`United States Patent Office
`Patented Sept. 13, 1966
`
`1
`
`2
`
`3,272,700
`STABHLIZED AQUEOUS SOLUTION 0F
`TETRACAINE SALT
`to
`Irwin S. Slippe, North Greenhush, N.Y., assiguor
`Sterling Drug 1nc., New York, N.Y., a corporation of
`Delaware
`No Drawing. Filed Oct. 3, 1963, Ser. No. 313,422
`1 Claim.
`(Cl. 1167—52)
`
`This application is a continuation~in»part of my co-
`pending application Serial No. 167,955, filed January 22,
`1962, now ab-andonded.
`This invention relates to an improved aqueous solution
`of an acid-addition salt of 2—dimethylaminoethyl 4-u—
`butylaminobenzoate and to a method of maintaining
`clarity in said solution.
`also
`4-n—butylaminobenzoate,
`2-dimethy1aminoethyl
`known generically as tetracaine,
`is a well-known com-
`mercial
`local anesthetic.
`It has been sold for almost
`twenty-five years in the form of its hydrochloride in aque-
`ous solution in various concentrations adapted for pro-
`longed spinal anesthesia, for surface anesthesia for dental
`practice, etc.
`'
`Manufacturers of such solutions, while enjoying com-
`mercial success over the years with these readily accepta-
`ble and efficacious aqueous preparations have been at the
`same time faced with the persistent problem of how to
`increase the storage life of the solutions. On standing,
`these tetracaine solutions have the disadvantage of yield-
`ing small quantties of precipitated 4—n—buty1aminobenzoic
`acid, a hydrolysis degradation product of tetracaine. The
`4—n-buty1aminobenzoic acid, which is relatively insoluble
`in aqueous solutions, separates as crystals or produces
`cloudiness in the solution.
`.I have now found that the precipitation of 4-n-butyl-
`:arninobenzoic acid from solutions of tetracaine salts, for
`instance the hydrochloride, is prevented by incorporating
`in the solutions a small quantity of an oxyethylated alkyl-
`phenol-formaldehyde polymer. The resulting solutions,
`the composition aspect of my invention, have increased
`shelf life when stored for long periods at room tempera-
`ture (25° C.) and even at temperatures of 37°, 40° and
`50° C. or when heated as high as 121° C. for periods of
`one to three hours.
`The oxyethylated alkylphenol-formaldehyde polymers
`useful in the compositions of the invention are prepared
`by condensing a mole of an alkylphenol with 0.5—1.0
`mole of formaldehyde and reacting the product thus ob-
`tained with 8—60 moles of ethylene oxide, as described in
`US. Patent 2,454,541. Particularly useful polymers are
`the oxyethylated p - tertiary - octylphenol - formaldehyde
`polymers produced by condensing approximately equimo-
`lar amounts of patertiary-octylphenol and formaldehyde
`and then reacting the product with 10-20 moles of ethyl-
`ene oxide. A preferred compound of this group is the
`product containing ten ether groups per p-tertiary—octyl-
`phenol nucleus which is known under the brand names,
`“Superinone” and “Triton WR—1339,” chemically as oxy—
`ethylated tertiary octylphenol formaldehyde polymer or
`p—isooctylpoly-oxyethylenephenol
`formaldehyde polymer,
`and, genetically as tyloxapol
`[1. Am. Med. Assoc, 181,
`243 (1962)]; the preparation of a closely similar and
`equivalently useful compound is described in Example 1
`of U.S. Patent 2,454,541, where-in eleven moles of ethyl-
`ene oxide are used.
`Aqueous solutions of the invention preferably have
`about 0.4 to about
`1 percent
`(weight per volume) of
`-
`an oxyethylated alkylphenol
`formaldehyde polymer.
`Greater quantities of the polymer, up to about 10 per—
`cent or more, can be used but to no particular advantage.
`Preferred embodiments are aqueous solutions containing
`about 0.1 to 2 percent of 2—dimethylaminoethyl 4-n-buty1-
`
`aminobenzoate hydrochloride and about 0.4 to 1 percent
`of tyloxapol. A particularly preferred embodiment con-
`tains 1.0 percent of tetracaine hydrochloride and 0.8 per-
`cent of tyloxapol.
`Another aspect of my invention resides in a method for
`maintaining clarity in an aqueous solution of a pharmaceu-
`tically—acceptable salt of 2-dimethylaminoethyl 4-n—butyl—
`aminobenzoate which comprises incorporating in said solu-
`tion normally subject to precipitation or cloudiness on
`storage an oxyethylate‘d alkylpheuol—formaldehyde poly-
`mer in amount sufficient to keep the hydrolysis degrada-
`tion product 4-n—‘butylaminobenz-oic acid in solution on
`storage. Preferred essential ingredients of said solution
`and preferred percentages thereof are presented herein-
`above.
`My invention is further illustrated by the following
`specific embodiments without, however, limiting it thereto.
`U.S.rP. grade ingredients are used in the following
`examples.
`
`Example I
`
`The following aqueous solutions containing 1 percent
`(weight per volume, i.e., 1 g. per 100 ml.) tetracaine hy-
`drochloride containing 0, 0.1, 1.0 and 10 percent tyloxapol
`were prepared:
`Ingredient
`1A
`1B
`10
`1D
`
`Tetracaine hydrochloride. _ _ .
`1. 0
`1. 0
`1. 0
`1. 0
`Sodium chloride _____________
`0.67
`0.67
`0. 67
`0. 67
`Acetone sodium bisulfite_____
`0.20
`0. 20
`0. 20
`0.20
`Tyloxapol _____________________________
`0. 1
`1. 0
`10. 0
`
`
`The solutions were prepared by dissolving the ingredi-
`ents in distilled water and then were poured into 2 ml.
`flint ampuls, sterilized by heating at 220° F. for three
`minutes and stored at 122° F. (50° C.).
`The solutions were assayed for free 4-n4buty1amino-
`benzoic acid (BABA) initially and after one and eight
`months storage at 50° C. with the following results:
`
`Preparation
`
`BABA, rug/ml.
`DH
`
`Initial
`1 month
`8 months
`Initial
`Final
`at 50° C.
`at 50° C.
`
`
`10
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`1A ____________
`1B ____________
`10 ____________
`1D ............
`
`0.015
`0. 018
`0.015
`0.019
`
`0.103
`0. 119
`0.150
`0. 105
`
`0.129
`0. 139
`0.378
`0. 429
`
`3. 5
`3. 4
`3. 5
`3. 4
`
`3. 5, 3. 1
`3. 15
`3.08
`2. 61
`
`55
`
`60
`
`70
`
`None of the ampuls stored for 8 months at 50° C.
`showed any sign of crystallization after being allowed to
`cool and to stand at room temperature overnight. How-
`ever, on refrigerating at 5° C., some amorphous precipi-
`tate separated in the control (1A) and in the 0.1% tyloxa-
`pol solution (1B). No precipitate formed, even after
`a full week in the refrigerator, in the solutions containing
`1% (1C) or 10% (1D) tyloxapol.
`'
`It is seen from the above results that 0.1% tyloxapol
`did not prevent the precipitation of BA-BA in the solu-
`tion containing 0.14 mg. of BABA per m1. and that 1.0%
`tyloxapol did prevent the precipitation of as much as
`0.38 mg. of BABA per ml., the latter representing 3.8%
`decomposition of the tetracaine hydrochloride.
`It is also
`seen that 10.0% tyloxapol prevented the precipitation of
`0.43 mg. of BABA per ml., which represents only 4.3%
`decomposition of tetracaine hydrochloride.
`
`Page 1 of 5
`
`LUPIN EX 1041
`
`LUPIN EX 1041
`
`Page 1 of 5
`
`
`
`3,272,700
`
`3
`Example 2
`
`tetracaine hy-
`The following solutions of 1 percent
`drochloride containing 0, 0.2, 0.4, 0.6 and 0.8 percent
`tyloxapol were prepared:
`
`Ingredient
`2A
`2B
`20
`2D
`2E
`
`
`5.0
`5.0
`5.0
`5.0
`Tetracaine hydrochloride, g.
`5.0
`.__
`3. 35
`3. 35
`3. 35
`3. 35
`Sodium chloride, g __________
`_-_ 3. 35
`
`1. 0
`1. 0
`1. 0
`1. 0
`Acetone sodium bisulfite, g._
`.
`1. 0
`4.0
`3.0
`2.0
`1. 0
`Tyloxapol, g ______________________________
`
`
`
`
`500 500 500 500Water for injection. ml, q.s. ad ________ 500
`
`
`Each of the above solutions was prepared as follows:
`The acetone sodium bisulfite was dissolved in about 400
`ml. of distilled water containing the tyloxapol. The so-
`dium chloride and tetracaine hydrochloride were then
`dissolved, respectively; and the pH of the solution was
`checked and adjusted to 4.6. Distilled water was added
`to give 500 m1. of solution which was filtered through
`an ultra fine frit glass filter into a sterile system and then
`filled into 2 m1. flint ampuls under aseptic conditions.
`The ampuls were heated at 220° F. for three minutes,
`submitted for chemical assay and some were then stored
`at 40° 0., some in a refrigerator (about 5° C.) and some
`at room temperature (about 20—25° C.).
`The results of the initial assay are summarized as fol-
`lows:
`
`4
`at 40° C. after submitting some of the ampuls for initial
`chemical assay.
`The results of the initial assay follow:
`
`Ingredient
`3A
`3B
`3C
`3D
`3E
`
`
`9.73
`9.67
`9. 57
`9. 69
`9. 69
`Tetracaine H01, mg.[ml__________
`8. 50
`6. 40
`4. 40
`2. 33
`Tyloxapol, mg./ml __
`_______
`0. 027
`0. 027
`0. 033
`0. 033
`BABA, mg./ml_
`_
`0. 034
`
`
`
`
`3. 9 3. 9 3. 85 3. 76pH_____________ 3. 70
`
`
`
`The solutions stored at 40° C. were assayed for BABA
`after three and six months with the following results:
`
`3 mo. at 40° C.
`
`6 mo. at 40° C.
`
`12 mo. at 40° C.
`
`Solution
`
`10
`
`15
`
`BABA,
`pH
`BABA,
`pH
`BABA,
`mg./m1.
`mg./ml.
`mg./m1.
`
`
`pH
`
`0. 09
`3. 75
`0. 10
`3. 80
`0. 11
`C. 21
`3. 80
`0. 19
`3. 80
`0. 11
`0.31
`3. 80
`0.19
`3. 80
`0. 11
`0. 32
`3. 70
`0.20
`3. 75
`0. 11
`0.34
`3.65
`0. 30
`3. 70
`0. 11
`
`
`
`
`3. 08
`3. 09
`3. 81
`3. 60
`3. 58
`
`After storage for six months at 40° C., solutions 3B, 3C,
`3D and 3E remained clear and solution 3A yielded crys-
`tals when chilled for two hours in an ice bath. After
`storage for twelve months at 40 C., solutions 3C, 3D
`and 3E remained clear and solutions 3A and 3B yielded
`crystals when chilled for five hours in an ice bath.
`
`Example 4
`
`The following solution containing 0.15 percent tetra-
`caine hydrochloride and 0.8 percent of tyloxapol was pre-
`pared:
`
`Mg./ml.
`Ingredient:
`Tetracaine HCl __________________________
`1.5
`Sodium chloride _________________________
`8.6
`Calcium chloride-ZHZO ___________________ 0.33
`Potassium chloride _______________________ 0.30
`Tyloxapol _______________________________
`8.0
`
`The anesthetic and the three inorganic chlorides were
`dissolved in most of the distilled water, the tyloxapol
`added and dissolved, the pH adjusted to 5.2 by addition
`of 0.1 N sodium hydroxide solution, and the remaining
`water added. The solution was filtered through an ultra
`fine frit glass filter into a sterile system and then filled
`into 100 m1. glass stoppered flint vials. The vials were
`heated at 220° F. for thirty minutes and stored at 37° C.
`for twelve months. Assays initially and after six and
`twelve months are summarized as follows:
`
`
`Ingredient
`Initial,
`6 Ind/37° 0.,
`12 mo./37° C.,
`mg./ml.
`mg./m1.
`ngml.
`
`
`1.32
`1. 46
`1. 48
`Tetracaine________________
`0. 6
`7.6
`8. 0
`Tyloxapol. __
`
`0.056
`0.034
`0.015
`BABA______
`
`
`
`5. 5 4. 2pH_______________________ 4. 45
`
`The solution after twelve months at 37° C. was clear
`and colorless.
`
`4O
`
`45
`
`55
`
`60
`
`Ingredient
`2A
`2B
`2C
`2D
`2E
`
`
`3O
`
`9. 6
`9. 7
`9. 7
`9. 7
`9. 5
`Tetracaine 1101, ngml_______________
`
`7. 30
`5. 50
`4. 6
`_________ 2. 35
`Tyloxapol, ngml. _ _____.
`
`0. 025
`--. 0. 022 0. 024 0. 025 0. 024
`BABA, lug/m]__________
`
`
` 2. 902. 953. 00pH____________________________________ 3. 35 2. 90
`
`
`
`
`The solution stored at 40° C. were assayed for BABA
`after three and six months with the following results:
`
`Solution
`
`3 mo. at 40° C.
`6 mo. at 40° C.
`
`
`BABA,
`pH
`BABA,
`pH
`mg./ml.
`rug/m1.
`
`
`
`
`0. 098
`O. 159
`0. 167
`0. 171
`0. 171
`
`3. 05
`2. 95
`3. 00
`3. 00
`3. 05
`
`0. 103
`0. 202
`0. 253
`0. 283
`0. 292
`
`3. 05
`2. 95
`2. 95
`2. 90
`2. 88
`
`After storage for six months at 40° C., solutions 2C,
`2D and 2E remained clear and solutions 2A and 2B
`yielded crystals when chilled for six hours in an ice bath.
`Thus, it is seen that 0.2% tyloxapol did not prevent the
`precipitation of BABA in the solution containing 0.20
`mg. of BABA per ml. and 0.4%, 0.6% and 0.8% tyloxa-
`pol did prevent the precipitation of as much as 0.25 mg,
`0.28 mg. and 0.29 mg, respectively, of BABA per ml.
`Example 3
`
`The following solutions of 1 percent tetracaine hydro-
`chloride containing 0, 0.2, 0.4, 0.6 and 0.8 percent tyloxa-
`pol were prepared as in Example 2 but adding a lactic
`acid-sodium lactate buffer:
`
`
`3E
`3D
`30
`3B
`3A
`Ingredient
`“—T——_ 65
`
`2.5
`.
`2.
`2.5
`.
`Cl,
`_____
`'
`0. 925
`0.32?
`0. 92:
`0.925
`0. 322
`ggiiggiugfilgidefg______
`
`0.5
`0.5
`0.5
`0.5
`0.5
`Acetone spdium bisulfite,
`
`___: "'ifé‘
`(fig
`{(5)
`f? w
`ggditigilfaétga'té'(s‘d‘ia3Z-fxil'f:
`sashes .7... °~sss
`°-sss
`°~sss
`°~sss
`°-sss
`Ad
`1: d H_____________________
`3.98
`4.05
`4.03
`4.05
`4.0
`am or met: Ion, q.s. a , m ___
`
`ms 9 p
`3
`
`Example 5
`~
`-
`~
`.
`FOHPW‘ng th? procedure descr‘bed 1“ Example 2’ the
`followmg solution containing 1.0 percent tetracaine hy-
`drochloride and 0.80 percent of tyloxapol was prepared:
`I
`d
`.
`Quantity
`ngre ient:
`Tetracaine HCl __________________________g__ 50.00
`Tyloxapol ______________________________ g__ 40.00
`Sodium chloride _________________________ g__ 33.50
`The pH was adjusted to the above values using lactic
`Acetone sodium bisulfite __________________ g-_ 10.00
`acid. The solutions were filled into sterile 2 ml. flint
`ampuls, heated at 220° F. for three minutes and stored 75 Water for injection, q.s. ad _______________m1__ 5000
`
`7O
`
`Page 2 of 5
`
`
`
`Page 2 of 5
`
`
`
`5
`Results of the initial assay and assays after storage at
`37° C. for twelve months and at room temperature (25°
`C.) for twenty—three months are given as follows:
`
`
`3,272,700
`
`
`
` Ingredient Initial 12 mo., 37° C. 23 mo., 25" C.
`
`
`
`til
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`40
`
`6
`by standard procedures and the presence of the tyloxapol
`in the solutions was found not to have any significant
`change on the local anesthetic activity, toxicity, or irritan-
`cy when compared with corresponding solutions with-
`out
`the tyloxapol. For example,
`the average duration
`of urethral anesthesia in rabbits was 137:9.0 minutes
`for
`1.0 percent
`tetracaine hydrochloride alone and
`1611193 minutes for 1.0 percent tetracaine hydrochlo-
`ride with 1.0 percent tyloxapol; these data show that the
`addition of tyloxapol had slight if any effect on dura-
`tion of anesthesia by tetracaine hydrochloride alone. Sim-
`ilarly, no significant change in local anesthetic activity
`occurred when 1 percent tyloxapol was added to a 0.25
`or 0.50 percent tetracaine hydrochloride solution when
`tested by the intradermal wheal test in guinea pigs.
`The acute oral toxicity in mice of tetracaine hydrochlo-
`ride plus a 2 percent aqueous solution of tyloxapol was
`not significantly different from that of tetracaine hydro-
`chloride in distilled water without tyloxapol. When a
`25 percent aqueous solution of tyloxapol alone was studied
`for toxic effects in mice, no deaths occurred with oral
`doses as high as 10,000 mg./kg.,
`i.e., LD50 >10,000
`mg./kg.
`The acute intravenous LD50 determinations in mice car-
`ried out with 1.0 percent tetracaine hydrochloride alone,
`with 1.0 percent tetracaine hydrochloride containing 1.0
`percent tyloxapol, and with 0.25 percent tetracaine hydro-
`chloride containing 1.0 percent tyloxapol were respective-
`ly: 6.7:0.7, 631-06 and 62:06 mg./kg. in terms of
`tetracaine hydrochloride. Thus, the addition of tyloxapol
`to tetracaine hydrochloride, in the concentrations studied,
`had no significant effect on the acute intravenous LD50
`for tetracaine hydrochloride in mice. When a 25 per-
`cent concentration of tyloxapol alone was studied intra-
`venously for toxic effects in mice, the LD50 was >10,000
`mg./kg.
`The solution embodiment of my invention described
`above in Example 5 (also as Examples 2E and 6B) has
`been studied clinically by leading anesthetists accustomed
`These solutions were prepared following the procedure
`to doing spinal anesthesias. These investigators tested the
`described in Example 2 and in addition to heating some
`solution in 420 patients ranging in age from 13 to 89
`of the ampulled solution at 220° F. for three minutes,
`and found it
`to be safe and effective for its intended
`as in Example 2, some of the solution was assayed with
`no heating and some assayed after heating for different
`purpose. They obtained good results with 384 patients,
`times indicated below. My solution with tyloxapol as-
`fair results with 31 patients, and poor results with only
`45 5 patients; side effects were mild and were observed in
`sayed as follows:
`
`
`
`
`9.38
`9. 22
`9. 64
`Tetracaine HCl, mg./ml. ___
`8.42
`8.4
`7.94
`Tyloxapol, rug/ml__________
`0. 23
`0. 31
`BABA, mg./m1_____________________
`
`
` 3. 503. 70pH _________________________ 3. 68
`
`
`The two stored solutions were clear and colorless after
`the storage periods. Also, the same solution was stored
`for thirty-four months at 25° C., was next heated at 250°
`F. for twenty minutes, and, on assay, was found to con—
`tain only 0.26 mg./m1. of BABA and to have a pH of
`3.70.
`this embodiment gave good results
`As noted below,
`when tested clinically.
`
`Example 6
`the following
`For comparative heat stability studies,
`solutions of 1 percent tetracaine hydrochloride containing
`0 and 0.8 percent tyloxapol were prepared, the former
`solution (6A) being a presently commercial preparation
`and the latter (63) being a preferred embodiment of my
`invention.
`
`6A
`6B
`Ingredient
`
`1. 00
`1.00
`Tetracine 1101, g__________________________
`0.80
`Tyloxapol, g_______________________
`
`0.67
`Sodium chloride, g________
`0.67
`0.20
`Acetone sodium bisulfite, g._
`0.20
`
`
`100.00
`Water for injection, m1., q.s. a
`100.00
`
`
`Solution 6B
`Not
`220° F.,
`121° 0.,
`121° 0.,
`121° 0.,
`121° (3.,
`Heated
`3 min.
`15 min.
`30 min.
`45 min.
`60 min.
`
`
`9. 7
`9. 8
`9. 7
`9. 8
`9.8
`9. 9
`Tetracaine H01, mg./ml.
`8.2
`8. 2
`8.2
`8. 2
`8. 2
`8. 2
`Tyloxapol, rug/ml_______
`0. 069
`0. 053
`0. 042
`0. 029
`0.014
`0. 012
`BABA, rug/ml ________
`
`
`3.15
`3.15
`3.15
`3.15
`3.15
`3. 35
`pH
`
`
`The commercial preparation with no tyloxapol assayed
`as follows:
`
`
`55 only a small number of patients, e.g., mild hypotension
`(7), nausea (4), vomiting (11) and headache (1).
`
`Solution 6A
`Not
`220" F.,
`121° 0.,
`121° 0.,
`121° 0.,
`121° _C.,
`Heated
`3 min.
`15 min.
`30 min.
`45 min.
`60 mm.
`
`
`Tetracaine H01, mg./ml.
`BABA __________________
`pH ......................
`
`9. 7
`0. 010
`3. 40
`
`9. 8
`0. 013
`3. 70
`
`9.9
`O. 032
`3. 70
`
`9. 8
`0. 044
`3. 60
`
`9. 7
`0. 059
`3. 60
`
`’19. 7
`0. 072
`3. 50
`
`. Crystal formation when chilled in refrigerator (about 4° 0.).
`
`From the above results, it is noted that the presence of
`tyloxapol did not induce the hydrolysis of the tetracaine,
`the BABA concentrations being about the same for the
`two solutions when treated the same. However, the prep-
`aration with no tyloxapol (6A) showed crystal forma-
`tion when heated at 121° C. for sixty minutes and then
`stored in a refrigerator (about 4° C.) for a few days.
`In contrast, my solution (6B) even when heated at 121°
`C. for as long as three hours and then stored in a refrig-
`A stabilized aqueous solution of a pharmaceutically-
`erator for a few days showed no crystal formation.
`acceptable acid-addition salt of 2-dimethy1aminoethy1 4-
`The aqueous solutions of my invention were tested 75 n—butylaminobenzoate having as the stabilizing agent be-
`
`Other aqueous local anesthetic solutions can be pre-
`pared in accordance with the foregoing description by
`using,
`in addition to the essential
`ingredients of tetra-
`caine hydrochloride and oxyethylated alkylphenol—form—
`aldehyde polymer, other anesthetics, preservatives, buf-
`fering agents, etc., provided they are mutually compatible
`with the essential ingredients of the solution.
`I claim:
`
`70
`
`Page 3 of 5
`
`Page 3 of 5
`
`
`
`3,272,700
`
`7
`tween about 0.4 to about 1.0 percent tyloxapol per 0.1
`to 2 percent of said benzoate.
`
`.
`References Cited by the Exammer
`UNITED STATES PATENTS
`5/1953 Gaunt ______________ 167—-58
`8/1953
`hdflbr ______________ 167——58
`3/1959 Johnson ____________ 167—65
`
`5
`
`2,637,679
`$649318
`2,880,138
`
`8
`Drill, Pharmacology in Medicine, sec. ed., McGraw-
`Hill, 1958, page 106.
`Monash, Arch. Dermatol., vol. 76, No. 6, pages 752—
`756, December 1957_
`Sisley, Encyclopedia of Surface-Active Agents, Chem.
`PUb- C0» 1952. Pages 538-539-
`
`JULIAN S. LEVITT, Primary Examiner.
`
`OTHER REFERENCES
`Clark, Chem. Abst., volume 48, pages 10937—10938,
`1954.
`
`10 FRANK CACCIAPAGLIA, 111., Examiner.
`
`Page 4 of 5
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`Page 4 of 5
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`UNITED STATES PATENT OFFICE
`
`CERTIFICATE OF CORRECTION
`
`Patent No. 3,272,700
`
`September 13,
`
`15
`
`Irwin S. Shupe
`
`It is hereby certified that error appears in the above numbered pat—
`ent requiring correction and that the said Letters Patent should read as
`corrected below.
`
`line 30, for "quantties" read —- quantities ——;
`Column 1,
`column 3,
`line 69, fourth Table,
`third coluanline 6, for
`”0.975" read —— 0.075 —e; columns 5 and 6, fourth Table,
`seventh column,
`line 1, for "39.7” read —— 9.7 --;
`same column
`line 2, for ”0.072” read -— a0.072 ——.
`
`Signed and sealed this 5th day of September 1967.
`
`(SEAL
`Arrest:
`
`ERNFSH"WCS“HDER
`Attesting Officer
`
`EIHKARD.L BBI$mflfli
`Commissioner of Patents
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`Page 5 of 5
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`Page 5 of 5
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