U.S. patent application number 17/098923 was filed with the patent office on 2021-05-06 for formulation for use in a method of treatment of pain.
The applicant listed for this patent is NEVAKAR Inc.. Invention is credited to Tushar Hingorani, Iouri V. Ilitchev, Varun Khurana, Jack Martin Lipman, Navneet Puri, Kumaresh Soppimath, Vivek Yadav, Tao Zhang.
Application Number | 20210128507 17/098923 |
Document ID | / |
Family ID | 1000005340835 |
Filed Date | 2021-05-06 |
![](/patent/app/20210128507/US20210128507A1-20210506\US20210128507A1-2021050)
United States Patent
Application |
20210128507 |
Kind Code |
A1 |
Khurana; Varun ; et
al. |
May 6, 2021 |
FORMULATION FOR USE IN A METHOD OF TREATMENT OF PAIN
Abstract
Formulations, methods of manufacturing, methods of stabilizing,
kits, and uses as medicament are provided, for example for the
treatment of pain. The formulations can comprise gabapentin
optionally combined with at least one non-opioid pain drug in an
aqueous carrier. The pharmaceutical formulation can have a pH of
about 2.0 to about 10.0. The at least one non-opioid pain drug can
be acetaminophen. The components can be included in any amount
suitable for purposes of obtaining properties desirable for an
injectable infusion, for example an intravenous infusion.
Inventors: |
Khurana; Varun; (Raritan,
NJ) ; Yadav; Vivek; (Henderson, NV) ; Lipman;
Jack Martin; (West Milford, NJ) ; Zhang; Tao;
(Towaco, NJ) ; Ilitchev; Iouri V.; (Hillsborough,
NJ) ; Hingorani; Tushar; (Bridgewater, NJ) ;
Soppimath; Kumaresh; (Plainsboro, NJ) ; Puri;
Navneet; (Lebanon, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NEVAKAR Inc. |
Bridgewater |
NJ |
US |
|
|
Family ID: |
1000005340835 |
Appl. No.: |
17/098923 |
Filed: |
November 16, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16091614 |
Oct 5, 2018 |
10874626 |
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17098923 |
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PCT/US2017/026640 |
Apr 7, 2017 |
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16091614 |
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62319526 |
Apr 7, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 31/195 20130101; A61K 31/167 20130101; A61K 31/197 20130101;
A61K 45/06 20130101 |
International
Class: |
A61K 31/195 20060101
A61K031/195; A61K 9/00 20060101 A61K009/00; A61K 31/167 20060101
A61K031/167; A61K 45/06 20060101 A61K045/06; A61K 31/197 20060101
A61K031/197 |
Claims
1-32. (canceled)
33. A pharmaceutical composition comprising, in a unit dosage form,
an analogue of gamma-aminobutyric acid and an aqueous carrier,
wherein the pharmaceutical composition exhibits no more than about
6% degradation of the analogue of gamma-aminobutyric acid after
sterilization of the pharmaceutical composition, as determined by
HPLC assay.
34. The pharmaceutical composition of claim 33, wherein the
sterilization comprises filtration.
35. The pharmaceutical composition of claim 33, wherein the
analogue of gamma-aminobutyric acid is pregabalin.
36. The pharmaceutical composition of claim 33, further comprising
a non-opioid pain drug.
37. The pharmaceutical composition of claim 36, wherein the
non-opioid pain drug is acetaminophen.
38. The pharmaceutical formulation of claim 37, wherein the
analogue of gamma-aminobutyric acid is present in the
pharmaceutical formulation at a concentration of about 1 to about
200 mg/mL and the acetaminophen is present in the pharmaceutical
formulation at a concentration of about 1 to about 400 mg/mL.
39. The pharmaceutical composition of claim 33, wherein the
pharmaceutical composition has a pH of about 4 to about 8.
40. The pharmaceutical composition of claim 33, wherein the
pharmaceutical composition has a pH of about 5.5.
41. The pharmaceutical composition of claim 33, wherein the unit
dosage form is a liquid unit dosage form.
42. The pharmaceutical composition of claim 33, wherein the aqueous
carrier is water.
43. The pharmaceutical composition of claim 33, wherein the
pharmaceutical composition further comprises a buffer.
44. The pharmaceutical composition of claim 33, wherein the
pharmaceutical composition further comprises an isotonicity
adjusting agent.
45. The pharmaceutical composition of claim 44, wherein the
isotonicity adjusting agent is sodium chloride.
46. The pharmaceutical composition of claim 44, wherein the
isotonicity adjusting agent is mannitol.
47. The pharmaceutical composition of claim 33, wherein the
pharmaceutical composition exhibits no more than about 5% of a
lactam impurity after the sterilization as determined by HPLC
assay, wherein the lactam impurity is derived from the analogue of
gamma-butyric acid.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application Ser. No. 62/319,526, filed on Apr. 7, 2016 the contents
of which are incorporated by reference in their entireties for all
purposes.
TECHNICAL FIELD
[0002] Embodiments of the disclosure relate generally to
formulations and methods of treating pain and, in particular,
formulations comprising gabapentin or analogues of
gamma-aminobutyric acid (GABA), optionally combined with at least
one non-opioid pain drug.
BACKGROUND
[0003] Gabapentin, 1-(aminomethyl) cyclohexane acetic acid, is a
structural analogue of the neurotransmitter gamma-aminobutyric
acid. The oral absorption of gabapentin is dose-dependent due to a
saturable L-amino acid transport mechanism in the intestine. Thus,
the oral bioavailability varies inversely with dose. Following a
dosing regimen of 900, 1200, 2400, 3600 and 4800 mg/day given in 3
divided doses, the bioavailability of gabapentin is approximately
60%, 47%, 33% and 27% respectively. Plasma concentrations are
proportional with dose up to 1800 mg daily and then plateau at
approximately 3600 mg daily.
[0004] Peroral administration of gabapentin to treat pain, for
example in acute post-procedural pain relief, has been documented
by various clinical studies. However, the peroral route has
disadvantages, including uncertainty for use as pre-procedural
medication. For example, gabapentin has a dose dependent extent of
bio-availability, and oral absorption may be impaired because of
loss of gastrointestinal function or restrictions on oral intake.
For example, oral administration of gabapentin yields lower plasma
concentrations because of its low bioavailability.
[0005] Accordingly, there is a need for an injectable
pharmaceutical formulation comprising gabapentin or a derivative of
gamma-aminobutyric acid for treating pain in general, including but
not limited to post-procedural pain.
SUMMARY
[0006] In an embodiment, the present disclosure relates to
formulations comprising gabapentin or a derivative of
gamma-aminobutyric acid; in certain embodiments, the formulations
further comprise at least one non-opioid pain drug in an aqueous
carrier. The pharmaceutical formulation can have a pH of about 4.0
to about 8.0. In an embodiment, the derivative of
gamma-aminobutyric acid is pregabalin. In another embodiment, the
non-opioid pain drug is acetaminophen.
[0007] In other embodiments, the present disclosure provides
methods of manufacturing a therapeutically effective injectable
pharmaceutical formulation.
[0008] In other embodiments, the present disclosure provides
methods of stabilizing a therapeutically effective injectable
pharmaceutical formulation.
[0009] In other embodiments, the present disclosure provides kits
comprising at least one dosage form comprising an injectable
pharmaceutical formulation and instructions for administering the
at least one dosage form.
[0010] In other embodiments, the present disclosure provides uses
of gabapentin or a derivative of gamma-aminobutyric acid optionally
combined with at least one non-opioid pain drug for preparation of
a medicament to treat pain, wherein the medicament is administered
by a dosing regimen.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 provides Table 2 showing the stability of gabapentin
in the presence of different stabilizers and solvents.
[0012] FIG. 2 provides Table 10 showing the stability of the
acetaminophen and gabapentin formulation at different pH ranges (pH
range 4.0-8.0).
[0013] FIG. 3 provides a graph showing the results of a tail-flick
test: the black circles (.circle-solid.) represent the vehicle, the
square (.box-solid.) represents morphine, the triangle
(.tangle-solidup.) represents acetaminophen, the inverted triangle
() represents gabapentin, and the diamond (.diamond-solid.)
represents acetaminophen and gabapentin combined.
DETAILED DESCRIPTION
[0014] The following detailed description is exemplary and
explanatory and is intended to provide further explanation of the
present disclosure described herein. Other advantages, and novel
features will be readily apparent to those skilled in the art from
the following detailed description of the present disclosure.
[0015] The term "injectable infusion" should be construed to
include different kinds of injectable delivery systems, including
parenteral infusion, intravascular infusion, intra-arterial
infusion, and intravenous infusion.
[0016] The term "formulation" should be construed to include an
injectable infusion system comprising gabapentin, or a derivative
of gamma-aminobutyric acid optionally combined with at least one
non-opioid pain drug, and optionally a buffer, optionally an
antioxidant, optionally a preservative, optionally a stabilizing
agent, optionally an isotonicity adjusting agent, for parenteral
delivery to a subject.
[0017] The term "pain" should be construed to include all forms and
intensities of pain, including but not limited to acute pain,
chronic pain, nociceptive pain, inflammatory pain, pathological
pain, pre-surgical pain, surgical pain, post-surgical pain and
neuropathic pain.
[0018] The term "procedure" should be construed to include
different kinds of operations, including medical operations and
surgical operations.
[0019] The term "subject" should be construed to include patients,
for example medical or surgical patients, and other individuals
suffering from pain, for example post-procedural pain.
[0020] To overcome the disadvantages of the conventional oral
administration of gabapentin to treat pain, the inventors herein
discovered an injectable pharmaceutical formulation comprising
gabapentin or a derivative of gamma-aminobutyric acid optionally
combined with at least one non-opioid pain drug for administration.
The formulations may be administered at any time, including
pre-procedure, peri-procedure, intra-procedure and/or
post-procedure for treating pain, including post-procedural pain.
As discussed above, there are disadvantages and uncertainties of
oral absorption of gabapentin, including dose-dependent decrease in
bioavailability. The inventors have discovered that these
disadvantages can be solved by parenteral route of administration
of a pharmaceutical formulation comprising gabapentin or a
derivative of gamma-aminobutyric acid optionally combined with at
least one non-opioid pain drug. The pharmaceutical formulations of
the present disclosure can achieve efficient and effective
management of pain, including post-procedural pain. No such
formulation is available in the market or reported in the
literature.
[0021] Embodiments of the disclosure provide injectable
pharmaceutical formulations and methods. In one embodiment, a
formulation per the present disclosure comprises gabapentin or a
derivative of gamma-aminobutyric acid optionally combined with at
least one non-opioid pain drug in an aqueous carrier. In one
embodiment, the derivative of gamma-aminobutyric acid is
pregabalin. The aqueous carrier can be any aqueous carrier suitable
for purposes of obtaining properties desirable for an injectable
infusion, including, for example (without limitation), one or more
of water, saline, lactated Ringer's solution, and Ringer's acetate
solution.
[0022] In one embodiment, the non-opioid pain drug can be a
non-steroidal anti-inflammatory drug. Suitable non-steroidal
anti-inflammatory drugs for use in the present formulations and
methods can comprise one or more of the following: acetaminophen,
Aspirin (acetylsalicylic acid), Diflunisal, salicylic acid,
salicylates, Salsalate, Ibuprofen, Dexibuprofen, Naproxen,
Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin,
Loxoprofen, indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac,
Diclofenac, Aceclofenac, Nabumetone, Piroxicam, Meloxicam,
Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Phenylbutazone,
Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic
acid, Celecoxib and combinations thereof. In one embodiment, the
non-opioid pain drug comprises acetaminophen.
[0023] In one embodiment, the pharmaceutical formulation can
comprise one or more of the following: an antioxidant, a buffer, a
preservative, a stabilizing agent, and an isotonicity adjusting
agent. The buffer can be any buffer suitable for purposes of
obtaining properties desirable for an injectable infusion,
including, for example (without limitation), one or more of acetic
acid, sodium acetate, citric acid, sodium hydroxide, cysteine
hydrochloride, sodium dihydrogenphosphate, and disodium
hydrogenphosphate. The buffer can be included in any amount
suitable for purposes of obtaining properties desirable for an
injectable infusion, for example in an amount of about 0.1 mM to
200 mM.
[0024] In one embodiment, the pharmaceutical formulation can be
free from preservatives. In other embodiments, the pharmaceutical
formulation can comprise one or more preservative agents suitable
for purposes of obtaining properties desirable for an injectable
infusion, including, for example (without limitation), one or more
of quaternary ammonium salts, surfactant and disinfectant agents,
for example benzalkonium chloride, cetremide or cetrimonium
chloride or bromide, benzododecinium bromide, miramine,
cetylpyridinium chloride, polidronium chloride or
polyquarternium-1, polyquaternium-42 (also known as polexitonium),
sepazonium, etc., mercurial derivatives, for example phenylmercury
salts (acetate, borate or nitrate), mercuriothiolate sodium
(otherwise called thiomersal or thimerosal), mercurobutol,
amidines, for example chlorhexidine digluconate or
polyhexamethylene biguanide (PHMB), alcohols, for example phenol,
thimerosal, benzyl alcohol, phenoxyethanol, chlorobutanol or
phenylethanol, phenoxyethanol, and parabens or esters, for example
parahydroxybenzoic acid, methylparaben, and propylparaben. In one
embodiment, the concentration of the preservatives is between about
0.001% w/w and less than about 5% w/w of the total composition, for
example between about 0.003% and about 2.0% w/w of the total
formulation.
[0025] In one embodiment, the pharmaceutical formulation can
comprise one or more isotonicity agents suitable for purposes of
obtaining properties desirable for an injectable infusion,
including, for example (without limitation), sodium chloride,
glycerol, and thioglycerol.
[0026] In one embodiment, the pharmaceutical formulation can
comprise pharmaceutically acceptable excipients, for example one or
more of buffers, preservatives, and antioxidants, and any
pharmaceutically acceptable mixture thereof.
[0027] In one embodiment, the pharmaceutical formulation can be
free from antioxidants. The inventors have unexpectedly discovered
that pharmaceutical formulations according to the present
disclosure with no antioxidants, and particularly with no N-acetyl
cysteine, have increased stability.
[0028] In other embodiments, the pharmaceutical formulation can
comprise one or more antioxidants suitable for purposes of
obtaining properties desirable for an injectable infusion,
including, for example (without limitation), one or more of
hydrophobic anti-oxidants, for example butylated hydroxytoluene,
butylated hydroxyanisole, propyl gallate, and .alpha.-tocopherol,
DL-tocopherol, .alpha.-tocopherol acetate, Tocopherol Polyethylene
Glycol Succinate (Vitamin E TPGS), L-cysteine, or hydrophilic
anti-oxidants, including sodium EDTA and thioglycerol. In one
embodiment, the concentration of the antioxidants is between 0.005%
and 5% w/w of the total formulation. In one embodiment, the one or
more antioxidants can improve the stability of the pharmaceutical
formulation.
[0029] In one embodiment, the pharmaceutical formulation according
to the present disclosure has a pH suitable for purposes of an
injectable infusion. For example, the pH can be about 2.0 to about
10.0, about 4.0 and 8.0, or about 6.0 to about 7.0. In one
embodiment, one or more buffer systems are used to stabilize the pH
at a desired value or range. Suitable buffers include, for example
(without limitation) citric acid buffer, acetic acid buffer, maleic
acid buffer, phosphoric acid buffer, succinic acid buffer, and
tartaric acid buffer. The buffer strength can be any buffer
strength suitable for purposes of an injectable infusion, for
example (without limitation) between about 0.1 mM to 200 mM.
[0030] In one embodiment, administration of the injectable
pharmaceutical formulation according to the present disclosure to a
subject occurs at least one of pre-procedure, peri-procedure,
intra-procedure and/or post-procedure. In one embodiment,
administration of the injectable pharmaceutical formulation to a
subject is intravascular, for example intravenous. In one
embodiment, administration of the injectable pharmaceutical
formulation is to a subject having pain, including for example,
post-procedural pain. In one embodiment, the pharmaceutical
formulation according to the present disclosure treats
post-procedural pain.
[0031] In one embodiment, the pharmaceutical formulation according
to the present disclosure is packaged in a container. The container
can be any container suitable for purposes of injectable infusion,
including, for example (without limitation), a polymer bag, for
example an infusion bag, or a glass bottle. In one embodiment, the
polymer bag is further packaged in an aluminum over-wrap. In one
embodiment, the polymer bag or aluminum over-wrap comprises an
oxygen scavenger or an oxygen barrier. In another embodiment, an
oxygen scavenger or oxygen barrier is between the polymer bag and
the aluminum over-wrap or external to the aluminum over-wrap. In
one embodiment, the pharmaceutical formulation according to the
present disclosure comprises an aqueous solution comprising an
oxygen scavenger.
[0032] In one embodiment, the polymer bag comprises a dual chamber
bag. In this embodiment, the gabapentin or the derivative of
gamma-aminobutyric acid is separated from the at least one
non-opioid pain drug. The gabapentin or the derivative of
gamma-aminobutyric acid can be separated from the at least one
non-opioid pain drug by any suitable barrier. In another
embodiment, the gabapentin or the derivative of gamma-aminobutyric
acid and the non-opioid pain drug are in separate polymer bags, and
can either be mixed in a single container prior to administration,
or mixed during administration, for example by direction of both
into a single IV line via a Y-connector.
[0033] The term "oxygen scavenger" or "oxygen barrier" should be
construed to include a substance that consumes, depletes or reduces
the amount of oxygen from a given environment without negatively
affecting the pharmaceutical formulation. Suitable oxygen
scavenging elements include, for example (without limitation)
compositions comprising metal particulates reactive with oxygen
such as transition metals selected from the first, second or third
transition series of the periodic table of the elements, and
include manganese II or III, iron II or III, cobalt II or III,
nickel II or III, copper I or II, rhodium II, III or IV, and
ruthenium, for example disposed within a polymer matrix that can be
coated onto or incorporated into a container. The transition metal
is, for example, iron, nickel or copper. Other examples of oxygen
scavenging element may be enzymes which consumes, depletes or
reduces the amount of oxygen from the given environment without
negatively affecting the pharmaceutical formula.
[0034] In one embodiment, the pharmaceutical formulation according
to the present disclosure comprises a 100 mL aqueous solution
packaged in the polymer bag. In another embodiment, the
pharmaceutical formulation according to the present disclosure
comprises a 250 mL aqueous solution packaged in the polymer bag. In
another embodiment, the pharmaceutical formulation according to the
present disclosure comprises a 500 mL aqueous solution packaged in
the polymer bag. In another embodiment, the pharmaceutical
formulation according to the present disclosure comprises a 1000 mL
aqueous solution packaged in the polymer bag.
[0035] In one embodiment, the gabapentin or the derivative of
gamma-aminobutyric acid comprises a minimum of about 100 mg to
about 2000 mg per container, for example about 500 mg to about 1000
mg, or from about 500 mg to 1500 mg. In one embodiment, the
container optionally includes at least one non-opioid pain drug
comprising a minimum of about 100 mg to about 2000 mg per
container, for example about 500 mg to about 1000 mg, or about 500
mg to about 1500 mg.
[0036] In one embodiment, the concentration of the gabapentin or
the derivative of gamma-aminobutyric acid is less than about 99%
(w/v) and the concentration of the optional non-opioid pain drug
concentration is less than about 99% (w/v). The concentration of
the gabapentin or the derivative of gamma-aminobutyric acid can be
about 1 to 200 mg/mL and the concentration of the optional
non-opioid pain drug can be about 1 to 200 mg/mL. In another
embodiment, the concentration of the gabapentin or the derivative
of gamma-aminobutyric acid can be about 1 to 400 mg/mL and the
concentration of the optional non-opioid pain drug can be about 1
to 400 mg/mL.
[0037] In one embodiment, the single dose of the pharmaceutical
formulation described herein comprises gabapentin, or a derivative
of gamma-aminobutyric acid, in the amount of 100-1200 mg, 400-1000
mg, 400 mg, or 800 mg. In an embodiment, the single dose of the
pharmaceutical formulation described herein comprises gabapentin,
or a derivative of gamma-aminobutyric acid, in the amount of
100-1200 mg, 400-1000 mg, 400 mg, or 800 mg, optionally combined
with a non-opioid pain drug in the amount of in the amount of
100-2000 mg, 400-1600 mg, 800 mg, or 1000 mg. In an embodiment, the
single dose of the pharmaceutical formulation described herein
comprises gabapentin, in the amount of 100-1200 mg, 400-1000 mg,
400 mg, or 800 mg combined with a non-opioid pain drug in the
amount of in the amount of 100-2000 mg, 400-1600 mg, 800 mg, or
1000 mg, wherein the non-opioid drug comprises acetaminophen.
[0038] In one embodiment, the pharmaceutical formulations of the
present disclosure are sterilized by any means of sterilization
suitable for purposes of injectable infusion, including, for
example (without limitation), filtration through 0.22 micron
filters, steam sterilization, radiation (e.g., gamma, electron
beam, microwave), or ethylene oxide sterilization.
[0039] In one embodiment, an injectable infusion comprising the
pharmaceutical formulations according to the present disclosure can
have desirable properties, including, for example (without
limitation) desirable stability properties, pharmacokinetic
properties, and bioavailability. One skilled in the art can readily
determine the stability properties of the present formulations, for
example by employing standard testing procedures. For example,
stability samples can be assayed for lactam and gabapentin by an
HPLC procedure as set forth in Pharmaceutical Research, Vol. 9, No.
5, 1992, Stability Studies of Gabapentin in Aqueous Solutions by E.
Zour, et al., the entire disclosure of which is herein incorporated
by reference. In this procedure, the HPLC system uses a diode array
detector. The samples are assayed on a reversed-phase B C18
Ultrashpere ODS 5-.mu.m, 4.6 mm.times.25-cm, column. The mobile
phase comprises of a water-methanol-acetonitrile (55:35:10) mixture
and the flow rate can be 1.0 ml/min. The detection is carried out
at 210 nm. All samples assayed are diluted 10-fold and then 50
.mu.l of the sample is injected into the HPLC system. In one
embodiment, HPLC retention times of gabapentin and lactam are found
to be about 3.1 and about 13.3 min. Initial studies indicated that
at neutral pH, gabapentin or derivatives of gamma-aminobutyric acid
have an aqueous shelf life of about 2 to about 6 months at room
temperature (25.degree. C.), with a lactam limit of about 0.5%.
Formulations of the present invention have a shelf-life of about
4-24 months at room temperature, for example about 18 to 24 months,
and this can be longer, and lactam limits of about 0.5% and this
can be less.
[0040] In another example, high-performance liquid chromatography
(HPLC) method can been used for the simultaneous determination of
the main impurities of the non-opioid pain drug. For example, HPLC
can be used for simultaneous determination of the main impurities
of acetaminophen, including for example n-propionyl-p-aminophenol,
3-chloro-4-hydroxyacetanilide, 4'-hydroxyacetophenone,
4-hydroxyacetophenone oxime, 4-acetoxyacetanilide and
4'-chloroacetanilid, as set forth in Journal of Chromatographic
Science, Vol. 50:335-342, 2012, HPLC Separation of Acetaminophen
and its Impurities Using a Mixed-mode Reversed-Phase/Cation
Exchange Stationary Phase, by O. Calinescu, et al., the entire
disclosure of which is herein incorporated by reference. The
chromatographic separation can be achieved on an Eclipse XDB-18
reversed-phase column using a gradient elution, with solvent A:
0.01 M phosphate buffer at pH 3.0 and solvent B: methanol. Levels
of these impurities in the present formulations are well within
acceptable limits, as are known in the art.
[0041] In one embodiment, parenteral administration of the
pharmaceutical formulation achieves a bioavailability of the
gabapentin or the derivative of gamma-aminobutyric acid of about
20% to about 100% and elimination half-life of the gabapentin or
the derivative of gamma-aminobutyric acid is about 4 to about 8
hours. In one embodiment, parenteral administration of the
pharmaceutical formulation achieves a bioavailability of gabapentin
or the derivative of gamma-aminobutyric acid that is higher than a
bioavailability achieved by oral administration. In one embodiment,
parenteral administration of the pharmaceutical formulation
achieves an elimination half-life of gabapentin or the derivative
of gamma-aminobutyric acid that is longer than elimination
half-life achieved by oral administration.
[0042] In one embodiment, methods of manufacturing a
therapeutically effective injectable pharmaceutical formulation are
provided. The methods can comprise dissolving gabapentin or a
derivative of gamma-aminobutyric acid optionally combined with at
least one non-opioid pain drug in an aqueous carrier, and adjusting
a pH of the pharmaceutical formulation to about 4.0 to about 8.0.
The formulation can comprise one or more formulations as described
above.
[0043] In one embodiment, methods of stabilizing a therapeutically
effective injectable pharmaceutical formulation are provided. The
methods can comprise dissolving gabapentin or a derivative of
gamma-aminobutyric acid optionally combined with at least one
non-opioid pain drug in an aqueous carrier, dissolving a buffer in
the aqueous carrier, and adjusting a pH of the pharmaceutical
formulation to about 4.0 to about 8.0 using the buffer. The
formulation can comprise one or more formulations as described
above. Stability of the formulations can be determined by any
suitable means known in the art, for example those methods
described above.
[0044] In one embodiment, kits comprising at least one dosage form
comprising an injectable pharmaceutical formulation and
instructions for administering the at least one dosage form are
provided. The formulation can comprise one or more formulations as
described above. The therapeutic instructions can comprise the step
of intravascularly administering to a subject who has pain the
pharmaceutical formulation.
[0045] In one embodiment, uses of gabapentin or a derivative of
gamma-aminobutyric acid optionally combined with at least one
non-opioid pain drug for preparation of a medicament to treat
post-procedural pain, wherein the medicament is administered by a
dosing regimen, are provided. The dosing regimen can comprise
intravascularly, for example intravenously, administering to a
subject who has pain an injectable pharmaceutical formulation. The
formulation can comprise one or more formulations as described
above.
[0046] The dosage of the present formulations provided to a subject
will vary depending upon the active ingredients being administered,
the purpose of the administration, such as prophylaxis or therapy,
and the state of the subject and/or level of pain, the manner of
administration, and the like. In therapeutic applications,
formulations described herein are provided to a subject already
suffering from pain, in an amount sufficient to at least partially
ameliorate the symptoms of the pain and/or its complications,
including, for example (without limitation) post-procedural pain.
An amount of present formulations comprising an active ingredient
adequate to accomplish this is defined as a "therapeutically
effective amount." The dosage to be used in the treatment of a
specific case must be subjectively determined by and would be
apparent to the ordinarily skilled physician or medical
professional. The variables involved for determining a
therapeutically effective amount of the present formulations
include the specific condition and the size, age, weight, gender,
disease penetration, type of procedure, and response pattern of the
subject. The compounds can be administered intravascularly, for
example intravenously. The present formulations can be provided as
a unit dose, for example as an infusion, which taken together
comprise a therapeutically effective amount. For example, a unit
dose comprising a formulation of the invention can be administered
once daily or multiple times daily, for example 1, 2, 3, 4, 5 or 6
times in a 12 or 24-hour period. If multiple unit doses are
administered in a given time period, they can be administered at
substantially even time intervals. For example, if two unit doses
are administered in a 12-hour period, they can be given to the
subject 6 hours apart. Multiple unit doses are administered in a
given time period can also be administered at substantially uneven
time intervals. In one embodiment, a unit dosage form comprises a
formulation of the invention in the form of an injectable infusion
for intravenous administration.
[0047] The usual daily (i.e., 24-hour time period) dose depends on
the specific compound, method of treatment and condition treated.
The usual daily dose for the gabapentin or derivative of
gamma-aminobutyric acid is about 1 to 500 mg/mL for parenteral
application, for example 8 mg/mL, and for the at least one
non-opioid pain drug is about 1 to 500 mg/mL for parenteral
application, for example 10 mg/mL.
[0048] In an embodiment, a pharmaceutical formulation of the
present disclosure comprises gabapentin, acetaminophen; in an
aqueous carrier, wherein the pharmaceutical formulation has a pH of
about 5.0 to about 7.0, and wherein a concentration of the
gabapentin is about 5 to 15 mg/mL and a concentration of the
acetaminophen is about 5 to 15 mg/mL wherein such a formulation is
suitable for intravenous administration and wherein such a
formulation is useful for the treatment of pain.
[0049] The following examples are given to illustrate exemplary
embodiments of the present disclosure. It should be understood,
however, that the present disclosure is not to be limited to the
specific conditions or details described in these examples.
EXAMPLES
[0050] In the following Examples, "GBP" is used to mean gabapentin,
and "APAP" is used to mean acetaminophen
Example 1
Composition of Gabapentin (GBP) Formulation in Water for Injection
and Buffered Vehicles
[0051] Required quantities of Water for injection (WFI) were
combined with Citrate Phosphate Buffer (10 mM), and Acetate Buffer
(10 mM) in three separate manufacturing tanks. Gabapentin (GBP) was
added to each of tanks to obtain a concentration of 10 mg/ml, and
the pH was readjusted to 5.5 using HCl or NaOH. The bulk solution
tanks were filled into 10 mL glass vials with a target fill volume
of 10 mL and then stoppered and sealed. Samples were tested for
assay and impurities. Samples were steam sterilized at 121.degree.
C. for 15 min and were analyzed for assay and impurity levels.
TABLE-US-00001 TABLE 1 Gabapentin Formulations Example A Example B
Example C Water for injection Citrate Phosphate Acetate Buffer
(WFI) Buffer (10 mM) (10 mM) Ingredients Amount/mL (mg) Gabapentin
10 Sodium Hydroxide q.s. Hydrochloric Acid q.s. Vehicle q.s. 1 mL
pH 5.5 GBP Lactam GBP Lactam GBP Lactam Assay (T0) (%) 102.0 ND
102.3 ND 101.7 ND Post Sterilization 97.4 3.30 96.8 3.85 95.6 4.08
(%) Data in Table 1 demonstrates that unbuffered gabapentin (10
mg/mL) at pH of about 5.5 had significantly higher assay and lower
level of impurity compared to gabapentin in presence of citrate and
acetate buffer.
Example 2
Composition of Gabapentin (GBP) Formulation in Presence of
Different Stabilizers and Solvents
[0052] GBP containing formulations were prepared by dissolving GBP
to a concentration of 9 mg/mL in acetate buffer. Additional
stabilizers and solvents were added as indicated in Table 2 below.
A first set of samples were tested for assay and impurities after
the initial preparation of formulation, Another set of samples were
steam sterilized at 121.degree. C. for 15 min and were tested for
assay and impurity levels.
[0053] As shown in Table 2 (FIG. 1), GBP was found to be more
stable in solutions containing polyvinyl pyrrolidone (PVP) at a
concentration of 10 mg/mL. Table 2 also depicts the stability of
GBP in other solvents and stabilizers in the following order:
PVP>Glycine>Lysine>Propylene
Glycol>Sorbitol>PEG400>Glycerol>Mannitol>Sodium
Oleate>.beta.-cyclodextrin>Deoxychloic
Acid>CMC>L-Glutamic Acid.
Example 3
Stability of GBP, APAP and APAP+GBP Formulation at pH 5.5
[0054] Formulation compositions were prepared by dissolving GBP
and/or APAP as indicated in Table 3 and 4 and the pH was adjusted
to 5.5 using HCl or NaOH.
TABLE-US-00002 TABLE 3 Stability of APAP, GBP and APAP + GBP
formulations in water for injection at pH 5.5 Q R S Water for
injection (WFI) Ingredients Amount/mL (mg) Amount/mL (mg) Amount/mL
(mg) Gabapentin 9 9 Acetaminophen 10 10 Sodium Hydroxide q.s. pH
5.5 q.s. pH 5.5 q.s. pH 5.5 Hydrochloric Acid q.s. pH 5.5 q.s. pH
5.5 q.s. pH 5.5 Vehicle q.s. 1 mL q.s. 1 mL q.s. 1 mL GBP Lactam
APAP GBP Lactam APAP Assay (T0) (%) 99.1 ND 100.2 102.3 ND 101.2
Assay 2 Month 97.6 ND 100.4 99.1 ND 101.3 (%)
TABLE-US-00003 TABLE 4 Stability of APAP, GBP and APAP + GBP
formulations in acetate buffer at pH 5.5 T U V Acetate Buffer (10
mM) Ingredients Amount/mL (mg) Amount/mL (mg) Amount/mL (mg)
Gabapentin 9 9 Acetaminophen 10 10 Sodium Hydroxide q.s. pH 5.5
q.s. pH 5.5 q.s. pH 5.5 Hydrochloric Acid q.s. pH 5.5 q.s. pH 5.5
q.s. pH 5.5 Vehicle q.s. 1 mL q.s. 1 mL q.s. 1 mL GBP Lactam APAP
GBP Lactam APAP Assay (T0) (%) 100.6 ND 101.6 101.8 ND 101.8 Assay
2 Month (%) 98.0 ND 101.0 96.6 ND 100.7
[0055] As can be seen from Tables 3 and 4 above, all the three
formulations were stable for up to 2 months at 25.degree. C. No
significant difference in stability of formulations were observed
in formulations prepared in water for injection or acetate buffer.
Generation of lactam impurity was not observed in either oldie
formulation sets prepared with water for injection or acetate
buffer.
Example 4
Pharmacokinetics and Toxicologic Profile in Rats for Acetaminophen,
Gabapentin Alone or in Combination
[0056] Formulation compositions were prepared by dissolving GBP
and/or APAP as indicated in Table 5 and the pH was adjusted to 5.5
using HCl or NaOH. As observed in the previous study acetate buffer
does not play any role in stabilizing the formulation, therefore
the formulation compositions mentioned in Table 5 were prepared
without use of acetate buffer.
[0057] Male rats were administered Acetaminophen (10 mg/mL) or
Gabapentin (8 mg/mL) alone or in combination with a vehicle control
to evaluate the pharmacokinetic and toxicologic profile over a 24 h
period following a 15 minute IV infusion. Blood samples were
collected over a 24 h period at which time the rats were
exsanguinated and blood collected for Clinical Pathology
(Chemistry, Hematology and Coagulation) evaluation. Finally, all
animals were necropsied (all exterior and interior cavities and
organs were examined) and the site of infusion in the jugular vein,
lung, liver and kidney underwent histopathologic evaluation.
TABLE-US-00004 TABLE 5 Composition of APAP, GBP and APAP + GBP
formulations employed for in vivo studies. W X Y Water for
injection (WFI) Amount/mL Amount/mL Amount/mL Ingredients (mg) (mg)
(mg) Gabapentin 8 8 Acetaminophen 10 10 Sodium Hydroxide q.s. q.s.
q.s. Hydrochloric Acid q.s. q.s. q.s. Vehicle q.s. 1 mL q.s. 1 mL
q.s. 1 mL pH 5.5 5.5 5.5
TABLE-US-00005 TABLE 6 Pharmacokinetic (PK) parameters observed
after 15 min infusion of APAP, GBP and APAP + GBP formulations in
rats. Bioequivalent Range Acetaminophen PK Gabapentin PK (80-125%)
C.sub.max AUC C.sub.max AUC C.sub.max AUC Group (ng/mL) (ng h/mL)
(ng/mL) (ng h/mL) (ng/mL) (ng h/mL) Saline 0 0 0 0 Acetaminophen
10,135 7,285 8,108-12,669 5,828-9,106 Gabapentin 20,138 37,663 APAP
+ GBP 13,550 8,526 20,029 42,701 16,110-25,172 30,130-47,079
[0058] Results from this study demonstrate that treatment of rats
with either acetaminophen or gabapentin alone or in combination in
this formulation did not alter the Clinical Pathology (Clinical
Chemistry, Hematology or Coagulation Parameters) for these animals.
Further there were no changes in the histopathology in any tissue
sampled compared to the vehicle control.
[0059] PK parameters were analyzed after 15 min infusion of APAP,
GBP and APAP+GBP formulations in rats. Maximal plasma concentration
of acetaminophen (C.sub.max) obtained for APAP+GBP combination
formulation was found to be 30% higher when compared with C.sub.max
obtained after administering APAP alone. Whereas no change was
observed in PK profile of GBP in the presence of APAP. The
combination of APAP and GBP did not alter the total exposure (AUC,
Area Under the Curve) compared to either drug given alone.
[0060] Results from this study demonstrate that under the
conditions of this study this new formulation of APAP+GBP does not
induce hemolysis of rat blood, alter clinical pathology parameters,
nor induce changes in key tissues in the rats (infusion site, lung,
liver, kidney and brain).
Example 5
Solubility Studies of APAP, GBP and APAP+GBP at Different pH (pH
Range 4.0-8.0)
[0061] Solubility samples were prepared by dissolving APAP in water
at 50 mg/mL concentration and adjusting the pH in the required
range. As can be seen from Table 7 no significant difference in
solubility of APAP was observed in the overall pH range from
4.0-8.0.
TABLE-US-00006 TABLE 7 pH dependent solubility studies of APAP +
GBP at different pH range (4.0-8.0) Sample Acetaminophen(mg/mL) pH
4.0 13.8 pH 4.5 14.1 pH 5.0 13.9 pH 5.5 13.9 pH 6.0 13.8 pH 6.5
13.9 pH 7.0 13.9 pH 7.5 13.9 pH 8.0 14.2
TABLE-US-00007 TABLE 8 pH dependent solubility studies of GBP at
different pH range (4.0-8.0) Sample Gabapentin (mg/mL) pH 4.0 129.2
pH 4.5 125.8 pH 5.0 106.1 pH 5.5 101.3 pH 6.0 99.5 pH 6.5 97.5 pH
7.0 99.0 pH 7.5 98.6 pH 8.0 98.7
[0062] Saturation solubility samples were prepared by addition of
150 mg/mL of GBP in water and adjusting the pH in the required
range. As can be seen from Table 8 solubility of GBP was higher at
lower pH range (4.0-5.0) and was found to .about.98 mg/ml at the pH
range of 6.0-8.0.
TABLE-US-00008 TABLE 9 pH dependent solubility studies of APAP +
GBP at different pH range (4.0-8.0) Sample Acetaminophen (mg/mL)
Gabapentin (mg/mL) pH 4.0 32.9 125.7 pH 4.5 31.7 129.8 pH 5.0 30.7
126.7 pH 5.5 30.2 124.1 pH 6.0 28.8 120.0 pH 6.5 28.4 117.4 pH 7.0
30.5 122.3 pH 7.5 27.8 122.9 pH 8.0 31.3 123.0
[0063] Solubility samples were prepared by dissolving APAP and GBP
in water at 50 and 150 mg/mL concentration, respectively and
adjusting the pH in the required range. As can be seen from Table
9, solubility of APAP solubility was increased to .about.30 mg/mL
in presence of GBP which is more than twice the solubility values
obtained all the same pH range for APAP alone (Table 7).
[0064] Also significant increase in the solubility of GBP in
presence of APAP was also observed at pH range of 5.0-8.0 in
comparison to solubility values obtained in the same pH range for
GBP alone (Table 8).
Example 6
Stability of APAP+GBP Formulation at Different pH (pH Range
4.0-8.0)
[0065] Formulation compositions were prepared by dissolving APAP
and GBP in water at 10 and 8 mg/mL concentration, respectively and
adjusting the pH in the required range.
[0066] As can be seen from Table 10 (FIG. 2), lactam impurity
generated in 1 month stability samples were well below the
specifications (<0.5%) at pH 5.5-7.0 (40.degree. C./75% RH).
Also, lactam impurity was not detected in 1 month stability samples
at pH 5.5-7.5 (40.degree. C./75% RH). It is known that APAP
undergoes hydrolytic degradation to form para-aminophenol. The
mechanism involving hydrolysis was proposed by Koshy K. T. et al (J
Pharm Sci. 1961 February; 50:113-8). Koshy et al has reported that
the hydrolysis of APAP is minimum in the pH range 5 to 7 and it is
desirable to keep the pH of the medium between 5 and 6 to obtain
maximum shelf life for the APAP product. As reported in Table 10,
APAP assay values obtained at pH 5.0-6.0 were .about.100% and low
lactam impurity levels (<0.5%) were obtained for GBP around the
same pH range (5.0-6.0). Hence, the pH of 5.5 was selected for
APAP+GBP formulation prepared for future studies.
Example 7
In Vitro Hemolysis of Formulation of Acetaminophen, Gabapentin
Alone or in Combination
[0067] APAP and GBP alone or in combination were evaluated in the
in vitro hemolysis test using four biologic matrices (mouse, rat,
dog and human whole unclotted blood) to determine the hemolytic
potential for each on red blood cells. Blood was mixed with either
Acetaminophen (2.5, 5, 10 mg/mL), Gabapentin (2, 4, 8 mg/kg) or the
combination, along with a saline control and positive control (2%
SDS) and incubated for 15 min at 37.degree. C.
TABLE-US-00009 TABLE 11 Detection of hemolysis in mouse whole blood
(male), rat whole blood (male), beagle dog whole blood (male),
human (pooled) whole blood GBP GBP GBP (2 mg/mL) (4 mg/mL) (8
mg/mL) Species % Hemolysis Mouse Blood 0 0 0 Rat Blood 0 0 0 Dog
Blood 0 0 0 Human Blood 0 2 0 APAP APAP APAP (2.5 mg/mL) (5 mg/mL)
(10 mg/mL) Species % Hemolysis Mouse Blood 3 4 4 Rat Blood 2 0 0
Dog Blood 0 0 5 Human Blood 0 0 0 APAP APAP APAP (10 mg/mL) + (10
mg/mL) + (10 mg/mL) + GBP GBP GBP (2 mg/mL) (4 mg/mL) (8 mg/mL)
Species % Hemolysis Mouse Blood 0 2 0 Rat Blood 0 0 2 Dog Blood 2 0
1 Human Blood 4 2 0
TABLE-US-00010 TABLE 12 Criteria for Determination of Hemolysis
Percent Hemolysis Interpretation <10% Not Hemolytic 10%-25%
Relative Boundary (Possibly Hemolytic) >25% Hemolytic
[0068] Based on the results of this study (Table 11 and 12), in the
current formulation and concentrations tested, APAP and GBP alone
or in combination were not considered to be hemolytic to Red Blood
Cells under the conditions tested (15 min at 37.degree. C.) in
mouse, rat, dog or human whole unclotted blood.
Example 8
Pharmacodynamic Parameters in Mice for Acetaminophen, Gabapentin
Alone or in Combination
[0069] Two pharmacodynamic parameters were evaluated in the mouse
model to evaluate the effects of Acetaminophen (1000 mg/dose),
Gabapentin (800 mg/dose) and the combination. Mouse tail flick test
was conducted to evaluate test somatic pain and mouse
rotorod/acelorod test evaluated behavioral changes, specifically
somnolence or dizziness
[0070] A negative control (vehicle) and the test agents
(Acetaminophen, Gabapentin or the combination) were administered by
an IV route 30 minutes before the initiation of testing. In each
case a positive control was administered as described below.
A. Tail-Flick Test:
[0071] The test evaluates somatic pain by measuring the time
(seconds) required to elicit a tail flick response induced by
focused radiant heat. A 15-sec cut-off is used to prevent tissue
damage. The study evaluated baseline measurements (before dosing)
and at 30 minutes before the initiation of the study (time 0) the
mice were administered a 15-minute IV infusion of either the
Vehicle, Acetaminophen (10 mg/mL), Gabapentin (8 mg/mL) or the
combination at a dose of 1.7 mL/kg. The positive control, Morphine
(0.6 mg/kg, 5 mg/kg by the IP route) 30 minutes prior to the
initiation of the study. The measurements were conducted at 1, 2,
4, and 6 hours after the initiation of the study FIG. 1. One-way
ANOVA followed by Dunnett's test is applied for comparison between
vehicle control and test article treated groups. P<0.05 is
considered significant.
[0072] Results from this study indicate that the combination of
Acetaminophen and gabapentin in the current formulation are
superior to either compound alone under the conditions of this
study.
[0073] As shown in FIG. 3, Mice were administered either Vehicle,
Acetaminophen (10 mg/mL), Gabapentin (8 mg/mL) or a combination of
the two test agents by a 15 minute IV infusion 30 minutes before
the start of the study. A baseline was measured before
administration of the test agents and at 1, 2, 4 and 6 h post the
start of the study. The effect of the compounds was evaluated in
the standard Tail-Flick test.
(B) RotoRod/Acelerorod Test:
[0074] Male ICR mice were trained on a RotoRod/Acelerod at a
continuous accelerating speed from 4 to 30 rpm/min during a time
period of 4 minutes for at least 3 times on day 0. Vehicle or test
article at a single dose is administered by intravenous infusion
over 15 minutes starting 30 minutes before the test period starts
and chlorpromazine (30 mg/kg, PO) was administered by oral gavage
60 minutes before the start of the test period. At 1, 2, 4, and 6
hours after the start of the test the mice are placed on the
accelerating rotorod (increasing from 4 to 30 rpm/min during a 4
min period) and the time (seconds) the mouse remained on the
rotorod was recorded. One-way ANOVA followed by Dunnett's test is
applied for comparison between vehicle control and test article
groups. P<0.05 is considered significant.
[0075] Results from this study indicate that at a dose of 10 mg
Acetaminophen/mL, or 8 mg Gabapentin/mL or in combination, there
was no statistically significant decrease in motor control compared
to the vehicle control (see FIG. 4).
[0076] As shown in FIG. 4, Mice were administered either Vehicle,
Acetaminophen (10 mg/mL), Gabapentin (8 mg/mL) or a combination of
the two test agents by a 15 minute IV infusion 30 minutes before
the start of the study. A baseline was measured before
administration of the test agents and at 1, 2, 4 and 6 h post the
start of the study. The effect of the compounds was evaluated in
the standard RotoRod/Acelerorod test.
[0077] Table 5 below provides a list of exemplary non-opioid pain
drugs for use in pharmaceutical formulations according to the
present disclosure, including exemplary daily dosage in mg. These
non-opioid pain drugs in the following total amounts can be
substituted into the formulations of Examples above.
TABLE-US-00011 TABLE 5 Exemplary non-opioid pain drugs NSAID Daily
Dose Aspirin 250 mg Ibuprofen 800 mg Naproxen 500 mg Indomethacin
15 mg Ketorolac 120 mg Diclofenac 150 mg Meloxicam 15 mg Celecoxib
200 mg Mefenamic acid 500 mg Acetaminophen 4000 mg
[0078] While the present disclosure has been discussed in terms of
certain embodiments, it should be appreciated that the present
disclosure is not so limited. The embodiments are explained herein
by way of example, and there are numerous modifications, variations
and other embodiments that may be employed that would still be
within the scope of the present disclosure.
* * * * *