I||||||||||||||||||l||||l|1|||1||||||||||||llllllllllllillflllllllll
`
`USOOS756036A
`
`United States Patent
`
`[19]
`
`Grosswald et a1.
`
`[11] Patent Number:
`
`5,756,036
`
`[45] Date of Patent:
`
`May 26, 1998
`
`[54]
`
`[75]
`
`[73]
`
`[211
`
`[22]
`
`[631
`
`[51]
`
`[52]
`
`[58]
`
`[56]
`
`METHOD FOR THE MANUFACTURE OF
`PHARMACEUTICAL CELLULOSE
`CAPSULES
`
`Inventors: Ralph R. Grosswald, Fairfield. Iowa;
`Jefi'ory B. Anderson. Springville; Clair
`S. Andrew. Provo. both of Utah
`
`Assignee: GS Technologies, Inc.. Fairfield, Iowa
`
`Appl. No.: 461,026
`
`Filed:
`
`Jun. 5, 1995
`
`Related U.S. Application Data
`
`Continuation of Ser. No. 377,669, Jan. 24, 1995, Pat. No.
`5,698,155, which is a continuation of Ser. No. 893,091, May
`29, 1992, abandoned, which is a continuation—in-part of Ser.
`No. 708,023, May 31, 1991, abandoned.
`
`U.S. C1.
`
`Int. CL6 ........................... B29C 41/14;1329c 41/40;
`B29C 41/46
`.......................... 264/304; 264/301; 264/327;
`264/402; 425/270; 425/275
`Field of Search ................................... .. 264/306. 255.
`264I299. 304. 305; 425/269—275, 327.
`402
`
`1/1981 Bodenmann et a1,
`.................. 206/528
`4,247,006
`5/1936 Tomka etal. ............
`.. 2644401
`4,591,475
`
`12/1936 Hughes ...... ..
`425/270
`4,627,808
`
`... .. 264/25
`11/1987 Lukas ...... .
`4,705,658
`425/275
`7/1938 Sauter ......
`4,758,149
`
`471990 Chiba et al.
`.424/78
`4,917,885
`
`......
`..... 29/451
`2/1991 Muto et a1.
`4,993,137
`2/1991 Stevanovich
`425/270
`4,993,935
`
`3/1991 Lebrun .............
`425/209
`4,997,359
`............................. 425/272
`7/1991 M1110 et al.
`5,032,074
`FOREIGN PATENT DOCUMENTS
`
`1
`European Pat, OH.
`1/1981
`0056325
`9/1983 European Pat. OE.
`0102832
`0401832A 12/1990 European Pat. 011..
`2259387
`12/1972 Germany,
`8027378
`3/1980
`Japan.
`84222676 10/1984
`Japan.
`87120178
`5/1987
`Japan.
`87120179
`5/1987
`Japan.
`89145626
`6/1989
`Japan.
`3724
`211896 United Kingdom.
`W091/l9487 12/1991 WIPO.
`
`01mm PUBLICATIONS
`
`Ridgway. K.. Ed. (1987) “Hard Capsules Development and
`Technology.” The Pharmaceutical Press. London, pp. 56—5 8.
`Parke, R.F., “Hydroxypropylmethylcellulose Capsules”.
`Oct. 20. 1966.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`Primary Examiner--—Angela Ortiz
`Attorney, Agent, or Firm—John L. Lee
`
`[57]
`
`ABSTRACT
`
`1/1915 Winchester .
`1,125,619
`1/1931 Colton .
`1,787,777
`1,978,829 10/1934 Wilkie ......................................... 34/12
`
`3/1942 Sch/erer ..
`2,299,039
`18/58
`
`2,526,683 10/1950 Murphy ..
`167/83
`
`2,575,789 11/1951 Bogin
`18/25
`3/1954 Kath ............................................ 18/25
`2,671,245
`2,869,178
`1/1959 Kath .
`.......................... 202/60
`3,399,803
`9/1968 Oglevee eta].
`3,493,407
`2/1970 Greminger et a].
`. 106/189
`
`3,508,678
`4/1970 Grahame! a].
`220/60
`3,617,588
`11/1971 Langman
`264/25
`
`.. 264/40
`111972 Oglevee .
`..
`3,632,700
`5/1972 Graham et al.
`06/632 R
`3,664,495
`
`..
`425/270
`3,794,453
`2/1974 Padillaet a1.
`
`. 219/385
`3,842,242 10/1974 Chisholm
`4,001,211
`1/1977 Sarkar ....................................... 536/84
`
`A method and apparatus for manufacturing pharmaceutical
`capsules use an aqueous solution of a thennogelling cellu-
`lose ether composition and use capsule body pins and
`capsule cap pins as molds. The method involves heating the
`pins, dipping the pins into the solution to cause the solution
`to gelatinize on the surface of the pins. removing the pins
`and drying the gelatinized solution on the surface of the pins
`to form capsule bodies and capsule caps. Pins are heated
`pre—dip and post-dip to facilitate gelating. Counterflow air is
`applied to provide drying from the inside. Capsule parts are
`removed by gripping. Capsule parts may have a thick wall
`and a stiffening ring.
`
`20 Claims, 15 Drawing Sheets
`
` 7
`
`ELEVATOR
`SECTION
`
`/83
`
`l
`SPlNNER
`
`82
`{84
`86X.
`TABLE
`J
`
`
`LOWER DRYING KILN
`AUTOMATICS
`
`
`
`
`
`I SECTION |
`
`
`
`86/“
`
`85
`
`DIPPER
`SECTION
`
`GREASER
`SECTION
`
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`
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`
`

`

`US. Patent
`
`May 26, 1993
`
`Sheet 1 of 15
`
`5,756,036
`
`E:«2%:o..0:mul‘a
`
`
`
`E:moan:9.9...mm!
`
`_omm
`
`vm
`
`
`
`2.:x62.55Emma
`
`E:moan:S.2...
`
`
`
`:m<moEn:N.m.n.
`
`
`
`22.8mmE53memorEEquE2.5.@253zocbmmzozbmm$30..
`
`
`
`
` zozbmm
`
`$0.5;me
`
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`
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`
`
`
`
`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 2 of 15
`
`5,756,036
`
`
`
`FIG. 3
`
`(PRIOR ART)
`
`
`
`FIG.4
`
`(PRIOR ART)
`
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`
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`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 3 of 15
`
`5,756,036
`
`FlG.6 (PRIORART)
`
` 'II'III'I'"\
`
`FIG.5 (PRIORART)
`
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`
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`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 4 of 15
`
`5,756,036
`
`
`
`2.5.3:55mun—m:
`
`
`
`mmmqmmu
`2078mm
`morzzogq
`_zozbmm_m4m<h%
`karma;
`§3:9225$23
`
`mm
`
`mo...<>m._m
`
`zozbmm
`
`q.de
`
`om
`
`Mylan v. Qualicaps, |PR2017-00203
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`
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`
`
`
`
`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 5 of 15
`
`5,756,036
`
` 3
`
`mom
`
`mo
`m
`
`Mylan v. Qualicaps, |PR2017-00203
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`
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`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 6 of 15
`
`5,756,036
`
`FIG.BD
`
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`
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`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 7 of 15
`
`5,756,036
`
`813 q
`
`826
`
`ODOODOOOOOOOOOOOOO ~
`
`FIG'BE
`
`FIG. 8F
`
`
`
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`
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`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 8 of 15
`
`5,756,036
`
`
`
`U)
`3
`'2
`g
`t—
`:3
`<
`
`on
`0'
`._
`L‘-
`
`WU)
`mm
`my
`
`2 :
`
`‘E
`0.
`mm
`cu
`
`[‘0
`N
`
`m c
`
`n
`
`&
`
`3'»
`
`co
`N
`
`a}: 8
`X
`N
`'
`o
`m
`
`
`
`K.
`
`a)
`
`~—
`m
`L\\o
`
`V
`
`Z.
`
`1 z (
`
`DZ
`
`Mylan v. Qualicaps, |PR2017-00203
`QUALICAPS EX. 2046 - 9/28
`
`
`
`E E
`
`O O
`
`: m
`
`&
`D
`
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`QUALICAPS EX. 2046 - 9/28
`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 9 of 15
`
`5,756,036
`
`
`
`
`
`
`
`
`
`
`‘
`.
`I7
`l‘;
`:
`
`
`uwnnn'l'awunr'llllulu
`
`
`1“““\“" \\\\‘\“.“‘&“\\" ‘\‘\‘\‘:]\“VA\“‘\\V§L\\\\“‘A“§\“‘\‘
`A 'l’ll I'll! I'll] . 'IIIIJ'III'.“ I’ll/III '17Ill/
`"II/A II'II/
`
`
`
`
`113
`
`m
`
`
`~— filWIN
`
`
`
`
`mmmzmr 1mmmmm
`
`Mylan v. Qualicaps, |PR2017-00203
`QUALICAPS EX. 2046 - 10/28
`
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`QUALICAPS EX. 2046 - 10/28
`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 10 of 15
`
`5,756,036
`
`BODY SIDE
`
`FIG. 100
`
`A3
`
`2 4
`
`
`
`__________._____/
`
`
`
`1214161820
`13151719
`
`BODY SIDE
`
`Mylan v. Qualicaps, |PR2017-00203
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`
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`
`

`

`US. Patent
`
`May 26,1998
`
`Sheet 11 of .15
`
`5,756,036
`
`
`
` 'I
`
`'9
`‘IIIIIIII;
`
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`
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`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 12 of 15
`
`5,756,036
`
`143 ..
`
`143 "
`
`.r
`
`MZQJ‘142
`lzgj
`C9
`
`
`32
`
`.- 141
`
`Mylan v. Qualicaps, |PR2017-00203
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`
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`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 13 of 15
`
`5,756,036
`
`NL
`
`n1-
`
`
`
`
`
`PIDCONTROLLER
`
`FIG.15
`
`154
`
`
`CIRCULATING
`
`.—
`K)‘_
`
`Mylan v. Qualicaps, |PR2017-00203
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`
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`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 14 of 15
`
`5,756,036
`
`
`
`
`32\
`
`FIG. 16B
`/
`
`IO!
`
`:
`
`103
`
`,63
`
`7
`
`FIG. 16C
`
`162
`
`
`
`iLJLJMLJn
`
`
`VIII/IIIIIIIIIIIA
`
`28
`
`-SP.INNER
`162 g
`7’):
`’I/A
`
`2'
`
`'
`
`x161
`
`22
`
`AUTOMAT'CS
`
`GREASER
`SECTiON
`
`DIPPER
`SECTION
`
`FIG. 16A
`
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`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 15 of 15
`
`5,756,036
`
`II'III'. 1..
`
`
`FIG.18
`
`Q.i
`
`v. I. '1 a.11/
`
`
`
`181
`
`‘72
`
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`

`

`1
`METHOD FOR THE MANUFACTURE OF
`PHARMACEUTICAL CELLULOSE
`CAPSULES
`
`5.756.036
`
`2
`first column of each of Tables 1 and 2. These tables are
`
`copied from the February. 1987 Specification Sheet of the
`CAPSUGEL Division of Warner-Lambert Company for its
`PRE-FITTM. SNAP—FITTM and CONT-SNAPTM series of
`This application is a continuation application Of US Sen 5 hard gelatin capsules. Table 1 shows the external diameter.
`No. 08/377/669. filed Jan. 24. 1995. US. Pat. No. 5.698.155.
`obtained by optical measurements. of a body and a cap of
`which is a continuation application of U.S. Ser. No. 07/893.
`each size of CAPSUGEL capsule. (Diameter is diflicult to
`091. filed May 29. 1992. now abandoned. which is a
`measure precisely because of the slightly tapered shape and
`continuation-in-part application of U.S. Ser. No. 07/708.023
`the flexibility of the gelatin capsule parts.) Table 2 shows the
`filed May 31. 1991. now abandoned
`target wall thickness of a body and a cap of each type and
`size of CAPSUGEL capsule. Table 3. copied from the
`Scherer LOX—1TIM specification sheet. gives the external
`diameter of the Scherer LOX—II‘MTM capsule caps and
`bodies in a range of sizes.
`
`it]
`
`TECHNICAL FIELD
`
`The invention relates generally to methods and apparatus
`used in the manufacture of pharmaceutical capsules.
`
`15
`
`BACKGROUND OF THE INVENTION
`
`TABLE 1
`
`
`CAPSUGEL CAPSULE PART, EXTERNAL DIAMETER
`
`“Em” SNAP‘FITT“ 0’ COM-SNAP T"
`
`Body
`
`Cap
`
`Pharmaceutical capsules presently in general use are
`made of gelatin and the techniques for the manufacture of
`gelatin capsules are well developed. Compositions for cel- 20
`lulose capsules are also well known. but the first cellulose
`composition that was used commercially to manufacture
`cellulose capsules did not reliably break down in the user’s
`digestive system. When this fact was discovered. the com-
`,
`mercial manufacture of cellulose capsules was discontinued.
`mm
`1mm
`mm
`mm
`sues
`An improved cellulose composition was later patented by
`Sarkar and several patents disclose methods for manufac— —_——'__—_
`turing cellulose capsules from the improved cellulose com-
`000
`0373
`9-60
`0394
`“3-00
`position. However.
`in the fifteen years since the Sarkar
`00
`0.324
`8.23
`0.339
`8.60
`patent issued. and in spite of many attempts. none have 30
`Del
`0191
`7.33
`0.300
`7.70
`succeeded. in manufacturing cellulose capsules in quantity.
`0
`0291
`738
`0.303
`7.70
`usmg the improvedcomposmon. With suific1entun1fornnty
`to be suitable for filling in modern high-speed filling
`1
`0263
`6‘68
`0275
`6'98
`machines. Until the present invention was made. cellulose
`2
`0241
`5-13
`0.252
`5““
`capsules manufactured in quantity from the improved com- 35
`3
`0.221
`5.61
`0.231
`5.88
`position suifered imperfections such as wrinkles. starred
`4c]
`0201
`5.“
`0312
`5’38
`ends and corrugations. These imperfections result in cap—
`4
`0.201
`5.11
`0.212
`5.38
`sules either breaking. faihng to separate. or Jamming 1n the
`high_specd fining Malina
`5
`0.185
`4.70
`0.193
`4.89
`
`Prior Art Gelatin Capsules
`Prior art gelatin capsules. as shown in FIGS. 1A. 1B and
`1C. are made in a range of sizes including sizes listed in the
`
`25
`
`40
`
`Tolerance: 10.001 (10.03 mm)
`
`TABLE 2
`
`
`CAPSUGEL CAPSULE PART SINGIE WALL THICKNESS
`
`
`PRE-FI’I‘ TM
`
`SNAP-FIT or CONT-SNAP TM
`
`Body
`
`Cap
`
`B_oay
`
`Cap
`
`Size
`
`000
`
`00
`
`0 el
`
`0
`
`1
`
`2
`
`3*
`
`4 el
`
`4
`
`mm
`
`Inches
`
`mm
`
`Inches
`
`Inches
`
`0.0042
`10.0009
`0.0041
`10.0009
`—
`
`0.0040
`10.0008
`0.0039
`0.0008
`0.0038
`10.0008
`0.0034
`10.0008
`—
`
`0.107
`10.023
`0.104
`10.023
`-—
`
`0.102
`10.020
`0.099
`10.020
`0.096
`10.020
`0.086
`10.020
`—
`
`0.0044
`10.0012
`0.0042
`10.0012
`——
`
`0.0042
`10.0010
`0.0041
`10.0010
`0.0040
`10.0010
`0.0036
`10.0010
`—
`
`0.112
`10.030
`0.109
`10.030
`—
`
`0.107
`10.025
`0.104
`10.025
`0.102
`10.025
`0.092
`10.025
`——
`
`0.0034
`
`0.086
`
`0.0036
`
`0.089
`
`mm
`
`—
`
`0.107
`10.023
`0.104
`10.020
`0.104
`10.020
`0.102
`10.020
`0.099
`10.020
`0.089
`10.020
`0.094
`10.020
`0.086
`
`Inches
`
`—
`
`0.0043
`10.0012
`0.0042
`10.0010
`0.0042
`10.0010
`0.0041
`10.0010
`0.0040
`10.0010
`0.0036
`10.0010
`0.0038
`10.0010
`0.0035
`
`mm
`
`—
`
`0.109
`10.030
`0.107
`10.025
`0.107
`10.025
`0.104
`10.025
`0.102
`10.025
`0.092
`10.025
`0.096
`10.025
`0.091
`
`—
`
`0.0042
`10.0009
`0.0041
`10.0008
`0.0041
`10.0008
`0.0040
`10.0008
`0.0039
`10.0008
`0.0035
`100008
`0.0037
`10.0008
`0.0034
`
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`
`

`

`5.756.036
`
`TABLE 2-continued
`___—_—_—_—————-—————-—
`
`CAPSUGEL CAPSULE PARTI SINGLE WAIL THICKNESS
`
`PRE-FIT 1'“
`
`SNAP—FIT or COM-SNAP T“
`
`Body
`
`Cap
`
`Body
`
`Cap
`
`Size
`Inches
`mm
`Inches
`mm
`Inches
`mm
`Inches
`mm
`
`10.0008
`10.020
`10.0010
`10.025
`10.0008
`10.020
`10.0010
`10.025
`5
`0.0034
`0.086
`0.0036
`0.092
`—
`——
`—
`——
`10.0008
`10.020
`10.0010
`10.025
`
`3“ SNAP-FIT TM Body Target — 0.0034 1 0.0008
`
`TABLE 3
`
`SCHERER LOX-IT 7“ CAPSULE PART DIAMETER
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`45
`
`50
`
`55
`
`65
`
`about to push a capsule part 53 01f a pin from the area 44
`above the dip line with pushing face 52. A side view of a
`prior art stripper having a pivot 61 and a spring 62 is shown
`in FIG. 6. FIG. 7 shows a knife 71 trimming a capsule part
`to remove the rough edge 72 and create a clean edge 73.
`US. Pat. Nos. 1.978.829 (to Wilkie). 3.632.700 (to
`Oglevee). 3.794.453 (to Padilla et a1.). 4.705.658 (to Lukas)
`and 4.997.359 (to Lebrun) are all directed to processes for
`manufacturing gelatin capsules. The Wilkie patent discloses
`an apparatus for drying capsules by directing a stream of air
`at the part of the capsule that contains the most moisture. A
`fine stream of air passing through a hole in a plate is directed
`to the closed end of the capsule so that a greater drying effect
`is experienced on the closed ends of the capsule than on the
`sides of the capsule. A plate is provided having multiple
`holes spaced to match the position of the pins. The leevee
`patent discloses a method for insuring capsule wall thickness
`uniformity by measuring the viscosity of the liquid gel
`solution in the dipping tank and causing corrective change in
`viscosity by changing the evaporative exposure or by adding
`lower viscosity gel to the tank. The Padilla patent discloses
`an air duct directing cooling air onto freshly dipped capsule
`mold pins for improved wall thickness characteristics. The
`duct is an air conduit for moving cool air upwardly against
`the rounded ends of the coated pins for uniform flow. The
`duct encloses a zone surrounding the array of pins. The
`Lukas patent is directed to reducing the drying time in the
`manufacture of hard shell gelatin capsules. Pins are irradi-
`ated with microwave energy until the gelatin dries. The
`Lebrun patent discloses a dipping bath. having a plurality of
`small wells and an impeller for maintaining the solution in
`the wells at a constant temperature. The pins dip into the
`wells.
`
`Prior Art Capsule Forming Pins
`US. Pat. No. 4.758.149 to Sauer is directed to a capsule
`forming pin having a cylindrical sidewall and a groove
`extending around the cylindrical sidewall. the groove having
`a non—angular cross-sectional profile. both the cylindrical
`sidewall and the groove having a smooth burnished-
`hardcned surface. Sauter discloses in FIG. 3A. item C and
`column 4. line 45. that a prior-art capsule cap pin for a “0”
`(“zero”) size capsule has a diameter at the cut-point of
`02973—02978 inch (7551—7564 mm). The prior-art cap—
`sule body pin at
`the cut-point
`is 02848—02853 inch
`(7234—7.247 mm).
`For a range of popular sizes of gelatin capsules. Table 4
`shows the nominal cut-point diameter for the prior art body
`pin and the prior art cap pin used in forming. respectively.
`the gelatin capsule body and the gelatin capsule cap.
`
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`
`
`
`
`
`
`
`
`0 l 2 3Size 4
`
`CAP
`0.301 ”
`0.272"
`0.250"
`0.230"
`0.210"
`DIAMETER"
`(10.003)
`BODY
`DIAMETER‘
`0.200"
`0.220"
`0.240"
`0.262”
`0.289"
`(10.003)
`
`*DETERMINED AT CUT EDGE
`
`US. Pat. No. 3.399.803 to Oglevee et al. is directed to a
`hard-shell self-locking pharmaceutical capsule having a cap
`part and a body part. the parts adapted for machine filling.
`Oglevee discloses mold pins having a uniform taper or
`candle-shape such as to avoid suction when the part is
`removed from the pin and to provide a wedging fit between
`the capsule cap and the capsule body. Oglevee also discloses
`the shaping of the cap and body to provide a semi-locked
`position and a locked position. A single groove in the cap
`and a matching single groove in the body provide a mechani-
`cal lock.
`U.S. Pat. Nos. 3.508.678 and 3.664.495 both to Graham
`et a1. disclose a capsule cap having an indent. in addition to
`a locking groove, which defines a prelock position by
`providing either an elastic friction fit with the capsule body
`(US. Pat. No. 3.664.495) or a mechanical lock between the
`indent of the cap and the groove in the body (US. Pat. No.
`3.508.678).
`US. Pat. No. 4.247.006 to Bodenrnann et a1. discloses a
`capsule body having a reduced diameter in the area of its
`open end. and funher the capsule cap and the capsule body
`each having an indentation to provide for a positive engage-
`ment of the body and the cap.
`Prior Art Process for Gelatin Capsules
`US. Pat. No. 1.787.777 to Colton describes the “Colton”
`machine used in the manufacture of gelatin capsules. Key
`elements in the prior art manufacture of gelatin capsules are
`illustrated in FIGS. 1—7. FIG. 1A shows the parts of a
`capsule having a body 1 and a cap 2. The parts are shown in
`FIG. 13 in a prelock position 3 held in position by prelock
`dimples 4. The parts are also shown in FIG. 1C in a filled
`position 5 held in position by locking rings 6. FIG. 2 shows
`elements of the traditional “Colton” capsule manufacturing
`machine. The elements are a greaser section 21. a dipper
`section 22. spinners 23. upper drying kiln 24. lower drying
`kiln 26. table section 27 and automatics 28. A pinbar. having
`thirty pins 31 mounted to a bar 32. is shown in FIG. 3. FIG.
`4 shows gel 41 formed around a pin 31 to a dip line 42. Also
`shown is the trim line (cut-point) 43 and the area 44 on the
`pin above the dip line. FIG. 5 shows a prior art stripper 51
`
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`5
`
`6
`
`5.756.036
`
`apparatus for preheating capsule pins in a “Colton” capsule
`machine. A tray is provided containing spheroidal particles
`heated to a predetermined temperature. The pins are dipped
`into the heated particles just prior to being dipped in the
`solution.
`
`5
`
`TABLE 4
`
`PIN CUT-POINT DIAMETER
`
`Body
`
`Cap
`
`Sizes
`Inches
`mm
`Inches
`mm
`
`00
`0.3195
`8.12
`0.3355
`8.52
`0
`0.2855
`7.25
`0.2975
`7.56
`1
`0.2575
`6.54
`0.2685
`6.82
`2
`0.2355
`5.98
`0.2455
`6.24
`3
`0.2155
`5.47
`0.2255
`5.73
`
`0.20454.970.19554 5.19
`
`
`
`
`Prior Art Process for Cellulose Capsules
`An improved methyl cellulose ether composition that may
`be used in the present invention is disclosed in US. Pat. No.
`4.001.211 to Sarkar. Sarkar also discloses a process for the
`manufacture of capsules from his improved methyl cellulose
`ether composition. The improved methyl cellulose ether
`composition disclosed by Sarkar is an aqueous solution of a
`thermal gelling methyl cellulose ether composition suitable
`for use in preparing pharmaceutical capsules by an aqueous
`dip coating process using preheated pins and having a
`methoxyl D5 of about 1.5—2.0. a C2—C3 hydroxyalkyl MS of
`about 01—04. a 2 wt. percent aqueous solution viscosity of
`about 2—10 cps at 20° C. and a thermal gel point of about
`50°~80° C.. and a 15-30 wt. percent aqueous solution
`viscosity of about LOGO—10.000 cps at 20° C.. said compo-
`sition having as a 15—30 wt. percent aqueous solution: (A)
`essentially Newtonian fluid properties as defined by a power
`law coefficient. 11. of 0.9—1.0 at shear rates of between
`0.1—10 sec—1. and (B) a 50 sec gel yield strength of at least
`150 dynes/cm2 at 65° C.
`US. Pat. No. 4.993.137 to Muto is directed to the manu—
`facture of capsules made from the improved methyl cellu-
`lose etha composition of Sarkar. Muto discloses a process
`for gelling the solution by dipping solution—coated pins into
`thermally controlled water. In the Muto process. the solution
`is gelled on the surface of the pins by first dipping the pins
`into solution and thereby coating the pins with solution and
`then dipping the coated pins into heated water to set the gel.
`US. Pat. Nos. 2.526.683 (to Murphy). 2.671.245 (to
`Kath). 3.617.588 (to Langman) and 3.842.242 (to Chisholm)
`are directed to methods of manufacture of capsules from
`methyl cellulose (the original methyl cellulose, not the
`improved methyl cellulose disclosed by Sarkar). The Mur—
`phy patent is the original patent for the manufacture of
`methyl cellulose capsules. This patent discloses the preheat-
`ing of pins prior to dipping so that the solution adheres to
`pins in gelled form.
`the use of a sequence of different
`“successively warmer temperatures” through the drying
`kiln. drying using infrared lamps. and cooling by air. Mur-
`phy accomplished a mechanization for the manufacture of
`cellulose capsules. However this method was found to be
`inadequate when (later) it was applied to the improved
`cellulose of the Sarkar patent. The Kath patent discloses
`apparatus for manufacturing either gelatin or methyl cellu-
`lose capsules. It discloses the use of tracks and a plurality of
`pins. The pins are moved along the tracks and moved.
`rotated and gyrated as needed through the various stations.
`This patent contains detailed mechanical disclosure. The
`Langman patent is directed to elimination of unwanted
`thermal gelation in the coating bath by the use of low
`viscosity hydroxyalkayl cellulose ethers and the rapid
`immobilization of the dip coating by induction heating after
`removal of the pins from the bath. The Chisholm patent is
`directed to heating the pins prior to dipping and discloses
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`The prior art for the manufacture of pharmaceutical
`capsules from the improved therrnogelling methyl cellulose
`ether compositions disclosed in the Sarkar patent contain a
`number of unresolved problems. These unresolved problems
`include skinning. wrinkling. starred ends and corrugations in
`the wall of the capsule parts. and damage to the capsule parts
`occurring during removal from the pins. These problems
`cause breaking. failure to separate or jamming in the high—
`speed filling machines. There is no discussion in the prior art
`of the source of these problems.
`None of the above mentioned patents disclose a method
`for making cellulose capsules of sufficient uniformity and
`rigidity that
`they may be filled on modern high-speed
`capsule filling machines. This uniformity and rigidity has
`now been accomplished using the process and capsule
`improvements that are the subject of the present invention.
`SUMMARY OF THE INVENTION
`
`A method and apparatus for manufacturing pharmaceuti-
`cal capsules. each capsule consisting of a capsule body and
`a capsule cap. uses an aqueous solution of a thermogelling
`cellulose ether composition and uses capsule body pins and
`capsule cap pins as molds. A group of pins is mounted on a
`bar. The method involves heating the pins; dipping the pins
`into the solution to cause the solution to gelatinize on the
`surface of the pins; removing the pins from the solution;
`drying the gelatinized solution on the surface of the pins to
`form capsule bodies and capsule caps; and removing the
`capsule bodies and capsule caps from the pins. In one
`embodiment of the present
`invention.
`the time interval
`between heating and dipping may vary from bar to bar. To
`compensate. each bar is heated to a different temperature
`according to the time interval associated with the bar. Pins
`may be heated by radiant energy or by hot air or via the bar
`at a plurality of thermally isolated stations. Additionally a
`portion of the bar may be heated to a predetermined tem-
`perature. The process includes heating the pins before dip-
`ping and heating the pins after dipping. The dipping dishes
`for capsule bodies and capsule caps are spaced apart farther
`than in the traditional Colton machine and a pre-dip heating
`area is located between the dipping dishes. After the pins
`have been dipped and removed from the solution they are
`heated again to further gelatinize the solution on the surface
`of the pins. Drying the pins includes providing counterfiow
`movement of air through an enclosure over the pins such that
`the pins initially encounter relatively humid air and. as they
`become drier. they encounter increasingly drier air. Also. the
`pins are heated so that the capsule bodies and capsule caps
`are dried from the inside-out. Removing the capsule parts
`from the pins involves gripping the capsule parts between
`opposing gripping surfaces. In one embodiment the capsule
`parts have a thicker wall than the equivalent size gelatin
`capsule and capsule bodies include a stiffening ring.
`Problems in the prior art are overcome in one embodiment
`of the present invention as follows. In preheat. to compen-
`sate for differential cooling from some bars wailing longer
`than others to dip. thermally isolated heating elements are
`provided below the bars and radiant heaters are provided
`above the bars to allow selective heating of bars or portions
`of bars to eliminate temperature differences at the time of
`dip. To allow preheat in the dipper area without the problems
`associated with Chisholm’s heated particle method.
`the
`
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`5.756.036
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`7
`
`dipping dishes are moved away from the centerline and
`thermal convection heaters and radiant heaters are inserted.
`For the same purpose. thermal conduction heating via the
`back of the bars is also provided. To achieve the level of
`uniformity necessary for high-speed filling and to eliminate
`the skinning over and wrinkling associated with the outside-
`in drying of the prior art due to air blowing directly over the
`pins. inside-out drying is provided Post-dip heating is used
`in addition to pre-dip heating. Post-dip heating continues the
`gelling process after dip. assures rapid firming of the cellu-
`lose film. and supports inside—out drying. To avoid the
`uneven or excessively rapid drying that causes deformation
`in the prior art. an appropriate relationship is maintained
`between water vapor pressure in the capsules and water
`vapor pressure in the surrounding air through the drying
`process. A fully enclosed drying kiln is provided to support
`inside-out drying. humidity control of air surrounding the
`pins. and energy efficiency. To avoid damaging the open end
`of the capsule part during removal of the part from the pin.
`which often occurs when the prior art technique is used on
`cellulose capsule parts. a gripper is provided. To eliminate
`the jamming in the filling machines due to oversize parts. the
`pin is undersized to compensate for the unexpected difier—
`ential in shrinkage between the cellulose capsule and the
`gelatin capsule. To avoid malfunction in filling machines
`caused by flexibility of the capsule part and deformation out
`of round. a pin is further undersized to allow a thicker
`capsule wall. Also the body pin adds an extra circumferential
`reinforcing ring to the capsule body between the lock ring
`and the dome.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIGS. 1A. 1B and 1C show a prior art capsule body and
`cap.
`FIG. 2 shows the elements of the traditional (prior art)
`capsule manufacturing machine.
`FIG. 3 shows pins mounted on a pinbar (prior art).
`FIG. 4 shows a pin dipped to a dip line (prior art).
`FIG. 5 shows a prior art stripper pushing a capsule part of
`a pln.
`FIG. 6 shows a prior art stripper.
`FIG. 7 shows a knife trimming the rough edge of the
`capsule (prior art).
`FIG. 8A shows a schematic embodiment of the present
`invention. including a preheat section and a kiln enclosure.
`FIG. 8B is a schematic cross-sectional elevation view of
`the drying la'ln showing the enclosure and air flow.
`FIG. 8C shows location of the heating elements and fans
`in the enclosure of FIG. 8B.
`FIG. 8D shows a schematic plan View of all sections
`between the split deck and the spinners.
`FIGS. 8E and SF show two elevation views of the
`convection preheat system.
`FIG. 8G shows the insulation box for the table section.
`FIG. 9 shows a schematic embodiment of the present
`invention. including locations of the several preheat sec—
`dons
`
`FIGS. 10A and 103 show temperature sensors and under-
`deck heaters associated with the split deck
`FIG. 10C shows a group of cap pinbars and the corre-
`sponding group of body pinbars.
`FIG. 10D shows the split deck layout for the bars of FIG.
`10C.
`
`FIG. 11 shows non-contact temperature sensors and over-
`head heaters associated with the split deck.
`
`8
`FIGS. 12 and 13 show a plan and elevation view respec-
`tively of a dipper section preheat arrangement.
`FIGS. 14A and 14B show two views of a preheater with
`air ducts for selectively heating pins.
`FIG. 15 shows the gel dish temperature control scheme.
`FIGS. 16A. 16B and 16C show apparatus for heating the
`pins through the pinbar to permit post-dip gelling in the
`spinner section and “inside-out drying” in the drying kiln.
`FIG. 17 illustrates the process of removing the capsule
`part from the pin.
`FIG. 18 gives detail of the stripper of FIG. 6 as modified
`for the present invention.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The present invention provides improvements over the
`method of manufacture of pharmaceutical capsules dis-
`closed in US. Pat. No. 4.001.211 to Sarkar. The Sarkar
`cellulose composition is particularly suited for preparing
`pharmaceutical capsule shells which dissolve at a rate com-
`parableto gelatin capsules. Delay release characteristics can
`be obtained by incorporation of a less water-soluble cellu-
`lose such as ethyl cellulose as described by Greminger and
`Windover in US Pat. No. 2.887.440.
`In a preferred
`embodiment. the present invention uses the improved ther-
`mogelling methyl cellulose ether compositions disclosed in
`the Sarkar patent. including a thermal gelling methyl cellu—
`lose ether composition suitable for use in preparing phar—
`maceutical capsules by an aqueous dip coating process using
`preheated pins and having a methoxyl D5 of about 1.5—2.0.
`a C2--C3 hydroxyalkyl MS of about 0.1—0.4. a 2 wt. percent
`aqueous solution viscosity of about 2-10 cps at 20° C. and
`a thermal gel point of about 50°—80° C.. and a 15—30 wt.
`percent aqueous solution viscosity of about LOGO—10.000
`cps at 20° C., said composition being further characterized
`by having as a 15—30 wt. percent aqueous solution: (A)
`essentially Newtonian fluid properties as defined by a power
`law coefficient. n. of 0.9—1.0 at shear rates of between
`01—10 sec". and (B) a 50 sec gel yield strength of at least
`150 dynes/cm2 at 65° C.
`The apparatus of the present invention. in a preferred
`embodiment.
`is based on the type of capsule machine
`disclosed in US. Pat. No. 1.787.777 to Colton and US. Pat.
`No. 2.671.245 to Kath. The machine that was modified to
`embody the present
`invention was a “Colton” capsule
`machine manufactured by R & J Engineering Corporation.
`100 Hansen Avenue. Kitchener. Ontario. Canada N2C 2 E2.
`1. General
`The present invention provides a production process and
`a fully mechanized production apparatus that may use the
`modified cellulose in US. Pat. No. 4.001.211 to Sarkar for
`manufacturing pharmaceutical capsules of sufficient unifor-
`mity and rigidity that they may be filled on modern high—
`speed capsule filling machines. Capsules may be made in a
`range of sizes similar to the range of sizes in Tables 1—3. For
`a given capsule the capsule bodies and capsule caps have
`ditferent dimensions as illustrated for the prior art capsules
`in FIGS.
`lA—lC. The process involves a series of steps
`performed by one machine. Each capsule part is made by
`dipping a hot stainless steel pin into a cellulose gel solution
`and drying the gel to form a hard film over the pin. The pins
`are mounted in a row on a bar as illustrated in FIG. 3. FIG.
`
`10
`
`15
`
`20
`
`25
`
`35
`
`45
`
`50
`
`55
`
`65
`
`4 shows a pin with a gel coating. Body pins are mounted on
`one set of bars and cap pins are mounted on a corresponding
`set of bars so that corresponding bodies and caps may pass
`through the entire process in phase with each other and
`
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`9
`
`10
`
`5.756.036
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`emerge from the process facing each other positioned for
`assembly as a capsule.
`The process. in a first embodiment. is arranged so that the
`bars travel in a continuous loop illustrated in FIG. 8A. The
`process steps in this embodiment are:
`Preheating the pin bars (Preheat Section);
`Oiling the pins (Greaser Section);
`Dipping the pins into cellulose solution (Dipper Section);
`Spinning the coated pins (Spinner Section);
`Drying the gel (Upper and Lower Drying K