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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a new and useful drug delivery device.
Specifically, the invention concerns a drug delivery device for
administering a drug to achieve a local or systemic physiological or
pharmacological effect wherein the device comprises a plurality of
projections for penetrating the stratum corneum of the epidermis, and a
reservoir containing a drug in immediate proximity with the projections
for supplying a drug for percutaneous administration through the stratum
corneum penetrated by the projections.
2. Description of the Prior Art
A long felt need existed in the medical art, prior to this invention, for a
drug delivery device for use in the percutaneous administration of a drug.
This need existed because the art lacked a device for percutaneously
administering a drug at a programmed rate of drug administration to
achieve a particular drug level in the circulatory system for a
preselected period of time, and also because the art lacked a device for
percutaneously administering a drug that essentially overcame the skin'
natural barrier to penetration by bacterial, chemical or other external
substances. The skin'S barrier to penetration stems from both its
morphological and marcomolecular organization
Morphologically, the composite epithelial layer of the skin, also called
epidermis, is the part of the skin endowed with the barrier against
penetration, and it consists of four layers. These layers are an outermost
layer called stratum corneum and three underlying layers called stratum
granulosum, stratum malpighii and stratum germinativum. The stratum
corneum is a heterogenous layer of flattened, relatively dry, keratinised
cells with a dense underlying layer commonly called the horny layer. In
the past, it was generally held that this horny layer acted as the barrier
to the penetration of external substances into the body. J. Invest.
Dermat., Vol 50, pages 19 to 26, 1968. Now, it is generally held that the
whole stratum corneum and not a discrete cellular layer functions as a
barrier to the penetration of substances into the body. The whole stratum
corneum is held to be a barrier because of a chemical keratin-phospholipid
complex that exists in the stratum corneum and acts along with the horny
layer as a barrier to the penetration of substances into the body. For
this invention, the whole stratum corneum is considered as the natural
barrier to penetration. J. Invest. Dermat., Vol 50, pages 371 to 379,
1968; and, ibid, Vol 56, pages 72 to 78, 1971.
The stratum corneum, which is about 15 microns thick when dry and about 48
microns thick when fully hydrated, acts as a barrier for an extremely
large variety of compounds. The barrier holds for compounds with large
molecular volumes, for compounds substituted with functional groups, for
small soluble molecules, for non-electroytes, and the like. J. Invest.
Dermat., Vol 52, pages 63 to 70, 1969. Once a compound is made to pass
through the stratum corneum, for example, by surgically stripping the
stratum corneum, there is no major hindrance to penetration of the
remaining epidermal layers or the dermis. After this, the compound enters
into the circulation via the capillaries. Progress in the Biological
Sciences in Relation to Dermatology, 2nd Ed., pages 245, 1964, Univ.
Press, Cambridge; and, J. of Drug and Cosmetic Ind., Vol 108, No. 2, pages
36 to 39 and 152 to 154, 1971.
In view of the above presentation, once a drug has penetrated through the
stratum corneum, with the aid of the drug delivery device of the
invention, penetration through the remaining layers of the skin proceeds
readily. Absorption of a drug into the stratum corneum with no further
penetration is considered retention and not percutaneous penetration. The
passage of the drug into local or systemic circulation is considered as a
further or continuing result of percutaneous penetration of drug
administered according to this invention. As used herein, the term
"percutaneous" means penetration through the skin to the local or systemic
circulatory system by puncturing, scraping, or cutting the stratum corneum
but not puncturing, scraping, or cutting to a substantial extent, the
interior layers of the skin.
Those skilled in the art will appreciate that drug retention, as discussed
above, is usually achieved by using devices known as scarifiers or
vaccinating instruments. These instruments and their results are
significantly different from the drug delivery device of this invention
and its results. For example, scarifiers and like instruments usually
scarify, that is, they scratch or make small cuts or an area for
vaccination as reported in Webster's Seventh New Collegiate Dictionary,
1969, page 769; and, Stedman's Medical Dictionary, 1966, page 1728. These
instruments are used by the medical art for a single, quick, application
of a massive dose of vaccine and they are not used by the medical arts as
a drug delivery device for the controlled and prolonged administration of
effective amounts of a drug for local therapy or systemic therapy.
Representative of prior art sacrifiers and vaccinating instruments are
U.S. Pat. No. 2,947,787 which discloses a bubble containing a biological
fluid and an injector with prongs of 1 to 10 millimeters in length for
rupturing the bubble and for applying a single, topical application of the
fluid; U.S. Pat. No. 2,893,392, disclosing an envelope containing a
biological liquid and an injector with prongs of 1 to 5 millimeters for
penetrating the envelope, scarifying the skin and applying a single dose
of vaccine thereto; U.S. Pat. No. Re. 25,637 illustrating a capsule and a
serrated scarifier for dispensing a vaccine and scratching the skin with
the same instrumentality; and U.S. Pat. Nos. 3,123,212; 2,522,306;
3,351,059, and the like that disclose scarifiers with prongs of at least
150 microns in length for making superficial incision in the skin for
applying a vaccine thereto. Thus, as taught by the prior art, these
instruments have a single, immediate use while the drug delivery device of
this invention can be designed for the continual, prolonged, controlled
release of a drug to produce a local or systemic effect. Also, the
projections of the drug delivery device of this invention are designed to
penetrate the stratum corneum for the administration of a drug without
contacting the body nerves for achieving an essentially painless drug
administration.
Objects of the Invention
Accordingly, in view of the above presentation, it becomes an immediate
object of this invention to make available to the art a novel and useful
device for penetrating the stratum corneum for administering a drug
through the stratum corneum.
Another object of the invention is to provide a drug delivery device having
a means for perforating the stratum corneum for administering a drug
percutaneously from a drug reservoir embodied within the drug delivery
device.
Still yet another object of the invention is to provide a drug delivery
device having hollow skin puncturing projections with an aperture for
percutaneously administering a drug through the hollow members from a drug
source.
Yet still another object of the invention is to provide a drug delivery
device comprising stratum corneum puncturing projections for
percutaneously administering a drug from a drug source by diffusing a drug
from the source and through the puncturing projections.
Another object of the present invention is to provide a novel article of
manufacture for penetrating mammalian skin for enhancing drug
administration therethrough to achieve local therapy or systemic therapy.
Another object of the invention is to provide a drug delivery device
comprising projections for penetrating the stratum corneum, a reservoir
containing a drug and a membrane interposed between the projections and
the reservoir for the program release of a drug from the reservoir to the
projections.
Another object of this invention is to provide a drug delivery device for
the continuous administration of controlled amounts of drugs through the
stratum corneum for prolonged periods of time to achieve local therapy or
systemic therapy.
Yet still another object of the present invention is to provide a low cost
drug delivery device for use in the percutaneous administration of a drug.
These objects, as well as other objects, features and advantages will
become more readily apparent from the following detailed description, the
drawings, and the accompanying claims.
SUMMARY OF THE INVENTION
This invention concerns a drug delivery device for use in the percutaneous
administration of a drug for local therapy or systemic therapy. The device
generally comprises a reservoir containing a drug, and a multiplicity of
puncturing projections extending from at least a part of the reservoir's
surface and wherein the projections are adapted for perforating the
stratum corneum of the skin to enhance percutaneous drug administration.
In the drug delivery device of the invention, the projections and the
reservoir can be constructed as a unit piece or the projections and the
reservoir can be fabricated from parts into the drug delivery device.
BRIEF DESCRIPTION OF THE DRAWINGS
In the accompanying drawings, which are not drawn to scale but rather to
emphasize the puncturing projections:
FIG. 1 is a schematic cross-sectional view illustrating a drug delivery
device of unit construction made according to the invention.
FIG. 2 is a bottom elevational fragmentary view depicting a drug delivery
device with a plurality of hollow apertured pointed projections extending
from a drug source.
FIG. 3 is another schematic cross-sectional enlarged view illustrating
another embodiment of the drug delivery device made with a backing member.
FIG. 4 shows a side view of an embodiment of a drug delivery device of a
plurality of projections fixedly mounted onto a drug reservoir.
FIG. 5 illustrates a drug delivery device of a plurality of projections and
a reservoir with a membrane, for controlling the rate of release from the
reservoir, interposed between the projections and the reservoir.
FIG. 6 is a schematic cross-sectional view illustrating another embodiment
of the drug delivery device with the puncturing projections and reservoir
integral with a supporting member for holding the device on the skin.
FIG. 7 is a diagrammatic illustration of one embodiment of the drug
delivery device placed on the skin with the projections penetrating the
stratum corneum for percutaneously administering a drug.
In the drawings and the specification, like parts in related figures are
identified by like number. The terms appearing earlier in the
specification and in the description of the drawings, as well as
embodiments thereof, are further described elsewhere in the disclosure.
DETAILED DESCRIPTION OF THE DRAWINGS
Turning now to the drawings in detail, one embodiment of the new drug
delivery device is generally indicated in FIG. 1 by the number 10. Device
10 is a single piece device comprising a plurality of projections 12
extending outwardly from one surface 14 of a drug reservoir 16 and it is
made from a polymer material or the like. Projections 12 are fabricated in
this embodiment in a needle-like design, that is, hollow or with a
passageway for a drug 20 and with the free end of the projections having a
wall defining an opening or aperture 18 of a preselected size and shape.
The projection's end extending from the drug reservoir also has an opening
11 for the passage of the drug 20. Reservoir 16 contains the drug or a
solution of drug 20 in communication with the passageway within each
projection 12. Projections 12 are adapted to puncture and penetrate the
stratum corneum of the epidermis and to administer drug 20 from the drug
reservoir 16 into the body by percutaneous absorption. In operation, when
device 10 is applied to the stratum corneum, projections 12 penetrate the
stratum corneum for the passage of a drug 20 from the reservoir 16 through
the passageway in projections 12 and through apertures 18 where drug 20 is
administered beneath the stratum corneum.
FIG. 2 illustrates another drug delivery device of the invention. In FIG.
2, a drug delivery device 10 is shown formed of two separate parts that
when suitably joined together act in concert to function as a single piece
drug delivery device. One part of this two part drug delivery device 10 is
comprised of a plurality of puncturing projections 12 constructed from a
thin metal, alloy or polymer base 24 with the projections extended
outwardly from the exposed surface of base 24. Projections 12 usually are
round and formed with a passageway and a sharp opening 28 at their free
end. The end of projections 12 at base 24 also are made with an opening 11
for permitting a drug 20 to pass from drug reservoir 16 into passageway of
projections 12. The other part of the two part drug delivery device 10 is
drug reservoir 16 positioned and over-layed on base 24. Drug reservoir 16
generally is made from a moldable polymer in the form of a hollow
container, a solid, or the like and it is held on base 24 by molding the
reservoir on the base or it is held on the base by an adhesive layer
interposed on the peripheries between the base and reservoir. Drug
reservoir 16 wall 13 over-layed on base 24 is optionally formed with
openings (not shown) in axial alignment with openings 11 of projections
12, or alternatively wall 13, as shown, is made of a material permeable to
drug 20, as by diffusion, to release drug from the reservoir to the
projections at a predetermined, controlled rate. Thus, drug 20 contained
in drug reservoir 16 can be in communication with the passageway of
projections 12 through openings in wall 13 or through a barrier of a drug
release rate controlling material.
FIG. 3 illustrates another drug delivery device of the invention. In FIG.
3, a drug delivery device 10 is shown comprising a drug reservoir 16
containing a drug 20, a base 24 positioned on one face surface of the
reservoir and consisting of a plurality of puncturing projections 12 that
extend outwardly from the exposed surface of base 24, and a backing member
30 positioned on the face surface of the reservoir distant from base 24.
Backing member 30 also can be placed on the side walls of reservoir 16,
which is advantageous if the walls are permeable to drug 20, as this
prevents drug loss from reservoir 16. In this embodiment, reservoir 16 is
illustrated as being a matrix having drug 20 distributed therethrough and
being permeable to passage of the drug by diffusion. Base 24 and
projections 12 are made of a drug release rate controlling material,
permeable to passage of the drug 20, and act to regulate the rate of
passage of drug 20 diffusing from reservoir 16 to projections 12. Drug
entering projections 12 diffuses through their length. Thus, the drug
delivery device of this embodiment functions through the drug release rate
controlling base to percutaneously administer drug 20 at a precisely
controlled rate to the puncturing projections for administration through
the stratum corneum.
Turning now to FIG. 4 there is illustrated another embodiment for
administering drug through the stratum corneum. As seen in FIG 4, a drug
delivery device 10 is comprised of a drug reservoir 16 that contains a
drug, a solution of drug, or a solid pharmaceutical composition containing
a drug 20, and a backing member 30 on one face surface of drug reservoir
16. While this embodiment illustrates a device with a backing member, it
is to be understood that the backing member is optional for this and other
embodiments of the device. Reservoir 16 wall distant from backing member
30 is made of a drug release rate controlling material, permeable to drug
as by diffusion, to control the flow of drug from reservoir 16. This wall
bears thereon an adhesive layer 31 for maintaining a multiplicity of
puncturing projections 12 that act as a means for effecting passage of
drug from reservoir 16 through the stratum corneum. Projections 12 are
formed from a single piece of material adapted to overlie an area of skin
and they are sufficiently sharp for puncturing the stratum corneum of the
skin. The projections can be hollow or solid and in this embodiment they
are illustrated as solid projections, impermeable to passage of drug 20.
Projections 12 can be made to touch each other at their origin (not shown)
or they can be formed with an aperture 32 spaced between each projection
for enhancing the movement of drug 20 released from reservoir 16 about the
outer surface of projections 12. In this device, a drug is administered at
a controlled rate of release from reservoir 16 through its drug release
rate controlling wall, to flow through apertures 32 and then along the
outer surface of projections 12 and through the stratum corneum to achieve
local or systemic therapy.
FIG. 5 illustrates another drug delivery embodiment of the invention. In
this embodiment, a drug delivery device 10 is comprised of a drug
reservoir 16 that contains a drug 20 and has a wall 39 optionally formed
with (1) an aperture (not shown) or mulitplicity of apertures of varying
dimensions defining a passageway or passageways through wall 39 to permit
drug to flow therethrough, or (2) formed of a drug release rate
controlling material, as shown, permeable to passage of drug as by
diffusion to meter the flow of drug from the reservoir. A membrane 34,
also formed of a drug release rate controlling material, is carried by
wall 39. The purpose of membrane 34 is two fold; first to meter drug
release from reservoir 16 when wall 39 is formed with apertures, and
secondly, to cooperate with wall 39 when it is formed of a material
permeable to drug for achieving a precise control of drug release from
reservoir 16. A base member 24 consisting of a multiplicity of puncturing
projections 12 is carried on the surface of membrane 34 distant from wall
39. Base member 24 and puncturing projections 12 can be made from a
material permeable to the passage of drug 20, as shown, with the
projections extending from the base. Alternatively, the projections can be
hollow and formed with a wall or walls of a material that is permeable to
the passage of drug and whose wall or walls define an internally disposed
space within the projections, that is empty, or filled with a liquid such
as water, a hydrogel or the like. Base member 24 and puncturing
projections 12 can also be formed from a single piece of stainless steel,
vitallium, or a polymer with the projections fabricated as round, hollow
needles with openings at both ends, usually with the opening distal from
the base beveled for facilitating essentially painless penetration through
the stratum corneum for administering a drug released by membrane 34
through the stratum corneum. An optional, pressure sensitive adhesive
layer 31 usually is charged on the outer periphery of membrane 34 and it
is provided for positioning the device on the skin during administration
and to give a releasable grip between the device and the skin. The device
also can have a backing member 30 that is adapted for over-lay on the
surface of the reservoir distant from projections 12. The backing member
can also be placed on the remaining free surfaces of reservoir 16 and its
purpose is to prevent unwanted passage of the drug through the surfaces of
the reservoir, especially when the reservoir is made from a material
permeable to drug. An auxillary purpose of the backing member is to
provide support for the device.
In FIG. 6, there is illustrated another embodiment of the invention. In
FIG. 6, a drug delivery device 10 is comprised of a drug reservoir 16
containing one or more drugs 20 and bearing on one of its surfaces a
backing member 30. The surface of reservoir 16 distant from backing member
30 is formed of a drug release rate controlling material and bears thereon
a thin layer of an adhesive 31 that serves three purposes: first, it
positions a plurality of stratum corneum puncturing projections 12 with
openings 18 on the reservoir; second, it provides a means for releasably
affixing the device to the skin; and third, it holds a bandage cover 33 on
the device for maintaining the integrity of the device when it is not in
use. In use, the bandage cover is stripped from the device before the
device is applied to the skin.
The accompanying drawing, FIG. 7, is presented to further facilitate an
understanding of the invention. In FIG. 7, a drug delivery device 10,
generally fabricated according to the description presented in describing
FIGS. 1 to 6 inclusive, is comprised of backing member 30, a drug
reservoir 16 containing a drug 20 and puncturing projections 12 containing
drug 20, is shown in a drug administration position. The drug delivery
device is illustrated with its puncturing projections 12 piercing the
natural, outer layer of the epidermis, the stratum corneum 35. As
mentioned above, the major barrier properties of the skin, such as
resistance to penetration, reside with the stratum corneum. The inner
division of the epidermis generally comprises three layers commonly
identified as stratum granulosum 36, stratum malpighii 37 and stratum
germinativum 38. Once the drug is administered beneath the stratum
corneum, there is essentially little or no resistance to penetration or to
absorption through the stratum granulosum, stratum malpighii and stratum
germinativum for absorption and circulation of drug into the body.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with this invention, a multiplicity of projections 12 for
puncturing the stratum corneum are present on one face surface of the drug
delivery device in any predetermined arrangement, for example, as a
cluster of projections spaced in rows having any desired number, or in any
spaced apart relation of one projection to each other. As used herein, the
term "puncturing projections" includes any projections adapted to
puncture, penetrate, scrape or cut the stratum corneum. The projections
can be of any geometric shape and diameter that lends itself to be made
into projections, such as needles, spikes, tines, pointed triangles,
pointed cones, pyramidal points, hollow or solid, with or without an
opening at one or at both ends thereof, and the like. The projections are
usually at any angle that corresponds to the angle of the body skin.
Generally, the projections are at an angle of approximately 90.degree. to
the surface of the reservoir, but they can be disposed at any angle that
will facilitate penetration of the stratum corneum. The projections can
exist, as mentioned above, in any pattern and they are usually about 0.5
mm to 5 mm apart. The projections are fabricated with a width or diameter
that facilitates penetration of the stratum corneum for achieving
administration of a drug. The upper limit is governed by the width or
diameter which can conveniently penetrate the stratum corneum and the
lower limit is governed by limitations on manufacturing projections of
extremely fine diameter for penetrating the stratum corneum. Generally,
the dimensions of the projections will correspond to the standard medical
gauge needle dimensions, such as 15 gauge through 40 gauge and the like.
The projections can also have the dimensions that correspond to other
standard gauge needles, such as standard insulin needles, immunization
needles, and the like. The height of the projections is subject to
variation that corresponds to the natural thickness of the stratum
corneum, for one of the principal features of the invention is that the
projections are to penetrate the stratum corneum without penetrating
interior layers of the skin and without contacting the nerves of the skin.
Usually, the projections will be about 5 microns to about 100 microns in
length, with the length for most applications being about 10 to 20
microns, 20 to 40 microns, or about 30 to 50 microns, generally 20
microns.
Puncturing projections 12 can be fabricated as hollow projections with
openings at both ends to function as a conduit for the flow of drug from
the reservoir through the stratum corneum. When the projections are hollow
with openings at their ends, it is advantageous to block the free ends of
the projections prior to use (as by cover 33 in FIG. 6) to prevent
premature drug release. In addition, the projections can be hollow but
with no openings at their distal ends. In this case, they are formed of a
material permeable to passage of the drug at a controlled rate so that
drug entering the projections from the reservoir is administered through
the stratum corneum by passage through the walls of the projections. Such
projections can be filled with a liquid, hydrogel, sol, gel or the like
for transporting a drug through the projections and through the stratum
corneum. The projections can also be formed of a solid material permeable
to passage of the drug, in which projections the drug is carried from the
reservoir through the stratum corneum by diffusion of the drug through the
projections at a programmed rate of drug administration. When it is
desired to form the projections of a soft drug release rate controlling
material, the projections can be reinforeced with wires or needles to
facilitate puncturing of the stratum corneum. Also, whether the
projections are hollow or solid, drug released from the reservoir at a
programmed rate can be carried through the stratum corneum by flowing
along the exterior surface of the projections.
The puncturing projections 12 and base 24, as described above, can be made
from a wide variety of materials. One class of suitable materials is
polymers and the polymeric derivatives thereof. The polymers acceptable
for forming puncturing projections of solid design (which carry drug along
their exterior surface) or projections made with a passageway and openings
at both ends are materials characterized by properties such as a high
degree of impact strength, good hardness, resistance to deformation, good
tensile strength, does not adversely effect the drug or the host, and
readily lend themselves to forming puncturing projections for penetrating
or piercing the stratum corneum. Examples of materials include,
acrylonitrile-styrene copolymers; acetal homopolymers and copolymers;
acrylics; methyl methacrylics; phenolics; melamine fomaldehyde resins;
poly(ethylene terephthalate); acrylonitrile and methacrylonitrile polymers
and copolymers thereof; cross-linked alkyl and aryl silicone polymers;
polycarbonates; halogenated vinyl chloride polymers and copolymers;
phenylene oxide condensation polymer; poly(sulfone) resins; aliphatic and
aromatic polyamides and polyimides; and the like. Puncturing projections
12 and base 24 of this design can also be made from other materials such
as metals and alloys. Examples of metals and alloys include stainless
steel; tungsten steel; manganese steel; tantalum; titanium alloys
consisting of nickel, molybdenum and chromium; vitallium alloys consisting
of cobalt, chromium and molybdenum; and the like.
The puncturing projections 12 and drug reservoir 16 of drug delivery device
10 that comprise a single piece drug delivery device are formed by art
known methods for processing plastics, such as injection molding,
compression and transfer molding, and the like. In one embodiment the
device is made by first mixing plastic pellets or powders and a drug and
then feeding the mixture into a heated barrel of a molding machine. Next,
after the plastic drug mixture softens, it is conveyed by the thrust of a
ram into a template comprising a mold of predetermined design of
projections and reservoir where the plastic drug mixture cools and forms
to give drug delivery device. The puncturing projections 12 and base 24 of
a two part device are made by standard manufacturing techniques, before
they are joined to a reservoir. The projections and base are made, for
example, from a polymeric material that can be processed by molding,
thermoforming, deep drawing, injection, extrusion coating, laminating, and
like techniques. In forming the puncturing projections by these
techniques, for example, in the thermoforming process a sheet of plastic
is softened by heat until pliable and then forced by air pressure against
a cold mold surface where the plastic sheet cools and retains the
projection shape of the mold. In the deep drawing technique, a sheet of
polymer is warmed sufficiently to be readily deformable and a plurality of
vacuum retaining cups are used to draw therein the polymer to form the
puncturing projection means. The just described techniques manufacture
puncturing projections that are hollow to permit a drug from the reservoir
to enter into the projections to travel and diffuse through the material
into a host. The techniques also are used to make projections 12 extending
from base 24. The puncturing projections can also be made by these
techniques with a small aperture at the tips of the puncturing projections
for increasing the rate of drug administration into a host. The puncturing
projections when solid are easily formed by molding, casting, coating and
laminating into molds, and the like. The puncturing projections when made
of metals or alloys are generally made by conventional needle drawing,
single or multiple punching operations, stamping, forging, and the like
techniques. For example, in one embodiment a plurality of puncturing
projections is formed in a punching operation from a thin strip of metal,
for example, stainless steel, with a die to first punch out the metal, and
then bending the punched metal outwardly from the plane of the strip to
form sharply pointed, shaped puncturing projections.
Drug reservoir 16 can comprise various forms and shapes such as hollow,
solid, laminated and the like, and it is made from material that does not
adversely effect the drug. The reservoir can be made, as described above
and as illustrated in FIG. 1, in open flow communication with the
puncturing projections to permit a drug to flow to the puncturing
projections. The reservoir can also be made, separate from the
projections, as described above and illustrated in FIG. 2, with a wall
having openings that function to meter the release of drug from the
reservoir to the puncturing projections when the openings and the
projections are in axial alignment with each other. Alternatively, the
reservoir can be separated from the projections by having a wall that acts
as a barrier and is made of a drug release rate controlling material, such
as a polymeric membrane, as illustrated in FIGS. 2 through 7, that
functions to control thr rate of passage or release of drug from the
reservoir to the projections.
The reservoir can have various shapes and structures and it can be formed
by standard manufacturing techniques. For example, in one embodiment, the
reservoir can be molded into the form of a hollow container with one or
more drugs contained therein and it can have one wall fabricated with
openings for metering the flow of drug from the reservoir to the
projections, or it can have a wall of a drug release rate controlling
material to regulate the flow, as by diffusion, of a drug through the wall
to the puncturing projections. The reservoir can also be made in the form
of an envelope formed from laminae of polymeric material permeable to the
passage of the drug enclosed therein, with the laminae nearest the
puncturing projections acting as a rate controlling barrier to regulate
the flow of drug from the reservoir to the projections. The envelope can
be made of many laminae of like polymeric structure or the laminae may be
of unlike polymeric structure, with the laminae nearest the puncturing
projections regulating the flow of drug from the reservoir to the
projections.
The reservoir also can be made of double layer films of like or unlike
chemical and physical structure with the drug dispersed throughout one, or
more than one of the films. The walls of this reservoir, as with a hollow
container or the like, can be of any thickness, and the thickness will
depend on the nature of the reservoir and the drug contained therein.
Usually, the reservoir wall will have a thickness of from 0.001
millimeters to 10 millimeters thick, or the like. Another embodiment of
the invention comprises a reservoir of a solid matrix housing the drug
distributed therethrough, as illustrated in FIG. 3. The manufacture of
this embodiment is accomplished by adding to the matrix material the drug
in solid or liquid form and subsequently converting the matrix to a solid
by curing, cooling and the like. The drug can also be distributed in the
matrix by immersing the solid matrix in the drug to effect diffusion of
the drug into the matrix. Additionally, the drug in the reservoir can be
present in other forms, for example, a fluid colloidal form as a sol, a
colloid in a more solid form than a sol, such as a gel, and the like.
Thus, the reservoir of the drug delivery device of the invention, whether
integrally formed with the puncturing projections or independently formed
and suitably fixed to the puncturing projections, serves as a drug
container for supplying drug to the puncturing projections. When the drug
in the reservior is in open flow communication with the projections, the
drug release rate is governed by passage through the projections.
Alternatively, when the reservoir wall is of a drug release rate
controlling material, the drug is metered through the reservoir wall with
its rate of passage controlled by composition, fabrication design, and
thickness of the reservoir wall adjacent to the projections, for
percutaneous administration by the puncturing projections of the drug
delivery device.
Generally, the reservoir is made from synthetic or naturally occurring
polymeric materials, including those described above as being suitable for
forming the projections 12 and base 24 and those described hereinafter as
being drug release rate controlling.
As described above with reference to the drawings, projections 12, base 24,
wall 13 of reservoir 16, wall 39 of reservoir 16, and/or membrane 34 can
be formed of a drug release rate controlling material. Such materials are
permeable to passage of the drug at a controlled, predetermined rate, by
diffusion of drug through the material or by passage of drug through
microscopic pores in the material. Exemplary drug release rate controlling
materials are polymers such as poly(ethylene); poly(propylene);
poly(tetrafluoroethylene); poly(vinyl chloride); poly(vinylidene
chloride); chloride); poly(chlorotrifluorethylene); poly)isobutylene);
poly(acrylonitrile); poly(vinylpyrrolidone); poly(ethylene terephthalate);
poly(vinyl alcohol); poly(vinyl) methyl ether); poly(vinyl acetate);
sodium(polystyrene (polystyrene sulfonate); and the like.
Representative of copolymers of various compositional proportions having
drug release rate controlling properties are, by way of non-limited
example, copolymers such as vinyl chloride copolymer with a compositional
range of 92 to 8 to 50 to 50; vinylidene chloride acrylonitrile
composition of 92 to 8 and 80 to 20; vinylidene
chloride-acrylonitrile-vinyl chloride of 75 to 80/10/10 to 15; vinylidene
chloride isobutylene of 70 to 30; vinyl chloride acrylonitrile copolymer;
vinyl chloride diethyl fumariate copolymer; acrylonitrile vinyl acetate
copolymer; vinylidene chloride vinyl chloride copolymer 40/60 and 10/90;
vinylidene chloride acrylontrile copolymer 60/40 and 12/88; vinyl chloride
acrylonitrile copolymer 80/20, 75/25, 50/50 and the like, styrenemaleic
anhydride copolymers; vinyl chloride butyl-.alpha.-chloroacrylate;
polyethylene vinyl acetate; and the like.
Another class of suitable drug release rate controlling materials include
the organopolysiloxanes, also known as silicone rubbers. These rubbers
include the conventional heat curable silicone rubbers and ambient
temperature vulcanizable silicone rubbers. The silicone rubbers include
those which are converted to the rubbery state by the action of heat and
are predominantly linear organopolysiloxanes characterized by an average
degree of substitution of about two organic groups attached directly to
silicone per silicon atom. Generally, the organic groups are monovalent
hydrocarbon radicals such as alkyl, aryl, alkenyl, alkaryl, aralkyl and
the like; as exemplified by methyl, phenyl, vinyl radicals and the like.
Variations of the organic groups in the silicone rubber can be used to
vary the solubility of the drug in the polymer and hence it can control
the speed of migration of the drug through the polymer. Typical examples
include poly[ di(alkyl siloxanes] , such as poly[ dimethylsiloxane],
copolymers such as methylphenyl and dimethylpolysiloxane, and the like.
The room temperature vulcanizable silicone rubbers are also commercially
available and known to the art. In general, they employ the same silicone
polymers as mentioned above although the polymers often contain a greater
amount of silicon bonded hydroxy groups. This type of silicone rubber
cures at room temperature in the presence of catalysts, such
2-ethylheoxate, di-(2-ethyhexyl) adipate, stannous methyl adbietate and
the like. Exemplary methods for preparing silicone rubbers are set forth
in U.S. Pat. Nos. 2,541,137; 2,723,966; 2,863,846; 2,890,188; 2,927,907;
3,002,951; and 3,035,016.
Another class of drug release rate controlling materials are the
hydrophilic polymers of monoesters of an olefinic acid, such as acrylic
acid, methacrylic acid, and the like. Exemplary polymers of this class
include poly(hydroxyethylacrylate) and poly(hydroxyyethylmethacrylate) and
the like. The acrylate polymers are commercially available and their
preparation is described in U.S. Pat. Nos. 2,976,576; 3,220,960; Belgian
Pat. No. 701,813, and the like. When using these hydrophilic polymers, the
drug is often dissolved in a solvent such as a lower alcohol to promote
passage of the drug through the polymer.
The rate of passage of a drug through a drug release rate controlling
material is usually influenced by factors such as the structure of the
materials, its degree of saturation, the presence of cross-linking, the
solubility of the drug in the material, the thickness of the material, and
the like. Thus, selection of particular drug release rate controlling
materials will be dependent on the particular drug to be administered. The
rate of drug diffusion through different drug release rate controlling
materials can easily be ascertained by standard techniques known to the
art as recorded in J. Pharm. Sci., Vol 52, pages 1145 to 1149, 1963; ibid,
Vol 53, pages 798 to 802, 1964; ibid, Vol 54, pages 1459 to 1464, 1965;
ibid, Vol 55, pages 840 to 843 and 1224 to 1239, 1966; Encyl. Polymer Sci.
Technol., Vols 5 and 9, pages 65 to 82 and 794 to 807, 1968; the
references cited therein, and the like.
The reservoir, as above described, can be joined to the puncturing
projections, for example, as in FIGS. 2 through 7, by art known methods,
such as by forming, molding, curing, and cooling the reservoir on the
puncturing projections or the base, or by adhesively joining the reservoir
to the puncturing projections or to the base. The reservoir can be joined
to the puncturing projections, or to the base, or to the membrane (34 in
FIG. 5) by adhesively joining the periphery of the reservoir thereto to
permit the drug to travel from the reservoir to the puncturing projections
without passing through the adhesive. The adhesive also can be applied to
the total interface surface between the projections and the reservoir, the
surface between the reservoir and membrane, the surface between the
membrane and projections, and between reservoir and base in a thin layer
to permit drug migration therethrough according to the practice of this
invention. Exemplary adhesives include acrylic polymers such as esters of
acrylic acid with alcohols such as n-butanol, n-pentanol, iso-pentanol,
2-methyl butanol, 1-methyl methyl butanol, 3-methyl pentanol, and the
like. the copolymers can also be used, as copolymerized with ethylenically
unsaturated monomers such as acrylic acid methacrylic acid, acrylamide,
methacrylamide, N-alkoxymethyl acrylamides, N-alkoxymethyl
methacrylamides, itaconic acid, vinyl acetate, N-branched alkyl meleamic
acids wherein the alkyl group has 10 to 24 carbon atoms, glycol
diacrylates, or mixtures of these; elastomeric silicone polymers;
polyurethane elastomers, rubbery polymers such as polyisobutylene | | |
