U.S. patent number 3,926,188 [Application Number 05/523,720] was granted by the patent office on 1975-12-16 for laminated drug dispenser.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Richard W. Baker, Robert M. Gale.
United States Patent |
3,926,188 |
Baker , et al. |
December 16, 1975 |
Laminated drug dispenser
Abstract
A three layer laminate drug dispenser comprising a core lamina
of a crystalline drug of low water solubility dispersed
homogeneously in a polymer matrix of permeability, P, to the drug,
the lamina having a thickness, 2t, and a surface area, A,
interposed between outer laminas made of a drug release rate
controlling polymer of permeability, P', to the drug, each outer
lamina having a thickness, t',and the combined, exposed surface
area of the outer laminas being A' wherein the expression ##EQU1##
and the expression ##EQU2## k being a constant whose value is
dependent upon the geometrical shape of the dispenser.
Inventors: |
Baker; Richard W. (Bend,
OR), Gale; Robert M. (San Jose, CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
24086191 |
Appl.
No.: |
05/523,720 |
Filed: |
November 14, 1974 |
Current U.S.
Class: |
424/427; 424/486;
604/294 |
Current CPC
Class: |
A61M
31/002 (20130101); A61K 9/0004 (20130101); A61K
9/0092 (20130101); A61K 9/0051 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61M 31/00 (20060101); A61M
031/00 (); A61K 027/12 () |
Field of
Search: |
;128/156,260,268,2R,156,213 ;206/.5 ;424/19-21 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Medbery; Aldrich F.
Attorney, Agent or Firm: Ciotti; Thomas E. Sabatine; Paul L.
Mandell; Edward L.
Claims
We claim:
1. An active agent dispenser comprising a laminate of:
a. a core lamina of particles of a crystalline active agent of low
water solubility dispersed in a solid material having a
permeability, P, to the agent, the core lamina having a thickness
2t, and an exposed surface area, A, from which agent is released,
and being partially covered by;
b. at least one outer lamina made of an active agent release rate
controlling polymer having a permeability, P', to the agent, a
thickness, t', and an exposed surface area, A', from which agent is
released wherein ##EQU18## is greater than about 2 and ##EQU19## is
at least three times ##EQU20## k being a constant whose value is
dependent upon the geometrical shape of the laminate.
2. The dispenser of claim 1 wherein the agent is a drug.
3. The drug dispenser of claim 2 wherein ##EQU21## is greater than
3 and ##EQU22## is at least 10 times ##EQU23##
4. The drug dispenser of claim 2 wherein P is substantially greater
than P'.
5. The drug dispenser of claim 4 wherein P is substantially greater
than P' because of the porosity of the core lamina caused by the
quantity of drug therein.
6. The drug dispenser of claim 2 wherein the drug initially
comprises 30 to 75% by weight of the core lamina.
7. The drug dispenser of claim 2 wherein the solubility of the drug
in water is less than 4% by weight.
8. The drug dispenser of claim 2 wherein the drug is
chloramphenicol, physostigmine or hydrocortisone, and the dispenser
is sized and shaped for insertion in the cul-de-sac of a human
eye.
9. The dispenser of claim 1 wherein the dispenser is a three layer
sandwich-type laminate, said core lamina being sandwiched between a
pair of said outer lamina.
10. The dispenser of claim 9 wherein the laminate has the
geometrical shape of a thin circular disc and k is 8.
11. The dispenser of claim 9 wherein the laminate has the
geometrical shape of a thin elliptical disc and k is 4.
12. The dispenser of claim 1 wherein the dispenser is a
concentric-type laminate, said outer lamina being outerly
concentric to said core lamina and covering the axial surface of
said core lamina.
13. The dispenser of claim 12 wherein the laminate is cylindrical
in shape and k has a value of 1/8.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a laminated dispenser for dispensing
active agents by a diffusion mechanism. More specifically it
relates to dispensers comprising a three layer sandwich-type
laminate which dispense crystalline drugs of low water
solubility.
2. Description of the Prior Art
Numerous sustained release dispensers, particularly ones for
dispensing drugs, have been developed recently which comprise an
active agent which is confined within a polymer and which dispense
an agent by a diffusion mechanism in which the agent permeates
through the polymer. The aim of these devices is to dispense the
drug at a more or less constant rate for a prolonged period of time
which results in improved therapy compared to drugs delivered by
periodic ingestion of pills, injections or drops. Basically such
dispensers are of two types: monolithic and reservoir. In a
monolithic device the drug or other active agent is dispersed in a
polymer which is permeable to the drug. The time rate of release of
agent from such devices has been studied and reported..sup.1 It is
proportional to time.sup..sup.-1/2. A plot of release rate versus
time for a monolithic device gives a curve which starts at a high
rate and continuously declines. Notwithstanding this varying
release rate, monolithic devices have the commercial attractiveness
of being inexpensive to make.
In a reservoir device the active agent is confined within a
container formed of a polymer which is permeable to the agent. The
agent may be neat or combined with a solid or liquid carrier. In
copending, commonly assigned applications Ser. Nos. 42,786 and
185,208, filed June 2, 1970 and Sept. 30, 1971, respectively,
embodiments of reservoir devices in which the agent release is
substantially constant are disclosed. The two basic features of
those embodiments which permit such release are: formulating the
agent in a liquid or solid carrier whose permeability to the drug
is greater than the permeability of the polymer defining the
container to the agent; and maintaining the concentration of the
agent in the carrier at saturation for the effective dispensing
lifetime of the device. For some agents such reservoir embodiments
are the only type of diffusion device for dispensing the agent at a
practical controlled rate. Such embodiments also provide the
advantages of providing a substantially constant release of agent--
which is an important factor as regards efficacy and safety in many
therapeutic regimens. The disadvantages of reservoir devices as
compared to monolithic devices is economic-- the former being more
complex and hence more costly to make than the latter.
SUMMARY OF THE INVENTION
This invention resides in the discovery that certain active agents
(e.g. drugs) may be dispensed from a laminated dispenser comprising
an agent-containing core lamina partially covered by at least one
rate controlling outer lamina at an approximately constant rate
provided there is a particular correlation between the respective
permeabilities, thicknesses and exposed surface areas of the core
lamina and the outer lamina(s). Specifically the invention is a
drug dispenser comprising a laminate of (a) a core lamina of
particles of a crystalline drug of low water solubility dispersed
in a solid material having a permeability, P, to the drug, the core
lamina having a thickness, 2t, and an exposed surface area, A, from
which agent is released and being at least partially covered by (b)
at least one outer lamina made of a drug release rate controlling
polymer having a permeability, P', to the drug, a thickness, t',
and an exposed surface area, A', from which drug is released
wherein ##EQU3## is greater than about 2 and ##EQU4## is at least
three times ##EQU5## k being a constant whose value is dependent
upon the geometrical shape of the laminate.
Preferably ##EQU6## is greater than 3 and ##EQU7## is at least 10
times ##EQU8##
The laminated drug dispenser of this invention may be in the form
of a three layered sandwich or in the form of a concentric
laminate. This type of device combines the good drug release
kinetics of the reservoir devices with the ease and cheapness of
manufacture of monolithic devices.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings like reference numerals refer to like parts,
and:
FIG. 1 is a cross-sectional view of a drug dispenser of this
invention;
FIG. 2 is a graphical representation of the release rates of the
devices described in Example 1, infra;
FIG. 3 is a graphical representation of the release rates of the
devices described in Example 2, infra;
FIG. 4 is a graphical representation of the release rates of the
devices described in Example 3, infra; and
FIG. 5 is an elevational perspective view of another drug dispenser
of this invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 illustrates a drug dispenser, generally designated 10, of
this invention. Dispenser 10 is a three layer sandwich-type
laminate in the shape of a thin, circular disc comprising a core
lamina 11 sandwiched between two outer laminas 12,13. Core lamina
11 consists of solid particles of drug 14 dispersed within a matrix
material 15. Material 15 has a permeability, P, and core lamina 11
has a thickness, 2t. The edge 16 of core lamina 11 defines the
surface area, A, thereof which is exposed to the environment.
Outer laminas 12,13 each have a thickness, t', and a permeability,
P', to the drug. Surfaces 17,18 of laminas 12,13 define a combined
surface area, A', thereof which is exposed to the environment. (The
area defined by the axial edges of laminas 12,13 is also exposed
but is negligible relative to area A'.)
Dispenser 10 releases drug 14 at surfaces 16,17 and 18 by a
diffusion mechanism. Drug molecules initially dissolve in matrix
material 15 and permeate therethrough either to exposed surface 16
or to outer laminas 12,13 and therethrough to exposed surfaces
17,18. The molecules which reach exposed surfaces 16,17,18 are
removed or cleared therefrom through contact with body fluids
and/or body tissue. When the respective permeabilities and
thicknesses of core lamina 11 and outer laminas 12,13 are
correlated as set forth above, that is ##EQU9## is greater than
about 2, drug will be released from surfaces 17,18 at a
substantially constant rate as long as matrix material 15 is
saturated with the drug. In contrast, drug is released from edge 16
at a constantly declining rate proportional to
time.sup..sup.-1/2.
However, by correlating the permeabilities, thicknesses and exposed
surface areas of core lamina 11 and outer laminas 12,13 as set
forth above, the amount of drug released from edge 16 is
substantially less than the amount of drug released from surfaces
17,18. Accordingly, the overall release rate from dispenser 10 is
dominated by the release rate of drug from surfaces 17,18 and thus
the overall release rate approximates the substantially constant
release rate from those surfaces. In this respect, the greater the
magnitude of ##EQU10## and the greater the difference between the
magnitude of the expression ##EQU11## and the magnitude of the
expression ##EQU12## the closer is this approximation. If ##EQU13##
is less than 2, the outer membranes do not control the drug release
rate which declines proportional to time.sup..sup.-1/2. If
##EQU14## the area of exposed core is too high or the permeability
of the core is too high and release of drug from the edge
predominates and again the release rate declines proportional to
time.sup..sup.-1/2. In the intermediate region, however, which is
the subject of this invention, neither of these effects
predominates and drug release is almost constant with time. The
release rates of these laminates are, of course, not as constant as
the release rates of comparable prior art reservoir devices in
which the core is not exposed to the environment. However, for many
therapies the degree of release rate constancy afforded by these
laminates is acceptable. Thus they provide a viable, less expensive
alternative to the reservoir devices in such instances.
FIG. 5 illustrates another drug dispenser, generally designated 19,
of the invention. Dispenser 19 is a concentric-type laminate in the
shape of a cylinder comprising a cylindrical core lamina 20 and an
outer concentric lamina 21 which covers the axial surface of core
lamina 20. Core lamina 20, like core lamina 11, comprises particles
of drug 14 dispensed within a matrix material 15. It is
functionally equivalent to core lamina 11. The ends 22,23 of core
lamina 20 define the surface area, A, thereof which is exposed to
the environment. Core lamina 20 has a diameter, 2t. Outer
concentric lamina 21 has a permeability, P', to the drug and has a
thickness, t'. Lamina 21 is functionally identical to laminas 12,13
and may be made from the same materials as the latter. The axial
surface 24 of lamina 21 defines the surface area, A', thereof which
is exposed to the environment. (The area defined by the radial
edges of lamina 21 is also exposed but is negligible relative to
area A'.)
Dispenser 19 releases drug 14 at surfaces 22,23,24 by a diffusion
mechanism identical to that described above with respect to
dispenser 10. The correlations between the thicknesses,
permeabilities and exposed surface areas of laminas 20,21 of
dispenser 19 required to permit dispenser 19 to release drug at a
substantially constant rate are the same as those described above
with respect to dispenser 10.
Drug 14 is solid (crystalline) and should have a low water
solubility. Low water solubility is a requirement so that the drug
does not function to any significant extent as an osmotic
attractant to imbibe water from the use environment into core
lamina 11. If substantial water is imbibed, the drug 14 may be
released by an osmotic bursting mechanism rather than a diffusion
mechanism. This would affect the release rate of drug in an
undesirable manner. The degree of water solubility will in many
instances depend on the permeability of matrix material 15 to
water. If material 15 has a high permeability to water, the water
solubility of the drug should be correspondingly low and vice
versa. Drugs which are less than about 4% by weight soluble in
water are preferred.
The particle size of drug 14 is not critical. Particle sizes in the
range of 1 to 20.mu. will normally be used since they are easy to
handle and may be readily dispersed homogeneously in matrix
material 15 by conventional techniques.
The loading of drug 14 in core lamina 11 is important because it
may affect the permeability of core lamina 11 to the drug. At high
drug loadings (greater than about 25% by weight) lamina 11 has a
tendency to become microporous over the device's lifetime. This
occurs because as drug particles 14 dissolve in matrix 15 and
diffuse therefrom, voids are left in the matrix. At such high drug
loadings, the void volume is sufficient to make the portion of
lamina 11 which has been depleted of drug microporous. Such
microporosity will cause the permeability of core lamina 11 to
increase. Indeed, high drug loadings provide a means for making the
permeability of the core lamina 11 substantially greater than the
permeability of the outer laminas even though the same polymer is
used in both. The drug loading of lamina 11 will depend upon the
drug dosage regimen desired, with higher loadings providing greater
dosages and/or more sustained release. Usually the loading will be
in the range of 30 to 75% by weight of the core lamina.
The nature of the drug will depend upon the therapy for which the
device is intended. Drugs which produce a localized effect at the
administration site or a systemic effect at a site remote from the
administration site may be used. 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,
anti-parasitic agents, hypoglycemic drugs and ophthalmic drugs.
Matrix material 15 may be made from a polymeric material which is
homogeneous and substantially imperforate (i.e., it has no man-made
perforations) or it may be made from a polymer which has been made
microporous by conventional techniques. In either instance its
permeability to the drug should be known. (Known techniques are
available to determine the permeabilities of such materials. See
for instance U.S. Pat. No. 3,710,795.) Examples of substantially
imperforate polymers which may be used are 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, vinlyidene chloride-acrylonitrile copolymer, vinyl
chloride-diethyl fumerate copolymer, silicone rubbers, especially
the medical grade poly(dimethylsiloxanes), ethylene-propylene
rubber, silicone-carbonate copolymers and vinylidene chloridevinyl
chloride copolymer.
Microporous materials have pores which range in size from at least
about 10 A 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 diethylaminoacetate, 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), and In:
"Synthetic Polymer Membranes," by R. E. Kesting, McGraw-Hill,
1971.
Outer laminas 12,13 may be made from the same polymers as matrix
material 15, provided, of course, that the permeability of the
material 15 to the drug is greater than the permeability of the
material forming laminas, 12,13. It will be appreciated that either
of outer laminas 12,13 may be made from a drug-impermeable
material. In such an instance, the effective thickness (the maximum
thickness through which the drug must permeate to reach a permeable
outer lamina) of core lamina 11 will be twice that of an embodiment
in which both laminas 12,13 are drug permeable and the exposed
outer lamina surface area from which drug is released will be half
that of an embodiment in which both laminas 12,13 are drug
permeable. It is also within the scope of this invention to make
laminas 12,13 from different polymeric materials of different drug
permeability and to make them of different thicknesses.
The shape and size of the dispenser of this invention will depend
upon the environment in which it is intended to be used. If the
dispenser is intended to be implanted or inserted, its size and
shape will be compatible with the size and shape of the
implantation or insertion site. For instance, if it is intended to
be used as an ocular insert, it will be sized and shaped for
insertion and retention in the eye. Likewise, if intended for
insertion in other body cavities, such as the vagina, uterus, mouth
and gastrointestinal tract, it will be sized and shaped
accordingly. In most instances it will be acceptable to employ
regular shapes. As indicated above, the value of k in the
expression ##EQU15## will depend on the geometrical shape of the
dispenser. For three-layered sandwich elliptical shaped dispensers
such as dispenser 10, k has a value of 4. Its value for other
sandwich-type dispensers of regular geometrical shape may be
calculated, (e.g., for a circle it is 8). For cylindrical
concentric laminate dispensers such as are listed above as useful
for dispenser 19, k has a value of 1/8. The value of k for other
concentric laminates of other cross-sectional shapes (e.g.,
hexagonal, square, elliptical) may be calculated.
The sandwich-type laminates of this invention may be manufactured
according to well-known techniques. Depending upon the particular
polymers comprising the core lamina and outer laminas, the laminate
may be bonded together with or without binders. Various binders are
well known in the art. See for instance the Encyclopedia of Polymer
Science and Technology, John Wiley & Sons, Vol. 8, 1968. If a
binder is used, it, of course, should be compatible with the
polymers constituting the laminas and should not affect or
interfere with the drug permeation through the laminas or alter the
drug deleteriously in any manner. Conventional laminating machines
and techniques may be used, with the particular temperatures and
pressures employed varying with the polymers involved. The
laminates may be formed as continuous sheets and the dispensers of
this invention cut or punched therefrom by known techniques. The
concentric-type laminates of the invention may also be formed by
well-known techniques such as coextrusion.
While the dispensers have hereinabove been described as dispensers
for releasing drugs for human or animal therapy, it will also be
appreciated that they may be used to release other active agents in
other environments, provided such agents are solid and have low
water solubility as described above. Such active agents include,
for example, pesticides, herbicides, germicides, biocides,
algicides, rodenticides, fungicides, insecticides, anti-oxidants,
plant growth promoters and inhibitors, preservatives, surfactants,
disinfectants, catalysts, fermentation agents, nutrients, plant
minerals, sex sterilants, plant hormones, air purifiers,
microorganism attenuators and the like.
EXAMPLES
The following examples illustrate the dispensers of this invention
and their performance relative to dispensers outside the scope of
the invention as defined herein, and are not intended to limit the
scope of the invention in any manner.
Example 1
A. A physostigmine (Eserine) dispenser, such as might be inserted
in the eye to dispense Eserine thereto, was made as follows. Fifty
parts Eserine (particle size approximately 5 microns), and 50 parts
of ethylene/vinyl acetate copolymer (brand name, Elvax 40) were
mixed homogeneously on a rubber mill. The resulting mixture was
melt pressed into a 200 micron thick film. This film was then
placed in a vacuum/heat laminator and a 150 micron thick sheet of
ethylene/vinyl acetate copolymer (brand name, Elvax 40) was
laminated to each side of it. Duplicate 5.8 mm .times. 13.5 mm
ellipses were punched from the resulting three layer laminate. P,
P', A and A', for these elliptical dispensers were determined and
the values for the expressions ##EQU16## were calculated therefrom
and are reported in Table 1 below.
B. Duplicate Eserine dispensers were made in accordance with part A
above except that the outer laminas were each 75 microns thick. The
data for these dispensers are also reported in Table 1 below.
C. For comparison, duplicate Eserine dispensers were made in
accordance with part A above except that the outer laminas were
each 13 microns thick. The data for these dispensers are also
reported in Table 1 below.
Table 1
__________________________________________________________________________
P P' A A' P t' A' .sup.. k .sup.2 (cm.sup.2) (cm.sup.2) t P' A
__________________________________________________________________________
1 A 230 70 0.0650 1.23 4.93 1,430 1 B 230 70 0.0650 1.23 2.46 1,430
1 C 230 70 0.0650 1.23 0.43 1,430
__________________________________________________________________________
The release rates of the dispensers of A, B and C were determined
by placing individual devices in polymer mesh bags and suspending
the bags from a vertically reciprocating bar into vessels
containing 50 ml water stirred at 37.degree.C. The Eserine
concentration in the water was measured at regular intervals by UV
analysis, the water being changed after each measurement. Eserine
release rates were calculated from the measurements. FIG. 2 is a
plot of these release rates versus time. As indicated by the plots
of FIG. 2, the release rate of the dispensers of B is substantially
more constant than that of the dispensers of C and that of A is
even more constant than B. This is a reflection of the increasing
value of the expression ##EQU17## as reported in Table 1.
Example 2
Two sets of chloramphenicol dispensers were made by the general
procedure of Example 1A. The core lamina was made from 66 parts
chloramphenicol (particle size approximately 5 microns) and 34
parts copolymer and was 125 microns thick. The outer laminas were
50 microns thick and 17.5 microns thick, respectively. The data for
these two sets, designated 2A and 2B, are reported in Table 2
below.
Table 2 ______________________________________ P P' A A' P t' A'
.sup.. k .sup.2 (cm.sup.2) (cm.sup.2) t P' A
______________________________________ 2A 90 16 0.1 1.23 4.5 605 2B
90 16 0.1 1.23 1.6 605 ______________________________________
The release rates of dispensers 2A and 2B were determined by the
procedure described in Example 1. FIG. 3 is a plot of these release
rates versus time.
Example 3
Two sets of hydrocortisone dispensers were prepared by the general
procedure of Example 1A. The core lamina was made from 60 parts
hydrocortisone (particle size approximately 2 microns) and 40 parts
polymer and was 150 microns thick. The outer laminas were 50
microns thick and 17.5 microns thick, respectively. The data for
these two sets, designated 3A and 3B, are reported in Table 3
below.
Table 3 ______________________________________ P P' A A' P t' A'
.sup.. k .sup.2 (cm.sup.2) (cm.sup.2) t P' A
______________________________________ 3A 72 1.9 0.1 1.23 25.3 605
3B 72 1.9 0.1 1.23 8.8 605
______________________________________
The release rates of dispensers 3A and 3B were determined by the
procedure described in Example 1. FIG. 4 is a plot of these release
rates versus time.
Modifications of the dispensers described herein which are obvious
to persons of skill in the art are intended to be within the scope
of the following claims.
* * * * *