U.S. patent application number 13/288077 was filed with the patent office on 2012-03-01 for aripiprazole complex formulation and method.
This patent application is currently assigned to Bristol-Myers Squibb Company. Invention is credited to Vijay Naringrekar, MANOJ NERURKAR.
Application Number | 20120053145 13/288077 |
Document ID | / |
Family ID | 31946748 |
Filed Date | 2012-03-01 |
United States Patent
Application |
20120053145 |
Kind Code |
A1 |
NERURKAR; MANOJ ; et
al. |
March 1, 2012 |
ARIPIPRAZOLE COMPLEX FORMULATION AND METHOD
Abstract
An aripiprazole formulation is provided which includes the
antipsychotic agent aripiprazole in the form of an inclusion
complex in a .beta.-cyclodextrin, preferably, sulfobutyl ether
.beta.-cyclodextrin (SBECD), which in the form of an injectable
produces reversible generally minimal to mild irritation at the
intramuscular injection site. A method for minimizing or reducing
irritation caused by aripiprazole at an intramuscular injection
site and a method for treating schizophrenia employing the above
formulation are also provided.
Inventors: |
NERURKAR; MANOJ; (Pune,
IN) ; Naringrekar; Vijay; (Princeton, NJ) |
Assignee: |
Bristol-Myers Squibb
Company
|
Family ID: |
31946748 |
Appl. No.: |
13/288077 |
Filed: |
November 3, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13046124 |
Mar 11, 2011 |
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13288077 |
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12417067 |
Apr 2, 2009 |
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13046124 |
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11452782 |
Jun 14, 2006 |
7550445 |
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12417067 |
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10642366 |
Aug 14, 2003 |
7115587 |
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11452782 |
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60404713 |
Aug 20, 2002 |
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Current U.S.
Class: |
514/58 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 9/0019 20130101; A61K 47/6951 20170801; A61K 47/02 20130101;
B82Y 5/00 20130101; A61K 31/496 20130101; A61K 47/12 20130101; A61P
25/18 20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/58 |
International
Class: |
A61K 31/724 20060101
A61K031/724; A61P 25/18 20060101 A61P025/18 |
Claims
1. An aqueous injectable formulation having a pH of from about 3.5
to about 5, comprising: a) a complex comprising aripiprazole and
sulfobutyl ether-.beta.-cyclodextrin; b) tartaric acid; c) sodium
hydroxide; and d) water for injection.
2. The formulation as defined in claim 1 which contains 2 mg
aripiprazole/ml, 5 mg aripiprazole/ml or 7.5 mg
aripiprazole/ml.
3. The formulation as defined in claim 1 having a pH of about
4.3.
4. The formulation as defined in claim 1 comprising from about 0.1
to about 2.5% by weight aripiprazole.
5. The formulation as defined in claim 1 comprising from about 0.2
to about 1.5% by weight aripiprazole.
6. The formulation as defined in claim 1 wherein the sulfobutyl
ether-.beta.-cyclodextrin is present in an amount from about 100 to
about 700 mg/ml of solution.
7. The formulation as defined in claim 1 wherein the tartaric acid
is present in an amount from about 7 to about 9 mg/ml.
8. The formulation as defined in claim 1 wherein the tartaric acid
and the sodium hydroxide are present in amounts to impart a pH of
about 4.3 to the formulation.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This Continuation application claims the benefit of U.S.
Ser. No. 13/046,124 filed Mar. 11, 2011, which is a continuation
application which claims the benefit of U.S. Ser. No. 12/417,067
filed Apr. 2, 2009, now abandoned, which is a Continuation
application which claims the benefit of U.S. Ser. No. 11/452,782
filed Jun. 14, 2006, now U.S. Pat. No. 7,550,445, which is a
Continuation application which claims the benefit of U.S. Ser. No.
10/642,366 filed Aug. 14, 2003, now U.S. Pat. No. 7,115,587, which
claims the benefit of U.S. Provisional Application Ser. No.
60/404,713 filed Aug. 20, 2002, now expired.
FIELD OF THE INVENTION
[0002] The present invention relates to an aripiprazole inclusion
complex with a substituted-.beta.-cyclodextrin, an aripiprazole
formulation which includes aripiprazole in the form of the above
inclusion complex, an injectable formulation which contains the
above complex of aripiprazole, a method for reducing irritation
normally caused by aripiprazole at an intramuscular injection site
employing the above injectable formulation and a method for
treating schizophrenia employing the above formulation.
BACKGROUND OF THE INVENTION
[0003] U.S. Pat. No. 5,006,528 to Oshiro et al. discloses
7-[(4-phenylpiperazino)-butoxy]carbostyrils, which include
aripiprazole, as dopaminergic neurotransmitter antagonists.
[0004] Aripiprazole which has the structure
##STR00001##
is an atypical antipsychotic agent useful in treating
schizophrenia. It has poor aqueous solubility (<1 .mu.g/mL at
room temperature). When formulated as an intramuscular (IM)
injectable solution, aripiprazole has been found to cause
unacceptable (moderate to severe) tissue irritation at the muscular
site with many water-miscible co-solvent systems, and
water-immiscible solvent and co-solvent systems such as hexonoic
acid:medium chain triglyceride (10:90), polyethylene glycol
400:ethanol:lactic acid (35:15:50), benzyl alcohol:sesame oil
(10:90), benzyl alcohol:medium chain triglyceride (10:90), benzyl
alcohol:tributyrin (5:95), and polysorbate 80 in 25 mM tartaric
acid.
[0005] Cyclodextrins are known for their use in increasing
solubility of drugs. They function by forming inclusion complexes
with hydrophobic molecules. Unfortunately, there are many drugs for
which cyclodextrin complexation either is not possible or produces
no apparent advantages as disclosed by J. Szejtli, Cyclodextrins in
Drug Formulations: Part II, Pharmaceutical Technology, 24-38,
August, 1991.
[0006] U.S. Pat. Nos. 5,134,127 and 5,376,645 each to Stella et al.
disclose sulfoalkyl ether cyclodextrin derivatives and their use as
solubilizing agents for water-insoluble drugs for oral, intranasal
or parenteral administration including intravenous and
intramuscular. Stella et al. disclose an inclusion complex of the
water-insoluble drug and the sulfoalkyl ether cyclodextrin
derivative and pharmaceutical compositions containing same.
Examples of sulfoalkyl ether cyclodextrin derivatives disclosed
include mono-sulfobutyl ether of .beta.-cyclodextrin and
monosulfopropyl ether of .beta.-cyclodextrin. Examples of
water-insoluble drugs are set out in column 7 starting at line 25
and include, among others, benzodiazepines, chlorpromazine,
diazepam, mephorbarbital, methbarbital, nitrazepam, and
phenobarbital.
[0007] U.S. Pat. No. 6,232,304 to Kim et al. discloses inclusion
complexes of aryl-heterocyclic salts such as the tartrate salt of
ziprasidone in a cyclodextrin such as .beta.-cyclodextrin
sulfobutyl ether (SBECD), and hydroxypropyl-.beta.-cyclodextrin
(HPBCD), and use of such inclusion complexes in oral and parenteral
formulations.
[0008] Japanese Patent Application No. 09301867A2 dated Nov. 25,
1997 discloses antidepressant compositions in the form of tablets
containing aripiprazole.
[0009] EP1145711A1 dated Oct. 17, 2001 (based on U.S. Application
Serial No. 2000-547948 filed Apr. 12, 2000) discloses flash-melt
oral dosage formulations containing aripiprazole.
[0010] U.S. Pat. No. 5,904,929 to Uekama et al. discloses
trans-mucosal and transdermal pharmaceutical compositions
containing a drug and a peracylated cyclodextrin as a solubilizing
agent. Examples of drugs include antidepressants such as
amitriptyline HCl, amoxapine, butriptyline HCl, clomipramine HCl,
desipramine HCl, dothiepin HCl, doxepin HCl, fluoxetine, gepirone,
imipramine, lithium carbonate, mianserin HCl, milnacipran,
nortriptyline HCl and paroxetine HCl; anti-muscarinic agents such
as atropine sulphate and hyoscine; sedating agents such as
alprazolam, buspirone HCl, chlordiazepoxide HCl, chlorpromazine,
clozapine, diazepam, flupenthixol HCl, fluphenazine, flurazepam,
lorazepam, mazapertine, olanzapine, oxazepam, pimozide,
pipamperone, piracetam, promazine, risperidone, selfotel, seroquel,
sulpiride, temazepam, thiothixene, triazolam, trifluperidol and
ziprasidone; anti-migraine drugs such as alniditan and sumatriptan;
beta-adrenoreptor blocking agents such as atenolol, carvedilol,
metoprolol, nebivolol and propranolol; anti-Parkinsonian drugs such
as bromocryptine mesylate, levodopa and selegiline HCl; opioid
analgesics such as buprenorphine HCl, codeine, dextromoramide and
dihydrocodeine; parasympathomimetics such as galanthamine,
neostigmine, physostymine, tacrine, donepezil, ENA 713 (exelon) and
xanomeline; and vasodilators such as amlodipine, buflomedil, amyl
nitrite, diltiazem, dipyridamole, glyceryl trinitrate, isosorbide
dinitrate, lidoflazine, molsidomine, nicardipine, nifedipine,
oxpentifylline and pentaerythritol tetranitrate.
BRIEF DESCRIPTION OF THE INVENTION
[0011] In accordance with the present invention, there is provided
an inclusion complex of aripiprazole in a
substituted-beta-cyclodextrin. It has been found that the inclusion
complex of aripiprazole is substantially more water-soluble
relative to the non-complexed aripiprazole.
[0012] Surprisingly and unexpectedly, it has been found that when
aripiprazole is complexed with a substituted .beta.-cyclodextrin
such as sulfobutyl ether-.beta.-cyclodextrin, it may be formulated
as an injectable which delivers aripiprazole to the muscular site
with unexpectedly diminished irritation as compared to injectables
containing uncomplexed aripiprazole.
[0013] In addition, in accordance with the present invention, a
pharmaceutical formulation is provided which is formed of an
inclusion complex of aripiprazole and a
substituted-.beta.-cyclodextrin, and a pharmaceutically acceptable
carrier therefor.
[0014] In a preferred embodiment, the pharmaceutical formulation of
the invention will be in the form of an aqueous parenteral or
injectable formulation. However, the pharmaceutical formulation of
the invention may be in other dosage forms such as lyophilized
injectable, oral (for example tablets, capsules, elixirs and the
like), transdermal or transmucosal forms or inhalation forms.
[0015] Further, in accordance with the present invention, a method
is provided for administering injectable aripiprazole without
causing unacceptable irritation at the site of injection wherein
the above described injectable formulation is administered,
preferably intramuscularly, to a patient in need of treatment.
[0016] Still further in accordance with the present invention, a
method is provided for treating schizophrenia which includes the
step of administering to a patient in need of treatment the above
described formulation, preferably in injectable form, without
causing undue irritation at the site of injection, whether it be at
a muscular site or other site.
DETAILED DESCRIPTION OF THE INVENTION
[0017] Aripiprazole has poor water solubility and thus is difficult
to formulate as an aqueous injectable. In accordance with the
present invention, it as been found that the water-solubility of
aripiprazole may be sufficiently increased to allow it to be
formulated as an aqueous injectable by complexing aripiprazole with
a substituted-.beta.-cyclodextrin. In effect, the cyclodextrin
inhibits precipitation of the aripiprazole at the site of
injection. The aqueous injectable formulation containing the
complex of aripiprazole and the substituted-.beta.-cyclodextrin may
be administered preferably intramuscularly without causing
unacceptable irritation at the muscular site. This is indeed
surprising and unexpected since, as indicated above, a host of
water-miscible co-solvent systems and water-immiscible co-solvent
systems have been found to be unacceptable as carriers for
injectable aripiprazole formulations because of the unacceptable
irritation profile of such formulations. On the other hand, the
aqueous injectable formulation of the invention delivers
aripiprazole without causing unacceptable irritation at the site of
injection.
[0018] As will be seen hereinafter, the aripiprazole formulation in
the form of an aqueous injectable will include an acid buffer and a
base to adjust pH to desired levels.
[0019] The substituted-.beta.-cyclodextrin suitable for use herein
refers to sulfobutyl ether .beta.-cyclodextrin (SBECD) and
hydroxypropyl-.beta.-cyclodextrin (HPBCD), with SBECD being
preferred.
[0020] The term "undue irritation" or "unacceptable irritation" at
the site of injection or at the muscular site refers to moderate to
severe irritation which is unacceptable to the patient and thereby
impacts unfavorably on patient compliance.
[0021] The term "reduced irritation" at the site of injection or at
the muscular site refers to generally minimal to mild irritation
which is acceptable to the patient and does not impact unfavorably
on patient compliance.
[0022] The aripiprazole will form a complex with the
substituted-.beta.-cyclodextrin which complex may be dissolved in
water to form an injectable formulation. However, physical mixtures
of aripiprazole and the substituted-.beta.-cyclodextrin are within
the scope of the present invention as well.
[0023] The complex or the physical mixture may also be compressed
into a tablet or may be filled into capsules.
[0024] The aripiprazole formulations of the invention may be formed
of dry physical mixtures of aripiprazole and the
substituted-.beta.-cyclodextrin or dry inclusion complexes thereof
which upon addition of water are reconstituted to form an aqueous
injectable formulation. Alternatively, the aqueous injectable
formulation may be freeze dried and later reconstituted with water.
Thus, the inclusion complex in accordance with the invention, may
be pre-formed, formed in situ or formed in vivo (in the
gastrointestional tract or the buccal cavity). All of the above are
contemplated by the present invention.
[0025] The aripiprazole formulation of the invention in the form of
an aqueous injectable will include an acid buffer to adjust pH of
the aqueous injection within the range from about 3.5 to about 5.
Examples of acid buffers suitable for use herein include acids such
as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic
acid and the like, and organic acids such as oxalic acid, maleic
acid, fumaric acid, lactic acid, malic acid, tartaric acid, citric
acid, benzoic acid, acetic acid, methanesulfonic acid,
toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid and
the like. Acid salts of the above acids may be employed as well.
Preferred acids are tartaric acid, citric acid, and hydrochloric
acid. Most preferred is tartaric acid.
[0026] The injectable formulation of the invention will have a pH
within the range from about 3.5 to about 5, preferably from about 4
to about 4.6, and most preferably about 4.3. In formulating the
injectable, if necessary, the pH may be adjusted with a base such
as an alkali metal hydroxide such as NaOH, KOH, or LiOH, preferably
NaOH, or an alkaline earth metal hydroxide, such as Mg(OH).sub.2 or
Ca(OH).sub.2.
[0027] In preparing the aqueous injectable formulation of the
invention, the substituted-.beta.-cyclodextrin will be employed in
a weight ratio to the aripiprazole within the range from about 5:1
to 400:1, preferably from about 10:1 to about 100:1. Each type of
cyclodextrin employed requires a different ratio to inhibit or
prevent precipitation of aripiprazole at the injection site. In
preferred embodiments of the aqueous injectable of the invention,
the substituted-.beta.-cyclodextrin will be SBECD which will be
employed in a weight ratio to aripiprazole within the range from
about 5:1 to about 400:1, preferably from about 20:1 to about 40:1.
The cyclodextrin may be present in an amount greater than that
needed to complex the aripiprazole since the additional
cyclodextrin could aid in dissolution of the aripiprazole.
[0028] The aripiprazole will be present in the aqueous injectable
formulation in an amount within the range from about 0.1 to about
2.5% by weight, preferably from about 0.2 to about 1.5% by weight
based on the total injectable formulation.
[0029] In preferred embodiments, the aripiprazole will be present
in the aqueous injectable formulation to provide from about 1 to
about 20 mg/mL of formulation, preferably from about 1.5 to about 8
mg/mL of formulation.
[0030] In more preferred embodiments, the formulations of the
invention will provide 2 mg aripiprazole/mL, 5 mg/mL and 7.5 mg/mL.
Fill volumes will preferably be 0.5 mL and 2 mL.
[0031] A preferred injectable formulation is as follows: [0032] (1)
aripiprazole--in an amount to provide from about 1.5 to about 8
mg/mL of solution. [0033] (2) SBECD--in an amount from about 100 to
about 200 mg/mL of solution. [0034] (3) acid buffer (preferably
tartaric acid)--in an amount from about 7 to about 9 mg/mL of
solution to adjust pH from about 3.5 to about 5. [0035] (4) base to
adjust pH, preferably an alkali metal hydroxide, preferably
NaOH--in an amount to adjust pH from about 4 to 4.6 [0036] (5)
water qs to 1 mL.
[0037] The aripiprazole injectable formulation of the invention may
be prepared as follows: Tartaric acid or other acid buffer is
dissolved in water for injection. The
substituted-.beta.-cyclodextrin (preferably SBECD) is dissolved in
the acid buffer-water solution. Aripiprazole is then dissolved in
the solution. The pH of the solution is adjusted to within the
range from about 3.5 to about 5, preferably about 4.3 by adding
base, such as sodium hydroxide or other alkali metal hydroxide or
alkaline earth metal hydroxide. Additional water for injection is
added to obtain the desired batch volume.
[0038] The resulting solution is aseptically filtered, for example,
through a 0.22.mu. membrane filter and filled into vials. The vials
are stopped and sealed and terminally sterilized.
[0039] The aqueous injectable formulation of the invention will
provide an amount of aripiprazole of at least 2 mg aripiprazole/mL,
preferably at least 5 mg aripiprazole/mL, when the amount of
aripiprazole provided by the complex is measured at a cyclodextrin
concentration of 5% w/v in water.
[0040] The aripiprazole formulations of the invention are used to
treat schizophrenia in human patients. The preferred dosage
employed for the injectable formulations of the invention will be a
2 ml injection containing 7.5 mg aripiprazole/mL or a dose of 15 mg
given three times daily at two hour intervals. The injectable
formulation is preferably administered intramuscularly although
subcutaneous and intravenous injections are effective as well.
[0041] The following example represents a preferred embodiment of
the invention.
Example
[0042] A clear colorless aripiprazole injectable solution (2 mg
aripiprazole/mL, 4 mg/vial) essentially free of particulate matter
by visual inspection was prepared as follows.
[0043] A stainless steel batching vessel was charged with an
appropriate amount of water for injection USP.
[0044] With continuous stirring, 78 g tartaric acid granular USP
and 1500 g sulfobutyl ether .beta.-cyclodextrin (SBECD) was added
to the batching vessel and was dissolved in the water.
[0045] Aripiprazole 20 g was added to the batching vessel and
stirring was continued until the aripiprazole was dissolved.
[0046] Sodium hydroxide 1N was added to the above solution to
adjust the pH thereof to about 4.3.
[0047] Additional water for injection USP was added to the above
solution to adjust to the final batch size to 10 L with
stirring.
[0048] The above solution was aseptically filtered through a 0.22
.mu.M membrane filter into a sterilized container 4 mg amounts of
the above solution were aseptically filled into sterilized vials
which were then aseptically stoppered with sterilized stoppers to
seal the vials.
* * * * *