U.S. patent number 3,659,600 [Application Number 05/013,278] was granted by the patent office on 1972-05-02 for magnetically operated capsule for administering drugs.
This patent grant is currently assigned to Hans H. Estin, Leonard W. Cronkhite, Jr. and William W. Wolbach. Invention is credited to Edward W. Merrill.
United States Patent |
3,659,600 |
Merrill |
May 2, 1972 |
MAGNETICALLY OPERATED CAPSULE FOR ADMINISTERING DRUGS
Abstract
An implantable capsule for delivering drugs when subjected to a
magnetic force outside the body and controlled by the patient. The
capsule has a means movable under a magnetic force to effect
contact of the medicament in the capsule with a drug-permeable
wall. When contacted, the drug diffuses through the wall into the
body. When it is desired to cease drug administration, the capsule
is subjected to an opposite magnetic force to seal the permeable
wall from contact with the drug.
Inventors: |
Merrill; Edward W. (Cambridge,
MA) |
Assignee: |
Hans H. Estin, Leonard W.
Cronkhite, Jr. and William W. Wolbach, (Boston, MA)
|
Family
ID: |
21759142 |
Appl.
No.: |
05/013,278 |
Filed: |
February 24, 1970 |
Current U.S.
Class: |
604/891.1;
604/288; 604/249; 604/131 |
Current CPC
Class: |
A61M
31/002 (20130101) |
Current International
Class: |
A61M
31/00 (20060101); A61m 031/00 () |
Field of
Search: |
;128/172,2,213,260,1,222,2.1E,2.1P,2P |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Gaudet; Richard A.
Assistant Examiner: Mitchell; J. B.
Claims
I claim:
1. A capsule suitable for implantation in the human body which
comprise
a wall,
end sections attached to said wall to define a closed hollow
chamber,
a medicament within said chamber,
a portion of said wall being formed of a permeable cross-linked
elastomeric composition,
an open hollow magnet in said chamber being movable under a
magnetic force to seal or expose the permeable wall portion to the
medicament,
and a spring means in said chamber between said magnet and one of
said end sections biasing said magnet toward a position to effect
sealing of said permeable wall portion from said chamber.
2. The capsule of claim 1 wherein the permeable wall is formed of a
cross-linked silicone rubber.
3. The capsule of claim 1 wherein the permeable wall portion is
provided with a reinforcing means.
Description
This invention relates to a capsule activated by magnetic force to
release a medicament.
Capsules implanted into the human body to administer long-acting
drugs such as regulatory hormones over long periods have in general
been simple passive systems. The drug diffuses from the capsule
interior through the capsule walls into the body at a rate governed
exclusively by the wall thickness and the concentration of the
drug. No independent control is imposed either by the exterior
chemical milieu of the patient or by any action on the part of the
patient, to regulate the rate of drug diffusion or when
administration is initiated and ceased. Since the patient either
does not have a continuous need for the drug but usually has a need
governed by a convenient schedule or when physiological sensation
informs him of the need for the drug, it would be highly desirable
to provide a drug-filled capsule implanted into the patient for the
purpose of administering the drug on a non-continuous basis and/or
on any convenient schedule desired by the patient through the use
of means solely within his control.
The present invention provides capsules suitable for implantation
into the body for administering a drug from the interior of the
implanted capsule to the body by subjecting the capsule to magnetic
force from a source located outside of the body. When the magnetic
force is applied from one direction, a magnetic means within the
capsule is caused to move thereby effecting delivery of a quantity
of a drug from a storage compartment in the capsule from which it
diffuses through a permeable wall portion of the capsule into
living tissue.
Only a portion of the capsule wall need be constructed of a
material permeable to a drug contained in the capsule while the
remainder of the capsule wall is non-permeable to the drug. A
magnetically activatable means in the capsule is adapted to move
within the capsule either linearly or rotationally under a magnetic
force to provide or terminate contact of the drug-permeable wall
portion and the drug in the capsule as desired. When the drug and
permeable wall are brought into contact, the drug begins to diffuse
into the permeable wall and thence, subsequently, into the body.
When the drug and permeable wall are removed from contact, the
permeable wall releases drugs already in it, at an ever decreasing
rate, and finally is exhausted of drug. Administration of the drug
can be controlled easily by the patient by positioning the source
of the magnetic force outside the body to move the magnetically
activatable means and provide or terminate contact of the drug and
permeable wall for the period desired by the patient.
The process of this invention for administering drugs, and the
capsule therefor provide substantial advantages over presently
available means for administering drugs from an implanted capsule,
in that administration is within the exclusive control of the
patient. Furthermore, the present invention permits the
administration of drugs from implanted capsules which drugs were
previously administered by other means due to the need for
non-continuous administration.
FIG. 1 is a sectional view of a cylindrical capsule of this
invention especially suited for contraceptive drugs such as
progestin, taken along the midplane coextensive with its major axis
showing the magnetically operable means in two positions.
FIG. 2 is a sectional bottom view of a capsule of FIG. 1 taken
along line 2--2 and provided with additional structural
supports.
Referring to FIG. 1 the retaining capsule 1 having a cylindrical
shape is defined by ends 2 and 3, non-permeable cylindrical wall 4
and permeable wall 5 supported on screen 6 to provide mechanical
strength. The retaining capsule 1 contains a magnetic hollow piston
7, a spring 8 and either a drug solution or the drug itself. The
spring 8, drug and piston 7 can be inserted into the capsule 1 by
removing cap 3 and thereafter sealing the cap 3 in place. The
spring 8, has a low spring constant which maintains the piston 7
against the end 2 in the rest state. When the capsule is subjected
to a magnetic force from a source outside the body, the piston 7 is
moved to a position B shown by the dotted lines. The piston
movement compresses the spring 8, and, because piston 7 is hollow,
the contained drug, drug solution, or drug suspension moves through
the piston 7 and contacts permeable wall 5. The drug diffuses
through the wall 5 at a diffusion rate controlled by the thickness
of wall 5 and the concentration of the drug. The rate of
administration of the drug is controlled by the surface area of
wall 5 and the drug diffusion rate. When it is desired to stop drug
administration, as for example, to turn off a contraceptive hormone
in order to permit conception, the patient reverses the process,
and magnetically attracts the piston 7 to position A which movement
is assisted by spring 8. When the piston is in position A, the wall
5 is effectively sealed from contact with the drug. Spring 8
maintains piston 7 in a fail-safe position; that is to say, unless
a magnet force is intentionally applied to move piston 7, the
neutral position of piston 7 is to seal the wall 5 from contact
with the drug.
Referring to FIG. 2, the capsule of FIG. 1 is modified to include
supports 10 extending between the end piece 2 and the wall 4 to
provide a rigid support for membranes 5. The interior surface 11 of
the supports 10 conform to that of the interior surfaces of end
piece 2 and wall 4 to permit smooth and undisturbed movement of
piston 7 and also to reduce the possibility of damaging wall 5. Any
number of supports 10 can be used with 3, 4 or 6 being
preferred.
The end pieces and rigid wall of the capsule are constructed of
materials which are non-magnetic, and non-toxic, do not degrade the
drug, have long durability in contact with body fluids and
negligible permeability. Furthermore, any material used in the
formation of the capsule must have the fundamental properties of
high mechanical strength against fracture by accidental blows.
Suitable materials for use in the capsule are non-magnetic metals
such as tantalum, non-magnetic stainless steels, platinum, or the
like or non-metals such as polycarbonates or the like. The free
moving piston 7 must be of ferro-magnetic materials, and in general
it must be coated to prevent its corrosion in or contamination of
the contained drug or drug solution. The piston can be coated with
ceramic enamels by high temperature fusion, organic enamels of high
strength and abrasion resistance such as phenol-formaldehyde resin,
or the like.
The permeable membrane is preferably made of a cross-linked
elastomer or a network polymer in a swollen solvated state which is
highly permeable to the drug. Generally speaking, polymers in their
glassy state are not desirable for this purpose, because of their
inordinately low permeability, but cellulose acetate Loef type
reverse osmosis membranes, suitably modified to increase pore size,
may be used. The elastomeric material employed to form the
permeable wall must be non-toxic, cross-linkable to the desired
elastic modulus, inert to the drug and have a finite permeability
to the contained drug to give accurate slow release of the drug
into the body upon implantation. Non-toxic additives, usually
employed in the elastomeric materials, may be employed include
fillers such as silica or the like, provided only that the capsule
retains its final shape after its processing and the drug can be
diffused through the elastomer. For a lipid soluble medicament or
drug, including steroid hormones such as the progestins, and
estrogen, it is preferred to employ silicone rubbers i.e.,
organopolysiloxane wherein the organic groups attached is the
silicon atom preferably methyl, phenyl, vinyl, or combinations
thereof. This preference is because silicone rubbers have relative
freedom from toxic products of vulcanization, and are inert as an
implanted material.
In general, the permeable wall of the cylindrical capsule can be
formed by compression molding and vulcanization, or by an
equivalent procedure so that the wall material is cross-linked
while being contained between mating interior and exterior molds to
produce a product having a smooth continuous surface co-extensive
with the interior surface of the capsule. Cross-linking can be
effected in any manner well known in the art, including ionizing
radiation which is especially appropriate to silicone elastomers.
After cross-linking, the permeable wall is treated to remove
by-products of the cross-linking step, if any, which may be toxic
or which may degrade the drug. Thus, for example, phenyl benzoate
produced by thermal decomposition of benzoyl peroxide initiator can
be removed by extraction. The membrane is bonded to the wall of the
capsule in any convenient manner. Thus, the membrane can be molded
and cross-linked while in contact with the non-permeable capsule
wall to thereby provide an effective seal. The surface of the wall
also can be modified or coated with a material to effect a strong
seal with the membrane. Thereafter, the decomposition products from
the cross-linking step can be removed from the membrane prior to
filling the capsule.
Once the cylindrical capsule has been filled with the drug, the
sliding piston and the retaining spring, it is convenient to seal
the end plate 3 by some relatively permanent means, such as with a
permanent non-toxic adhesives such as epoxy or by heat sealing the
material if it be polymeric, such as a polycarbonate or the
like.
It is essential that the sliding piston move freely but snugly
within the capsule to provide effective sealing or contact of the
permeable wall and drug. The piston material or coating used on the
piston should not adhere to any of the surfaces with which it
contacts and there must be geometric precision between the sliding
piston and the interior surface of the capsule. The length of the
sliding piston is significantly greater than the corresponding
length of the permeable wall, so that when it is in the closed
position leakage of the drug is minimized. Generally, the capsule
is 4 to 15mm. long and 2 to 10mm. wide the piston being about
2.5mm. to 10mm. long. It is desirable to minimize the piston wall
thickness to maximize the amount of drug in the capsule. While the
capsule of this invention is described with reference to a
magnetically operable means comprising a hollow piston, it is to be
understood that the magnetically operable means can be of any
geometric shape so that it moves freely but snugly within the
capsule to provide effective sealing of the drug and permeable wall
and permits contact of the drug and permeable wall when
desired.
When the drug is a solid rather than a liquid it is desirable to
form a solution thereof with a solvent or a dispersion thereof in
an inert carrier liquid. The solvent employed should dissolve the
drug to afford the preparation of concentrated solution, and must
be inert to both the drug and the elastomeric material. A suitable
carrier liquid should be inert to the drug, and capable of
suspending the drug when the drug is rendered into microparticles.
Thus, ideally the carrier liquid has the same density as the drug.
Accordingly, the choice of solvent and elastomer is made depending
upon the drug used to fill the capsule.
The particular elastomer and solvent employed for a given drug are
chosen in accordance with the criteria set forth above for the
drug-solvent-elastomer system. Commonly employed solvents and
carrier liquids useful in the present invention include glycols,
such as propylene glycol; glycerol; selected animal fats;
hydrogenated vegetable oils; mineral oil; silicone oils and
mixtures thereof. Silicone oils include not only the common
homopolymers poly [dimethyl siloxane] , but also the homopolymers
poly [diphenyl siloxane], poly [methyl phenyl siloxane], poly
[methyl, B-carboxyethyl siloxane , and random copolymers and
interpolymers based on the mer units of the above stated
homopolymers. Colloidal silica may conveniently be used as a
thickening agent to maintain dispersion of suspended drug, above or
in combination with polymeric additives to assist in maintaing
dispersion.
The following example illustrates the present invention and is not
intended to limit the same.
EXAMPLE I
A cylindrical capsule of the form shown in FIG. 1 having an
internal diameter of 0.600 cm. and an internal length of 1.2 cm. is
formed by injection molding from polycarbonate, with six supporting
pillars, (10 in FIG. 2) equally spaced, being used as a frame on
which a silicone membrane is subsequently cast. Stainless wire
(20mil. diameter) is spirally wound over the six pillars so as to
form a support for the silicone composition. Ends of the wire are
seized by forcing them into holes drilled in the polycarbonate body
above and below the membrane area, then heat sealing.
The total height of the pillars defining the membrane area is
0.40cm. A dummy plug is driven into the capsule so as to form an
internal mold surface, and silicone RTV rubber of the acetoxy type
is forced through the stainless steel wire and around the posts
until it fills the space bonded by the dummy plug. A cellophane
tape is applied externally by means of a dental clamp to support
the liquid silicone, and air cure is allowed to occur for 24 hours,
followed by immersion in 90.degree. C., water for 1 hour to extract
residual acetic acid and complete hydrolysis of the silicone rubber
now solidified as a membrane around the stainless steel wire, the
polycarbonate posts and the upper and lower portions of the
polycarbonate body.
The dummy is removed and the capsule is filled through its open end
3 (FIG. 1) with a suspension of 25 parts estrogen hormone in 75
parts dimethyl silicone oil of viscosity 1,000 centipose, thickened
by 1/3 part of Cubosil(TM) silica. A hollow cylinder formed of soft
magnetic iron, machined and then coated with a ceramic to cover all
areas, having a length of 0.60cm., an inside diameter of 0.35cm.,
and an outside diameter of 0.570cm. is inserted through the open
end of the capsule and placed in the closed position but is over
the membrane area. A tantalum spring exerting a force of 1.5 grams
when fully collapsed, 0.6 grams when fully extended, is placed
behind the hollow iron cylinder. A threaded end plate 3 is then
screwed into the end of the capsule, eliminating all air from
inside the capsule. Superficial heat sealing is used too at the
external junction of the capsule body and the end plate to insure
against leakage. The heat sealing is accomplished by a rapid use of
a miniature gas oxygen torch to effect superficial fusion without
heating the main body of the capsule.
The capsule is designed for implantation in the upper thigh, at a
depth of 1/2cm., with the end 3 nearest the surface. A 40-gram
AiNiCor rod magnet taped over the skin immediately above magnet is
sufficient to keep the internal hollow iron cylinder in the open
position, for release of the contraceptive estrogen. Removal of the
magnet allows immediate close of the membrane area from access of
the estrogen-silicone oil suspension, and within 8 hours the rate
of release of estrogen falls exponentially a value approximate by 5
percent of that corresponding to full open position (magnetic
retraction of the hollow iron wire).
* * * * *