United States Patent Office
`
`3,493,407
`Patented Feb. 3, 1970
`
`3,493,407
`PREPARATION OF 1\<ffiDICINAL CAPSULES FROM
`HYDROXYALKYLCELLULOSE ETHERS
`George K. Greminger, Jr., and Lewis E. Davis, Midland,
`Mich., assignors to The Dow Chemical Company, Mid· 5
`land, Mich., a corporation of Delaware
`No Drawing. Continuation-in-part of applications Ser. No.
`485,615 and Ser. No. 485,616, both Sept. 7, 1965. This
`application May 26, 1967, Ser. No. 641,457
`Int. Cl. COSb 21/24; A61k 9/04
`U.S. Cl. 106-189
`
`1
`
`8
`
`Cla:~s 10
`~·
`
`2
`clarity and solution rate. Indeed under conditions such
`as encountered in the alimentary tract, the solution rate
`of th~se capsules is superior to prior methylcellulose
`capsules and comparable to standard gelatin capsules.
`HYDROXY ALKYLCELLULOSE ETHERS
`Essential
`is a
`low viscosity, water-soluble C2-C4
`hydroxyalkylcellulose ether such as hydroxypropyl(cid:173)
`methylcellulose, hydroxybutylmethylcellulose and by(cid:173)
`droxyethylethylcellulose. Particularly effective is a low
`viscosity, water soluble hydroxypropylmethylcellulose
`with a Z-hydroxypropoxyl content of about 4-15 weight
`percent and a methoxyl content of about 18-32 weight
`percent. Other CrC4 hydroxyalkylcellulose ethers con-
`taining about 0.15-0.30 hydroxyalkyl and 1.6-1.8 alkyl
`groups per anhydroglucose units can be used.
`To achieve a desired capsule wall thickness of about
`4 mils in a single dip, the cellulose ether solution must
`contain about 10-30 and preferably 20-30 weight percent
`20 of the cellulose ether and have an operational viscosity
`within the range of about 1,000-12,000 cps. This requires
`a hydroxyalkylcellulose ether having a standard Z per(cid:173)
`cent aqueous viscosity at zoo C. of about 2-20 cps. and
`preferably about 2-7 cps. Such low viscosity hydroxy-
`25 alkylcellulose ethers are now available by processes such
`as described by Beaver U.S. Patent 3,108,890.
`AQUEOUS SOL VENTS
`Of considerable importance in the present process is
`the solubility of these hydroxyalkylcellulose ethers in
`water and aqueous mixtures of C 1-C3 alcohols which
`permits preparation and use at about room temperature
`of solutions containing up to about 30 weight percent of
`the cellulose ether. Since the capsule body is formed by
`drying of the dip coating on the capsule-forming pin, the
`preferred aqueous solvent is water or a volatile aqueous
`alcohol such as methanol, ethanol or isopropanol. Also
`the aqueous alcohol should contain at least 15 weight per(cid:173)
`cent water and preferably 15-40 weight percent. With
`less than 15 weight percent water the capsules have poor
`tensile strength.
`NON-AQUEOUS SOL VENTS
`Alternately a non-aqueous solvent system consisting
`essentially of 15-50 weight percent of a C 1-C3 alcohol
`and 85-50 weight percent of a C1-C3 chlorinated aliphatic
`hydrocarbon or a C6-C7 aromatic hydrocarbon can be
`used. To obtain rapid drying, a volatile solvent with each
`component having a boiling point between 30°-120° C. is
`50 preferred. Particularly suitable are methanol, isopropanol,
`methylene chloride, chloroform, carbon tetrachloride,
`ethylene dichloride, propylene dichloride, benzene and
`toluene. A minor amount of water such as occasionally
`present in the organic solvents can be tolerated, but the
`55 total water content should not exceed about 3-4 weight
`percent.
`
`ABSTRACT OF lliE DISCLOSURE
`Improved cellulose ether medicinal capsules are pre(cid:173)
`pared by forming the capsules from a solution containing
`about 10-30 weight percent of a hydroxyalkylmethyl(cid:173)
`cellulose and having an operational viscosity of about
`1,000-12,000 cps.
`
`15
`
`This application is a continuation-in-part of applica(cid:173)
`tions Ser. No. 485,615 and 485,616, filed by G. K.
`Greminger and L. E. Davis on Sept. 7, 1965, and now
`abandoned.
`
`BACKGROUND
`Medicinal capsules have long been made of gelatin.
`In spite of the recognized deficiencies of gelatin capsules
`under conditions of low or high humidity and examina- 30
`tion of many natural and synthetic polymers as a replace(cid:173)
`ment, none have found significant commercial acceptance.
`In U.S. Patent 2,5Z6,683 Murphy describes the prepara(cid:173)
`tion of capsules from methylcellulose by a thermal gela(cid:173)
`tion dip process. However, the clarity and rate of solution 35
`of these methylcellulose capsules in the alimentary tract
`were inadequate for commercial acceptance.
`Highly plasticized water-soluble cellulose ether com(cid:173)
`positions suitable for molding or extrusion at 1500-170°
`C. are recommended by Silvernail U.S. Patent 2,602,755 40
`for preparing flexible films or molded capsules. Such
`highly plasticized cellulose ether compositions were de(cid:173)
`veloped as indicated by Greminger and Weaver in U.S.
`Patent Z,810,659 because of the difficulties encountered
`in conventional casting and dipping operations from 45
`aqueous solutio:1 because of high viscosity and thermal
`gelation.
`
`STATEMENT OF THE INVENTION
`
`It has now been discovered that certain hydroxyalkyl(cid:173)
`cellulose ethers characterized by a viscosity of 2-20 cps.,
`and preferably 2-7 cps., as a 2% aqueous solution at
`zoo C., can be used to prepare a solution containing
`10-30 weight percent, and preferably 20-30 weight per(cid:173)
`cent of the cellulose ether from which suitable medicinal
`capsules can be obtained in a single dip coating operation.
`More specifically the hydroxyalkylcellulose ethers are
`water-soluble ethers containing about 4-15 weight per(cid:173)
`cent of C 2-C4 hydroxyalkoxyl and about 18-32 weight 6o
`percent of C1-C2 alkoxyl groups.
`Capsules can be formed from both aqueous and non(cid:173)
`aqueous solutions of these low viscosity hydroxyalkyl(cid:173)
`cellulose ethers with conventional equipment. The process
`is not dependent on thermal gelation and the capsules re- 65
`main firm and sturdy under conditions of extreme
`humidity. Also, they can be heat sealed. Without requir(cid:173)
`ing large amounts of plasticizer, they have both enhanced
`
`PROCESS CONDITIONS
`Capsule bodies can be prepared from suitable aqueous
`or non-aqueous solutions of the hydroxyalkylcellulose
`ether using commercial gelatin dip coating capsule
`machines such as described in ~v1ur.phy U.S. Patent
`2,526,683. A capsule-forming die, generally having rigid
`stainless steel pins mounted on a supporting member and
`coated with a lubricant grease, Teflon, polyethylene or
`other similar material for easy release of the dried capsule
`part, is immersed in a substantially bubble-free, solution
`,of the low viscosity hydroxyalkylcellulose ether. For
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1006 - Page 1
`
`

`
`3,493,407
`
`5
`
`3
`proper operation the solution must have a viscosity of
`about 1,000-12,000 cps. at the operational temperature
`which conveniently is about room temperature. As the die
`is gradually withdrawn from the dip coating solution, the
`excess material drains off leaving a wet coating on the
`pin from which the capsule body is formed by evaporation
`of the solvent coating. Depending on the specific solvent
`used, drying may require 10-20 minutes or more at room
`temperature. More rapid drying can be obtained using a
`warm air oven and an elevated temperature suitable for
`the particular cellulose ether-solvent system. Finally the
`dried hydroxyalkylcellulose capsule body is removed from
`the capsule-forming die, trimmed and assembled into a
`complete medicinal capsule.
`Of critical importance in forming medicinal coatings
`with automatic commercial dip coating units is the opera(cid:173)
`tional viscosity of the cellulose ether solution used in
`coating the capsule forming pins. Proper coating of the
`pins and drainage of excess solution requires an opera(cid:173)
`tional viscosity in the range from about 1,000-12,000
`cps. at the operating temperature, normally about 20-
`500 C. Non-uniform coating and uneven run down are
`encountered with cellulose ether solutions which are either
`too thin or too viscous.
`As noted above the molecular weight of the hydroxy(cid:173)
`alkylcellulose ether, as measured by the standard 2 per(cid:173)
`cent aqueous viscosity at zoo C., and its solution con(cid:173)
`centration are important factors in controlling the opera(cid:173)
`tional viscosity. With the preferred 2-7 cps. hydroxy(cid:173)
`alkylmethyl cellulose ethers, 20-30 weight percent solu(cid:173)
`tions can be prepared with operational viscosities ranging
`from about 2,000-12,000 cps. which yield capsules with
`a wall thickness of about 4 mils using a commercial dip
`coating unit.
`Normally the finished capsules are relatively clear and
`transparent. However, if opaque capsules are desired, a
`minor amount of an inert, non-toxic pigment such as·
`powdered charcoal or finely divided titanium dioxide can
`be incorporated in the coating composition. Likewise con(cid:173)
`ventional non-toxic dyes and fillers can be added in minor
`amount. If increased flexibility is required, an appropriate
`plasticizer such as glycerine, propylene glycol or hydroxy(cid:173)
`propylglycerine can be included in moderate amount, e.g.
`10-20 percent.
`is particularly suited for preparing
`This process
`medicinal capsules which dissolve under conditions of
`use at a rate comparable to conventional gelatin capsules.
`However, the formulation can be modified by incorpora(cid:173)
`tion of a less water-soluble cellulose ether such as ethyl(cid:173)
`cellulose if delayed release characteristics are desirable. 50
`To illustrate further the present invention and its
`advantages, the following examples are given. Unless
`otherwise specified, all parts and })ercentages are by
`weight. Solution viscosities are determined by the method
`of ASTM D-1347-64.
`
`35
`
`4
`several seconds and then were slowly withdrawn. The
`excess solution stripped from the coated pins as they were
`withdrawn. Then the coated pins were slowly revolved
`about the median horizontal axis of the supporting mem(cid:173)
`ber for 10-15 minutes at room temperature until sufficient
`solvent evaporated to leave a clear, non-flowing film on
`the pins. The pins were transferred to a warm air oven
`and dried at 35°-40° C. for an additional 20-40 minutes.
`After cooling the dried capsule pieces were str1pped
`10 from the stainless steel pins and trimmed to the desired
`size. They had a uniform thickness of 3-4 mils. They were
`clear, moderately flexible, and strong enough to withstand
`normal handling, yet dissolved readily in water.
`(B) In another test, clear capsules were prepared from
`15 a 20 percent solution of Methocel 60 HG, 5 cps., in 70
`percent aqueous methanol. This aqueous methanol solu(cid:173)
`tion had an operational viscosity of about 4300 cps. at
`2r c_
`(C) Similar results have been obtained with aqueous
`20 isopropanol and other C 1-C3 alcohols can be used. For
`maximum concentration of the hydroxypropyl methyl(cid:173)
`cellulose in these solvents, the aqueous alcohol should
`contain from about 60-85 percent alcohol and 40-15 per(cid:173)
`cent water. \Vith an aqueous alcohol containing less than
`25 about 60 percent alcohol, the cellulose ether content gen(cid:173)
`erally must be reduced to keep the operational viscosity
`within acceptable limits.
`(D) In further work, a Colton C-4 capsule machine
`equipped with No. 3 pins and used commercially to
`30 prepare gelatin capsules was used with several lots cf
`hydroxypropylmethyl cellulose. No significant modifica(cid:173)
`tion of the equipment was required to use an aqueous
`methanol solution of the cellulose ether. Uniformly good
`capsule bodies and caps were made and joined on a con(cid:173)
`tinuous basis using a 25 percent solution in 70% aqueous
`methanol of a hydroxypropylmethyl cellulose ( Methocel
`60 HG) which had a standard 2% viscosity of 4.0 cps.
`and an operational viscosity of about 6,000-9,000 cps.
`40 The capsules had a uniform wall thickness of about 3.8-
`4.3 mils.
`A 26% solution of the same cellulose ether had an
`operational viscosity of about 11,600 cps. and gave cap(cid:173)
`sules with a wall thickness of about 4.2-4.4 mils. A slight
`run down was evident with the 11,600 cps. solution, but
`45 not enough to prevent satisfactory joining of the capsule
`parts. With a 22% solution and an operational viscosity
`of about 3,500 cps., more serious run down was en(cid:173)
`countered although satisfactory capsules with wall thick-
`nesses of 3.8-4.1 mils were obtained.
`Another
`lot of the hydroxypropylmetbyl cellulose
`which had a standard 2% viscosity of 4.7 cps., a 25%
`solution in 70% aqueous methanol had a viscosity at
`operating temperature of about 16,500 cps. Suitable cap(cid:173)
`sules could not be made because severe run down during
`55 drying until the operational viscosity was reduced below
`about 12,000 cps. by increasing the operational temper(cid:173)
`ature or decreasing the cellulose ether concentration.
`EXAMPLE 2
`Aqueous system
`Following the general procedure described in Example
`1A, capsules were prepared from a 20 percent solution of
`Methocel 60 HG, 5 cps., in water having an operational
`viscosity of about 2000-2500 cps. at zzc C. The coated
`pins were rotated at room temperature for 30-45 minutes
`prior to drying in the warm air oven at 35°--40° C. for
`30-60 minutes. The dried capsules were in appearance
`and properties essentially the same as the capsules pre-
`70 pared from aqueous methanol solution.
`EXAMPLE 3
`Non-aqueous systems
`(A) To a solution of 700 parts methylene chloride and
`75 300 parts methanol was added 240 parts of the 5 cps.
`
`EXAMPLE 1
`Aqueous alcohol systems
`
`·(A) To 800 parts of 80 percent aqueous methanol 60
`was added 200 parts of Methocel 60 HG, 5 cps. This
`hydroxypropylmethylcellulose from The Dow Chemica1
`Company contains 7-12 weight percent 2-hydroxy(cid:173)
`propoxyl and 28-30 weight percent methoxyl ·groups. It
`has a 2 percent aqueous solution viscosity of 5 cps. at 65
`20° C. and a thermal gel point of about 60° C. The mix(cid:173)
`ture was stirred slowly at room temperature until the
`cellulose ether dissolved. The resulting clear 20 percent
`solution had a viscosity of about 300Q-3500 cps~ at
`room temperature, about 22 o C.
`Capsules were prepared from this aqueous solution
`using #0 capsule-forming pins machined from type 316
`stainless steel and lightly coated with a cottonseed oil
`lubricant grease. The pins were dipped into the hydroxy(cid:173)
`propylmethylcellulose solution at room temperature for
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1006 - Page 2
`
`

`
`3,493,407
`
`5
`hydroxypropylmethyl cellulose described in Example 1A.
`The resulting clear 20% solution of the cellulose ether
`a viscosity of about 3,100 cps. at 2r C. Capsules were
`prepared from this non-aqueous solution using #0 stain(cid:173)
`less steel capsule-forming pins essentially as described in
`Example lA. The resulting capsules had a uniform thick- 5
`ness of 3-4 mils. They were clear, moderately flexible,
`and strong enough to withstand normal handling under
`conditions of extreme humidity, yet dissolved readily in
`water.
`(B) In a similar manner, clear capsules were prepared
`from a 15% solution of 5 cps. hydroxypropylmethyl
`cellulose in the 70/30 methylene chloride/methanol sol(cid:173)
`vent having an operational viscosity of about 1,500 cps.
`However, a 25% solution with an operational viscosity of 15
`about 5,400 cps. gave poorer results in a manual dip
`coating operation at room temperature.
`
`10
`
`6
`90 HG prepared by irradiation, and 15 cps. Methocel 60
`HG prepared by conventional methods. Methocel 90 HG
`contains 4-12 percent hydroxypropoxyl and 19-24 percent
`methoxyl groups. For comparison films of Methocel MC
`containing 27.5-31.5 percent methoxyl groups and no
`hydroxyalkyl groups and a commercial gelatin film were
`also included in the tests. The cellulose ether films had a
`thickness of about 2.2 mils while the gelatin film was
`3.7 mils.
`Standard 2.5 x 15.0 em. test strips were prepared from
`the test films. Tensile strengths were measured at room
`temperature and Z5-30 percent relative humidity. The
`relative rates of dissolution at body temperature were
`measured by suspending the test strips in a water bath at
`37±1 o C. with a 0.5 g. weight clipped to the lower end.
`The time to failure was measured with a stop watch.
`Typical results are given in Table 2.
`
`TABLE 2.-FILM PROPERTIES
`
`Film
`
`Thickness Elongation,
`(mil)
`percent
`
`Tensile
`Strength
`(p.s.i.)
`
`Solution
`rate, 37° c.
`(sec./mil)
`
`Methocel60 HG, 5 cps •.........
`Methocel60 HG, 15 cps_ •••••..•
`Methocel90 HG, 10 cps •........
`Methocel MC, 10 cps.--------···
`Gelatin _________________________
`
`2.2
`2.2
`2. 2
`2. 2
`3. 7
`
`12-15
`8. 5-9. 5X10"
`12-15
`9. G-9.6XliJ3
`12-15
`7. 5-8. 5XliJ3
`9. tHO. 5XHJ3
`12-15
`4-7 10. 5-11. 5X11J3
`
`7. 5
`10.0
`15.8
`25.4
`22.6
`
`(B) In another test 4 mil capsules prepared on a com(cid:173)
`mercial dip coating unit were filled with a mixture of
`sugar and a water-soluble yellow dye, immersed in 0.1
`N HCl at 36.9° C., and the time for the solution to tum
`yellow measured as an indication of the capsule solu(cid:173)
`bility. Typical results from triplicate runs are given in
`Table 3.
`
`TABLE 3
`
`Dissolution test
`
`Dissolution time, min.
`Capsule material:
`Gelatin ----------------------------- 1.25-1.5
`Hydroxypropylmethylcellulose 1 -------- 1.5-Z.Z5
`Methyl cellulose 2 ---------------------
`25
`1 Methocel 60 HG.
`2 Methocel MC.
`
`40
`
`8
`
`(C) Other water-soluble CrC4 hydroxyalkyl methyl
`cellulose ethers having a Z percent aqueous solution vis(cid:173)
`cosity of 2-ZO cps. at 20° C. and containing 4-15 weight 30
`percent hydroxyalkoxyl and 18-3Z weight percent meth(cid:173)
`oxyl groups can be used in this process wtih satisfactory
`results.
`(D) As a rapid evaluation of several chlorinated sol(cid:173)
`vent/alcohol systems, films were cast on glass plates 35
`using a 5-10% solution of 5 cps. Methocel 60 HG. The
`dried films were evaluated according to the following
`scale:
`Rating
`Description:
`·Excellent-absolutely clear, free of gels or fibers,
`very smooth ---------------------------- 10
`Good--clear, a few gels or fibers, free of "orange
`peel" effect -----------------------------
`Fairly good-slight haze, some "orange peel"
`effect ---------------------------------
`Fair-moderate haze, noticeable "orange peel"
`effect, slightly rough surface ---------------
`Poor-very hazy, quite rough ---------------
`Very poor-extremely hazy, very rough and brit-
`tle ------------------------------------
`Failure-very rough, too brittle to remove from
`0
`plate ----------------------------------
`Typical results from several solvent systems are given
`in Table 1. A rating of at least 5 and preferably 7-10 is
`desirable for a system to be used in preparing medicinal 55
`capsules.
`TABLE I.-SOLVENT SYS'l'EMS FOR 5 CPS. METHOCEL 60 HG
`
`7 45
`
`5
`3
`
`We claim:
`1. In a process for preparing telescoping medicinal cap(cid:173)
`sules by dip-coating a capsule-forming die, drying the coat(cid:173)
`ing to form a capsule member, and then assembling the
`capsule body and cap, the improvement which comprises
`50 using as the dip-coating bath a non-thermal gelling solu(cid:173)
`tion of:
`(A) About 10-30 weight percent of a water soluble
`hydroxyalkylcellulose ether having a viscosity of
`about Z-20 cps. as a Z percent aqueous solution at
`zoo C., said cellulose ether containing about 4-15
`weight percent C2-C4 hydroxyalkoxyl groups and
`18-32 weight percent C 1-C2 alkoxyl groups; and
`(B) A solvent consisting essentially of:
`(1) From 15-40 weight percent water and from
`60-85 weight percent of a C1-C3 alcohol; or
`(2) A non-aqueous mixture of from 15-50 weight
`percent of a C 1-C3 alcohol, and from 85-50
`weight percent of a C1-C3 chlorinated aliphatic
`hydrocarbon or a Cs-C7 aromatic hydrocarbon,
`said mixture containing less than about 4 weight
`percent water;
`said dip-coating solution having a viscosity of about 1,000-
`12,000 cps. at the dip-coating tempe!'ature.
`2. The process of claim 1 wherein the water soluble
`hydroxyalkylcellulose has a viscosity of about 2-7 cps.
`as a Z percent aqueous solution at zoo C.
`3. The process of claim 1 wherein the cellulose ether
`contains about 4-15 weight percent hydroxypropoxyl and
`75 about 18-3Z weight percent methoxyl groups.
`
`Solvent System
`CH,CJ,a,!eOH .•.. _____ ,. ______
`CH,Clo/EtOH ......... ---------
`CH
`Cl,ji-PrOH ________________
`2
`CHC!s/MeOH •.. -----··--·-----
`CHCla/EtOH .•. ----·-----·----
`CHCla/i-PrOH _________ . _______
`
`Rating with Solvent Ratio I of-
`
`80/20
`
`70/30
`
`60/40
`
`50/50
`
`8
`7. 5
`8
`8
`7. 5
`8
`
`6
`7. 5
`7
`8
`7.5
`7.5
`
`5
`5
`6.5
`7
`7
`4. 5
`
`t Weight ratio chlorinated solvent/alcohol.
`EXAMPLE 4
`Capsule properties
`(A) To illustrate the physical properties of the cellu(cid:173)
`lose ether capsules prepared from the hydroxyalkyl-cel(cid:173)
`lulose ethers, films of several hydroxyalkylcellulose ethers
`were cast from aqueous alcohol on a glass plate by stand(cid:173)
`ard techniques. Among the hydroxyalkylcellulose ethers
`tested were 5 cps. Methocel 60 HG and 10 cps. Methocel
`
`60
`
`65
`
`70
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1006 - Page 3
`
`

`
`7
`4. The process of claim 1 wherein the cellulose ether
`contains 7-12 weight percent hydroxypropoxyl groups and
`28-30 weight percent methoxyl groups.
`5. The process of claim 1 wherein the alcohol is meth(cid:173)
`anol.
`6. The process of claim 1 wherein the solvent is a mix(cid:173)
`ture of 15-40 weight percent water and 85-60 weight per(cid:173)
`cent methanol.
`7. The process of claim 1 wherein the chlorinated hy(cid:173)
`drocarbon is methylene chloride.
`8. The process of claim 1 wherein the dip-coating bath
`is a solution of 20-30 weight percent of a hydroxypropyl(cid:173)
`methykellulose, having a viscosity of about 2-7 cps. as
`a 2 percent aqueous solution at zoo C., in 60-85 percent
`aqueous methanol, said solution having an operational 15
`viscosity of about 1,000-12,000 cps. at a temperature be(cid:173)
`tween 20-50° C.
`
`5
`
`10
`
`3,493,407
`
`8
`References Cited
`UNITED STATES PATENTS
`10/1950 ~urphy ------------- 167--83
`5/1958 Savage-------------- 106--197
`5/1958 Silvernail et al. ______ 106--197
`611958 Win dover et al. ------ 106--197
`8/1958 Swinehart et al. ______ 106--197
`10/1966 Klug --------------- 106--197
`FOREIGN PATENTS
`5 I 1960 Great Britain.
`833,834
`ALLAN LIEBER~AN, Primary Examiner
`
`2,526,683
`2,835,666
`2,836,506
`2,839,419
`2,849,328
`3,278,521
`
`U.S. CL X.R.
`106--197, 190, 170; 206--84; 220--8; 264-301; 424-35
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1006 - Page 4