U.S. patent number 3,923,939 [Application Number 05/477,297] was granted by the patent office on 1975-12-02 for process for improving release kinetics of a monolithic drug delivery device.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Richard W. Baker, Alan S. Michaels, Felix Theeuwes.
United States Patent |
3,923,939 |
Baker , et al. |
December 2, 1975 |
Process for improving release kinetics of a monolithic drug
delivery device
Abstract
A process for improving the release kinetics of a monolithic
active agent delivery device comprising a shaped body of a
dispersion of particulate active agent, such as a drug, with a
polymer matrix, such as ethylene/vinylacetate copolymer, by
substantially reducing the initial burst of active agent from the
device when it is placed in its environment of use. The process
involves prior to placing the body in its use environment removing,
such as by water washing, the particulate drug from the exterior
surface of the body to form an agent depleted layer of polymer
matrix voided by the removal of the agent, the thickness of the
layer being at least 5% of the overall body thickness.
Inventors: |
Baker; Richard W. (Mountain
View, CA), Michaels; Alan S. (Atherton, CA), Theeuwes;
Felix (Los Altos, CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
23895337 |
Appl.
No.: |
05/477,297 |
Filed: |
June 7, 1974 |
Current U.S.
Class: |
264/49; 264/109;
264/344; 424/486; 128/832; 264/233; 424/469; 604/57; 604/523 |
Current CPC
Class: |
A61K
9/0039 (20130101); A61K 9/0004 (20130101); A61K
9/0051 (20130101); A61P 31/00 (20180101); A61P
5/00 (20180101) |
Current International
Class: |
A61K
9/00 (20060101); B29D 027/00 () |
Field of
Search: |
;264/233,344,49,109
;424/21,22 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Anderson; Philip
Attorney, Agent or Firm: Ciotti; Thomas E. Sabatine; Paul L.
Mandell; Edward L.
Claims
We claim:
1. Method for substantially reducing the initial burst of active
agent release from a monolithic active agent delivery device when
said device is placed in its environment of use, said device
comprising a shaped body of a dispersion of particulate active
agent within a polymer matrix comprising prior to placing said
shaped body in said environment, removing the particulate agent
from the exterior surface of said body to form an agent depleted
layer of polymer matrix voided by such removal of particulate
active agent, the thickness of said layer being at least about 5%
of the overall thickness of the body.
2. The method of claim 1 wherein said removing is done by washing
the body in a liquid which is inert relative to said polymer
matrix.
3. The method of claim 2 wherein said liquid is water.
4. The method of claim 2 wherein said device is a diffusion type
device and said washing is carried out at an elevated temperature
at which diffusion of the agent from the matrix is enhanced.
5. The method of claim 2 wherein the polymer matrix is an
ethylene/vinyl acetate copolymer and the washing is carried out at
about 50.degree.C to about 60.degree.C.
6. The method of claim 2 wherein the device is an osmotic bursting
type device and the washing is carried out at an elevated
temperature at which imbibition of said liquid by the active agent
is enhanced.
7. The method of claim 1 wherein the thickness of the layer is
about 5% to 25% of the overall thickness of the body.
8. In a process for making a monolithic drug delivery device
comprising a dispersion of solid particulate drug in a polymer
matrix comprising the steps of forming a dispersion of the solid
particulate drug within said matrix and forming the dispersion into
a shaped body adapted for placement in the environment of use of
the device, the improvement comprising the additional step of
removing the solid particulate drug from the surface of said body
to form a drug depleted layer of polymer matrix voided by the
removal of the particulate solid drug therefrom, the thickness of
said layer being at least about 5% of the overall thickness of said
body.
9. The improvement of claim 8 in which the thickness of said layer
is about 5% to about 25% of the overall thickness of the body.
10. The improvement of claim 8 wherein said removing is done by
washing the body in a liquid which is inert relative to the polymer
matrix.
11. The improvement of claim 10 wherein the liquid is water.
12. The improvement of claim 10 wherein the device is a diffusion
type device and said washing is carried out at an elevated
temperature at which diffusion of the drug from the matrix is
enhanced.
13. The improvement of claim 12 wherein the polymer matrix is made
of an ethylene/vinyl acetate copolymer and the elevated temperature
is from about 50.degree.C to about 60.degree.C.
14. The improvement of claim 10 wherein the device is an osmotic
bursting type device and the washing is carried out at an elevated
temperature at which the imbibition of liquid by the active agent
is enhanced.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a process for improving the active agent
release kinetics of a monolithic active agent delivery device.
2. Description of the Prior Art
Monolithic devices for sustainedly releasing drugs or other active
agents are well known in the art. One type of monolithic device
consists of a shaped body of particulate, usually solid, drug
dispersed uniformly in a polymer matrix permeable to the drug by
diffusion. The polymer matrix may be substantially imperforate and
homogeneous in which case the drug dissolves in and permeates
through the polymer material itself. Alternatively, the matrix may
be microporous, the pores of which contain a drug-permeable liquid
or gel medium, in which case the drug will preferentially dissolve
in and permeate through the medium in the pores. It is of course
possible to use a polymer matrix which is both microporous and made
of a polymer permeable to the drug in which case movement of the
drug through the matrix is via a combination of the above described
modes.
Another type of monolithic device for use in releasing active
agents into aqueous environments, such as drugs into the various
cavities of the human body, consists of a shaped body of discrete
particulate osmotic solute/active agent depots dispersed in and
surrounded by an active agent impermeable but water permeable
polymer matrix whose cohesive strength is exceeded by the osmotic
pressure generating ability of the individual depots. Such devices
release their active agent by an osmotic bursting mechanism in
which water is imbibed osmotically into the depots nearest the
exterior surfaces of the device, thereby dissolving those depots'
contents and generating pressure therewithin sufficient to cause
the surrounding polymer matrix to rupture thus allowing release of
the agent therefrom and access by the environment to the next
nearest depots and serially so forth. These monolithic "osmotic
bursting" devices are the subject matter of commonly assigned,
copending application Ser. No. 354,359 filed Apr. 25, 1973 and now
abandoned, the disclosure of which is incorporated by reference
herein.
These monolithic devices are attractive commercially because they
are inexpensive and easily fabricated relative to other devices
such as laminated devices or capsule devices. Also, in the case of
some drugs, a monolithic device is the only type of device capable
of practically and sustainedly releasing the drug at a
therapeutically effective rate.
The active agent release kinetics of these monolithic devices
exhibit a feature which is often undesirable, namely the release
begins at a high rate--called an "initial burst"--which rapidly
decreases to a significantly lower rate. The kinetics of monolithic
diffusion for a device having a thin rectangular cross sectional
shape (i.e., the device is shaped as a flat slab) may be expressed
by the equation.sup.1 :
in which M.sub.t is the agent released at time, t, C.sub.s is the
agent solubility in the polymer matrix, C.sub.o is the total
concentration of agent in the polymer matrix, C.sub.o being much
greater than C.sub.s, D is the agent's diffusion coefficient in the
polymer matrix and A is the surface area of the device (both
sides). Equations defining the release kinetics of other simple
geometries, such as a cylinder and a sphere are also
known.sup.2.
In a plot of the above equation with dM.sub.t /dt plotted against
t, the release rate in the initial stage of release is extremely
high and drops off very quickly to a level markedly below the rate
in the initial stage. Corresponding plots for monolithic diffusion
devices of other simple geometry, such as a rod-like cylinder or
sphere, follow the same general release rate pattern as the simple
slab described above.
The release kinetics for monolithic osmotic bursting devices have
been found empirically to also exhibit an initial burst which
decreases rapidly to a significantly lower rate. However the
release rate plateaus after the initial decrease in the osmotic
bursting devices whereas it continuously decreases in the diffusion
devices.
In both types of devices this initial burst of active agent may be
undesirable because it results in overdosing, toxicity or side
reactions, or may not conform to the optimal dosage regimen for a
particular active agent.
The initial high level or "burst" in the release rate of active
agent from a monolithic device may be reduced by coating the body
with a layer of pure polymer matrix. Such a coated device is taught
(the coating is used for a different purpose) in U.S. Pat. No.
3,577,512 issued May 4, 1971 to T. H. Shepherd et al. However this
coating procedure has the disadvantage of lowering the entire
release rate profile (i.e., the entire dM.sub.t /dt vs. t plot) of
the device. Such lowering may result in release rates below those
required for efficacy. Also, if the device has an irregular shape,
it is usually quite difficult to devise a manufacturing procedure
to make a continuous, uniform coating on the device in a
reproducible manner.
SUMMARY OF THE INVENTION
This invention is a process for improving the release kinetics of
the above described monolithic active agent delivery devices by
substantially eliminating the initial burst of active agent release
without significantly lowering the entire release rate profile of
the device. This novel process comprises, prior to placing the
device in its intended environment of use, removing the particulate
agent from the exterior surface of the device to form an agent
depleted layer of polymer matrix voided by the removal of the
particulate agent.
In a preferred embodiment of this process the removal of
particulate agent from the surface of the device is done by washing
the device in a liquid which does not deleteriously affect the
polymer matrix at a temperature which enhances the removal of agent
from the matrix.
The devices made by the invention process are placed in fluid
containing environments into which the agent is released by
diffusion or by osmotic bursting. Depending on the particular
active agent involved the environment may be a body cavity, a
stream, an aquarium, soil, a chemical reactor or the like.
Embodiments intended to release drug within body cavities may be
placed within the gastrointestinal tract, mouth, eye, uterus,
vagina and other cavities.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 is a vertical, sectional view of a disc-shaped monolithic
diffusion type drug delivery device made in accordance with the
invention process;
FIG. 2 is an enlarged view of a portion of the section of FIG. 1
taken along line 2--2 of FIG. 1;
FIG. 3 is a graphic representation of the release kinetics of a
prior art monolithic diffusion drug delivery device;
FIG. 4 is a graphic representation of the improvements in the
release kinetics of the device represented in FIG. 3 which may be
realized by subjecting that device to the process of this
invention;
FIG. 5 is a graphic representation of several prior art devices of
the same geometry as the device of FIG. 3 but having different
loadings of active agent; and
FIG. 6 is a graphic representation of the improvements in the
release kinetics of the devices of FIG. 5 which may be realized by
subjecting those devices to the process of this invention;
FIG. 7 is a vertical, sectional view of a disc-shaped monolithic
osmotic bursting drug delivery device made by the invention
process;
FIG. 8 is an enlarged view of a portion of a section of FIG. 7
taken along line 8--8 of FIG. 7;
FIG. 9 is a graphic representation of the release kinetics of a
prior art monolithic osmotic bursting drug delivery device; and
FIG. 10 is a graphic representation of the improvement in the
release kinetics of the device of FIG. 9 which may be realized by
treating that device in accordance with the process of this
invention.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 depicts a disc-shaped monolithic diffusion type active agent
delivery device, generally designated 10, comprising a particulate
active agent 11, such as drug, dispersed in a polymer matrix 12.
The particles of agent 11 may be liquid, semi-solid or solid but
are preferably solid.
"Active agents" as used herein include those compositions of matter
which when dispensed in their environment of use produce a
predetermined, beneficial and useful result. Such agents include
for example pesticides, herbicides, germicides, biocides,
algicides, rodenticides, fungicides, insecticides, anti-oxidants,
plant growth promotors and inhibitors, preservatives, surfactants,
disinfectants, catalysts, fermentation agents, nutrients, drugs,
plant minerals, sex sterilants, plant hormones, air purifiers,
micro-organism attenuators and the like.
"Drug" as used herein broadly includes physiologically or
pharmacologically active substances for producing a localized
effect at the administration site or a systemic effect at a site
remote from the administration site. Such drugs include inorganic
and organic compounds, for example, drugs which act on the central
nervous system such as hypnotics and sedatives, psychic energizers,
tranquilizers, anticonvulsants, muscle relaxants and anti-parkinson
agents, antipyretics and anti-inflammatory agents, local
anesthetics, anti-spasmodics and antiulcer agents, prostaglandins,
anti-microbials, hormonal agents, estrogenic steroids,
progestational steroids, such as for contraceptive purposes,
sympathomimetic drugs, cardiovascular drugs, diuretics,
antiparasitic agents, hypoglycemic drugs and ophthalmic drugs.
In the osmotic bursting devices the active agent must either itself
be water soluble to the extent that the osmotic pressure of a
saturated solution thereof exceeds the osmotic pressure of the
external environment of use or it must be mixed with a compatible
osmotically effective solute such as an inorganic or organic salt
capable of generating such an osmotic pressure. Such pressure
provides the necessary driving force by which the osmotic bursting
mechanism is effected. Methods of calculating or measuring osmotic
pressure are well known. See for example, S. Glasstone, Textbook of
Physical Chemistry, MacMillan & Co., London (1960).
As indicated above, in the monolithic diffusion devices the polymer
forming the polymer matrix may be substantially imperforate and
homogeneous or microporous. Examples of substantially imperforate
polymers which may be used are poly(methylmethacrylate),
poly(butylmethacrylate), plasticized poly(vinylchloride),
plasticized soft nylon, natural rubber, poly(isoprene),
poly(isobutylene), poly(butadiene), poly(ethylene), poly(vinylidene
chloride), cross-linked poly(vinylpyrrolidone), chlorinated
poly(ethylene) poly(4,4'-isopropylidene diphenylene carbonate),
ethylene-vinylacetate copolymer, plasticized ethylene-vinylacetate
copolymer, vinylidene chloride-acrylonitrile copolymer, vinyl
chloride-diethyl fumerate copolymer, silicone rubbers, especially
the medical grade poly(dimethylsiloxanes), ethylene-propylene
rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl
chloride copolymer, vinyl chloride-acrylonitrile copolymer and
vinylidene chloride-acrylonitrile copolymer.
Microporous materials which may be used in making monolithic
devices have pores which range in size from at least about 10A to
several hundred microns, but usually not more than about 100
microns. Examples of materials from which microporous structures
may be made are regenerated, insoluble, nonerodible cellulose,
acylated cellulose, esterified cellulose, cellulose acetate
propionate, cellulose acetate butyrate, cellulose acetate
phthalate, cellulose acetate diethylamino-acetate, poly(urethanes),
poly(carbonates), modified insoluble collagen, cross-linked
poly(vinyl alcohol), epoxy resins and poly(olefins) or
poly(vinylchlorides). These materials may be made microporous by
well known procedures such as coprecipitation or leaching out
incorporated salts, soap micelles, starch or like materials. See,
for example, J. D. Ferry, Chemical Reviews, 18, 373 (1935).
Diffusive media which may be used to fill the pores of the porous
materials should be compatible with the environment of use. Also
the active agent should leave only limited solubility in the medium
(10 ppm to 10,000 ppm on a weight basis) so that the active agent
is released by diffusion rather than by simple dissolution.
Representative media are saline, glycerin, ethylene glycol,
propylene glycol, water, emulsifying and suspending agents such as
methyl cellulose mixed with water, mixtures of propylene glycol
monostearate and oils, gum tragacanth, sodium alginate, poly(vinyl
pyrrolidone), poly(oxyethylene stearate), fatty acids such as
linoleic, and silicone oil. Other representative media are set
forth in Remington's Pharmaceutical Sciences, pages 246 to 269 and
1338 to 1380, 1970, published by Mack Publishing Co., Easton,
Pas.
The polymers used to make the osmotic bursting devices may be
defined in terms of their permeabilities to active agent and water
and their tensile strength and maximum elongation (which delimit
their cohesive and rupture strength). Normally these materials will
have water permeabilities of about ##EQU1## a tensile strength of
about 14 to 700 kg/cm.sup.2 (preferably 35 to 210 kg/cm.sup.2), and
a maximum elongation of 10% to 2000% (preferably 200% to 1700%).
They also should have a high degree of impermeability to the active
agent i.e., active agent permeabilities less than 10.sup..sup.-7
cm.sup.2 /sec.
Typical polymers for forming the osmotic bursting devices include
unplasticized cellulose acetate, cellulose nitrate with 11%
nitrogen, cellulose diacetate, cellulose triacetate, agar acetate,
amylose triacetate, beta glucan acetate, beta glucan triacetate,
cellulose acetate, acetaldehyde dimethyl acetate, cellulose acetate
ethyl carbamate, cellulose acetate phthalate, cellulose acetate
methyl carbamate, cellulose acetate succinate, cellulose acetate
dimethaminoacetate, cellulose acetate ethyl carbonate, cellulose
acetate chloroacetate, cellulose acetate ethyl oxatate, cellulose
acetate methyl sulfonate, cellulose acetate butyl sulfonate,
cellulose acetate propionate, cellulose acetate butyl sulfonate,
cellulose acetate propionate, cellulose acetate p-toluene
sulfonate, triacetate of locust gum bean, cellulose acetate with
acetylated hydroxy-ethyl cellulose, hydroxylated and unhydroxylated
ethylene-vinyl acetate copolymers, highly plasticized polyvinyl
chloride, homo- and copolymers of polyvinyl acetate, polymers of
acrylic acid and methacrylic acid, polyvinyl alkyl ethers,
polyvinyl fluoride, polycarbonates, polymeric epoxides, copolymers
of an alkylene oxide and alkyl glycidyl ether, semi-permeable
polyurethanes, semi-permeable polyglycolic or polylactic acid and
derivatives thereof and derivatives of polystyrene such as
poly(sodium styrenesulfonate) and poly(vinylbenzyltrimethylammonium
chloride). Ethylene-vinyl acetate copolymers, either alone or mixed
with other materials, are especially useful for forming the osmotic
bursting device. Preferred among the ethylene-vinyl acetate
copolymers are those having a melt index above about 20 g/min and a
vinyl acetate content above about 20%, such as from 20-45%.
In the diffusion devices the concentration of active agent
dispersed in the polymer matrix will primarily depend upon the
desired dosage level for the device. Normally the concentration of
active agent will be in the range of 5 to 70 weight percent based
on the polymer matrix. Its particle size will usually be in the
range of 0.1 to 100 microns.
In the osmotic bursting devices the active agent depot loading
(which depends on the size and number of depots percent volume) is
important. The depots will usually comprise 5% to 70% by weight of
the device. In this range sufficient polymer is present to
adequately encapsulate the depots and maintain the device's
integrity after a substantial amount of the agent depots have been
released. The depot size will usually range between 0.1 and 100
microns in diameter.
The shape of the device made from the above described active
agent/polymer dispersions will depend on the intended environment
of use. In most environments complex shapes will be unnecessary and
thus for convenience and economy the device will have a simple
shape such as flat disc, a cylindrical rod, or a sphere. For
specific embodiments such as an embodiment intended for use in the
eye to release an ophthalmic drug therein, the device will usually
be in the shape of a flat disc, oval, ellipse or kidney.
The device will be sized according to the environment and desired
dosage. Drug delivery devices for implanting in the body will be
sized in accordance with the dimensions of the implant size. For
instance for ocular inserts for inserting in a cul-de-sac of the
eye the device will normally have a length of 4 to 20 mm, a width
of 1 to 15 mm and a thickness of 0.1 to 4 mm and will usually
contain 1 to 200 mg ophthalmic drug.
The active agent/polymer dispersions may be formed by mixing the
two components by conventional techniques. Likewise, the
dispersions may be formed into shaped bodies by conventional
techniques such as solvent casting, extruding, roll milling, melt
pressing, cutting, punching and the like.
After the dispersion is formed into the desired shape (this may be
its final form for introducing into the use environment or some
intermediate form such as a large sheet or roll) but before it is
placed in the environment of use, the particles of active agent are
removed from the exterior surface layer of the body in accordance
with the process of this invention. This may be done by washing the
body with a liquid which is inert relative to the polymer matrix
(in other words the liquid should not deleteriously affect the
polymer matrix either physically or chemically such as by
dissolving, disintegrating, or chemically reacting with the
matrix). For convenience and economy the wash liquid will usually
be aqueous, with water being preferred.
In a diffusion device the washing of the device causes active agent
which is dissolved in the polymer matrix at the surface to diffuse
into the wash liquid which in turn causes agent particles located
at or near the surface to dissolve into the polymer and be diffused
therefrom. In the case of the osmotic bursting devices the washing
causes any agent at the surface to be dissolved and water to be
imbibed by the encapsulated agent depots causing them to burst and
release their contents. In both types of devices this washing
ultimately results in the active agent being depleted from a
surface layer of desired thickness. In the device shown in FIGS. 1
and 2 the drug has been depleted from a layer, designated A, at the
exterior surface of the device leaving voids 14. The number and
size of the voids in the matrix will depend on the concentration
and particle size of the dispersed active agent. In this regard it
has been observed that the voids tend to irreversibly shrink, i.e.,
the porosity of the layer decreases, if the device is permitted to
dry after the washing. This phenomenon is believed to make the
layer of a dried device act more like a coating of pure matrix in
that it may be less permeable to the agent than the remainder of
the matrix. In any event voids 14 affect the release kinetics of
device 10 because they form preferred pathways (indicated by small
arrows) for the active agent to diffuse along.
FIGS. 7 and 8 illustrate a monolithic osmotic bursting active agent
delivery device, generally designated 15, which has been prewashed
in accordance with the invention process. Device 15 comprises
discrete active agent/osmotic solute depots 16 encapsulated within
a polymer matrix 17. As shown in FIG. 8 the prewashing has depleted
the active agent depots from a layer, designated B, at the surface
of the device leaving voids 18. Voids 18 are similar to voids 14 of
device 10 except that voids 18 are substantially interconnected due
to the bursting mechanism by which the active agent was
released.
The process conditions of the wash, e.g., time and temperature,
will be selected to provide an agent depleted layer of
predetermined thickness. Given a desired layer thickness the wash
temperature and time will depend on the particular polymer and
active agent involved. In a diffusion device wash times may be
shortened by employing temperatures at which diffusion is enhanced.
In an osmotic bursting device wash times may be shortened by using
temperatures at which water inbibition by the depots is enhanced.
In almost all instances this means that elevated temperatures
(above ambient temperature) below the matrix melt temperature and
below that which might adversely affect the agent in any manner
will shorten the wash time. For most polymers and agent wash
temperatures in the range of about 50.degree.C to about 60.degree.C
may be used advantageously. For both types of devices it is
desirable to carry out the wash with agitation to ensure good
clearance of the released agent from the exterior of the
device.
Although any degree of prewashing will improve the release kinetics
of the device, it is desirable to remove active agent from a layer
which represents at least about 5% of the total thickness or
diameter of the device. Usually the thickness of the layer will
comprise about 5% to about 25% of the overall thickness or
diameter. It should be understood that in most devices the layer
appears at both sides or both edges of the device and that the
above percentages relate to only a single appearance of the layer.
In other words in a spherical device the layer would appear at both
ends of a diameter and thus the total diametrical drug depleted
portion of the device would represent at least about 10% of the
entire diameter.
EXAMPLES
The invention process and the improvement in release kinetics
realized by using it are further illustrated by the following
examples.
Example 1
A. A monolithic diffusion device such as might be used to dispense
a drug intrauterinely is made by mixing 20 parts progesterone (5-10
micron particle size) into a methylene chloride solution of 80
parts ethylene-vinyl acetate copolymer (the drug loading is
approximately 20% by volume). This mixture is cast into a 0.2 cm
thick sheet from which a rectangular body having a total surface
area of 1 cm.sup.2 is cut. This rectangular body is placed in a
simulated uterine environment where it releases progesterone by
diffusion. This release is monitored, the plot of which is shown in
FIG. 3. As seen in FIG. 3 the initial release rate of progesterone
is in the neighborhood of 150 .mu.g/day and drops off rapidly
during the first 100 days to about 40 .mu.g/day after which the
release curve slowly and continuously declines until the solid
progesterone is exhausted.
B. Three rectangular bodies of a progesterone/ethylene-vinyl
acetate copolymer dispersion are prepared as in A. Each is washed
in water at 50.degree.C; the first until a drug free surface layer
0.020 cm thick is formed; the second until a drug free layer 0.033
cm thick is formed; and the third until a drug free layer 0.047 cm
thick is formed. Each device is then placed in the simulated
uterine environment as described in A and the progesterone release
therefrom is monitored and plotted, the plots of which are shown in
FIG. 4. As shown by these plots the initial release rate relative
to the unwashed device is decreased respectively by about 30%, 60%
and 70% in the washed devices. Also the release rate during the
major portion of the device's lifetime (c.a. 100 days to 500 days)
is not significantly decreased by the washing.
Example 2
A. A device identical with that of Example 1A and two other devices
identical to the same except in drug loading (one contained half
the amount of progesterone and the other contained double the
amount of progesterone) are prepared and tested as in Example 1A.
Their release plots are illustrated in FIG. 5.
B. Three devices identical to those of A are prepared and prewashed
in water at 50.degree.C until a 0.047 cm thick drug-free layer is
formed in each. These washed devices are then tested as in Example
1A. Their release plots are shown in FIG. 6.
As is readily seen by comparing FIGS. 5 and 6 the washing
eliminated the initial burst in the progesterone release while not
significantly affecting the release rate over the bulk of each
device's lifetime.
Example 3
A. An osmotic bursting device such as might be used to dispense
drug to the eye is made by mixing 30 parts pilocarpine nitrate with
70 parts of ethylene/vinyl acetate copolymer on a laboratory rubber
mill. The well dispersed mixture which contains pilocarpine nitrate
particles with an average diameter of between 1 and 10 microns is
then pressed into a flat film 500 microns thick from which an
ellipse shaped body 13.5 mm by 6.5 mm is cut. This body is placed
in simulated lachrymal fluid at 37.degree.C where it releases
pilocarpine nitrate by an osmotic bursting mechanism. This release
is monitored, the plot of which is shown in FIG. 9. As seen in FIG.
9 the initial pilocarpine nitrate release rate is about
175.mu.g/hour and drops off rapidly during the first 25 hours to
about 25 .mu.g/hour.
B. Five devices identical to those of A are prepared and soaked in
water at 37.degree.C for 15, 30, 60 and 120 minutes and 24 hours
respectively. Each device is then tested as in A. Their pilocarpine
nitrate release plots are shown in FIG. 10. As shown by these plots
the washing decreases the initial release rate by about 20%, 40%,
50%, and 90% respectively. Also, there is little variation in
release rate between the unwashed and washed devices after 25
hours.
Example 4
Osmotic bursting ocular inserts are made by dispersing 30 parts
tetracycline hycrochloride in 70 parts ethylene/vinyl acetate
copolymer (Elvax 220) on a rubber mill, melt pressing the
dispersion into a flat film 500 microns thick and cutting 13.5 mm
.times. 5.8 mm ellipses therefrom. Individual ellipses are washed,
0, 15, 30, 60 and 120 minutes respectively, in water at
50.degree.C, dried and then placed in simulated lachrymal fluid.
The average tetracycline hydrochloride release over the first 7
hours of release is respectively 26, 18, 17, 12 and 9
.mu.g/hour.
Example 5
Inserts were made and tested as in Example 4 except that a
different ethylene/vinyl acetate copolymer (Elvax 40) was used. The
average tetracycline hydrochloride release over the first 7 hours
is, respectively, 25, 15, 12, 9 and 6 .mu.g/hour.
Various modifications of the invention process will be obvious to
those of ordinary skill in the active agent formulations art. Such
modifications are intended to be within the scope and spirit of the
following claims.
* * * * *