Stable pharmaceutical compositions of short-acting .beta.-adrenergic receptor blocking agents

A pharmaceutical composition for parenteral administration is disclosed which comprises from about 0.01% to about 30% of a .beta.-adrenergic blocking compound of the formula ##STR1## wherein Ar represents a substituted or unsubstituted aromatic group or heterocyclic group; W represents alkylene of from 1 to about 10 carbon atoms; and B represents --NR.sub.2 COR.sub.1, --NR.sub.2 CONR.sub.1 R.sub.3, --NR.sub.2 SO.sub.2 R.sub.1, --NR.sub.2 SO.sub.2 NR.sub.2 R.sub.3, or --NR.sub.2 COOR.sub.1 wherein R.sub.1, R.sub.2 and R.sub.3 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl, except that R.sub.1 is not hydrogen when B is --NR.sub.2 SO.sub.2 R.sub.1 or --NR.sub.2 COOR.sub.1, or R.sub.1 and R.sub.3 may together with N form a 5 to 7 membered heterocyclic group or W and B together denote Z which represents lower alkyl or aralkyl; or a pharmaceutically acceptable salt thereof in a hydroalcoholic solution including from about 5% to about 50% ethanol by volume of a physiologically acceptable polyhydric compound; from about 0.05 to about 2 molar physiologically acceptable buffering agent; said hydroalcoholic solution having a pH of from about 2.0 to about 4.0. The pharmaceutical compositions are useful in the treatment or prophylaxis of cardiac disorders.

BACKGROUND OF THE INVENTION 
The .beta.-adrenergic receptor blocking agents comprise an important group 
of approved therapeutic agents. They have the common pharmacological 
property of blocking the action of agonists of .beta.-adrenergic receptor 
sites in that they compete with the agonists for receptor sites. Various 
physiological responses, characteristic of the tissue which is involved, 
occur as a result of blocking of the receptor site. Beta-adrenergic 
blocking agents have a variety of pharmacokinetic properties, some of 
which may influence side effects. Commonly, these agents are administered 
to patients suffering from ischemic heart disease or myocardial infarction 
for the purpose of reducing the work conducted by the heart, namely heart 
rate and contractile force. Reducing heart work reduces oxygen demand and 
may in fact, increase oxygen supply. Reducing the work required of the 
heart can thereby minimize or prevent further tissue damage and can 
relieve the pain of angina pectoris. 
The use of .beta.-adrenergic receptor blocking agents to decrease 
myocardial oxygen requirements and control dysrhythmia after acute 
myocardial infarction has, however, been somewhat limited in view of the 
potential for producing long-lasting cardiac depression. It has therefore 
been suggested (Erhardt, et al, J Med Chem, 1982, Vol. 25, pp 1402-1407) 
that .beta.-adrenergic blocking agents having an ultrashort duration of 
action could minimize or eliminate this limitation. Such agents could be 
administered by intravenous infusion to rapidly obtain desired levels of 
.beta.-adrenergic blockade; allow rapid adjustment of blockade as might be 
required; and reduce the risk of resultant long-lasting cardiac depression 
since the effects of the agent would rapidly dissipate upon the 
termination of the infusion. 
As described in the Erhardt, et al publication, supra as well as 
publications by Zaroslinski, et al, Life Sciences, Vol. 31, pp 899-907, 
1982 and Erhardt, et al, J Med Chem, Vol 25, 1982, pp 1408-1412, certain 
compounds containing ester functions have been found to possess 
.beta.-adrenergic blocking action of relatively short duration of action 
in vivo. Consequently, these compounds minimize the disadvantages of 
previous .beta.-blocking agents. The ester groups in these compounds are 
however, somewhat unstable in aqueous solutions such as those used for 
intravenous administration. As a consequence, such solutions have a 
relatively short shelf life. Pharmaceutical compositions of short-acting 
.beta.-blocking agents which are stable in solution and therefore have a 
relatively long shelf life are desirable since they would facilitate 
storage and commercial distribution. 
SUMMARY OF THE INVENTION 
The present invention is directed to stable pharmaceutical compositions for 
parenteral administration of compositions useful in the treatment of 
patients having a cardiac condition such as hypertension, angina pectoris 
and the like and for the treatment of arrhythmias and myocardial 
infarction. The compositions are particularly suited for the 
administration of short-acting .beta.-adrenergic receptor blocking agents 
such as the (arylcarbonyloxy) propanolamines containing esters. 
More specifically, the invention is directed to a pharmaceutical 
composition for parenteral administration comprising from about 0.01 to 
about 30% by weight of a .beta.-adrenergic receptor blocking agent of the 
formula 
##STR2## 
wherein Ar represents a substituted or unsubstituted aromatic group or 
heterocyclic group; W represents alkylene of from 1 to about 10 carbon 
atoms; and B represents --NR.sub.2 COR.sub.1, --NR.sub.2 CONR.sub.1 
R.sub.3, --NR.sub.2 SO.sub.2 R.sub.1, NR.sub.2 SO.sub.2 NR.sub.1 R.sub.3, 
or --NR.sub.2 COOR.sub.1 wherein R.sub.1, R.sub.2 and R.sub.3 may be alike 
or different and may be hydrogen, alkyl, alkoxyalkyl cycloalkyl, alkenyl, 
alkynyl, aryl, heteroaryl, or aralkyl, except that R.sub.1 is not hydrogen 
when B is --NR.sub.2 SO.sub.2 R.sub.1 or --NR.sub.2 COOR.sub.1, or R.sub.1 
and R.sub.3 may together with N form a 5 to 7 membered heterocyclic group, 
or a pharmaceutically acceptable salt thereof, in a hydroalcoholic or 
aqueous solution which comprises from about 0.05 to about 2 molar 
concentration of a physiologically acceptable buffer; from about 5 to 
about 50% ethanol by volume; from about 5 to about 50% by volume of a 
physiologically acceptable liquid polyhydric compound wherein the 
polyhydric compound is propylene glycol, a polyethylene glycol having a 
molecular weight of from about 200 to about 600 daltons or glycerol; said 
hydroalcoholic or aqueous solution having a pH of from about 2.0 to about 
4.0. 
The invention will be particularly described with reference to the 
following compound 
##STR3## 
namely N-(1,1-Dimethyl-2-ureidoethyl)-2-hydroxy-3-(O-fluorobenzoyloxy) 
propylamine. 
The terms "loweralkyl" and "loweralkoxy" as used herein refer to straight 
or branched chain alkyl radicals containing from 1 to 6 carbon atoms 
including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, 
sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 
2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. 
The term "halo" as used herein refers to chloro, bromo, fluoro and iodo. 
The term "pharmaceutically acceptable salts" includes nontoxic acid 
addition salts of the compounds of the invention which are generally 
prepared by reacting the free base with a suitable organic or inorganic 
acid. Representative salts include the hydrochloride, hydrobromide, 
sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, 
stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, 
citrate, maleate, fumarate, succinate, tartrate, and like salts. Also 
included are metallic salts such as the sodium or potassium salt of the 
acid. 
The present compositions may be administered to warm-blooded animals 
parenterally. They can generally be administered with a pharmaceutical 
carrier. The term "pharmaceutical carrier," for the purpose of the present 
invention, is intended to refer to any medium that is suitable for the 
preparation of a parenteral dosage form, and thus includes a 
pharmaceutically acceptable vehicle or solvent such as is ordinarily used 
in the preparation of intravenous or intramuscular solutions. 
A pharmaceutical composition containing the described compounds can be 
administered to warm-blooded animals in parenteral dosage form at the 
desired concentration level to achieve effective .beta.-blocking activity 
for a particular disease condition. A generally effective dosage level and 
rate of administration is 1-500 .mu.g/kg/minute.

DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the present invention, it has been discovered that a 
stable pharmaceutical composition having a relatively long shelf life can 
be prepared using short-acting, ester-containing .beta.-adrenergic 
receptor blocking agents such as (arylcarbonyloxy) propanolamines. 
More specifically, the invention is directed to a pharmaceutical 
composition for parenteral administration comprising from about 0.01 to 
about 30% by weight of a .beta.-adrenergic receptor blocking agent of the 
formula 
##STR4## 
wherein Ar represents a substituted or unsubstituted aromatic group, 
including monocyclic, polycyclic and heterocyclic ring systems; W 
represents a straight or branched chain alkylene of from 1 to about 10 
carbon atoms; and B represents --NR.sub.2 COR.sub.1, --NR.sub.2 CONR.sub.1 
R.sub.3, --NR.sub.2 SO.sub.2 R.sub.1, --NR.sub.2 SO.sub.2 NR.sub.1 
R.sub.3, or --NR.sub.2 COOR, wherein R.sub.1, R.sub.2 and R.sub.3 may be 
the same or different and may be hydrogen, alkyl, of from 1 to about 10 
carbon atoms, alkoxyalkyl wherein the alkyl groups may be the same or 
different and contain from 1 to about 10 carbon atoms, cycloalkyl of from 
3 to about 8 carbon atoms, alkenyl of from 3 to about 10 carbon atoms, 
alkynyl of from 3 to about 10 carbon atoms, aryl which includes monocyclic 
or polycyclic aromatic or heterocyclic ring systems of from 2 to about 10 
carbon atoms such as phenyl, thiophenyl, imidazole, oxazole, indole, and 
the like, aralkyl wherein the alkyl group contains from about 1 to about 6 
carbon atoms and the aryl group represents substituted or unsubstituted 
monocyclic or polycyclic aromatic or heterocyclic ring systems of from 2 
to about 10 carbon atoms, such as benzyl, phenethyl, 
3,4-dimethoxyphenethyl, 1,1-dimethyl-2-(3-indolyl)-ethyl and the like, 
except that R.sub.1 is not hydrogen when B is --NR.sub.2 SO.sub.2 R.sub.1 
or --NR.sub.2 COOR.sub.1, or R.sub.1 and R.sub.3 may together with N form 
a 5 to 7 membered heterocyclic group, such as pyrrolidine, piperidine, 
piperazine, morpholine or thiomorpholine, or W and B together denote Z 
which represents lower alkyl or aralkyl. Aromatic (Ar) substituents may 
include lower alkyl of from 1 to about 10 carbon atoms, alkenyl of from 2 
to about 10 carbon atoms, alkynyl of from 2 to about 10 carbon atoms, 
alkoxy wherein the alkyl group contains from 1 to about 10 carbon atoms, 
halogen, acetamido, amino, nitro, alkylamino of from 1 to about 10 carbon 
atoms, hydroxy, hydroxyalkyl of from 1 to about 10 carbon atoms, cyano, 
arylalkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms 
and the aryl group represents substituted or unsubstituted phenyl and 
groups of the formula 
##STR5## 
wherein R.sub.4 is lower alkyl, aryl or aralkyl and A is a direct bond, 
alkylene of from 1 to about 10 carbon atoms or alkenylene of from 2 to 
about 10 carbon atoms or a pharmaceutically acceptable salt thereof. The 
.beta.-blocking agent is contained in a hydroalcoholic or aqueous solution 
which comprises from about 0.05 to about 2 molar concentration of a 
physiologically acceptable buffer; from about 5 to about 50% ethanol by 
volume; from about 5 to about 50% by volume of a physiologically 
acceptable liquid polyhydric compound wherein the polyhydric compound is 
propylene glycol, a polyethylene glycol having a molecular weight of from 
about 200 to about 600 daltons or glycerol; said hydroalcoholic or aqueous 
solution having a pH of from about 2.0 to about 4.0. 
Included in the present invention are pharmaceutical compositions including 
compounds of the formula 
##STR6## 
wherein Ar represents an aromatic group which may be unsubstituted or 
substituted with alkyl of from 1 to about 6 carbon atoms, alkenyl of from 
2 to about 6 carbon atoms, alkynyl of from 2 to about 10 carbon atoms, 
alkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms, 
halogen, acetamido, amino, nitro, alkylamino of from 1 to about 6 carbon 
atoms, hydroxy, hydroxyalkyl of from 1 to about 6 carbon atoms, cyano or 
arylalkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms 
and the aryl group is substituted or unsubstituted phenyl; W represents 
alkylene of from 1 to about 10 carbon atoms; and B represents --NR.sub.2 
COR.sub.1, --NR.sub.2 CONR.sub.1 R.sub.3, --NR.sub.2 SO.sub.2 R.sub.1, 
--NR.sub.2 SO.sub.2 NR.sub.1 R.sub.3, or --NR.sub.2 COOR.sub.1 wherein 
R.sub.1, R.sub.2 and R.sub.3 may be the same or different and represent 
hydrogen, alkyl of from 1 to about 6 carbon atoms, alkoxyalkyl wherein the 
alkyl groups may be the same or different and contain from 1 to about 6 
carbon atoms, cycloalkyl of from 3 to about 8 carbon atoms, alkenyl of 
from 2 to about 6 carbon atoms, alkynyl of from 2 to about 6 carbon atoms, 
aralkyl wherein the alkyl group contains from 1 to about 6 carbon atoms 
and the aryl group represents substituted or unsubstituted monocyclic or 
polycyclic aromatic or heterocyclic ring systems of from 2 to about 10 
carbon atoms, or a substituted or unsubstituted aromatic or heterocyclic 
group of from 2 to about 10 carbon atoms wherein the substitutent groups 
may be alkyl of from 1 to about 6 carbon atoms, except that R.sub.1 is not 
hydrogen when B is --NR.sub.2 SO.sub.2 R.sub.1 or --NR.sub.2 COOR.sub.1, 
or R.sub.1 and R.sub. 3 may together with N form a 5 to 7 membered 
heterocyclic group; and the pharmaceutically acceptable salts thereof. 
The present invention also includes pharmaceutical compositions including 
compounds of the formula 
##STR7## 
wherein Ar represents phenyl which is unsubstituted or substituted with 
alkyl of from 1 to about 6 carbon atoms, alkoxy wherein the alkyl group 
contains from 1 to about 4 carbon atoms, halogen, hydroxy, nitro, amino, 
phenoxy, or benzyloxy; W represents alkylene of from 1 to about 6 carbon 
atoms; and B represents --NR.sub.2 COR.sub.1, --NR.sub.2 CONR.sub.1 
R.sub.3, --NR.sub.2 SO.sub.2 R.sub.1, --NR.sub.2 SO.sub.2 NR.sub.1 
R.sub.3, or --NR.sub.2 COOR.sub.1, wherein R.sub.1, R.sub.2 and R.sub.3 
may be the same or different and represent hydrogen, alkyl of from 1 to 
about 6 carbon atoms, alkoxyalkyl wherein the alkyl groups may be the same 
or different and contain from 1 to about 6 carbon atoms, cycloalkyl of 
from 3 to about 8 carbon atoms, a substituted or unsubstituted aryl group 
of from 5 to about 6 carbon atoms, or a 5 to 7 membered heterocyclic 
group, except that R.sub.1 is not hydrogen when B is --NR.sub.2 SO.sub.2 
R.sub.1 or --NR.sub.2 COOR.sub.1, or R.sub.1 and R.sub.3 may together with 
N form a 5 to 7 membered heterocyclic group; and the pharmaceutically 
acceptable salts thereof. 
Additionally the present invention includes pharmaceutical compositions 
including compounds of the formula 
##STR8## 
wherein X.sub.1, X.sub.2 and X.sub.3 may be the same or different and 
represent hydrogen, halogen, hydroxy, hydroxyalkyl of from 1 to about 6 
carbon atoms, nitro, amino, alkyl of from 1 to about 6 carbon atoms, 
phenoxy benzyloxy, or alkoxy wherein the alkyl group contains from 1 to 
about 4 carbon atoms; W represents alkylene of from 1 to about 6 carbon 
atoms; and B represents --NR.sub.2 COR.sub.1, --NR.sub.2 CONR.sub.1 
R.sub.3, --NR.sub.2 SO.sub.2 R.sub.1, --NR.sub.2 SO.sub.2 NR.sub.1 
R.sub.3, or --NR.sub.2 COOR.sub.1 wherein R.sub.1, R.sub.2, and R.sub.3 
may be the same or different and represent hydrogen, alkyl of from 1 to 
about 6 carbon atoms, alkoxyalkyl wherein the alkyl groups may be the same 
or different and contain from 1 to about 6 carbon atoms, cycloalkyl of 
from 3 to about 8 carbon atoms, phenyl, benzyl, or a 5 to 7 membered 
heterocyclic group, except that R.sub.1 is not hydrogen when B is 
--NR.sub.2 SO.sub.2 R.sub.1 or --NR.sub.2 COOR.sub.1, or R.sub.1 and 
R.sub.3 may together with N form a 5 to 7 membered heterocyclic group; and 
the pharmaceutically acceptable salts thereof. 
Preferred compositions are those including compounds of the present 
invention of the formula 
##STR9## 
wherein, X.sub.1, X.sub.2 and X.sub.3 may be the same or different and 
represent hydrogen, halogen, hydroxy, hydroxyalkyl of from 1 to about 6 
carbon atoms, nitro, amino, benzyloxy, phenoxy, alkyl containing from 1 to 
about 6 carbon atoms, or alkoxy wherein the alkyl group contains from 1 to 
about 6 carbon atoms; W represents ethylene, 1-methylethylene, or 
1,1-dimethylethylene, and Y is --COR.sub.1, --CONR.sub.1 R.sub.3, 
--SO.sub.2 R.sub.1, --SO.sub.2 NR.sub.1 R.sub.3, or --COOR.sub.1, wherein 
R.sub.1 and R.sub.3 may be the same or different and may be hydrogen, 
alkyl containing from 1 to about 6 carbon atoms, alkoxyalkyl wherein the 
alkyl groups may be the same or different and contain from 1 to about 6 
carbon atoms, substituted or unsubstituted phenyl, substituted or 
unsubstituted heterocyclic group of from 2 to about 10 carbon atoms, 
aralkyl wherein the alkyl group contains from 1 to about 6 carbon atoms 
and the aryl group represents substituted or unsubstituted phenyl, or a 
heterocyclic group of from 2 to about 10 carbon atoms, except that R.sub.1 
is not hydrogen when Y is --SO.sub.2 R.sub.1 or COOR.sub.1, or R.sub.1 and 
R.sub.3 may together with N form a 5 to 7 membered heterocyclic group; and 
the pharmaceutically acceptable salts thereof. 
Particularly preferred compositions are those including compounds of the 
following formulae 
##STR10## 
wherein X.sub.1, X.sub.2 and X.sub.3 may be the same or different and 
represent hydrogen, halogen, hydroxy, nitro, amino, alkyl of from 1 to 
about 4 carbon atoms, or benzyloxy; W represents alkylene of from 1 to 
about 6 carbon atoms; and R.sub.1 represents alkyl of from 1 to about 6 
carbon atoms, alkoxyalkyl wherein the alkyl groups may the same or 
different and contain from 1 to about 4 carbon atoms, cycloalkyl of from 3 
to about 8 carbon atoms, phenyl, benzyl, or a 5 to 7 membered heterocyclic 
group; and the pharmaceutically acceptable salts thereof. 
##STR11## 
wherein X.sub.1, X.sub.2 and X.sub.3 may be the same or different and 
represent hydrogen, halogen, hydroxy, nitro, amino, alkyl of from 1 to 
about 4 carbon atoms, or benzyloxy; W represents alkylene of from 1 to 
about 6 carbon atoms; and R.sub.1 and R.sub.3 may be the same or different 
and represent hydrogen, alkyl of from 1 to about 6 carbon atoms, 
alkoxyalkyl wherein the alkyl groups may be the same or different and 
contain from 1 to about 4 carbon atoms, cycloalkyl of from 3 to about 8 
carbon atoms, phenyl, or benzyl, or R.sub.1 and R.sub.3 may together with 
N form a 5 to 7 membered heterocyclic group; and the pharmaceutically 
acceptable salts thereof. 
##STR12## 
wherein X.sub.1, X.sub.2 and X.sub.3 may be the same or different and 
represent hydrogen, halogen, hydroxy, nitro, amino, alkyl of from 1 to 
about 4 carbon atoms, or benzyloxy; W represents alkylene of from 1 to 
about 6 carbon atoms; and R.sub.1 represents alkyl of from 1 to about 6 
carbon atoms, alkoxyalkyl wherein the alkyl groups may be the same or 
different and contain from 1 to about 4 carbon atoms, cycloalkyl of from 3 
to about 8 carbon atoms, phenyl, benzyl, or a 5 to 7 membered heterocyclic 
group; and the pharmaceutically acceptable salts thereof. 
##STR13## 
wherein X.sub.1, X.sub.2 and X.sub.3 may be the same or different and 
represent hydrogen, halogen, hydroxy, nitro, amino, alkyl of from 1 to 
about 4 carbon atoms, or benzyloxy; W represents alkylene of from 1 to 
about 6 carbon atoms; and R.sub.1 and R.sub.3 may be the same or different 
and represent hydrogen, alkyl of from 1 to about 6 carbon atoms, 
alkoxyalkyl wherein the alkyl groups may be the same or different and 
contain from 1 to about 4 carbon atoms, cycloalkyl of from 3 to about 8 
carbon atoms, phenyl, benzyl, or R.sub.1 and R.sub.3 may together with N 
form a 5 to 7 membered heterocyclic group; and the pharmaceutically 
acceptable salts thereof. 
##STR14## 
wherein X.sub.1, X.sub.2 and X.sub.3 may be the same or different and 
represent hydrogen, halogen, hydroxy, nitro, amino, alkyl of from 1 to 
about 4 carbon atoms, or benzyloxy; W represents alkylene of from 1 to 
about 6 carbon atoms; and R.sub.1 represents alkyl of from 1 to about 6 
carbon atoms, alkoxyalkyl wherein the alkyl groups may be the same or 
different and contain from 1 to about 4 carbon atoms, and the 
pharmaceutically acceptable salts thereof. 
Compounds of the present invention exist as two sterioisomers due to the 
presence of an asymmetric carbon atom. The present invention includes 
either stereoisomeric form as well as racemic mixtures. For compounds in 
which R.sub.1, R.sub.2 or R.sub.3 represent alkenyl, both cis and trans 
isomers are within the scope of the invention. For compounds in which Ar 
is a substituted aromatic ring, the substituents may be in the ortho, meta 
or para positions to the propoxy carbonyl side-chain. 
The compounds described herein may be prepared by any available procedure. 
Compounds prepared as the acid addition salts may be converted to the free 
base by reaction with an appropriate base such as sodium carbonate or 
sodium bicarbonate. Preparation of specific compounds used in the 
pharmaceutical compositions of the present invention is described in 
co-pending U.S. application Ser. No. 320,773; filed Nov. 12, 1981. 
The compounds described herein are not limited to any particular 
stereoisomeric configuration. Such compounds may be administered as their 
pharmaceutically acceptable acid addition salts, e.g., as the 
hydrochloride, sulfate, phosphate, gluconate, tartrate, etc. 
Compounds in accordance with the present invention exist as two 
stereoisomers due to the presence of an asymmetric carbon atom. This 
invention includes either stereoisomeric form, as well as racemic 
mixtures. Chiral compounds can be prepared by classical resolution 
according to the method described in U.S. Pat. No. 4,076,939. 
Alternatively, the chiral compounds can be prepared by asymmetric 
synthesis procedures. 
In preferred compositions, the .beta.-blocking agent incorporated in the 
pharmaceutical composition is selected from one of the following 
compounds. 
__________________________________________________________________________ 
Compound 
X.sub.1 
X.sub.2 
X.sub.3 
W R.sub.1 R.sub.3 
__________________________________________________________________________ 
COMPOUNDS OF FORMULA VI: 
1 H H F CH.sub.2 CH.sub.2 
CH(CH.sub.3).sub.2 
2 H H F C(CH.sub.3).sub.2 CH.sub.2 
##STR15## 
3 H H F CH(CH.sub.3)CH.sub.2 
CH.sub.3 
4 H H F C(CH.sub.3).sub.2 CH.sub.2 
CH.sub.3 
5 H H F C(CH.sub.3).sub.2 CH.sub.2 
CH(CH.sub.3).sub.2.(HOOC).H.sub.2 O 
6 H H F C(CH.sub.3).sub.2 CH.sub.2 
##STR16## 
7 H H F C(CH.sub.3).sub.2 CH.sub.2 
##STR17## 
8 H H F CH.sub.2 CH.sub.2 
##STR18## 
9 H H F (CH.sub.2).sub.2 CH.sub.2 
O(CH.sub.2).sub.2 OCH.sub.3.(HOOC).sub.2 
10 H H H C(CH.sub.3).sub.2 CH.sub.2 
##STR19## 
11 H H Cl 
C(CH.sub.2).sub.2 CH.sub.2 
NO.(HOOC).sub.2 
12 3-OH 
4-OH 
H (CH.sub.3).sub.2 CH.sub.2 
##STR20## 
13 4-OH 
H H C(CH.sub.3).sub.2 CH.sub.2 
##STR21## 
14 2-CH.sub.3 
4-OH 
H C(CH.sub.3).sub.2 CH.sub.2 
##STR22## 
15 3-OH 
5-OH 
H C(CH.sub.3).sub.2 CH.sub.2 
##STR23## 
16 4-NH.sub.2 
H H C(CH.sub.3).sub.2 CH.sub.2 
##STR24## 
COMPOUNDS OF FORMULA VII: 
17 H H F C(CH.sub.3).sub.2 CH.sub.2 
H H 
18 H H F C(CH.sub.3).sub.2 CH.sub.2 
H CH.sub.3 
19 H H F C(CH.sub.3).sub.2 CH.sub.2 
H 
##STR25## 
COMPOUND OF FORMULA IX: 
20 H H F C(CH.sub.3).sub.2 CH.sub.2 
CH.sub.3 CH.sub.3 
COMPOUND OF FORMULA X: 
21 H H F C(CH.sub.3).sub.2 CH.sub.2 
C.sub.2 H.sub.5 
__________________________________________________________________________ 
These compounds are active .beta.-blocking agents as illustrated by the 
following data of duration and potency. 
The duration of .beta.-blockade was determined in vivo using 
pentobarbital-anesthetized dogs instrumented for measurement of heart rate 
using a Beckman cardiotachometer triggered electronically by a phasic 
aortic blood pressure signal. Both vagus nerves were severed in the 
cervical region and the animals were mechanically ventilated. The 
experimental design used employed a 3-hour infusion of test compound. 
Bolus doses of isoproterenol (0.5 .mu.g/kg) were used to assess the degree 
of .beta.-blockade and recovery from .beta.-blockade after determination 
of the infusion. The doses were spaced at 10-minute intervals and were 
given before, during and following the infusion of test compounds. The 
infusion rate was adjusted so that at the end of the 3-hour infusion 
period the degree of isoproterenol inhibition averaged about 50% of 
control. Following termination of blocker infusion, percent recovery from 
.beta.-blockade was computed and the time associated with 80% recovery 
estimated. The results are contained in Table I. 
TABLE 1 
______________________________________ 
.beta.-Blocking Activity In Vivo 
Potency Recovery Time (min) 
Compound (mg/kg/180 min) 
% I.sup.a 
50% 80% N.sup.b 
______________________________________ 
4 2.7 61 7 35 2 
5 0.6 62 .+-. 5 
10 .+-. 2 
22 .+-. 6.sup.c 
6 
6 1.4 61 8 .+-. 3 
12 .+-. 3.sup. 
3 
7 1.8 68 8 19 1 
8 10.3/21.9 43/55 3,4 6/36 2 
21 6.5 .+-. 1.8 49 .+-. 4 
3 .+-. 1 
8 .+-. 3 
3 
17 0.7 49 21 2 
12 0.08 95 &gt;60 &gt;60 1 
Propranolol 
0.2 67 .+-. 6 
&gt;60 &gt;60 2 
______________________________________ 
.sup.a Percent inhibition of heart rate response to isoproterenol 
.sup.b Number of experiments 
.sup.c 2/6 experiments did not recover to 80% within 60 min 
The compositions of the present invention consist of a hydroalcoholic 
solution containing an above described .beta.-blocking compound (or its 
pharmaceutically acceptable salt) at a concentration of from about 0.01 to 
about 30% by weight. Concentrations of less than about 0.01% (weight) of 
the .beta.-blocking compounds in solutions generally do not provide 
effective .beta.-blocking activity at practical infusion rates, while 
there is generally no added benefit to having concentrations greater than 
about 30% (weight) of the .beta.-blocker in solution. In particularly 
preferred compositions, the concentration of .beta.-blocking compound in 
solution is from about 0.01 to about 10% by weight. 
The hydroalcoholic solution preferably contains from about 5 to about 50% 
by volume ethanol. Ethanol has been found to be important in the 
stabilization of the .beta.-blocking compound according to the present 
invention. 
The hydroalcoholic solutions also preferably contain from about 5 to about 
50% by volume of physiologically acceptable liquid polyhydric compound. 
Physiologically acceptable liquid polyhydric 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; polyethylene glycols having a molecular weight of 
from about 200 to about 600 daltons; and glycerine. Preferred liquid 
polyhydric compounds include alkyls of from 1 to 10 carbon atoms having 
two or more adjacent hydroxyl groups, and polyethylene glycols having a 
molecular weight of from about 200 to about 600 daltons. Glycerin is less 
preferred, because solutions containing it have been observed to discolor 
on storage at 55.degree. C. A particularly preferred liquid polyhydric 
compound is propylene glycol. Liquid polyhydric compounds, in conjunction 
with ethanol are useful stabilizing components of the .beta.-blocking 
compounds in the hydroalcoholic solution according to the present 
invention. In particularly preferred compositions, the volume ratio of 
ethanol to the liquid polyhydric compound is about 1:1. 
Stability of the .beta.-blocking compound in solution is affected by the pH 
of the solution. In preferred compositions, the pH of the hyroalcoholic 
solution ranges from about 2.0 to about 4.0. When the pH of the solution 
is less than about 2.0 or greater than about 4.0, degradation of the 
.beta.-blocking compound was observed. In particularly preferred 
compositions, the pH ranges from about 2.8 to about 3.2, and in the most 
preferred compositions, the pH ranges from about 2.8 to about 3.0. The pH 
is preferably maintained by a physiologically acceptable buffering agent 
at a concentration of from about 0.05 to about 2 molar. Preferred 
buffering agents include tartrate buffers, acetate buffers, 
trishydroxymethylaminomethane, and the like; and amphoteric compounds such 
as glycine, cystine, and the like. Tartrate buffers are particularly 
preferred. The molar ratio of the .beta.-blocking compound to buffering 
agent advantageously is about 1:1 to about 3:1. 
The .beta.-blocking compounds used in the pharmaceutical compositions of 
the present invention are made quite stable by the hydroalcoholic solution 
of the present invention. Typical compositions exhibit shelf lives from 12 
months to 24 months, compared to about 1 week for the same compounds in 
conventional aqueous preparations. These compositions thus facilitate 
commercial distribution and storage of the above described short-acting 
ester-containing .beta.-blockers. 
The pharmaceutical compositions of the present invention are preferably 
added to a physiologically acceptable infusion medium to a final 
concentration of .beta.-adrenergic compound as deemed necessary by the 
patient's condition and needs, and thereby parenterally administered to 
the patient. 
The dosages and rates of administration of these compositions generally 
depend upon the patient's needs and the particular .beta.-blocking 
compound employed. These dosages and rates of administration are described 
in U.S. Pat. No. 4,387,103 issued June 7, 1983. 
In order to illustrate the manner in which the above compositions may be 
prepared and the properties of the compositions, reference is made to the 
following examples, which, however, are not meant to limit or restrict the 
scope of the invention in any respect. 
For convenience, the invention will be exemplified with respect to the 
sulfate salt of the compound of formula II. 
A stability indicating high pressure liquid chromatographic (HPLC) assay 
was developed for the compound of formula II which was suitable to monitor 
the compound and its degradation product(s) during the early phase of 
formulation studies. The method of HPLC analysis is described hereafter. 
Formulation screening was conducted to determine the parameters essential 
for an acceptable product. Based on these data, the composition of the 
formulations containing both active and inactive ingredients were 
ascertained. Representative formulations were packaged in ampuls and 
placed on accelerated and room temperature stability test. At various time 
intervals, samples from stability stations were removed and assayed for 
potency of the compound. Based on the stability data, the formula 
composition is stable. 
Initially, the solubility of the compound was determined in various 
vehicles. The amount dissolved was measured by HPLC (Table 2). The pKa is 
8.17 and the aqueous solution is acidic (1% is about pH 1). Based on this 
acidic nature, a tartrate buffer was selected. It was foun that the molar 
ratio of active .beta.-blocking agent to buffer was critical, 1:1 to 3:1 
to stabilized product. 
In order to determine the pH at which the formulation would show maximum 
stability, a kinetic degradation study was employed. pH of solutions 
ranging from 2-4, containing 0.1M each of the compound of formula II and 
tartrate buffer were stored at 75.degree. C. At various time intervals, 
samples were taken and assayed for the compound. 
The kinetic data obtained was plotted as a log of drug concentration versus 
time. The apparent first-order rate constants were calculated from the 
slopes of the linear regression lines fitted to log (C)=log (Co)-2.303 kt 
where C is drug concentration at time t, Co is the initial drug 
concentration and k is the apparent first-order rate constant. 
The kinetics of degradation of the drug at 75.degree. C. and at various pH 
values was followed by monitoring the potency of the drug at different 
stability times. The logarithm of the potency versus time in all cases 
produced linear plots. The apparent first-order rate constants were 
calculated from the slopes of the linear regression lines (not shown) and 
are presented in FIG. 1. 
The results showed a pseudo first-order degradation kinetic pattern. The pH 
of the stable region was determined, and considering physiological pH, a 
pH range of 2.8 to 3.4 was selected for formulation purpose. 
The ratio of the two organic vehicles, namely propylene glycol and alcohol 
were determined by making solutions of the compound of formula II in the 
vehicle and testing the stability at 75.degree. C. Samples were removed 
after specified times and measured for potency. The rate of degradation at 
various ratios of propylene glycol and alcohol were determined and plotted 
as shown in FIG. 2. Results point out a 1:1 ratio of the two substances 
minimizes degradation while at the same time not providing too high a 
concentration of either of them. 
FIG. 3 illustrates the stability of the compound of formula II in 
hydroalcoholic solution buffered at pH 3 by sodium tartrate. An identical 
stability study was conducted with a solution without buffering agent 
(FIG. 4). Because the kinetic pattern follows pseudo first order, the 
potency at 75.degree. C. upon storage was converted to natural logarithm 
prior to plotting. Results clearly show that the buffered preparation is 
approximately twice as stable as the unbuffered product. The rate of 
degradation as measured by the slope is 3.87.times.10.sup.-2 day.sup.-1 
(buffered) while it is 7.09.times.10.sup.-2 day.sup.-1 (unbuffered). 
The sulfate salt of the compound of Formula II in aqueous solution when 
stored at 75.degree. C. degraded about 70% in one week. In contrast, when 
formulated in the pharmaceutical composition as noted and placed under the 
same storage conditions, it degraded only about 25%. Thus, a significant 
three fold increase in stability resulted when the proper composition was 
used to formulate the product. 
The results of this comparison are represented in FIG. 5. Samples for the 
study were prepared and tested as follows: 
a. Thermal at 105.degree. C.--A solution of the sulfate salt was prepared 
comprising 200 .mu.g/mL in methanol. One mL of solution was evaporated and 
the residue (2 .mu.g of the salt was placed in an oven set at 105.degree. 
C. Several vials were prepared in the same manner, and removed for testing 
at various times. In each case, 4 mL of mobile phase was added (final 
conc. 50 .mu.g/mL) for subsequent HPLC evaluation. The results are plotted 
as curve A in FIG. 5. 
b. Aqueous at 75.degree. C.--10 mg of sulfate salt of Formula II were 
dissolved in 100 mL of deionized water. A 2 mL portion of this solution 
was transferred to a vial and placed in a 75.degree. C. oven. A series of 
vials were prepared and evaluated at various intervals. Each time 2 mL of 
mobile phase was added to the vial (final conc. 50 .mu.g/mL) for 
subsequent HPLC evaluation. The results are plotted as curve B in FIG. 5. 
c. Forced Degradation of the Formulation was carried out using a solution 
containing the sulfate salt of Formula II, 100 mg/mL, in Acetate Buffer 
(0.35M) containing 20% of Propylene Glycol:Ethanol (50:50) having a pH 
3.17. The formulation solution was divided into 2 parts, placed in 
55.degree. C. and 75.degree. C. ovens and tested periodically. To evaluate 
the formulation, the solution was diluted 1 mL to 100 mL of mobile phase, 
then 5 mL to 100 mL in mobile phase (final conc.--50 .mu.g/mL) for 
subsequent HPLC evaluation. 
The rates of decomposition were monitored by HPLC and compared to the 
respective initial concentrations at 220 nm. In order to insure that the 
peak was that of the sulfate salt and not an impurity, excipient or 
product of decomposition, the peak was scanned using a variable wavelength 
detector (200-300 nm). Using the Perkin-Elmer LC-75 Detector Stop Flow 
System described below: 
A 70 .mu.L portion of the sulfate salt degraded samples were injected 
manually into the HPLC L-75 equipped with a variable wavelength detector, 
programmed to scan wavelengths from 200 to 320 nm. When the sulfate salt 
reached the detector cell, the flow of mobile phase was stopped and the 
scan initiated from 200 to 320 nm. In this manner, only the peak 
corresponding to the sulfate salt was measured. 
On the basis of these results, a preferred composition of formulation was 
selected as shown in Example 1. The formulations were packaged and placed 
on long-term stability. Test results are shown in Example 2. Although 
there were some potency losses at elevated temperatures, there were no 
significant losses either at room temperature, high intensity light or 
refrigeration. 
Ordinarily, with compositions of the invention, it is preferred to 
experience less than a 10% potency loss at 40.degree. C. over a 
three-month period or over a twelve- to twenty-four month period at room 
temperature. Based on the kinetic pattern at about 40.degree. C., it is 
believed that a 10% potency loss at a three-month period extrapolates to a 
10% potency loss at 24 months at room temperature. Without stabilization 
as described herein, the compound of formula II loses 10% potency within a 
week when stored at room temperature. 
ANALYTICAL METHOD 
Samples were dissolved or diluted with the mobile phase, methanol--pH 3.4 
phosphate buffer solution. The resulting solutions were diluted with 
benzoic acid internal standard solution and chromatographed on a octadecyl 
silane column with detection at 229 nm. The selectivity of the 
chromatographic system for intact compound was demonstrated by resolving 
the parent drug from synthetic intermediates, potential impurities and 
reaction products resulting from accelerated degradation conditions. The 
method is linear, quantitative, rugged and reproducible with a sensitivity 
of 2 ug/ml. Either peak height or peak area ratios can be used for 
quantitation. 
TABLE 2 
______________________________________ 
SOLUBILITY PROFILE OF THE SULFATE 
SALT OF THE COMPOUND OF FORMULA II 
Solubility, 
Solvent % w/w 
______________________________________ 
Water for Injection USP (WFI) 
50.70 
Propylene Glycol USP (PG) 
3.47 
Alcohol USP (EtOH) 2.24 
Polyethylene Glycol 200 USP (PEG) 
2.64 
WFI (5%), PEG (95%) 3.83 
WFI (5%), EtOH (95%) 7.50 
WFI (5%), PG (95%) 5.60 
WFI (5%), EtOH (45%), PG (50%) 
7.20 
WFI (5%), EtOH (45%), PEG (50%) 
5.21 
EtOH (35%), PG (35%), PEG (30%) 
4.37 
EFI (5%), PG (30%), PEG (30%), EtOH (35%) 
6.04 
______________________________________ 
EXAMPLE 1 
______________________________________ 
Each 5 ml Ampul Contains: 
______________________________________ 
Salt of the Compound of Formula II 
0.25 g 
Alcohol 0.75 ml 
Propylene Glycol 0.75 ml 
Water for Injection, q.s. to 5 ml 
______________________________________ 
Buffer to pH 2.8-3.0 with 75 mg Tartaric Acid, Sodium Hydroxide, NF added 
as needed to adjust pH. 
Packaging is in a 5 ml clear glass (Type 1) ampul. 
The formulation is a clear, colorless, sterile, nonpyrogenic solution of 
the active .beta.-blocking agent in Propylene Glycol, Alcohol, USP and 
Water for Injection, (15:15:70) at a concentration of 50 mg/ml. 
Procedure 
The ampuls and glassware for compounding, filtering and filling were washed 
and depyrogenated. The filter assembly, filling tube assembly and other 
parts and equipment were sterilized. A 10N NaOH solution was prepared. The 
sulfate salt of the compound of formula II and tartaric acid were weighed 
out and placed in a glass vessel. Water for injection (WFI) was added to 
dissolve the materials. The pH was adjusted to 2.9 in the aqueous phase 
with 10N NaOH and propylene glycol was added. The ethanol was then added 
and the mixture was stirred to dissolve the solid materials. Water for 
injection was added to the final volume and the solution was filtered 
through a 0.2 .mu.m membrane. The solution was then placed in ampuls which 
were sealed, leak tested and inspected. 
EXAMPLE 2 
Ampuls prepared according to the procedure of Example 1 were selected and 
placed on stability test. At each stability time one ampul of each 
solution was removed. The pH, potency and the physical appearance of the 
solutions was determined. The concentration of the drug was determined by 
a high performance liquid chromatographic (HPLC) method. The results are 
tabulated in Tables 3 and 4 for 5 and 10 ml ampuls. 
The glossary for the abbreviations used in the tables is as follows: 
TZ--Initial, zero time 
RT--Room temperature, 15.degree.-30.degree. C. 
EL40--40.degree. C. 
EL55--55.degree. C. 
REF--Refrigerated 
NL--Natural Light 
IL--High intensity light, about 1200 ft. candles 
W--Weeks 
M--Months 
TABLE 3 
__________________________________________________________________________ 
Container Size: 5 ML 
Test 
Station 
Potency 
Test 
Value 
Change 
PH 
Time 
(%) Value 
Change 
Physical Observations 
__________________________________________________________________________ 
ALL 
TZ 100.9 
0.0 3.54 
0.000 
Clear Colorless Solution 
RT 
4W 100.3 
-0.6 3.42 
-0.12 
Clear Colorless Solution 
3M 101.7 
0.8 3.50 
-0.04 
Clear With Faint Yellow Color 
EL40 
4W 95.7 
-5.2 3.40 
-0.14 
Clear Colorless Solution 
3M 83.3 
-12.6 
3.50 
-0.04 
Clear With Faint Yellow Color 
EL55 
2W 95.2 
-5.7 3.52 
-0.02 
Clear Colorless Solution 
4W 85.3 
-15.6 
3.43 
-0.11 
Clear Colorless Solution 
2M 76.1 
-24.8 
3.43 
-0.11 
Clear Colorless Solution 
3M 65.7 
-35.2 
3.50 
-0.04 
Clear With Faint Yellow Color 
REF 
3M 101.0 
0.1 3.53 
-0.01 
Clear With Faint Yellow Color 
NL 
3M 102.4 
1.5 3.51 
-0.03 
Clear With Faint Yellow Color 
IL 
2W 101.1 
0.2 3.52 
-0.02 
Clear Colorless Solution 
__________________________________________________________________________ 
TABLE 4 
__________________________________________________________________________ 
Container Size: 10 ML 
Test 
Station 
Potency 
Test 
Value 
Change 
PH 
Time 
(%) Value 
Change 
Physical Observations 
__________________________________________________________________________ 
ALL 
TZ 104.5 
0.0 3.57 
0.00 
Clear Colorless Solution 
REF-757-25 
RT 
4W 101.7 
-2.3 3.44 
-0.13 
Clear Colorless Solution 
3M 101.3 
-3.2 3.48 
-0.09 
Clear With Faint Yellow Color 
EL40 
4W 99.2 
-5.3 3.41 
-0.16 
Clear Colorless Solution 
3M 93.9 
-10.6 
3.48 
-0.09 
Clear With Faint Yellow Color 
EL55 
2W 95.7 
-8.8 3.56 
-0.01 
Clear Colorless Solution 
4W 86.3 
-18.2 
3.42 
-0.15 
Clear Colorless Solution 
2M 77.3 
-27.2 
3.45 
-0.12 
3M 62.6 
-41.9 
3.49 
-0.08 
Clear With Faint Yellow Color 
REF 
3M 104.7 
0.2 3.47 
-0.10 
Clear With Faint Yellow Color 
NL 
3M 103.2 
-1.3 3.47 
-0.10 
Clear With Faint Yellow Color 
IL 
2W 103.1 
-1.4 3.53 
- 0.02 
Clear Colorless Solution 
__________________________________________________________________________