`
`3,035,973
`Patented May 22, 1S62
`
`1
`
`3,035,973
`GELATIN CAPSULE CONTAINING CALCIUM
`DIOCTYL SULFOSUCCINATE
`Lyell J. Klotz, Cincinnati, Obio, assl;,rnor to Lloyd
`Brothers, Inc., Cinclnnali, Ohio, a eorporalion of Ohio
`No Drawing. Filed Aug. 1, 1958, Ser. No. 752,410
`4 Claims.
`(CI. 167-56)
`
`2
`pared from ~elatin plnsticized with sorbitol in which di(cid:173)
`octy! sodium sultosuccinate was not appreciably soluble.
`However, this possible solution to the "leaker" problem
`failed as it wns found that the snbstitution of sorbitol for
`5 glycerine created other problem;. Specifically, it was
`found that so mucll sorbitol was required to prepare a
`non-leaking capsule that the capsule deveolped a "bloom''
`<>n iL~ surface, i.e. bccrune white lllld opaque due to
`crystaUi7.ation of the excessive amount of required sor-
`10 h[tal. and in this condition was unsaleable. Replace(cid:173)
`ment of the sorb-itol with about 50% or more of glycer(cid:173)
`ine reduced the ''blooming .. problem but resulted in in(cid:173)
`creased "lcakcr.;" and posed still another problem, ic.
`the formation of what for a better term I have called "fiat·
`15 leN." In the "flatters," the capsule loses its form (i.e. be(cid:173)
`comes misshapen), flattens and collapses and in this form
`is also unsaleable. Attempt~ to find a suitable solvent for
`diocryl sodium sulfosuc-cinate which would prevent irs
`pas..~ge into the plasticizer of lihe shell and attempts to
`20 find a substitute plasticizer which would neither take up
`the dioctyl sodium sulfosucr:inate nor "bloom" nor re·
`suit in the formation of "flattersw were unsuccessful.
`Accordingly, and to check further into the above theo(cid:173)
`retical possibilities, calcium dioctyl sulfosuccinatc was
`25 prepared a~ noted below. It was found to be iJlliolublc
`in glycetine nnd like polyhydroxy plastlicizen; but soluble
`in oils including mineral and vegetable oils such as com
`oil, peanut oil, cottonseed oil, etc:., as well as equivalent
`non-aqueous inert oil-type solvents such 11!1 liquid poly-
`30 ethrlene glycols 200-400. Calcium dioctyl sulfosucci(cid:173)
`nate was then dissolved in mineral oil and corn oil and
`encapsulated in glycerine plasticized soft gelatin capsules
`to provide 240 mg. of the cnlcium ~nit per capsule. Con(cid:173)
`trol capsules using the same oils and glycerine plnsticiz.cd
`35 gelatin with tbe same amount of dioctyl sodium sulfa.
`succinate (240 mg. capsules) were also prepared. All
`capsules were then subjected to an accelerated "Jeaker
`test" at 40• C. and 30% relative humidity. The results
`nre shown in the following table.
`
`40
`
`The present invention relates to calcium dioctyl suJ.
`fosuccinate, i.e. the calcium salt of the bis(2-ethylhexyl)
`ester of a sulfosuccinic acid, and more specilicnlly to a
`dosage unit containing n non-aqueous, i.e. oil. solution
`of calcium dioctyl sulfosuccinatc in a wft gelntin capsule.
`This combination is unique due to its freedom from what
`is kn,own in the art as ''leakers," i.e. capsules that leak
`at the seams on standing.
`The t1se of dioctyl sodium sulfosuccinate (also known
`as Aerosol QT) in milk, fruit juices and the like for
`treating coru;tipation has been proposed heretofore. Wil(cid:173)
`son and Dickinson J.A.M.A., val. 158, pages 261-263
`See also Vaughan application Serial No.
`(1955).
`537,873, filed September 30, 1955, now abandoned. The
`use of dioctyl sodium sulfosuccinate for the treatment of
`constipation has been demonstrated as safe, reliable and
`effective and it is available today for this. purpose in
`various forms.
`One of the preferred ways of administering dioctyl so(cid:173)
`dium sulforuceinate is in solution in n 5-uitable non·
`aqueous solvent in soft gelatin capsule form. Tbe lllon(cid:173)
`aqueous solvent (such as liquid polyethylene glycol, min(cid:173)
`eral oil, com oil, etc.) mulSt be inert, i.e. not exert any
`appreciable solvent action on the gelatin comprising the
`shell. Difficulties, however, have been encountered in
`preparing <Sufficiently concentrated solutions in such sol·
`vents so that capsule" of de.~irable (small) size and con·
`tent can be used
`(see' Klotz application Serial No.
`581,855, filed May I. 1956. now Patent 2,885,32:!), but
`one of the primary difficulties has been in the presence
`of "leakers." Indeed. unless used promptly, hundreds of
`thousands of dollars have been ·lost on "rcmmsn due to
`tlle leakitl£ of the solution of dioetyl sodium sulfosucci(cid:173)
`nate from soft gdatin capsules, where even one Ienker
`messes up the whole container and makes it unsalcablc.
`Attempts to solve this problem by usc of different sol-
`vents, modified gelatin formulations, etc. have proven un(cid:173)
`successful. Unless used shortly after encapsulating,
`lcakers have been found to tum up on standing when
`solutions of dioctyl sodium sulfosuccinate arc placed in
`soft gelatin capsules.
`l n my inve.-;tigaticns in this field it was noted that it is
`L'le prnctice of the trnde to plasticize th~: gelatin used
`in making ~son gelatin" capsu·les ·with up to abuot 20 per(cid:173)
`cent glycerine or equivalent polyhydroxy aliphatic plas(cid:173)
`ticizers such as mixtures of glycerine and sorbitol con- 65
`taining up to 50 percent sorbitol, 1,2,6-hcxanetriol (tri·
`hydroxy-hc::t.'Ulc) and the like. In fact, unless a plastic(cid:173)
`izer is used, the gelatin becomes hard and brittle and is:
`unsuitable for use for these reasoN in this field.
`In my investigations it was also noted that dioctyl so(cid:173)
`dium sulfosuccinate was extremely soluble in glycerine 60
`and like plasticizers and that this might explain, at lenst
`in part, the cause of "leakcrs." For example, it appeared
`possible that the dioctyl sodium sulfosuccinate in solu(cid:173)
`tion in Lie core might gradually pass into the glycerine
`in the gelatin snd cause loss of adhesion of the heat and 65
`Indeed, this
`pre.•.sun! se.'l!cd seams of the capsule shell.
`appt.-ared like a good possibility as it was further found
`that a substantially mm-leaking capsule could he pre-
`
`45
`
`50
`
`TABLE
`
`o::
`
`.lo!ln~r~L._
`Corn~-
`Mincral
`~· ~
`Curn~ ... " ~
`
`Extended te~ts using non-aqueous oil solutions of cal(cid:173)
`cium dioctyl sulfosuccinate in glycerine or like plastic(cid:173)
`ized ~oft gelatin capsules under conditions encountered
`in storage in this field has shown them to be substantially
`free from Ienker;. For overnll solubility and freedom
`[rom !eakers corn oil is generally preferred.
`The calcium salt can be prepared by the following il(cid:173)
`lusttntive processes.
`
`Example I
`88 grams of dioctyl sodium sulfosuccinate is first dis(cid:173)
`sclved in lOO cc. of isopropanol and 25 grams of calcium
`chloride is dissolved in 50 cc. of methanol. The wlu(cid:173)
`tions arc then mixed and stirred for about 3 boUTS and
`then cooled with ice. The sodium chloride which precipi(cid:173)
`tates in the cool mixture ls removed by filtration and
`most of the alcohol is evaporated from the resulting fil(cid:173)
`trate '1'-ith heat. The liquid remaining is poured into 88
`cc. of water, and the resulting precipitate washed \\itb
`wn!er until free of chloride ion. The washed calcium salt
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1026, Pg. 1 of 2
`
`
`
`3,0311,973
`
`4
`Example JY
`
`3
`is !hen dried. The magnesium salt of dioctyl sulfosuc(cid:173)
`cinato can be prepared in a similar manner by the usc
`of magnesium chloride in place of calcium chloride.
`T'ne calcium salt can also be prepared by dissolving
`the sodium salt in isopropanol, cooling, adding sulfuric 5
`acid, num,ing the mixture to stand in an ice balh, filtering
`off the resulting sodium sulfate precipitate, nnd rea.:ting
`the resulting dioctyl ester of sulfosuccinic acid with ex(cid:173)
`cess c:::!cium carbonate. After removal of excess car(cid:173)
`bonate by filtration the calcium salt can be recovered
`from the filtrate by evaporating off the alcohol and dry·
`ing. The calcium salt can also be prepared by the nen·
`t:a liz.ation of the free acid ( dioctyl ester of sulfosuccinic
`acid} with calcium hydroxide, The ma~um salt can
`be prepared in a similar manner by use of magnesium
`carbonate or magnesium hydroxide.
`The calcium in the calcium salt is combined with
`two molecules of the bis(2-ethylhcxyl) ester of sulfosuc(cid:173)
`cinic acid and bas the generic formula C.OHT•Ca0 14S2•
`The calcium salt has properties generally similar to the
`sodium salt although tests indicate the caldum salt to
`have even greater surface active wetting properties (l 0-
`40% greater depending on ctlnccntration) and to be a
`more efficient fecal softener.
`It is soluble in inert non(cid:173)
`aqueous solvents suth as mineral oil and vegetable oils
`such as corn oil, liquid polyethylene glycol and the like
`and can be used in place of the sodium salt as a fecal
`softencr in sort gelatin c:~psule.~ in solut1ons of this type
`with little or no danger of uleakers." Due to its g:rea.t
`solubility the use of additives such as glyceryl oleates (see
`Klotz application, supm) to increase the solubility of the
`calcium su!fosuccinate are not required to obtain the con·
`centrations necessary for use \\>ith smaU easy-to-take cap(cid:173)
`sules. However, since the concentration necessary to
`produce 240 mg. calcium dioctyl sulfosuccinate in the
`convenient number 8 capsule is very near the saturation
`point, the addition of a small amount, e.g. 1-10 percent
`by volume, of glyceryl monooleate may be desirable and
`is in fact preferred to consistently insure a solution which
`will not "gel" at lowered temperatures. The following
`examples are illustrative.
`Example 11
`C:Jicium dioct}'l sulfosuccinate-----------sm--
`Corn oil, qUantity sufficient to make 25,000 ml.
`The calcium salt is dissolved in the oil with warming and
`the resUlting solution then encapsulated in glycerine
`plasticized soft gelatin capsules in accordance '1\ith stand·
`ard practices in the art to provide 100,000 #4 minims 50
`In a
`capsules containing 60 mg. of the calcium salt.
`similar manner c:~psule.~ can be readily made contain-ing
`40-240 mg. of calcium dioctyl suUosuccinate.
`Example 11I
`12.6 55
`Calcium dioctyl su!fosuccinate ___________ kg__
`Glyceryl monooleate--------------------'-- 1.8025
`Corn oil, quantity sufficient to make 24.025 1.
`The calcium salt is dL<solved in the glyceryl monoolcate
`and about 7 liters of oil with heating and then cooled nnd
`upon cooling sufficient com oil is added to bring the so(cid:173)
`lution to the required volume. The resulting solution
`is then encapsulated in standard glycerine plasticized soft
`gelatin capsules to provide 52,500 capsules containing
`about 240 mg. of the calcium salt per capsule. The solu· 65
`tion in thc capsules so prepared docs not ''gel" even at
`temperatures below room tempemture and the capsules
`are substantially free from leakcrs.
`The calcium dioctyl sulfosuccinate of the present in(cid:173)
`vention can be combined with other medicaments includ· 'TO
`ing 1,8-dihydroxyanthraquinone (danthron) or like ca(cid:173)
`thartic in a similar manner to that described in the copend·
`ing Vaughan application Serinl No. 623,282, filed No(cid:173)
`vember 20, 1956, now Patent No. 2,847,346. The fol·
`loWing example is illustrative.
`
`6,000
`
`Gm.
`Calcium dioctyl sulfosucdnate ----------------- 300
`1,8-dihydroxynntbraquinonc -------------------- 250
`Polye6ylcne glycol 2{}0 q.s. ad 2500 cc.
`The calcium dioctyl sulfosuccinate is first dissolved in
`about 1500 cc. of polyethylene glycol with warming. To
`facilitate solution and particularly lo maintain the suc-
`10 cinate in solution a small amount (e.g. about 1-5 per·
`~n!) glyceryl mono- or di-oleates can be added as de·
`scribed in tbe Klotz application, supra. The dantbron
`in fmcly divided form is then thoroughly mi:<ced with the
`succinate solution. To aid in stabilizing the suspension
`15 small amount~ of viscosifying (suspending) agents such
`as ·hydrogenated vegetable oil, white be~ and the
`like can be added to the composition in accordance with
`standard practices in this art if desired. Tbe composi(cid:173)
`tion is then t>rought up to 2500 cc. with polyethylene
`20 glycol 200 and encapsulated into :moo glycerine or like
`plasticized soft gelatin (about 0.5 cc. each) capsules.
`Each capsule contains about 60 mg. of calcium dioctyl
`sulfosucdnate and SO mg. of daothron. Formulations of
`this type are also free from "leakers."
`25 My im·estigations show that in place of the calcium
`sa.:t the magnesium salt and all toher equivalent pbanna(cid:173)
`ceuticaUy acceptable salts of the dioctyl ester of sulfosuc(cid:173)
`cinic acid (i.e. non-toxic metallic salts which do not lib(cid:173)
`erate toxic ions on ionization) can be used in the present
`110 invention providing they, like the calcium salt, (a) are
`soluble in inert non-aqueous oil solvents {e.g. mineral
`oil, fatty oils such as the vegetable and animal oils, liquid
`polyethylene glycol, etc.) useful in making sclutioo.s for
`soft gelatin capsules !lfld (b) are substantially insoluble
`35 in the plasticizer (e.g. glycerine, 1,2,&-.hexane trial, mix(cid:173)
`iltres such ll'S glycerine containing up to 50 percent sor·
`bitol, etc.) and like substances used in the manufacture
`of soft gelatin in lbe capsule art. Alkaline earth metals
`such as the calcium and magDC~.ium salts of dioctyl sul-
`40 fosuccinate (as distinguished from the alkali metal salts)
`nrc illustrative salts having these solubility characteristic'
`which are required to eliminate "leakers" as well as
`"ffatters" in the soft gelatin capsule art. The use of these
`or equivalent non.toxic salts in place of dioctyl sodium
`45 sulfosuccinatc is also highly desirable where the intake
`of sodium ions is medically contra-indicated.
`This applicati{)n is a continuation-in-part of application
`Serial No. 737,226, filed May 23, 1958, now abandoned.
`I claim:
`I. A composition in dosage unit form comprising a
`glycerine plastici7.ed gelatin-soft gelatin capsule contain(cid:173)
`ing about 40-240 mg. of calcium dioctyl sulfosuccinate
`dissolved in a non·aqueous inert oil.
`2. A composition in accnrdallce with claim 1 where
`the oil is com oil.
`3. A composition in accordance with claim 1 where the
`solution contains about 1-10% by volume of glyceryl
`monoolcate.
`4. A composition in accordance with claim 1 where
`60 the composition contains 1 ,8-dihyd.roxyaothraquinone.
`
`References Cited in the llle of this patent
`UNITED STATES PATEz..'TS
`Jaeger ---------------- June 14, 1936
`Meyer ---------------- Feb. 14, 1952
`Valentine ------------- Apr. 8, 1958
`Vaughan -------------- Apr. 12, 1958
`\laughan -------------- SepL 9, 1958
`Bryan --------------- Jan. 20, 1959
`Cardaciotto ------------ Jan. 27, 1959
`Cardaciotto ------------ Jan. 27, 1959
`
`2,028,091
`2,585,903
`2,830,010
`2,847,346
`2,851,394
`2,870,060
`2,871,157
`2,871,158
`
`OTHER REFERENCES
`J.A.M.A., WJ1son article, May 28, 1955, pp. 261-263.
`
`75
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1026, Pg. 2 of 2
`
`