U.S. patent number 3,851,648 [Application Number 05/405,616] was granted by the patent office on 1974-12-03 for zero-order release device.
This patent grant is currently assigned to Mead Johnson & Company. Invention is credited to Dana Brooke.
United States Patent |
3,851,648 |
Brooke |
December 3, 1974 |
**Please see images for:
( Certificate of Correction ) ** |
ZERO-ORDER RELEASE DEVICE
Abstract
A diffusible solid is released by diffusion into a fluid medium
from a cavity within a container through an opening therein at a
rate which is independent of the amount of solid present in the
container. Zero-order release is effected by the shape of the
cavity and the opening. The rate is related to the solubility and
to the diffusion constant of the solid in the fluid medium. For a
given substance, the rate of release is determined by cavity shape
and dimensions of the diffusion opening. The device is adapted for
use in both liquid and gaseous media and can be used for the
zero-order release of drug substances into the system of a living
organism, and for non-medical uses.
Inventors: |
Brooke; Dana (Evansville,
IN) |
Assignee: |
Mead Johnson & Company
(Evansville, IN)
|
Family
ID: |
23604450 |
Appl.
No.: |
05/405,616 |
Filed: |
October 11, 1973 |
Current U.S.
Class: |
424/467; 239/57;
422/1; 119/534; 43/131; 239/60; 424/473 |
Current CPC
Class: |
A61M
31/002 (20130101); A61M 37/00 (20130101); A61J
3/08 (20130101); A01M 7/0092 (20130101); A61F
6/14 (20130101); A61K 9/0004 (20130101); A61K
9/2072 (20130101) |
Current International
Class: |
A01M
7/00 (20060101); A61K 9/00 (20060101); A61K
9/20 (20060101); A61J 3/00 (20060101); A61J
3/08 (20060101); A61F 6/00 (20060101); A61F
6/14 (20060101); A61M 37/00 (20060101); A61M
31/00 (20060101); A61m 031/00 (); A61m
007/00 () |
Field of
Search: |
;128/260,130,270,268,272X,2R,214E ;119/156,25X,26 ;260/75,86.1,2.5
;222/386.5,54 ;239/6X,57X,44 ;206/47 ;23/267A ;43/131X |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Medbery; Aldrich F.
Attorney, Agent or Firm: Carnahan; Robert E. Uloth; Robert
H.
Claims
What is claimed is:
1. A device for the automatic release at a substantially constant
predetermined rate of a diffusible solid into a fluid medium into
which said solid has a propensity to diffuse when said device is
immersed in said medium which comprises,
a container which is insoluble in said medium, impermeable thereto,
and impermeable to said solid,
said container having a slot in the surface thereof defining an
elongated opening of uniform length and width having two ends and
two sides with the narrower dimension at the ends and the longer
dimension at the sides, said slot communicating in its entirety
with
an internal cavity within said container said cavity being defined
by an accuate wall and
a pair of parallel congruent planar end walls arranged at right
angles to said slot and adjacent the ends thereof,
and a pair of inwardly extending congruent planar side walls
adjacent the opposite sides of said slot and in substantially
divergent radial relation to said slot, and extending to said rear
wall.
a means for diffusing said solid from within said cavity into the
immersing medium including a diffusible solid housed within said
cavity as a homogenous mass in bonded relation to the inner wall
surface of the cavity and having a surface thereof facing and
opposing said slot opening to expose the diffusable solid surface
to said fluid medium when said device is immersed therein.
2. The device defined in claim 1 wherein the entire volume of the
cavity is occupied by said solid.
3. The device defined in claim 1 wherein less than the entire
volume of said cavity is occupied by said solid such that the rear
wall of said cavity is entirely covered thereby and the surface
thereof opposite said slot is of arcuate concave configuration
defining a segment of a cylinder wall the axis of which lies within
said slot.
4. The device of claim 1 wherein the side walls of said cavity are
positioned with respect to one another at an angle in the range of
from 30.degree. to 270.degree..
5. The device of claim 1 wherein the rear wall of said cavity is of
arcuate concave configuration defining a segment of a cylinder wall
the axis of which lies within said slot.
6. The device of claim 1 adapted for use in a gaseous medium and
said solid possesses a vapor pressure such that sublimation thereof
occurs under ambient conditions.
7. The device of claim 1 wherein said fluid medium is a liquid.
8. The device of claim 1 wherein said solid is biologically active
and release thereof into said medium is for the purpose of exerting
a biological effect in the medium.
9. The device of claim 8 wherein said solid is a drug substance and
said medium is a biological liquid.
10. The device of claim 8 wherein said solid is a suspension or a
dispersion of a particulate pure drug substance in an inert carrier
solid wherein said carrier solid is substantially insoluble in said
medium but permeable to diffusion of said drug substance.
11. The device of claim 1 wherein said device is sized and shaped
for placement and retention within the uterine cavity of a mammal
and said solid is a biologically active substance.
12. The device of claim 11 wherein said solid possesses hormonal
activity.
13. The device of claim 11 wherein said container is a cylinder
approximately 3.2 cm. in length and 0.24 cm. in diameter.
14. The device of claim 13 wherein said slot is arranged in an
axial direction on the side of said cylinder, the width of said
slot is from about 0.02 to about 0.06 cm., the angle formed by said
side walls of said cavity is from about 30.degree. to about
140.degree., and said solid has a solubility in said medium from
about 1.7 mcg./ml. to about 570 mcg./ml.
15. The device of claim 1 wherein said container is a ring adapted
for placement and retention within the vagina of a mammal, said
solid is a biologically active substance, and said slot and cavity
are positioned concentrically on said ring.
16. The device of claim 15 wherein said slot traverses the entire
circumference of said ring.
17. The device of claim 15 having multiple concentrically
positioned slots and cavities.
Description
FIELD OF THE INVENTION
There is provided a device for dispensing a vapor from a subliming
solid into a gaseous medium or a solid solute into a liquid medium
at a constant rate during a prolonged period of time. The device
may be used as a medicator such as a surgical implant, tampon,
suppository, intrauterine device, or intravaginal device for
delivery of a drug or growth regulating substance into the system
of a living organism, or for other uses such as water or air
treatment.
SUMMARY OF THE PRIOR ART
Certain pesticides are sublimable solids and various devices have
been used for delivery of the vapor thereof such as decorative
cannisters, pet collars, etc., to the locale to be treated. Moth
proofing and insecticidal agents have been delivered in this
fashion. Various means have been used for the delivery of drugs and
other biologically active substances to the mammalian body by means
of specifically fabricated tablets, implants, intrauterine devices,
ocular inserts, catheter tubes, etc. which were designed to release
the active substance at a predetermined rate. Examples of such
devices are illustrated in the following patents. Levesque, U.S.
Pat. No. 2,987,445 patented June 6, 1961; Long and Volkman, U.S.
Pat. No. 3,279,996 patented Oct. 18, 1966; Rudel, U.S. Pat. No.
3,656,483 patented Apr. 18, 1972; Jacobs, U.S. Pat. No. 3,113,076
patented Dec. 3, 1963; Stephenson, et al., U.S. Pat. No. 3,146,169
patented Aug. 25, 1964; and Wepaic, U.S. Pat. No. 3,598,127
patented Aug. 10, 1971.
SUMMARY OF THE INVENTION
This invention provides a device comprised of a container of rigid
material which is impermeable to the fluid medium into which it is
desired to dispense a diffusible solid which is contained within
the device. The container may be of any convenient size and shape
to fit the particular application under consideration. Housed
within the container is a cavity communicating through a slot in
the surface of the container with the exterior medium through which
the contained solid is dispensed. The solid is dispensed by the
processes of dissolution of vaporization within the container into
the fluid medium which enters through the slot, and diffusion of
the dissolved or vaporized solid outwardly through the slot into
the surrounding medium. Zero-order release results from the
configuration of the cavity and slot which is such as to provide an
increasing surface area of diffusible solid exposed to the fluid
medium within the container as the length of the path through which
the dissolved or sublimed solid must diffuse to reach the exterior
increases. A constant ratio of area of dissolution or sublimation
surface to diffusion distance is maintained. The device is
applicable to various drug delivery systems, and to non-medical
uses such as the dispensing of insecticides, pesticides, perfumes,
and water treatment with germicides in swimming pools, toilets,
etc.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a device of the present invention
which is cylindrical in form and contains a rectangular slot
lengthwise on one side thereof which communicates with a cavity
within the cylindrical container the cross-section of which is
shaped like a slice of pie.
FIG. 2 is a view in cross-section of the device of FIG. 1 along
line 2--2 showing the drug partially filling the cavity.
FIG. 3 is a perspective view of a device of the present invention
in which the container is ring-shaped and the diffusion slot is
arranged concentrically upon the upper surface thereof.
FIG. 4 is a view in cross-section of the device shown in FIG. 3
along line 4--4.
FIG. 5 is a collection of graphs in which the rate of release of a
diffusible solid from the device of FIG. 1 is related to its
solubility, and the dimensions of the cavity and the slot.
FIG. 6 is a perspective view of a device of the present invention
which is comprised of a hollow container in the form of a right
circular cylinder bisected along the axis thereof and having an
elongated diffusion slot located on the bisecting surface along the
axis.
DETAILED DESCRIPTION OF THE INVENTION
In FIG. 1, the cavity 15 is illustrated by broken lines and the
slot through which it communicates with the exterior is indicated
by 20. The slot is of uniform length and width. The narrower
dimension or width is situated at the ends 21 and 24 of the slot.
The elongated dimension is located at the sides of the slot
represented by 22 and 23. Drug substance or other active ingredient
to be dispensed 25 is contained within cavity 15 and is outlined by
a broken line in the drawing. The cavity fill should be a solid
under ambient conditions. The end walls of cavity 15 are
represented by 30 and 31. End walls 30 and 31 lie in parallel
planes which are at right angles to slot 20, adjacent to the ends
thereof, and are congruent in shape. The side edges of end walls 30
and 31 of cavity 15 are represented by 32, 33, 34, and 35. They are
of equal length and are arranged radially and inwardly divergent
with respect to slot 20 so that end walls 30 and 31 are pie-shaped
in the embodiment shown. Also, the rear wall 40 of cavity 15 is
arcuate in contour defining a portion of the wall of a phantom
cylinder whose axis lies substantially within slot 20 and the side
edges 32, 33, 34, and 35 of end walls 30 and 31 are substantially
radii of the phantom cylinder. The side walls 45 and 46 of cavity
15 are situated. adjacent opposite sides 22 and 23 of slot 20 and
in radial relation to said slot. They are congruent in shape.
FIG. 2 is a cross-section of the device of FIG. 1 taken along line
2--2 of FIG. 1 in a plane parallel with the planes of end walls 30
and 31 of cavity 15. Like numbers in FIG. 2 refer to like features
of FIG. 1. Cavity 15 of the device shown in FIGS. 1 and 2 is only
partially filled with drug substance 25, 26 representing the
surface of drug substance 25 which is opposite slot 20.
Cavity 15 houses drug substance 25 in bonded relation to side walls
45 and 46 and end walls 30 and 31 thereof. By bonded relation is
meant in close contact so that fluid medium 50 and 51 which
surrounds container 10 and which fills the void portion of cavity
15 cannot seep between the side walls or the end walls of said
cavity and the drug substance 25. In this fashion only one surface
26 of drug substance 25 is exposed to fluid medium 51 within cavity
15.
The release of drug 25 from carrier 10 is controlled by dissolution
and diffusion processes. This includes dissolution of drug 25 into
fluid medium 51 at surface 26 thereof, and diffusion therefrom in
solution to slot 20 and thence into the surrounding medium 50. The
release rate of drug 25 through slot 20 into the surrounding medium
50 is a function not only of the solubility and diffusion
coefficient of the drug in the receiving fluid 50 but also of the
dimensions of slot 20 and of the angle between side walls 45 and 46
of cavity 15. Initially cavity 15 may be filled flush with slot 20
with a single pellet of drug substance 25. As the drug is dissolved
and diffused from the carrier, fluid 50 from the surrounding medium
diffuses into the cavity as shown by 51 in FIG. 2 to replace the
drug which has dissolved and diffused out.
FIG. 2 represents the cross-section of a carrier from which about
50 percent of the initial drug fill has been released. The arcuate
drug surface 26 shown in FIG. 2 is naturally formed as a result of
the dissolution and diffusion processes. If it is desired to
prepare a drug carrier which is only partially filled with drug
substance at the outset as shown in FIG. 2, then the surface of the
drug substance should be provided with an arcuate contour as shown
at 26 in FIG. 2.
The reason for the arcuate contour of drug surface 26 is that the
rate of diffusion of drug substance 25 through medium 51 to slot 20
is inversely proportional to the distance d separating drug surface
26 from slot 20 and directly proportional to the area A of drug
surface 26. The ratio of A to d remains constant so long as slot 20
lies along the axis of a section of a cylindrical surface 26 formed
by drug substance 25. The rate of release R of drug substance 25
from slot 20 is governed by the expression shown in Equation I.
R = DLCs/(h/a + 1/.theta.)
EQUATION I
In Equation I, .theta. is the angle (expressed in radians, 1 radian
= 57.3.degree.) between side walls 45 and 46 of cavity 15. D is the
diffusion coefficient of drug 25 in medium 50 and Cs is the
solubility thereof. The symbol a is the width of slot 20 and L is
the length of slot 20. The symbol h is the distance from slot 20 to
that closest hypothetical point in medium 50 where the
concentration of drug substance 25 is zero. As a practical matter,
for drugs with relatively low solubilities a negligible or
substantially zero concentration is reached at a relatively short
distance from slot 20. The values for D and h for a specific drug
substance may be determined by the method of Roseman and Higuchi,
J. Pharm. Sci., 59, 353 (1970). For release of the progestational
steroid medroxyprogesterone acetate to vaginal tissues, they have
calculated the values D=0.6 cm.sup.2 /day and h=0.058 cm.
The mathematical relationship of Equation I shows that since a, L,
and .theta. are fixed by the dimensions of cavity 15, then the rate
of release R depends upon D, h, and Cs, all constants for any
specific drug substance. Thus as long as drug is present and the
arcuate surface 26 thereof is exposed to medium 51, the rate of
release will be constant. The mathematical relationship of Equation
I further dictates that an increase in L will cause a proportionate
increase in the release rate R. An increase in a will cause an
increase in rate R but as a is made larger, its influence on rate
declines. The rate R can be increased by increasing .theta. but
like a and unlike L the effect is not linear. For a series of
related drug materials having similar diffusion constants D and
values h, the release rates of various members from devices having
the same dimensions are substantially proportional to their
solubilities Cs. If the values for D and h have not been previously
determined as above, a trial and error approach to construction of
the device to provide the desired release rate may be used.
It is preferred that rear wall 40 of cavity 15 have arcuate
configuration as shown in FIGS. 1 and 2 similar to that of drug
surface 26 such that rear wall 40 forms the wall of a cylinder the
axis of which lies within slot 20. In this circumstance a steady
state of release of drug substance 25 will be maintained until the
drug is entirely exhausted from the device. When rear wall 40 is
flat or has another configuration other than the arcuate form
shown, a constant rate of drug release will be maintained only
until drug surface 26 intercepts wall 40 and exposes a portion
thereof. From that time until all of the drug is exhausted, the
release rate R from slot 20 will be less than the steady state
zero-order condition. This may not pose a serious problem in some
circumstances, and accordingly, the configuration of rear wall 40
is not limited in this invention to the arcuate form shown. Only
drug surface 26 is required to be arcuate in form to provide
zero-order release after dissolution and diffusion processes under
operating conditions have reached equilibrium.
FIG. 3 illustrates another embodiment of the invention comprising
an intravaginal ring 55 having an overall outside diameter of 6 or
7 centimeters and a cross-sectional diameter of about 1 centimeter.
The ring serves as a container corresponding to 10 of FIG. 1 which
houses a cavity 60 shown by broken lines in FIG. 3 corresponding to
cavity 15 of FIG. 1. Cavity 60 communicates with liquid medium 50
on the exterior of ring 55 through a slot 65 in the side thereof.
Slot 65 in the device illustrated lies circumferentially on the
uppermost surface of ring 55. FIG. 4 is a cross-section of the
intravaginal ring shown in FIG. 3 along line 4--4. This illustrates
the configuration of the slot and cavity along the uppermost
surface of the ring in concentric position. In this instance, the
length L of slot 65 corresponds to the circumference of the slot.
In the configuration shown with the slot along the upper surface, a
steady state of release is achieved by dissolution and diffusion of
drug substance 70, shown in FIG. 4 by the hashed mark area, since
the length of exposed drug surface remains constant and equal to L.
If the slot were placed on the outer or the inner surfaces of the
intravaginal ring the exposed drug surface would decrease or
increase respectively as drug substance 70 diffused from cavity 60
resulting in a slightly decreasing or increasing rate of release. A
still further embodiment of the intravaginal ring not shown
involves a ring similar to that of FIG. 3 with multiple cavities to
provide for still higher rates of drug release, or for drugs having
very low solubilities.
Referring again to FIG. 1, drug substance 25 may be filled into
cavity 15 in the molten state and then permitted to solidify. This
is particularly suitable if the drug substance is stable at its
melting point and solidifies in a form such that the dissolution
properties are isotropic. A compressed solid may also be used as
cavity fill. Another means of using the device of the present
invention is to fill cavity 15 with a suspension of drug substance
in a thixotropic gel or liquid monomer. In the latter instance, the
monomer is caused to polymerize in place. In the former, a firm gel
forms on allowing the fill to stand in the quiescent state. So long
as the drug substance diffuses through the polymer or gel matrix
and the matrix is insoluble in the liquid medium in which the
device is immersed, a steady state of release of drug substance
through the diffusion slot will be achieved. In this instance, the
diffusion coefficient of the drug substance through the polymer or
gel matrix and the partitioning of drug between matrix and fluid is
taken into account in calculating the release rate. In some
instances, the release rate may be greater under these
circumstances than when a solid pellet 25 of drug substance is used
as illustrated in FIG. 1.
FIG. 6 is a drawing of another embodiment of the invention in which
the container 75 is in the form of a right circular cylinder which
is bisected lengthwise by a plane in which the axis of the cylinder
lies. The planar bisecting face is represented by the numeral 80.
Diffusion slot 85 lies along the axis of the bisected cylinder on
the planar face of the container. The inner side of the arcuate
cylinder wall 81 constitutes the rear wall of cavity 90 which is
the interior of the container. Rear wall 81 thus has the arcuate
concave configuration as is preferred for zero-order release during
the entire residence time of diffusible solid within the container
while it is immersed in the medium into which it is desired to
dispense the solid. End walls 82 and 83 are congruent and
positioned adjacent the ends of slot 85 and at right angles thereto
as is required. The portions of planar bisecting face 80 of
container 75 on either side of slot 85 comprise the two side walls
of cavity 90 corresponding to side walls 45 and 46 of cavity 15 of
the device pictured in FIG. 1. In this instance, the angle .theta.
between the side walls is 180.degree.. Other embodiments of the
invention may be constructed with an angle .theta. from about
30.degree. to about 270.degree.. In such instance, the cavity is
formed as in FIG. 6 in the shape of a segment of a right circular
cylinder having the diffusion slot located along the axis.
For the cylindrical device of FIG. 1, having diffusion slot 20 on
the side thereof, the angle .theta. between side walls 45 and 46 of
cavity 15 may vary from about 30.degree. to about 140.degree.. The
angle employed is selected to afford the desired release rate. The
cavity of maximum volume, and thus greatest total diffusible solid
capacity, which can be constructed within a cylindrical device of
the type shown in FIG. 1 has an angle .theta. of 1.36 radians or
78.degree.. The foregoing is determined by geometric
considerations.
Substances having a wide range of solubilities may be dispensed by
the devices of the present invention. By the use of an intravaginal
ring similar to that shown in FIG. 3, a release rate of 50 mcg./day
of a steroid or other substance having a solubility of as low as
1.7 mcg./ml. may be achieved. For an intrauterine device embodying
a container as pictured in FIG. 1, the same release rate can be
assured for substances having solubilities of up to about 570
mcg./ml. Substances having this full range of solubilities may be
dispensed with devices of the type shown in FIG. 6. Release rates
can be further manipulated by the use of wax, polymer, or gel
matrices such as petroleum wax, cholesterol, silicone rubber,
polymeric hydrophilic hydrogels, and thixotropic gels prepared from
polyethylene glycol, carboxymethylcellulose, or carboxyvinyl
polymer as the continuous phase of a suspension of crystalline
diffusible solid to be dispensed within the cavity.
DESCRIPTION OF SPECIFIC EMBODIMENTS
FIG. 5 is a collection of graphs in which the rate of release R
expressed in micrograms per day is plotted as ordinate and
solubility Cs in micrograms per milliliter is plotted as abscissa
for delivery of a drug substance from a cylindrical intrauterine
device similar to that of FIG. 1 having radius 0.12 cm and slot
length 3.2 cm. Each of the lines plotted on these coordinates is
for a different device having the values for the angle .theta. and
slot width a shown at the right hand side of the graph. The values
of Roseman and Higuchi (loc. cit.) for medroxyprogesterone acetate
of D = 0.6 cm.sup.2 /day and h = 0.058 cm were used for these
calculations. For drug substances having similar D and h values and
solubilities of the order of 100 micrograms per milliliter release
rates upwards of 100 micrograms per day may be achieved.
Medroxyprogesterone acetate has a solubility of 3.25 mcg/ml
(Roseman and Higuchi, loc. cit.) and release rates of from about
2.5 to 6 mcg/day can, therefore, be achieved with the devices
referred to in FIG. 5. Thus by reference to FIG. 5, various release
rates can be achieved for a drug of given solubility by selection
of the appropriate angle .theta. and slot width a.
Experimental:
The system was tested experimentally by measuring the amount of
stearic acid released from a device fabricated from stainless steel
and immersed in USP alcohol. The prism-shaped device was 2.5 inches
long, 1.0 inches wide at the base, and 0.63 inches high from the
base to the slot. The sides, base, and one end were made of 18
gauge stainless steel. The other end was cut from three-sixteenths
inch stainless steel and was drilled to provide a filling port
which could be closed with a stainless steel bolt. All of the
joints were silver soldered. A larger filling port was made in the
base of the prism-like device by cutting a hole of appropriate size
and soldering in place a stainless steel nut to be closed with a
stainless steel bolt. Solvent resistant gaskets were used at both
filling ports. The slot width (a) was 0.030 inches and the
effective slot length (L) was 2.263 inches. The angle .theta. was
80.degree..
For filling, the slot was covered with a sheet of polyethylene and
the device was inverted. Molten stearic acid was added through the
large port in increments. The device was rocked back and forth and
the portions allowed to solidify after each addition. The device
held approximately 9.5 g. of stearic acid. After the port was
closed, the polyethylene was carefully removed from the slot.
The release of stearic acid from the device into USP alcohol was
measured by placing the device in the bottom of a double-walled
beaker with an inside diameter of 11.0 cm. containing 1,000 ml. of
alcohol. The bolt used to close the port in the base served as a
pedestal for the device. The beaker was kept at 30.degree.C. and
its contents were stirred with a three bladed propeller (radius 2
cm., blade pitch 30.degree.) rotated at 50 rpm 2.5 cm. below the
solvent surface. The distance between the top of the device and the
propeller was 4.9 cm. A cover with a hole for the stirrer and one
for the sampling port was kept on the beaker.
Solvent samples were withdrawn periodically. Alcohol at
30.degree.C. was added to the beaker to maintain volume. The
stearic acid concentration in the samples was estimated
colorimetrically after extraction from the sample. A 10 ml. aliquot
of the ethanolic solution containing stearic acid was removed from
the beaker and placed in a separatory funnel. A 50 ml. volume of
aqueous 0.01 M pH 7.0 phosphate buffer containing 0.1 percent
methylene blue (USP grade) and 20 ml. of redistilled reagent grade
chloroform were added. When a 5 ml. sample was used, an additional
5 ml. of alcohol was added to it. The separatory funnel was shaken
and the layers were allowed to separate. A 5 ml. portion of the
chloroform layer was diluted to 100 ml. with methanol and the
density of blue color was estimated photometrically at 640 nm
against an appropriate standard. The blue color was stable after
approximately 30 minutes. The absorbance was linearly dependent on
the concentration of stearic acid in the sample. The complete data
for three trials according to this procedure are listed in Table
I.
TABLE I
__________________________________________________________________________
RELEASE OF STEARIC ACID FROM ZERO-ORDER DEVICE Trial I Trial II
Trial III Time Released Time Released Time Released
__________________________________________________________________________
16 hr. 118 mg. 2 hr. 72.6 mg. 19 hr. 263 mg. 24 hr. 236 mg. 24 hr.
378 mg. 26.5 hr. 272 mg. 41 hr. 524 mg. 31 hr. 306 mg. 43 hr. 436
mg. 48 hr. 541 mg. 48 hr. 609 mg. 51 hr. 570 mg. 64 hr. 721 mg. 55
hr. 748 mg. 67 hr. 801 mg. 67 hr. 779 mg. 72 hr. 977 mg. 75 hr. 902
mg. 72 hr. 813 mg. 79.5 hr. 947 mg. 94.5 hr. 1110 mg. 89 hr. 1000
mg. 102.8 hr. 1360 mg. 95.5 hr. 1010 mg. 91 hr. 1230 mg. 103.5 hr.
1420 mg. 114 hr. 1600 mg. 93 hr. 1070 mg. 129.5 hr. 1840 mg. 115
hr. 1600 mg. 96 hr. 1150 mg. 130.5 hr. 1810 mg. 128 hr. 1770 mg.
118.5 hr. 1310 mg. 143 hr. 2000 mg. 134 hr. 1780 mg. 119.5 hr. 1310
mg. 151 hr. 2070 mg. 151 hr. 2090 mg. 137.5 hr. 1590 mg. 167 hr.
2450 mg. 158 hr. 2130 mg. 138.5 hr. 1600 mg. 175 hr. 2360 mg. 161.5
hr. 1850 mg. 182 hr. 2440 mg. 168 hr. 1870 mg. 199 hr. 2680 mg.
184.5 hr. 2100 mg. 206 hr. 2760 mg. 192 hr. 2170 mg. 223 hr. 2990
mg. 207.5 hr. 2400 mg. 230.5 hr. 3180 mg. 216 hr. 2350 mg. 247.5
hr. 3360 mg. 232.5 hr. 2860 mg. 248.5 hr. 3120 mg. 235 hr. 2830 mg.
270 hr. 3490 mg. 240 hr. 2810 mg. 271 hr. 3440 mg. 257 hr. 2870 mg.
282.5 hr. 3500 mg. 261 hr. 3210 mg. 285.5 hr. 3640 mg. 265 hr. 3350
mg. 290 hr. 3780 mg. 285 hr. 3620 mg. 307 hr. 3930 mg. 285.5 hr.
3610 mg. 314 hr. 3860 mg. 313.8 hr. 4010 mg. 331 hr. 4090 mg. 314.8
hr. 4070 mg. 330 hr. 4240 mg.
__________________________________________________________________________
The linear regression analysis for each trial is summarized in
Table II. The coefficient of determination (r.sup.2) was 0.99 in
each case indicating that the data for the release rate are
zero-order.
TABLE II
__________________________________________________________________________
SUMMARY OF REGRESSION ANALYSIS ON EACH TRIAL AND ON COMPOSITE OF
ALL DATA Trial Trial Trial Composite I II III Data
__________________________________________________________________________
Release Rate, mg./hr. 12.73 14.24 12.89 12.72 SD (slope), mg./hr.
0.23 0.41 0.24 0.18 r.sup.2 0.990 0.990 0.991 0.985 Intercept, mg.
-12.7 -48.3 +74.2 -21.9 SD (intercept), mg. 44.5 41.3 47.2 33.1 N
32 14 30 76
__________________________________________________________________________
The following compositions illustrate cavity fill solids for use in
the present invention comprising dispersions of steroid compounds
in solid matrices of various types.
______________________________________ Composition 1. Wax Matrix
White Wax, USP 10.0 g. Megestrol Acetate, microfine 2.0 g.
______________________________________
The white wax is melted and the megestrol acetate is added with
mixing. The molten mixture is then poured into the cavity of a
device such as is illustrated in FIG. 1, and rapidly solidified by
cooling to ensure uniform drug dispersion. The amount of megestrol
acetate employed in Composition 1 may be varied, and the white wax
may be substituted by cholesterol.
______________________________________ Composition 2. Silicone
Rubber Matrix Silicone rubber elastomer 10.0 g. (viscosity
35000-70000 cps.; sp. gr. (25.degree. C) 1.13 .+-. 0.03) Megestrol
Acetate, microfine 0.1 g. Stannous octanoate catalyst 0.05 g. (tin
content .gtoreq.26%) ______________________________________
The megestrol acetate is suspended in the elastomer with thorough
mixing, several drops of stannous octanoate catalyst are added. The
mixture is promptly filled into the cavities of devices of FIG. 1
and allowed to polymerize.
The following compositions are for thixotropic gels which form
solid matrices for dispensing a diffusible solid from a device of
the present invention. These are employed while fluid to fill the
cavity of the device and then allowed to set-up to form a firm
matrix.
______________________________________ Composition 3.
Carboxypolymethylene Gel Active ingredient, microfine 2 to 10%
Sorbital solution, USP 40% Dioctyl sodium sulfosuccinate 0.02%
Carboxypolymethylene 1.2% Thiomerosol 0.004% Sodium hydroxide, q.s.
pH 6.5 Water qs 100.0 ml. Composition 4. Carboxymethylcellulose Gel
Active ingredient, microfine 2 to 10% Carboxymethylcellulose 3.5%
Glycerin 8.0% Polysorbate 80 USP 0.1% Methyl parabens 0.2% Water qs
100.0 ml. Composition 5. Polyethylene Glycol Gel Active ingredient,
microfine 2 to 10% Polyethylene glycol 4000 10% Methylcellulose
USP, 4000 cps 0.3% Water qs 100.0 ml.
______________________________________
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