US 3608549 A
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Description (OCR text may contain errors)
United States Patent Edward W. Merrill Cambridge, Mass.
Jan. 15, 1970 Sept. 28, 1971 Hans H. Estln, Leonard W. Cronlthlte, Jr. and William W. Wolbeeh, trustees of the Charles River Foundation Inventor Appl. No. Filed Patented Assignee METHOD OFADMlNlSTERING DRUGS AND CAPSULE THEREFOR 8 Claims, 8 Drawing Figs.
u.s. CI. 128/260, 119/51,424/14 Int. Cl ..A6ln1 31/00 References Cited UNITED STATES PATENTS 2,671,451 3/1954 Bolger 128/260 3,093,831 6/1963 Jordan 3/1 3,118,439 1/1964 Perrenoud.... 128/2 3,428,729 2/1969 Anderson 424/19 3,485,235 12/1969 Felso 128/2 Primary Examiner-Richard A. Gaudet Assistant Examiner-G. F. Dunne Attorney- Kenway, Jenney & Hildreth ABSTRACT: An implantable capsule for delivering a medicament to live animals having a permeable elastomeric wall and containing a mixture of medicament and matrix material which melts between 40 C. and 47 C. The capsule also contains a metal coil capable of being inductively heated by a coil external to the body. When delivery of medicament is desired, the coil is inductively heated to melt the mixture and effect diffusion of medicament through the permeable wall.
PATENTED SEP28l97l 3,608,549
I 5 INVENTOR EDWARD w. MERRILL METHOD OF ADMINISTIERING DRUGS AND CAPSULE THEREFOR This invention relates to a method for administering a medicament and to a capsule adapted to release a medicament upon being heated inductively.
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 usually 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 noncontinuous basis and/or on any convenient schedule desired by the patient through the use of a means solely within his control.
The present invention provides a capsule suitable for implantation into the body and a method for administering a drug from the interior of the implanted capsule to the body by subjecting the capsule to an electrical field located outside of the body to effect inductive heating in the capsule. When the capsule is heated, the rate of release of the drug from the capsule interior is substantially increased. When influence of the electrical field on the capsule is ceased, the capsule is cooled and the rate of release of the drug from the capsule is substantially zero.
A secondary but inescapable effect amplifies the delivery of drugs to the circulatory blood. When the capsule is heated in that the surrounding tissue, sensing the temperature rise responds by vasodilation, whereby blood flow to the heated area is significantly increased. This effect speeds delivery of the medicament that diffuses from the capsule into the surrounding tissue.
The walls of the capsule are constructed with a material at least a portion of which is permeable to the drug contained in the capsule. The drug in the capsule is dispersed or dissolved in a matrix material meltable from a crystalline state at a temperature in excess of ambient body temperature, or is surrounded immediately by a polymeric substance meltable from a crystalline state at a temperature in excess of ambient body temperature. A closed loop metal conductor immersed in the matrix material is capable of inductive response to an induction heater located outside the body. The drug is administered to the body by subjecting the conduction to an inductive field so that it is heated sufficiently want: to melt the matrix material or meltable polymeric material thereby creating a fluid through which the rate of diffusion of the medicament is greatly enhanced. Heating is continued for a period to permit diffusion of the desired dosage of drug into the body. The administration of the drug is terminated by the patient by removing the induction field to crystallized the matrix material or surrounding polymeric material by cooling and thereby substantially reduce or terminate diffusion of the drug through the matrix.
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 exclusively within the 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 noncontinuous and large dosage administration.
FIG. I shows a capsule of prolate ellipsoidal shape symmetrical about an axis of revolution, containing an iron ring coated with ceramic material.
FIG. 2 is a cross-sectional view of the capsule of FIG. I taken along section 2-2.
FIG. 3 is a cross-sectional view of a capsule having a meltable polymer matrix.
FIG. 4 is a cross-sectional view of the capsule of FIG. 3 along section 44.
FIG. 5 is a cross-sectional view of the capsule of FIG. 3 along section 5-5.
FIG. 6 is a perspective view of a capsule containing two iron toroids.
FIG. 7 is a cross-sectional view of the capsule of FIG. 6 along section y-y.
FIG. 8 is a capsule containing iron spheres.
Referring to FIGS. 1 and 2, the toroidal iron ring 1 is contained in the medicament-matrix mixture 2 and the encapsulating silicone sheath 3. When the ring 1 is energized by an exterior induction field, the matrix material 2 becomes liquid allowing the diffusion coefficient of the steroid hormone greatly to increase so that the steroid hormone is released through the exterior shell around the chamber 4. Removal of the exterior induction source allows the iron toroid l to return to body temperature thereby permitting crystallization of the matrix phase 2. The capsule of FIG. 1 is implanted with the major axis of the ellipsoid revolution approximately parallel with a lower or upper limb such as the forearm.
FIGS. 3, 4 and 5 show a capsule having a prolate ellipsoid shape and having symmetry about its major axis of revolution, but distinguished by having a meltable polymeric material that controls the diffusion rate. In the capsule of FIG. 3, a toroidal iron ring 5 is coated with a ceramic enamel to prevent ionic reactions. A cylindrical layer of meltable polymeric matrix material 6 such as poly stearyl acrylate surrounds a volume 8 containing the medicament which may be, variously, pure medicament, medicament in a meltable matrix, or medicament dissolved in an appropriate inert liquid such as silicone oil. The iron toroid 5 surrounding meltable polymeric material 6 and medicament containing volume 8 are contained in fixed relationship to each other by the encapsulating substance 7, which is preferably cross-linked silicone rubber. Upon exposure to an exterior induction field the meltable polymeric material 6 changes from its crystalline state (a state of high resistivity to diffusion) to a visco elastic state characterized by a high coefficient of diffusion for the medicament. If at the same time, the medicament is dispersed in a suitable matrix material within the volume 8, and if the matrix material be appropriately chosen, it will also melt so that the diffusion of the medicament is accelerated through the intervening substance between volume 8 and polymer 6 and from the exterior surface of polymer 6 through the wall material 7 to the surrounding tissue of the animal or human in which this capsule is implanted. Alternatively, if the medicament exists in a pure liquid state in volume 8, or is in a true solution in an inert solvent, the only change in diffusion rate coincident with the application of the exterior induction field arises from the melting of the polymeric material in the circumferential volume 6. Generally, the material at the extremities of the circumferential volume 6 remain unmelted thereby forcing the major diffusion of the medicament out through the peripheral zone. The capsule of FIG. 3 is implanted with the major axis approximately aligned with a limb such as a forearm or lower extremity.
Referring to FIGS. 6 and 7 a perspective view is shown with respect to coordinate axis x, y and z and the corresponding cross-sectional diagram through the origin on the x-y plane is indicated. Two iron toroids 9 and 10, 9 having a smaller diameter than 10 so as to fit within it, both being ceramic coated for protection against electrolytic degradation, are fixed within a spherical elastomeric shell 12 and lie inside of a substance in the volume 11 which is a mixture of medicament and a meltable matrix material. By external coils, eddy currents are induced in the toroid 9 or the toroid 10 or both, depending upon the orientation of the spherical capsule within the animal or human patient after implantation. In general, when one toroid is aligned with the external coil in approximately the same plane, it will be the most energized, whereas the other one will be the least energized. However, the power dissipation is not significantly position dependent, because between the two toroid elements 9 and 10, with a given number of turns in the exterior coil, sufficient power can be dissipated to melt the matrix material in volume 11. This therefore, greatly facilitates the diffusion of the medicament through the wall 12, which may consist of any inert crosslinked elastomeric material permeable to the medicament and physiologically inert. Absolute retention of the matrix material, with exclusive diffusion of the medicament, is assured when the matrix material is a polymeric crystalline material such as polystearyl acrylate, of moderate molecular weight (25,000 to 100,000).
Referring to FIG. 8, which represents a spherically symmetrical capsule, minute ceramic coated iron spheres 13 are packed nearly in juxtaposition (with a volume percentage over proximately 60 percent) inside of a spherical elastomeric shell 15, which preferably consists of silicone rubber suitably crosslinked. Medicament is mixed with a meltable matrix phase so as diffuses surround the indivdual toroidal particles 14 as shown. When this kind of capsule is implanted in a limb of an animal or patient and the limb is surrounded by an exterior coil carrying alternating current, each one of the ceramic coated iron spheres acts as a short circuited conductor and heat is generated relatively uniformly throughout the enclosed volume of the shell 15. When a suitable temperature is reached, the matrix material melts into a fluid state, the diffustion coefficient of the medicament is vastly increased, and it then diffuses through the wall material at a greatly enhanced rate.
The capsule wall can be constructed of any nontoxic, which does not become heated in an induction field is not permeable to the matrix and has at least a portion thereof permeable to the drug in its fluid state. Furthermore, any material used in the formation of the capsule wall must have the fundamental properties of high mechanical strength against fracture by accidental blows.
The permeable wall is made of a cross-linked elastomer or a network polymer in a swollen solvated state which is permeable to the drug. Generally speaking, polymers in their glassy state are not desirable for this purpose, because of their inordinately low permeability. The elastomeric material employed to form the wall must be nontoxic, 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. Nontoxic, nonelutable additives, may be employed in the elastomeric materials including 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. Generally speaking, hydrocarbon rubbers and silicone elastomers are satisfactory for steroids. It is preferred to employ silicone rubbers i.e., organopolysiloxanes wherein the organic group attached is the silicon atom, is preferably methyl, phenyl, and/or vinyl. This preference is because silicone rubbers have very high permeability to carbon dioxide, susceptibility to swelling by the commonly employed drug solvents such as by alcohols, are easily cross-linked by ionizing radiation and thus can be obtained free from toxic products of chemical vulcanization, and are inert as an implanted material. The thickness of the permeable wall is such that it is self sustaining, mechanically and structurally strong to resist impact forces and permits diffusion of the drug at a controlled rate. The permeable wall thickness depends upon the particular elastomer employed but ordinarily should be between about 0.5 mm. to 1 mm.
Alternatively, a portion of the capsule wall may be made of a nonpermeable material including nonmetals such as polycarbonate and the ceramic pyroceram(TM). When the capsule wall is made of two differing materials, the permeable portion can be formed by compression molding and vulcanization while being contained between mating interior and exterior molds to produce a product having a smooth continuous surface coextensive with the interior surface of the remainder of the capsule. Alternatively, the permeable membrane can be attached to the nonpermeable portion of the capsule wall by heat sealing or by employing an adhesive. Cross linking can be effective by any manner known in the art, including free radical generation, by ionizing radiation or by thermal decomposition of chemical initiators. After cross-linking, the permeable wall can be treated to remove byproducts of the cross-linking step, if any, which may be toxic or which may degrade the drug. Thus, for example, phenyl benzoate produced by decomposition of benzoyl peroxide initiator can be removed by extraction.
Prior to sealing the capsule, it is filled with the drug and matrix material as well as the induction loop. The matrix material should be biologically inert and have the characteristic property of undergoing a first order phase transition from a crystalline, microcrystalline, or micellar state to a liquid state in a limited temperature range above a normal body temperature but below that which would cause damage to the surrounding body tissue. It is preferred that this phase transition occur at a temperature range between and including 40 C. and 47 C. Matrix materials particularly useful, include lauric acid having a melting point of 44 C., glycerol trilaurate having a melting point of 464 C., poly [heptadecyl acrylate], i.e., polyacrylic acid fully esterified with heptadecanol, melting point 40 C., and poly [stearyl acrylate], having a melting point of about 43 C. Alternatively, the matrix can take the form of a concentrated aqueous dispersion of lecithin which produces micelles when cool thereby substantially reducing drug diffusion to the interior surface of the capsule.
In use, the capsule containing these elements is implanted surgically in the limb of the human patient or an animal in such a position that the contained metal loop or loops may experience induction of a current by an external induction coil thereby sufficiently raising its temperature to melt the surrounding matrix without endangering the surrounding tissue by overheating. The underlying principle of this invention takes advantage of the extremely low diffusivities of molecular compounds through crystalline and microcrystalline substances relative to diffusivities through the same substances when liquified which can change by a factor of the order of ten or even more. Thus, prior to melting the matrix, it serves as an effective difiusion barrier. Upon melting the matrix, the enhanced diffusivity is in the order of at least ten fold or greater. The medication will then diffuse through the capsule wall at a rate governed primarily by the properties of the wall. When it is desired to reduce the rate of diffusion, the external induction coil is removed and the matrix returns to ambient temperature of the body (about 37 C. in humans and mammals) and the capsule reverts to its original form wherein the matrix is not liquified.
The medication must be to a certain extent soluble in the matrix material to enhance the diffusion thereof through the matrix. In general, no restriction is placed on the nature of the medicament contained in this matrix except that it shall be significantly soluble though not limitlessly soluble in the matrix material when molten and further its total mass concentration must be sufficiently low so as not seriously to alter the melting point or melting range of the matrix material. Thus, for example, when the initial mixture of drug and medicament produces a solution having a melting point of 36 C. which upon gradual release of the medication is elevated to 50 C., the mixture would have a limited utility in the context of this invention. Usually, however, the medication is released in the implanted capsule; it has a relatively high molecular weight and is supplied in very small absolute quantities, so that the mass molar concentration in the matrix usually will be very small.
Representative drugs and medlcaments which can be employed in this invention are listed by Long and Folkman, U.S. Pat. No. 3,279,996.
The amount of power needed to completely melt the matrix phase is in the order of about 20 calories or about wattseconds. Thus, provision of 1 watt power to the coil by induction over a period of 100 seconds would furnish the energy necessary to melt the matrix. Once the matrix phase has been melted to a temperature of approximately 44 C., the power of about one-fourth watt will be required to maintain the matrix phase in a liquid condition. Thus the usual operation would be to actuate the induction coil surrounding the limb in which the capsule is implanted at a rate so as to give a net input of about 1 watt for about 100 seconds and then reduce the power to about one-fourth of a watt for a few minutes to an hour to enhance delivery of the drug by diffusion. When delivery of the drug is to be terminated, the exterior induction coil is simply removed and the capsule returns to its normal temperature to solidify the matrix.
After the capsule is filled, it or the permeable wall portion can be coated with a nonporous, nontoxic material such as copolymers of vinylidene chloride and acrylonitride (Saran) to prevent diffusion of the drug prior to implantation. The coating is removed prior to implantation. Y
The following examples illustrate the present invention and are not intended to limit the same.
EXAMPLE l A capsule having the form of a prolate ellipsoid with a major axis of ml. and a minor axis of 5 ml., contains a spherical hollow section concentric with its center of mass having a diameter of 4 ml. A low-carbon steel ring having a median diameter of 3.5 ml. and a gauge thickness of 1/32,000 inch is coated with a 10 mil. (1/ 10,000 inch) layer of low melting ceramic material, such as ceramic paint. It is placed in the capsule so that the plane of the ring is at right angles to the major axis and equidistant from the ends of the capsule. It is convenient to form the capsule in two halves by compression molding and partial cross linking, then joining the two halves after insertion of the iron toroid. The rest of the volume is then filled with a mixture containing glycerol trilaurate in which is dispersed 100 milligram percent of the steroid hormone testerone. This capsule is useful when implanted in the neck of cattle with the major axis approximately aligned in the direction of the cervical vertebrae. The capsule is activated by a collar around the neck of the cattle, consisting of several turns of an insulated conductor. This may be activated by con necting the coil to a 60-cycle alternating-current source. The number of turns and the voltage on the coil on the neck of the cattle is so chosen as to produce a power dissipation of approximately one-fourth watt in the implanted capsule containing the ceramically coated iron ring. It is convenient to ac tivate the external induction ring for a period of several hours when the cattle is confined in a stall.
EXAMPLE [I A capsule designed for contraceptive use in human beings consists of a prolate ellipsoidal body of the form shown in FIG. 3 approximately l0 mm. long and 3 mm. in diameter at the mid plane. The exterior capsule shell is formed from pure poly Y dimethyl siloxane ultimately vulcanized by ionizing radiation.
A soft iron ring or toroid of approximately 25 mils. (l/25,000 inch) gauge, having been coated with a phenolic lacquer and then baked, to assure complete protection against electrolytic degradation, is inserted at the midplane of a circumferential chamber 6 of FIG. 3 that is to contain poly (stearyl acrylate) in the interior volume of this capsule. ln the hollow space 8 shown in FIG. 3, is placed a saturated solution of the hormone progestin in a carrier consisting of glycerol trimyristate, which is already molten at body temperature of 37 C. This capsule is implanted in the forearm at a depth less than 1 cm., with a major axis aligned approximately with the forearm axis. When enhancement of protection against conception is desired, a ring consisting of several loops of a conductor suitably insulated is placed over the forearm and activated by 60-cycle house current, thereby inducing eddy currents in the toroid contained within the implanted capsule. The external induction loop is chosen in respect to its number of loops so as to produce a dissipation of ap roxjmately 0.2 of a watt in the implanted coil. At this rate 0 dissipation, the capsule comes to a steady state interior temperature of approximately 45 C. at its midplane, thereby maintaining the surrounding sheaths of poly stearyl acrylate in a molten condition. This produces enhanced delivery of the progestin.
1. A capsule suitable for implantation in the human body which comprises:
a wall to define a closed hollow chamber,
at least a portion of said wall being formed of a permeable cross-linked elastomeric composition,
and said chamber containing a composition comprising a matrix material and a medicament soluble in said matrix when molten, said matrix material and medicament having a melting point between 40 C. and 47 (3., and a metal piece in contact with said matrixmaterial, said metal piece being capable of being inductively heated by a coil external to the body.
2. The capsule of claim 1 wherein the entire wall is made from a permeable cross-linked elastomeric composition.
3. The process for administering a medicament which comprises implanting in a live animal the capsule of claim 1 and thereafter subjecting the capsule to an induction field to melt the matrix.
4. The process for administering a drug which comprises implanting in a live animal the capsule of claim 2, and thereafter subjecting the capsule to an induction field to melt the matrix.
5. The capsule of claim 1 wherein the permeable wall is formed of a cross-linked silicone rubber.
6. The capsule of claim 2 wherein the permeable wall is formed of a cross-linked silicone rubber.
7. The process of claim 3 wherein the permeable wall is formed of a cross-linked silicone rubber.
8. The process of claim 5 wherein the permeable wall is formed of a cross-linked silicone rubber.