US3678756A - Capsules and method for testing capsules for wall integrity - Google Patents

Abstract

Capsules having a cross-linked permeable continuous elastomeric shell are tested for leaks and for wall strength by a process in which gas or vapor is suddenly formed within the capsule to inflate acceptable capsules but to split, explode, or leave uninflated capsules with defective, weak, or leaking elastomeric shells. Methods useful for sudden formation of gas are: previous long exposure of the capsules to an inert gas at high pressure followed by sudden release of external pressure, incorporation of a solid vaporizable core around which the elastomeric shell is formed followed by subsequent rapid vaporization of the core, and formation of the elastomeric shell around a core that contains a significant quantity of vaporizable solvent held therein by capillary forces, when the core is microporous, or by solvation energy in the case of cross-linked polymeric materials. The acceptable inflated capsules are then separated from the unacceptable capsules on the basis of size or density. The acceptable capsules can be filled with a solid material such as a drug by immersing the capsules in a solution of the solid material to effect effusion of the solution into the capsule and subsequently evaporating the solvent from the capsules.

Description

[ 51 July 25, 1972 i [54] CAPSULES AND METHODFOR TESTING CAPSULES FOR WALL INTEGRITY [72] Inventor: Edward W. Merrill, Cambridge, Mass.

[73] Assignee: Hans W. Estin, Leonard W. Crankhite, Jr. 8: William W. Welbach Trustees of The .Charles River Foundation 22 Filed: Sept. 23, 1969 211 Appl.No.: 860,196

128/272, 260, DIG. 3

[ ABSTRACT Capsules having a crosslinked permeable continuous elastomeric shell are tested for leaks and for wall strength by a process in which gas or vapor is suddenly formed within the capsule to inflate acceptable capsules but to split, explode, or

leave uninflated capsules with defective, weak, or leaking elastomeric shells. Methods useful for sudden formation of gas are: previous long exposure of the capsules to an inert gas at high pressure followed by sudden release of external pressure, incorporation of a solid vaporizable core around which the elastomeric shell is formed followed by subsequent rapid vaporization of the core, and formation of the elastomeric shell around a core that contains a significant quantity of vaporizable solvent held therein by capillary forces, when the core is microporous, or by solvation energy in the case of cross-linked polymeric materials. The acceptable inflated capsules are then separated from the unacceptable capsules on [56] References Cited the basis of size or density. The acceptable capsules can be filled with a solid material such as a drug by immersing the UNITED STATES PATENTS capsules in a solution of the solid material to effect efi'usion of 1 590 736 6/1926 Clark the solution into the capsule and subsequently evaporating the 2,228,122 1/1941 Lowey ...73/49.3 x Swen fmm capsules- 3,279,996 10/1966 Long, Jr.'et a1 1 28/272 X 10 Claims, Drawing Figure Primary Examiner-- Louis R. Prince Assistant Examiner-William A. Henry, II Attorney-Kenway, Jenney & Hildreth I 3 4 5 PEESSURE CAPSULE CAPSULE SOLVENT COATING CHAMBER SEPARATION IMMERSION EVAPORATION REMOVAL UNACCEPTABLE CAPSULE DISCARD Patented July 25, 1972 EDWARD W MERRILL Bu y MW ATTORNEYS CAPSULES AND METHOD FOR TESTING CAPSULES FOR WALL INTEGRITY This invention relates to a method for testing the wall integrity of capsules having cross-linked, elastomeric, permeable, continuous walls. More specifically this invention relates to a method for testing the wall integrity of capsules which are to be filled with a solid drug material.

Encapsulated drugs and processes for making the same have taken almost innumerable forms, including mating cylindrical shells mechanically pressed one inside the other, gelatin cap sules made from hemispheres of gelatin to encapsulate fish liver oils and capsules made by dipping solid drugs in suitable solutions whereby a temporary coating is applied sufficiently strong to contain the drug in a package. Except for those capsules designed specifically for implantation, all other capsules are intended to disintegrate upon exposure to gastric or intestinal fluids. Recently it has been found that certain drugs may be administered over long periods by encapsulating them in an elastomer such as silicone rubber and implanting the capsule in a patient. (See Long and Folkman U.S. Pat. No. 3,279,996). It is obviously essential that the wall of capsules intended for implantation for the delivery, for example, of hormones have long term stability of their diffusive properties and of their mechanical properties and above all that the capsules,'with 100% certainty, are assured of being free of leaks, lest the contained drug escape too rapidly after implantation thereby causing hazard to the health of the patient.

Capsules suitable for implantation are usually made with a shell comprising cross-linked (vulcanized) elastomeric materials in order to endow them with elastic adaptability to the surrounding tissue under stress and long term durability, while retaining their permeability properties. For these reasons, it is customary to use elastomeric polymers capable of being subsequently crosslinked by suitable chemical means, usually in combination with elevated temperatures. Suitable elastomeric polymers are the polymers of isoprene, butadiene, siloxanes (silicone rubber), and coor ter-polymers of ethylene and propylene, isobutylene and isoprene, butadiene and styrene, butadiene and acrylonitrile, and many others. Regardless of the crosslinking agent employed such as sulfur, peroxides, or other vulcanizing agent, elevated temperature levels for significant periods of time are required to obtain the desired degree of cross-linking. Temperatures in excess of 150 centigrade and times usually in excess of minutes, are typical of the conditions under which most pharmaceutical products intended for gradual release would be destroyed, denatured or partially decomposed with evolution of toxic side products. For these reasons it is undesirable to form a capsule of unvulcanized elastomer around the pharmaceutical product and then vulcanize the elastomeric shell.

Presently, available alternatives to the use of high temperature include the use of ionizing radiation to effect cross-linking of polymers at or below room temperature, but the radiation that creates the chemical effect in the elastomer would necessarily interact adversely with a contained pharmaceutical product. Another alternative means for avoiding high temperature vulcanization processes is to take advantage of easily provoked chemical reactions at room temperature; for example, the room temperature vulcanization (RTV) of a class of silicone rubber, the ends of whose molecules in their fluid form have been capped by trifunctional acetoxy groups. When exposed to air containing moisture at room temperatures the acetoxy groups are hydrolyzed to release acetic acid and form silanol groups which then immediately react by condensation with the elimination of water, to create a three dimensional siloxane network between the ends of the previously linear polymer molecules. During the self-vulcanization, the acidity necessarily is increased to levels which readily denature most drugs and pharmaceutical products that might be contained in capsules of this type.

As an alternative, it is possible to form elastomeric capsules of any desired shape while leaving a hole in the wall thereof so that the capsules after complete vulcanization and other processing, may be filled with the desired drug via a hollow needle. However, this mode of operation introduces problems attendant with the subsequent plugging of the hole and with providing means for demonstrating that the hole has been effectively and permanently plugged. When the hole has been effectively and permanently plugged. When the hole through which the drug is introduced is not totally plugged the drug will be released at an undesirably rapid rate and/or the capsule will become unfit for use due to the introduction of foreign matter therein. Thus while this method eliminates the problems associated with contaminating the drug because of the cross-linking step, the disadvantages introduced regarding the lack of certainty of the plug and the accompanying risk to the patient during use render this method of filling capsules undesirable.

It would be highly desirable to provide a method for testing the wall integrity of capsules which eliminates the undesirable problems associated with drug contamination caused by the step of cross-linking the elastomeric material and the lack of certainty associated with plugging holes in the capsule wall.

In accordance with the present invention, the vapor pressure of a gas or a vapor contained in the hollow interior of a capsule having cross-linked, permeable, elastomeric wall material is increased so as to inflate acceptable capsules but to explode or leave uninflated unacceptable capsules. The inflated capsules are then separated from unacceptable capsules on the basis of size or density.

in one embodiment of this invention the gas pressure in the capsule is increased by subjecting it to a high gas pressure for a sufficient period to fill the interior of the capsule with an inert gas. The gas pressure on the exterior of the capsule is then reduced to cause inflation of the acceptable capsules. In another embodiment, the vapor pressure in the capsule is increased by vaporizing a solid material in the capsule used to mold or form the capsule.

While the description of the method of testing capsules provided by this invention is made with reference to capsules which are to be filled with a drug, it is to be understood that the process of'the invention is useful in the testing of capsules which are to be filled with any solid material so long as the solid material is capable of being dissolved in a solvent and to form a solution capable of being subsequently effused in solution through the pores of the elastomeric material forming the capsule walls.

The present invention provides substantial advantages over the prior art. Thus the process of this invention provides a means whereby substantial amounts of a drug can be saved by not being introduced into unacceptable: capsules. In addition since the cross-linking of the elastomer is complete before the drug is introduced, contamination or degradation of the drug as a result of the conditions encountered during cross-linking is eliminated. In addition, since the capsules which are filled with the drug have been previously tested for defects and since no holes are introduced into the capsule wall during filling, there is percent certainty that during use, the drug-filled capsules will not release the drug at a too rapid rate which is hazardous to the health of the patient. The introduction of an inflating gas, and its subsequent removal also provide means for purging the capsules of air or oxygen.

FIG. 1 is a schematic representation of one embodiment of this invention wherein the acceptable capsules are inflated by means of increased gas pressure in the exterior walls and are subsequently filled with a drug in accordance with the procedure described in my copending application, Ser. No. 860,195 filed Sept. 23, 1969 now U.S. Pat. No. 3,609,937 issued Oct. 5, 1971.

Referring to FIG. 1, the capsules are placed in a pressure chamber 1, and subjected therein to a gas pressure for a sufficient period to fill the interior of the capsules with gas. The pressure is then reduced in the pressure chamber to cause in flation of acceptable capsules and deflation or explosion of unacceptable capsules. While the acceptable capsules are in an inflated state, all the capsules are transported from pressure chamber 1 to a capsule separation step 2, wherein the acceptable capsules are separated from the unacceptable capsules which are discarded.

The acceptable capsules, whether in the inflated state or after they have become deflated are directed to a capsule immersion step 3 wherein they are immersed in a solution of the drug for a sufficient period to cause effusion of the gas from the capsules and countereffusion of the solution into the capsules. The capsules, filled with the drug solution are removed from the capsule immersion step 3 and directed to a solvent evaporation step 4 wherein the capsules are heated at a moderate temperature to evaporate the solvent and cause effusion of the solvent from the capsule interior to leave the solid drug therein. The drug filled capsules are then directed to step 5 to remove any coating of the drug on the exterior surfaces of the capsules. The capsules are removed from step 5 and are ready for use.

In carrying out the process of this invention, spherical or other shaped capsules are formed from elastomeric material so processed that the resulting hollow capsule is chemically cross-linked (vulcanized) and contains no intentional hole of any kind. When necessary, the capsules are treated to remove any by-products from the cross-linking step which may degrade the drug. The cross-linked hollow capsules are placed in a pressure vessel which is then closed. An inert gas such as carbon dioxide is admitted into the vessel at a high pressure level, and the capsules are allowed to rest in this environment for a period of time after which the pressure of the gas is suddenly released. The pressure can be reduced to atmospheric pressure or the capsules can be placed in a vacuum. Upon the release of the pressure, the acceptable capsules having no holes and having relatively strong walls become inflated due to the gas under such high pressure therein. The unacceptable capsules either become deflated or explode. All of the capsules are transported to an apparatus which effects separation of the larger acceptable capsules from the smaller unacceptable capsules such as a sieve containing holes slightly greater in diameter than the inflated capsule. All those capsules or fragments thereof that, by reason of defects pass through the holes, are discarded and only those capsules which are inflated by reason of the contained high pressure gas are retained.

The capsule to be tested is formed from an elastomer which is linked to a degree so that it retains its shape and its flexibility. lts cross-linked elastomer should be compliantly resilient andhave an initial elastic modulus in tension of between about 40 p.s.i. and 500 p.s.i. so that it can withstand the pressure exerted during inflation while retaining its shape under forces normally encountered in the body. The capsule can be any shape which renders it suitable for implantation such as spherical, elliptical, pillow-shaped or the like. The thickness of the capsule walls is such that the capsule is self-sustaining, mechanically and structurally strong to resist impact forces and permits diffusion of the drug at a controlled rate. The wall thickness depends upon the particular elastomer employed but ordinarily should be between about 1 mm. to 2 mm., and the capsule should be between about one-half cm. to 2.0 cm. across the major axis so that a sufficient quantity of the drug can be retained therein.

Exposure of the capsules to a non-condensable inert gas such as carbon dioxide under high pressure serves to accomplish two ends simultaneously: firstly to replace the contained oxygen and nitrogen gases and secondly to lead to a high gas pressure inside of the capsule as a consequence of effusion of the gas through the capsule wall.

When the formed capsules are exposed to high gas pressure for example carbon dioxide at 30 atmospheres pressure in the pressure vessel the capsules may instantaneously buckle. However, since the compressive strength of most materials far exceeds tensile strength, no significant mechanical test of a capsule is involved in this step. The pressurizing gas gradually effuses into the capsule to replace the gas present in the capsule prior to the pres'surizing step which effuse outwardly. After a period of time depending upon the capsule wall thickness and the permeability of its wall, the capsule and the gas pressure inside and outside the capsule are in equilibrium.

Suitable, inert, noncondensable gases which can be employed are carbon dioxide, nitrogen, hydrogen, helium, and the like. A suitable high pressure which can be employed is that which will cause moderate inflation of the capsules when the pressure is reduced to atmospheric pressure or lower and will normally be within the range of p.s.i. to 2,000 p.s.i. It is preferred to employ an inert gas present only in negligible concentration in air so that the rate of effusion and countereffusion of the gas is substantially increased. Thus, it is preferred to employ carbon dioxide, hydrogen or helium.

When the external pressure is suddenly released, the gas in those capsules having perfect walls can only escape by gradual effusion whereas capsules having gross leaks will immediately lose their gas pressure and those which are mechanically weak will explode. Consequently, acceptable capsules rapidly expand at this stage and thereafter gradually decrease to their normal size over a period of hours. This permits ease of separating inflated acceptable capsules from unacceptable capsules on the basis of size or buoyancy. For example, the inflated capsules can be retained on a screen having holes of a diameter slightly larger than that of the original capsule, while defective capsules or fragments of exploded capsules pass through the screen to be discarded. Alternatively, the capsules can be separated on the basis of buoyancy since the inflated capsules are more buoyant than the defective capsules. A moving stream of gas or a liquid can be employed for the separation.

In one embodiment of this invention, capsules made from wall materials that are cross-linked at or below room temperature can be tested for wall integrity without using a gas pressurizing step. In this embodiment, the capsules are expanded by suddenly vaporizing a solid material which vaporizes at moderate temperature such as napthalene, camphor, pdichlorobenzene, or ordinary water ice contained in the cap sules or by vaporizing a liquid solvent contained in a core material which subsequently becomes the reservoir for the drug to be contained.

The easily vaporizable solid is present in the capsules by virtue of the particular technique used to form the capsule. Ice spheres cooled to below 0 may be dipped in a paste of poly (alkyl siloxane), acetoxy terminated, or any other material which vulcanizes at or near room temperature. Thecapsules are then vulcanized in any convenient manner such as by transferring the ice-containing capsule to a mineral oil bath and bubbling air therethrough to remove acetic acid and progressively cure the capsule. This treatment can be effected in about 3 hours at about 5 C. Thereafter the capsules can be transferred to a warm water bath to complete extraction of acetic acid, for about l hour when ice is employed. Thereafter the capsules are heated to vaporize the contained water to a pressure of about 7 atmospheres. The inflated capsules are then separated from the unacceptable capsules in the manner described above.

The following description illustrates one method whereby the capsules which have been tested in accordance with this invention can be filled with a drug. The capsules that have proved to be leak free and of high tensile strength while still containing significant qualities quantities of gas are immersed in the nearly saturated solution of the drug to be introduced. The solvent swells the walls of the capsule to varying degrees depending upon the elastomeric composition and the solvent used and causes an increase in the volume of the capsule and its permeability to gas as well as to the solvent solution. As the gas effuses out through the wall its partial pressure in the interior drops while the drug solution effuses into the capsules. The ultimate equilibrium state is reached when the concentration of gas is substantially identical in composition with the solution at the exterior wall of the capsule. It is highly desirable to operate with nearly saturated solution of the drug in order that when the subsequent step of removing the solvent is commenced immediate crystallization of the drug within the capsule will be accomplished.

Following the filling period, the capsules are treated to evaporated the solvent inside the capsule such as by exposing the capsule to a current of air or inert gas whereby the solvent is evaporated and dissolved drug is precipitated by crystallization of the drug in the capsule.

Toward the end of the evaporation process the previously solvent-swollen capsule wall begins to shrink and the contained drug occupies most if not all of the volume of the final capsule. Obviously the wall of the capsule has finite permeability for the contained drug and therefore during the evaporation step some of the drug will effuse out with the solvent and may be deposited as a powdery film on the capsule. This film may be easily removed by subsequent mechanical processes such as by washing.

The elastomeric materials employed to make the capsules of this invention are vulcanized by well known vulcanizing procedures in which adequate temperatures and period of time can be used to insure products of high strength and quality. It has been found that these procedures effect the production of capsules having a maximum wall integrity and uniformity. As an optional step, depending upon the elastomeric polymer used and its compounding ingredients, it may be necessary to carry out a step to remove by-products obtained from the vulcanizing step. Thus a solvent extraction may be employed to remove from thecross-linked elastomeric material by-products obtained from the decomposition of cross-linking initiators such as to remove phenyl benzoate obtained from the decomposition of benzoyl perioxide initiator. This step may not be requiredwhen for example previously purified linear polymer is used and where cross-linking is effected by ionizing radiation such as in a Van de Graff generator.

The solvent employed should dissolve the drug to afford the preparation of concentrated solutions thereof and must be inert to the drug. The choice of solvent depends upon the drug to be employed and upon its compatibility with the elastomeric material employed in the capsule. Suitable solvents include alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, and the like; detones such as dimethyl ketone, diethyl ketone, methyl ethyl ketone and the like; aliphatic hydrocarbons such as pentane, hexane, heptane or the like; aromatic hydrocarbons such as benzene, toluene, xylene, or the like; and mistures thereof.

Representatives of the drug which can be encapsulated by this process are listed in the above-cited Long and Folkman Patent. The solubility of these drugs are well known and the choice of solvents to be employed therewith is made in accordance with the criteria set forth above.

Any pharmaceutically acceptable cross-linked elastomeric material may be used that has a low but finite permeability to the contained drug to give accurate slow release of the drug upon implantation. Any additives usually employed in the elastomeric materials may be employed such as fillers, or the like, provided only that the capsule after its processing retains its final shape. Generally speaking, hydrocarbon rubbers and silicone elastomers are satisfactory for drugs having significant water solubility. Drugs with high lipid solubility may require encapsulation in the more polar elastomers such as polyurethanes or the like. However, it is also feasible to encapsulate drugs with high lipid solubility in lipophilic elastomers such as silicone rubber, by designing the capsule with a relatively thick wall, thus making a long diffusion path for the drug, or by compounding the elastomer with a significant content of platelike filler, such as gold flake, platinum flake, or mica, that significantly reduces its permeability. It will be understood that capsules with thicker walls or with significant filler content will require greater gas pressure in external pressurization or greater internal vapor pressure to produce the subsequent degree of volume expansion of acceptable capsules whereby they are separated from defective capsules. Silicone rubber is preferred because of its very high permeability to carbon dioxide, its susceptibitlity to swelling by alcohols, its relative freedom from toxic products of vulcanization, and its inertness in an implanted material.

The following examples illustrate the present invention and are not intended to limit the same.

EXAMPLE I Spheres initially 2 mm. in diameter are formed by pouring a syrup containing 10 wt polyvinyl alcohol (99 percent deacetylated) 8 wt formaldehyde and 82 wt water, acidified with sulfuric acid to a normality 0.1N, into spherical molds of 2 mm. diameter and heating the material for 50 minutes at 70 C. This causes cross-linking so that a porous gel is formed, being chemically polyvinyl alcohol co-acetal, containing at equilibrium with isotonic saline about -88 wt water. The spheres thus formed are dehydrated in a low temperature oven to a state such that they contain 50 wt water, and have a diameter of about 1.7 mm. They are then dipped in acetoxy-terminated polydimethyl silox-ane at 20 C. Hydrolysis begins immediately at the interface between the contained gel sphere and the silicone pre'polymer, resulting in cross-linking of the silicone rubber, after about 5 hours. The resultant capsules are next tested for integrity by plunging them in a glycerol bath heated to C. Immediately vaporization of the water in the gel results, to inflate acceptable capsules but explode capsules with weak silicone shells and fails to inflate capsules with pinhole leaks, since the steam generated rapidly escapes. The acceptable capsules are separated from the others by methods recited above. This type of capsule is particularly useful for containing alcohol drugs, such as insulin, and is filled with these drugs by allowing them to dwell in nearby saturated alcohol solutions of the drug. The alcohol is subsequently evaporated leaving the drug in the porous gel within the silicone rubber capsule shell. Because the interior gel was treated with a high content of water, it seeks to re-establish the equilibrium with available water. Thus when the capsule is implanted, the slow diffusion of water from living tissue causes the interior to swell toward its initial diameter (2 mm.) thereby placing the silicone rubber shell in moderate tension.

EXAMPLE II Capsules especially suitable for containing lipid soluble drugs are made in the following manner; a silicone rubber polymer, such as linear polydimethyl siloxane capped with acetoxy groups, first is diluted with a suitable solvent, e.g., an ether, to a volume fraction of polymer of as low as one-third. The resulting paste is forced into mating hemispherical molds formed, for example from microporous porcelain, microporous polyvinyl chloride, or any rigid material capable of transmitting vapors of water and of acetic acid but inert toward the solvent in the silicone rubber composition. The mold and its contents are stored in a chamber saturated with water vapor and with the solvent in the silicone rubber so that evaporation of solvent cannot occur through the porous mold, but hydrolytic cross-linking can occur.

The cross-linking reaction is substantially complete typically after 8 hours at 30 C. and the spherical pieces formed, containing practically all of the solvent with which they were compounded. The capsules are now exposed to circulating warm air to vaporize the solvent, thereby shrinking them in proportion to the percent of solvent that was removed. The resulting silicone rubber core pieces are in a state of elastic strain, and when given the opportunity subsequently to expand by imbibing a solvent, will do so. These silicone rubber core pieces are now employed with a vulcanizable elastomeric compound by dipping the cores in, or spraying the core with a latex or a solution of the elastomeric compound, or by wrapping the cores with sheeted, plastically adhesive elastomeric compound, or by any other convenient method. The elastomeric compound may contain as its principal or only elastomer any of the following: poly-1,4 cis isoprene, poly-1,4 cis butadiene, butadiene-styrene, butadieneacrylonitrile, or polychloroprene. The polar butadieneacrylonitrile and polychloroprene polymers being relatively inert toward lipid drugs, are to be preferred when slow release fect thermal vulcanization. After the core has been enveloped with the elastomeric compound in the form of a shell, this shell material is vulcanized by any method leading to chemical cross-linking of the elastomeric molecules, including thermal cross-linking, radiation cross-linking, and cross-linking effected by contact with a suitable external agent, for example, sulfonyl chloride in the case of the hydrocarbon rubbers.

The finished capsules, containing solvent-free silicone rubber cores and the chosen elastomeric coatings now in a vulcanized or cross-linked form, are soaked for a period of an hour or more in a solvent which is the same as that used in the original silicone rubber mixture (for example an ether), or a solvent of comparable solvating power toward the silicone rubber. This solvent is chosen for convenience so as to have a vapor pressure of the order of 3 to 30 atmospheres at temperatures between 100 and 200 C. Upon immersion in this solvent, the external elastomeric shell becomes swollen though relatively less than the silicone core and in any case permits transmission of the solvents into the silicone core. This core now attempts to swell back to the size in which it was crosslinked, against the tension exerted on it by the exterior elastomeric coating. It is sufficient to fill the interior silicone core with 10 vol% solvent to carry out the testing for integrity, even though the initial content of solvent was much greater (for example 67 percent).

The testing is carried out by rapidly heating the capsule to a temperature such that the absolute partial pressure of the solvent is at least 3 atmospheres, preferably more. This causes rapid vaporization of the solvent in the silicone core, but owing to the instance of the exterior elastomer shell, if perfect (strong, and free of pin-holes) the vaporized solvent is contained for a period causing expansion of the exterior shell, thus, providing the basis for separation of acceptable from non-acceptable capsules. This may be carried by passing the capsules over a mesh which retains only the inflated ones. Alternatively, when the silicone core pieces are compounded with substantial percentages of barium sulfate (to permit subsequent X-ray detection), around 40 to 70 percent by wt., the entire capsule when not inflated has a specific gravity in excess of 1.3. Thus, it is possible to float acceptable inflated capsules on the surface of a hot 150 C.) glycerol water bath, whereas those capsules that fail to inflate sink to the bottom of the bath.

The acceptable capsules are then filled by soaking the capsules in a concentrated solution of the lipophilic drug, for ex- EXAMPLE 111 It is possible to simplify the overall process by filling the capsule with the drug and then testing, if it is permeable to accept loss of drug in unacceptable capsules. This is accomplished by carrying out all the steps of the previous embodiment, recited above, through the vulcanization of the exterior elastomeric shell. At this point, the capsules not yet tested are immersed in a solution of the drug to be contained (e.g., estrogen) in a highly volatile solvent (e.g., dimethyl ether). The capsules gradually swell as the silicone rubber interior cores avidly imbibe the solution. The capsules are then rapidly heated to about 100 C, which rapidly vaporizes the ether and expands the exterior shells of acceptable capsules, so that they may be separated from the unacceptable capsules. This temperature is, however, not sufficient to cause denaturation of the estrogen, since oxygen is of necessity excluded. Following classification, the acceptable capsules are subjected to further drying to remove the residual solvent.

EXAMPLE IV The following composition is prepared on a two-roll mill:

poly (dimethylsiloxane) with 0.1 mol% The silicone rubber composition is sheeted out to a thickness of about 4.0 mm. which is then stamped from discs, approximately 1.1 cm. in diameter. The discs are placed in a companion mold having a male and a female part, each of hemispherical shape such that, when the parts are fully closed, the discs are deformed into hemispherical shells having an outer diameter of 1.0 am, an inner diameter of 0.8 cm., and a depth slightly greater than the outer radius of 0.55 cm. The two parts of the mold containing the composition are quickly brought to a temperature of C. which initiates the vulcanization process. At the end of approximately 4 minutes, the male part of the mold is removed leaving the female (hollow) part holding the now gelled but incompletely cross-linked silicone rubber in the form of a hemispherical shell. Two female mold sections each containing a hemispherical shell are brought together under moderate pressure so that the shells are joined at their rims to form a complete spherical capsule. The vulcanization process is continued by heating the molds to 100 C. for an additional 20 minutes. Thereafter, the hollow spherical capsules are sufiiciently cross-linked to resist collapse and also form the spherical shells by the coalescence and cross-linking of molecules between the originally contiguous rim surfaces. Either one of the two female molds enclosing the spherical capsules is removed and the capsule, resting in the other mold, is cured for 10 hours at 210 C. in an air oven to effect total decomposition of the peroxide, evolution of volatile by-products, and completion of the cross-linking reacnon.

The cross-linked capsules are placed in a pressure vessel, and carbon dioxide is admitted into the vessel from a cylinder until the pressure is 450 psi. For best results the capsules remain in the vessel under this pressure for 1 hour. The gas pressure is then suddenly released, the vessel is opened and the capsules are poured over a square weave mesh screen having a clearance between wires of 1.1 cm. Alternatively, a sheet with punched holes of 1.1 cm. may be used. Defective capsules and those with pinholes rapidly lose carbon dioxide and shrink to their initial diameters, whereupon they fall through the holes. Acceptable capsules retain the carbon dioxide and immediately expand to a diameter of 1.3 cm. or more (depending on the tensile modulus which is a function of filler loading, vulcanizing conditions, elastomer composition, etc.). The carbon dioxide deffuses through the capsule wall, flushing out gases previously contained in the capsule. While the capsule is till slightly inflated, it is immersed in an ethyl alcohol solution of insulin to be diffused into the capsule for a period of 5 days. The capsules are then removed from the solution, heated to about 50 C. for about 6 hours to remove solvent from the capsule interior to obtain capsules filled with insulin.

1 claim:

1. The process of forming filled, structurally strong, holefree capsules which comprises testing capsules for leaks and for strength, said capsules having a continuous wall formed of a cross-linked permeable elastomeric material by increasing vapor pressure of a vaporizable material within the capsule without puncturing the wall to generate vapor therefrom and thereby cause inflation of only acceptable capsules, separating the inflated capsules from unacceptable capsules, and replacing the vapor with a solid or a liquid material by immersing the capsule in a solution comprising the liquid or the solid dis solved in a solvent for a sufiicient period to cause effusion of the solution into the capsule and countereffusion of the vapor from the capsule, removing the capsule from the solution and evaporating solvent from the interior of the capsule.

2. The method for testing capsules for leaks and for strength, said capsules having a continuous wall formed of a cross-linked permeable elastomeric material which comprises; subjecting the exterior of the hollow capsules to an elevated gas pressure for a sufficient period to fill the capsule interior by diffusion through the continuous wall with an inert gas at elevated pressure, reducing the gas pressure on the exterior of the hollow capsules to cause inflation of only acceptable capsules and separating the inflated capsules from unacceptable capsules.

3. The process of claim 2 wherein the elevated pressure is between 100 p.s.i. and 2,000 psi.

4. The process of claim 2 wherein the pressurizing gas is carbon dioxide.

5. The process of claim 2 wherein the acceptable capsules are separated from unacceptable capsules by placing the capsules previously treated with the gas on a sieve having holes of a diameter slightly smaller than the diameter of the inflated capsules and larger than the non-inflated capsules.

6. The process of claim 1 wherein capsules having cores are separated by flotation on a bath of specific gravity such that unacceptable capsules sink while the acceptable capsules float by reason of their inflation.

7. The process of claim 1 wherein the vaporizable material is a solvent dissolved in a polymer core, said solvent separated from the group consisting of a lower alcohol, a lower ether and mixture thereof.

8. The process of claim 1 wherein the vaporizable material is a solvent held by capillarity in a porous core said solvent selected from the group consisting of a lower alcohol, a lower ether and mixture thereof.

9. The process of claim 1 wherein the pressure in the capsules is increased by vaporizing water therein.

10. The process of claim 9 wherein the elastomer is a silicone rubber vulcanized at room temperature.

Claims (9)

1. 2. The method for testing capsules for leaks and for strength, said capsules having a continuous wall formed of a cross-linked permeable elastomeric material which comprises; subjecting the exterior of the hollow capsules to an elevated gas pressure for a sufficient period to fill the capsule interior by diffusion through the continuous wall with an inert gas at elevated pressure, reducing the gas pressure on the exterior of the hollow capsules to cause inflation of only acceptable capsules and separating the inflated capsules from unacceptable capsules.
2. 3. The process of claim 2 wherein the elevated pressure is between 100 p.s.i. and 2,000 p.s.i.
3. 4. The process of claim 2 wherein the pressurizing gas is carbon dioxide.
4. 5. The process of claim 2 wherein the acceptable capsules are separated from unacceptable capsules by placing the capsules previously treated with the gas on a sieve having holes of a diameter slightly smaller than the diameter of the inflated capsules and larger than the non-inflated capsules.
5. 6. The process of claim 1 wherein capsules having cores are separated by flotation on a bath of specific gravity such that unacceptable capsules sink while the acceptable capsules float by reason of their inflation.
6. 7. The process of claim 1 wherein the vaporizable material is a solvent dissolved in a polymer core, said solvent separated from the group consisting of a lower alcohol, a lower ether and mixture thereof.
7. 8. The process of claim 1 wherein the vaporizable material is a solvent held by capillarity in a porous core said solvent selected from the group consisting of a lower alcohol, a lower ether and mixture thereof.
8. 9. The process of claim 1 wherein the pressure in the capsules is increased by vaporizing water therein.
9. 10. The process of claim 9 wherein the elastomer is a silicone rubber vulcanized at room temperature.

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