U.S. patent application number 12/205303 was filed with the patent office on 2011-01-20 for co-solvent compositions and methods for improved delivery of dantrolene theraputic agents.
This patent application is currently assigned to US WorldMeds, LLC. Invention is credited to Abeer Al-Ghananeem, Patrick DeLuca, George Digenis, Ahmad Malkawi.
Application Number | 20110015243 12/205303 |
Document ID | / |
Family ID | 40316940 |
Filed Date | 2011-01-20 |
United States Patent
Application |
20110015243 |
Kind Code |
A2 |
Malkawi; Ahmad ; et
al. |
January 20, 2011 |
CO-SOLVENT COMPOSITIONS AND METHODS FOR IMPROVED DELIVERY OF
DANTROLENE THERAPUTIC AGENTS
Abstract
The present invention provides for methods of using tert-butyl
alcohol (TBA) co-solvent systems in the formulation and production
of a pharmaceutical agent with low solubility. The present
invention also provides for pharmaceutical compositions made using
the novel co-solvent system. In one embodiment, the invention
provides for a method of making dantrolene sodium (DS) formulation
for intravenous use (DS-IV). This instantaneous reconstitution of
the DS-IV product constitutes a significant improvement in the
pharmacotherapy of patients undergoing malignant hyperthermia
during surgery.
Inventors: |
Malkawi; Ahmad; (Lexington,
KY) ; Al-Ghananeem; Abeer; (Lexington, KY) ;
DeLuca; Patrick; (Lexington, KY) ; Digenis;
George; (Louisville, KY) |
Correspondence
Address: |
FROST BROWN TODD, LLC
2200 PNC CENTER
201 E. FIFTH STREET
CINCINNATI
OH
45202
UNITED STATES
513-651-6800
513-651-6981
patents@fbtlaw.com
|
Assignee: |
US WorldMeds, LLC
4010 Dupont Circle Ste. L-07
Louisville
KY
40207
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20090093531 A1 |
April 9, 2009 |
|
|
Family ID: |
40316940 |
Appl. No.: |
12/205303 |
Filed: |
September 5, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60/978,626 |
Aug 23, 2010 |
|
|
|
Current U.S.
Class: |
514/390 ;
514/392; 548/316.1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 9/19 20130101; A61K 31/4166 20130101; A61K 31/4168 20130101;
A61K 9/08 20130101; A61P 9/06 20180101 |
Class at
Publication: |
514/390 ;
514/392; 548/316.1 |
International
Class: |
A61K 31/4168 20060101
A61K031/4168; A61K 31/4166 20060101 A61K031/4166; C07D 405/12
20060101 C07D405/12 |
Claims
1. A pharmaceutical composition comprising: (a) an aqueous solvent;
and (b) an organic co-solvent; and (c) at least one active
pharmaceutical compound having the formula: ##STR4## wherein A has
the formula ##STR5## in which R is from one to two substitutes
selected from the group consisting of nitro, cyano, amino, chloro,
bromo, acetyl, cargboxy, methyl, trifluorimethyl, and hydrogen; X
is a member of the group consisting of carbonyl and methylene; and
Y is a member of the group consisting of hydroxyethyl, butyl,
hydrogen, and r-pyridylethyl.
2. The pharmaceutical composition of claim 1 wherein the active
pharmaceutical compound is selected from the group consisting of
1-[5-(p-nitrophynyl) furfurylideneamino]hydantoin,
1-[5-(p-aminophenyl)furfurylideneamino]hydantoin,
1-[5-(p-chlorophenyl)furfurylideneamino]hydantoin,
1-[5-(2,4-dichlorophenyl)furfurylideneamino]hydantoin,
1-[5-(2,4-dichlorophenyl)furfurylideneamino]hydantoin,
1-[5-(2,methyl-r-nitrophenyl)furfurylideneamino]hydantoin,
1-[5-(p-nitrophenyl)furfurylideneamino]-2-imidazolidinone, and
1-[5-(p-cyanophenyl)furfurylideneamino]hydantoin.
3. A pharmaceutical composition comprising: (a) an aqueous solvent;
and (b) an organic co-solvent; and (c) dantrolene sodium as an
active pharmaceutical compound.
4. The composition of claim 1 wherein the organic co-solvent is
selected from the group consisting of tertiary butyl alcohol (TBA),
n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone,
ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane,
methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl
acetate, carbon tetrachloride, dimethyl sulfoxide,
hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid,
and cyclohexane, ethyl acetate, acetone, dimethylsulfoxide,
chlorobutanol, acetic acid and mixtures thereof.
5. A stable and lyophilized formulation of dantrolene sodium made
by the process comprising a) dissolving dantrolene sodium in an
alkaline solution of water and organic co-solvent solution
comprising between about 1% to about 99% (v/v) organic co-solvent
to form a pre-lyophilization solution; and b) lyophilizing the
pre-lyophilization solution.
6. The stable and lyophilized formulation of claim 5 wherein the
residual concentration of organic co-solvent in the final
lyophilized product is less than about 0.5%.
7. The stable and lyophilized formulation of claim 5 wherein the
concentration of DS degradants in the final lyophilized product is
less than about 8%.
8. The lyophilized preparation according to claim 5, wherein the
preparation is packaged in a vial or other pharmaceutically
acceptable container.
9. The lyophilized preparation according to claim 6, wherein the
preparation is substantially stable with respect to the amount of
DS-IV for at least about six months when stored at 5.degree. C.
10. A pharmaceutical unit dosage form comprising a pharmaceutical
composition of dantrolene sodium formed by the reconstitution of
the lyophilized preparation of claim 5.
11. A pharmaceutical dosage form of claim 10, wherein the
pharmaceutical dosage form comprises about 10 mg to about 30 mg of
dantrolene sodium.
12. A pharmaceutical dosage form of claim 10, wherein the
pharmaceutical dosage form comprises about 15 mg to about 25 mg of
dantrolene sodium.
13. A pharmaceutical dosage form of claim 10, wherein the
pharmaceutical dosage form comprises a trace amount of one or more
organic solvents,
14. A pharmaceutical composition of dantrolene sodium according to
claim 13 wherein the organic solvent is selected from the group
consisting of one or more of tertiary butanol, n-propanol,
n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate,
dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl
ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon
tetrachloride, dimethyl sulfoxide, hexafluoroacetone,
chlorobutanol, dimethyl sulfone, acetic acid, and cyclohexane.
15. A pharmaceutical composition of dantrolene sodium according to
claim 13 wherein the organic solvent is selected from the group
consisting of one or more of ethanol, methanol, propanol, butanol,
isopropanol, and tertiary butanol.
16. A pharmaceutical composition according to claim 15, wherein the
organic solvent is tertiary butanol.
17. A method of preparing a dantrolene sodium lyophilized
preparation comprising, a) dissolving dantrolene sodium in a
stabilizing concentration of an alcohol solvent comprising between
about 1% to about 99.99% (v/v) alcohol to form a pre-lyophilization
solution; and b) lyophilizing the pre-lyophilization solution.
18. A method according to claim 17, wherein the alcohol
concentration is between about 1% to about 99.9%.
19. A method according to claim 17, wherein the alcohol is selected
from one or more of methanol, ethanol, propanol, iso-propanol,
butanol, and tertiary-butanol.
20. A method according to claim 19, wherein the alcohol is
tertiary-butanol.
21. A method according to claim 20, wherein the tertiary butanol is
at a concentration of about 1% to 99.9%.
22. A method according to claim 17, wherein an excipient and a pH
adjusting agent are added before lyophilization.
23. A method according to claim 22, wherein the excipient comprises
mannitol and sodium hydroxide.
24. A method according to claim 23, wherein the dantrolene sodium
concentration is about 0.1 to about 1 mg/mL.
25. The lyophilized powder obtained from the method according to
claim 24.
26. A method according to claim 17 wherein step b) comprises: i)
freezing the pre-lyophilization solution to a temperature below
about -40.degree. C. to form a frozen solution; ii) holding the
frozen solution at or below -40.degree. C. for at least 2 hours;
iii) ramping the frozen solution to a primary drying temperature
between about -40.degree. C. and about 20.degree. C. to form a
dried solution; iv) holding for about 10 to about 70 hours; v)
ramping the dried solution to a secondary drying temperature
between about 25.degree. C. and about 40.degree. C.; and vii)
holding for about 5 to about 40 hours to form a dantrolene sodium
lyophilized preparation.
27. A method according to claim 26, wherein the alcohol is
tertiary-butanol.
28. A method according to claim 27, wherein the tertiary butanol is
at a concentration of about 1% to 30%.
29. The lyophilized powder obtained from the method according to
claim 28.
30. A method according to claim 17 further comprising, prior to
step a), the step of dissolving the dantrolene sodium in an aqueous
solution at elevated temperatures.
31. A method according to 31, wherein the aqueous solution is
heated the solution to a temperature of about 40.degree. C. to
about 70.degree. C., for a time sufficient to substantially
solubilize the dantrolene sodium.
32. A method according to 32, further comprising the step of
cooling the aqueous solubilized dantrolene solution to a
temperature about 15.degree. C. to about 30.degree. C. prior to
adding the alcohol solvent.
33. A formulation for lyophilization comprising dantrolene sodium
at a concentration of about 0.1 to about 5 mg/mL, mannitol at a
concentration of about 2 to about 100 mg/mL, tertiary-butyl alcohol
at a concentration of about 1 to about 99% (v/v) and an amount of
aqueous alkaline solution adequate to adjust the pH at a range of
from about 9.5 to about 10.5.
34. A lyophilized preparation made from the method according to
claim 33.
35. A method of treating a medical condition in a patient
comprising dissolving the preparation of claim 34 in a
pharmaceutically acceptable carrier to produce a pharmaceutically
acceptable solution and administering to the patient a
therapeutically effective amount of the solution, wherein the
condition is amenable to treatment with the preparation.
36. A method of treating according to claim 35, wherein the
condition is malignant hyperthermia.
37. A method of treating according to claim 36 further comprising
administering the dissolved preparation of claim 34 in combination
with one or more additional active agents wherein the additional
agent is given prior, concurrently, or subsequent to the
administration of the preparation of claim 34.
38. A method of treating according to claim 37 wherein the
additional agent is.
39. A pharmaceutical dosage form according to claim 8, wherein the
vial or other pharmaceutically acceptable container contains
dantrolene sodium at a concentration of about 10 to about 500
mg/container.
40. A dantrolene sodium pre-lyophilization solution or dispersion
comprising dantrolene sodium, between about 1% to about 99.9% (v/v)
alcohol, excipient and water
41. A pre-lyophilization solution or dispersion of dantrolene
sodium comprising dantrolene sodium, mannitol, tertiary-butyl
alcohol, and alkalinized sterile water and having a pH in the range
of about 9.5 to about 10.5.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application Ser. No. 60/978,626, which was filed on Oct. 9, 2007,
the entirety of which is incorporated herein by reference for all
purposes.
FIELD OF THE INVENTION
[0002] The present invention relates generally to a co-solvent
system for formulation and production of a pharmaceutical agent
with increased solubility. The present invention also provides for
methods of using tert-butyl alcohol (TBA) co-solvent systems in the
formulation and production of a pharmaceutical agent with low
solubility. The present invention also provides for pharmaceutical
compositions made using the novel co-solvent system. In one
embodiment, the invention provides for a method of making a
dantrolene formulation for intravenous use. The resulting product
has the ability of rapid reconstitution of the dantrolene product,
which constitutes a significant improvement in the pharmacotherapy
of patients undergoing malignant hyperthermia during surgery.
BACKGROUND OF THE INVENTION
[0003] Dantrolene sodium (1-[[5-(p-nitrophenyl)
furfurylidene]-amino]hydantoin sodium salt) is described in U.S.
Pat. No. 3,415,821, incorporated herein by reference in its
entirety. It can be used as a skeletal muscle relaxant particularly
in controlling the manifestations of clinical spasticity resulting
from upper neuron disorders (Physicians' Desk Reference, 36th
Edition, 1982). It is also used in the prevention and treatment of
malignant hyperthermia in humans (Friesen et al., Can. Anaesth.
Soc. J. 26:319-321, 1979).
[0004] In connection with the use of dantrolene sodium in
hyperthermic crisis it was observed that there was an elimination
of the arrhythmias accompanying such crisis [Salata et al., Effects
of Dantrolene Sodium on the Electrophysiological Properties of
Canine Cardiac Purkinje Fibers, J. Pharmacol. Exp. Ther.
220(1):157-166 (January) 1982], incorporated herein by reference in
its entirety. Dantrolene sodium is useful as a cardiac
antiarrhythmic agent in hypothermic and normothermic warm-blooded
animals as described in U.S. Pat. No. 4,543,359, incorporated
herein by reference in its entirety.
[0005] It is also known that dantrolene sodium prevents or reduces
arrhythmia in hypothermic and normothermic warm-blooded animals. In
particular, dantrolene sodium is effective in the treatment of
supraventricular tachycardias, in suppressing slow responses in
infracted tissues and in abolishing ventricular premature beats or
tachycardias originating in these tissues, and in correcting
ventricular rhythm disturbances due to reentry.
[0006] Malignant hyperthermia had a mortality rate of nearly 80
percent at the time it was identified in 1960. Treatment consisted
only of cooling the patient and treating the specific symptoms, but
not the underlying cause. Since 1979, the antidote drug dantrolene
sodium has been available for the treatment of malignant
hyperthermia and has contributed greatly to a dramatic decline in
mortality. The syndrome must be identified and treated early for a
successful outcome.
[0007] Dantrolene sodium for injection comes as a dry powder that
must be dissolved in sterile water prior to injection. Generally,
it is supplied in small glass containers containing enough powder
to give about 16 to about 20 mg of the active drug.
[0008] Although most cases of malignant hyperthermia respond to
2.5-4.0 mg/kg of dantrolene initially, some patients need
significantly more to bring the episode under control. In addition,
recrudescence is a possibility within the first few days of
treatment. Finally, because of the need for continued treatment for
at least 48 hours after malignant hyperthermia at a dose of about 1
mg/kg every 4 hours, the Malignant Hyperthermia Association of the
United States (MHAUS) recommends that 36 vials be stocked.
[0009] The active pharmaceutical ingredient (API) (DS) undergoes
slow hydrolytic decomposition in aqueous media. This degradation is
accelerated at higher (alkaline) pH values and is enhanced by
elevated temperatures. Thus, these conditions should be avoided as
much as possible during the production of the final product
(DS-IV).
[0010] The insolubility of DS in water necessitates its dissolution
at a considerably higher pH than its pKa value. The higher pH of
its formulation requirement results in: a) the alkaline hydrolysis
(loss of potency) of DS, and b) susceptibility of its solution to
carbon dioxide during its introduction into vials (filling of
vials). The atmospheric carbon dioxide (CO.sub.2) appears to
interact with the alkaline (e.g., NaOH) content of the filled vials
resulting in the reduction of the pH of their solution resulting in
a possible undesirable effect in the DS formulation. Thus, the
above two phenomena require that the dissolution of the DS (API) at
the time of its formulation process and the subsequent introduction
of its solution to vials be expedited prior to the commencement of
its freeze-drying.
[0011] There is a significant need in the art for a satisfactory
formulation of dantrolene sodium with greater solubility in a
formulation that remains stable enough for practical use.
[0012] The present invention teaches the use of a novel organic
solvent/water co-solvent system that reduces (a) freezing time of
the DS-W formulation, (b) its freeze-drying time and (c) the
reconstitution time of the DS freeze-dried product. A faster
reconstitution of the DS-IV product provides a great
pharmacotherapeutic advantage in the treatment of patients
exhibiting the life-threatening condition of malignant hyperthermia
(MH) while undergoing surgery. On average, these patients generally
require a rapid intravenous (IV) infusion of nine to ten (9-10)
vials of DS-IV product, generally comprising from about 2.5 to
about 10 mg/kg patient weight, and each reconstituted with about 60
mL of sterile water for injection (WFI) (See, for example, Merck
Manual, 18.sup.th Edition, 2006). In many cases, the number of
DS-IV vials used ranges from about 10 to about 20 but can be even
more. Cases of MH requiring as many as 36 vials of DS-IV have been
recorded. The length of time to reconstitute the necessary 10-36
vials (at approximately 1 to 3 min each) creates a significant
issue when considering MH death can occur in as short time as 30
min from onset.
[0013] Organic co-solvent systems encompass a wide variety of
organic solvents (examples: tert butyl alcohol, ethanol,
n-propanol, n-butanol, iso-propanol, ethyl acetate, acetone, methyl
acetate, methanol, carbon tetrachloride, dimethylsulfoxide,
chlorobutanol, cyclohexane, and acetic acid).
[0014] The formulation of Caverject.TM. (Alprostadil) (Pfizer) is
an example of sterile marketed injectable product that has been
freeze-dried from a TBA-water solution. Table 1 lists several
examples of freeze-dried preparations using co-solvent systems.
TABLE-US-00001 TABLE 1 Examples of compounds freeze-dried with
co-solvent system. Drug Co-solvent System Reference Alprostadil 20%
v/v tert- Teagarden (CAVERJECT .RTM. S.Po.) butanol/water et al.,
1998a Aplidine 40% v/v tert- Nuijen et butanol/water al., 2000
Amoxicillin sodium 20% v/v tert- Tico Grau butanol/water et al.,
1988 Gentamicin sulfate tert-Butanol/water Baldi et al., 1994
N-Cyclohexyl-N-methyl-4- 50% v/v tert- Benjamin (2-oxo-1,2,3,5-
butanol/water and Visor, tetrahydroimidazo-[2.1-b] 1989
quinazolin-7-yl) oxybutyratnide with ascorbic acid Cyclohexane
1.2-diamine tert-Butanol Tanno et Pi(II) al., 1990 complex
Fructose-1,6-diphosphate tert-Butanol/water Sullivan and Marangos,
1998 Annamycin tert-Butanol/dimethyl Zou et al., sulfixide/water
1999 Cephalothin sodium 5% w/w isopropyl Koyama alcohol/water et
al., 1988 Cephalothin sodium 4% ethanol, 4% Cise and methanol or 4%
Roy, acetone/water 1981 Prednisolone Carbon tetrachloride/ DeLuca
et acetate/polyglycolic acid hexafluoroacetone al., 1989a
sesquihydrate Gabexate mesylate Ethanol/water Kamijo et al., 1987
Piraubidin hydrochloride Ethanol/water Kaneko et al., 1993
Progesterone, coronene, Chlorobutanol Tesconi et fluasterone,
phenytoin hemihydrate/Dimethyl al., 1999 sulfone Poly
(lactide-co-glycolide) Acetic acid Meredith et al., 1996
Dioleoylphosphatidylcholine Cyclohexane Felgner and
dioleoylphophatidyl and glycerol Eppstein, 1991 Vecuroniumbromide
Acetonitrile Jansen, 1997 Bovine pancreatic trypsin Dimethyl Desai
and inhibitor sulfoxide/1% water Klibanov, 1995
BRIEF SUMMARY OF THE INVENTION
[0015] The present invention relates generally to a co-solvent
system for formulation and production of a pharmaceutical agent
with increased solubility. This invention also relates generally to
a method of freeze-drying a pharmaceutical formulation using a
co-solvent system.
[0016] The present invention also provides for methods of using
tert-butyl alcohol (TBA) co-solvent systems in the formulation and
production of a pharmaceutical agent with low solubility. The
present invention also provides for pharmaceutical compositions
made using the novel co-solvent system.
[0017] In one embodiment, the invention provides for a method of
making dantrolene sodium (DS) formulations for intravenous use
(DS-IV). This substantially instantaneous reconstitution of the
DS-IV product constitutes a significant improvement in the
pharmacotherapy of patients undergoing malignant hyperthermia
during surgery. In one embodiment, this substantially complete
dissolution is accomplished in less than about 30 seconds. In one
embodiment, this substantially complete dissolution is accomplished
in about 10 to about 20 seconds.
[0018] In one embodiment, the present invention provides for the
production of the DS-IV product involving three (3) major steps.
These are as follows: [0019] 1. Formulation of the active
pharmaceutical ingredient (API) dantrolene sodium at an alkaline
pH. [0020] 2. Addition of a co-solvent to make the DS solution; and
filling the vials containing the solution ("fill" solution) to be
lyophilized. [0021] 3. A lyophilization cycle of the DS solution to
produce the freeze-dried sterile DS-IV product.
[0022] The present invention is also directed to stable
pharmaceutical compositions of dantrolene sodium, in particular
lyophilized dantrolene sodium and its use in treatment of various
disease states, especially neural diseases and malignant
hyperthermia and other conditions involving high fever.
[0023] An embodiment of the invention is a pharmaceutical
composition of dantrolene sodium comprising trace amounts of
organic solvent after reconstitution of a lyophilized
pharmaceutical composition of dantrolene sodium as described
herein.
[0024] Another embodiment of the invention is a lyophilized
preparation of dantrolene sodium comprising about 0.001% to about
0.3% dantrolene sodium after reconstitution. Another embodiment of
the invention is a lyophilized preparation of dantrolene sodium
comprising about 0.01% to about 0.1% dantrolene sodium after
reconstitution. Yet another embodiment of the invention is a
lyophilized preparation of dantrolene sodium comprising about
0.015% to about 0.05% dantrolene sodium after reconstitution.
[0025] In preferred aspects of the invention, the dosage form can
be about 5 to about 50 mg of dantrolene sodium, about 10 to about
30 mg of dantrolene sodium, about 10 mg to about 20 mg of
dantrolene sodium, and about 20 mg of dantrolene sodium.
[0026] Yet another embodiment of the invention is a pharmaceutical
dosage form that includes a lyophilized preparation of dantrolene
sodium containing not more than about 0.05% to about 1%, preferably
0.6% to about 0.7%, DS-UV (w/w). In certain embodiments, dosage
forms can be about 5 to about 720 mg of dantrolene sodium, about 10
to about 300 mg of dantrolene sodium, about 10 to about 100 mg of
dantrolene sodium, and about 12 mg to about 22 mg of dantrolene
sodium.
[0027] In still another embodiment, the invention includes a
pharmaceutical composition of dantrolene sodium including
dantrolene sodium containing not more than about 5% of one or more
organic solvents after reconstitution of a lyophilized
pharmaceutical composition of dantrolene sodium as disclosed
herein.
[0028] In different aspects of this embodiment, the organic solvent
is selected from one or more of tertiary butanol, n-propanol,
n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate,
dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl
ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon
tetrachloride, dimethyl sulfoxide, hexafluoroacetone,
chlorobutanol, dimethyl sulfone, acetic acid, and cyclohexane.
[0029] In one specific embodiment, the organic solvents include one
or more of ethyl, methyl, propyl, butyl alcohol. In another
embodiment, the organic solvent is tertiary butanol, also known as
TBA, t-butanol, tert-butyl alcohol or tertiary butyl alcohol, alone
or in combination with one or more additional solvents. In another
embodiment, the organic solvent comprises at least 20, 30, 40, 50,
60, 70, 80, 90, 95, 98 99 or more percent (v/v) alcohol in
combination with one or more additional solvents. In another
embodiment, the organic solvent comprises at least 20, 30, 40, 50,
60, 70, 80, 90, 95, 98 99 or more percent (v/v) butanol in
combination with one or more additional solvents. In another
embodiment, the organic solvent comprises at least 30 percent (v/v)
tertiary butanol in combination with one or more additional
alcohols.
[0030] Another embodiment of the invention is a process for
manufacturing a lyophilized preparation of dantrolene sodium which
includes controlling the particle size of dantrolene sodium in the
final product.
[0031] Another embodiment of the invention is a dantrolene sodium
pre-lyophilization solution or dispersion comprising one or more
organic solvents where the solution or dispersions include at least
one stabilizing concentration of an organic solvent such that the
dantrolene sodium product produced during lyophilization is capable
of rapid reconstitution. In one embodiment, the dantrolene sodium
product is cable of substantial reconstitution in a carrier in less
than about 10, 8, 5, 4, 3, 2, or 1 minute(s). In another
embodiment, the dantrolene sodium product is cable of substantial
reconstitution in a carrier in less than about 30 seconds. In
another embodiment, the dantrolene sodium product is cable of
substantial reconstitution in a carrier in less than about 20
seconds. In another embodiment, the dantrolene sodium product is
cable of substantial reconstitution in a carrier in about 10-20
seconds.
[0032] An aspect of this embodiment is the lyophilized powder
produced from the pre-lyophilization solution or dispersion.
[0033] The invention also discloses methods for preparing a
dantrolene sodium lyophilized preparation that includes dissolving
dantrolene sodium in a stabilizing concentration of an alcohol
solvent of between about 1% to about 99.9% (v/v alcohol to form a
pre-lyophilization solution; and lyophilizing the
pre-lyophilization solution; wherein the dantrolene sodium
lyophilized preparation made from such methods comprises an
excipient.
[0034] Other alcohol concentrations include about 1% to about 99%,
about 1% to about 70%, about 2% to about 60%, about 3% to about
50%, about 2% to about 40%, about 2% to about 35%. Preferred
concentrations of alcohol are from about 2% to about 30%.
[0035] In one embodiment, the alcohols include one or more of
methanol, ethanol, propanol, iso-propanol, butanol, and
tertiary-butanol. In another embodiment, the alcohol is
tertiary-butanol (tertiary butyl alcohol or TBA). In another
embodiment, the concentration of tertiary-butanol is about 0.5% to
about 30%. In another embodiment, the concentration of
tertiary-butanol is about 1% to about 20%. In another embodiment,
the concentration of tertiary-butanol is about 2% to about 10%. An
aspect of this embodiment is the addition of excipients before
lyophilization. In one embodiment, excipients are mannitol, sodium
hydroxide (NaOH) or mixtures thereof.
[0036] In one embodiment, the pre-lyophilized concentrations of
dantrolene sodium are from about 0.1 mg/mL to about 50 mg/mL. In
another embodiment, the pre-lyophilized concentrations of
dantrolene sodium are from about 0.2 mg/mL to about 10 mg/mL. In
another embodiment, the pre-lyophilized concentrations of
dantrolene sodium are from about 0.2 mg/mL to about 5 mg/mL. In yet
another embodiment, the pre-lyophilized concentrations of
dantrolene sodium are from about 0.2 mg/mL to about 1 mg/mL.
[0037] In one embodiment of the invention, there is provided a
method for preparing a dantrolene sodium lyophilized preparation
comprising a) dissolving dantrolene sodium in a solution of water
and organic co-solvent solution comprising between about 1% to
about 99% (v/v) organic co-solvent to form a pre-lyophilization
solution; and b) lyophilizing the pre-lyophilization solution.
[0038] In another embodiment, lyophilizing the pre-lyophilization
solution comprises [0039] i) cooling the pre-lyophilization
solution to a temperature capable of forming a frozen solution;
[0040] ii) holding the frozen solution a temperature capable of
forming a frozen solution, for a time sufficient to substantially
freeze the solutions; [0041] iii) ramping the frozen solution to a
primary drying temperature; [0042] iv) holding at a primary drying
temperature at a temperature and for a time sufficient to form a
substantially dried lyophilized product; [0043] v) optionally
ramping the dried solution to a secondary drying temperature; and
[0044] vi) optionally holding at the secondary drying temperature
at a temperature and for a time sufficient to form a substantially
dried dantrolene sodium lyophilized preparation.
[0045] In another embodiment of the invention, there is provided a
stable and lyophilized formulation of dantrolene sodium made by the
process comprising a) dissolving dantrolene sodium in a solution of
water and organic co-solvent solution comprising between about 1%
to about 99% (v/v) organic co-solvent to form a pre-lyophilization
solution; and b) lyophilizing the pre-lyophilization solution.
[0046] In another embodiment, lyophilizing the pre-lyophilization
solution comprises: i) freezing the pre-lyophilization solution to
a temperature below about -20.degree. C. for a time sufficient to
substantially freeze the solution; ii) drying the frozen solution
at a drying temperature between about -60.degree. C. and about
30.degree. C. to form a dantrolene sodium lyophilized
preparation.
[0047] In another embodiment, lyophilizing the pre-lyophilization
solution comprises: i) freezing the pre-lyophilization solution to
a temperature below about -40.degree. C. for a time sufficient to
substantially freeze the solution; ii) drying the frozen solution
at a drying temperature between about -50.degree. C. and about
30.degree. C. for about 1 to about 100 hours to form a dantrolene
sodium lyophilized preparation.
[0048] In another embodiment, lyophilizing the pre-lyophilization
solution comprises: i) freezing the pre-lyophilization solution to
a temperature below about -40.degree. C. to form a frozen solution;
ii) holding the frozen solution at or below -40.degree. C. for at
least 2 hours; iii) ramping the frozen solution to a primary drying
temperature between about -40.degree. C. and about 30.degree. C. to
form a dried solution; iv) holding for about 10 to about 70 hours;
v) ramping the dried solution to a secondary drying temperature
between about 20.degree. C. and about 40.degree. C.; and vii)
holding for about 5 to about 40 hours to form a dantrolene sodium
lyophilized preparation.
[0049] In another embodiment, the lyophilization cycle includes
starting with the pre-lyophilization solution at a shelf
temperature for loading of about 0.degree. C. to about 30.degree.
C., about 5.degree. C. to about 25.degree. C., about 5.degree. C.
to about 15.degree. C.
[0050] In another embodiment, the lyophilization cycle includes
ending with unloading at about 0.degree. C. to about 30.degree. C.,
about 5.degree. C. to about 25.degree. C., about 5.degree. C. to
about 15.degree. C., in a pharmaceutically acceptable container
that is hermetically sealed.
[0051] In another embodiment, the lyophilization cycle includes
wherein the pressure is about 50 to about 200 microns, about 50 to
about 150 microns, about 100 to about 150 microns throughout
primary drying and about 50 to about 200 microns, about 50 to about
150 microns, about 100 to about 150 microns throughout secondary
drying.
[0052] Another embodiment of the invention is the lyophilized
powder or preparation obtained from the methods of preparing a
dantrolene sodium lyophilized preparation disclosed herein.
[0053] The invention also involves dantrolene sodium formulations
for lyophilization that include an excipient and a stabilizing
concentration of an organic solvent. In one embodiment, the organic
solvent further comprises an alkali. In one embodiment, the
pre-lyophilization solution comprises about 1 to about 1000 mg/mL
excipient. In another embodiment, the pre-lyophilization solution
comprises about 1 to about 500 mg/mL excipient. In another
embodiment, the pre-lyophilization solution comprises about 10 to
about 100 mg/mL excipient. One formulation includes dantrolene
sodium at a concentration of about 0.01 to about 15 mg/mL, mannitol
at a concentration of about 1 to about 200 mg/mL, tertiary-butyl
alcohol at a concentration of about 1% to about 50% (v/v) and
water. Another formulation includes dantrolene sodium at a
concentration of about 0.05 to about 5 mg/mL, mannitol at a
concentration of about 8.0 mg/mL to about 100 mg/mL, tertiary-butyl
alcohol at a concentration of about 1% to about 30% (v/v) and
water. Included in this embodiment of the invention are the
lyophilized preparations made from such dantrolene sodium
formulations.
[0054] Included in the inventions are methods of treating a medical
condition in a patient that involve administering a therapeutically
effective amount of a pharmaceutical composition of the invention
where the condition is amenable to treatment with the
pharmaceutical composition.
[0055] Included in the inventions are the use of the pharmaceutical
compositions or pharmaceutical preparations of the invention in the
manufacture of a medicament for the treatment of a medical
condition, as defined herein, in a patient that involve
administering a therapeutically effective amount of a
pharmaceutical composition of the invention where the condition is
amenable to treatment with the pharmaceutical composition.
[0056] Also included in the invention are methods of treating in
which the pharmaceutical compositions of the invention are in
combination with one or more additional therapeutic agents where
the additional agent is given prior, concurrently, or subsequent to
the administration of the pharmaceutical composition of the
invention.
[0057] The invention also encompasses a pharmaceutical dosage form
of dantrolene wherein the dosage form comprises a vial or other
pharmaceutically acceptable container. Preferred concentrations of
dantrolene sodium include about 1 to about 500 mg/container, about
5-50 mg/container, about 5 mg to about 20 mg/container and about 10
mg to about 20 mg/container.
[0058] The present invention also includes pre-lyophilized
pharmaceutical compositions of dantrolene sodium. In one embodiment
the pre-lyophilized composition includes dantrolene sodium,
mannitol, tertiary-butyl alcohol, sodium hydroxide and water.
[0059] In one embodiment, the active pharmaceutical compounds that
can be used in the present invention include dantrolene,
aminodantrolene, azumolene, and salts and mixtures thereof. In one
embodiment, the active pharmaceutical are dantrolene sodium,
31/2H.sub.2O, azumolene sodium, 2H.sub.2O and aminodantrolene
sodium.
[0060] These methods may employ the compounds of this invention in
a monotherapy or in combination one or more additional therapeutic
agents. Such combination therapies include administration of the
agents in a single dosage form or in multiple dosage forms
administered at the same time or at different times.
[0061] In another embodiment, the active pharmaceutical compound
further comprises at least one additional agent selected from
general anesthetics; hypnotic/sedatives/antianxiety drugs;
antiepileptics; antipyretic/analgesic/anti-inflammatory agents;
analeptic/antihypnotic agents; antiparkinsonian drugs;
psychotropic/neurotropic drugs; cns drugs; local anesthetics;
skeletal muscle relaxant; autonomic drugs; antispasodics;
antivertigo drugs; sense organ drugs; cardiotonics; antiarrhythmic
drugs; diuretics; antihypertensive drugs; vasoconstrictors;
vasodilators; cardiovascular drugs; respiratory stimulants;
antitussives; expectorant's; brochodilators; antidiarrheal
drugs/drugs for controlling intestinal function; peptic ulcer
remedies; stomachics/digestants; laxatives/clysters; cholagogues;
gastrointestinal drugs; thyroid/parathyroid hormone drugs; anabolic
steroid drugs; corticoid drugs; male hormone drugs;
estrogen/progestin drugs; hormone drugs; urinary tract drugs;
oxytocics; vitamins; hemostatics; anticoagulants; liver disease
remedies; antidotes; arthrifuges; antidiabetics; metabolism drugs;
antitumor drugs; antiallergic agents; antibiotics; sulfa drugs;
antituberculosis drugs; antileprotics; synthetic antimicrobial
agents; antiviral agents; chemotherapeutic drugs; anthelmintics;
and narcotics.
[0062] In another embodiment, the active pharmaceutical compound is
a hypertonic solution that further contains at least one additional
agent selected from adenine nucleosides, nucleotides, amino acids,
mannitol, vitamin C, glutathione, vitamin E, magnesium, dantrolene,
corticosteroids, promazine, nicholin, 21-amino steroids,
non-steroidal anti-inflammatory agents, calcium antagonists, and
K-ATP channel openers.
[0063] These and other embodiments of the invention are described
herein below or are evident to persons of ordinary skill in the art
based on the following disclosures.
[0064] The above summary of the present invention is not intended
to describe each embodiment or every implementation of the present
invention. Advantages and attainments, together with a more
complete understanding of the invention, will become apparent and
appreciated by referring to the following detailed description and
claims taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] This invention, as defined in the claims, can be better
understood with reference to the following drawings:
[0066] FIG. 1 shows a schematic diagram of the formulation
procedure for cooling and addition of co-solvent. The diagram is a
pictorial representation of the formulation procedure for the
preparation of the rapidly reconstituted freeze-dried DS-IV product
using a TBA-aqueous co-solvent system. Mixing and Cooling is
accomplished as follows: To an aqueous (WFI) solution of mannitol
containing enough of NaOH to bring the pH to 10.1-10.3 at
50.degree. C., DS (API) is added. Mixing at 50.degree. C. continues
for 20 minutes. This is followed by a period of cooling down to
25.degree. C. when TBA is added.
[0067] In the following description of the illustrated embodiments,
references are made to the accompanying drawings, which form a part
hereof, and in which is shown by way of illustration various
embodiments in which the invention may be practiced. It is to be
understood that other embodiments may be utilized and structural
and functional changes may be made without departing from the scope
of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0068] Before the present methods and compositions are described,
it is to be understood that this invention is not limited to the
specific methodology, devices, formulations, and compositions
described as such may, of course, vary. It is also to be understood
that the terminology used herein is for the purpose of describing
particular embodiments only, and is not intended to limit the scope
of the present invention, which will be limited only by the
appended claims.
[0069] It must be noted that as used herein and in the appended
claims, the singular forms "a", "and", and "the" include plural
referents unless the context clearly dictates otherwise.
[0070] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods, devices, and materials are now
described. All references, publications, patents, patent
applications, and commercial materials mentioned herein are
incorporated herein by reference for all purposes including for
describing and disclosing the cell lines, vectors, and
methodologies which are reported in the publications which might be
used in connection with the invention. Nothing herein is to be
construed as an admission that the invention is not entitled to
antedate such disclosure by virtue of prior invention.
[0071] In order to provide a clear and consistent understanding of
the specification and claims, including the scope to be given such
terms, the following definitions are provided:
[0072] The specification contains the following abbreviations:
Active Pharmaceutical Ingredient (APT), Dantrolene Sodium (DS),
Dantrolene Sodium Intravenous (DS-IV), Generally Regarded as Safe
(GRAS), Potassium Hydroxide (KOH), Malignant Hyperthermia (MH),
Sodium Hydroxide (NaOH), Tertiary Butyl Alcohol, t-butanol,
tertiary butanol, or tert-butyl alcohol (TBA), and United States
Pharmacopeia (USP).
[0073] The term "administration" of the pharmaceutically active
compounds and the pharmaceutical compositions defined herein
includes systemic use, as by injection (especially parenterally),
intravenous infusion, suppositories and oral administration
thereof, as well as topical application of the compounds and
compositions. Intravenous administration is particularly preferred
in the present invention.
[0074] "Ameliorate" or "amelioration" means a lessening of the
detrimental effect or severity of the disease in the subject
receiving therapy, the severity of the response being determined by
means that are well known in the art.
[0075] By "compatible" herein is meant that the components of the
compositions which comprise the present invention are capable of
being commingled without interacting in a manner which would
substantially decrease the efficacy of the pharmaceutically active
compound under ordinary use conditions.
[0076] The terms "effective amount" or "pharmaceutically effective
amount" refer to a nontoxic but sufficient amount of the agent to
provide the desired biological result. That result can be reduction
and/or alleviation of the signs, symptoms, or causes of a disease,
such as neural diseases and malignant hyperthermia, or any other
desired alteration of a biological system. Such amounts are
described below. An appropriate "effective" amount in any
individual case may be determined by one of ordinary skill in the
art using routine experimentation.
[0077] As used herein, the term "excipient" means the substances
used to formulate active pharmaceutical ingredients (API) into
pharmaceutical formulations; in a preferred embodiment, an
excipient does not lower or interfere with the primary therapeutic
effect of the API. Preferably, an excipient is therapeutically
inert. The term "excipient" encompasses carriers, diluents,
vehicles, solubilizers, stabilizers, bulking agents, acidic or
basic pH-adjusting agents and binders. Excipients can also be those
substances present in a pharmaceutical formulation as an indirect
or unintended result of the manufacturing process. Preferably,
excipients are approved for or considered to be safe for human and
animal administration, i.e., GRAS substances (generally regarded as
safe). GRAS substances are listed by the Food and Drug
administration in the Code of Federal Regulations (CFR) at 21 CFR
182 and 21 CFR 184, incorporated herein by reference. In one
embodiment, the excipients include, but are not limited to,
hexitols, including mannitol and the like as well as sodium or
potassium hydroxides (NaOH or KOH) and mixtures thereof.
[0078] As used herein, the terms "formulate" refers to the
preparation of a drug, e.g., dantrolene, in a form suitable for
administration to a mammalian patient, preferably a human. Thus,
"formulation" can include the addition of pharmaceutically
acceptable excipients, diluents, or carriers and pH adjusting
agents.
[0079] As used herein, the term "lyophilized powder" or
"lyophilized preparation" refers to any solid material obtained by
lyophilization, i.e., freeze-drying of an aqueous solution. The
aqueous solution may contain a non-aqueous solvent, i.e. a solution
composed of aqueous and one or more non-aqueous solvent(s). In one
embodiment, a lyophilized preparation is one in which the solid
material is obtained by freeze-drying a solution composed of
aqueous and one or more non-aqueous solvents. In one embodiment,
the non-aqueous solvent is an alcohol. In one specific embodiment,
the non-aqueous solvent comprises at least butanol. In one specific
embodiment, the non-aqueous solvent comprises at least tert-butyl
alcohol.
[0080] The term "organic solvent" means an organic material,
usually a liquid, capable of dissolving other substances. As used
herein, "trace amount of an organic solvent" means an amount of
solvent that is equal to or below recommended levels for
pharmaceutical products, for example, as recommended by ICH
guidelines (International Conferences on Harmonization,
Impurities--Guidelines for Residual Solvents. Q3C. Federal
Register. 1997; 62(247):67377). The lower limit is the lowest
amount that can be detected.
[0081] By "pharmaceutically acceptable" or "pharmacologically
acceptable" is meant a material which is not biologically or
otherwise undesirable, i.e., the material may be administered to an
individual without causing any undesirable biological effects or
interacting in a deleterious manner with any of the components of
the composition in which it is contained.
[0082] As used herein, a "pharmaceutically acceptable carrier" is a
material that is nontoxic and generally inert and does not affect
the functionality of the active ingredients adversely. Examples of
pharmaceutically acceptable carriers are well known and they are
sometimes referred to as dilutents, vehicles or excipients. The
carriers may be organic or inorganic in nature. Examples of
pharmaceutically acceptable carriers that may be present in the
present lyophilized formulations may be gelatin, lactose, starch,
cocoa butter, dextrose, sucrose, sorbitol, mannitol, gum acacia,
alginates, cellulose, talc, magnesium stearate, polyoxyethylene
sorbitan monolaurate, polyvinylpyro-lidone (PVP) and other commonly
used pharmaceutical carriers. In one embodiment, the pharmaceutical
carrier comprises mannitol. In addition, the formulation may
contain minor amounts of pH adjusting agents such as sodium
hydroxide (NaOH) additives such as flavoring agents, coloring
agents, thickening or gelling agents, emulsifiers, wetting agents,
buffers, stabilizers, and preservatives such as antioxidants.
[0083] By "physiological pH" or a "pH in the physiological range"
is meant a pH in the range of approximately 7.2 to 8.0 inclusive,
more typically in the range of approximately 7.2 to 7.6
inclusive.
[0084] The term "pharmaceutical composition" as used herein shall
mean a composition that is made under conditions such that it is
suitable for administration to humans, e.g., it is made under GMP
conditions and contains pharmaceutically acceptable excipients,
e.g., without limitation, stabilizers, pH adjusting agents such as
NaOH, bulking agents, buffers, carriers, diluents, vehicles,
solubilizers, and binders. As used herein pharmaceutical
composition includes but is not limited to a pre-lyophilization
solution or dispersion as well as a liquid form ready for injection
or infusion after reconstitution of a lyophilized preparation.
[0085] A "pharmaceutical dosage form" as used herein means the
pharmaceutical compositions disclosed herein being in a container
and in an amount suitable for reconstitution and administration of
one or more doses, typically about 1-2, 1-3, 1-4, 1-5, 1-6, 1-10,
or about 1-20 doses. Preferably, a "pharmaceutical dosage form" as
used herein means a lyophilized pharmaceutical composition
disclosed herein in a container and in an amount suitable for
reconstitution and delivery of one or more doses, typically about
1-2, 1-3, 1-4, 1-5, 1-10, 1-20, or about 1-30 doses. The
pharmaceutical dosage form can comprise a vial or syringe or other
suitable pharmaceutically acceptable container. The pharmaceutical
dosage form suitable for injection or infusion use can include
sterile aqueous solutions or dispersions or sterile powders
comprising an active ingredient which are adapted for the
extemporaneous preparation of sterile injectable or infusible
solutions or dispersions. In all cases, the ultimate dosage form
should be sterile, free of endotoxins and particulates, within the
USP requirements, fluid and stable under the conditions of
manufacture and storage. The liquid carrier or vehicle can be a
solvent or liquid dispersion medium comprising, for example, water,
ethanol, a polyol such as glycerol, propylene glycol, or liquid
polyethylene glycols and the like, vegetable oils, nontoxic
glyceryl esters, and suitable mixtures thereof. The prevention of
the growth of microorganisms can be accomplished by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
[0086] By "stable pharmaceutical composition" is meant any
pharmaceutical composition having sufficient stability to have
utility as a pharmaceutical product. The shelf-life or expiration
can be that amount of time where the active ingredient degrades to
a point below 90% purity. For purposes of the present invention
stable pharmaceutical composition includes reference to
pharmaceutical compositions with specific ranges of impurities as
described herein.
[0087] As used herein, the term "subject" encompasses mammals and
non-mammals. Examples of mammals include, but are not limited to,
any member of the Mammalia class: humans, non-human primates such
as chimpanzees, and other apes and monkey species; farm animals
such as cattle, horses, sheep, goats, swine; domestic animals such
as rabbits, dogs, and cats; laboratory animals including rodents,
such as rats, mice and guinea pigs, and the like. Examples of
non-mammals include, but are not limited to, birds, fish and the
like. The term does not denote a particular age or sex.
[0088] As used herein, the terms "treating" or "treatment" of a
disease include preventing the disease, i.e. preventing clinical
symptoms of the disease in a subject that may be exposed to, or
predisposed to, the disease, but does not yet experience or display
symptoms of the disease; inhibiting the disease, i.e., arresting
the development of the disease or its clinical symptoms, such as by
suppressing hyperthermia; or relieving the disease, i.e., causing
regression of the disease or its clinical symptoms.
[0089] As used herein, the term "vial" refers to any walled
container, whether rigid or flexible.
General
[0090] The invention provides for stable, pharmaceutically
acceptable compositions prepared from an active pharmaceutical
agent. In particular, the invention provides formulations for the
lyophilization of active pharmaceutical agents with low solubility
upon reconstitution with physiological buffer or saline. The
lyophilized powder obtained from the formulations made by the
present invention is more easily reconstituted.
[0091] The invention also provides for stable, pharmaceutically
acceptable compositions prepared from dantrolene. In particular,
the invention provides formulations for the lyophilization of
dantrolene sodium. The lyophilized powder obtained from such
formulations is more easily reconstituted than the presently
available lyophilized powder of dantrolene.
[0092] In one embodiment, the active pharmaceutical compounds that
can be used in the present invention include dantrolene,
aminodantrolene, azumolene, and salts and mixtures thereof. In one
embodiment, the active pharmaceutical compounds are dantrolene
sodium, 31/2H.sub.2O, azumolene sodium, 2H.sub.2O and
aminodantrolene sodium.
[0093] The present invention further provides formulations of
dantrolene useful for treating various disease states, especially
neural diseases and malignant hyperthermia. The formulations
described herein can be administered alone or in combination with
at least one additional therapeutic agent.
[0094] Another aspect of the invention is conditions and means for
enhancing the solubility of dantrolene sodium during the
lyophilization reconstitution process.
[0095] As described herein, a lyophilized formulation of dantrolene
sodium is achieved following removal of an organic solvent in
water. The most typical example of the solvent used to prepare this
formulation is alcohol. In one embodiment, the alcohol is butanol.
In another embodiment, the alcohol is tertiary butanol (TBA). Other
organic solvents can be used including ethanol, n-propanol,
n-butanol, isoproponal, ethyl acetate, dimethyl carbonate,
acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl
ketone, acetone, 1-pentanol, methyl acetate, methanol, carbon
tetrachloride, dimethyl sulfoxide, hexafluoroacetone,
chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane. These
preceding solvents may be used individually or in combination.
Useful solvents must form stable solutions with dantrolene sodium
and must not react chemically or appreciably degrade or deactivate
the API. The solubility of dantrolene sodium in the selected
solvent must be high enough to form commercially useful
concentrations of the drug in solvent. Additionally, the solvent
should be capable of being removed easily from an aqueous
dispersion or solution of the drug product, e.g., through
lyophilization or vacuum drying. In one embodiment, a solution
having a concentration of about 1-80 mg/mL is used; in another
embodiment, a solution of about 0.05 to 10 mg/mL is used, in
another embodiment, a solution of about 0.1 to about 3.5 mg/mL is
used.
[0096] A pharmaceutically acceptable lyophilization excipient can
be dissolved in the aqueous phase during the formulation process.
Examples of excipients useful for the present invention include,
without limitation, sodium or potassium phosphate, citric acid,
tartaric acid, gelatin, glycine, and carbohydrates such as lactose,
sucrose, maltose, glycerin, dextrose, dextran, trehalose and
hetastarch. Mannitol is a preferred excipient. Other excipients
that may be used if desired include antioxidants, such as, without
limitation, ascorbic acid, acetylcysteine, cysteine, sodium
hydrogen sulfite, butyl-hydroxyanisole, butyl-hydroxytoluene or
alpha-tocopherol acetate, or chelators and pH adjusting agents.
[0097] A typical formulation and lyophilization cycle useful in
accordance with the present invention is provided below.
Lyophilization can be carried out using standard equipment as used
for lyophilization or vacuum drying. The cycle may be varied
depending upon the equipment and facilities used for the
fill/finish.
[0098] In accordance with a typical embodiment of the present
invention, an aqueous pre-lyophilization solution or dispersion is
first formulated in a pharmaceutically acceptable compounding
vessel. The solution is aseptically filtered into a sterile
container, filled into an appropriate sized vial, partially
stoppered and loaded into the lyophilizer.
[0099] In one embodiment, using lyophilization techniques described
herein, the solution is lyophilized until moisture content in the
range of about 0.01 to about 8.0 percent is achieved. The resulting
lyophilization powder can be readily reconstituted with Sterile
Water for Injection, or other suitable carrier, to provide liquid
formulations of dantrolene sodium, suitable for internal
administration e.g., by parenteral injection. For intravenous
administration, the reconstituted liquid formulation, i.e., the
pharmaceutical composition, is preferably a solution.
[0100] In one embodiment, the method for lyophilizing the
pre-lyophilization solution comprises: [0101] i) cooling the
pre-lyophilization solution to a temperature below about
-30.degree. C., preferably below about -40.degree. C., to form a
frozen solution; [0102] ii) holding the frozen solution at or below
-30.degree. C., preferably at or below -40.degree. C., more
preferably at or below -50.degree. C., for at least 1 hour,
preferably for at least 2 hours; more preferably for 2-4 hours;
[0103] iii) ramping the frozen solution to a primary drying
temperature between about -45.degree. C. and about 20.degree. C. to
form a dried solution, wherein the ramping occurs over a period of
at least 1 hour, preferably for at least 2 hours; more preferably
for 2-3 hours; [0104] iv) holding at a temperature of about
20.degree. C. for about 10 to about 70 hours; preferably 20 to
about 50 hours; more preferably about 30 to about 40 hours; most
preferably from about 30 hours to about 35 hours; [0105] v) ramping
the dried solution to a secondary drying temperature between about
25.degree. C. and about 50.degree. C., preferably at least
30.degree. C., more preferably at least 35.degree. C., most
preferably at least 40.degree. C., wherein the ramping occurs over
a period of at least 30 minutes, preferably for at least 1 hour;
more preferably for 1-2 hours; and [0106] vi) holding at the
secondary drying temperature for about 1 to about 30 hours;
preferably 2 to about 20 hours; more preferably about 3 to about 10
hours; most preferably from about 5 hours to about 7 hours; to form
a dantrolene sodium lyophilized preparation.
[0107] In another embodiment, the method for lyophilizing the
pre-lyophilization solution further comprises the steps: [0108]
vii) ramping the dried solution to a temperature between about
25.degree. C. and about 40.degree. C., preferably less than
35.degree. C., more preferably less than 30.degree. C., wherein the
ramping occurs over a period of at least 30 minutes, preferably for
at least 1 hour; more preferably for 1-2 hours; and [0109] viii)
holding at the new temperature for at least 1 hour, preferably for
at least 2 hours; more preferably for 2-4 hours; to form a
dantrolene sodium lyophilized preparation.
[0110] In one embodiment of the invention, the pressure is about 70
to about 130 microns throughout primary drying cycle, preferably
the pressure is about 80 to about 120 microns throughout primary
drying and more preferably from about 90 to about 110 microns
throughout primary drying. In another embodiment of the invention,
the pressure is about 90 to about 150 microns throughout secondary
drying cycle, preferably the pressure is about 100 to about 140
microns throughout secondary drying and more preferably from about
110 to about 130 microns throughout secondary drying.
[0111] In another embodiment, the method for lyophilizing the
pre-lyophilization solution comprises: [0112] i) starting with a
shelf temperature of about 25.degree. C. for loading; [0113] ii)
freezing to about -40 to -50.degree. C. over about 2-4 hours;
[0114] iii) holding at -45.degree. C. for about 2-3 hours; [0115]
iv) ramping to about 20.degree. C. over about 2-3 hours; [0116] v)
holding at about 20.degree. C. for 30-35 hours; [0117] vi) ramping
to about 40.degree. C. over about 1-2 hour; [0118] vii) holding at
about 40.degree. C. for about 5-7 hours; [0119] vii) ramping to
about 30.degree. C. over about 1-2 hours; and [0120] ix) holding at
about 30.degree. C. for about 2-4 hrs; [0121] to form a dantrolene
sodium lyophilized preparation.
[0122] In one embodiment, the pre-lyophilization solution has a
starting temperature above about 5.degree. C., preferably above
15.degree. C., to facilitate loading.
[0123] In another embodiment, the pre-lyophilization solution is
frozen at a temperature of about -40.degree. C. to about
-50.degree. C., to form a frozen solution.
[0124] In another embodiment, the pre-lyophilization solution or
dispersion normally is first formulated in a pharmaceutically
acceptable container by:
[0125] 1) adding an excipient, such as mannitol (about 0 to about
500 mg/mL) with mixing to water at ambient temperature, 2) adding
an organic solvent (0.5-99.9% v/v), such as TBA to the aqueous
solution with mixing at about 20-35.degree. C., 4) adding
dantrolene sodium to the desired concentration with mixing, 5)
adding water to achieve the final volume, and 6) cooling the
solution to a temperature of from about 10.degree. C. to about
30.degree. C., preferably about 25.degree. C. In one embodiment,
the excipient may be added during a later step such as after adding
the organic solvent. Although the preceding steps are shown in a
certain order, it is understood that one skilled in the art can
change the order of the steps and quantities as needed. Quantities
can be prepared on a weight basis also.
[0126] In another embodiment, the pre-lyophilization solution or
dispersion normally is first formulated in a pharmaceutically
acceptable container by:
[0127] 1) adding an excipient, such as mannitol (about 0 to about
500 mg/mL) with mixing with sterile water at ambient temperature
and enough sodium hydroxide (NaOH) in 100% sterile water to bring
the pH to 10.1 to 10.3.degree. C., 2) adding dantrolene sodium to
the desired concentration with mixing, 3) adding sterile water to
achieve the final volume, 4) heating the solution to about
40.degree. C. to about 70.degree. C., preferably about 45.degree.
C. to about 60.degree. C., more preferably about 50.degree. C. for
a time sufficient to substantially solubilize the dantrolene
sodium, 5) cooling the solution to about 10.degree. C. to about
35.degree. C., preferably to a temperature about 30.degree. C.,
more preferably to a temperature less than about 30.degree. C.,
more preferably to a temperature less than about 26.degree. C.,
adding an organic solvent (0.5-99.9% v/v), such as TBA to the
aqueous solution with mixing at about 20-35.degree. C., and 6)
cooling the solution to about 10.degree. C. to about 30.degree. C.,
preferably about 5.degree. C. In one embodiment, the excipient may
be added during a later step such as after cooling the solution in
step 5) or after adding the organic solvent. Although the preceding
steps are shown in a certain order, it is understood that one
skilled in the art can change the order of the steps and quantities
as needed. Quantities can be prepared on a weight basis also.
[0128] The pre-lyophilization solution or dispersion can be
sterilized prior to lyophilization, sterilization is generally
performed by aseptic filtration, e.g., through a 0.22 micron or
less filter. Multiple sterilization filters can be used. Additional
sterilization of the solution or dispersion can be achieved by
other methods known in the art, e.g., radiation.
[0129] In this case, after sterilization, the solution or
dispersion is ready for lyophilization. Generally, the filtered
solution will be introduced into a sterile receiving vessel, and
then transferred to any suitable container or containers in which
the formulation may be effectively lyophilized. Usually the
formulation is effectively and efficiently lyophilized in the
containers in which the product is to be marketed, such as, without
limitation, a vial, as described herein and as known in the
art.
[0130] A typical procedure for use in lyophilizing the
pre-lyophilization solutions or dispersions is set forth below.
However, a person skilled in the art would understand that
modifications to the procedure or process may be made depending on
such things as, but not limited to, the pre-lyophilization solution
or dispersion and lyophilization equipment.
[0131] Initially, the product is placed in a lyophilization chamber
under a range of temperatures and then subjected to temperatures
well below the product's freezing point, generally for several
hours. In one embodiment, the product is chilled below the freezing
point of the solution preferably to about -5.degree. C., more
preferably to about -10.degree. C. or lower, even more preferably
to about -20.degree. C. or lower. In one embodiment, the
temperature will be at or below about -40.degree. C. for at least 2
hours. After freezing is complete, the chamber and the condenser
are evacuated through vacuum pumps, the condenser surface having
been previously chilled by circulating refrigerant. Preferably, the
condenser will have been chilled below the freezing point of the
solution preferably to about -40.degree. C. In another embodiment,
the condenser will have been chilled to about -45.degree. C. or
lower, in another embodiment to about -60.degree. C. or lower.
Additionally, evacuation of the chamber should continue until a
pressure of about 10 to about 600 mTorr, preferably about 50 to
about 150 mTorr is obtained.
[0132] The product composition is then warmed under vacuum in the
chamber and condenser. This usually will be carried out by warming
the shelves within the lyophilizer on which the product rests
during the lyophilization process at a pressure ranging from about
10 to about 600 mTorr. The warming process will optimally take
place very gradually. In one embodiment, the warming process will
take place over the course of several hours. In one embodiment, the
product temperature is initially increased from about -40.degree.
C. to about 20.degree. C. and maintained for about 10-70 hours. In
another embodiment, the product temperature is initially increased
from about -46.degree. C. to about 20.degree. C. and maintained for
about 20-40 hours.
[0133] Additionally, the product temperature can be increased to a
temperature to about 25.degree. C.-40.degree. C. over a period of
0-20 hours.
[0134] To prevent powder ejection of the lyophilisate from vials,
complete removal of the organic solvent and water should be done
during the initial drying phase. Complete drying can be confirmed
by stabilization of vacuum, condenser temperature and product shelf
temperature. After the initial drying, the product temperature
should be increased to about 25.degree. C.-40.degree. C. and
maintained for about 5-40 hours.
[0135] Once the drying cycle is completed, the pressure in the
chamber can be slowly released to atmospheric pressure (or slightly
below) with sterile, dry-nitrogen gas (or equivalent gas). If the
product composition has been lyophilized in containers such as
vials, the vials can be stoppered, removed and sealed. Several
representative samples can be removed for purposes of performing
various physical, chemical, and microbiological tests to analyze
the quality of the product.
[0136] The lyophilized dantrolene formulation is typically marketed
in pharmaceutical dosage form. The pharmaceutical dosage form of
the present invention, although typically in the form of a vial,
may be any suitable container, such as ampoules, syringes,
co-vials, which are capable of maintaining a sterile environment.
Such containers can be glass or plastic, provided that the material
does not interact with the dantrolene formulation. The closure is
typically a stopper, most typically a sterile rubber stopper,
preferably a bromobutyl rubber stopper, which affords a hermetic
seal.
[0137] After lyophilization, the dantrolene lyophilization powder
may be filled into containers, such as vials, or alternatively the
pre-lyophilization solution can be filled into such vials and
lyophilized therein, resulting in vials which directly contain the
lyophilized dantrolene formulation. Such vials are, after filling
or lyophilization of the solution therein, sealed, as with a
stopper, to provide a sealed, sterile, pharmaceutical dosage form.
Typically, a vial will contain a lyophilized powder including about
10-500 mg/vial, preferably about 100 mg/vial, dantrolene sodium and
about 5 mg-3.0 g/vial, preferably about 3.0 g/vial, mannitol. In
another embodiment, the amount of dantrolene sodium is about 5 to
about 100 mg/container, about 5-50 mg/vial, about 10 mg to about 30
mg/vial and about 10 mg to about 20 mg/vial.
[0138] The lyophilized formulations of the present invention may be
reconstituted with water, preferably Sterile Water for Injection,
or other substantially sterile fluid such as co-solvents, to
provide an appropriate solution of dantrolene sodium for
intravenous administration.
[0139] The results shown in Table 1 indicate that dantrolene sodium
solubility is dependant on temperature and the amount of alcohol in
aqueous solutions. For the alcohols tested, the solubility of
dantrolene sodium increased as the concentration of alcohol
increased. The formation of a precipitant was also dependent on the
temperature and time.
[0140] Alcohols varied in their effect on solubility. Without
wishing to be bound to any particular theory, smaller alcohols such
as methanol and ethanol have less of an effect on solubility as
compared with larger alcohols (tertiary-butanol and n-butanol).
However, the shape of the alcohol is also important. For example
tert-butanol was found to be better than iso-butanol in preventing
precipitation in this system. The alcohol with the greatest effect
on solubility was tertiary-butanol.
[0141] The pharmaceutical compositions of the present invention
comprise specifically defined dantrolene compounds, used in a safe
and effective amount, together with a pharmaceutically acceptable
carrier.
[0142] The dantrolene compounds used in the compositions of the
present invention are those having the following structural
formulae: ##STR1##
[0143] wherein
[0144] A is a member of the group consisting of furyl ##STR2##
[0145] in which R is from one to two substitutes selected from the
group consisting of nitro, cyano, amino, chloro, bromo, acetyl,
cargboxy, methyl, trifluorimethyl, and hydrogen;
[0146] X is a member of the group consisting of carbonyl and
methylene; and
[0147] Y is a member of the group consisting of hydroxyethyl,
butyl, hydrogen, and r-pyridylethyl.
[0148] In certain embodiments, the active compound is one or more
of the following compounds: [0149]
1-[5-(p-nitrophenyl)furfurylideneamino]hydantoin; [0150]
1-[5-(p-aminophenyl)furfurylideneamino]hydantoin; [0151]
1-[5-(m-nitrophenyl)furfurylideneamino]hydantoin; [0152]
1-[5-(p-chlorophenyl)furfurylideneamino]hydantoin; [0153]
1-[5-(2,4-dichlorophenyl)furfurylideneamino]hydantoin; [0154]
1-[5-(2,methyl-4-nitrophenyl)furfurylideneamino]hydantoin; [0155]
1-[5-(p-nitrophenyl)furfurylideneamino]-2-imidazolidinone; [0156]
1-[5-(p-cyanophenyl)furfurylideneamino]hydantoin; and
pharmaceutically acceptable salts thereof.
[0157] The active pharmaceutical ingredient (API) dantrolene sodium
(DS) (USP) is a hemiheptahydrate salt; 1-[5-(4-nitrophenyl)
furfurylidene amino]imidazolidine-2,4-dione, containing 14.5-17.0%
of water (3-1/2 moles) and has a molecular weight of 399. The
anhydrous salt has a molecular weight of 336.
[0158] Dantrolene sodium (USP) is an orange, odorless powder with a
melting point of 279-280.degree. C. It is completely soluble in
propylene glycol, slightly soluble in ethanol and methanol, and is
insoluble in H.sub.2O (15 mg/L). Higher solubility in water at pH
8.0 or greater is exhibited by dantrolene sodium. Its free acid
form (dantrolene) is totally insoluble (mg/L), and it is a weak
acid with a pKa of about 7.5. However, the extremely low solubility
of the free acid prevents an accurate determination of its pKa. The
FDA approved lyophilized dantrolene sodium for intravenous
injection (DS-IV) product (USP 2007) contains 20 mg of hydrated DS
(API) (16.8 mg on the anhydrous basis), 3.0 grams of mannitol and
enough NaOH to achieve a pH=9.5 (approximately) upon reconstitution
with 60 mL of water for injection. The reconstituted product is
administered as a rapid infusion to patients exhibiting the
life-threatening condition of thermal hyperthermia during
surgery.
[0159] Dantrolene sodium has a formula of Formula II: ##STR3##
[0160] Dantrolene is an antagonist of the type 3 ryanodine receptor
and is commonly given as the sodium salt (sodium dantrium), which
is hydrated
1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione
sodium salt. Dantrolene is prescribed in the treatment of clinical
spasticity resulting from upper motor neuron disorders such as
spinal chord injury, cerebral palsy, stroke, or multiple sclerosis.
Dantrolene is also effective in reversing the hypermetabolic
process of malignant hyperthermia, a genetic disorder of skeletal
muscle that is triggered by exposure to anesthetics and certain
relaxants.
[0161] Other therapeutic uses for dantrolene are known in the art.
For example, Dreyer, U.S. Pat. No. 5,597,809, teaches the use of
NMDA-receptor antagonists, and also dantrolene, for the treatment
of optic neuritis. U.S. Pat. No. 5,506,231 to Lipton teaches the
use of dantrolene for the treatment of three conditions
specifically associated with AIDS: dementia, myelopathy, and
blindness. Dantrolene has been used clinically to treat malignant
hypothermia, as it is known to reduce cellular energy requirements,
creating a hypothermic environment. Kiyoshi (Patent Abstracts of
Japan (1994), publication number 06263636) discloses the use of
dantrolene for treatment of cerebral nerve diseases such as
geriatric dementia, Parkinson's disease and Huntington's
disease.
[0162] Non-therapeutic uses for dantrolene include cryopreservation
of blood vessels. See U.S. Pat. Nos. 5,158,867; 5,149,621;
5,145,769 and 5,122,110, incorporated herein in their entirety.
[0163] Tertiary butyl alcohol (TBA) possesses favorable properties
to be utilized in aqueous co-solvent systems for the freeze-drying
of pharmaceutical products. The favorable physical properties of
TBA include its high vapor pressure, low melting point (freezes
completely in most freeze dryers with low expenditure of energy)
and readily sublimes (increases sublimation rates) during the
primary drying stage of the freeze-drying process. Added to these
desirable physical properties, TBA possesses low toxicity as an
organic solvent (permissible residual limit about the same as ethyl
alcohol, i.e. <5,000 ppm). TABLE-US-00002 TABLE 2
Physicochemical properties of TBA Property Value Formula: C4 H10 O
Glass Transition -93.degree. C. Melting Point 25.degree. C. Boiling
Point 84.6 .+-. 8.0.degree. C. Density 0.804 .+-. 0.06 g/cm3
Enthalpy of Vaporization 37.89 .+-. 6.0 kJ/mol Molecular Weight
74.12 pKa 15.37 .+-. 0.29
[0164] Without wishing to be bound by theory, the utilization of a
TBA-aqueous co-solvent system into the DS-IV formulation appears to
lead to the following beneficial results: [0165] i. It
substantially reduces the freezing time of the "fill solution"
(solution that is introduced into the vials) of the formulation.
[0166] ii. It causes an approximate two-fold decrease in the drying
time of the freeze-dried cake of the DS-IV product in the course of
its production. [0167] iii. It substantially reduces the
reconstitution time of the freeze-dried (lyophilized) DS-IV product
from minutes to less than 60, 50, 40, 30, 20, 10 or fewer seconds.
This provides a significant improvement in the pharmacotherapy of
patients exhibiting the life-threatening condition of malignant
hyperthermia during surgery.
EXAMPLES
[0168] The following Examples are provided to illustrate certain
aspects of the present invention and to aid those of skill in the
art in practicing the invention. These Examples are in no way to be
considered to limit the scope of the invention in any manner.
Example 1
Formulation of DS-IV Product
[0169] In one embodiment, the DS-IV product is a lyophilized
(freeze-dried) powder containing approximately 16.8 mg of anhydrous
dantrolene sodium (API) (DS) (equivalent to 20 mg of hydrous DS
(API) containing 14.5% to 18% of moisture), 3 g of mannitol and
enough NaOH to achieve a pH value of approximately 8.8 to 10.9 upon
reconstitution with 60 mL of water for injection (WFI) per
vial.
[0170] Without wishing to be bound by theory, it is believed that
due to the fact that DS (API) is highly insoluble, it must be
dissolved at an alkaline environment (above its pKa 7.4 value).
Since DS is susceptible to an alkaline hydrolysis, it must be
dissolved as rapidly as possible during its formulation step. To
achieve a rapid dissolution of DS, higher temperatures have to be
utilized. The alkalinity (pH value), temperature and duration of
heating of the liquid DS formulation play a role in the strength
(percent of API) of the final lyophilized DS-IV product. The
conditions may be appropriately adjusted to achieve a favorable
strength (94-97%) in the final product.
[0171] It is known that an aqueous co-solvent system may be used to
facilitate the dissolution of an insoluble drug. When an aqueous
co-solvent system consisting of 5%, 10% and 20% TBA was used in the
DS formulation, the drug (DS) (API) remained unsolubilized even
after 90 minutes of mixing time at room temperature. Surprisingly,
the addition of TBA to the aqueous portion of the DS formulation
did not increase the solubilization rate of DS (API) as is the case
with the majority of drug formulations in which the TBA-aqueous
co-solvent system is used. However, it was discovered that the use
of the TBA shortened the freezing time of the pre-lyophilized
"fill" solution, the freeze-drying time and the reconstitution of
the freeze-dried cake of the DS-IV product.
[0172] FIG. 1 shows the preferred manner by which solubilization of
DS is achieved if the API (DS) is first mixed with its formulation
constituents (e.g., about 3 g of mannitol and enough of NaOH in
100% sterile water to bring the pH to about 8.8 to about 11,
preferably, from about 10 to about 10.5, more preferably from about
10.1 to about 10.3) at about 50.degree. for a period of about 20
minutes.
[0173] This is followed by a period of cooling (about 45-60 min)
down to about 25.degree. C. The TBA is subsequently added at about
25.degree. C. (See FIG. 1) to complete the formulation process.
Importantly, the addition of TBA at about 25.degree. C. does not
cause any undesirable loss of the strength (percent of API) of the
formulation. This is substantiated by the fact that when the
TBA-treated formulation was freeze-dried, the final reconstituted
product of DS-IV exhibited strength of 95.+-.1% (See Table 3).
TABLE-US-00003 TABLE 3 Summary of percent (%) assay of DS-IV vials
TBA % Assay % 0 95.94 .+-. 0.54 5 96.40 .+-. 0.60 10 94.66 .+-.
0.24 20 96.22 .+-. 0.70
The Impact of TBA on the Freeze-Drying Process of DS-IV
Formulation
[0174] In general, the presence of TBA solvent affects the freezing
characteristics of a solution. Furthermore, it significantly
impacts the crystal morphology of the ice, the drying rates, the
surface area of the dried cake and reconstitution times of
lyophilisates (freeze-dried cake) [2].
[0175] The size and shape of the ice crystals depend on the nature
and quantity of the organic solvents used in co-solvent system.
Thermal analysis studies have been used to evaluate the various
stable and metastable states which form with TBA-water systems
during freezing. Adding TBA at different ratios was found to cause
the formation of large needle-shaped ice crystals, which when
sublimed they created a more porous and less resistant matrix which
facilitated the drying process. Thus, drying times can be decreased
by approximately 30-50% [3].
Impact of TBA on Sublimation Rates
[0176] Improvements in the rate of mass transfer of a solvent
through a partially dried cake layer increases the sublimation rate
and hence it decreases the time for the primary drying phase of the
freeze-dry cycle. This leads in the overall reduction of the
freeze-drying process which translates in considerable savings in
energy and cost of product manufacturing.
Reduction in Drying Time and Freezing Time of DS-IV Product
Cake
[0177] The present invention reveals that the introduction of about
2% to about 20% TBA into the DS-IV formulation results in an
approximate two-fold reduction in drying time of its lyophilisate.
The increased drying rate is probably caused by the formation of
needle-shaped ice crystals which create a porous structure, which
in turn facilitate the mass transfer of water vapor due to
decreased cake resistance and the increase in its surface area.
[0178] A typical example of freeze-drying cycle of DS-IV product,
produced with about 5% TBA aqueous co-solvent system, comprises of
the following segments: 1) starting with a shelf temperature of
about 25.degree. C. for loading; 2) freezing to about -40 to
-50.degree. C. over about 2-4 hours; 3) holding at -45.degree. C.
for about 2-3 hours; 4) ramping to about 20.degree. C. over about
2-3 hours; 5) holding at about 20.degree. C. for 30-35 hours; 6)
ramping to about 40.degree. C. over about 1-2 hour; 7) holding at
about 40.degree. C. for about 5-7 hours; 8) ramping to about
30.degree. C. over about 1-2 hours; 9) holding at about 30.degree.
C. for about 2-4 hrs. The pressure is about 90-110 microns
throughout primary drying and 110-130 microns throughout secondary
drying.
[0179] Compared to the original freeze drying cycle (with no TBA),
the addition of TBA in the DS-IV formulation, has reduced the total
freeze-drying cycle duration by 33% (i.e., from 75 hours to about
50 hours or less).
Enhancement in the Reconstitution Time of the Lyophilized DS-IV
Product by TBA
[0180] Due to the increased porous structure of the DS-IV
lyophilized product which was created by the introduction of TBA,
the reconstitution time of the DS-UV product was decreased from 1
to 3 minutes per vial to less than 10 seconds (See Table 4). This
almost instantaneous reconstitution of the DS-IV lyophilized powder
constitutes a significant improvement in the treatment of patients
with malignant hyperthermia. The recommended DS dose for treatment
of MH ranges from 1 mg/kg to 10 mg/kg. If we consider that each
vial containing 0.02 g of DS (API), then the above recommended
doses translate to a minimum of four (4) vials to a maximum of 36
vials per MH episode. The Merck Manual (18.sup.th edition, 2006)
recommends a treatment for MH that starts with 2.5 mg/kg (9-10
vials). It is also recommended that treatment should be initiated
immediately after symptoms of MH develop. On the average, patients
exhibiting MH require a rapid intravenous (IV) infusion of nine to
ten (9-10) (2.5 mg/kg) vials of DS-IV product, each reconstituted
with 60 mL of sterile water for injection (WFI). In many cases, the
number of DS-IV vials used ranges from 10-20. Cases of MH requiring
as many as 36 vials of DS-IV have been recorded. The length of time
to reconstitute 10-36 vials (1 to 3 min each required for
reconstitution) creates an issue when considering death due to MH
can occur in as short time as 30 min from onset. In adult patients,
temperatures exceeding 41.degree. C. (105.8.degree. F.) could prove
fatal in periods of MH exceeding 30 min (Merck Manual, 18.sup.th
Edition, 2006). TABLE-US-00004 TABLE 4 Reconstitution times of
DS-IV product before and after utilization of the TBA-aqueous
co-solvent system TBA % Time (sec) 0 <90 5 <10 10 <10 20
<10
[0181] It has now been discovered that dantrolene sodium prevents
or reduces arrhythmia in hypothermic and normothermic warm-blooded
animals. In particular, dantrolene sodium is effective in the
treatment of supraventricular tachycardias, in suppressing slow
responses in infracted tissues and in abolishing ventricular
premature beats or tachycardias originating in these tissues, and
in correcting ventricular rhythm disturbances due to reentry.
[0182] In addition, information regarding procedural or other
details supplementary to those set forth herein is described in
cited references specifically incorporated herein by reference.
[0183] It would be obvious to those skilled in the art that
modifications or variations may be made to the preferred embodiment
described herein without departing from the novel teachings of the
present invention. All such modifications and variations are
intended to be incorporated herein and within the scope of the
claims.
REFERENCES
[0184] 1. Practical aspects of lyophilization using non-aqueous
co-solvent systems. Dirk L. Teagarden, and David S. Baker.
Department of Sterile Products Development, Pharmacia Corporation,
7000 Portage Road, Kalamazoo, Mich. 49001-0199, USA [0185] 2. The
effect of tertiary butyl alcohol on the resistance of the dry
product layer during primary drying. Pharmaceutical Research, Kasra
Kasraian and Patrick DeLuca. 12 (4), 491-495, 1995 [0186] 3.
Thermal analysis of the tertiary butyl alcohol-water system and its
implications on freeze-drying. Pharmaceutical Research, Kasra
Kasraian and Patrick DeLuca. 12 (4), 484-490, 1995 [0187] 4.
Freeze-drying of tertiary butanol/water co-solvent systems: a case
report on formation of friable freeze-dried powder oftobramycine
sulfate. Journal of Pharmaceutical Sciences. Wittaya-Areekul
Sackchai et. al. 91(4), 1147-55, 2002
* * * * *