US 3924622 A
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Description (OCR text may contain errors)
United States Patent [191 Brooke Dec. 9, 1975  Assignee: Mead Johnson & Company,
22 Filed: Nov. 26, 1974 211 Appl. No.: 527,477
Related US. Application Data  Continuation-impart of Ser. No. 405,616, Oct. 11,
1973, Pat. NO. 3,851,648.
 US. Cl. 128/260; 119/25; 128/272;
239/57; 43/131  Int. Cl. A61M 31/00; A61M 7/00  Field of Search 128/2 R, 130, 214 E, 260,
3,545,439 12/1970 Duncan 128/260 3,641,237 2/1972 Gould et a]. 128/260 X 3,661,326 5/1972 Wilson 239/60 3,677,711 7/1972 Bond 239/57 X 3,851,648 12/1974 Brooke 128/260 Primary ExaminerAldrich F. Medbery Attorney, Agent, or Firm-Robert H. Uloth; Robert E. Carnahan [5 7] ABSTRACT A diffusible solid is released by diffusion into a fluid medium from a cavity within a container through an opening therein at a rate which is independent of the amount of solid present in the container. Zero-order release is effected by the shape of the cavity and the opening. The rate of release is related to the solubility and to the diffusion constant of the solid in the fluid medium. For a given substance, the rate of release is determined by cavity shape and dimensions of the diffusion opening. The method is adapted for use in both liquid and gaseous media and can be used for the zero-order release of drug substance into the system of a living organism, and for non-medical uses.
11 Claims, 6 Drawing Figures Sheet 1 of 4 US. Patent Dec. 9, 1975 U.S. Patent Dec. 9, 1975 Sheet 2 of4 3,924,622
FIGURE 3 FIGURE 4 US. Patent Dec. 9, 1975 Sheet 4 of4 3,924,622
FIGURE 6 ZERO-ORDER RELEASE METHOD CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of my copending application Ser. No. 405,616, filed Oct. 11, 1973, now US. Pat. No. 3,851,648, patented Dec. 3, 1974.
FIELD OF THE INVENTION There is provided a method for dispensing a vapor from a subliming solid into a gaseous medium or a solid solute into a liquid medium at a constant rate during a prolonged period of time. The method may be embodied in a medicator such as a surgical implant, tampon, suppository, intrauterine device, or intravaginal device for delivery of a drug or growth regulating substance into the system of a living organism, or for other uses such as water or air treatment.
SUMMARY OF THE PRIOR ART Certain pesticides are sublimable solids and various devices have been used for delivery of the vapor thereof, such as decorative cannisters, pet collars, etc., to the locale to be treated. Moth proofing and insecticidal agents have been delivered in this fashion. Various means have been used for the delivery of drugs and other biologically active substances to the mammalian body by means of specifically fabricated tablets, implants, intrauterine devices, ocular inserts, catheter tubes, etc. which were designed to release the active substance at a predetermined rate. Examples of such devices are illustrated in the following patents. Levesque, US. Pat. No. 2,987,445 patented June 6, 1961; Long and Volkman, US Pat. No. 3,279,996 patented Oct. 18, 1966; Rudel, US. Pat. No. 3,656,483 patented Apr. 18, 1972; Jacobs, US. Pat. No. 3,113,076 patented Dec. 3, 1963; Stephenson, et al., US. Pat. No. 3,146,169 patented Aug. 25, 1964; and Wepaic, US. Pat. No. 3,598,127 patented Aug. 10, 1971.
SUMMARY OF THE INVENTION The method employs a device comprised of a container of rigid material which is impermeable to the fluid medium into which it is desired to dispense a diffusible solid which is contained within the device. The container may be of any convenient size and shape to fit the particular application under consideration. Housed within the container is a cavity communicating through a slot in the surface of the container with the exterior medium through which the contained solid is dispensed. The solid is dispensed by the processes of dissolution or vaporization within the container into the fluid medium which enters through the slot, and diffusion of the dissolved or vaporized solidoutwardly through the slot into the surrounding medium. Zeroorder release results from the configuration of the cavity and slot which is such as to provide an increasing surface area of diffusible solid exposed to the fluid medium within the container as the length of the path through which the dissolved or sublimed solid must diffuse to reach the exterior increases. A constant ratio of area of dissolution or sublimation surface to diffusion distance is maintained. The device is applicable to various drug delivery systems, and to nonmedical uses such as the dispensing of insecticides, pesticides, perfumes, and water treatment with germ icides in swimming pools, toilets, etc.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view of a device for use in the present process which is cylindrical in form and contains a rectangular slot lengthwise on one side thereof which communicates with a cavity within the cylindrical container the cross-section of which is shaped like a slice of pie.
FIG. 2 is a view in cross-section of the device of FIG. 1 along line 22 showing the drug partially filling the cavity.
FIG. 3 is a perspective view of a device for use in the present process in which the container is ring-shaped and the diffusion slot is arranged concentrically upon the upper surface thereof.
FIG. 4 is a view in cross-section of the device shown in FIG. 3 along line .4-4.
FIG. 5 is a collection of graphs in which the rate of release of a diffusible solid from the device of FIG. 1 is related to its solubility, and the dimensions of the cavity and the slot. 4
FIG. 6 is a perspective view of a device for use in the present process which is comprised of a hollow container in the form of a right circular cylinder bisected along the axis thereof and having an elongated .diffusion slot located on the bisecting surface along the axis.
DETAILED DESCRIPTION OF THE INVENTION In FIG. 1, the cavity 15 is illustrated by broken lines and the slot through which it communicates with the exterior is indicated by 20. The slot is of uniform length and width. The narrower dimension or width is situated at the ends 21 and 24 of the slot. The elongated dimension is located at the sides of the slot represented by 22 and 23. Drug substance or other active ingredient to be dispensed 25 is contained within cavity 15 and is outlined by a broken line in the drawing. The cavity fill should be a solid under ambient conditions. The end walls of cavity 15 are represented by 30 and 31. End walls 30 and 31 lie in parallel planes which are at right angles to slot 20, adjacent to the ends thereof, and are congruent in shape. The side edges of end walls 30 and 31 of cavity 15 are represented by 32, 33, 34, and 35. They are of equal length and are arranged radially and inwardly divergent with respect to slot 20 so that end walls 30 and 31 are pie-shaped in the embodiment shown. Also, the rear wall 40 of cavity 15 is arcuate in contour defining a portion of the wall of a phantom cylinder whose axis lies substantially within slot 20 and the side edges 32, 33, 34, and 35 of end walls 30 and 31 are substantially radii of the phantom cylinder. The side walls 45 and 46 of cavity 15 are situated adjacent opposite sides 22 and 23 of slot 20 and in radial relation to said slot. They are congruent in shape.
FIG. 2 is a cross-section of the device of FIG. 1 taken along line 22 of FIG. 1 in a plane parallel with the planes of end walls 30 and 31 of cavity 15. Like numbers in FIG. 2 refer to like features of FIG. 1. Cavity 15 of the device shown in FIGS. 1 and 2 is only partially filled with drug substance 25, 26 representing the surface of drug substance 25 which is opposite slot 20.
Cavity 15 houses drug substance 25 in sealed relation to side walls 45 and 46 and end walls 30 and 31 thereof. By sealed relation is meant in close contact so that fluid medium 50 and 51 which surrounds container 10 and which fills the void portion of cavity 15 cannot seep between the side walls or the end walls ofsaid cavity and the drug substance 25. In this fashion only one surface 3 26 of drug substance 25 is exposed to fluid medium 51 within cavity 15.
The release of drug 25 from carrier is controlled by dissolution and diffusion processes. This includes dissolution of drug 25 into fluid medium 51 at surface 26 thereof, and diffusion therefrom in solution to slot 20 and thence into the surrounding medium 50. The release rate of drug 25 through slot 20 into the surrounding medium 50 is a function not only of the solubility and diffusion coefficient of the drug in the receiving fluid 50 but also of the dimensions of slot 20 and of the angle between side walls 45 and 46 of cavity 15. Initially cavity may be filled flush with slot with a single pellet of drug substance 25. As the drug is dissolved and diffused from the carrier, fluid 50 from the surrounding medium diffuses into the cavity as shown by 51 in FIG. 2 to replace the drug which has dissolved and diffused out.
FIG. 2 represents the cross-section of a carrier from which about 50 percent of the initial drug fill has been released. The arcuate drug surface 26 shown in FIG. 2 is naturally formed as a result of the dissolution and diffusion processes. If it is desired to prepare a drug carrier which is only partially filled with drug substance at the outset as shown in FIG. 2, then the surface of the drug substance should be provided with an arcuate contour as shown at 26 in FIG. 2.
The reason for the arcuate contour of drug surface 26 is that the rate of diffusion of drug substance through medium 51 to slot 20 is inversely proportional to the distance d separating drug surface 26 from slot 20 and directly proportional to the area A of drug surface 26. The ratio of A to d remains constant so long as slot 20 lies along the axis of a section of a cylindrical surface 26 formed by drug substance 25. The rate of release R of drug substance 25 from slot 20 is governed by the expression shown in Equation I.
Equation I In Equation I, 6 is the angle (expressed in radians, 1 radian 57.3) between side walls and 46 of cavity 15. D is the diffusion coefficient of drug 25 in medium 50 and C, is the solubility thereof. The symbol a is the width of slot 20 and L is the length of slot 20. The symbol h is the distance from slot 20 to that closest hypothetical point in medium 50 where the concentration of drug substance 25 is zero. As a practical matter, for solids with relatively low solubilities or vapor pressures a negligible or substantially zero concentration is reached at a relatively short distance from slot 20. The values for D and h for a specific drug substance may be determined by the method of Roseman and I-Iiguchi, J. Pharm. Sci., 59, 353 (1970). For release of the progestational steroid medroxyprogesterone acetate to vaginal tissues, they have calculated the values D=O.6 cm /day and h=0.058 cm.
The mathematical relationship of Equation I shows that since a, L, and 9 are fixed by the dimensions of cavity 15, then the rate of release R depends upon D,.h, and Cs, all constants for any specific drug substance. Thus as long as drug is present and the arcuate surface 26 thereof is exposed to medium 51, the rate of release will be constant. The mathematical relationship of Equation I further dictates that an increase in L will cause a proportionate increase in the release rate R. An increase in a will cause an increase in rate R but as a is made larger, its influence on rate declines. The rate R can be increased by increasing .9 but like a and unlike L the effect is not linear. For a series of related drug materials having similar diffusion constants D and values h, the release rates of the various materials from devices having the same dimensions are substantially proportional to their solubilities Cs. If the values for D and h have not been previously determined as above, a trial and error approach to construction of the device to provide the desired release rate may be used.
It is preferred that rear wall 40 of cavity 15 have arcuate configuration as shown in FIGS. 1 and 2 similar to that of drug surface 26 such that rear wall 40 forms the wall of a cylinder the axis of which lies within slot 20. In this circumstance a steady state of release of drug substance 25 will be maintained until the drug is entirely exhausted from the device. When rear wall 40 is flat or has another configuration other than the arcuate form shown, a constant rate of drug release will be maintained only until drug surface 26 intercepts wall 40 and exposes a portion thereof. From that time until all of the drug is exhausted, the release rate R from slot 20 will be less than the steady state zero-order condition. This may not pose a serious problem in some circumstances, and accordingly, the configuration of rear wall 40 is not limited in this invention to the arcuate form shown. Only drug surface 26 is required to be arcuate in form to provide zero-order release after dissolution and diffusion processes under operating conditions have reached equilibrium.
FIG. 3 illustrates another embodiment of the invention comprising an intravaginal ring 55 having an overall outside diameter of 6 or 7 centimeters and a crosssectional diameter of about I centimeter. The ring serves as a container corresponding to 10 of FIG. 1 which houses a cavity shown by broken lines in FIG. 3 corresponding to cavity 15 of FIG. 1. Cavity 60 communicates with fluid medium 50 on the exterior of ring 55 through a slot in the side thereof. Slot 65 in the device illustrated lies circumferentially on the uppermost surface of ring 55. FIG. 4 is a cross-section of the intravaginal ring shown in FIG. 3 along line 4-4. This illustrates the configuration of the slot and cavity along the uppermost surface of the ring in concentric 'position. In this instance, the length L of slot 65 corresponds to the circumference of the slot. In the configuration shown with the slot along the upper surface, a steady state of release is achieved by dissolution and diffusion of drug substance 70, shown in FIG. 4 by the hashed mark area, since the length of exposed drug surface remains constant and equal to L. If the slot were placed on the outer or the inner surfaces of the intravaginal ring the exposed drug surface would decrease or increase respectively as drug substance diffused from cavity 60 resulting in a slightly decreasing or increasing rate of release. A still further embodiment of the intravaginal ringnot shown involves a ring similar to that of FIG. 3 with multiple cavities to provide for still higher rates of drug release, or for drugs having very low solubilities.
Referring again to FIG. 1, drug substance 25 may be filled into Cavity'lS in the molten state and then permitted to solidify. This is particularly suitable if the drug substance is stable at its melting point and solidifies in a form such that the dissolution properties are isotropic. A compressed solid may also be used as cavity fill. Another means of using the device of the present invention is to fill cavity with a suspension of drug substance in a thixotropic gel or liquid monomer. In the latter instance, the monomer is caused to polymerize in place. In the former, a firm gel forms on allowing the fill to stand in the quiescent state. So long as the drug substance diffuses through the polymer or gel matrix and the matrix is insoluble in the liquid medium in which the device is immersed, a steady state of release of drug substance through the diffusion slot will be achieved. In this instance, the diffusion coefficient of the drug substance through the polymer or gel matrix and the partitioning of drug between matrix and fluid is taken into account in calculating the release rate. In some instances, the release rate may be greater under these circumstances than when a solid pellet of drug substance is used as illustrated in FIG. 1.
FIG. 6 is a drawing of another embodiment of the invention in which the container 75 is in the form of a right circular cylinder which is bisected lengthwise by a plane in which the axis of the cylinder lies. The planar bisecting face is represented by the numeral 80. Diffusion slot 85 lies along the axis of the bisected cylinder on the planar face of the container. The inner side of the arcuate cylinder wall 81 constitutes the rear wall of cavity 90 which is the interior of the container. Rear wall 81 thus has the arcuate concave configuration as is preferred for zero-order release during the entire residence time of the diffusible solid within the container while it is immersed in the medium into which it is desired to dispense the solid. End walls 82 and 83 are congruent and positioned adjacent the ends of slot 85 and at right angles thereto as is required. The portions of planar bisecting face 80 of container 75 on either side of slot 85 comprise the two side walls of cavity 90 corresponding to side walls 45 and 46 of cavity 15 of the device pictured in FIG. 1. In this instance, the angle 6 between the side walls is 180. Other embodiments of the invention may be constructed with an angle 6 from about to about 270. In such instance, the cavity is formed as in FIG. 6 in the shape of a segment of a right circular cylinder having the diffusion slot located along the axis.
For the cylindrical device of FIG. 1, having diffusion slot 20 on the side thereof, the angle 9 between side walls 45 and 46 of cavity 15 may vary from about 30 to about 140. The angle employed is selected to afford the desired release rate. The cavity of maximum volume, and thus greatest total diffusible solid capacity, which can be constructed within a cylindrical device of the type shown in FIG. 1 has an angle 9 of 1.36 radians or 78. The foregoing is determined by geometric considerations.
Substances having a wide range of solubilties or vapor pressures may be dispensed by the device of the present invention. By the use of an intravaginal ring similar to that shown in FIG. 3, a release rate of 50 mcg./day of a steroid or other substance having a solubility of as low as l.7 meg/ml. may be achieved. For an intrauterine device embodying a container as pictured in FIG. 1, the same release rate can be assured for substances having solubilities of up to about 570 meg/ml. Substances having this full range of solubilities may be dispensed with devices of the type shown in FIG. 6. Release rates can be further manipulated by the use of wax, polymer, or gel matrices such as petroleum wax, cholesterol, silicone rubber, polymeric hydrophilic hydrogels, and thixotropic gels prepared from polyethylene glycol, carboxymethylcellulose, or carboxyvinyl polymer as the continuous-phase of a suspension of crystalline diffusible solid to be dispensed within the cavity.
DESCRIPTION OF SPECIFIC EMBODIMENTS I FIG. 5 is a collection of graphs in which the rate of release R expressed in micrograms per day is plotted as ordinate and solubility Cs in micrograms per milliliter is plotted as abscissa for delivery of a drug substance from a cylindrical intrauterine device similar to that of FIG. 1 having radius 0.12 cm and slot length 3.2 cm. Each of the lines plotted on these coordinates is for a different device having the values for the angle 6 and slot width a shown at the right hand side of the graph. The values of Roseman and Higuchi loc. cit.) for medroxyprogesterone acetate of D=O.6 cm lday and h=0.05 8 cm were used for these calculations. For drug substances having similar D and h values and solubilities of the order of 100 micrograms per milliliter release rates upwards of 100 micrograms per day may be achieved. Medroxyprogesterone acetate has a solubility of 3.25 mcg/ml (Roseman and Higuchi, loc. cit.) and release rates of from about 2.5 to 6 meg/day can, therefore, be achieved with the devices referred to in FIG. 5. Thus by reference to FIG. 5, various release rates can be achieved for a drug of given solubility by selection of the appropriate angle 9 and slot width a.
Experimental The system was tested experimentally by measuring the amount of stearic acid released from a device fabricated from stainless steel and immersed in USP alcohol. The prism-shaped device was 2.5 inches long, 1.0 inches wide at the base, and 0.63 inches high from the base to the slot. The sides, base, and one end were made of 18 gauge stainless steel. The other end was cut from 3/ 16th inch stainless steel and was drilled to provide a filling port which could be closed with a stainless steel bolt. All of the joints were silver soldered. A larger filling port was made in the base of the prism-like device by cutting a hole of appropriate size and soldering in place a stainless steel nut to be closed with a stainless steel bolt. Solvent resistent gaskets were used at both filling ports. The slot width (a) was 0.030 inches and the effective slot length (L) was 2.263 inches. The angle 9 was For filling, the slot was covered with a sheet of polyethylene and the device was inverted. Molten stearic acid was added through the large port in increments. The device was rocked back and forth and the portions allowed to solidify after each addition. The device held approximately 9.5 g. of stearic acid. After the port was closed, the polyethylene was carefully removed from the slot.
The release of stearic acid from the device into USP alcohol was measured by placing the device in the bottom of a double-walled beaker with an inside diameter of 11.0 cm. containing 1,000 ml. of alcohol. The bolt used to close the port in the base served as a pedestal for the device. The beaker was kept at 30C. and its contents were stirred with a three bladed propeller (radius 2 cm., blade pitch 30) rotated at 50 rpm 2.5 cm. below the solvent surface. The distance between the top of the device and the propeller was 4.9 cm. A cover with a hole for the stirrer and one for the sampling port was kept on the beaker.
Solvent samples were withdrawn periodically. Alcohol at 30C. was added to the beaker to maintain volume. The stearic acid concentration in the samples was estimated colorimetrically after extraction from the sample. A 10 ml. aliquot of the ethanolic solution containing stearic acid was removed from the beaker and placed in a separatory funnel. A 50 ml. volume of aqueous 0.01 M pH 7.0 phosphate buffer. containing 0.1% methylene blue (USP grade) and ml. of redistilled reagent grade chloroform were added. When a 5 ml. sample was used, an additional 5 ml. of alcohol was added to it. The separatory funnel was shaken and the layers were allowed to separate. A 5 ml. portion of the chloroform layer was diluted to 100 ml. with methanol and the density of blue color was estimated photometrically at 640 nm against an appropriate standard. The blue color was stable after approximately minutes. The absorbance was linearly dependent on the concentration of stearic acid in the sample. The complete data 8 The following compositions illustrate cavity fill solids for use in the present invention comprising dispersions of steroid compounds in solid matrices of various types.
Composition 1. Wax Matrix. White Wax, USP Megestrol Acetate, microfine for three trials according to this procedure are listed in 20 ployed in Composition 1 may be varied, and the white Table I. wax may be substituted by cholesterol.
TABLE I RELEASE OF STEARIC ACID FROM ZERO-ORDER DEVICE Trial I Trial 11 Trail 111 Time Released Time Released Time Released 16 hr. 118 mg. 2 hr. 72.6 mg. 19 hr. 263 mg.
236 mg. 24 hr. 378 mg. 26.5 hr. 272 mg. 24 hr. 41 hr. 524 mg. 31 hr. 306 mg. 43 hr. 436 mg. 48 hr. 541 mg. 48 hr. 609 mg. 51 hr. 570 mg. 64 hr. 721 mg. hr. 748 mg. 67 hr. 801 mg. 67 hr. 779 mg. 72 hr. 977 mg. 75 hr. 902 mg. 72 hr. 813 mg. 79.5 hr. 947 mg. 94.5 hr. 1110 mg. 89 hr. 1000 mg. 102.8 hr. 1360 mg. 95.5 hr. 1010 mg. 91 hr. 1230 mg. 103.5 hr. 1420 mg. 114 hr. 1600 mg. 93 hr. 1070 mg. 129.5 hr. 1840 mg. l 15 hr. 1600 mg. 96 hr. 1150 mg. 130.5 hr. 1810 mg. 128 hr. 1770 mg. 118.5 hr. 1310 mg. 143 hr. 2000 mg. 134 hr. 1780 mg. 119.5 hr. 1310 mg. 151 hr. 2070 mg. 151 hr. 2090 mg. 137.5 hr. 1590 mg. 167 hr. 2450 mg. 158 hr. 2130 mg. 138.5 hr. 1600 mg. hr. 2360 mg. 161.5 hr. 1850 mg. 182 hr. 2440 mg. 168 hr. 1870 mg. 199 hr. 2680 mg. 184.5 hr. 2100 mg. 206 hr. 2760 mg. 192 hr. 2170 mg. 223 hr. 2990 mg. 207.5 hr. 2400 mg. 230.5 hr. 3180 mg. 216 hr. 2350 mg. 247.5 hr. 3360 mg. 232.5 hr. 2860 mg. 248.5 hr. 31.20 mg. 235 hr. 2830 mg. 270 hr. 2490 mg. 240 hr. 2810 mg. 271 hr. 3440 mg. 257 hr. 2870 mg. 282.5 hr. 3500 mg. 261 hr. 3210 mg. 285.5 hr. 3640 mg. 265 hr. 3350 mg. 290 hr. 3780 mg. 285 hr. 3620 mg. 307 hr. 3930 mg. 285.5 hr. 3610 mg. 314 hr. 3860 mg. 313.8 hr. 4010 mg. 331 hr. 4090 mg. 314.8 hr. 4070 mg. 330 hr. 4240 mg.
The linear regression analysis for each trial is summarized in Table II. The coefficient of determination (r was 0.99 in each case indicating that the data for the 55 release rate are zero-order.
Composition 2. Silicon Rubber Matrix. Silicone rubber elastomer (viscosity 35000-70000 cps.; sp. gr. (25C) 1.13 i 0.03) Megestrol Acetate, microfine 0.1 g. Stannous octanoate catalyst 0.05 g. (tin content 2 26%) TABLE II SUMMARY OF REGRESSION ANALYSIS ON EACH TRIAL AND ON COMPOSITE OF ALL DATA Trial Trial Trial Composite 1 11 III Data Release Rate, mg./hr. 12.73 14.24 12.89 12.72 SD (slope), mg./hr. 0.23 0.41 0.24 0.18 r 0.990 0.990 0.991 0.985 Intercept, mg. l 2.7 48.3 +74.2 21.9
SD (intercept), mg. 44.5 41.3 47.2 33.1 N 32 14 30 76 Composition 3. Carboxypolymethylene Gel.
Active ingredient, microfine 2 toll%- Sorbitol solution, USP 40% Dioctyl sodium sulfosuccinate 0.02% Carbox ypolymethylene 1.2% Thiomerosol 0.004% Sodium hydroxide, q.s. pH 6.5 Water qs 100.0 ml.
Composition 4. Carboxymethylcellulose Gel.
Active ingredient, microfine 2 to l0% Carboxymethylcellulose 3.5% Glycerin 8.0% Polysorbate 80 USP 0.l% Methyl paraben 0.2% Water qs 100.0 ml.
Composition 5. Polyethylene Glycol Gel.
Active ingredient, microfine 2 to Polyethylene glycol 4000 10% Methylcellulose USP, 4000 cps 0.3% Water qs 100.0 ml.
In those instances wherein the diffusible solid is dissolved or suspended in a liquid medium and filled into the container and the medium then solidified in situ to a solid matrix, a solidified matrix is selected which is insoluble in the external fluid medium into which it is desired to deliver the diffusible substance and which is permeable to diffusion of the substance or drug to be delivered. The rate of release of the diffusible active ingredient in this instance is described on the basis of the same considerations and by the same formula shown above in Equation I but the diffusion constant of the diffusible substance through the solid matrix, referred.
to as D,,,, and the partition coefficient of the diffusible solid between the solid matrix and the liquid external medium into which it is to be delivered, referred to as K, also affect the rate of release of the diffusible substance. Equation II is a modification of Equation I in which these factors are taken into account R: D l h D K 9 1:
Equation II 0.6 cm. /d, D to be 0.0035 cm, /d, and K to be 260. These values for K'and D are based upon experimental measurements employing a silicone rubber matrix prepared by polymerization in situ of a silicone elastomeric composition such as is illustrated in Composition 2 hereof. When the factor is less than 1, the rate of release would be greater when the diffusible agent is dispersed in a silicone rubber matrix than when the pure drug is used to fill the cavity of the carrier device.
When an aqueous thixotropic gel is used as a solid matrix in a device such as shown in FIG. 1, the rate of release is; comparable to that of a simple device filled with the pure drug when a gellingagent is selected which does not bind or otherwise influence dissolution ordiffusion of the solid to be delivered, and when an aqueous gel'having a composition substantially similar to the surrounding liquid medium is used to deliver the diffusible solid.
What is claimed is:
1. Method for the automatic release at a desired substantially constant predetermined rate R of a difiusible solid into a fluid medium into which said solid has a propensity to diffuse wherein said solid has diffusion constant (D) and solubility (C with respect to said medium which comprises l. introducing said solid into a cavity within a container, said container being impervious to said solid and said medium during the period of delivery of said solid and having a slot-like port having uniform length and width and having two ends and two sides with the narrower dimension (a) at the ends and the longer dimension (L) at the sides, said port communicating in its entirety with said cavity, said cavity being defined by a rear wall, and a pair of parallel congruent planar end walls arranged at right angles to said slot and adjacent to the ends thereof, and a pair of inwardly extending congruent planar side walls adjacent the opposite sides of said slot and in substantially divergent radial relation to said slot and extending to said rear wall, said introduction being carried out so as to completely cover the rear wall of said cavity with said solid and seal said solid to the walls thereof, and expose a single surface thereof to the slot-like port in facing relation thereto for contact with said medium, and
2. immersing said container into said medium so that the medium enters the slot and contacts said exposed surface of said solid, and
3. adjusting the dimensions (a), (L), and (9), wherein (9) is the angle subtended by the side walls of said cavity, so that said rate R is achieved and is defined by the expression 1 1 formed into an arcuate concave configuration defining a segment of a cylinder wall the axis of which lies within said slot 4. The method of claim 1 wherein said solid is introduced into said container to form therein a uniform dispersion thereof in a solid matrix, said matrix being insoluble in said fluid medium and permeable to said 5. The method of claim 4 wherein prior to introduction said matrix is in the liquid state, said solid being dissolved or uniformly suspended therein and after said introduction the liquid matrix is solidified.
6. The method of claim 5 wherein said matrix prior to introduction is molten and said method is carried out at a temperature lower than the solidification temperature of said matrix.
7. The method of claim 6 wherein said matrix is white wax, USP. 7
8. The method of claim 5 wherein said liquid matrix is a polymerizable composition, and solidification is accomplished by polymerization thereof.
9. The method of claim 8 wherein said polymerizable composition comprises a silicone rubber elastomer.
10. The method of claim 5 wherein said matrix is a thixotropic gel.
11. The method of claim 10 wherein said thixotropic gel is an aqueous composition containing a gelling agent selected from the group consisting of carboxypolymethylene, carboxymethylcellulose, and polyethylene glycol.