United States Patent [19]
`Escobar et al.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`5,017,609
`May 21, 1991
`
`[54] PHARMACEUTICAL COMPOSITION AND
`METHOD OF TREATMENT OR
`PROPHYLAXIS OF CARDIAC DISORDERS
`[75] Inventors: Agustin Escobar, Aquadilla, P.R.;
`Dietmar Wagenknecht, Zion, I1l.;
`Ahmad W. Malick, Edison, N].
`E. I. Du Pont de Nemours and
`Company, Wilmington, Del.
`[21] Appl. No.: 437,293
`[22] Filed:
`Nov. 16, 1989
`
`[73] Assignee:
`
`[63]
`
`Related US. Application Data
`Continuation of Ser. No. 289,501, Dec. 23, 1988, aban
`doned, which is a continuation of Ser. No. 810,547,
`Dec. 18, 1985, abandoned, which is a continuation-in
`part of Ser. No. 598,061, Apr. 9, 1984, abandoned.
`
`[51] Int. Cl.5 ............................................ .. A61K 31/24
`[52] US. Cl. ................................ .. 514/538; 514/821
`[58] Field of Search ............. .. 514/510, 511, 522, 524,
`514/529, 532, 534, 538, 821
`References Cited
`U.S. PATENT DOCUMENTS
`
`[56]
`
`3,742,023 6/1973 Koppe et a1. ................. .. 260/471 R
`
`3,872,147 3/1975 Koppe et a1. . . . . . . .
`
`. . . . . . .. 260/465
`
`546/207
`4,146,630 3/1979 Kampe et a1.
`424/248.53
`4,191,765 3/1980 Fritsch et a1.
`4,346,093 8/1982 Friebe et a1. .............. .. 546/271
`
`4,387,103 6/1983 Erhardt et al. . . . . .
`. . . . .. 560/22
`4,829,086 5/1989 Bodor ................................ .. 514/538
`
`FOREIGN PATENT DOCUMENTS
`
`0041491 12/1981 European Pat. Off. .......... .. 514/538
`
`OTHER PUBLICATIONS
`Remington’s Pharmaceutical Sciences, 16th ed. (1980),
`pp. 214, 238, 1253-1256 and 1463-1468.
`Morrison and Boyd, Organic Chemistry, 3rd Edition,
`Sec. 20.16, p. 675.
`L. H. Smith, Journal of Applied Chemistry and Biotech
`nology, 2s(3)=201-212 (197s).
`
`Hisashi Nogami et al., Chemical and Pharmaceutical
`Bulletin, vol. 10, pp. 1158-1160 (1962).
`Joseph M. Talmage et al., Journal of Pharmaceutical
`Sciences, vol. 57, No. 6, pp. 1073-1074 (Jun. 1968).
`Pharmaceuticals, v01. 66, p. 6499, 68878k (1967).
`H. A. Garrera et a1., Rev. Latinoamer, Quim., 7:4-8
`(1976).
`P. B. Sheth et al., Journal of Pharmaceutical Sciences,
`vol. 56, No. 8, pp. 983-986 (Aug. 1967).
`M. Balakrishnan et al., Tetrahedron Letters, No. 45, pp.
`4617-4620 (1972).
`H. A. Garrera eta1., Rev. Latinoamer, Quim., 5:201-205
`(1974).
`Primary Examiner-Joseph A. Lipovsky
`Attorney, Agent, or Firm-Bernard, Rothwell & Brown
`[57]
`ABSTRACT
`A pharmaceutical composition is disclosed, which con
`tains a short-acting B-blocking compound of the for
`mula
`
`H
`R1OCA
`
`I
`ocuzcncnzmm
`
`wherein R1 may be an alkyl, cycloalkyl, alkenyl, alky
`nyl, alkyl carboxymethyl, aryl carboxymethyl, aryl or
`aralkyl, A may be an alkylene or alkenylene, X may be
`independently amino, hydrogen, halogen, hydroxy,
`alkoxy, aryloxy, aralkyl, cyano, amido or tri?uoro
`methyl, n is an integer from 1 to about 4, R may be an
`alkyl, propargyl, dimethylpropargyl or hydroxyalkyl;
`or a pharmaceutically acceptable salt thereof in a hy
`droalcoholic solution further containing a physiologi
`cally acceptable buffering agent, ethanol and a physio
`logically acceptable liquid polyhydric compound. A
`method for treatment or prophylaxis of cardiac disor
`ders using the composition of the present invention is
`also disclosed.
`
`10 Claims, 2 Drawing Sheets
`
`MYLAN ET AL. - EXHIBIT 1026
`
`

`
`U.S. Patent
`
`May 21, 1991
`
`Sheet 1 of 2
`
`5,017,609
`
`3 a
`
`Q2 E E E 3
`
`
`s 15% s_ .655. .22
`
`is mi:
`
`Q: a
`
`I
`
`QC
`
`2.
`
`0.0
`
`655.- .s 8.
`
`

`
`US. Patent
`
`May 21, 1991
`
`Sheet 2 of 2
`
`5,017,609
`
`FIG 2.
`
`as
`
`so
`
`25
`
`l5
`
`l0
`
`s
`
`o
`
`
`
`
`
`RATE cousmn 2° "
`
`a x lo‘2 PER DAY
`
`

`
`1
`
`PHARMACEUTICAL COMPOSITION AND
`METHOD OF TREATMENT OR PROPHYLAXIS
`OF CARDIAC DISORDERS
`
`This is a continuation of application Ser. No.
`07/289,501, ?led Dec. 23, 1988, now abandoned which
`is a continuation of application Ser. No. 810,547, ?led
`Dec. 18, 1985, now abandoned which is a continuation
`in-part of Ser. No. 598,061, ?led Apr. 9, 1984, now
`abandoned.
`
`5
`
`5,017,609
`2
`tion represents substituted or unsubstituted monocyclic
`or polycyclic aromatic ring systems of from 6 to about
`10 carbon atoms; A is an alkylene from about 1 to about
`5 carbon atoms, or alkenylene of from 2 to about 5
`carbon atoms; X is independently amino, hydrogen,
`halogen, hydroxy, alkoxy, aryloxy, aralkyl, cyano,
`amido, or trifluoromethyl; n is an integer from 1 to
`about 4; R is alkyl having from 1 to about 5 carbon
`atoms, propargyl, dimethylpropargyl, or hydroxyalkyl
`- 0
`,having from 1 to about 6 carbon atoms; and its pharma
`ceutically acceptable salts in a hydroalcoholic solution
`further comprising from about 0.05 to about 2 molar
`physiologically acceptable buffering agent; from about
`5 to about 60% by volume ethanol; from about 5 to
`about 60% by volume of a physiologically acceptable
`liquid polyhydric compound; and said hydroalcoholic
`solution having a pH of from about 4.0 to about 6.0. A
`method for the treatment or prophylaxis of cardiac
`disorders in a mammal comprising parenteral adminis
`tration of the composition of the invention to such
`mammal is also disclosed.
`
`20
`
`BACKGROUND OF THE INVENTION
`The present invention relates to pharmaceutical com
`positions which contain short-acting B-adrenergic
`blocking agents. More particularly, the invention con
`cerns novel compositions in which ester-containing
`l3-blocking drugs are stabilized against hydrolysis dur
`ing shipping and storage.
`In the past, the emphasis in B-blocker research has
`been to develop stable drugs which could be adminis
`tered to cardiac patients over relatively long periods of
`time. However, often it is desirable in the critical care
`setting to quickly reduce heart work or improve rhyth
`micity during a cardiac crisis, e.g., during or shortly
`after a myocardial infarction. Conventional B-blocking
`agents can be employed for such treatment, but their
`long durations of action can cause undesirable side ef
`fects.
`Recently, certain compounds containing ester func
`tions have been found to possess ,B-adrenergic blocking
`activity. (See U.S. Pat. No. 4,387,103 to Erhardt, et al.,
`‘June 7, 1983.) These compounds generally have a short
`duration of action in vivo, and do not possess the disad
`vantages of the conventional B-blockers described
`above. The ester groups in these compounds have, how
`ever, been found to be somewhat unstable in aqueous
`environments, such as intravenous infusion solutions.
`The practical effect of this instability is that conven
`tional compositions containing the compounds have
`relatively short shelf lives, thus making commercial
`distribution and storage dif?cult.
`Therefore, there remains a need for pharmaceutical
`preparations of short-acting B-blockers which are stable
`in vitro and have a relatively long storage life.
`
`SUMMARY OF THE INVENTION
`In accordance with the present invention, disclosed
`herein is a pharmaceutical composition for the treat
`ment or prophylaxis of cardiac disorders in a mammal
`comprising from about 0.1 to about 30% by weight of a
`B-adrenergic blocking compound having the formula
`
`(70»
`
`fl)
`RIOCA
`
`OH
`OCHZCHCHZNHR
`
`55
`
`where R1 is an alkyl having from 1 to about 6 carbon
`atoms, cycloalkyl of from 3 to about 5 carbon atoms,
`alkenyl of from 2 to about 5 carbon atoms, alkynyl of
`from 3 to about 5 carbon atoms, alkyl carboxymethyl
`where the alkyl is from 1 to about 5 carbon atoms, aryl
`carboxymethyl in which the aryl portion contains from
`6 to about 10 carbon atoms, aryl of from 6 to about 10
`carbon atoms, or aralkyl wherein the alkyl portion con
`tains from 1 to about 6 carbon atoms and the aryl por
`
`60
`
`65
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1: A graphic depiction of the effect of various
`pH levels on the potency of methyl 3-(p-phenoxy
`propanolamine) propionate over time.
`FIG. 2: A graphic depiction of rate of degradation of
`methyl 3-(p-phenoxypropanolamine) propionate at 55°
`C. and at various pH levels.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`In accordance with the present invention, it has been
`discovered that a stable pharmaceutical composition
`possessing a relatively long shelf life can be prepared
`using short-acting, ester-containing B-blockers of the
`formula:
`
`(30"
`
`OH
`
`OCI'I2CHCH2NHR
`
`R logA
`
`where R1 may be an alkyl having from 1 to about 6
`carbon atoms such as methyl, ethyl, propyl, t-butyl,
`isopentyl, and the like; cycloalkyl of from 3 to about 5
`carbon atoms such as cyclopropyl, cyclopentyl, methyl
`cyclopropyl, and the like; alkenyl of from 2 to about 5
`carbon atoms such as ethenyl, propenyl, 2-methyl-2
`butenyl, and the like; alkynyl of from 3 to about 5 car
`bon atoms such as ethynyl, propynyl, 3-methyl-l-buty
`nyl, and the like; alkyl carboxymethyl where the alkyl is
`from 1 to about 5 carbon atoms such as methyl carboxy
`methyl, ethyl carboxymethyl, propyl carboxymethyl,
`and the like; aryl carboxymethyl in which the aryl por
`tion contains from 6 to about 10 carbon atoms such as
`phenyl carboxyrnethyl, napthyl carboxymethyl and the
`like; aryl of from 6 to about 10 carbon atoms such as
`phenyl, 2-tolyl, 2-methoxyphenyl, naphthyl, and the
`like; or aralkyl in which the alkyl portion contains from
`1 to about 6 carbon atoms and the aryl portion repre
`sents substituted or unsubstituted monocyclic or poly
`cyclic aromatic ring systems of from 6 to about 10 car
`bon atoms such as benzyl, phenethyl, l-naphthylpropyl,
`3,4-dimethoxyphenethyl, naphthylethyl, and the like.
`
`

`
`3
`A may be an alkylene from about 1 to about 5 carbon
`atoms such as methylene, ethylene, propylene, and the
`like; or alkenylene of from 2 to about 5 carbon atoms
`such as ethenylene, propenylene, isobutylenylene, and
`the like.
`X is independently amino, hydrogen, halogen, hy
`droxy, alkoxy of from about 1 to about 10 carbon atoms
`such as methoxy, ethoxy and the like, of from about 6 to
`about 10 carbon atoms such as phenyloxy and the like,
`wherein the alkyl portion contains from 1 to about 6
`carbon atoms and the aryl portion contains from 6 to
`about 10 carbon atoms such as phenylmethyl, p-methyl
`benzylmethyl dimethylbenzyl, phenyl t-butyl, 3,4-dime
`thoxyphenethyl and the like, (preferably dimethylben
`zyl, phenyl t-butyl, 3,4-dimethoxyphenethyl), cyano,
`amido, or tri?uoromethyl, and n is an integer from 1 to
`about 4.
`R may be an alkyl having from 1 to about 5 carbon
`atoms such as methyl, ethyl, propyl, t-butyl, isopentyl,
`and the like; propargyl; dimethylpropargyl; or hydrox
`yalkyl having from 1 to about 6 carbon atoms such as
`hydroxymethyl, hydroxyethyl, 2-hydroxypentyl and
`the like.
`In preferred compounds, R1 is ethyl or methyl, A is
`ethylene, X is hydrogen, the
`
`25
`
`35
`
`5,017,609
`4
`kyl wherein the alkyl portion contains from about 1 to
`about 6 carbon atoms and the aryl portion contains from
`about 6 to about 10 carbon atoms. According to this
`embodiment, the Rl-containing group preferably is in
`the ortho- or para-position with respect to the R-con
`taining group. Preferably, R1 is a lower alkyl or alkenyl
`group having from 1 to about 3 carbon atoms, and X is
`hydrogen, lower alkoxy of from 1 to about 5 carbon
`atoms, lower alkyl of from 1 to about 5 carbon atoms,
`halogen or cyano. When the X substituent is a halogen,
`X preferably is fluorine. R1 preferably is methyl or
`ethyl, with methyl being particularly preferred. Ac
`cording to this embodiment, R preferably is lower alkyl
`of from 1 to about 5 carbon atoms or aralkyl wherein
`the alkyl portion contains from 1 to about 5 carbon
`atoms and the aryl portion contains from 6 to about 10
`carbon atoms. In particularly preferred embodiments, R
`is isopropyl, t-butyl or 3,4-dimethoxyphenethyl, and X
`is hydrogen with n being 4. When R1 is methyl or ethyl,
`A preferably is ethylene, and R is isopropyl, t-butyl or
`3,4-dimethoxyphenethyl. Most preferably, R is isopro
`pyl
`Methods for producing the above-described com
`pounds are known in the prior art. For example, U.S.
`Pat. No. 4,387,103 to Erhardt et al. (incorporated herein
`by reference) discloses methods for preparing above
`de?ned compounds wherein A is alkylene. Methods for
`preparing above-de?ned compounds wherein A is alke
`nylene are described in U.S. Pat. No. 4,191,765 to
`Fritsch et al. (incorporated herein by reference).
`The above-described ,B-blocking compounds may be
`separated into optically active enantiomers using con
`ventional methods. While both con?gurations are ac
`tive ,B-blockers, the l-isomers have been found to be
`more active than their dextrorotary counterparts.
`In one embodiment of the present invention, the com
`position contains a pharmaceutically acceptable acid
`addition salt of an above described B-blocking com
`pound, e.g., a hydrochloride, sulfate, phosphate, gluco
`nate, tartrate, etc. salt.
`The composition of the present invention consists of
`a hydroalcoholic solution containing an above de
`scribed B-blocking compound (or its pharmaceutically
`acceptable salt) at a concentration of from about 0.1 to
`about 30% by weight. Concentrations of less than about
`0.1% (weight) of the B-blocking compounds in solu
`tions generally do not provide effective B-blocking
`activity at practical infusion rates, while there is gener
`ally no added bene?t to having concentrations greater
`than about 30% (weight) of the ,B-blocker in solution. In
`particularly preferred compositions, the concentration
`of B-blocking compound in solution is from about 1 to
`about 30% by weight.
`One component of the hydroalcoholic solution is
`ethanol, preferably at a concentration of from about 5 to
`about 60% by volume. Ethanol has been found to be
`important in the stabilization of the B-blocking com
`pound according to the present invention.
`The hydroalcoholic solution also contains a physio
`logically acceptable liquid polyhydric compound, pref
`erably at a concentration of from about 5 to about 60%
`by volume. Physiologically acceptable liquid polyhyd
`ric compounds include, but are not limited to, alkyls of
`from 1 to about 10 carbon atoms having two or more
`adjacent hydroxyl groups such as ethylene glycol,
`propylene glycol, glycerol and the like; polyethyleneg
`lycols having a molecular weight of from about 200 to
`
`45
`
`group is in the para position with respect to the side
`chain containing the —R group, and/ or —-R is repre
`sented by —W—B where —W—- is an alkylene contain
`ing from 1 to about 10 carbon atoms, and -—-B is —NR
`2COR3, —NR2CONR3R4, —NR2SO2R3, —NR
`2SO2NR3R4, —NRZCOOR5 or —NHR6, where R2, R3,
`R4 and R5 may each be hydrogen, lower alkyl of from
`about 1 to about 10 carbon atoms, lower alkoxyalkyl of
`from 1 to about 10 carbon atoms, lower alkoxyaryl
`wherein the alkoxy portion contains from 1 to about 6
`carbon atoms and thearyl portion contains from 6 to
`about 10 carbon atoms, lower cycloalkyl of from 3 to
`about 10 carbon atoms, lower alkenyl of from 1 to about
`10 carbon atoms, lower alkynyl of from 1 to about 10
`carbon atoms, aryl of from 6 to about 10 carbon atoms,
`heteroaryl of from about 4 to about 10 carbon atoms or
`aralkyl wherein the alkyl portion contains from 1 to
`about 6 carbon atoms and the aryl portion contains from
`6 to about 10 carbon atoms, except that R3 and R5 are not
`hydrogen when E is —NR2SO2R3 or —NR2COOR5, or
`R3 and R4may together with N form a 5-to 7-membered
`heterocyclic group, and R5 is unsubstituted or substi
`tuted pyridinyl, phenyl, naphthyl or indoyl the optional
`R5 substituents being the same as X de?ned above. In
`one embodiment, R2, R3, R4 and R5 are hydrogen, or
`R3 and R4 together with N form a 5-7 membered heter
`ocyclic group.
`In one embodiment, R1 is lower alkyl of from 1 to
`about 5 carbon atoms or lower alkenyl of from 2 to
`about 5 carbon atoms; A is alkylene of up to about 3
`carbon atoms; X is lower alkyl of from 1 to about 10
`carbon atoms, lower alkenyl of from 2 to about 10 car
`bon atoms, lower alkynyl of from 2 to about 10 carbon
`atoms, lower alkoxy of from 1 to about 10 carbon
`atoms, halogen, acetamido, amino, nitro, alkylamino of
`from 1 to about 10 carbon atoms, hydroxy, lower hy
`65
`droxyalkyl of from 1 to about 10 carbon atoms, or cy
`ano; n is an integer of from about 1 to about 4; R is
`lower alkyl of from 1 to about 10 carbon atoms or aral
`
`50
`
`55
`
`

`
`5,017,609
`6
`5
`about 600 daltons; and glycerin. Preferred liquid poly
`acid and 0.2M disodium hydrogen phosphate solutions
`hydric compounds include alkyls of from 1 to about 10
`(Table I).
`carbon atoms having two or more adjacent hydroxyl
`In each case an appropriate amount of methyl-3-(p
`groups, and polyethyleneglycols having a molecular
`Phenoxypropanolamine) propionate to give a ?nal con
`weight of from about 200 to about 600 daltons. Glycerin
`centration of 100 mg/ml was accurately weighed and
`is less preferred, because solutions containing it have
`transferred to a calibrated ?ask. The buffer solution was
`been observed to discolor on storage at 55° C. A partic
`then added to the flask and the contents stirred until the
`ularly preferred liquid polyhydric compound is propy
`drug had completely dissolved. The pH of each solution
`lene. glycol. Liquid polyhydric compounds, in conjunc
`was determined, this data is given in Table 1. Each
`tion with ethanol are useful stabilizing components of
`buffered drug solution was filled into 5 ml ?int ampuls.
`the B-blocking compounds in the hydroalcoholic solu
`The ampuls were partially ?lled with 3 ml of solution
`tion according to the present invention. In particularly
`and then sealed. Sufficient ampuls were prepared so that
`preferred compositions, the volume ratio of ethanol to
`there was at least one for each stability time. Samples of
`the liquid polyhydric compound is about 1:1.
`all ?ve solutions were placed in a 55° C. oven. At each
`Stability of the B-blocking compound in solution is
`stability time one ampul of each solultion was removed.
`affected by the pH of the solution. In preferred compo
`The pH, potency and the physical appearance of the
`sitions, the pH of the hydroalcoholic solution ranges
`solutions was determined. The concentration of the
`from about 4.0 to about 6.0. When the pH of the solu
`drug was determined by a high performance liquid
`chromatographic (HPLC) method. The physical ap
`, tion is less than about 4.0 or greater than about 6.0,
`degradation of the B-blocking compound was observed.
`pearance of the solutions remained unchanged at all
`In particularly preferred compositions, the pH ranges
`stability times.
`from about 4.6 to about 5.4, and in most preferred com
`The kinetic data obtained was plotted as a log of drug
`positions, the pH ranges from about 4.9 to about 5.1.
`concentration versus time. The apparent ?rst-order rate
`The pH is preferably maintained by a physiologically
`constants were calculated from the slopes of the linear
`acceptable buffering agent at a concentration of from
`regression lines ?tted to log (C)=log (Co)--2.303 kt
`about 0.05 to about 2 molar. Preferred buffering agents
`where C is drug concentration at time t, Co is the initial
`include acetate buffers, such as sodium acetate and
`drug concentration and k is the apparent first-order rate
`acetic acid; trishydroxymethylaminomethane; sodium
`constant. This method was also used for Examples II
`through V.
`, phosphate (mono and dibasic); phosphoric acid; sodium
`citrate; citric acid; and amphoteric compounds such as
`The kinetics of degradation of the drug at 55° C. and
`glycine, cystine and the like. Acetate buffers are partic
`at various pH values was followed by monitoring the
`ularly preferred. The molar ratio of the _B-blocking
`potency of the drug at different stability times. The
`compound to buffering agent advantageously is about
`logarithm of the potency versus time in all cases pro
`3:1.
`duced linear plots. These‘data are shown in FIG. 1. The
`The B-blocking compounds used in the pharmaceuti
`apparent ?rst-order rate constants were calculated from
`cal compositions of the present invention are surpris
`the slopes of the linear regression lines and are pres
`ingly rendered quite stable by the hydroalcoholic solu
`ented in Table II. The maximum change in the pH,
`tion of the present invention. Typical compositions
`which in all cases occurred when the sample for the last
`exhibit shelf lives from 20 to 36 months, compared to 2
`data point was obtained, is also given in Table II.
`to 3 months for the same compounds in conventional
`The pH rate pro?le at 55° C. for the drug is presented
`preparations. These compositions thus facilitate com
`in FIG. 2. The line joining the data points is only drawn
`mercial distribution and storage of the above described
`to show the trend and does not represent actual data.
`short-acting ester-containing B-blockers.
`The degradation rate increases both at low and high pH
`The pharmaceutical compositions of the present in
`values in the range studied (pH 2.0514 7.14). This may
`vention are preferably added to a physiologically ac
`be due to acid or base catalysed hydrolysis at the two
`ceptable infusion medium to a ?nal concentration of '
`extremes. The lowest rate observed in this study at pH
`B-adrenergic compound of from about 50 ug/ml/min to
`5.37 is almost 64 times slower than the highest observed
`about 600 ug/ml/min percent by weight, and thereby
`at pH 2.05.
`parenterally administered to the patient.
`The dosages and rates of administration of these com
`positions generally depend upon the patient’s needs and
`the particular B-blocking compound employed. These
`dosages and rates of administration are described in the
`above-mentioned U.S. Pat. No. 4,387,103.
`The invention is further illustrated by the following
`examples, which are not intended to be limiting.
`
`0
`
`50
`
`55
`
`EXAMPLE I
`The Effect of pH on they Degradation of Methyl
`3-(p-Phenoxypropanolamine) proprionate
`The kinetics of degradation of methyl-3-(p-Phenoxy
`propanolamine) propionate (sometimes referred to as
`“the drug”) in ?ve aqueous buffers at 55° C. was stud
`ied. All buffer solutions were prepared in Water for
`Injection, USP (deionized and distilled water). Five
`buffer solutions, pH 2.16, 3.05, 4.08, 5.63 and 7.44 were
`prepared by combining various amounts of 0.1M citric
`
`65
`
`TABLE I
`pH of Citrate-Phosphate Buffers Used
`Composition No.
`2
`3
`4
`
`l
`
`5
`
`Amount of Dibasic
`Sodium Phosphate,
`Heptahydrate
`(NazHPQUHgO)
`(Wt %)
`Amount of Citric
`Acid, Monohydrate
`(?sCeHsov-Plzo)
`(wt %)
`pH of Buffer
`Solution
`Amount of the Drug
`(wt %)
`pH of buffer
`Solution Containing
`Dissolved Drug
`
`0.06
`
`1.00
`
`2.4
`
`3.09
`
`2.08
`
`L69
`
`1.30
`
`0.89
`
`0.21
`
`2.16
`
`3.05
`
`4.08
`
`7.44
`
`l0
`
`10
`
`2.05
`
`2.97
`
`3.92
`
`7.14
`
`

`
`5,017,609
`
`7
`TABLE II
`Apparent First Order Rate Constants For
`Hydrolysis of the Drug in Buffers at 55° C.
`l
`2
`3
`4
`2.05
`2.97
`3.92
`5.37
`34.01
`7.03
`1.30
`0.53
`
`pH
`it, day"1 X
`10-2
`53.16
`9.87
`2.04
`ti, day
`0.9916
`0.9995
`0.9991
`r”
`_.02s
`-0.22
`-0.04
`Aphb
`“Correlation coefficient for the linear regression
`[Difference between initial and final pH (terminal sample).
`
`130.40
`0.9375
`0.71
`
`5
`
`5
`7.14
`4.8
`
`1444
`0.9988
`_0.s9
`
`10
`
`8
`Table IV also presents stability of the drug in a vehi
`cle containing 50% (V/V) PG in water. When this is
`compared to the drug stability in a vehicle containing
`50% V/V PG in citrate-phosphate buffer, it can be seen
`that the half-life in the buffered formulation is almost
`twice as long.
`The data presented in this section shows that PG has
`a signi?cant stabilizing effect on the drug.
`TABLE IV
`Apparent First-Order Rate Constants (55" C.) for The
`Degradation of the drug (100 mg/ml) in Vehicles
`Containing Citrate-Phosphate Buffer (0.16M, pH 5.4)
`and Propylene Glycol (PG)
`k X 102,
`ti,
`day-1*
`day“
`
`15
`
`Formulation
`
`r‘"
`
`Time Span of
`Study (Days)
`
`PG 70%, Buffer
`30% V/V
`PG 50%, Buffer
`50% V/V
`PG 30%, Bum?!‘
`70% V/V
`PG 10%, Buffer
`90% V/v
`PG 50%, water
`50% V/V
`
`0.423
`
`161.2
`
`0.9968
`
`0.616
`
`112.6
`
`0.9989
`
`0.769
`
`90.2
`
`0.9997
`
`0.949
`
`73.1
`
`0.9992
`
`1.371
`
`50.6
`
`0.9903
`
`“Correlation coefficient of the linear regression line.
`‘See Example 1
`
`135
`
`135
`
`135
`
`52
`
`30
`
`EXAMPLE IV
`Stability of Methyl 3-(p-Phenoxypropanolamine)
`propionate (the drug) in Vehicles Containing
`Citrate-Phosphate Buffer (0.16M, pH 5.4) and either
`PEGZOO or Propylene Glycol (PG)
`Table V presents stability data of the drug in 50%
`(V/V) PEG 200 in buffer, and 50% (V/V) Propylene
`Glycol in buffer. The greatest stability observed was in
`the case of the formulation containing propylene glycol
`(PG).
`
`TABLE V
`Apparent First-Order Rate Constants (55' C.) for
`The Degradation of the drug (100 mg/ml) in Vehicles
`Containing Citrate-Phosphate Buffer (0.16M, pH 5.4)
`and either PEG 200 or Propylene Glycol
`k >< 101,
`q,
`Time Span of
`day““ my r‘“
`Study (Days)
`
`Formulation
`
`45
`
`50
`
`PEG 200 50%,
`Buffer 50% V/V
`Propylene Glycol
`50%, Buffer 50% V/V
`
`0.793
`
`87.4
`
`0.9796
`
`0.616
`
`112.6
`
`0.9989
`
`44
`
`135
`
`"Correlation coefficient of the linear regression line.
`'See Example 1
`
`EXAMPLE II
`Stability of Methyl 3-(p-Phenoxypropanolamine)
`propionate (the drug) in One or Two Component
`Vehicles Containing Ethanol and Citrate-Phosphate
`Buffer (pH 4.0)
`Stability of the drug in 10% (V /V) alcohol in buffer,
`30% (V/V) alcohol in buffer and ethanol, USP is given
`in Table III. It can be seen from the data in Table III,
`that incorporation of 10% ethanol in the buffer in
`creases the stability of the drug. The stabilizing effect is
`quite dramatic when ethanol content is increased to
`30% V/V, in this case the degradation rate is almost
`one third of the rate in buffered solution without etha
`nol. When the drug was formulated in just ethanol,
`USP, the stability was marginally worse than 30% etha
`nol in buffer vehicle. This suggests that the stabilization
`effect is maximized at certain ethanol concentrations in
`the vehicle and beyond that no bene?t is to be gained by
`adding more ethanol in the formulation. In addition, in
`the all ethanol formulation the HPLC tracing revealed
`evidence of transesteri?cation of the drug to an ethyl
`ester.
`
`TABLE III
`Apparent First-Order Rate Constants (55° C.) for The
`'
`Degradation of the drug (100 mg/ml)
`In Vehicles Containing Phosphate-Citrate Buffer
`(pH 4.0) and/or Ethanol, USP
`k X 102,
`ti,
`day-1'
`day‘
`1.304
`53.2
`
`r‘“
`0.9375
`
`Formulation
`Phosphate-Citrate
`buffer (pH 4.0)
`Buffer Containing
`10% V/V Ethanol,
`USP
`Buffer Containing
`30% V/V Ethanol,
`USP
`0.9703
`134.4
`0.516
`Ethanol, USP
`“Correlation coefficient of the linear regression line.
`‘See Example 1
`
`-
`
`1.071
`
`64.7
`
`0.9896
`
`0.411
`
`168.7
`
`0.9474
`
`Time Span of
`Study (Days)
`26
`
`38
`
`24
`
`44
`
`55
`
`EXAMPLE III
`Stability of Methyl 3-(p-Phenoxypropanolamine)
`propionate (the drug) in Vehicles Containing Citrate
`Phosphate Buffer (0.16M, pH 5.4) and Propylene
`Glycol (PG)
`Stability of the drug was investigated in vehicles
`containing varying amounts of citrate-phosphate buffer
`and propylene glycol (PG) (Table IV). The proportion
`of PG in these mixtures varied from 10% to 70%. In
`creasing the PG concentration increases the stability of 65
`the drug. Within the range studied there is a linear rela
`tionship between stability of the drug and PG content in
`the vehicle.
`
`EXAMPLE V
`Stability of Methyl 3-(p-Phenoxypropanolamine)
`propionate (the drug) in One, Two or Three
`Component Vehicles Containing Ethanol, Propylene
`Glycol (PG) and Citrate-Phosphate Buffer (0.16M, pH
`5.4) or Water
`The stability of the drug was studied ?rst in two
`systems, the ?rst vehicle consisted of 70% (V/V) PG
`and 30% (V/V) ethanol whereas the second was 50:50
`mixture of the two. The results are given in Table VI. It
`can be seen that the stability of the drug in the 50:50
`mixture was greater.
`
`

`
`5,017,609
`
`10
`TABLE VIII-continued
`Physical Appearance and pH of the Drug Over Time
`in Various Environments
`Storage,
`pI-I Change
`Environment Months pI-I From Initial
`
`3
`
`6
`
`I
`
`4.9
`
`4.9
`
`4.9
`
`—0.1
`
`—0.1
`
`—0.1
`
`10
`
`LC‘
`
`‘High intensity light cabinet (600-1200 Foot Candles)
`
`Appearance
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`.Clear, faint
`yellowish solution
`
`9
`TABLE VI
`Apparent First-Order Rate Constants (55° C.) for
`The Degradation of the drug (100 mg/ml) in One, Two or
`Three Component Vehicles Containing Ethanol,
`Propylene Glycol (PG) and Citrate-Phosphate Buffer
`(0.16M, pH 5.4) or Water
`k X 102,
`ti,
`t“
`day-l’
`day‘
`0.118
`586.7 0.8615
`
`Formulation
`PG 70%, Ethanolb
`30% V/V
`PG 50%, Ethanolb
`50% V/V
`PG 70%, Ethanol"
`20%, qs with Water
`PG 70%, Ethanol‘I
`20%, qs with Buffer
`130.4 0.9375
`0.531
`Buffer (pH 5.4)
`"Correlation coefficient of the linear regression line.
`thanol
`‘Sec Example I
`
`0050
`
`1374.3 0.2014
`
`0.446
`
`155.5 0.9683
`
`0.226
`
`306.2 0.9808
`
`Time Span of
`Study (Days)
`119
`
`56
`
`119
`
`119
`
`26
`
`EXAMPLE VI
`_ Stability of Methyl 3-(p-Phenoxypropanolamine)
`propionate (the drug) in Vehicles Containing Sodium
`Acetate Buffer, Ethanol and Propylene Glycol (PG)
`Stability of the drug (100 mg/ml) was tested in vehi
`cles containing 0.1M sodium acetate buffer, 0% Etha
`nol, and 10% Propylene glycol under various storage
`conditions for different time periods.
`Stability results are given in Tables VII and VIII.
`The data indicates that the rate of degradation is tem
`perature dependent. No change in physical appearance
`was observed during the experiment.
`TABLE VII
`Potency of the Drug Over Time in Various Environments
`Storage,
`% of Labeled
`% Change From
`Months
`Amount
`Initial
`
`Environment
`
`55' C.
`
`40' C.
`
`100.7
`Initial
`101.3
`I
`89.3
`1
`94.3
`1;
`90.7
`2
`99.9
`1
`99.8
`3
`95.8
`6
`102.7
`1
`101.5
`3
`95.8
`6
`102.8
`5
`LC‘
`‘High intensity light cabinet (GD-12(1) Foot Candles)
`
`15-30‘ C.
`
`—
`+0.6
`—ll.4
`—6.4
`— 10.0
`—0.8
`—0.9
`-4.9
`+2.0
`+0.8
`—4.9
`+2.1
`
`TABLE VIII
`Physical Appearance and pH of the Drug Over Time
`in Various Environments
`Storage,
`pH Change
`Environment Months pH From Initial
`
`Appearance
`
`Initial
`
`5.0
`
`——
`
`EXAMPLE VII
`Stability on Methyl 3-(p-Phenoxypropanolamine)
`Propionate (the drug) in Vehicles Containing Sodium
`Acetate Buffer, Ethanol and Propylene Glycol
`Stability of the drug (100 mg/ ml) was tested in vehi
`cles containing 0.1M sodium acetate buffer, 10% Etha
`nol and 10% Propylene glycol under various storage
`conditions for different time periods.
`,
`Stability results are given in Tables IX and X. The
`(data indicates that the rate of degradation is tempera
`ture dependent. No change in physical appearance was
`observed during the experiment.
`TABLE IX
`Potency of the Drug Over Time in Various Environments
`Storage,
`% of Labeled
`% Change From
`Months
`Amount
`Initial
`
`Environment
`
`20
`
`5
`
`30
`
`99.2
`
`55' C.
`
`40° C.
`
`15-30‘ C.
`
`5° C.
`
`LC‘
`ML"
`
`Initial
`(3-24-82)
`i
`96.6
`1
`90.0
`2
`90.4
`1
`95.1
`3
`94.2
`6
`90.4
`1
`99.8
`3
`97.3
`6
`98.1
`3
`98.5
`6
`98.8
`I
`98.7
`3
`97.3
`6
`97.5
`‘High intensity light cabinet (600-l2t'X] Foot Candles)
`"Eastem diffuse sunlight
`
`—
`
`—2.6
`—9.2
`—8.8
`—4.1
`—5.0
`—8.8
`+0.6
`- - 1.9
`— 1.1
`—0.7
`-0.4
`—0.5
`-1.9
`- 1.7
`
`TABLE X
`Physical Appearance and pH of the Drug Over Time
`in Various Environments
`Storage,
`pI-I Change
`Environment Months pl-I From Initial
`
`Appearance
`
`5.1
`
`—
`
`45
`
`50
`
`55' C.
`
`40' C
`
`15-30’ C.
`
`I
`
`1
`
`I!
`
`2
`
`1
`
`3
`
`6
`
`l
`
`4.8
`
`4.8
`
`4.8
`
`4.7
`
`4.9
`
`4.9
`
`4.7
`
`5.0
`
`—0.2
`
`—0.2
`
`—0.2
`
`-0.3
`
`—0.1
`
`—0.1
`
`—0.3
`
`0
`
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`
`Initial
`(3-24-82)
`i
`
`55' C.
`
`40' C
`
`65
`
`15-30‘ C.
`
`1
`
`2
`
`l
`
`3
`
`6
`
`l
`
`3
`
`6
`
`5.1
`
`5.0
`
`5.0
`
`5.1
`
`4.9
`
`4.9
`
`5.1
`
`4.9
`
`5.1
`
`0
`
`—0.1
`
`—0.1
`
`0
`
`—0.2
`
`—0.2
`
`0
`
`—0.2
`
`0
`
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`yellowish solution
`Clear, faint
`
`

`
`5,0l7,609
`
`12
`
`11
`TABLE X-continued
`Physical Appearance and pH of the Drug Over Time
`in Various Environments
`Storage,
`pH Change
`Environment Months pH From Initial
`
`Appearance
`
`5’ C.
`
`LC‘
`
`NL"
`
`3
`
`6
`
`§
`
`3
`
`6
`
`5.0
`
`5.1
`
`5.3
`
`5.0
`
`5.0
`
`—0.1
`
`0
`
`+0.2
`
`—0.l
`
`—O.l
`
`‘High intens