`
`H. SPONNOBLE
`MIXING VIAL CONSTRUCTION
`
`Filed July 51, 1963
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`3,464,414
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`IN VENTOR.
`HAPB V SPO/V/(OBLF
`
`Bass and Spangenberg
`v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,010
`Exhibit 1035
`
`
`
`nited States Patent 0
`
`3,464,414
`Patented Sept. 2, 1969
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`1
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`3,464,414
`MIXING VIAL CONSTRUCTION
`Harry Sponnoble, Orange, Calif, assignor to The
`Upjohn Company, Kalamazoo, Mich., a corpora
`tion of Delaware
`Continuation-impart of application Ser. No. 752,907,
`Aug. 4, 1958. This application July 31, 1963, Ser.
`No. 299,039
`Int. Cl. A61j 1/00; 136541 ]/04, 79/00
`U.S. Cl. 128—-272
`
`1 Claim
`
`15
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`ABSTRACT OF THE DISCLOSURE
`A plural compartmented mixing vial is disclosed which
`has upper and lower chambers separated from one an
`other by a center sealing plug of butyl rubber coated with
`silicone ?uid. The upper chamber is liquid ?lled while
`the lower chamber contains a desiccated pharmaceutical
`product. A piston located at the top of the upper liquid
`containing chamber when compressed, hydraulically dis
`charges the center plug into the lower chamber allowing
`mixing of the contents just prior to use. The sealing plug
`prevents moisture from passing into lower chamber since
`butyl rubber prevents moisture transmission there
`through. The silicone ?uid aids as a lubricant in easy dis
`placement of the butyl plug when the piston is actuated.
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`This application is a continuation-in-part of my ap
`plication Ser. No. 752,907, ?led Aug. 4, 1958, and now
`abandoned. The invention disclosed herein relates to an
`improvement in a plural compartment mixing vial con
`struction and, more particularly, relates to an improved
`center seal plug which may 'be placed between the com- -
`partments for temporarily isolating same from each other.
`It has been previously suggested to provide a two com
`partment mixing vial with a constriction between the
`compartments thereof de?ning a seat against which a
`natural or synthetic rubber plug was seated to thereby
`isolate the compartments from each other. One of the
`compartments is adapted to contain a solid material, such
`as a desiccated pharmaceutical product, while the other
`compartment is adapted to contain a liquid, such as an
`aqueous diluent or solvent for the solid material. A piston
`is snugly and slidably disposed at one end of the liquid
`containing compartment and is arranged so that it can be
`manually forced into said compartment to pressurize the
`liquid therein and thereby exert suf?cient hydraulic pres
`sure on the plug to discharge it into the solids-containing
`compartment whereupon the liquid enters the compart
`ment and is mixed with the solid material therein. Such
`vials are especially well adapted for use as packages for
`those pharmaceutical products which are used in solution
`form but are best stored in dry or solid form. In partic
`ular, such vials are useful for packaging parenteral form
`ulations which are not stable for a prolonged period of
`time and, thus, must be formed immediately before use,
`usually by mixing the medicinal ingredients which are in
`a sterile powder form with a suitable sterile diluent which
`consists essentially of water. However, prior vial construc
`tions of this type have not attained substantial com
`mercial acceptance because an excessive amount of
`moisture is transmitted from the liquid-containing com
`partment into the solids-containing compartment and, since
`many sterile powder formulations are sensitive to water,
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`2
`the medicinal agents become unstable during prolonged
`storage, particularly when stored at elevated temperatures.
`Inasmuch as parenteral formulations are frequently stored
`by the purchaser thereof for an appreciable period of
`time before use, it is apparent that the quality of such a
`product could be, and was, deleteriously aifected during
`long storage in the prior vial constructions and this pre
`vented substantial commercial acceptance of this type of
`package.
`The problem of providing a structure for temporarily
`isolating a compartment containing a solid pharmaceu
`tical product from a compartment containing an aqueous
`solution to prevent water transference therebetween has
`long been recognized by workers in the art and great
`amounts of time, effort and expense have been expended
`to solve same but without commercially acceptable re
`sults, insofar as I am aware, prior to the present invention.
`It was believed that the water passed through the micro
`scopic cracks and crevices in the mating walls of the vial
`andthe plug which are inherently present as a result of
`the manufacturing operation thereof. Accordingly, the art
`has attempted to solve this problem by using a more
`deformable rubber plug and applying an increased pres
`sure thereon when seating same against the internal wall
`of the vial so that the plug will deform to more com
`pletely ?ll such cracks and crevices. The art has also in
`creased the length of the plug and the seat portion of the
`vial in order to provide a longer surface of contact be
`tween the seat and the plug to minimize such moisture
`transmission. Neither of these expedients has successfully
`solved the afore-mentioned problem.
`A further problem involved in prior vial construction of
`the aforementioned type arose from the fact that the plug
`is of substantially cylindrical shape and therefore has
`relatively little size tolerance. In many instances a natural
`rubber plug will, on storage of a given vial and partic
`ularly where the plug is in continuous contact with an
`aqueous solution, tend to change in size and thereby
`materially change the pressure required to move the plug
`into the solids-containing compartment. In some instances,
`natural rubber plugs have been known to shrink su?i
`ciently upon prolonged storage of the vial and upon being
`in contact with an aqueous solution such that the seal lbe
`tween the compartments is substantially impaired. To
`cure this, the prior art has attempted to use rubber plugs
`of maximum resiliency in order to accept a high degree of
`compression. This leads to the use of an oversize plug and,
`since the plug is cylindrical rather than tapering, thus
`renders the insertion of the plug very di?icult.
`A still further problem of prior vial constructions of the
`afore-mentioned type arose from the fact that plugs of
`rubber tend to vary in regard to their frictional char
`acteristics with respect to the vial wall and the tolerances
`between the internal wall of the vial and the external
`wall of the plug vary from batch to batch depending upon
`the composition and the manner in which the plugs are
`compounded and molded. This, in turn, causes very great
`di?‘iculty in effecting, and perhaps even renders impossible,
`the proper insertion of the plugs in the vials and also
`causes variations in the amount of pressure which the
`user must exert on the piston to displace the plug into the
`solids-containing compartment. While such variation is
`ordinarily of little or no consequence in the use of the
`vial, a user who manipulates a substantial number of the
`vials one after the other, as when making a series of in
`jections, may notice such variations and may feel as a
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`result thereof that the product packaged therein is of in
`ferior workmanship and this, of course, will detrimentally
`affect the commercial acceptance of the product. More
`over, where the plug is so dimensioned with respect to
`vial so as to have optimum qualities as far as preventing
`moisture transference is concerned, the plug may actually
`seize upon or so tightly engage the seat of the vial that
`it cannot be displaced therefrom by operation of the piston.
`Although considerable e?ort has been made to solve the
`problem of obtaining a plug which can be displaced from
`the seat of ‘such a vial in a uniform manner, it has not been
`possible heretofore to provide a plug capable of operation
`in such a. uniform manner which will also satisfactorily
`prevent the transmission of water from the liquid-contain
`ing to the solids-containing compartment.
`'
`A plug suitable for temporarily isolating the com
`partments of a two compartment mixing vial must have
`additional characteristics which have further complicated
`the problem of providing a suitable plug structure. Rub
`bery compositions are often reactive with the medicinal
`ingredients and, thus, may cause contamination thereof.
`Further, during continuous contact of the plug with ‘an
`aqueous solution, as is required for the purposes of the
`present invention, various ingredients of the plug may be
`leached or attacked and may enter into solution therewith
`and, thus, may render the liquid un?t for use as a diluent
`in a parenteral formulation.
`'
`'
`~
`Accordingly, the objects of the invention include the
`following:
`(1) To provide an improved plug for use in a plural
`compartment mixing vial to temporarily isolate the corn
`partments from each other;
`‘
`'
`(2) To provide an improved plug, as aforesaid, which
`will virtually eliminate transference of moisture from one
`compartment to the other;
`(3) To provide an improved plug, as aforesaid, which
`will sealingly engage the internal wall of the vial be
`tween the compartments with a substantiallly uniform
`pressure so that it may be displaced from such sealing
`engagement by application of a suitable pressure, which
`pressure will be substantially uniform for vials of similar
`construction;
`(4) To provide an improved plug, as aforesaid, which
`will not deleteriously affect the contents of either of the
`compartments;
`(5) To provide an improved plug, as aforesaid,'which
`may be continuously exposed to a liquid diluent consisting
`essentially of Water without either permitting transference
`of moisture or effecting any contamination of the water
`or the solid materials; and
`-
`'
`(6) To provide an improved plug, as aforesaid, which
`is well adapted to be loaded by unskilled operators using
`automatic or semi-automatic ?lling machinery.
`(7) To provide an improved plug, as aforesaid, which
`can be inserted into the vial with greater ease and with
`less pressure, and which once positioned in the vial will
`remain in such ‘position with no tendency to slide into
`the upper or the lower compartment until it is forced
`to do so by the user of the vial.
`Other objects and advantages of the invention will be~
`come apparent to those acquainted with devices of this
`type upon reading the following description and inspect
`ing the accompanying drawing which is a central sectional
`view through a vial structure embodying the invention.
`In all of the foregoing discussion, as well as in the
`speci?c description hereinafter following, it has been
`and will continue to be assumed for illustrative purposes
`that the lower portion of the vial contains a soluble
`solid material and the discussion will proceed on this
`assumption. It will, however, be recognized that said
`compartment may within the scope of the invention con
`tain a dilutable liquid instead of or in addition to a
`soluble solid, providing only that the upper compart
`ment contains an aqueous material for diluting or placing
`into solution the material in said lower compartment,
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`4
`and all of the discussion herein will be understood ac
`cordingly.
`I have discovered, unexpectedly in view of the prior
`art, that the abovementioned problems are satisfactorily
`solved where the center seal plug for temporarily isolating
`the compartments from each other is formed of butyl
`rubber and the center seal plug is coated with a thin ?lm
`of a silicone. The term “butyl rubber” as used in the
`description and the annexed claims shall include both
`substantially pure butyl rubber and blends of butyl
`rubber with other rubbery materials so long as such
`blends have substantially the same physical and chemical
`characteristics as butyl rubber. The term “silicone” refers
`to organo-polysiloxanes. Contrary to the opinion of the
`other workers in the art, I have discovered that a primary
`cause of moisture transmission through natural rubber
`center seal plugs is the permeability of the plugs them
`selves to passage of moisture. That is, a substantial
`amount of the water which moves from the water-contain
`ing to the solids-containing compartment passes through
`the natural rubber plug rather than between the plug and
`the wall of the vial and, thus, no matter how tight a seal
`is provided between the plug and the vial, a substantial
`amount of moisture will be transferred, which amount
`has, in the past, been sufficient to deleteriously affect the
`solid contents of the other compartment, particularly
`where such contents are solid pharmaceutical ingredients
`sensitive to moisture.
`A further and unexpected advantage of the butyl
`rubber plugs of the invention lies in its relatively high
`resistance to shrinkage. The natural rubber center seal
`plugs, heretofore used, have a marked tendency to shrink
`upon aging either in air or in contact with water. Such
`shrinkage seriously impairs the seal between the com
`partments of the vial and permits still further moisture
`transference. A butyl rubber plug has a much higher
`degree of stability as regards shrinkage, either in air or
`in contact with an aqueous liquid, and hence maintains a
`much more reliable seal between the compartments. This
`is of particular advantage where both compartments con
`tain aqueous solutions. In such a case, transfer of water
`vapor between the compartments is of little consequence
`since the only effect thereof would be to change the
`relative concentrations of the solutions in the respective
`compartments and this can ordinarily be accommodated.
`On the other hand, if the plug should shrink sufficiently
`to permit seepage of a solution from one compartment
`into the other, the solute in such solution would be mixed
`with the solute in the other compartment prematurely
`and thus, a primary purpose of the vial, i.e., to isolate the
`solutes in the compartments from each other would be
`defeated. Therefore, it is apparent that substantial ad
`vantages .are attained by the butyl rubber center seal
`plug of the invention since its resistance to shrinkage
`effectively eliminates the possibility of the solutions in
`the respective compartments passing into the other and,
`thus, the aforesaid primary purpose of the vial is effec
`tively accomplished.
`I have further discovered that when a butyl rubber
`plug is coated with a thin ?lm of silicone, the insertion
`of the plug into the vial can be effected more easily and
`with less pressure than is the case with an uncoated plug
`which is otherwise identical and which is so dimensioned
`with respect to the vial as to have optimum properties
`as far as preventing moisture transference between the
`compartments is concerned. Further, the pressure re
`quired to displace the silicone-coated, butyl rubber plug
`into the lower compartment will be much more uniform
`for a series of vials of the same size. Silicone-coated, butyl
`rubber plugs will not stick to one another and they will
`slide easily along the parts of the stoppering machine and,
`hence, they can be placed in the vial with a minimum of
`difficulty. Insofar as I am aware, it has not been suggested
`previously to coat a butyl rubber plug for use in a mixing
`vial construction with a silicone. I have discovered, how
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`ever, that a butyl rubber plug coated with a thin silicone
`?lm effectively solves the problem of preventing moisture
`transference between the compartments of a. mixing vial
`and at the same time it provides substantially uniform
`operation.
`In discovering that a butyl rubber plug coated with a
`silicone ?lm satisfactorily solves the afore-mentioned prob
`lems I have disregarded the prior art teaching that the
`rubber plug should be as compressible and elastic as
`possible in order to effect a tight seal and that such a
`plug should be substantially compressed so that it will
`be in tight sealing engagement with the internal wall of
`the vial. Butyl rubber is substantially less elastic and
`compressible than other rubbery materials, and, in fact,
`is rather dead since it will not bounce to any appreciable
`extent. Thus, it would appear following the prior art
`teachings that a butyl rubber plug would be less satis
`factory than is a natural rubber plug for providing a seal
`between the compartments. However, I have discovered
`that such is not the case since a butyl rubber plug coated
`with a silicone ?lm will provide an effective seal between
`the compartments, which seal is of such effectiveness that
`moisture transmission therebetween is virtually eliminated.
`The effectiveness of the seal is enhanced by the fact that
`a butyl rubber plug coated with a silicone ?lm readily
`remains in the shape to which it is deformed or distorted
`when it is compressed into sealing engagement with the
`vial seat and has a higher degree of dimensional stability.
`Thus, when the butyl rubber plug coated with a silicone
`?lm is in sealing engagement with the vial seat, it will
`remain in such position, whereas plugs of more resilient
`rubbery materials will tend to work out of such position
`and, thus, will allow moisture transmission to occur.
`Insofar as I am aware, the present invention represents
`the ?rst instance wherein a butyl rubber plug of generally
`cylindrical shape has been coated with a silicon ?lm and
`has been used as a sealing device under conditions where
`the plug occupies a narrow passageway connecting a pair
`of compartments and is constantly in contact with a
`liquid diluent consisting essentially of water for a paren
`teral pharmaceutical formulation. Water, together with
`a suitable preservative, such as methylparaben, propyl
`paraben or chlorobutanol, and if needed, a solubilizing
`agent, such as dimethylacetamide, is used as a liquid
`diluent. It has not been previously considered by workers
`in the art that a butyl rubber plug coated with a silicone
`?lm could be used as a seal under conditions where it had
`to be in continuous contact with such an aqueous solu
`tion and would provide a satisfactory seal to prevent
`moisture transmission therethrough into a solids-contain
`ing compartment. Since many types of rubbery composi
`tions are frequently reactive with either the solid medicinal
`agents or with the diluent or, in some instances, the diluent
`attacks the plug so that certain ingredients thereof are
`placed in solution, it is apparent that the selection of a
`suitable material for a center seal plug is necessarily a
`difficult and time consuming task. Further, reports of
`workers in the art on the suitability of various com
`positions of plugs for various uses are confusing and con
`?icting and do not lead to a correct selection of a suitable
`composition of a plug for a particular use and, in par
`ticular, do not lead to the selection of an acceptable
`composition for a plug capable of preventing moisture
`transmission between a compartment ?lled with an
`aqueous solution and a compartment containing a solid
`sensitive to moisture.
`While butyl rubber is known to be somewhat difficult
`to adhere with other materials, I have discovered that a
`butyl rubber plug will accept sufficient silicone coating
`which can be baked thereon to form a plug suitable for
`use as a center seal plug in a two compartment mixing
`vial.
`Referring now to the drawing, there is shown a vial
`construction suitable for the purposes of the invention.
`It will be understood that this vial is disclosed for illus
`
`6
`trative purposes only since the center seal plug to which
`the invention relates can be used with any two compart
`ment vial having a seat between compartments. The vial
`10 has a closed bottom wall 11 and has a constriction or
`neck portion 12 of reduced diameter intermediate the
`ends thereof which divides the vial into a lower, solids
`containing compartment 13‘ and an upper, diluent-con
`taining compartment 14. An inwardly extending ridge 16
`is provided on the inner surface of the side wall of the
`upper compartment 14 and divides same into an upper
`section 15 and a lower section 20‘. A piston 17 is snugly
`but slidably disposed within the upper section 15 and is
`movable between the upper end thereof and a position
`substantially abutting against the ridge 16. The upper end
`of the vial 10 has an enlarged ?ange 18‘ extending around
`the periphery thereof. An annular retainer cap 19 is
`sleeved over the reduced portion 21 of the plunger 17
`and the peripheral portion thereof is turned downwardly
`and then inwardly to embrace the ?ange 18 and thereby
`prevent removal of the plunger 17 from the vial.
`A substantially cylindrical plug 22 is provided for
`sealingly contacting the neck portion 12 of the vial. The
`plug has a frusto-conical end portion 23‘ at the lower end
`thereof whereby the plug may be more easily centered in
`the neck portion 12. The plug is normally of somewhat
`larger external diameter than the internal diameter of
`the neck portion 12, and, thus, when the plug is inserted
`into the neck portion, it is deformed somewhat and an
`upwardly ?aring enlargement 24 is formed at the upper
`end thereof, which ?aring enlargement sealingly contacts
`the upper end of the neck portion 12. The plug 22 when
`compressed and seated in the neck portion 12 provides
`a ?uid tight seal between the lower compartment 13 and
`the upper compartment 14.
`The plug 22 is coated over its entire surface with a thin
`silicone ?lm 26. While not in all cases essential, the piston
`17 also is coated over its entire surface with a thin sili
`cone ?lm 27 and this will promote the ease of displacing
`the plug 22 and will provide even greater uniformity in
`the pressure required to do so.
`When the plunger 17 is moved downwardly within the
`upper compartment 14, a hydraulic pressure will be ‘.m
`posed upon the plug 22 by the liquid within the upper
`compartment and it will displace the plug from within the
`neck portion 12 into the lower compartment 13. When
`such occurs, the diluent within the upper compartment
`will be admitted into the lower compartment and the
`solids in such lower compartment may be placed in solu
`tion or suspension therewith.
`It is essential for the purposes of the invention that
`the plug 22 be formed of butyl rubber since it has been
`found that a butyl rubber plug is substantially less per
`meable to transfer of vapor or moisture than other rubbery
`materials. Further, since butyl rubber is a rather dead
`material, that is, it is not as elastic as other rubbery mate
`rials, the plug will not work out of the neck portion of
`the vial as sometimes occurs with other rubbery materials
`but must be deliberately displaced therefrom by moving
`the plunger within the upper compartment 13. The lesser
`elasticity of the butyl rubber plug is also advantageous
`since it provides for a more uniform operation of the
`plunger of the piston when the plug is to be displaced
`into the lower compartment. Further, it has been found
`that the use of a butyl rubber plug makes it possible to
`satisfactorily accommodate greater variation in the tol
`erances of the plug and the vial than is possible with
`natural rubber plugs because butyl rubber plugs readily
`remain in a deformed condition. The plug 22 is coated with
`a silicone ?uid, say as Dow Corning DC 35 Mold Release
`Emulsion, to enhance the ease of displacing the plug
`into the lower compartment. I have found that the hard
`ness of the butyl rubber plug should lie within a range
`of from 30 to 60 as measured by a Shore hardness test,
`and, preferably, should have a hardness of between 40 and
`50 (Shore).
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`7
`The silicone ?lms 26 and 27 are provided on the plug
`22 and the piston 17 by applying a silicone carried in
`a vaporizable liquid carrier to said plug and said piston,
`such as by placing plugs and pistons in an aqueous silicone
`emulsion. The excess emulsion is drained and then the
`plugs and pistons are heated in closed container to bake
`the silicone coating thereon. Thereafter, the carrier is evap
`orated leaving a thin, transparent silicone coating on the
`plugs and pistons.
`The silicones used are dimethylpolysiloxanes of various
`molecular weights and viscosities. They must be non
`irritating, non-toxic and non-volatile at the temperatures
`used for baking the silicone coating on the butyl rubber
`parts. I prefer to use a silicone ?uid having a viscosity
`of about 350 centistokes at 25° C., but silicone ?uids of
`somewhat lower or higher viscosity can be used. Of the
`presently commercially available silicone ?uids, those hav
`ing viscosities of 5 centistokes or lower at 25° C. are not
`suitable because they are too volatile. Silicone ?uids of
`higher viscosity (up to 60,000 centistokes at 25° C., or
`more) are usable but offer no advantage over the lower
`viscosity silicone ?uids.
`The preferred silicon ?uid is DC 35 emulsion (Dow
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`It is to be noted ‘that inner surfaces of the glass vial 10
`and particularly the neck portion 12 thereof are free from
`any coating so that the plug 22 contacts an uncoated
`glass surface. It has been found that to provide a coating,
`such as silicone coating, on the inner surface of the vial
`does not either by itself or in combination with a silicone
`coated butyl rubber plug, effectively solve the problems
`involved. In particular, the use of a silicone-coated vial
`and a silicone-coated butyl rubber plug is unsatisfactory
`because the plug can slide too easily and, thus, does not
`provide a reliable seal betwen the vial compartments.
`EXAMPLE
`A series of tests were run to determine the respective
`amounts of moisture transmisison with a natural rubber
`center plug and a butyl rubber center plug coated with
`a silicone ?lm as above described. In each instance, the
`vials were of the construction illustrated in the drawing
`in this application and each thereof contained identical
`solids in the lower compartment and identical liquids in
`the upper compartment. The percentage of moisture in
`the powder was determined for vials stored at different
`temperatures, the tests being made at the time intervals
`indicated in the following list.
`
`Percent of moisture in powder
`Storage temperature
`
`Butyl
`rubber
`
`40° C
`25° 0.
`4° 0.
`Natural
`Butyl Natural
`Butyl Natural
`Center seal composition _____ .1 rubber rubber rubber rubber rubber
`Storage period:
`Initial __________________ ._
`
`1 month ________________ . _
`
`2 months _______________ __
`
`3 months _______________ _.
`
`6 months _______________ . .
`
`9 months. _
`
`.._
`
`12 months ______________ __
`
`0.35
`0. l4
`0. 28
`1. 54
`
`0. 35
`0. l4
`0. 28
`None
`
`1. l2 _________ _.
`2. 8G
`0. 42 .
`2.48
`0. 42 ___________________________ __
`2. 48
`0. 49
`.
`3. 28
`0. 70
`. .
`5. 86
`0. 79
`3.39 ________ _ _
`5. 89
`0. 56
`3. 52 ________ _ .
`7. 35
`1. 27
`3. 96
`0. 41
`6. 54
`1. 37
`3,38
`0. 62
`8. 35
`1. 12
`4. 65
`1. 14
`7. 71
`0. 84 ________ 1.
`0. 77
`
`1. 06
`0. 98
`1. 10
`1.11
`0.35
`0. 70
`
`0. 70
`0. 42
`0.35
`0.35
`1. 10
`0. 77
`
`Corning) that is, an equeous emulsion having the follow
`ing formula (percentages by weight):
`35% dimethylpolysiloxanes
`1.75% oleic acid
`0.55% ethanol-diisopropanol amine
`Water q.s.
`The above-described silicone ?uid is diluted with water
`before it is applied to the butyl ruber parts. The preferred
`concentration of the silicone ?uid is 4% by weight of the
`total weight of the solution but a somewhat lower con
`centration, such as about 3% by weight can be used. More
`over, higher concentrations can be used with slightly im
`proved results although the 4% concentration is adequate
`for commercial purposes.
`The preferred procedure for applying the silicone coat
`ing consists in washing uncoated butyl rubber parts in a
`detergent (Dreft) solution in a laundry type washing
`machine having a rotating tub (Norwood Washer). The
`parts then are rinsed thoroughly in the washer with pyro
`gen free water. The parts then are rinsed in the Washer
`with a 4% by weight solution of DC 35 emulsion, said
`solution being 1.40% by weight dimethylpolysiloxanes.
`The excess emulsion is drained from the parts by tumbling
`in the washer. Thereafter the parts are placed in glass
`containers, covered and heated in an autoclave at 121° C.
`for 30 minutes which bakes on the silicone coating and
`also steriliz-es the parts. The parts are then dried in a hot
`air oven at 96-100° C.
`The procedure for applying the silicone coating can be
`varied considerably. For example, the silicone can be
`dissolved in a solvent, such as chloroform, and the butyl
`rubber parts dipped thereinto or the silicone solution can
`be sprayed thereon.
`
`Further, tests indicated that at least some types of natu-
`ral rubber plugs shrink appreciably upon aging, both in
`contact with aqueous material and dry, and thereby mate
`rially impair the seal otherwise existing between two
`compartments. This impairment of such seal was cured
`by the use of plugs of butyl rubber coated with a sili
`cone ?lm.
`From the above, it will be apparent that the use of a
`butyl rubber plug coated with a silicone ?lm virtually
`eliminates any signi?cant moisture transmission between
`the compartments.
`While a particular preferred embodiment of the inven
`tion has been disclosed hereinabove, this invention con
`templates such modi?cations or changes therein as lie
`within the scope of the appended claim.
`What is claimed is:
`1. A packaged pharmaceutical product comprising in
`combination:
`a substantially tubular glass body being closed at one
`end thereof and open at the other end thereof and
`having a cylindrical portion of reduced cross-sec
`tional area spaced from ‘both ends of the body, said
`body having a ?rst chamber and a second chamber
`on opposite sides of said cylindrical portion, said
`second chamber being adjacent said one end of said
`body, said cylindrical portion being of constant di
`ameter between the ends thereof and providing a
`passageway connecting said chambers and de?ning
`a seat therebetween, the internal wall of said seat
`being free of any coating;
`a one-piece, solid and cylindrical plug of butyl rubber
`having a coating consisting of a silicone ?uid, said
`plug ‘being nontoxic and having an outside diameter
`slightly larger than the inside diameter of said seat
`
`55
`
`60
`
`65
`
`70
`
`75
`
`
`
`3,464,414
`so that said plug is slideably removably positioned
`snugly within said cylindrical portion of reduced
`cross-sectional area to isolate said chambers from
`each other and thereby minimize the moisture vapor
`transmission between said chambers, the ease of dis
`placing the plug from the seat into the lower com
`partment being enhanced by the silicone fluid;
`a quantity of desiccated material in said second cham
`ber and a quantity of aqueous solvent substantially
`?lling said ?rst chamber; and
`substantially cylindrical piston means snugly disposed
`in and closing the other end of said body, said piston
`means being slideably movable axially inwardly of
`said body to act through said solvent against said
`plug for displacing said plug into said second cham
`ber to permit mixing of said solvent and said desic
`cated material.
`
`1 0
`References Cited
`UNITED STATES PATENTS
`8/1953 Parsons et al. _____ __ 128-272
`2,649,090
`9/1953 Umbdenstock ______ __ 128-—272
`2,652,182
`2,695,614 111/ 1954 Lockhart __________ __ 128—272
`2,908,274 10/1959 Bujan ____________ __ 128-—272
`FOREIGN PATENTS
`6/1958 Belgium.
`OTHER REFERENCES
`Rubber Age, “Development of Butyl Rubber,” pp. 15 8
`159, September 1943.
`
`568,541
`
`15 DALTON L. TRULUCK, Primary Examiner
`US. Cl. X.R.
`
`206-47; 2 l 5-—-6