Delivery system for physiologically active agents

A system for the controlled delivery of a physiologically active agent to a fluid environment having a semipermeable sheath with a plurality of pores, the sheath being imperforate except for the plurality of pores and defining a fully enclosed cavity for holding a physiologically active agent. A physiologically active agent is contained in the fully enclosed cavity for delivery to a fluid environment, with the plurality of pores being of a size to permit both the flow of fluid from the fluid environment through the semipermeable sheath into the cavity and the flow of fluid and physiologically active agent in solution out of the cavity into the fluid environment whereby the physiologically active agent is delivered from the semipermeable sheath exclusively through the plurality of pores.

BACKGROUND OF THE INVENTION 
The present invention relates generally to an improved system for the 
delivery of physiologically active agents and, more particularly, to an 
improved delivery system for the timed release of physiologically active 
agents. 
In recent years numerous devices have been devised which utilize osmotic 
flow to assist in the delivery of physiologically active agents. For 
example, both U.S. Pat. No. 4,265,874 to Bosen et al and U.S. Pat. No. 
4,298,003 to Theeuwes et al disclose methods and devices for the delivery 
of a drug where, as a result of osmotic flow, fluid passes through a 
semipermeable membrane and forces an insoluble drug or a solution of a 
soluble drug out of the device through an enlarged opening or passageway. 
The membrane of these devices allows the flux of water only, not the drug. 
The drug is forced out, under the influence of osmosis, through the 
enlarged opening or passageway which is separately drilled in the devices 
and whose size is orders of magnitude larger than the pores of the 
membrane. U.S. Pat. No. 3,832,458 reveals a device in which a silicon 
polymer wall is utilized to vary permeability to an internal active agent. 
The permeability is adjusted by fabricating the wall with varying amounts 
of N-vinyl-pyrrolidone. While this device represents an improved delivery 
technique, it has a significant disadvantage in that it represents a 
"first order" delivery system in which the driving force of drug delivered 
to the outside is the result of the internal concentration of drug alone. 
Thus the drug will be delivered at an initial rapid rate followed by a 
significantly lower rate until the active agent is expended. U.S. Pat. No. 
4,309,996 by Theeuwes discloses a somewhat different mechanism for 
delivery of drugs whereby a separate compartment filled by a net osmotic 
inflow is utilized to expand against a flexible internal partition which 
forces active agent out of a second compartment through a microporous 
structure thus attempting to approximate a steady delivery rate. 
In summary, while the prior art devices have resulted in improved delivery 
techniques, they are either somewhat complex, adding to the cost of the 
devices, or unable to control the precise drug delivery rate. It is 
therefore advantageous to provide a system which is flexible in that there 
are numerous variables which can be modified to control the delivery rate 
of the drug. 
SUMMARY OF THE INVENTION 
It is an object of the present invention to provide a new and improved 
system for delivering physiologically active agents. 
It is a further object of the present invention to provide a new and 
improved system for the delivery of a physiologically active agent which 
is less complex than prior art devices. 
It is an additional object of the present invention to provide a new and 
improved system for the delivery of physiologically active agents which 
permits more control and flexibility in the amount and rate of delivery of 
active agents than prior art devices. 
It is another object of the present invention to provide a new and improved 
system for the delivery of physiologically active agents which utilizes 
the pores of a semipermeable membrane to deliver the active agent to a 
surrounding fluid environment. 
Additional objects and advantages of the present invention will be set 
forth in part in the description which follows and in part will be obvious 
from the description or can be learned by practice of the invention. The 
objects and advantages are achieved by means of the processes, 
instrumentalities and combinations particularly pointed out in the 
appended claims. 
To achieve the foregoing objects and in accordance with its purpose, the 
present invention provides a system for the controlled delivery of a 
physiologically active agent to a fluid environment comprising a 
semipermeable sheath having a plurality of pores and being imperforate 
except for the plurality of pores and defining a fully enclosed cavity for 
holding a physiologically active agent. A physiologically active agent is 
contained in the fully enclosed cavity for delivery to a fluid 
environment, said plurality of pores being sized to permit both the flow 
of fluid from the fluid environment through the semipermeable sheath into 
the cavity and the flow of fluid and physiologically active agent in 
solution out of the cavity to the fluid environment whereby said 
physiologically active agent is delivered from said semipermeable sheath 
exclusively through said plurality of pores.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
In accordance with the invention, as shown in FIG. 1, a device 10, which is 
generally of circular configuration, but whose shape may vary as 
appropriate for differing sites of application, consists of a 
semipermeable sheath 19 which is made of two thin sheets 12 and 14. The 
thin sheets 12 and 14 are bound along their respective edges to form a 
sheath with an outside edge 16. As will be apparent hereafter, the 
delivery system according to the invention, is intended to be used in a 
fluid environment with sufficient fluid present to enable the system to 
operate as intended. Furthermore, as with the prior art devices, the 
system according to the invention, is particularly suitable for the 
delivery of active agents to animals and may be located with respect to 
the animal to be treated by positioning or implanting the system in a 
variety of locations such as the animal's rectum or gastrointestinal 
tract, etc. 
As can be seen in FIG. 2, thin sheets 12 and 14 define a cavity 18 which is 
intended to contain a physiologically active agent. Thin sheets 12 and 14 
are provided with a plurality of pores in order to be semipermeable and 
permit the passage of fluid therethrough. The semipermeable thin sheets 12 
and 14, when joined to form edge 16, result in a semipermeable sheath. 
The present invention utilizes the principle of osmotic flow which results 
from a difference in molecular concentration being present across a 
semipermeable membrane. 
According to the invention, cavity 18 will contain at least a 
physiologically active agent which will go into solution with fluid which 
will enter cavity 18. The physiologically active agent may or may not be 
fully soluble as long as it can be delivered from device 10 at a suitable 
and predictable rate. As will be described in more detail hereinafter, in 
a preferred embodiment of the invention, a macromolecule may also be 
present in cavity 18. The term macromolecule is intended to mean a large 
molecule such as a protein, carbohydrate, rubber or other natural or 
synthetic high polymer. 
The presence of an active agent in cavity 18 results in a net molecular 
concentration gradient being set up between the cavity 18 and the fluid 
environment in which the lens is used. This net molecular concentration 
gradient will result in flow of fluid from the fluid environment through 
the semipermeable sheath into cavity 18. This flow of fluid, generally 
referred to as osmotic flow, results from the net higher molecular 
concentration or net higher osmotic pressure which is present in cavity 18 
due to the presence of a physiologically active agent alone or the 
physiologically active agent and the macromolecule. That is, the body of 
fluid inside the semipermeable sheath is hypertonic with respect to the 
fluid outside of the semipermeable sheath, i.e. the fluid inside the 
semipermeable sheath has a higher osmotic pressure than the fluid outside 
the semipermeable sheath. See applicant's copending Application "Fluid 
Lens" Ser. No. 432,409, filed Sept. 30, 1982. 
When measured at any given instance, the osmotic pressure inside cavity 18 
will be higher than that of the fluid surrounding the device and, 
therefore, there will be a net inward flow of fluid. However, over a 
period of time fluid continuously enters and leaves cavity 18 which 
results in a dispersion of the active agent from cavity 18. While there 
will be continuing "steady-state" flux of fluid between the environment 
and internal fluid of the device, the net inflow of fluid volume will 
occur in the initial states under the influence of osmosis until the 
osmotic pressure and fluid inflow result in the device achieving its 
natural premolded configuration. The burst strength of the encapsulating 
polymer film and its seal exceed the maximum achievable osmotic pressure 
by at least several orders of magnitude. The continuing steady-state flux 
of fluid across the walls of the device will result in the dispersion of 
any active agent whose molecular size is such as to allow passage through 
the preselected pore diameter of the membrane wall. 
The osmotic flow which results due to molecular concentration differences 
is independent for each molecule involved. For example, in the above 
example if the macromolecule, designated A, and another molecule, 
designated B, were added to cavity 18, and went into solution and became 
part of the body liquid 19, molecule B would set up a concentration 
gradient across the semipermeable sheath independent of the gradient 
present as a result of macromolecule A. The osmotic flow resulting from 
the presence of molecule B would be independent of the osmotic flow 
resulting from the presence of macromolecule A. 
In a preferred embodiment of the invention a macromolecule would be 
complexed with the physiological agent and the macromolecule selected such 
that it would be larger than the pores of the semipermeable sheath, yet 
the complex would decay over a period of time thereby allowing the active 
agent to slowly disperse from the semipermeable sheath. 
The macromolecule, according to the invention, may be selected from any 
class of compounds with molecular weight and configuration sufficiently 
large to be excluded passage by the desired pore size. Generally suitable 
are the dextrans, amylopectins (hydroxyethylstarch), polyvinylpyrrolidone, 
polyethylene glycol, albumin and various other soluble polymers and/or 
proteins. Alternatively, emulsions with droplets containing active agent 
can be utilized as well. Microemulsions with droplets of a diameter range 
0.01 to 0.1 microns are transparent and optically clear and thus, 
preferable for optical systems whereas macroemulsions with droplet of size 
0.1 to 1 or 2 micrometers may be satisfactory in other uses. 
The active agents suitable for use in connection with the present invention 
include for examples: oxygen, preferentially bound to fluorocarbons; 
salicylates, catechols, halogens, barbiturates or other compounds 
complexed to a macromolecule such as polyethylene glycols; antibiotics 
such as chloramphenicol, sulfa or other medications complexed with a 
macromolecule such as polyvinylpyrrolidone; antiepileptic medications such 
as phenytoin complexed to albumin; antihistamines, quinine, procaine or 
other compounds complexed to a macromolecule such as sodium 
carboxymethylcellulose; salicylates complexed to the antibiotics 
oxytetracycline or tetracycline or other compounds complexed to a 
macromolecule such as salicylates or other macromolecules could be 
utilized such as caffeine or albumin. The above identified complexes have 
well known association constants. See generally Remington's Pharmaceutical 
Sciences, 16th Edition, Arthur Osol, Editor, Mack Publishing Co. 1980, pp. 
182-193 and Physical Pharmacy, 2d Edition, Martin et al, Lea & Febiger, 
1969, pp. 325-352. 
A given delivery rate of active agent and/or complexing molecule can be 
achieved through selection of appropriate membrane pore size, density, 
environmental conditions and binding molecule. Active agent and binding 
molecule form a molecular complex with an affinity for each other which 
can be expressed as an association constant, an easily determined quantity 
related to concentration and physicochemical environment. This constant is 
directly proportional to the concentration of the complex and inversely 
proportional to the product of the concentrations of active agent 
uncomplexed and binding molecule uncomplexed. It can thus be seen that if 
a nondiffusable binding molecule is chosen, the further dampening of a 
potentially rapid or exponential rate of delivery of active agent can be 
achieved. In simple form, if the association constant is represented as K, 
the molar concentration of the drug as (D), the binding molecule 
concentration as (B), and the bound complex as (B-D), the following 
represents the relationship described: K=(B-D)/(B)(D). 
The thickness of the semipermeable sheet material, utilized in connection 
with the invention, will depend on a number of factors and is directly 
related to the intended use of the delivery system. Generally, the 
membrane thickness will range from 5-10 micrometers, depending upon the 
material used and the intended configuration and concentration gradient. 
Sheet material could be selected from cellulose acetate, cellulose acetate 
butyrate, cellulose triacetate, poly-1, 4 butylene terephthalate (such as 
MYLAR.RTM.), polymethylmethacrylate, polypropylene (such as CRYOVAC.RTM.), 
polystyrene, polyvinyl acetate, polyvinyl chloride, polyvinyl fluoride, 
polyvinylidene chloride (such as SARAN.RTM.), polycarbonate or 
silicon-polycarbonate copolymers (such as NUCLEPORE.RTM.) and others. 
The transparent sheets can be made porous in a variety of ways. For 
example, the technique of nuclear track etching can be used, in which the 
polymer films are exposed to radioactive decay particles and products and 
then treated chemically to "etch" permanently the tracks of the particles 
through the film, thus creating pores of a size and density determined by 
the exposure time and etching process. The particle dose determines the 
hole density while the pore diameter is a function of etching time. The 
specific particles, dose, etchants, and other conditions to achieve 
desired pore sizes and density for the aforementioned polymer films are 
well known in the prior art. See Nuclear Tracks in Solids, Principals and 
Applications, R.L. Fleischer et al, University of California Press, 1975. 
For example, polycarbonate filters (such as NUCLEPORE.RTM.) are produced 
by exposure to U.sup.235 followed by sodium hydroxide etching. 
Polyvinylidene chloride (such as SARAN.RTM.) can be made microporous by 
exposure to fission fragments of Californium 252 followed by etching with 
potassium permanganate at 55 degrees Centrigrade. As an alternative to 
nuclear tracking etching, the newer advanced lasers such as 
frequency-doubled Neodymium-YAG, Excimer, tunable dye or other lasers may 
be used to produce pores of the desired size and density. 
Pores may also be created by forming membranes as integrated sheets of 
polymer containing "pore-formers," molecules which subsequently can be 
leached or dissolved out, leaving a predictable pore size. The leaching or 
dissolution can be accomplished prior to use or so selected to occur in 
the environment of use. For example, certain polymer films made of various 
polycarbonates, polyamides, or polyesters can include such pore formers as 
lithium carbonate, calcium phosphate, various polysaccharides, such as 
mannitol, CARBOWAX.RTM., etc. These above processes, and others for 
creating microporous membranes, are noted in the prior art literature and 
are compiled in such works as Synthetic Polymer Membranes by R. E. 
Kesting, McGraw-Hill, Inc., 1971. 
The pore size will preferably range between 50 Angstroms diameter to 1,000 
Angstroms; however, it may be possible to have pore sizes smaller than 50 
Angstroms, if desired. The pore size is selected depending on the 
molecular weight and configuration of the macromolecule. For example, a 
pore size of approximately 60 Angstroms will exclude a molecule having a 
molecular weight of about 10,000. A 100 Angstrom pore size will exclude a 
molecule having a 100,000 molecular weight. The exact three dimensional 
configuration of the molecules may, of course, produce exceptions. Pore 
density would be on the order of 10.sup.5 to 10.sup.10 per square cm; 
however, depending on the application of the device, pore densities less 
than 10.sup.5 per square cm may be used. 
The thin sheets 12 and 14 may be joined at their respective edges to form 
edge 16 in a variety of ways. Various heat and impulse sealers can be used 
with variations in temperatures, frequency, and times allowing for 
substantial flexibility depending upon the particular polymer. Various 
one-part and two-part compatible adhesive bonding systems such as EASTMAN 
910.RTM., EPON 828.RTM. and 3M CONTACT CEMENT.RTM. could also be used. In 
addition, some materials are suitable for bonding without using 
conventional bonding methods. For example vinylidene chloride may be 
sealed to itself while in the so-called "supercooled" state to form a 
strong bond without conventional dielectric heat or adhesive methods. 
Osmotic pressures generated in cavity 18 obviously will be significantly 
less than the burst strength of the semipermeable membranes. For example, 
the pressure generated by the macromolecule will be in the order of less 
than 0.34 atmosphere (5 pounds per square inch), while, for example, the 
burst strength of vinylidene chloride 1 mil thick is 30 pounds per square 
inch. 
The following specific examples of delivery systems, in accordance with the 
invention, are set forth as illustrative only, and should not in any way 
limit the scope and purpose of the present invention. 
A delivery system for the drug phenytoin, is constructed by forming a 
sheath made from planar sheets of polycarbonate membrane, with pore size 
of 0.015 micrometers, porosity 12.times.10.sup.8 /cm.sup.2 and thickness 6 
micrometers. The polycarbonate membrane is heated to 220 degrees 
centigrade, and molded by vacuum or pressure to a spherical cap of 6.0 mm 
diameter with radius of curvature, 6.4 mm. A 1/2 mm wide planar 
circumferential cuff is left about each empty spherical cap. Then, 25.mu. 
g of phenytoin, along with 100.mu.g of albumin are placed into one cap 
after which the opposing cap is utilized as a cover and the 
circumferential cuff of 1/2 mm is sealed together at 230-275 degrees 
centigrade. This creates an envelope of potential volume 11.92 cu mm. 
Placed in the fluid environment of use, the delivery system will fill to 
its normal volume. 
FIG. 3 is a plot of the delivery rate of systems according to the invention 
comparing the delivery rate of a system containing phenytoin-albumin 
complex with the delivery rate of a system containing phenytoin alone. In 
the first half-hour the system utilizing the drug phenytoin-albumin 
complex shows that 0.74% of its drug content by weight will have been 
expended and after one hour a total of 1.7% will have been expended, and 
so on for the following intervals: 2 hrs, 3.4%; 4 hrs, 5.4%; 10 1/2 hrs, 
12%; 24 hrs, 20.2%; 33 1/2 hrs, 27.2%. 
By contrast, an identical device containing only phenytoin without albumin 
will deliver at the indentical time intervals as noted above, the 
following percentages of the initial amount of drug placed in the device: 
1/2 hr, 1.47%; 1 hr, 2.97%; 2 hrs, 5.7%; 4 hrs, 9.6%; 10 1/2 hrs, 22.4%; 
24 hrs, 38%; 33 1/2 hrs, 47.2%. 
It will be understood that the above description of the present invention 
is susceptible to various modifications, changes and adaptations, and the 
same are intended to be comprehended within the meaning and range of 
equivalents of the appended claims.