United States Patent [19J
`Zeleznick et al.
`
`[II] Patent Number:
`[45] Date of Patent:
`
`5,002,973
`Mar. 26, 1991
`
`[75]
`
`[54] STABILIZED SULFITE-FREE
`CATECHOLAMINE COMPOSITIONS
`Inventors: Lowell Zeleznick, Irvine; Allan M.
`Raff, Walnut Creek, both of Calif.
`[73] Assignee: Dey Laboratories, Inc., Napa, Calif.
`[21] Appl. No.: 426,495
`
`[22] Filed:
`
`Oct. 23, 1989
`
`Related U.S. Application Data
`[63] Continuation-in-part of Ser. No. 138,629, Dec. 28,
`1987, abandoned.
`
`Int. Cl.5 ............................................ A61K 31/135
`[51]
`[52] U.S. Cl. .................................... 514/653; 514/654;
`514/970; 514/973; 514/836
`[58] Fjeld of Search ............... 514/653, 654, 970, 973,
`514/836; 424/45, DIG. 7
`References Cited
`U.S. PATENT DOCUMENTS
`2,698,823 3/1951 Bersworth eta!. ....... :. 424/DIG. 10
`3,808,317 4/1974 Hecht eta!. ........................ 514/973
`3,966,905 6/1976 Nite ..................................... 514/653
`
`[56]
`
`4,150,744 4/1979 Fennimore .......................... 206/205
`4,164,570 8/1979 Clough eta!. ...................... 514/653
`
`FOREIGN PATENT DOCUMENTS
`0150694 9/1981 Fed. Rep. of Germany ...... 514/973
`
`OTHER PUBLICATIONS
`Lachman-Antioxidants and Chelating; Agents As Sta(cid:173)
`bilizers in Liquid Dosage Forms, Drug Cosmet. Ind.
`102(2), 43-45, 146-149, (1968).
`
`Primary Examiner-Stanley J. Friedman
`Assistant Examiner-Raymond J. Henley, III
`Attorney, Agent, or Firm-Flehr, Hohbach, Test,
`Albritton & Herbert
`·
`
`[57]
`ABSTRACT
`Novel catecholamine solutions for physiological uses
`are provided at a pH in the range of 1.0-5.0, comprising
`catecholamine, acetylcysteine, chelating agent and buff(cid:173)
`ering agents. The compositions are stabilized from oxi(cid:173)
`dation without the use of sulfites and are preferably
`administered by inhalation.
`
`6 Claims, No Drawings
`
`ADAMIS EXHIBIT 1010
`Page 1 of 4
`
`

`

`1
`
`5,002,973
`
`2
`
`STABILIZED SULFITE-FREE CATECHOLAMINE
`COMPOSITIONS
`
`This is a continuation-in-part of application Ser. No. 5
`138,629 filed Dec. 28, 1987, now abandoned.
`The present invention is directed to novel catechol(cid:173)
`amine compositions which are physiologically useful
`and which are stabilized from oxidation without the use
`of sulfites.
`
`10
`
`wherein X is hydrogen or hydroxyl, R and R I are hy(cid:173)
`drogen or alkyl of from 1-6 carbon atoms, A, Band C
`are independently selected from the group consisting of
`H, hydroxy, alkoxy of I to 6 carbon atoms and hydroxy(cid:173)
`alkyl of I to 6 carbon atoms, with the proviso that at
`least one of A, B, or C is hydroxy or alkoxy. Preferably
`Rl is from 1-2 carbon atoms and R is hydrogen, methyl,
`ethyl, propyl or isopropyl. Preferably, A and Bare both
`hydroxy and Cis hydrogen. The alkoxy groups which
`may constitute A, B, or C include methoxy, ethoxy,
`n-propoxy, i-propoxy, n-butoxy, sec-butoxy, i-butoxy,
`t-butoxy, n-pentoxy and n-hexoxy. The hydroxy alkyl
`groups which may constitute A, B, or C include hy(cid:173)
`droxymethyl,
`1-hydroxyethyl, 2-hydroxyethyl,
`3-
`hydroxyprop-1-yl, 4-hydroxy-butyl, 5-hydroxypent-
`25 1-yl and 6-hydroxyhex-1-yl.
`Particularly preferred catecholamines include those
`in which A and B are hydroxy and C is hydrogen, such
`as, epinephrine (X=OH, RI=H, R=CH3), and iso(cid:173)
`etharine hydrochloride (X =OH, R 1 =ethyl, R = isopro(cid:173)
`pyl).
`A second component of the composition is acetylcys(cid:173)
`teine, preferably in an amount of0.05-2 .. 0% w/v, which
`serves as the the antioxidant. Acetylcysteine is physio(cid:173)
`logically acceptable and can be coadministered with the
`catecholamine by injection, topically by liquid or sprays
`or by inhalation, which is the preferred method of ad-
`ministration of the compositions according to the pres(cid:173)
`ent invention. The dosages to be administered of the
`catecholamine (an active pharmaceutical component of
`the composition) are well known in the art. Particularly
`preferred uses include use as a spray or aerosol for
`opthalmological, nasal, or respiratory disorders.
`A third component of the composition of the present
`invention is a chelating agent, particularly a chelating
`agent capable of binding heavy metals which are usu(cid:173)
`ally found in trace amounts in water. A preferred che-
`lating agent is edetate disodium. Since only trace
`amounts of heavy m~tals will be present, small amounts
`50 of the chelating agent will be required, usually in the
`range of 0.01-0.25% w/v.
`In order to obtain the desired pH range of 0.1-5.0, an
`appropriate buffer, preferably sodium citrate, adjusted
`with a small amount of mineral acid, such as hydrochlo-
`55 ric acid, will be employed. This should be adjusted to
`preferably be within a range of 2.5-5.0, most preferably
`within a range of about 2.8-3.5.
`The aqueous compositions according to the present
`invention will normally be relatively dilute aqueous
`60 solutions having about less than about 0.9 totaL weight
`percent of the above additives, usually less than about
`1.5 total weight of the additives, and generally more
`than about 0.5 total weight percent of the additives. The
`amount of the catecholamine, which includes such com-
`65 pounds as epinephrine, levarterenol, nordefrin, and
`isoetharine hydrochloride, will normally be present in
`at least about 0.1% w /v, in general not exceeding 10%
`w/v percent. For compositions which are intended for
`
`15
`
`BACKGROUND OF THE INVENTION
`Catecholamine compositions, such as epinephrine,
`are useful for various pharmaceutical purposes. As
`many types of organic compositions, catecholamines
`are sensitive to oxidation, and thus must be protected
`from oxidation in order to prolong shelf life and to
`prevent conversion to derivatives which are not as
`pharmaceutically effective and/or which may be harm- 20
`ful to the user. Oxidation of catecholamine can result in
`loss of titer of the active ingredient, formation of com-·
`po~nds which may have undesirable physiological ef(cid:173)
`fect and appearance of a dark color, which often makes
`the composition undesirable and unmarketable.
`Many pharmaceutical compositions, including cate(cid:173)
`cholamine compositions, have heretofore contained
`sulfites to stabilize the compositions from oxidation.
`However, use of sulfites has been found to be harmful
`and therefore there is a need to find methods for stabiliz- 30
`ing catecholamines for their various physiological uses
`without the use of sulfites.
`U.S. Pat. No. 3,966,905 discloses particular catechol(cid:173)
`amine solutions containing polyvinylpyrrolidone.
`U.S. Pat. No. 3,091,569 discloses a mucolytic process 35
`comprising contacting a mucous with a certain class of
`N-acylated sulfhydrl compounds.
`It is thus an object of the present invention to provide
`novel catecholamine-containing compositions which
`are sulfite-free.
`It is a further object of the present invention to pro(cid:173)
`vide novel catecholamine solutions which are stabilized
`from oxidation and suitable for inhalation.
`These and other objects will become apparent from
`the following description of the present invention to 45
`those of ordinary skill in the art.
`
`40
`
`SUMMARY OF THE INVENTION
`The present invention provides physiologically useful
`sulfite-free catecholamine-containing aqueous composi(cid:173)
`tions within a pH in the range of 0.1-5.0 consisting
`essentially of catecholamine, acetylcysteine (0.05-2.0%
`w/v), a chelating agent (0.01-0.25% w/v), and suitable
`buffering agents for maintaining pH.
`
`DESCRIPTION OF THE SPECIFIC
`EMBODIMENTS
`The aqueous compositions according to the present
`invention contain a pharmaceutically effective amount
`of a catecholamine. The amount which is present in the
`composition will depend upon the desired dosage unit
`for the particular use and the method of intended ad(cid:173)
`ministration. Usually the composition will contain from
`about 0.1-10% weight/volume catecholamine. By the
`term catecholamine it is meant all of the compositions
`generically known as catecholamines, including com(cid:173)
`pounds of the following formula:
`
`ADAMIS EXHIBIT 1010
`Page 2 of 4
`
`

`

`3
`inhalation, catecholamine will usually be present in
`about 0.08-1.0% w/v.
`Pharmaceutical quality N-acetyi-L-cysteine is readily
`available commercially or may be prepared by known
`methods such as disclosed, for example, in U.S. Pat. No.
`3,091,569 or by Pirie, et al., Biochem. J., 27, 1716-18
`(1933). Various catecholamines are also readily avail-
`
`AGE (month)
`
`LOWER SPEC
`UPPER SPEC
`LABEL CLAIM
`0
`0
`0
`I
`
`LOWER SPEC
`UPPER SPEC
`LABEL CLAIM
`0
`0
`0
`I
`I
`I
`2
`2
`2
`3
`3
`3
`
`LOWER SPEC
`UPPER SPEC
`LABEL CLAIM
`0
`0
`0
`
`able from commercial sources and their methods of
`synthesis and purification are well known in the art.
`The following example is presented by way of illus(cid:173)
`tration and is not intended to limit the invention in any
`way.
`
`EXAMPLE
`Three samples of sulfite-free isoetharine solutions
`containing 1% acetylcysteine were stored at 37o C., and
`assayed at approximately four-week intervals for iso(cid:173)
`etharine activity (vs. the label claim and original po(cid:173)
`tency at time zero) and pH. The three samples (each in
`triplicate) were stable at 37o C. for the three-month
`period of the test, which is equivalent to storage for two
`years at room-temperature (25o C.). In Table I, the
`
`5,002,973
`
`4
`assayed potency is given in percent of label claim. fol(cid:173)
`lowed in parenthesis by percent potency of original
`value at time zero, calculated as
`
`Value at time (I) ' 100
`Avg. of label claim values at ttme 0
`
`TABLE I
`Size of Package: 0. 5 M L
`Type of Package: 0. 5 M L Polypropylene
`l.M. Vial
`pH CLARITY
`
`lsoetharine
`
`COLOR
`
`ODOR
`
`BATCH A
`(0.92%)
`2.5
`(1.08%)
`5.5
`(1.0%) 4.0 CLEAR
`(IOO.Q)
`3.0 CLEAR
`(100.0)
`(100.0)
`(101.0)
`(104.0)
`(102.0)
`(99.5)
`(101.0)
`(99.3)
`(100.0)
`(101.0)
`(99.4)
`
`3.0 CLEAR
`
`2.9 CLEAR
`
`3.0 CLEAR
`
`BATCH B
`(0.92o/c)
`2.5
`(1.08%)
`5.5
`(1.0%) 4.0 CLEAR
`(100.0)
`3.0 CLEAR
`ooo:o)
`(100.0)
`(101.3)
`(101.3)
`(100.3)
`(100.3)
`(100.2)
`(100.1)
`(102.3)
`(101.3)
`(101.3)
`
`2.9 CLEAR
`
`3.0 CLEAR
`
`3.1
`
`CLEAR
`
`BATCH C
`(0.92%) 2.5
`(1.08%)
`5.5
`(1.0%) 4.0 CLEAR
`(100.0)
`3.1
`CLEAR
`(100.0)
`(100.0)
`(96.5)
`(97.3)
`(96.5)
`(99.4)
`(99.4)
`(99.4)
`(99.4)
`(101.3)
`( 100.3)
`
`3.2 CLEAR
`
`3.1
`
`CLEAR
`
`3.1
`
`CLEAR
`
`92% LC
`108% LC
`100% LC
`100.0
`98.9
`101.0
`101.0
`104.0
`102.0
`99.5
`101.0
`99.3
`100.0
`101.0
`99.4
`
`92% LC
`108% LC
`100% LC
`99.1
`101.0
`99.1
`101.0
`101.0
`100.0
`100.0
`99.9
`99.8
`102.0
`101.0
`101.0
`
`92% LC
`108% LC
`100% LC
`103.0
`104.0
`101.0
`99.1
`99.9
`99.1
`102.0
`102.0
`102.0
`102.0
`104.0
`103.0
`
`55
`
`COLORLESS
`COLORLESS
`
`TYPICAL
`TYPICAL
`
`COLORLESS
`
`TY·PICAL
`
`COLORLESS
`
`TYPICAL
`
`COLORLESS
`
`TYPICAL
`
`COLORLESS
`COLORLESS
`
`TYPICAL
`TYPICAL
`
`COLORLESS
`
`TYPICAL
`
`COLORLESS
`
`TYPICAL
`
`COLORLESS
`
`TYPICAL
`
`COLORLESS
`COLORLESS
`
`TYPICAL
`TYPICAL
`
`COLORLESS
`
`TYPICAL
`
`COLORLESS
`
`TYPICAL
`
`COLORLESS
`
`TYPICAL
`
`The foregoing invention has been described in some
`detail by way of illustration for the purposes of clarity
`and understanding. However, it will be obvious that
`60 certain changes and modifications may be practiced
`within the scope of the appended claims.
`What is claimed is:
`1. A physiologically acceptable sulfite-free catechola(cid:173)
`mine-containing aqueous composition at a pH range of
`65 2.8 to 3.5 consisting essentially of about 1.0% w/v of a
`catecholamine, from 0.05-2.0% w/v of acetylcysteine,
`0.01-0.25% w/v edetate disodium, and buffer, wherein
`said catecholamine is a compound of the formula
`
`ADAMIS EXHIBIT 1010
`Page 3 of 4
`
`

`

`5
`
`X
`
`A~R'
`'~ NHR
`
`c
`
`5,002,973
`
`6
`ing agent is present in an amount sufficient to maintain
`the pH of said compositions within said range.
`2. A composition according to claim 1 wherein said
`buffering agent comprises sodium citrate and hydro-
`5 chloric acid.
`3. A composition according to claim 2 wherein A and
`B are hydroxy and C is hydrogen.
`4. A composition according to claim 3 wherein X is
`10 hydroxyl, R 1 is ethyl and R is isopropyl.
`5. A composition according to claim 1 wherein A and
`B are hydroxy and C is hydrogen.
`6. A composition according to claim 5 wherein X is
`hydroxyl, R 1 is hydrogen and R is methyl.
`* * * * *
`
`wherein X is hydrogen or hydroxyl, R and R 1 are hy(cid:173)
`drogen or alkyl of from 1-6 carbon atoms; A, Band C
`are independently selected from the group consisting of
`H, hydroxy, alkoxy of I to 6 carbon atoms and hydroxy(cid:173)
`alkyl of I to 6 carbon atoms with the proviso that at
`least one of A, B or Cis hydroxy or alkoxy; said buffer- 15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`ADAMIS EXHIBIT 1010
`Page 4 of 4
`
`