Title: Methods for preparing pharmaceutical formulations
Abstract: The invention relates to pharmaceutical formulations and methods for preparing pharmaceutical formulations of histamine releasers. The present invention provides methods for determining the concentration of physiologically acceptable excipients for use in the formulations of the invention. The present invention also provides methods for suppressing pharmaceutically-induced histamine release by administering to an animal, the formulations of the present invention. A kit useful for preparing pharmaceutical formulations of histamine releasers is also provided.
Patent Number: 6,911,455 Issued on 06/28/2005 to Floyd, et al.
| Inventors:
|
Floyd; Alison G. (Durham, NC);
Hashim; Mir A (Durham, NC);
Lin; Peiyuan (Durham, NC);
Mook; Robert A. (Durham, NC);
Sefler; Andrea (Durham, NC);
Meserve; Kathleen Cornell (Durham, NC);
Ricciarelli; Patricia Neal (Durham, NC);
Spitzer; Timothy David (Durham, NC)
|
| Assignee:
|
SmithKline Beecham Corporation (Philadelphia, PA)
|
| Appl. No.:
|
149722 |
| Filed:
|
December 13, 2000 |
| PCT Filed:
|
December 13, 2000
|
| PCT NO:
|
PCT/US00/33772
|
| 371 Date:
|
June 13, 2002
|
| 102(e) Date:
|
June 13, 2002
|
| PCT PUB.NO.:
|
WO01/45741 |
| PCT PUB. Date:
|
June 28, 2001 |
| Current U.S. Class: |
514/308; 424/44 |
| Intern'l Class: |
A61K 031/47; A61K031/16.5 |
| Field of Search: |
514/308
|
References Cited [Referenced By]
U.S. Patent Documents
| 4309408 | Jan., 1982 | Pathak et al.
| |
| 5437872 | Aug., 1995 | Lee.
| |
| 5767112 | Jun., 1998 | Poli et al.
| |
| 6099864 | Aug., 2000 | Morrison et al.
| |
| 6177445 | Jan., 2001 | Bigham et al.
| |
| 6187789 | Feb., 2001 | Bigham et al.
| |
| 6380356 | Apr., 2002 | Griffin et al.
| |
| Foreign Patent Documents |
| 0 707 853 | Apr., 1996 | EP.
| |
| WO 98 4267/4 | Oct., 1998 | WO.
| |
| WO 98 4267/5 | Oct., 1998 | WO.
| |
| WO 99 2791/4 | Jun., 1999 | WO.
| |
Other References
Wien, R. "The Pharmacological Actions of Certain Aromatic Diamidines Possessing
Trypanocidal Activity," Ann. Trop. Med. Parasit (1943), 37.
MacIntosh, F.C., et al. "The Liberation of Histamine by Certain Organic Bases,"
J. Physiol. (1949) 109, 190-219.
West, G.B. "Ethylenediamine Tetraacetic Acid and Histamine Release from Rat Mast
Cells," Int. Archs Allergy Appl. Immun. 68:399-401, 1982.
Read, G.W., et al. "Competitive Inhibition of 48/80-Induced Histamine Release
by Benzalkonium Chloride and Its Analogs and the Polyamine Receptor in Mast Cells,"
Journal of Pharmacology and Experimental Therapeutics, 1982, vol. 222, no.
Frisk-Holmberg, M., et al. "Histamine Release from Rat Peritoneal Mast Cells
and Cat Paws Induced by Some Neuromuscular Blocking Agents," ACTA Physiol. Scand.
1971, 81:367-375.
"Histamine Release by Drugs, Peptides, Venoms, and Other Agents," Goodman & Gilman's
The Pharmacological Basis of Therapeutics, Ninth Edition, 1996, Chapter 25, pp. 583.
|
Primary Examiner: Kim; Vickie
Attorney, Agent or Firm: Fox; Jennifer L.
Parent Case Text
CROSS-REFERENCES TO RELATED APPLICATIONS
This application is a Rule 371 Application of PCT Application No. US00/33772,
filed 13 Dec. 2000, which claims priority to U.S. application Ser. No. 60/171,696,
filed 22 Dec. 1999.
Claims
1. A method for preparing a pharmaceutical formulation containing a histamine
releaser and a physiologically acceptable excipient, said method comprising combining
a therapeutically effective amount of said histamine releaser with a concentration
of the physiologically acceptable excipient; wherein said concentration of the
physiologically acceptable excipient, when combined in an aqueous solution with
the histamine releaser at or above critical micelle concentration, is sufficient
to reduce aggregation of the histamine releaser in the aqueous solution by at least
about 25 percent compared to aggregation of the histamine releaser in the aqueous
solution containing substantially no physiologically acceptable excipient; wherein
the histamine releaser is (Z)-2-chloror-1-{(3-{(1R, 2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4
-tetrahydro-2-isoquinolinio}propyl}-4-{3-[(1S, 2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4
-tetrahydro-2-isoquinolinio]propyl}-2-butenedioate dichloride or a pharmaceutically
acceptable salt thereof, and the physiologically acceptable excipient is selected
from the group consisting of divalent inorganic salts, organic carboxylic acids,
phosphoric acid, amino acids, chelating agents, albumins and combinations thereof.
2. The method according to claim 1, wherein the histamine releaser is a neuromuscular blocker.
3. The method according to claim 1, wherein the physiologically acceptable excipient
is selected from the group consisting of calcium chloride, sodium sulfate, magnesium
sulfate, tartaric acid, maleic acid, acetic acid, citric acid, succinic acid, glucuronic
acid, phosphoric acid, glycine, lysine, arginine, EDTA, bovine serum albumin, human
serum albumin and combinations thereof.
4. The method according to claim 1, wherein the concentration of the physiologically
acceptable excipient is determined by the steps of:
a) measuring aggregation of said histamine releaser in a reference solution consisting
essentially of said histamine releaser in a concentration at or above the critical
micelle concentration in the aqueous solution;
b) measuring aggregation of said histamine releaser in a comparative solution
consisting essentially of said histamine releaser and a pre-selected concentration
of the physiologically acceptable excipient in the aqueous solution, wherein the
concentration of said histamine releaser in the comparative solution is substantially
the same as the concentration of said histamine releaser in the reference solution;
c) optionally repeating step b) one or more times with a comparative solution
having a different pre-selected concentration of the physiologically acceptable
excipient;
d) identifying a concentration of physiologically acceptable excipient that is
sufficient to reduce aggregation of said histamine releaser in the comparative
solution by at least about 25 percent compared to aggregation of said histamine
releaser in the reference solution;
wherein said identified concentration of step d) is the concentration of the
physiologically acceptable excipient for combining with said histamine releaser
to prepare the pharmaceutical formulation.
5. A pharmaceutical formulation prepared according to claim 1.
6. The pharmaceutical formulation according to claim 5, wherein said histamine
releaser is a neuromuscular blocker.
7. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is selected from the group consisting of calcium chloride,
sodium sulfate, magnesium sulfate, tartaric acid, maleic acid, acetic acid, citric
acid, succinic acid, glucuronic acid, phosphoric acid, glycine, lysine, arginine,
EDTA, bovine serum albumin, human serum albumin and combinations thereof.
8. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of any two or more excipients selected from
the group consisting of glycine, EDTA, citric acid and calcium chloride.
9. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is citric acid in a concentration of from about 15 mM to about
300 mM.
10. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is EDTA in a concentration of from about 0.02 percent to about
1 percent.
11. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is calcium chloride in a concentration of from about 15 mM
to about 200 mM.
12. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of citric acid in a concentration of from
about 15 mM to about 100 mM and EDTA in a concentration of from about 0.02 percent
to about 1 percent.
13. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of citric acid in a concentration of from
about 15 mM to about 100 mM and calcium chloride in a concentration of from about
25 mM to about 75 mM.
14. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is glycine in a concentration of from about 10 mg/mL to about
100 mg/mL.
15. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of glycine in a concentration of from about
10 mg/mL to about 100 mg/mL and EDTA in a concentration of from about 0.02 percent
to about 1 percent.
16. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of glycine in a concentration of from about
10 mg/mL to about 100 mg/mL and citric acid in a concentration of from about 15mM
to about 100 mM.
17. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of glycine in a concentration of from about
10 mg/mL to about 100 mg/mL, citric acid in a concentration of from about 15 mM
to about 100 mM, and EDTA in a concentration of from about 0.02 percent to about
1 percent.
18. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is citric acid in a concentration of about 50 mM.
19. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is EDTA in a concentration of about 0.1 percent.
20. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is calcium chloride in a concentration of about 50 mM.
21. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of citric acid in a concentration of about
50 mM and EDTA in a concentration of about 0.1 percent.
22. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of citric acid in a concentration of about
50 mM and calcium chloride in a concentration of about 50 mM.
23. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is glycine in a concentration of about 12.5 mg/mL.
24. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of glycine in a concentration of about 12.5
mg/mL and EDTA in a concentration of about 0.1 percent.
25. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of glycine in a concentration of about 12.5
mg/mL and citric acid in a concentration of about 50 mM.
26. The pharmaceutical formulation according to claim 5, wherein the physiologically
acceptable excipient is a combination of glycine in a concentration of about 12.5
mg/mL citric acid in a concentration of about 50 mM, and EDTA in a concentration
of about 0.1 percent.
27. The pharmaceutical formulation according to claim 5, further comprising a
physiologically acceptable diluent.
28. The pharmaceutical formulation according to claim 5, wherein said formulation
has a pH of from about 2 to about 8.
29. A method of suppressing pharmaceutically-induced histamine release in an
animal being treated with the histamine releaser, said method comprising administering
to said animal the pharmaceutical formulation according to claim 5.
30. The method according to claim 29, wherein said step of administering the
pharmaceutical formulation comprises intravenously administering the pharmaceutical formulation.
31. A method for preventing cardiovascular and respiratory effects mediated by
pharmaceutically-induced histamine release in an animal being treated with the
histamine releaser, said method comprising administering to said animal the pharmaceutical
formulation according to claim 5.
32. The method according to claim 31, wherein said cardiovascular and respiratory
effects mediated by pharmaceutically-induced histamine release are selected from
the group consisting of flushing, hypotension, tachycardia, bronchoconstriction,
anaphylactoid reactions and anaphylactic shock, and combinations of any two or
more thereof.
Description
BACKGROUND OF THE INVENTION
The present invention relates to the use of pharmaceutically active agents known
to cause histamine release when intravenously administered to an animal. More particularly
the present invention relates to new methods of using such pharmaceutically active
agents and new formulations of such agents which address pharmaceutically-induced
histamine release.
The cardiovascular and respiratory effects indicative of undesirable degrees
of histamine release which are specific to some conventional pharmacological agents
have been troubling clinicians for decades. The clinical observations associated
with an undesirable degree of histamine release are typified by cutaneous flushing
about the face, neck and/or chest, sometimes accompanied by hypotension and/or
tachycardia and/or nausea and vomiting. In some cases, the physical manifestations
of an undesirably high degree of histamine release can include very serious and
potentially fatal reactions such as bronchospasm, wheezing, and anaphylactoid reactions
and anaphylactic shock. An explanation of the reason(s) that these pharmacological
agents cause histamine release in vivo has eluded scientists for years.
Conventional pharmacological agents which are known to cause or suspected
to be capable of causing histamine release include intravenously administered hypnotics,
analgesics, sedatives, optiates, anesthetics, neuromuscular blocking agents (i.e.,
"neuromuscular blockers"), contrast agents employed in imaging (i.e., radiographic
contrast media, radio imaging agents and other contrast agents, hereinafter collectively
"imaging agents"), hormones for diagnostic procedures, and certain antibiotics,
NSAIDs, anticoagulants, ACE inhibitors and benzodiazepine receptor antagonists.
These agents may be administered intravenously as a bolus or rapid infusion, which
can, in addition to their desired therapeutic, diagnostic or medicinal effect,
cause the release of histamine. Histamine release is often the most prevalent adverse
reaction of certain of these pharmacological agents.
Histamine release could occur through both immunologic and non-immunologic
mechanisms. The more immediate or rapid reactions elicited by these pharmacological
agents are believed to occur via release of histamine via a non-immunologic mechanism.
The latter are often referred to as anaphylactoid reactions.
The precise mechanism by which these drugs cause the release of histamine is
not clear. Mast cells and basophils are possible sources of the released histamine,
but other in vivo sources may also exist. Mechanistic studies, especially studies
conducted in vitro with mast cells are complicated by the tremendous heterogeneity
that exists not only between species, but within a single individual. Given the
number of different sources of histamine, it is possible that different mechanisms
in different cells and tissue may be involved at any one time.
Clinically, it is known that slowing the rate of injection of these agents
from 5 seconds to 30 seconds decreases the incidence of cardiovascular effects
typical of histamine release. Slowing the rate of administration is currently the
preferred method of avoiding the risks associated with substantial histamine release.
However, slowing the rate of administration is not an acceptable course of action
in some clinical situations. For example, slowing the rate of administration is
unacceptable in emergency medical situations, especially when anesthesia and intubation
prior to emergency surgical procedures must occur rapidly. Furthermore, it is known
that slowing administration of certain pharmacological agents can disproportionately
decrease the speed of onset of activity and/or the potency of the drug.
There remains a need in the art for methods of addressing the histamine release
side effect associated with these pharmacological agents.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a plot of the surface tension (mN/m) versus increasing concentration
of
Z-2-Chloro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-2-butenedioate
dichloride (designated "Compound 1") (mg/mL).
FIG. 2 is a graph depicting (-▴-) the proton NMR relaxation rate (T
1
value in secs.) for solutions containing 80 mM
(Z)-2-Chloro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tet
dichloride (designated "Compound 1"), and various concentrations of d
4-citrate
(3.13, 6.25, 12.5, 25 and 50 mM) in deuterated saline solution at pD 3, and (-●-)
the pharmaceutically-induced histamine release from rat basophilic leukemia cells
as a percent of control value, which is induced by exposure of the RBL cells to
a formulation containing 160 mM of the same compound, and various concentrations
of citric acid (5, 10, 25 and 50 mM) in distilled water at pH 3.
SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided a method
for preparing a pharmaceutical formulation containing a histamine releaser and
a physiologically acceptable excipient. The method comprises combining a therapeutically
effective amount of the histamine releaser with a concentration of the physiologically
acceptable excipient. The concentration of the physiologically acceptable excipient,
when combined in an aqueous solution with the histamine releaser at or above critical
micelle concentration, is sufficient to reduce aggregation of the histamine releaser
in the aqueous solution by at least about 25 percent compared to aggregation of
the histamine releaser in the aqueous solution containing substantially no physiologically
acceptable excipient.
According to a second aspect of the invention, there is provided another
method for preparing a pharmaceutical formulation containing a histamine releaser
and a physiologically acceptable excipient. The method comprises combining a therapeutically
effective amount of the histamine releaser with the physiologically acceptable
excipient. The physiologically acceptable excipient is present in a concentration
determined by a method comprising the steps of: a) measuring aggregation of the
histamine releaser in a reference solution consisting essentially of the histamine
releaser in a concentration at or above the critical micelle concentration in an
aqueous solution; b) measuring aggregation of the histamine releaser in a comparative
solution consisting essentially of the histamine releaser and a pre-selected concentration
of the physiologically acceptable excipient in the aqueous solution, wherein the
concentration of the histamine releaser in the comparative solution is substantially
the same as the concentration of the histamine releaser in the reference solution;
c) optionally repeating step b) one or more times with a comparative solution having
a different pre-selected concentration of the physiologically acceptable excipient
d) identifying a concentration of physiologically acceptable excipient that is
sufficient to reduce aggregation of the histamine releaser in the comparative solution
by at least about 25 percent compared to aggregation of the histamine releaser
in the reference solution. The identified concentration of step d) is the concentration
of the physiologically acceptable excipient for combining with the histamine releaser
to prepare the pharmaceutical formulation.
According to a third aspect, there is provided another method of preparing
a pharmaceutical formulation containing a histamine releaser and a physiologically
acceptable excipient. The method comprises combining a therapeutically effective
amount of the histamine releaser with a concentration of physiologically acceptable
excipient. The concentration of the physiologically acceptable excipient is determined
by a method comprising the steps of: a) measuring histamine release from a histamine-containing
biological sample in a reference mixture consisting essentially of: i) the histamine-containing
biological sample in a medium and ii) an aqueous solution of the histamine releaser
at a concentration sufficient to cause histamine release from the histamine-containing
biological sample; b) measuring histamine release from the histamine-containing
biological sample in a comparative mixture consisting essentially of: i) the histamine-containing
biological sample in medium and ii) an aqueous solution of the histamine releaser
and a pre-selected concentration of the physiologically acceptable excipient, wherein
the histamine releaser in the comparative mixture is present in a concentration
which is substantially the same as the concentration of histamine releaser in the
reference mixture of step a); c) optionally repeating step b) one or more times
with a comparative mixture having a different pre-selected concentration of the
physiologically acceptable excipient; and d) identifying a concentration of the
physiologically acceptable excipient sufficient to reduce histamine release from
the histamine-containing biological sample in the comparative mixture by at least
about 10 percent compared to histamine release from the histamine-containing biological
sample in the reference mixture. The identified concentration of step d) is the
concentration of physiologically acceptable excipient for combining with the histamine
releaser to prepare the pharmaceutical formulation.
According to a fourth aspect of the present invention, there are provided
methods for determining a concentration of a physiologically acceptable excipient
for combining with the histamine releaser to prepare the pharmaceutical formulation.
These methods are as described above in connection with methods for preparing the
pharmaceutical formulations of the present invention.
According to a fifth aspect of the present invention, there is provided
a method for determining a concentration of a physiologically acceptable excipient
that is sufficient to suppress pharmaceutically-induced histamine release in an
animal being treated with a histamine releaser. The method comprises: a) measuring
aggregation of the histamine releaser in a reference solution consisting essentially
of the histamine releaser in a concentration at or above the critical micelle concentration
in an aqueous solution; b) measuring aggregation of the histamine releaser in a
comparative solution consisting essentially of the histamine releaser and a pre-selected
concentration of the physiologically acceptable excipient in the aqueous solution,
wherein the concentration of the histamine releaser in the comparative solution
is substantially the same as the concentration of the histamine releaser in the
reference solution; c) optionally repeating step b) one or more times with a comparative
solution having a different pre-selected concentration of the physiologically acceptable
excipient; d) identifying a concentration of physiologically acceptable excipient
that is sufficient to reduce aggregation of the histamine releaser in the comparative
solution by at least about 25 percent compared to aggregation of the histamine
releaser in the reference solution. The identified concentration of step d) is
the concentration of the physiologically acceptable excipient that is sufficient
to suppress pharmaceutically-induced histamine release in an animal being treated
with a histamine releaser. The foregoing method may also be employed to determine
a concentration of a physiologically acceptable excipient which when combined in
an aqueous solution with the histamine releaser at or above critical micelle concentration,
is sufficient to reduce aggregation of the histamine releaser in the aqueous solution
by at least about 25 percent compared to aggregation of the histamine releaser
in an aqueous solution containing substantially no physiologically acceptable excipient.
According to a sixth aspect of the present invention, there is provided
another method for determining a concentration of a physiologically acceptable
excipient that is sufficient to suppress pharmaceutically-induced histamine release
in an animal being treated with a histamine releaser. The method comprises: a)
measuring histamine release from a histamine-containing biological sample in a
reference mixture consisting essentially of: i) the histamine-containing biological
sample in a medium and ii) an aqueous solution of the histamine releaser at a concentration
sufficient to cause histamine release from the histamine-containing biological
sample; b) measuring histamine release from the histamine-containing biological
sample in a comparative mixture consisting essentially of: i) the histamine-containing
biological sample in medium and ii) an aqueous solution of the histamine releaser
and a pre-selected concentration of the physiologically acceptable excipient, wherein
the histamine releaser in the comparative mixture is present in a concentration
which is substantially the same as the concentration of histamine releaser in the
reference mixture of step a); c) optionally repeating step b) one or more times
with a comparative mixture having a different pre-selected concentration of the
physiologically acceptable excipient; and d) identifying a concentration of the
physiologically acceptable excipient sufficient to reduce histamine release from
the histamine-containing biological sample in the comparative mixture by at least
about 10 percent compared to histamine release from the histamine-containing biological
sample in the reference mixture. The identified concentration of step d) is the
concentration of the physiologically acceptable excipient that is sufficient to
suppress pharmaceutically-induced histamine release in an animal being treated
with a histamine releaser. This concentration of excipient is advantageously employed
for the preparation of pharmaceutical formulations of the histamine releaser. The
foregoing method may also be employed to determine a concentration of a physiologically
acceptable excipient which when combined in a saline solution with the histamine
releaser at or above critical micelle concentration, is sufficient to reduce aggregation
of the histamine releaser in the saline solution by at least about 25 percent compared
to aggregation of the histamine releaser in a saline solution containing substantially
no physiologically acceptable excipient.
According to another aspect, the present invention provides pharmaceutical
formulations comprising a histamine releaser and a concentration of physiologically
acceptable excipient. The pharmaceutical formulations may be prepared according
to any of the methods of the present invention. The concentration of physiologically
acceptable excipient may be determined according to any of the methods of the present
invention. The present invention provides a pharmaceutical formulation comprising
a histamine releaser and a physiologically acceptable excipient wherein the concentration
of the physiologically acceptable excipient is sufficient to suppress pharmaceutically-induced
histamine release.
According to another aspect of the invention there is provided a method
for suppressing pharmaceutically-induced histamine release in an animal being treated
with a histamine releaser. The method comprises administering to the animal a pharmaceutical
formulation according to the present invention.
In another aspect, the present invention provides use of a pharmaceutical formulation
according to the invention for the manufacture of a medicament for suppressing
pharmaceutically-induced histamine release in an animal being treated with the
histamine releaser.
According to another aspect of the invention, there is provided a method
for preventing cardiovascular and respiratory effects mediated by pharmaceutically-induced
histamine release in an animal being treated with a histamine releaser. The method
comprises administering to the animal a pharmaceutical formulation according to
the present invention.
In another aspect, the present invention provides use of a pharmaceutical formulation
according to the invention for the manufacture of a medicament for preventing cardiovascular
and respiratory effects mediated by pharmaceutically-induced histamine release
in an animal being treated with the histamine releaser.
In yet another aspect, the present invention provides a kit for preparing a pharmaceutical
formulation of a histamine releaser. The kit comprises a) a physiologically acceptable
excipient, and b) instructions for preparing the pharmaceutical formulation according
to the methods of the present invention.
A preferred histamine releaser for use in the pharmaceutical formulations and
methods
of treatment of the present invention is
(Z)-2-chloro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydr
dichloride and pharmaceutically acceptable salts thereof. Thus, in another aspect,
the present invention provides a pharmaceutical formulation comprising a therapeutically
effective amount of
(Z)-2-chloro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2-isoquinolinio]pro
dichloride and pharmaceutically acceptable salts thereof; an excipient selected
from the group consisting of glycine in a concentration of from about 10 mg/mL
to about 30 mg/mL, citric acid in a concentration of from about 25 mM to about
75 mM, EDTA in a concentration of from about 0.1% to about 0.5%, calcium chloride
in a concentration of from about 25 mM to about 75 mM, and combinations thereof;
and a physiologically acceptable diluent, wherein said pharmaceutical formulation
is suitable for intravenous administration. The present invention also provides
methods for suppressing pharmaceutically-induced histamine release in an animal
being treated with
(Z)-2-chloro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2-isoquinolinio]prop
dichloride or a pharmaceutically acceptable salts thereof.
These and other aspects of the present invention are described further in the
Detailed Description of the Invention, which follows and in the claims.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
"Pharmaceutical agent" as used herein shall refer to agents having
therapeutic activity (i.e., agents administered to an animal, preferably a human,
for the treatment or prevention of a medical condition), agents having diagnostic
activity (i.e., agents administered to an animal, preferably a human, for aiding
or assisting in the diagnosis of a medical condition), and agents having other
medicinal utility (i.e., agents administered to facilitate medical and/or surgical
procedures) when administered to an animal, preferably a human (e.g., neuromuscular
blockers, anesthetics, analgesics and the like).
"Histamine releaser" as used herein refers to a pharmaceutical agent which
is selected from the group consisting of anesthetics, opiates, neuromuscular blockers,
imaging agents, hormones for diagnostic procedures, tricyclic glycopeptide antibiotics,
cephalosporin antibiotics, penicillin and penicillin derivative antibiotics, intravenously
administered non-steroidal anti-inflammatory agents (NSAIDs), anticoagulants, ACE
inhibitors, and benzodiazepine receptor antagonists, which when intravenously administered
as a rapid bolus or rapid infusion to an animal, causes elevation of plasma and/or
tissue concentrations of histamine above normal physiological levels. The histamine
releasers are characterized by a structure having one or more hydrophilic charged
(cationic or anionic) portions distanced from one or more hydrophobic portions.
More particularly, "histamine releasers" include pharmaceutical agents which when
intravenously administered as a rapid bolus or rapid infusion to an animal cause
a histamine release in vivo which is sufficient to produce physiological manifestations
selected from the group consisting of cutaneous flushing, itching, hives, edema,
nausea, vomiting, elevated gastric acid secretion, vestibular effects, cardiovascular
effects such as hypotension (fall in blood pressure), tachycardia (rise in heart
rate), and respiratory effects such as bronchoconstriction, anaphylactoid reactions
and anaphylactic shock, and combinations of any two or more of the foregoing. "Normal
physiological levels of histamine" can differ among species and among individual
members of a single species. Therefore, "normal physiological levels of histamine"
refers to an average plasma histamine level of an untreated animal of the same
species as that being treated with the histamine releaser. Normal physiological
levels of histamine of various species of animals is reported in INFLAMMATION:
BASIC PRINCIPLES AND CLINICAL CORRELATES (Eds. J. I. Gallin, I. M. Goldstein, and
R. Snyderman, Chap. 11
, Measurement of Histamine, p. 202, Raven Press, New
York, 1992; and Bertini, S. et al.,
Gen. Pharmac. 31:625-631 (1998).
As used herein, the term "therapeutically effective amount of a histamine releaser"
means an amount of the pharmaceutical agent which is a histamine releaser (defined
above), which amount is sufficient to achieve the desired pharmaceutical activity
(i.e., therapeutic activity, diagnostic activity or medicinal utility) of the agent.
Thus, in the embodiment wherein the histamine releaser is a neuromuscular blocker,
a "therapeutically effective amount of the histamine releaser" is the amount of
the neuromuscular blocker which is sufficient to cause skeletal muscle relaxation
in the animal to which the neuromuscular blocker is being administered. In the
embodiment wherein the histamine releaser is an anesthetic, a "therapeutically
effective amount of the histamine releaser" is the amount of anesthetic which is
sufficient to induce anesthesia in the animal to which the anesthetic is being
administered. In the embodiment wherein the histamine releaser is a an imaging
agent, a "therapeutically effective amount of the histamine releaser" is the amount
of imaging agent which is sufficient to produce an appropriate level of image contrast
in a diagnostic procedure in the animal to which the imaging agent is being administered.
One skilled in the art can readily determine the therapeutically effective amount
of a particular histamine releaser based upon the foregoing explanation and examples,
and conventional knowledge in the art regarding these pharmaceutical agents.
The term "physiologically acceptable excipient" means an agent, other than water,
which is utilized in the formulation of a pharmaceutical agent as a pharmaceutical
formulation, which is not deleterious to the animal to which the formulation will
be administered, and which does not substantially affect the pharmaceutical activity
of the pharmaceutical agent with which it is formulated. Typically, the physiologically
acceptable excipients are employed for the purpose of facilitating formulation
of the pharmaceutically active agent.
The term "aqueous solution" as used herein refers to solutions containing water
(including deuterated water), preferably distilled water, and "saline solutions"
(defined below), and which solutions contain substantially no other additives,
but which may be pH adjusted with hydrochloric acid or sodium hydroxide, as may
be necessary or desirable to stabilize or facilitate solubilization of certain
histamine releasers in aqueous solution.
The term "saline solution" as used herein refers to solutions containing approximately
0.9% sodium chloride solubilized in water (including deuterated water), preferably
distilled water, and which solutions contain substantially no other additives but
may be pH adjusted with hydrochloric acid or sodium hydroxide as may be necessary
or desirable to stabilize or facilitate solubilization of certain histamine releasers
in the saline solution.
The term "aggregation" as used herein refers to the average aggregate size of
a pharmaceutical agent, solubilized in aqueous solution. Aggregate size can be
a function of the conformation of the molecules or aggregates, or the number of
molecules forming the aggregate, or the hydrodynamic radius of the aggregate.
II. Histamine Release Generally
Although the reason(s) that these histamine releasers induce histamine release
have eluded scientists for years, our studies suggest that histamine release is
the result of a combination of at least two, possibly related, factors; namely,
the concentration of the histamine releaser and certain structural properties of
histamine releasers that can cause aggregation of the histamine releaser in solution
and in the blood upon intravenous administration to an animal.
It is now believed that histamine release may be related to the initial bolus
concentration of the histamine releaser, and that the critical events leading to
histamine release take place very soon after the injection. Slowing the rate of
injection effectively lowers the concentration of the histamine releaser since
intravenously injected histamine releasers are diluted by the flow of blood that
passes the injection site while the agent is being injected.
By studying surface tension properties of histamine releasers, it has been found
that certain histamine releasers tend to self-associate, or aggregate in aqueous
solution. It is now believed that this aggregation of the histamine releaser triggers
the histamine release. We have identified structural properties shared by the various
histamine releasers, which may cause aggregation.
The histamine releasers referred to in the present invention all share the common
structural features of one or more hydrophilic portions distanced from one or more
hydrophobic portions. For example, neuromuscular blockers are bis-quaternary ammonium
salts which possess two cationic charges at the ends of the molecule, separated
by a hydrophobic, lipophilic linker. In the case of non-steroidal (e.g., benzylisoquinoline-type)
neuromuscular blockers, the hydrophobic linker is typically long and flexible.
In the case of steroidal neuromuscular blockers, the hydrophobic linker may be
bulky and/or rigid.
Because of this structural characteristic, the histamine releasers are soluble
in both water and organic solvents. The structural and solubility characteristics
of histamine releasers are similar to surfactants and detergents. Surfactants and
detergents are known to aggregate in solution in a concentration dependent manner.
The presence of a charged hydrophilic portion distanced from a hydrophobic portion
of the molecule may impose on the histamine releaser a tendency to self-solvate
or aggregate in solution just as a detergent or surfactant, thus explaining the
observation of surface tension modifying properties of the histamine releasers.
Our studies indicate that histamine releasers may aggregate in solution. Possible
arrangements of aggregates in solution include but are not limited to dimers, trimers,
micelles, rods, plates and sheets. In general, histamine releasers tend to aggregate
in arrangements which seek to isolate the hydrophobic portion(s) of the molecule
from the aqueous solution in which it is dissolved. This can be accomplished, for
example, by forming micelles wherein the hydrophobic portion of the histamine releaser
molecule is oriented toward the center of the micelle and the charged hydrophilic
portion of the molecule is oriented outward from the center of the micelle. For
example, the molecules of a neuromuscular blocker could bend in the region of the
hydrophobic portion allowing multiple molecules to aggregate by positioning the
hydrophobic portion of each molecule in proximity to the hydrophobic portions of
other molecules, while extending the cationic, hydrophilic portion outward. This
aggregated arrangement of neuromuscular blocker molecules results in aggregation
with poly-cationic surfaces extending outward from the center of the aggregate.
It has been found that the degree of aggregation is concentration dependent, such
that higher concentrations of histamine releaser result in more aggregation and/or
higher order aggregates (e.g., micelles as compared to dimers).
Many pharmaceutical agents, including most neuromuscular blockers are administered
intravenously at concentrations in the millimolar (mM) range; a concentration range
at which it is likely the drug is partly aggregated and may be near its critical
micelle concentration. The "critical micelle concentration" is the concentration
at which molecules in a given environment aggregate to form micelles. The critical
micelle concentration of a given agent can be measured using the techniques describe
herein as well as other conventional techniques, including those described in Anacker,
E. W. (1970), MICELLE FORMATION OF CATIONIC SURFACTANTS IN AQUEOUS MEDIA,
Cationic
Suffactants, E. Jungermann. New York, Marcel Dekker, Inc.; Attwood, D. (1995),
Advances in Colloid and Interface Science 55: 271-303; and Mukerjee, P.
and K. J. Mysels (1971), CRITICAL MICELLE CONCENTRATIONS IN AQUEOUS SURFACTANT
SYSTEMS, Washington, D.C., U.S. Dept. of Commerce, the disclosures of which are
incorporated herein by reference.
As is known by those skilled in the art, critical micelle concentration is dependent
upon a number of factors. See, Attwood, D. and A. T. Florence (1983), SURFACTANT
SYTEMS: THEIR CHEMISTRY, PHARMACY, AND BIOLOGY, London, Chapman and Hall; Rosen,
M. J. (1978), SURFACTANTS AND INTERFACIAL PHENOMENA, New York, Wiley-Interscience;
Jungermann, E., Ed. (1970), CATIONIC SURFACTANTS, New York, Marcel Dekker, Inc.;
and Jonsson, B., B. Lindman, et al. (1998), SURFACTANTS AND POLYMERS IN AQUEOUS
SOLUTION, Chichester, John Wilet Sons (the disclosures of which are incorporated
herein by reference) for a discussion of the factors which can effect critical
micelle concentration. One such factor is the nature of the solution or suspension
in which the aggregates are forming. For example, the data obtained for
(Z)-2-chloro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trim
dichloride, an ultra-short acting neuromuscular blocker in water is consistent
with a critical micelle concentration at about 15 mg/mL (about 14 mM), while in
saline the data obtained for this drug is consistent with a critical micelle concentration
at between 40 and 80 mM. The concentration of neuromuscular blockers used clinically
typically ranges from about 1 to about 55 mM.
Aggregation of the histamine releaser and the critical micelle concentration
are highly dependent on many factors. One factor is the structure of the particular
histamine releaser molecule, including the presence and structure of one or more
hydrophobic domains distanced from one or more hydrophilic domains that often contain
cationic or anionic groups. In addition, aggregation and critical micelle concentration
are highly dependent on the concentration of the histamine releaser in solution,
the presence and concentration of other molecules in solution, pH, the identity
and valency of the counter-ion to any cationic or anionic groups, and on the temperature
and pressure of the solution.
Upon injection of the histamine releasers into blood, the resultant new solution
(i.e., the solution of histamine releaser in blood) is believed to change many
of the factors listed above very rapidly. Given the rapidly changing solution conditions
such as the ionic composition of blood and the presence of many other dissolved
solutes, cells, proteins, etc., it is reasonable to expect these conditions would
favor increased aggregation and/or a lower critical micelle concentration. Overall,
it is likely that these histamine releasers are already highly aggregated in the
formulation being administered and that the physical act of mixing with blood in
the vein upon injection may favor increased aggregation and/or the formation of micelles.
Aggregated histamine releaser molecules are now believed to induce histamine
release from cells, tissues and fluids in essentially the same manner as aggregated
molecules of surfactants. Aggregated molecules of surfactants can cause a detergent
action that can solubilize organic molecules in water, extract proteins from membranes,
and cause cell membranes to become permeable. Increasing the permeability of the
membrane makes it easier for molecules to enter the cell, and for molecules in
the cell, such as histamine molecules, to be released.
It has now been observed that histamine releasers tend to aggregate. These aggregates
may exhibit detergent-like properties. Accordingly, it is believed that the detergent-like
properties of the aggregated histamine releaser may cause cell membranes to become
disturbed possibly to the point that the cells rupture. The disturbance of cellular
membranes of histamine containing cells, or in tissues or fluids and/or rupture
of these cells may cause the release of intracellular components and molecules
into the surrounding environment. Surfactants and detergents are known to cause
the release of histamine by rupturing the cell membrane of mast cells, which are
known to store and release histamine. Other cell types may behave similarly. For
example, basophils present in blood are also known to store and release histamine
and would be expected to behave similar to mast cells when exposed to a surfactant
or aggregated histamine releaser.
Even lower order aggregates (i.e., dimers and trimers) may cause histamine release
that may or may not be related to detergent-like effects. See, Read, G. W. and
J. F. Lenney,
Journal of Medicinal Chemistry 15(3): p. 320-23 (1972). For
example, because bis-cationic agents such as neuromuscular blockers, carry two
ammonium groups per molecule, it is currently expected that histamine releasing
effects can be expected when as few as 2-4 molecules of neuromuscular blocker aggregate.
In addition to this direct mechanism explaining the release of histamine, it
is
also possible that histamine release can be caused by indirect mechanisms. Cells
that do not store histamine, such as endothelial cells lining blood vessels, may
cause the release of histamine by an indirect mechanism. Aggregates of histamine
releasers may cause the release of cellular components from endothelial cells (or
other cells which do not store histamine), and those components may travel to histamine-containing
cells and signal the release of histamine from those storage cells.
III. Methods of Making Formulations
The present invention provides several methods of making pharmaceutical formulations
containing a histamine releaser and a physiologically acceptable excipient, which
seek to address the above mentioned tendencies of histamine releasers to aggregate
and cause the release of undesirable levels of histamine upon administration in vivo.
A. Histamine Releasers
In particular, the histamine releasers referred to in the present invention and
which are employed in the methods of making pharmaceutical formulations, include
anesthetics, opiates, neuromuscular blockers, imaging agents, hormones for diagnostic
procedures, tricyclic glycopeptide antibiotics, cephalosporin antibiotics, penicillin
and penicillin derivative antibiotics, intravenously administered non-steroidal
anti-inflammatory agents (NSAIDs), anticoagulants, ACE inhibitors, and benzodiazepine
receptor antagonists, which have the structural features noted above in the definition
of the "histamine releaser." Preferably, the histamine releaser is selected from
the group consisting of anesthetics, opiates, neuromuscular blockers, and imaging
agents. More preferably the histamine releaser is a neuromuscular blocker.
Examples of anesthetics include but are not limited to thiopental and thiobutabarbital.
Examples of opiates include but are not limited to morphine, morpholinic derivatives
such as oxymorphone, nalbuphine hydrochloride, buprenorphine, hydromorphone, fentanil
and fentanil derivatives including remifentanil, sufentanil and alfentanil. Examples
of neuromuscular blockers include but are not limited to non-steroidal neuromuscular
blocking agents such as
(Z)-2-chloro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2-isoquinolinio
dichloride (hereinafter sometimes referred to as "Compound 1" for the sake of brevity),
mivacurium, atracurium, d-tubocurarine, metocurine, doxacurium, and gallamine;
steroidal neuromuscular blocking agents such as vecuronium, pancuronium, rocuronium,
and rapacuronium; and other neuromuscular blockers such as succinylcholine. Examples
of imaging agents include but are not limited to ioxaglic (ioxaglate) acid and
diatrizoate sodium.
Pharmaceutically acceptable salts of any of the foregoing are also
contemplated by the present invention. Thus, the present invention contemplates
the use of atracurium besylate, mivacurium chloride, vecuronium bromide, pancuronium
bromide, rapacuronium bromide, doxacurium chloride, succinylcholine chloride, morphine
sulphate, hydromorphone hydrochloride, pharmaceutically acceptable salts of Compound
1, and the like.
Combinations of any two or more of the above-referenced histamine releasers
into a single formulation are also contemplated, provided that the two or more
histamine releasers do not react in a manner which deleteriously impacts their
therapeutic activity.
Preferred histamine releasers for use in the present invention include
morphine, Compound 1, mivacurium, atracurium, vecuronium, pancuronium, rocuronium,
rapacuronium and succinylcholine chloride and pharmaceutically acceptable salts
thereof. Compound 1 and pharmaceutical formulations and methods of treatment using
this compound are described in PCT Publication Nos. 98/42674 and 98/42675, both
published Oct. 1, 1998, to Glaxo Wellcome Inc. and Cornell Research Foundation,
the subject matter of which are hereby incorporated by reference in their entirety.
In one preferred embodiment, the histamine releaser is Compound 1 or a pharmaceutically
acceptable salt thereof. In one preferred embodiment, the histamine releaser is
mivacurium or a pharmaceutically acceptable salt thereof. In one preferred embodiment,
the histamine releaser is atracurium or a pharmaceutically acceptable salt thereof,
e.g., atracurium besylate.
B. Physiologically Acceptable Excipients
According to the methods of the present invention the histamine releaser
is combined with a physiologically acceptable excipient, which may be a single
physiologically acceptable excipient or a combination of two, three or more physiologically
acceptable excipients. "Excipient" as used herein means both a single physiologically
acceptable excipient and a combination of two, three or more physiologically acceptable excipients.
Preferred excipients are those which are conventionally employed in approved
parenteral or injectable formulations. The excipients employed in the present invention
are physically characterized by the presence of charge (e.g., ionic excipients)
and/or the presence of organic residues which are capable of affecting the solvation
of the histamine releaser. More particularly, the excipients are capable of ionizing
in solution and/or may be solvating the histamine releaser or aiding in the salvation
of the histamine releaser.
Suitable excipients for use in the present invention may be selected from
a variety of categories, including but not limited to divalent inorganic salts
(i.e., inorganic salts having a divalent anion, a divalent cation, or both), organic
carboxylic acids, phosphoric acid, amino acids, chelating agents, albumins and
combinations thereof. Preferred excipients are selected from the group consisting
of divalent inorganic salts, organic carboxylic acids, phosphoric acid, amino acids,
chelating agents, albumins and combinations thereof. In one embodiment, the excipient
is a divalent inorganic salt. In one embodiment, the excipient is an organic acid.
In one embodiment, the excipient is a chelating agent. In one embodiment, the excipient
is an amino acid.
Examples of suitable divalent inorganic salts include but are not limited
to calcium chloride, magnesium sulphate, magnesium chloride, sodium sulphate, and
combinations thereof. Calcium chloride is a preferred excipient for use in the
present invention.
Examples of suitable organic carboxylic acids include but are not limited
to tartaric acid (which includes racemic tartaric acid, D-tartaric acid and L-tartaric
acid) maleic acid, acetic acid, citric acid, succinic acid, glucuronic acid, and
combinations thereof. "Citric acid" as used herein refers to citric acid and any
hydrates and salts thereof, i.e., citrates. Citric acid is a preferred excipient
for use in the present invention.
The term "phosphoric acid" as used herein also includes salts of phosphoric acid,
such as sodium phosphate. As will be readily apparent to one skilled in the art,
the use of phosphoric acid as an excipient in the instant invention will require
that it be provided in a concentration which is physiologically acceptable.
Examples of suitable amino acids include but are not limited to glycine,
lysine, arginine and combinations thereof. Glycine is a preferred excipient for
use in the present invention.
Examples of suitable chelating agents include but are not limited to ethylene
diamine
