U.S. patent application number 16/281676 was filed with the patent office on 2019-08-22 for stable nimodipine parenteral formulation.
This patent application is currently assigned to NORTIC HOLDINGS INC.. The applicant listed for this patent is NORTIC HOLDINGS INC.. Invention is credited to Vimal Kavuru, S. George Kottayil, Amresh Kumar, Kamalkishore Pati, Prasanna Sunthankar.
Application Number | 20190255033 16/281676 |
Document ID | / |
Family ID | 67617442 |
Filed Date | 2019-08-22 |
![](/patent/app/20190255033/US20190255033A1-20190822-P00001.png)
United States Patent
Application |
20190255033 |
Kind Code |
A1 |
Kottayil; S. George ; et
al. |
August 22, 2019 |
Stable Nimodipine Parenteral Formulation
Abstract
A nimodipine injection concentrate and diluted formulation
comprises nimodipine (base or salt), an effective amount of a
hydrophilic surfactant, and a pharmaceutically acceptable carrier
for injection which is an aqueous solution substantially free of
organic solvent, such that the nimodipine is substantially
contained in a concentrated injection solution, suspension,
emulsion or complex as a micelle or a colloidal particle or an
inclusion complex and the formulation is stable and clear. In
certain embodiments, the hydrophilic surfactant is polysorbate
80.
Inventors: |
Kottayil; S. George; (West
Windsor, NJ) ; Kumar; Amresh; (Painsboro, NJ)
; Sunthankar; Prasanna; (West Windsor, NJ) ;
Kavuru; Vimal; (Holmdel, NJ) ; Pati;
Kamalkishore; (Old Bridge, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NORTIC HOLDINGS INC. |
East Brunswick |
NJ |
US |
|
|
Assignee: |
NORTIC HOLDINGS INC.
East Brunswick
NJ
|
Family ID: |
67617442 |
Appl. No.: |
16/281676 |
Filed: |
February 21, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62633863 |
Feb 22, 2018 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/14 20180101; A61P
9/10 20180101; A61P 9/06 20180101; A61K 9/19 20130101; A61K 47/10
20130101; A61P 9/12 20180101; A61P 9/04 20180101; A61K 9/0019
20130101; A61K 31/451 20130101; A61K 47/02 20130101; A61K 9/107
20130101; A61K 47/26 20130101 |
International
Class: |
A61K 31/451 20060101
A61K031/451; A61K 9/00 20060101 A61K009/00; A61K 47/26 20060101
A61K047/26; A61K 47/10 20060101 A61K047/10; A61P 9/04 20060101
A61P009/04; A61P 9/06 20060101 A61P009/06; A61P 9/10 20060101
A61P009/10; A61P 9/12 20060101 A61P009/12; A61P 9/14 20060101
A61P009/14 |
Claims
1. A nimodipine concentrate formulation, comprising nimodipine base
or a pharmaceutically acceptable salt of nimodipine at a
concentration from about 10 mg/ml to about 50 mg/ml in an aqueous
carrier, and an effective amount of a hydrophilic surfactant
consisting of polysorbate 80, the formulation being lyophilized or
vacuum dried such that it contains from about 0 to about 0.5%
organic solvent, the nimodipine in the concentrate formulation
contained in micelles, the concentrate formulation further
comprising an optional preservative and an optional buffering
agent, the concentrate formulation being clear, colorless, stable,
and without crystalline nimodipine precipitate.
2. The nimodipine concentrate formulation of claim 1, wherein the
median particle size of micelles ranges from about 0.5 nm to about
350 nm.
3. The nimodipine concentration formulation of claim 1, wherein the
total volume of the concentrate formulation is from about 0.5 ml to
about 10 ml.
4. The nimodipine concentrate formulation of claim 3, wherein the
polysorbate 80 comprises from about 40% to about 99% of the
injection concentrate formulation.
5. The nimodipine concentration formulation of claim 1, which
contains from about 0 to about 300 mg organic solvent.
6. The nimodipine concentrate formulation of claim 1, which
contains from about 0 to about 100 mg alcohol per dose per 10 mg
dose of nimodipine.
7. The nimodipine concentrate formulation of claim 5, wherein the
organic solvent is dehydrated alcohol and the aqueous carrier is
water for injection.
8. The nimodipine concentrate formulation of claim 7, which
contains from about 0 to about 100 mg alcohol per dose per 10 mg
dose of nimodipine.
9. The nimodipine concentrate formulation of claim 1, which is
stored in a container wherein the dissolved oxygen content is about
2 ppm and the head space oxygen content is less than 5%.
10. The nimodipine concentrate formulation of claim 1, which (i) is
stable for at least 3 months when stored under ICH accelerated
conditions (ACC) at 40.degree. C..+-.2.degree. C./75% RH.+-.5% RH,
or (ii) is stable for at least 6 months when stored under ICH room
temperature conditions (CRT) at 25.degree. C..+-.2.degree. C./60%
RH.+-.5% RH, or (iii) both (i) and (ii).
11. The nimodipine concentrate formulation of claim 1, which can be
diluted in an aqueous carrier to a concentration from about 0.
0.001 mg/ml to about 0.5 mg/ml without crystalline nimodipine
precipitate.
12. A nimodipine formulation, comprising the nimodipine concentrate
formulation of claim 1 diluted in an aqueous carrier to a
concentration from about 0.001 mg/ml to about 0.5 mg/ml without
crystalline nimodipine precipitate, the nimodipine formulation
being stable such that the nimodipine does not phase separate at a
temperature from about 15.degree. C. to about 25.degree. C. and at
a pH from about 5 to about 8.
13. The nimodipine formulation of claim 12, which (i) is stable for
at least 3 months when stored under ICH accelerated conditions
(ACC) at 40.degree. C..+-.2.degree. C./75% RH.+-.5% RH, or (ii) is
stable for at least 6 months when stored under ICH room temperature
conditions (CRT) at 25.degree. C..+-.2.degree. C./60% RH.+-.5% RH,
or (iii) both (i) and (ii).
14. The nimodipine formulation of claim 13, wherein the aqueous
carrier is selected from the group consisting sodium chloride
injection, Ringers injection, isotonic dextrose injection, sterile
water for injection, dextrose, Lactated Ringers injection, and
total parenteral nutrition (TPN).
15. A method of treatment, comprising administering a
therapeutically effective dose of the formulation of claim 13 to a
human patient suffering from a condition selected from the group
consisting of aneurysms, subarachnoid hemorrhage, vasospastic
angina, Prinzmetal angina, stable angina, acute myocardial
infarction, myocardial arrest, arrhythmia, systemic hypertension,
pulmonary hypertension, congestive heart failure, coronary artery
surgery and hypertrophic cardiomyopathy.
16. A nimodipine infusion formulation, comprising a nimodipine base
or a pharmaceutically acceptable salt of nimodipine and an
effective amount of a hydrophilic surfactant consisting of
polysorbate 80 lyophilized or vacuum dried to a nimodipine
concentrate to remove alcohol or other organic solvent, the
lyophilized nimodipine concentrate diluted with a pharmaceutically
acceptable aqueous carrier for injection such that the nimodipine
infusion formulation can be administered at an infusion rate of
nimodipine from about 0.5 mg/hr to about 2.5 mg/hr and such that
the infusion does not provide alcohol in an amount of more than 6
mg/kg/day when infused into a human patient, the formulation
further comprising an optional preservative and an optional
buffering agent, the nimodipine infusion formulation being clear,
colorless, stable, and without crystalline nimodipine
precipitate.
17. The nimodipine infusion formulation of claim 16, wherein the
nimodipine in the nimodipine concentrate formulation is contained
in micelles at a concentration from about 10 mg/ml to about 50
mg/ml, and wherein the nimodipine in the nimodipine infusion
formulation is contained in micelles at a concentration from about
0. 0.001 mg/ml to about 0.5 mg/ml.
18. The nimodipine infusion formulation of claim 17, wherein the
polysorbate 80 comprises from about 40% to about 99% of the
injection concentrate and the polysorbate 80 comprises less than 1%
of the nimodipine infusion formulation.
19. The nimodipine concentrate formulation of claim 18, wherein the
organic solvent is dehydrated alcohol and the aqueous carrier is
selected from the group consisting sodium chloride injection,
Ringers injection, isotonic dextrose injection, sterile water for
injection, dextrose, Lactated Ringers injection, and total
parenteral nutrition (TPN).
20. A method of treatment, comprising intravenously administering
the nimodipine infusion formulation of claim 19 to a human patient
at a nimodipine infusion rate of from about 8 mg/day to about 50
mg/day.
Description
FIELD OF THE INVENTION
[0001] The present invention provides a stable nimodipine
concentrate and parenteral solution suitable for continuous
intravenous (IV) administration. The parenteral solution
composition consists of an aqueous solution of nimodipine
(concentrations ranging from about 0.5 to about 50 mg/ml), a
hydrophilic surfactant and an aqueous solvent, wherein the
formulation is essentially free of organic solvents.
BACKGROUND OF THE INVENTION
[0002] Nimodipine, a lipid soluble substituted 1,4-dihydropyridine
with vasodilatatory properties, is indicated for prophylaxis and
treatment of ischemic neurologic deficits caused by cerebral
vasospasms after subarachnoid hemorrhage (SAH). Currently,
nimodipine treatment of ischemic brain injury is the first-line
treatment. In man, nimodipine is rapidly absorbed after oral
administration, and peak concentrations are generally attained
within one hour. The terminal elimination half-life is
approximately 8 to 9 hours but earlier elimination rates are much
more rapid, equivalent to a half-life of 1-2 hours; a consequence
is the need for frequent (every 4 hours) dosing. Nimodipine is
eliminated almost exclusively in the form of metabolites and less
than 1% is recovered in the urine as unchanged drug. Numerous
metabolites, all of which are either inactive or considerably less
active than the parent compound, have been identified. Because of a
high first-pass metabolism, the bioavailability of nimodipine
averages 13% after oral administration. The bioavailability is
significantly increased in patients with hepatic cirrhosis, with
Cmax approximately double that in normal, which necessitates
lowering the dose in this group of patients.
[0003] Currently approved products in the US market are oral solid
and liquid dosage forms of nimodipine. Nimodipine is marketed in
the US as an oral dosage form, NIMOTOP.RTM. liquid-filled capsules
(Bayer Pharmaceuticals Corp.) and equivalent generics. NIMOTOP.RTM.
capsules and generic versions of the same each contain 30 mg of
nimodipine and are commonly administered in a two-capsule 60 mg
dose, and dosed every 4 hours. In the event that a patient is
unconscious or unable to swallow, the nimodipine capsule contents
are extracted by syringe and administered via an intraoral or an
intranasal (e.g., naso-gastric) tube. The medical practitioner
administering the dose may either unknowingly or due to improper
handling, extract less than the full amount of the liquid dose from
the capsule, thus introducing substantial risk of incomplete dosing
and placing undue burden on medical professionals. The incomplete
dosing is exacerbated by the relatively small dosage volumes
involved and high drug concentration of drug in the commercially
available capsules. Hence, a practitioner's failure to dose the
full amount of the high-concentration, small volume liquid from the
commercial capsules could lead to a significant under dose of
nimodipine. Also, the FDA has noted in warnings related to oral
nimodipine administration via nasogastric tubes that because a
standard needle does not fit on an oral syringe, the formulation
within a capsule is extracted using an intravenous syringe. The use
of intravenous syringes to extract nimodipine formulation from the
capsule increases the chance of medication being inadvertently
administered intravenously instead of by mouth or nasogastric
tube.
[0004] To quickly and effectively treat or control disease
progression following SAH, intravenous administration of nimodipine
is usually preferred. Intravenous (IV) Nimodipine is approved in
Europe and marketed in Europe by Bayer under the trade name
Nimotop.RTM.. The current commercially marketed injectable
nimodipine (Bayer's Nimotop.RTM.) available in Europe and other
regulated markets contains large amounts of organic solvent--about
23.7% ethanol (alcohol) and 17% polyethylene glycol 400, i.e. up to
50 g per daily dose (250 ml), equivalent to 1200 ml beer (5 vol %)
or 500 ml wine (12 vol %) per dose. The large amount of ethanol in
Nimotop is harmful for those suffering from alcoholism or impaired
alcohol metabolism and in pregnant or breast feeding women. Also,
high concentrations of ethanol may cause pain and irritation at the
injection site. IV Nimotop is most often infused continuously up to
three weeks. Due to the high alcohol content in Bayer's IV Nimotop
solution, it is diluted by co-infusing saline and dextrose by way
of a three-way stopcock. This may be harmful for those suffering
from alcoholism or impaired alcohol metabolism and should be taken
into account in pregnant or breast-feeding women, children and
high-risk groups such as patients with liver disease or epilepsy.
The amount of alcohol in this medicine may alter the effects of
other medicines. Nimodipine has poor water solubility and is
therefore difficult to formulate as an aqueous injectable. That is
the reason that Nimotop IV infusion solution utilizes up to 23.7%
of alcohol as a co-solvent to solubilize nimodipine.
[0005] U.S. Pat. No. 5,114,956 describes parenteral formulations
containing nimodipine, that contain 0.01-0.4% by weight of
nimodipine, relative to 100 parts by weight of a solvent consisting
of 30-70% by weight, preferably 45-70% by weight, of water, 15-40%
by weight, preferably 15-30% by weight, of propylene glycol and/or
polyethylene glycol, preferably with a mean molecular weight of
200, 400 and 600, 15-30% by weight, preferably 15-25% by weight, of
ethanol, and, where appropriate, customary auxiliaries and/or
additives.
[0006] Through its Adverse Event Reporting System (AERS) and other
sources, including published literature, the FDA has identified 31
cases of nimodipine errors between 1989 and 2009, with 25 involving
the administration of the contents of the oral capsule
intravenously according to the FDA. Four patients who received
nimodipine intravenously died, while another 5 suffered severe
reactions and one patient suffered permanent harm, according to the
agency.
[0007] Previously, our U.S. Pat. Nos. 10,092,557 and 10,092,553
disclosed a nimodipine injection concentrate and diluted
formulation comprises nimodipine (base or salt), an effective
amount of a hydrophilic surfactant, and a pharmaceutically
acceptable carrier for injection which is an aqueous solution, an
organic solvent, an oil, or a cyclodextrin, such that the
nimodipine is substantially contained in a concentrated injection
solution, suspension, emulsion or complex as a micelle or a
colloidal particle or an inclusion complex and the formulation is
stable and clear. In certain embodiments, the hydrophilic
surfactant is polysorbate 80. The diluted formulation which is a
stable directly infusible nimodipine formulation suitable for
parenteral administration in humans, comprises nimodipine in a
concentration from about 0.01 mg/ml to about 1.0 mg/ml, surfactant
(e.g., polysorbate 80), and a pharmaceutically acceptable organic
solvent comprising less than 2% w/v of the formulation.
[0008] There exists an unmet medical need for an easy to administer
nimodipine dosage form for patients who find it difficult or are
unable to swallow and patients who are unconscious. There exists a
further unmet medical need for a nimodipine formulation which
includes little or no organic solvent but yet is stable (e.g., the
formulation is a clear colorless liquid and does not include a
crystalline nimodipine precipitate). An additional imperative is
the need to eliminate serious life-threatening medication errors as
a result of improper administration of drug. As per the European
Commission guideline on `Excipients in the labelling and package
leaflet of medicinal products for human use` (SANTE-2017-11668)
mentioned in below table, for parentral route of administration the
recommended dose of less than 100 mg per dose and or 1-6 mg/kg/day
is preferred. There exists a further unmet medical need for a
nimodipine formulation which includes little or no organic solvent
but yet is stable (e.g., the formulation is a clear colorless
liquid and does not include a crystalline nimodipine
precipitate).
TABLE-US-00001 Route of Name Administration Threshold Information
for the Package Leaflet Comments Ethanol Oral, Less than 100 mg
This medicinal product contains This statement is to provide
parenteral per dose small amounts of ethanol (alcohol), reassurance
to parents and less than 100 mg per <dose>. children
concerning the low levels of alcohol in the product. Ethanol Oral,
100 mg per This medicinal product contains . . . The package
leaflet should parenteral dose vol % ethanol (alcohol), i.e. up to
. . . give the equivalent volume mg per <dose>, equivalent to
. . . ml of beer and wine, beer, . . . ml wine per <dose>.
nominally calculated Harmful for those suffering from assuming 5%
vol and 12% alcoholism. vol ethanol respectively. To be taken into
account in pregnant Separate warning statements or breast-feeding
women, children may be needed in different and high-risk groups
such as patients parts of the PL. with liver disease, or epilepsy.
Ethanol Oral, 3 g per dose This medicinal product contains . . .
parenteral vol % ethanol (alcohol), i.e. up to . . . mg per
<dose>, equivalent to . . . ml beer, . . . ml wine per
<dose>. Harmful for those suffering from alcoholism. To be
taken into account in pregnant or breast-feeding women, children
and high-risk groups such as patients with liver disease or
epilepsy. The amount of alcohol in this medicinal product may alter
the effects of other medicines. The amount of alcohol in this
medicinal product may impair your ability to drive or use machines.
Reference: Annex to the European Commission guideline on
`Excipients in the labelling and package leaflet of medicinal
products for human use` (SANTE-2017-11668).
EMA/CHMP/302620/2017/EN
OBJECTS AND SUMMARY OF THE INVENTION
[0009] The present invention aims to resolve solubility
deficiencies of previously approved nimodipine dosage forms by the
development of a robust, stable, and easy to administer nimodipine
infusion injection.
[0010] Another objective of the present invention is to provide the
composition and preparation of the nimodipine infusion solution and
its administration.
[0011] Another objective of the present invention is to provide
compositions that make it possible either to reduce the ethanol
concentrations greatly, or to eliminate ethanol completely from the
intravenous nimodipine infusion formulation.
[0012] Another objective of the present invention is to provide
injectable nimodipine formulations which include little or no
alcohol, but yet provide a stable formulation which does not
include a crystalline nimodipine precipitate and is clear and
colorless.
[0013] In accordance with the above objects and others, the
invention is directed to a nimodipine concentrate formulation,
consisting of nimodipine base or a pharmaceutically acceptable salt
of nimodipine in an aqueous carrier from about 0.5 mg/ml to about
50 mg/ml, preferably from about 10 mg/ml to about 50 mg/ml, in an
aqueous carrier, and an effective amount of a hydrophilic
surfactant, the formulation being lyophilized such that it is
substantially free from organic solvent or contains from about 0 to
about 0.5% organic solvent, the nimodipine in the concentrate
formulation contained in micelles, the concentrate formulation
further comprising an optional preservative, and an optional
buffering agent, the concentrate formulation being clear,
colorless, stable, and without or substantially without crystalline
nimodipine precipitate. In other preferred embodiments, the
invention is directed in part to a nimodipine concentrate
formulation, comprising nimodipine base or a pharmaceutically
acceptable salt of nimodipine in an aqueous carrier comprising from
about 10 mg/ml to about 50 mg/ml nimodipine for a total dose of
about 10 mg (based on nimodipine base), an effective amount of a
hydrophilic surfactant such that nimodipine in the concentrate
formulation is contained in micelles, and from about 0 to about 300
mg organic solvent, the concentrate formulation being clear,
colorless, stable, and does not contain a crystal nimodipine
precipitate. Preferably, the concentrate formulation is suitable
for injection when diluted with further aqueous carrier. In
preferred embodiments, the hydrophilic surfactant comprises from
about 1% to about 99.5% of the concentrate formulation. In certain
embodiments, the hydrophilic surfactant is polysorbate 80. In
certain embodiments, the pharmaceutically acceptable carrier is
water for injection. In certain embodiments, a unit dose of the
concentrate is diluted to a total volume of 5 ml with water for
injection and enclosed within a pharmaceutically acceptable
container, e.g., an ampule or vial. In certain embodiments, the
nimodipine injection concentrate further comprises an effective
amount of a preservative. In certain preferred embodiments, the
median particle size of micelles or nano-emulsions ranges from
about 0.5 nanometer to about 350 nanometers, or from about 0.5 nm
to about 200 nm, or from about 5 nm to about 50 nm. In certain
preferred embodiments, the organic solvent included in the initial
preparation of the concentrate formulation is substantially or
completely removed by evaporation under vacuum or another suitable
process known to those skilled in the art. Thus, in certain
preferred embodiments, the nimodipine concentrate formulation
contains less than 1% w/v organic solvent, and in most preferred
embodiments the nimodipine concentrate formulation is substantially
free or totally free of organic solvents/alcohol, e.g., such that
the nimodipine concentrate formulation contains from about 0 to
about 300 mg alcohol per dose per 10 mg dose of nimodipine, and
preferably about 100 mg or less alcohol per 10 mg dose of
nimodipine and/or 1-6 mg/kg/day. In certain preferred embodiments,
the nimodipine is substantially contained within micelles as a
nano-emulsion.
[0014] The invention is further directed in part to a nimodipine
infusion formulation, comprising a nimodipine base or a
pharmaceutically acceptable salt of nimodipine and an effective
amount of a hydrophilic surfactant consisting of polysorbate 80
lyophilized or vacuum dried to a nimodipine concentrate to remove
alcohol or other organic solvent, the lyophilized nimodipine
concentrate diluted with a pharmaceutically acceptable aqueous
carrier for injection such that the nimodipine infusion formulation
can be administered at an infusion rate of nimodipine from about
0.5 mg/hr to about 2.5 mg/hr and such that the infusion does not
provide alcohol in an amount of more than 6 mg/kg/day when infused
into a human patient, the formulation further comprising an
optional preservative and an optional buffering agent, the
nimodipine infusion formulation being clear, colorless, stable, and
without crystalline nimodipine precipitate. The nimodipine in the
nimodipine concentrate formulation is preferably contained in
micelles at a concentration from about 10 mg/ml to about 50 mg/ml,
and wherein the nimodipine in the nimodipine infusion formulation
is contained in micelles at a concentration from about 0.0.001
mg/ml to about 0.5 mg/ml. The polysorbate 80 preferably comprises
from about 40% to about 99% of the injection concentrate and the
polysorbate 80 comprises less than 1% of the nimodipine infusion
formulation. The organic solvent is preferably dehydrated alcohol
and the aqueous carrier is preferably selected from the group
consisting sodium chloride injection, Ringers injection, isotonic
dextrose injection, sterile water for injection, dextrose, Lactated
Ringers injection, and total parenteral nutrition (TPN). The
invention is further directed to a method of treatment, comprising
intravenously administering the nimodipine infusion formulation to
a human patient at a nimodipine infusion rate of from about 2 to 10
mg every five hours, or, e.g., from about 8 mg/day to about 50
mg/day.
[0015] The present invention is further directed in part to a
nimodipine solution suitable for injection, which can be prepared
from the above-described nimodipine concentrate which is diluted in
a pharmaceutically acceptable medium (e.g., saline to provide a
physiologically and pharmaceutically acceptable formulation) to a
solution for administration by infusion. The nimodipine solution
comprises from about 0.01 mg/ml to about 1.0 mg/ml nimodipine or a
pharmaceutically acceptable salt thereof in an aqueous carrier
suitable for injection, and an effective amount of a hydrophilic
surfactant such that nimodipine in the concentrate formulation is
contained in micelles, the nimodipine formulation having a volume
from about 50 ml to about 1000 ml and being clear, colorless and
does not contain a crystal nimodipine precipitate. In preferred
embodiments, the nimodipine solution contains from about 0.01% to
about 5% w/v of the hydrophilic surfactant. In preferred
embodiments, the nimodipine solution allows for parenteral
administration of a single 250 ml infusion bag or bottle to a human
patient, the diluted formulation containing less than about 2%,
more preferably less than about 1% w/v, or is substantially free of
organic solvent (e.g., alcohol). In certain embodiments, the
nimodipine solution further comprises an effective amount of a
pharmaceutically acceptable preservative. In certain preferred
embodiments, substantially all or all of the nimodipine contained
in the formulation is contained in micelles or nano-emulsions. The
concentrate and dilution prepared from the concentrate preferably
includes a low alcohol content, e.g., preferably less than 300 mg
per dose (e.g., per 10 mg dose of nimodipine), and in certain
preferred embodiments less than 200 mg alcohol per dose (per 10 mg
dose of nimodipine), or less than 100 mg alcohol per dose, or less
than 50 mg alcohol per dose, or less than 25 mg alcohol per dose
(per 10 mg dose of nimodipine), or less than 10 mg alcohol per dose
(per 10 mg dose of nimodipine), or less than 5 mg alcohol per dose
(per 10 mg dose of nimodipine). Expressed in another way, in
preferred embodiments, the concentrate and dilution prepared from
the concentrate preferably includes a low alcohol content, e.g.,
preferably from about 0 to about 300 mg per dose (e.g., per 10 mg
dose of nimodipine), or from about 0 to about 200 mg alcohol per
dose (per 10 mg dose of nimodipine), or from about 0 to about 100
mg per dose (e.g., per 10 mg dose of nimodipine), or from about 0
to about 50 mg alcohol per dose (per 10 mg dose of nimodipine), or
from about 0 to about 25 mg per dose (e.g., per 10 mg dose of
nimodipine), or from about 0 to about 10 mg alcohol per dose (per
10 mg dose of nimodipine), or from about 0 to about 5 mg alcohol
per dose (per 10 mg dose of nimodipine). Preferably, the volume of
the nimodipine solution can be, e.g., from about 50 ml to 1000 ml,
with a concentration of from about 0.01 mg/ml to about 1.0 mg/ml
nimodipine. Preferably, when diluted the nimodipine solution will
have less than about 300 mg alcohol contained in that volume (of
from about 50 ml to 1000 ml). In certain preferred embodiments of
the nimodipine solution (after dilution of the afore-mentioned
concentrate above), the median particle size of micelles or
nano-emulsions range from about 0.5 nanometer to about 350
nanometers, or from about 0.5 nm to about 200 nm, or from about 5
nm to about 50 nm. Preferably, the nimodipine concentrate after
dilution composition is clear and does not contain a crystal
nimodipine precipitate. In certain preferred embodiments, the
nimodipine is substantially contained within micelles as a
nano-emulsion.
[0016] In other embodiments, the invention is directed in part to a
method of preparing a nimodipine injection concentrate the solution
having a low ethanol content. This is accomplished by first
dissolving nimodipine or a pharmaceutically acceptable salt thereof
in an organic solvent (e.g., ethanol) and surfactant to form a
nimodipine concentrate, the surfactant being in an amount effective
to enable the formation of micelles in the surfactant. Thereafter,
the concentrate is diluted in a pharmaceutically acceptable aqueous
medium. The organic solvent (e.g., ethanol) contained in this
concentrate solution is then substantially removed by evaporation
under vacuum or by any other suitable means. After evaporation of
the organic solvent (e.g., ethanol), the concentrate formulation
preferably contains from about 0.5 mg/ml to about 50 mg/ml of
nimodipine in a mixture containing from about 1% to about 99.5% of
hydrophilic surfactant. The resultant nimodipine concentrate is
stable, clear, colorless, free from crystalline nimodipine
precipitate, and substantially, if not totally alcohol free. In
certain preferred embodiments of the nimodipine injection
concentrate, the median particle size of micelles or nano-emulsions
ranges from about 0.5 nanometer to about 350 nanometers, or from
about 0.5 nm to about 200 nm, or from about 5 nm to about 50
nm.
[0017] The invention is further directed to a method of preparing a
nimodipine concentrate formulation, comprising mixing nimodipine
base or a pharmaceutically acceptable nimodipine salt with an
organic solvent in an amount sufficient to dissolve the nimodipine;
adding a hydrophilic surfactant to the mixture of nimodipine and
organic solvent; diluting the mixture with an aqueous carrier; and
thereafter substantially removing organic solvent via
lyophilization to obtain a nimodipine concentrate that contains
from about 0.5 mg/ml to about 50 mg/ml, and preferably from about
10 mg/ml to about 50 mg/ml nimodipine in micelles, the concentrate
formulation being clear, colorless, stable, and without a crystal
nimodipine precipitate. The method may further comprise storing the
nimodipine concentration formulation with degassing and headspace
replacement with an inert gas. In certain preferred embodiments,
the lyophilization is continued until the nimodipine concentrate
formulation comprises from about 0.5 mg/ml to about 50 mg/ml
nimodipine and preferably from about 10 mg/ml to about 50 mg/ml,
for a total dose of about 10 mg nimodipine, and from about 0 to
about 300 mg organic solvent, or from about 0 to about 200 mg
organic solvent, or from about 0 to about 100 mg organic solvent.
In certain preferred embodiments, the aqueous carrier is
deoxygenated water, the organic solvent is dehydrated alcohol, and
the hydrophilic surfactant comprises polysorbate 80. In certain
embodiments, the invention further comprises diluting the
nimodipine concentrate formulation to a volume from about 50 ml to
about 1000 ml with a pharmaceutical acceptable carrier for
injection such that the nimodipine is present in a concentration
from about 0.01 mg/ml to about 1.0 mg/ml, preferably from about
0.001 mg/ml to about 0.5 mg/ml, the diluted formulation remaining
clear micellar solution and displaying no crystal precipitation of
nimodipine.
[0018] In certain preferred embodiments, the nimodipine is
substantially contained within micelles as a nano-emulsion. In
certain preferred embodiments, the formulation is stable when
exposed to conditions of 40.degree. C..+-.2.degree. C./75% RH.+-.5%
RH for at least 6 months; and/or which is stable when exposed to
conditions of 25.degree. C..+-.2.degree. C./60% RH.+-.5% RH for at
least 12 months.
[0019] In certain preferred embodiments, the nimodipine concentrate
has a volume from about 0.1 ml to about 10 ml, preferably about 1
ml, and is contained in an ampoule or vial.
[0020] In certain embodiments, the nimodipine injection concentrate
is diluted with water for injection, saline, dextrose or other
commonly available infusion solutions up to a concentration, e.g.,
from about 0.01 mg/ml to about 1.0 mg/ml nimodipine and remains a
clear solution and displays no crystal precipitation of nimodipine.
The nimodipine injection concentrate can preferably be diluted with
a suitable injection medium that allows for administration of,
e.g., a single 100 or preferably 250 ml infusion bag or bottle that
contains, e.g., less than 1% w/v alcohol in a predominantly aqueous
medium, the diluted injection medium remaining a clear solution
that displays no precipitation of nimodipine.
[0021] In certain preferred embodiments, the emulsifier is selected
from the group consisting of a phospholipid and a polyethylene
glycol.
[0022] In certain preferred embodiments, the nimodipine formulation
is contained within a single infusion bag or bottle for continuous
intravenous infusion.
[0023] The administration of the nimodipine formulation via
injection or infusion allows first pass metabolism of the
nimodipine by the liver to be minimized, and the nimodipine
formulations administered via injection have significantly improved
bioavailability as compared to oral nimodipine formulations. By
virtue of the nimodipine injectable formulations of the invention,
consistent levels of nimodipine can be maintained in the plasma and
CSF of the (e.g., human) patient.
[0024] In alternative embodiments to the above, the nimodipine
formulation is diluted with a suitable pharmaceutical carrier for
oral or nasal ingestion (e.g., a suitable aqueous solution).
[0025] In certain preferred embodiments of the above-described
nimodipine concentrate and formulation, the aqueous carrier is
selected from the group consisting of Sodium Chloride Injection,
Ringers Injection, Isotonic Dextrose Injection, Sterile Water
Injection, Dextrose, and Lactated Ringers Injection.
[0026] In certain preferred embodiments, the nimodipine formulation
further comprises one or more preservatives. Examples of suitable
preservatives include, e.g., phenols or cresols, mercurials, benzyl
alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid
esters, thimerosal, benzalkonium chloride, benzethonium chloride,
boric acid, p-hydroxybenzoates, phenols, chlorinated phenolic
compounds, alcohols, quarternary compounds, mercurials, and
mixtures of any of the foregoing.
[0027] In certain preferred embodiments of the nimodipine
concentrate formulation, the pharmaceutically acceptable carrier
comprises from about 0.1% to about 99.5% of the formulation.
[0028] In certain preferred embodiments, the nimodipine formulation
has a pH from about 3 to about 9, and in certain preferred
embodiments, preferably from about 4.5 to about 7.5 or 8.
[0029] The invention is further directed to a method of treating
human patients having a condition selected from an aneurysm,
subarachnoid hemorrhage, vasospastic angina, Prinzmetal angina,
stable angina, acute myocardial infarction, myocardial arrest,
arrhythmia, systemic hypertension, pulmonary hypertension,
congestive heart failure, coronary artery surgery and hypertrophic
cardiomyopathy, comprising continuously infusing an intravenous
nimodipine solution in accordance with the present invention over a
period of about three weeks. The nimodipine infusion rate may be,
e.g., from about 0.05 mg nimodipine per hour to about 5 mg
nimodipine per hour. In certain embodiments, the intravenous
nimodipine dose is from about 2 to 10 mg administered every five
hours. In certain embodiments, the nimodipine formulation is
administered via intravenous bolus, intravenous infusion,
intra-arterial, intraoral, or intranasal using a naso-gastric tube.
In certain embodiments, the method further comprises further
diluting to a 2.5.times.10.sup.-5 mole solution of nimodipine to
rinse the exposed arteries after clipping the aneurysm and before
an intravenous infusion of nimodipine administered to improve
patient outcome. The diluted formulation may be contained within an
infusion set and bag. In further embodiments, the infusion bag is
covered with ultraviolet light (UV) protective bags to further
protect the nimodipine from photo-degradation. In other preferred
embodiments, the nimodipine formulation is administered as a
continuous infusion. In methods of the invention, first pass
metabolism by the liver is minimized and bioavailability is
improved. Consistent levels of nimodipine are therefore maintained
in the plasma and CSF of the (e.g., human) patient. In certain
preferred embodiments, the nimodipine infusion concentrate is
introduced into an appropriate infusion bag (e.g., 250 ml bag
containing saline, dextrose, etc.) and the nimodipine is infused
into the human patient over a time period of about 12 hours as a
continuous infusion. Bayer's Nimotop.RTM. infusion solution is
infused via the central vein (probably because the high alcohol
content necessitates co-infusion of dextrose and lactate ringer).
In contrast, the infusion solution of the present invention is
formulated to be infused via the peripheral vein (which is much
less invasive than via the central vein). However, the infusion
solution of the invention can be infused via the peripheral or
central vein.
[0030] The present invention relates to a novel pharmaceutical
composition containing nimodipine base or any acceptable
pharmaceutical salt as active for continuous parenteral
administration.
[0031] The present invention available in particular in the form of
a solution for parenteral administration that is a sterile
preservative free premix ready for infusion with no further
dilution required prior to administration.
[0032] The present invention available in particular in the form of
a solution for parenteral administration that is in the form of a
concentrated injectable solution which can be diluted down in an
appropriate medium (e.g. saline) to a solution for administration
by infusion.
[0033] As used herein, the term "unit dose" refers to physically
discrete units suitable as unitary dosages for mammalian subjects,
each unit containing as the active ingredient a predetermined
quantity of the nimodipine. Examples of suitable unit doses of
nimodipine in accordance with the invention include clear solution
or micelles or nano-emulsion in suitable containers, e.g., in a
ampule or vial.
[0034] The term "comprising" is an inclusive term interpreted to
mean containing, embracing, covering or including the elements
listed following the term, but not excluding other unrecited
elements.
[0035] A "therapeutically effective amount" means the amount that,
when administered to an animal for treating a disease, is
sufficient to effect treatment for that disease.
[0036] As used herein, the term "treating" or "treatment" of a
disease includes preventing the disease from occurring in an animal
that may be predisposed to the disease but does not yet experience
or exhibit symptoms of the disease (prophylactic treatment),
inhibiting the disease (slowing or arresting its development),
providing relief from the symptoms or side-effects of the disease
(including palliative treatment), and relieving the disease
(causing regression of the disease).
[0037] By "stable" it is meant that substantially no degradation of
the concentrate intravenous infusion solution (the product) is
observed after storage for 1 month at 40.degree. C. In preferred
embodiments, the term "stable" with respect to the concentrate
intravenous infusion solution comprising the water-insoluble
nimodipine and surfactant(s) means that there is less than about 5%
degradation (and preferably less than 4%, or less than 3%, or less
than 2%, or less than 1.5%, or less than 1% degradation) of the
nimodipine and no observable precipitate after storage for 48
hours; or that the nimodipine micelle structure is thermally stable
during a terminal sterilization process by autoclaving at
121.degree. C. for 30 minutes, in that the mean diameter of the
colloidal structures does not change by more than about 50
nanometer comparing the colloidal structures before and after the
terminal sterilization process, or both.
[0038] The term "parenteral" as used herein, includes subcutaneous
injections, intravenous, intramuscular, intrasternal injection or
infusion techniques.
[0039] The term "substantially free of organic solvent" and/or
"substantially free of alcohol" means that the formulation contains
no more than 0.5% organic solution/alcohol, or preferably less than
0.4%, less than 0.3%, less than 0.2%, less than 0.1%, or less than
0.05% organic solvent/alcohol.
[0040] The term "substantially free of crystalline nimodipine
precipitate" or "substantially without nimodipine precipitate"
means that the nimodipine concentrate or diluted nimodipine
formulation remains a clear solution and free of all drug
precipitation that may be clinically significant (e.g., the
formulation would be considered to be safe and effective by a
regulatory authority such as the U.S. F.D.A.).
[0041] The term "without nimodipine precipitate"means that the
nimodipine concentrate or diluted nimodipine formulation remains a
clear solution and free of all drug precipitation that may be
clinically significant (e.g., the formulation would be considered
to be safe and effective by a regulatory authority such as the U.S.
F.D.A.).
[0042] All numbers expressing quantities of ingredients, reaction
conditions, and so forth used in the specification and claims are
to be understood as being modified in all instances by the term
"about." Accordingly, unless indicated to the contrary, the
numerical parameters set forth in the specification and attached
claims are approximations that may vary depending upon the desired
properties sought to be obtained by the present invention. At the
very least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of the claims, each numerical
parameter should be construed in light of the number of significant
digits and ordinary rounding approaches.
DETAILED DESCRIPTION
[0043] Nimodipine is a dihydropyridine calcium antagonist.
Nimodipine is isopropyl 2-methoxyethyl
1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate.
It has a molecular weight of 418.5 and a molecular formula of
C21H26N2O7. Nimodipine inhibits calcium ion transfer into these
cells and thus inhibits contractions of vascular smooth muscle. The
contractile processes of smooth muscle cells are dependent upon
calcium ions, which enter these cells during depolarization as slow
ionic transmembrane currents. In animal experiments, nimodipine had
a greater effect on cerebral arteries than on arteries elsewhere in
the body perhaps because it is highly lipophilic, allowing it to
cross the blood-brain barrier; concentrations of nimodipine as high
as 12.5 ng/mL have been detected in the cerebrospinal fluid of
nimodipine-treated subarachnoid hemorrhage (SAH) patients. The
precise mechanism of action of nimodipine in humans is unknown.
Although the clinical studies demonstrate a favorable effect of
nimodipine on the severity of neurological deficits caused by
cerebral vasospasm following SAH, there is no arteriographic
evidence that the drug either prevents or relieves the spasm of
these arteries. However, whether or not the arteriographic
methodology utilized was adequate to detect a clinically meaningful
effect, if any, on vasospasm is unknown.
[0044] Nimodipine as a pale yellow crystalline powder almost
insoluble in water(2.5 .mu.g/ml, 25.degree. C.) Therefore its
intrinsic solubility poses challenges in the development of an
injectable pharmaceutical formulation that is concentrated, stable
and dilutable. The present invention aims to resolve solubility
deficiencies of previously approved nimodipine dosage forms by the
development of a robust, stable, and easy to administer nimodipine
infusion injection. Another objective of the present invention is
to provide the composition and preparation of the nimodipine
infusion solution and its administration.
[0045] Although the present invention focuses on the drug
nimodipine, one skilled in the art will appreciate that the present
invention is applicable to other dihydropyridine calcium channel
blockers such as amlodipine, aranidipine, azelnidipine,
barnidipine, benidipine, cilnidipine, clevidipine, efonidipine,
felodipine, isradipine, lacidipine, lercanidipine, manidipine,
nicardipine, nifedipine, nilvadipine, nisoldipine, nitrendipine,
pranidipine, and the like. For purposes of the present invention,
in each instance where the drug nimodipine is mentioned, any of the
above drugs or other similar dihydropyridine calcium channel
blockers can be substituted in its place, and these drugs are meant
to be encompassed by the present disclosure.
[0046] Two key aspects of a pharmaceutically acceptable liquid
formulation, e.g., for parenteral use, are solubility of the drug
in the carrier (solvent) and the stability of the final formulation
(including but not limited to the ability of the formulation to
prevent the drug from precipitating out of solution). The prior art
is replete with examples of excipients used to solubilize poorly
water soluble drugs for oral and injectable dosage forms. Such
excipients include organic solvents, surfactants, triglycerides,
cyclodextrins and phospholipids.
[0047] The use of organic solvents such as ethanol is limited for
parenteral formulations because of possible precipitation of the
active (drug), pain, inflammation and hemolysis upon injection.
Ethanol is used for both solubility and stability reasons in the
prior commercially available forms of nimodipine. As previously
reported herein, the currently marketed nimodipine formulation in
Europe includes 23.7% ethanol.
[0048] In contrast to prior intravenous nimodipine formulations,
the intravenous nimodipine formulation of the present invention is
a solution comprising nimodipine, a hydrophilic surfactant and a
small quantity of organic solvent, wherein nimodipine is dissolved
in a small amount of organic solvent by mixing and further this
nimodipine solution is combined with a hydrophilic surfactant to
form micelles of nimodipine in a clear solution.
The Concentrate
[0049] One aspect of the present invention is directed to a
nimodipine injection concentrate. In such embodiments, the
nimodipine is mixed with a pharmaceutically acceptable carrier to
prepare a concentrated injection solution, suspension, emulsion or
complex. Thereafter, an effective amount of a hydrophilic
surfactant is added. Optionally, a pharmaceutically acceptable
medium for injection is added in a relatively small quantity (e.g.,
5 ml) in order to prepare the final nimodipine concentrate
formulation.
[0050] The nimodipine formulations of the present invention having
a low ethanol content may be prepared by dissolving the nimodipine
and/or a pharmaceutically acceptable salt thereof in ethanol and
(e.g., hydrophilic) surfactant. The concentrate may be prepared by
admixing a suitable amount of nimodipine to an organic solvent and
the hydrophilic surfactant together for a sufficient period of time
to form stable micelles. Thereafter, a suitable pharmaceutical
medium for injection (e.g., water for injection) is added to
prepare the final nimodipine concentrate formulation. Preferably,
the pharmaceutical medium (water) is deoxygenated. The ethanol
contained in this solution is then removed at least partially by
evaporation under vacuum or by any other suitable means. Examples
of other acceptable drying methods include rotavap (rotatory
evaporator), and oven dryer at low temperature. Solutions after
ethanol evaporation contain from about 0.5 mg/ml to about 50 mg/ml
of nimodipine in a mixture containing from about 1% to about 99.5%
of hydrophilic surfactant to be prepared as concentrate injection
solution which is stable and substantially alcohol free, if not
totally alcohol free. The term "substantially alcohol free" is
meant for purposes of the present invention that the concentrate
contains from about 0 to about 0.5% organic solvent (e.g.,
alcohol). The term "totally alcohol free" is meant for purposes of
the present invention that the concentrate contains from about 0%
organic solvent (e.g., alcohol)or levels that are not measurable by
typically used techniques, such as gas chromatography. The ethanol
is completely, or almost completely, removed via the aforementioned
evaporation step. For example, in a preferred embodiment, the
concentrate is subjected to lyophilization using a vacuum drying
cycle (e.g., a vacuum at about 75-100 millitorr at a suitable
temperature (e.g., room temperature of 25.degree. C.) for a
suitable time period (e.g., from about 1 to about 20 hours,
preferably from about 3 to about 10 hours). After lyophilization,
the product is a viscous liquid with little or no alcohol remains.
The concentrate and dilution prepared from the concentrate
preferably includes a low alcohol content, e.g., preferably less
than 300 mg per dose (e.g., per 10 mg dose of nimodipine), and in
certain preferred embodiments less than 200 mg alcohol per dose
(per 10 mg dose of nimodipine), or less than 100 mg alcohol per
dose, or less than 50 mg alcohol per dose, or less than 25 mg
alcohol per dose (per 10 mg dose of nimodipine), or less than 10 mg
alcohol per dose (per 10 mg dose of nimodipine), or less than 5 mg
alcohol per dose (per 10 mg dose of nimodipine). Expressed in
another way, in preferred embodiments, the concentrate and dilution
prepared from the concentrate preferably includes a low alcohol
content, e.g., preferably from about 0 to about 300 mg per dose
(e.g., per 10 mg dose of nimodipine), or from about 0 to about 200
mg alcohol per dose (per 10 mg dose of nimodipine), or from about 0
to about 100 mg per dose (e.g., per 10 mg dose of nimodipine), or
from about 0 to about 50 mg alcohol per dose (per 10 mg dose of
nimodipine), or from about 0 to about 25 mg per dose (e.g., per 10
mg dose of nimodipine), or from about 0 to about 10 mg alcohol per
dose (per 10 mg dose of nimodipine), or from about 0 to about 5 mg
alcohol per dose (per 10 mg dose of nimodipine). In certain
preferred embodiments of the nimodipine injection concentrate, the
median particle size of micelles or nano-emulsions ranges from
about 0.5 nanometer to about 350 nanometers, or from about 0.5 nm
to about 200 nm, or from about 5 nm to about 50 nm. Preferably, the
nimodipine concentrate formulation is clear and does not contain a
crystal nimodipine precipitate. In certain preferred embodiments,
the nimodipine is substantially contained within micelles as a
nano-emulsion. The 10 mg dose of nimodipine contained in the
concentrate is typically contained in about 5 ml of the concentrate
formulation, although the 10 mg dose of nimodipine may be contained
in, e.g., from about 0.5 ml to about 10 ml of formulation. After
vacuum drying, the nimodipine injection concentrate (containing a
10 mg dose of nimodipine) preferably is about 0.5 ml.
[0051] In certain embodiments of the present invention, the
hydrophilic surfactant comprises at least about 8% of the
formulation in the injection concentrate and at least 0.1% in the
final diluted injection solution. In other preferred embodiments,
the hydrophilic surfactant comprises from about 1% to about 95.5%
of the formulation, by weight of the injection concentrate and from
about 0.01% to about 2.5% of the final diluted injection
solution.
[0052] In certain preferred embodiments, the hydrophilic surfactant
comprises a pharmaceutically acceptable non-ionic surfactant. The
non-ionic surfactant is preferably included in an amount sufficient
to inhibit precipitation of drug substance from the
pharmaceutically acceptable medium for injection (e.g., aqueous
solution) after dilution. Non-ionic surfactants form stable
micelles with drug substance, can solubilize the drug and may
impart additional photo stability to the drug.
[0053] Using HLB values as a rough guide, hydrophilic surfactants
are considered those compounds having an HLB value greater than 10
particularly from 12 to 17. The hydrophilic non-ionic surfactant is
more soluble in water than in oil (having HLB higher than 10).
[0054] Pharmaceutically acceptable non-ionic surfactants useful in
the formulations of the present invention include but are not
limited to, for example, polyoxyethylene compounds, ethoxylated
alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene
compounds, propoxylated alcohols, ethoxylated/propoxylated block
polymers, and propoxylated esters, alkanolamides, amine oxides,
fatty acid esters of polyhydric alcohols, ethylene glycol esters,
diethylene glycol esters, propylene glycol esters, glyceryl esters,
polyglyceryl fatty acid esters, sorbitan esters, sucrose esters,
and glucose (dextrose) esters. Further examples are reaction
products of a natural or polyethoxylated castor oil and ethylene
oxide. The ethoxylated castor oil may have an ethylene oxide
content of 25 to 100 moles ethylene oxide per molecule, preferably
35 to 60 moles ethylene oxide per molecule. The natural or
polyethoxylated castor oil may be reacted with ethylene oxide in a
molar ratio of from about 1:35 to about 1:60, with optional removal
of the polyethoxylated component from the products. Non-ionic
hydrophilic surfactants useful in the present invention further
include alkylgluceosides; alkylmaltosides; alkylthioglucosides;
lauryl macrogolglycenides; polyoxyethylene alkyl ethers;
polyoxyethylene alkylphenols; polyethylene glycol fatty (mono- and
di-) acid esters; polyethylene glycol glycerol fatty acid esters;
polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl
fatty acid esters; polyoxyethylene glycerides; polyoxyethylene
sterols and analogues thereof; polyoxyethylene vegetable oils,
polyoxyethylene hydrogenated vegetable oils; reaction mixtures of
polyols and at least one member selected from the group consisting
of fatty acids, glycerides, vegetable oils, hydrogenated vegetable
oils, in sterols; sugar esters, sugar ethers; sucroglycerides;
fatty acid salts, bile salts, phospholipids, phosphoric acid
esters, carboxylates, sulfates, sulfonates. More specifically, the
nonionic surfactant may comprise, for example, polyoxyethylene
fatty alcohol esters, sorbitan fatty acid esters (Spans),
polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene
(20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan
monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate
(Tween 20) and other Tweens, sorbitan esters, glycerol esters,
e.g., Myrj and glycerol triacetate (triacetin), polyethylene
glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol,
polysorbate 80, poloxamers, poloxamines, polyoxyethylene castor oil
derivatives (e.g., Cremophor.RTM. RH40, Cremphor A25, Cremphor A20,
Cremophor.RTM. EL) and other Cremophors, sulfosuccinates, alkyl
sulphates (SLS); PEG glyceryl fatty acid esters such as PEG-8
glyceryl caprylate/caprate (Labrasol), PEG-4 glyceryl
caprylate/caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate
(Gelucire 444/14), PEG-6 glyceryl mono oleate (Labrafil M 1944 CS),
PEG-6 glyceryl linoleate (Labrafil M 2125 CS); propylene glycol
mono- and di-fatty acid esters, such as propylene glycol laurate,
propylene glycol caprylate/caprate; Brij.RTM. 700,
ascorbyl-6-palmitate, stearylamine, sodium lauryl sulfate,
polyoxethyleneglycerol triiricinoleate, and any combinations or
mixtures thereof. Although polyethylene glycol (PEG) itself does
not function as a surfactant, a variety of PEG-fatty acid esters
have useful surfactant properties. Among the PEG-fatty acid
monoesters, esters of lauric acid, oleic acid, and stearic acid are
most useful.
[0055] Examples of the same include PEG-8 laurate, PEG-8 oleate,
PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12
laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20
oleate. Polyethylene glycol fatty acid esters are also suitable for
use as surfactants in the compositions of the present invention,
such as PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate,
PEG-32 dilaurate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30
glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate,
and PEG-30 glyceryl oleate. The hydrophilic surfactant may further
comprise mixtures of any of the foregoing.
[0056] Polysorbate 80, an especially preferred hydrophilic
non-ionic surfactant in the formulations of the present invention,
is a surfactant commonly used in protein parenteral formulations to
minimize denaturation at the air-water interface. Polysorbate 80 is
also sometimes used in injectable solution formulations of small
molecules for the purpose of solubility enhancement due to micelle
formation. Polysorbates are nonionic surfactants of sorbitan
esters. Polysorbates useful in the present invention include, but
are not limited to polysorbate 20, polysorbate 40, polysorbate 60,
polysorbate 80 (Tween 80) and any combinations or mixtures thereof.
Other suitable preferred surfactants includes poloxamer, poloxamer
407, transcutol. The surfactant can be any surfactant suitable for
use in pharmaceutical compositions. Suitable surfactants can also
be ionic hydrophilic surfactants or hydrophobic surfactants.
Suitable hydrophilic surfactants can be anionic, cationic,
zwitterionic or non-ionic, although non-ionic hydrophilic
surfactants are presently preferred. Preferably, the nimodipine
formulations of the invention include at least one non-ionic
hydrophilic surfactant.
[0057] However, in other embodiments, the nimodipine formulations
may include mixtures of two or more non-ionic hydrophilic
surfactants, as well as mixtures containing at least one non-ionic
hydrophilic surfactant and at least one hydrophobic surfactant.
[0058] In certain embodiments, the surfactant can be one or more of
the surfactants described in U.S. Pat. No. 6,363,471, hereby
incorporated by reference.
[0059] In certain embodiments of the present invention, the organic
solvent is an alcohol (e.g., ethanol) and the solubilizer is
polysorbate.
[0060] In the above embodiments, the nimodipine is solubilized
using surface active agents as solubilizers via the formation of
colloidal particles called micelles and stabilized by using
co-solvents and/or appropriate substrates in the aqueous
formulation. This results in the formation of micelles, or minute
colloidal particles which surround the nimodipine molecule,
isolating it from the water molecules surrounding it, but forming a
clear aqueous solution. The liquid formulations are suitable for
use as parenteral, nasal or oral administration.
[0061] Water-miscible surfactant molecules like polysorbate
consists of both hydrophobic and hydrophilic portions that can
solubilize select poorly water-soluble drugs. Surfactants can also
self-assemble to form micelles once the surfactant monomer
concentration reaches the critical micelle concentration. Thus,
surfactants can solubilize drug molecules by either a direct
co-solvent effect or by uptake into micelles. The non-ionic
surfactants in commercially available solubilized oral and
injectable formulations include polyoxyl 35 castor oil (Cremophor
EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40),
polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), d--tocopherol
polyethylene glycol 1000 succinate (TPGS), Solutol HS-15, sorbitan
monooleate (Span 80), polyoxyl 40 stearate, and various
polyglycolyzed glycerides including Labrafil M-1944CS, Labrafil
M-2125CS, Labrasol, Gellucire 44/14, and Softigen 767.
[0062] In the present invention nimodipine formulation preferably
forms colloidal structures (micelles) about 10 nm in diameter. In
other preferred embodiments, the mean diameter of the colloidal
structures varies from about 0.5 nm to about 200 nm and more
preferably about 5 nm to about 50 nm. In the present invention, the
nimodipine micelle structure is thermally stable during a terminal
sterilization process by autoclaving at 121.degree. C. for 30
minutes.
[0063] Any suitable pharmaceutically acceptable water-miscible
organic solvent can be used in the present invention during the
preparation of the nimodipine concentrate formulation, although
alcohol is preferred. Selection of a suitable organic solvent will
depend in part upon the solubility of the active material
(nimodipine) in the solvent, the degree to which the solvent is
miscible in water, and the tolerability of the solvent. The solvent
should be physiologically acceptable. Examples of solvents that may
be used in the present invention include, but are not limited to,
various alcohols such as ethanol, glycols, glycerin, propylene
glycol, and various polyethylene glycols and dimethyl isosorbide
(DMI). Additional useful alcohols include but are not limited to
methanol (methyl alcohol), ethanol, (ethyl alcohol), 1-propanol
(n-propyl alcohol), 2-propanol (isopropyl alcohol), 1-butanol
(n-butyl alcohol), 2-butanol (sec-butyl alcohol),
2-methyl-1-propanol (isobutyl alcohol), 2-methyl-2-propanol
(t-butyl alcohol), 1-pentanol (n-pentyl alcohol),
3-methyl-1-butanol (isopentyl alcohol), 2,2-dimethyl-1-propanol
(neopentyl alcohol), cyclopentanol (cyclopentyl alcohol), 1-hexanol
(n-hexanol), cyclohexanol (cyclohexyl alcohol), 1-heptanol
(n-heptyl alcohol), 1-octanol (n-octyl alcohol), 1-nonanol (n-nonyl
alcohol), 1-decanol (n-decyl alcohol), 2-propen-1-ol (allyl
alcohol), phenylmethanol (benzyl alcohol), diphenylmethanol
(diphenylcarbinol), triphenylmethanol (triphenylcarbinol),
glycerin, phenol, 2-methoxyethanol, 2-ethoxyethanol,
3-ethoxy-1,2-propanediol, Di(ethylene glycol) methyl ether,
1,2-propanediol, 1,3-propanediol, 1,3-butanediol, 2,3-butanediol,
1,4-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol,
1,5-pentanediol, 2,3-pentanediol, 2,4-pentanediol, 2,5-pentanediol,
3,4-, pentanediol, and 3,5-pentanediol.
[0064] The nimodipine concentrates of the invention may be
contained in any pharmaceutically acceptable container (e.g.,
ampules, vials) in a unit dose for later dilution (e.g., at the
site and time of administration to a human patient).
Dilution
[0065] The injectable nimodipine formulations of the invention are
preferably clear, colorless and contain the nimodipine in micelles
or inclusion complexes, etc. which can be diluted with a
pharmaceutically acceptable carrier for injection (e.g., water for
injection) to produce a thermodynamically stable dispersion of
non-ionic surfactant nanoparticles which are micelles, inclusion
complexes, etc., as described and disclosed herein. The diluted
nimodipine formulation is stable, i.e., the nimodipine does not
phase separate across a broad range of temperatures (e.g., from
about 15.degree. C. to about 25.degree. C.) at a wide range of pH
(e.g., from about pH 5 to about pH 8). Thus, the nimodipine
injection concentrate disclosed herein, when diluted with water for
injection, saline, dextrose or commonly available infusion
solutions up to a concentration of 0.01 mg/ml remains a clear
solution and displays no precipitation of nimodipine. When diluted
to 10 times dilution of 0.01 mg/ml, there is preferably still no
precipitate (e.g., the limit would be, e.g., about 0.001
mg/ml).
[0066] In accordance with the present invention, the nimodipine
formulation allows for administration of a single 250 ml infusion
bag or bottle that contains IV nimodipine comprising, e.g., less
than 2% w/v or less than 1% w/v alcohol in a predominantly aqueous
medium, a distinct improvement over IV Nimotop. Preferably, the
nimodipine formulation may comprise less than about 0.5% w/v
alcohol in 250 ml formulation, as a ready-to-use formulation. This
lower alcohol content in the formulation provides many advantages
known to those skilled in the art, for example, making the
inventive nimodipine formulation amenable for administration to
patients suffering from alcoholism, impaired alcohol metabolism and
those who are pregnant and breast feeding. Stated another way, the
nimodipine concentrate (and therefore the nimodipine diluted
solution) of the present invention contains, e.g., from 0 to about
300 mg alcohol.
[0067] The present invention is a micellar formulation of
nimodipine that provides for greatly enhanced aqueous solubility
and stability including photo-stability. Nimodipine does not
precipitate out of this formulation even when diluted with water up
to 250 times its original concentration. The concentrate has a
nimodipine concentration from 10 mg/ml to 50 mg/ml, and that the
diluted form has a nimodipine concentration from 0.04 mg/ml to 0.2
mg/ml which can be up to 250 times greater.
[0068] In certain embodiments of the present invention, the
nimodipine injection concentrate is diluted in an infusion bag
containing water for injection or any commonly available
intravenous infusion solution. Infusion volumes can range from
about 50 ml to about 1000 ml. The current invention provides for
dilution of formulation in a single infusion bag and infused over a
specific period unlike Bayer's Nimotop intravenous injection which
requires a three-way stopcock auxiliary to infuse Nimotop solution
along with two other co-infusion solutions to prevent any drug
precipitation. The current invention provides for a single infusion
solution that does not precipitate upon dilution and/or
administration thus improving safety and efficacy.
[0069] In certain preferred embodiments, the nimodipine injection
can be further diluted to a 2.5.times.10.sup.-5 mole solution of
nimodipine to rinse the exposed arteries after clipping the
aneurysm and before an intravenous infusion of nimodipine
administered to improve patient outcome.
[0070] In certain preferred embodiments, the novel solvent free
(e.g., less than 1% w/v organic solvent such as ethanol) nimodipine
formulation can be administered intravenous bolus, intravenous
infusion, intra-arterial, intraoral, intranasal using a
naso-gastric tube.
[0071] In certain preferred embodiments, the nimodipine injection
after dilution with commonly available infusion solutions, the
infusion set and bag can be covered with ultraviolet light (UV)
protective bags to further protect it from photo-degradation.
[0072] The compounds of the invention may be administered
parenterally in formulations eventually containing conventional
non-toxic pharmaceutically acceptable carriers, adjuvants and
vehicles as desired.
[0073] Injectable preparations, for example sterile injectable
aqueous or oleaginous suspensions may be formulated according to
known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent. Among the acceptable
vehicles and solvents are water, Ringer's solution and isotonic
sodium chloride. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono or diglycerides, in addition fatty acids such as oleic acid
find use in the preparation of injectables. Suitable carriers for
intravenous administration include physiological saline or
phosphate buffered saline (PBS), and solutions containing
solubilizing agents, such as glucose, polyethylene glycol, and
polypropylene glycol and mixtures thereof.
[0074] The aqueous vehicle(s) useful in the nimodipine concentrate
and nimodipine solutions of the present invention include, by way
of example and without limitation, Sodium Chloride Injection,
Ringers Injection, Isotonic Dextrose Injection, Sterile Water
Injection, Dextrose, and Lactated Ringers Injection. Nonaqueous
parenteral vehicles include, by way of example and without
limitation, fixed oils of vegetable origin, cottonseed oil, corn
oil, sesame oil and peanut oil.
[0075] Antimicrobial agents in bacteriostatic or fungistatic
concentrations must be added to parenteral preparations packaged in
multiple dose containers which include phenols or cresols,
mercurials, benzyl alcohol, chlorobutanol, methyl and propyl
p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride,
benzethonium chloride, boric acid, p-hydroxybenzoates, phenols,
chlorinated phenolic compounds, alcohols, quarternary compounds,
mercurials, mixtures of the foregoing and the like. Isotonic agents
include, by way of example and without limitation, sodium chloride
and dextrose. Buffers include phosphate and citrate. Antioxidants
include sodium bisulfate. Local anesthetics include procaine
hydrochloride. Suspending and dispersing agents include sodium
carboxymethylcelluose, hydroxypropyl methylcellulose and
polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80
(TWEEN.RTM. 80) [A sequestering or chelating agent of metal ions
include EDTA.] Pharmaceutically acceptable pH adjusting agents
include, by way of example and without limitation, sodium
hydroxide, hydrochloric acid, citric acid or lactic acid. The
nimodipine formulations of the invention may additionally include
physiologically acceptable components such as sodium chloride and
like materials conventionally used to achieve isotonicity with
typical body fluids, pH buffers to establish a physiologically
compatible pH range and to enhance the solubility of the
nimodipine, preservatives, stabilizers and antioxidants and the
like.
[0076] In certain preferred embodiments, the injectable
formulations after dilution with water for injection and other
commonly available intravenous infusion solutions, the pH of final
diluted solution will be from about 3 to about 9, and in certain
preferred embodiments from about 4.5 to about 8. In some
embodiments of the present invention, the pH is adjusted using a
pharmaceutically acceptable buffer or alkalizing agent, with
suitable alkalizing agents and buffers including but not limited to
NaOH, KOH, triethylamine, meglumine, L-Arginine, sodium phosphate
buffer (either sodium phosphate tribasic, sodium phosphate dibasic,
sodium phosphate monobasic, or o-phosphoric acid), sodium
bicarbonate, and mixtures of any of the foregoing.
[0077] In certain other embodiments, the formulation may be made
isotonic via the addition of a tonicity agent, such as but not
limited to any pharmaceutically acceptable sugar, salt or any
combinations or mixtures thereof, such as, but not limited to
dextrose and sodium chloride. The tonicity agents may be present in
an amount from about 100 mOsm/kg to about 500 mOsm/kg, or from
about 200 mOsm/kg to about 400 mOsm/kg, or from about 280 mOsm/kg
to about 320 mOsm/kg.
Nimodipine Stability
[0078] Drug stability is the ability of the pharmaceutical dosage
form to maintain its physical, chemical, therapeutic and microbial
properties during the time of storage and usage by the patient. It
is measured by the rate of changes that take place in the
pharmaceutical dosage forms. Drug dosage can not be used after
known and unknown impurity levels exceed the limit, per guidelines
set by ICH. In addition, some products of drug degradation are
toxic and harmful to patients. Several factors affect drug
stability; among them oxidative degradation is one major factor.
This oxidative degradation rate is directly proportional to the
amount of oxygen available to drug, in the formulation. Temperature
increases oxidative degradation. Our experimental studies indicate
that a lower concentration of over head space and dissolved oxygen
provides additional stability to the nimodipine IV formulation.
Deaerated WFI for formulation preparation and inert gas blanketing
(purging with an inert gas such as nitrogen) while processing and
during the filling process provide a robust stable nimodipine IV
drug formulation. To attain a more stable drug formulation, the
dissolved oxygen content should be about 2.0 ppm in the nimodipine
formulation and headspace oxygen content should be less than 5%.
After dilution as described above, the nimodipine formulations of
the invention are preferably chemically stable up to at least 48
hours for continuous infusion.
Treatment with Nimodipine
[0079] In accordance with the present invention, intravenous
nimodipine solution can treat conditions such as, but not limited
to, aneurysms, subarachnoid hemorrhage, vasospastic angina,
Prinzmetal angina, stable angina, acute myocardial infarction,
myocardial arrest, arrhythmia, systemic hypertension, pulmonary
hypertension, congestive heart failure, coronary artery surgery and
hypertrophic cardiomyopathy.
[0080] Nimodipine is indicated for the treatment of ischaemic
neurological deficits following aneurysmal subarachnoid
haemorrhage. With respect to Nimotop.RTM. 0.02% solution for
infusion (Bayer plc), the recommended treatment is as follows: for
the first two hours of treatment 1 mg of nimodipine, i.e., 5 ml
Nimotop solution, (about 15 .mu.g/kg bw/h), should be infused each
hour via a central catheter. If it is well tolerated, the dose
should be increased after two hours to 2 mg nimodipine, i.e. 10 ml
Nimotop solution per hour (about 30 .mu.g/kg bw/h), providing no
severe decrease in blood pressure is observed. Patients of body
weight less than 70 kg or with unstable blood pressure should be
started on a dose of 0.5 mg nimodipine per hour (2.5 ml of Nimotop
solution), or less if necessary. Nimotop capsules are also
available in the U.S. for oral administration, each one containing
30 mg of nimodipine in a vehicle of glycerin, peppermint oil,
purified water and polyethylene glycol 400. The oral dose is 60 mg
every 4 hours for 21 consecutive days, preferably not less than one
hour before or two hours after meals.
[0081] In certain embodiments of the present invention, the IV
nimodipine solution can be continuously infused over a period of
about 3 weeks. The rate of infusion can be titrated based on
patient tolerance and avoiding a decrease in blood pressure. The
preferred infusion rate is from about 0.05 mg nimodipine per hour
to about 5 mg nimodipine per hour. A dose titration is not possible
with currently US FDA approved oral dosage forms.
[0082] In certain embodiments of the present invention, the IV
nimodipine dose is reduced to about 2 to 10 mg every five hours
compared to the current approved oral dose of 60 mg every four
hours without reduction in drug product efficacy and safety. The
current US FDA approved oral nimodipine drug product has high
first-pass metabolism resulting in numerous metabolites, all of
which are either inactive or considerably less active than the
parent compound. The bioavailability of nimodipine averages 13%
after oral administration. The first-pass metabolism is avoided via
intravenous administration, and intra-subject (patient) variability
associated with current approved oral dosage forms is reduced.
Also, the single bag and or bottle continuous intravenous infusion
of the nimodipine formulations of the invention is a convenient way
to administer the effective concentration of nimodipine to
unconscious patient and to patient having difficulty in swallowing
oral dosage forms.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0083] The following examples of formulations in accordance with
the present invention are not to be construed as limiting the
present invention in any manner and are only samples of the various
formulations described herein.
EXAMPLES 1-2
[0084] The formulation of Example 1-2 was prepared as follows:
nimodipine base was added to ethanol while stirring and mixing
until a clear solution is observed. Polysorbate 80 was then added
as a surfactant while stirring and mixing for 30 minutes to form
stable micelles. Sufficient water for injection (deoxygenated
water) was then added to the solution to generate 5 ml of
nimodipine injection concentrate. The ethanol is then completely,
or almost completely, removed by evaporation in a lyophilizer using
vacuum drying cycle at room temperature. After lyophilization, the
product is a viscous liquid with little or no alcohol remains. In
these examples, the lyophilization process includes a vacuum at
about 75-100 millitorr at 25.degree. C. until the final product is
obtained (little or no alcohol as per the present invention). The
ingredients of Examples 1-2 are set forth in Table 1 below:
TABLE-US-00002 TABLE 1 Example 1 Example 2 Composition Quantity in
mg Quantity in mg Concentrate Solution Nimodipine 10 10 Alcohol
(dehydrated) 1900 1900 Polysorbate 80 400 400 Water for injection
Qs 5 ml Qs 5 ml Ethanol Evaporation Process using Lyophilizer
Process temperature 25.degree. C. 25.degree. C. Vacuum applied 75
millitorr 100 millitorr Duration of process 3 hours 10 hours
[0085] The alcohol content of Examples 1-2 was determined using
high pressure liquid chromatography with a refractive index (RI)
detector and the results are shown in Table 2. A single dose
represents 10 mg of nimodipine infused over 5 hours.
TABLE-US-00003 TABLE 2 Example 1 Example 1 Example 2 (Before (After
(After IV ethanol ethanol ethanol Nimotop .RTM. evaporation)
evaporation) evaporation) Infusion Ethanol 1867 mg/ 263 mg/ 1.88
mg/ 10416 mg/ concentration dose dose dose dose per dose
EXAMPLES 3
[0086] The concentrated formulation of Example 2 with ethanol
content about 2 mg/dose was reconstituted with sterile 0.9% sodium
chloride solution up to 100 ml volume and filled in the amber color
glass bottle. The composition of the formulation is further
detailed in Table 3 below:
TABLE-US-00004 TABLE 3 Composition Qty/dose Concentrated
formulation of Equivalent to 10 mg of Nimodipine example 2 0.9%
Sodium chloride Quantity sufficient up to 100 mL Total 100 mL
EXAMPLE 4
[0087] Amber glass bottles were filled with the formulation of
Example 2 (Concentrate) and Example 3 (100 mL ready to infuse) with
a rubber stopper and flip-off seal and subjected to stability under
following conditions:
[0088] ICH accelerated conditions (ACC) at 40.degree.
C..+-.2.degree. C./75% RH.+-.5% RH; and
[0089] ICH room temperature conditions (CRT) at 25.degree.
C..+-.2.degree. C./60% RH.+-.5% RH
The International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use (ICH) is a project
that brings together the regulatory authorities of Europe, Japan
and the United States and experts from the pharmaceutical
industry.
[0090] Samples were analyzed to measure the Nimodipine assay,
impurities and physical stability (drug precipitation during
stability). The stability data is provided in Table 4 below.
CONCLUSION
[0091] It will be apparent to those skilled in the art that the
nimodipine concentrate and diluted formulations may be made using
different but equivalent methods, and that these formulations may
use other surfactants, carriers and emulsifiers beyond those
specifically mentioned herein. Such obvious modifications are
considered to be within the scope of the appended claims.
* * * * *