose and 3 mg of magnesium stearate. The second osmotic composition comprises 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 surface area of 1.8 cm2 and the semi-permeable wall has a thickness of 0.17 mm.

   The cumulative amount of drug released is illustrated in Figure 9.

Example 1A

  
Osmotic delivery systems are prepared containing a first composition comprising 25 to
100 mg of nifedipine, 100 to 325 mg of poly (ethylene oxide) with a molecular weight of 200,000, 2 to 10 mg of potassium chloride, 5 to 30 mg of hydroxypropyl methylcellulose and 2 to 10 mg of magnesium stearate , and a second composition comprising 30 to 175 mg of poly (ethylene oxide) with a molecular weight of
5,000,000, 20 to 75 mg of sodium chloride and 1 to 5 mg of magnesium stearate. The process of Example 1 is repeated to prepare osmotic devices corresponding to the following compositions: (a) an osmotic device comprising a first composition comprising
60 mg of nifedipine, 212 mg of poly (ethylene oxide),

  
6 mg of potassium chloride, 15 mg of hydroxypropyl methylcellulose and 6 mg of magnesium stearate, and a second composition comprising 102 mg of poly (ethylene oxide), 44 mg of sodium chloride and 3 mg of magnesium stearate, and (b) an osmotic device comprising a first composition comprising 90 mg of nifedi-pine, 318 mg of poly (ethylene oxide), 9 mg of potassium chloride, 22.5 mg of hydroxypropylmethylcellulose and 9 mg of stearate. magnesium, and a second composition comprising 102 mg of poly (ethylene oxide), 66 mg of sodium chloride and 4.5 mg of magnesium stearate. In one embodiment, the os-

  
  <EMI ID = 50.1>

  
puff or a jet of material applied to the exterior semipermeable wall. The jet or puff of material comprises 30 mg of nifedipine and hydroxypropylmethyl cellulose. When the osmotic device is in the fluid application medium, this layer provides instant availability of the drug for immediate therapy.

Example 2

  
The process of Example 1 is repeated, all

  
the conditions corresponding to the conditions as described above, with the exception that the drug in the compartment is replaced by a member of the group comprising beta-blocking drugs, anti-in-

  
  <EMI ID = 51.1>

  
parkinsonniens and diuretics.

Example 3

  
An osmotic therapeutic device for the oral, controlled and continuous release of verapamil, a drug blocking the calcium channels, is produced in the following way: 90 mg of verapamil, 50 mg of sodium carboxyvinyl polymer having a molecular weight of
200,000 and sold under the trade name of Carbopol polymer (registered trademark), 3 mg of sodium chloride, 7.5 mg of hydroxypropylmethylcellulose and 3 mg of magnesium stearate, and they are compressed in a Manesty press with a punch using a pressure of
1360 kg so as to obtain a layer of the drug composition.

   Then, 51 mg of carboxyvinyl polymer with a molecular weight of 3,000,000 and sold
- under the trade name Carbopol polymer
(registered trademark), 22 mg of sodium chloride and 2 mg of magnesium stearate are intimately mixed and added to the Manesty press, and compressed to form a layer of osmotic composition, expandable in contact with the layer of osmotic drug composition .

  
  <EMI ID = 52.1>

  
mixing 170 g of cellulose acetate having an acetyl content of 39.8% with 900 ml of methylene chloride and 400 ml of methanol, and spray coating the two-layer compartment-forming element in a machine coating by air suspension until a semi-permeable wall 0.13 mm thick surrounds the compartment. The coated device is dried for 72 hours at 50 [deg.] C and then

  
a 0.20 mm passageway is laser drilled through the semi-permeable wall to connect the drug-containing layer to the outside of the device so as to release the drug over an extended period of time.

Example 4

  
The process of Example 3 is repeated, all the conditions being identical, with the exception that the drug used in the osmotic device is fendilin, diazoxide, prenylamine or diltiazene.

Example 5

  
An osmotic therapeutic device for the distribution of sodium diclofenac, an anti-inflammatory drug, is prepared by first compressing, in a Manesty press, an osmotic drug composition containing 75 mg of sodium diclofenac, 300 mg of sorbitol, 30 mg of sodium bicarbonate, 26 mg of pectin, 10 mg of polyvinyl pyrrolidone and 5 mg of stearic acid, and compressing the composition in a cavity into a solid layer. Then, a second composition is introduced into the cavity, producing a higher force comprising 122 mg of pectin having a molecular weight of 90,000 to 130,000, 32 mg of mannitol, 20 mg of polyvinyl pyrrolidone and 2 mg of magnesium stearate and it is compressed. so as to form a second layer coming into contact with the first layer.

   The second layer has a density of 1.28 g / cm <3> and a hardness rating greater than 12 kg. Then, the two-layer core is enveloped with a semi-permeable wall comprising 85 g of cellulose acetate having an acetyl content of 39.8% and 15 g of polyethylene glycol
4000, with a content of 3% w / w of solid material in a wall-forming solvent comprising 1960 ml of methylene chloride and 819 ml of methanol. The coated device is dried for 72 hours at 50 [deg.] C, and then a laser passageway with a diameter of 0.26 mm is pierced through the wall. The semi-permeable wall

  
0.1 mm thick, the device is 3.3 cm2 in area and has an average drug release rate of 5.6 mg per hour over a 12 hour period. The cumulative amount released is illustrated

  
as in Figure 10. The small vertical bars represent the minimum and maximum drug release for five systems measured during this period.

Example 5A

  
The process of Example 5 is followed to produce an osmotic device in which the compartment contains a mixture of osmopolymers. The compartment contains a first composition weighing 312 mg and comprising 48% of sodium diclofenac, 38% of osmopolymer formed from poly (ethylene oxide) of a molecular weight

  
of 200,000, 10% of osmopolymer formed of poly (ethylene glycol) with a molecular weight of 20,000, 2% of sodium chloride and 2% of magnesium stearate, and a second composition weighing 150 mg e &#65533; comprising 93% poly (ethylene oxide) with a molecular weight of 5,000,000, 5% sodium chloride and 2% magnesium stearate.

Example 6

  
In this example, the osmotic pressure is raised for a number of compositions comprising an osmotic agent and an osmopolymer to show the advantages conferred by the present invention. The measurements are carried out by measuring the quantity of water soaked through the semi-permeable wall of a bag containing an osmotic agent or an osmopolymer, or else a composition comprising an osmotic agent and an osmopolymer. The semi-permeable wall of the bag is formed from cellulose acetate having an acetyl content of 39.8%. The measurements are made by weighing the dry ingredients of the semi-permeable bag, and then weighing the semi-permeable bag with filter paper, after which the bag is immersed in a water bath at 37 [deg.] C for different time periods.

   The increase in weight is due to the imbibition of water through the semi-permeable wall caused by the osmotic pressure gradient across the wall. The osmotic pressure curves are il.lustré by Figure 11. In Figure 11, the curve with the triangles represents the osmotic pressure of poly (ethylene) oxide with a molecular weight of
5,000,000, the curve with the circles represents

  
the osmotic pressure of a composition comprising poly (ethylene) oxide with a molecular weight of
5,000,000 and sodium chloride, the ingredients being present in the composition in the ratio of 9.5 parts of osmopolymer to 0.5 part of osmotic agent, the curve with the squares represents a composition comprising the same osmopolymer and osmotic agent in the ratio of 9 parts of osmopolymer to 1 part of osmotic agent, the curve with the hexagons represents the same composition comprising the osmopolymer and the osmotic agent in the ratio of 8 parts to 2 parts, and the line in dashed lines represents the osmotic agent formed from sodium chloride. Mathematical calculations are carried out using the form

  
  <EMI ID = 53.1>

  
bibition of water as a function of time, A represents the area of the semi-permeable wall and K represents the coefficient of permeability. Furthermore, in Figure 11, WH / Wp represents the amount of soaked water divided by the weight of osmopolymer and osmotic agent.

Example 7

  
An osmotic therapeutic device is prepared for the distribution of sodium diclofenac by sieving through a sieve with 0.42 mm openings a composition comprising 49% sodium diclofenac, 44% poly (ethylene) oxide a molecular weight of
- 100,000, 2% sodium chloride and 3% hydroxypropylmethylcellulose, and then mixing the sieved composition with an alcoholic solvent used in the ratio of 75 ml of solvent per 100 g of granulation. The wet granulation product is sieved through a <EMI ID = 54.1>

  
rature room for 48 hours under vacuum, we

  
passed through a sieve with 0.991 mm openings, and mixed with 2% magnesium stearate sieved through a sieve with 0.175 mm openings. The composition is compressed as described above.

  
Next, a composition comprising 73.9% of pectin with a molecular weight of 90,000 to 130,000, 5.8% of microcrystalline cellulose, 5.8% of a composition, is passed through a sieve with openings of 0.42 mm. polyvinylpyrrolidone, 14.3% sodium chloride and 2% sucrose, the latter is mixed with an organic solvent in the ratio of 100 ml of solvent to 100 g of granulation for 25 minutes, the whole is passed through

  
  <EMI ID = 55.1>

  
hours at room temperature under vacuum, again sieved through a sieve with 0.991 mm openings, mixed with 2% magnesium stearate, and then compressed on the above-mentioned compressed layer. The two-layer drug core is coated by plunging it into a wall-forming composition comprising 80% cellulose acetate having an acetyl content of 39.8%, 10% polyethylene glycol 4000 and 10% hydroxypropyl methylcellulose. A passageway is pierced in the wall communicating with the drug composition. The diameter of the passageway

  
  <EMI ID = 56.1>

  
The theoretical device is shown in Figure 12.

  
FIG. 13 represents the theoretical release rate in mg per hour from the osmotic device.

Example 8

  
The process of Example 7 is repeated, all the conditions being identical, except that the osmopolymer in the drug composition is a block copolymer of polyoxyethylene-polyoxypropylene having a molecular weight of approximately 12,500.

Example 9

  
An osmotic device is produced by following the above-mentioned methods. The device of this example comprises a single composition comprising 50% of sodium diclofenac, 46% of poly (ethylene) oxide with a molecular weight of 100,000, 2% of sodium chloride and 2% of magnesium stearate. The device has a semi-permeable wall comprising 90% cellulose acetate containing 99.8% acetyl and 10% polyethylene glycol
4000. The cumulative amount released by this device comprising the single composition is 40% of the device comprising two compositions. The cumulative amount released is illustrated in Figure 14.

Example 10

  
The cumulative average in vivo and in vitro releases of sodium diclofenac from an osmotic device comprising a first osmotic composition comprising 75 mg of sodium diclofenac, 67 mg of sodium oxide

  
  <EMI ID = 57.1>

  
sodium chloride, 4.5 mg of hydroxypropyl methylcellulose and 3.0 mg of magnesium stearate, and one
-this osmotic composition distant from the release passageway comprising 51 mg of poly (ethylene oxide) with a molecular weight of 5,000,000, 22.5 mg of sodium chloride and 1.5 mg of magnesium stearate , enveloped in a semi-permeable wall comprising 90% cellulose acetate having an acetyl content of
39.8% and 10% polyethylene glycol 4000 are measured in vivo and in vitro in laboratory dogs. The amounts of drug released at different time periods in vivo are determined by administering a series of devices to the animals and measuring the quantity released from the device corresponding to the appropriate period of time.

   The results are given in FIG. 15, where the circles with the bars represent the average cumulative releases in vitro and the triangles with the bars represent the average cumulative releases in vivo.

  
We measure, as we just described,

  
the cumulative average in vivo and in vitro releases of a device containing nifedipine. The osmotic device comprises a composition adjacent to

  
the passageway comprising 30 mg of nifedipine,

  
106.5 mg of poly (ethylene oxide) with a molecular weight of 200,000, 3 mg of potassium chloride, 7.5 mg of hydroxypropyl methylcellulose and 3 mg of magnesium stearate, a composition distant from the passageway comprising 52 mg of poly (ethylene oxide) with a molecular weight of 5,000,000, 22 mg of sodium chloride

  
and 1.5 mg of magnesium stearate, and a semipermeable wall comprising 95% of cellulose acetate having an acetyl content of 39.8% and 5% of hydroxypropyl-
-methylcellulose. Figure 16 shows the system release values. In Figure 16, the circles represent the average cumulative release in vivo and the triangles represent the average cumulative release in vitro.

Example 11

  
The process of Example 10 is carried out to produce an osmotic therapeutic distribution system comprising a first composition or drug composition weighing 638 mg and containing 96% of cephalexin hydrochloride, 2% of poviclone (polyvinyl pyrrolidone) and 2% of stearate. magnesium, a second composition or osmotic composition weighing 200 mg and containing 68.5% of poly (ethylene oxide) with a molecular weight of 5 x 106, 29.5% of sodium chloride and 2% of magnesium stearate , a semi-permeable wall weighing
55.8 mg consisting of 80% cellulose acetate with an acetyl content of 39.8%, 14% polyethylene glycol
4000 and 14% hydroxypropylmethylcellulose, and an osmotic orifice with a diameter of 0.039 mm. The device has an average release speed of approximately

  
54 mg per hour over a 9 hour period.

  
The new osmotic system of the present invention uses a double arrangement to achieve

  
precise drug release rates or rates that are difficult to deliver to the application environment while simultaneously maintaining the integrity and character of the system.

  
It should be understood that the present invention is in no way limited to the above embodiments and that many modifications can be made thereto without departing from the scope of this patent.


    

Claims (14)

1. Device for distributing a beneficial agent to a medium of use at a regulated speed, characterized in that it comprises: a) a wall formed at least in part of a composition permeable to the passage of an external fluid present in the medium of use, the wall surrounding and forming: b) a compartment; c) a first composition in the compartment, this first composition comprising a beneficial agent and an osmopolymer; d) a second composition in the compartment, this second composition comprising an osmopolymer; and e) a passageway in the wall, which connects the first composition and the exterior of the device to distribute the beneficial agent from the device. 2. Dispensing device according to claim 1, characterized in that the wall-forming composition comprises a member of the group comprising cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, diacetate cellulose, cellulose triacetate, ethylcellulose, cellulose acetobutyrate, cellulose acetopropionate, hydroxypropylmethylcellulose, hydroxyalkylcelluloses in which the alkyl groups are? lower alkyl groups, methylcel- <EMI ID = 58.1> substances. 3. Release device according to claim 1, characterized in that the first composition is in the compartment in the form of a layer, and in that the second composition is in the compartment in the form of a layer. 4. Release device according to claim 1, characterized in that the first composition  <EMI ID = 59.1> timent, and in that the second composition is soaked with external fluid passing through the wall in the compartment. 5. Release device according to claim 1, characterized in that the osmopolymer of the second composition has a higher molecular weight than the osmopolymer of the first composition. 6. Release device according to claim 1, characterized in that the beneficial agent is a medicament. 7. Release device according to claim 1, characterized in that the wall is a laminate comprising a semi-permeable strip and a microporous strip. 8. Release device according to claim 1, characterized in that the composition forming the wall contains polyethylene glycol. 9. Release device according to claim 1, characterized in that the osmopolymer of the first composition is poly (ethylene oxide). 10. Release device according to claim 1, characterized in that the osmopolymer of the second composition is poly (ethylene oxide). 11. Release device according to claim 1, characterized in that the agent is nifedipine, verapamil, diltiazene, diclofenac, propanolol, indomethacin, or cephalexin. 12. Distribution device according to claim 1, characterized in that the first composition comprises an osmotic agent. 13. Dispensing device according to claim 1, characterized in that the second composition comprises an osmotic agent. 14. Device for the regulated distribution of beneficial agent, as described above, in particular in the examples given, and / or as illustrated in the accompanying drawings.