U.S. patent application number 11/459200 was filed with the patent office on 2006-12-28 for process for producing injectable gabapentin compositions.
This patent application is currently assigned to Medtronic, Inc.. Invention is credited to David A. Clarahan, Dennis D. Elsberry, Keith R. Hildebrand, Deanna S. Lane, Linda M. Page, Jayantha H. Ratnayake.
Application Number | 20060293389 11/459200 |
Document ID | / |
Family ID | 34557352 |
Filed Date | 2006-12-28 |
United States Patent
Application |
20060293389 |
Kind Code |
A1 |
Hildebrand; Keith R. ; et
al. |
December 28, 2006 |
PROCESS FOR PRODUCING INJECTABLE GABAPENTIN COMPOSITIONS
Abstract
Injectable compositions containing gabapentin and processes for
preparing sterile injectable compositions containing gabapentin are
discussed. The process includes subjecting the compositions to
heat. Heating results in increased production of gabapentin lactam,
which has previously been shown to be toxic. Surprisingly, heated
injectable compositions containing gabapentin are found to be
non-toxic when administered intrathecally. Thus, heating for the
purposes of sterilization or to assure sterility provides a viable
option in the production of injectable compositions containing
gabapentin.
Inventors: |
Hildebrand; Keith R.;
(Houlton, WI) ; Page; Linda M.; (Woodbury, MN)
; Lane; Deanna S.; (Columbia Heights, MN) ;
Elsberry; Dennis D.; (Plymouth, MN) ; Clarahan; David
A.; (Blaine, MN) ; Ratnayake; Jayantha H.;
(Blaine, MN) |
Correspondence
Address: |
MEDTRONIC, INC.
710 MEDTRONIC PARK
MINNEAPOLIS
MN
55432-9924
US
|
Assignee: |
Medtronic, Inc.
Minneapolis
MN
|
Family ID: |
34557352 |
Appl. No.: |
11/459200 |
Filed: |
July 21, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10808113 |
Mar 24, 2004 |
|
|
|
11459200 |
Jul 21, 2006 |
|
|
|
10611459 |
Jul 1, 2003 |
6969383 |
|
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10808113 |
Mar 24, 2004 |
|
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60513681 |
Oct 23, 2003 |
|
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60513682 |
Oct 23, 2003 |
|
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Current U.S.
Class: |
514/561 |
Current CPC
Class: |
A61M 2202/0464 20130101;
A61K 31/52 20130101; A61M 2210/0693 20130101; A61M 5/14276
20130101; A61K 9/0019 20130101; A61L 2/0023 20130101; A61K 31/195
20130101; A61K 9/0085 20130101; A61L 2/0017 20130101 |
Class at
Publication: |
514/561 |
International
Class: |
A61K 31/195 20060101
A61K031/195 |
Claims
1. A process for preparing an injectable pharmaceutical composition
comprising gabapentin, the process comprising: preparing an
injectable composition comprising gabapentin and a pharmaceutically
acceptable vehicle; and heating the injectable composition to an
F.sub.0 equivalent of about 1 or greater to produce the injectable
pharmaceutical composition.
2. The process of claim 1, wherein the injectable composition is
heated to an F.sub.0 equivalent of about 2 or greater.
3. The process of claim 2, wherein the injectable composition is
heated to an F.sub.0 equivalent of about 3 or greater.
4. The process of claim 3, wherein the injectable composition is
heated to an F.sub.0 equivalent of about 4 or greater.
5. The process of claim 4, wherein the injectable composition is
heated to an F.sub.0 equivalent of about 8 or greater.
6. The process of claim 5, wherein the injectable composition is
heated to an F.sub.0 equivalent of about 12 or greater.
7. The process of claim 6, wherein the injectable composition is
heated to an F.sub.0 equivalent of about 18 or greater.
8. The process of claim 7, wherein the injectable composition is
heated to an F.sub.0 equivalent of about 24 or greater.
9. The process of claim 1, wherein the injectable pharmaceutical
composition comprises less than or equal to about 10% (w/v)
gabapentin lactam.
10. The process of claim 9, wherein the injectable pharmaceutical
compositioncomprises less than or equal to about 5% (w/v)
gabapentin lactam.
11. The process of claim 10, wherein the injectable pharmaceutical
composition comprises less than or equal to about 2% (w/v)
gabapentin lactam.
12. The process of claim 11, wherein the injectable pharmaceutical
composition comprises less than or equal to about 1% (w/v)
gabapentin lactam.
13. The process of claim 1, wherein the injectable pharmaceutical
composition comprises between about 0.5% (w/v) and about 10% (w/v)
gabapentin lactam.
14. The process of claim 1, wherein the injectable pharmaceutical
composition comprises between about 0.1 mg/ml and about 100 mg/ml
gabapentin.
15. The process of claim 14, wherein the injectable pharmaceutical
composition comprises between about 30 mg/ml to about 100 mg/ml
gabapentin.
16. The process of claim 15, wherein the injectable pharmaceutical
composition comprises about 80 mg/ml gabapentin.
17. The process of claim 1, wherein the injectable pharmaceutical
composition comprises between about 10 mg/ml and about 50 mg/ml
gabapentin.
18. The process of claim 1, wherein the injectable pharmaceutical
composition comprises between about 20 mg/ml and about 40 mg/ml
gabapentin.
19. The process of claim 1, wherein the injectable pharmaceutical
composition comprises about 30 mg/gabapentin.
20. The process of claim 1, further comprising filtering the
injectable composition.
21. The process of claim 20, further comprising aseptically placing
the filtered composition in a container to produce a container
housing the filtered composition.
22. The process of claim 21, wherein the heating comprises heating
the container housing the composition.
23. The process of claim 1, further comprising adjusting the pH of
the injectable composition.
24. The process according to claim 23, wherein the pH is adjusted
by adding sodium hydroxide, hydrochloric acid, or both to the
injectable composition.
25. The process of claim 1, wherein the heating comprises
autoclaving.
Description
RELATED APPLICATIONS
[0001] This application is a continuation application of Ser. No.
10/808,113, entitled "A PROCESS FOR PRODUCING INJECTABLE GABAPENTIN
COMPOSITIONS", filed Mar. 24, 2004, now allowed. U.S. Ser. No.
10/808,113 is a continuation in part application of Ser. No.
10/611,459, entitled "A METHOD FOR TREATING SEVERE TINNITUS", filed
Jul. 1, 2003, now U.S. Pat. No. 6,969,383, issued Nov. 11, 2005.
This application claims priority to the above-referenced
applications and also claims priority to Provisional Application
Ser. No. 60/513,682, entitled "INJECTABLE GABAPENTIN COMPOSITIONS",
filed Oct. 23, 2003, and Provisional Application Ser. No.
60/513,681, entitled "INTRATHECAL GABAPENTIN FOR TREATMENT OF PAIN
AND EPILEPSY", filed on Oct. 23, 2003. Each of the above-referenced
applications is herein incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] This application relates to injectable compositions and kits
comprising gabapentin and to processes for producing the same.
BACKGROUND OF THE INVENTION
[0003] Gabapentin is a pharmacological agent that mimics the
effects of GABA (.gamma.-aminobutyric acid), but gabapentin does
not appear to bind a GABA receptor (e.g., GABA.sub.A and GABA.sub.B
receptors) or have an effect on GABA uptake. Gabapentin has been
found to interact with the alpha-2-delta (.alpha..sub.2.delta.)
subunit of voltage-gated calcium channels. Many of the
pharmacological effects of gabapentin may be due to its interaction
with voltage-gated calcium channels. It is believed that gabapentin
decreases calcium ion flow into a neuron, rendering the neuron less
excitable. Inhibition of presynaptic calcium influx may prevent the
release of neurotransmitters. Thus, like GABA, gabapentin can
dampen overactive neural circuitry.
[0004] Solid formulations of gabapentin, such as NEURONTIN, are
currently available for oral administration. Oral gabapentin has
been primarily used to treat epilepsy although it has been used
off-label to treat neuropathic pain and has recently received an
FDA-approval for the treatment of one type of neuropathic pain,
post-herpetic neuralgia. Some gabapentin can access the CNS when
administered orally, because gabapentin is transported across the
gut and the blood-brain barrier. It is believed that gabapentin is
transported across the blood-brain barrier via an active and
saturable L-amino acid transporter. Thus, the amount of gabapentin
reaching CNS sites of action is limited. Because this transporter
is saturable, even if the concentration of gabapentin in the plasma
is increased, the amount which crosses the blood-brain barrier will
remain constant.
[0005] Solutions of gabapentin have been prepared extemporaneously
for direct administration to the CNS in preclinical animal studies.
In some studies, such solutions have been administered
intrathecally as a single bolus or as multiple boluses. However,
the administration of a solution to the CNS presents many concerns,
including the threat of serious infection. While such concerns are
not of considerable importance in preclinical animal studies, they
are of paramount importance in the context of administration to
humans.
[0006] Accordingly, the sterility of a solution comprising
gabapentin, which solution is to be administered to the CNS, cannot
be taken lightly. Typically, solutions are sterilized either by
heat or filtration. In the case of solutions containing gabapentin,
a sterilization process involving heat would generally be
considered undesirable. This is because heat would be expected to
result in decreased stability of gabapentin and increased
production of gabapentin lactam, having a chemical structure of
formula (I): ##STR1##
[0007] According to U.S. Pat. No. 6,054,482, "The lactams display a
certain toxicity and must, therefore, be avoided as far as
possible. For example, gabapentin has a toxicity (LD.sub.50, mouse)
of more than 8000 mg/kg, for the corresponding lactam (VI) a
toxicity of 300 mg/kg." Column 4, lines 50-53. As a sterilization
process involving heat may result in increased levels of the
gabapentin lactam, heating of solutions prior to administration to
the CNS of a patient would have been inadvisable.
SUMMARY OF THE INVENTION
[0008] An embodiment of the invention provides a process for
preparing a pharmaceutical injectable composition comprising
gabapentin. The process comprises heating the injectable
composition. Surprisingly, the inventors found that heating
injectable compositions comprising gabapentin do not cause
excessive toxicity when introduced into the CNS.
[0009] Heating of injectable compositions comprising gabapentin as
part of a sterilization process provides several advantages. For
example, using heat as form of terminal sterilization allows for
sterilization of large quantities of composition(s) comprising
gabapentin in an efficient manner. In addition, heat treatment
following filter sterilization allows for added assurance that a
composition comprising gabapentin is sterilized to a desired
F.sub.0 for administration to the CNS or other regions of a
patient. These and other advantages of the invention will become
evident upon reading the description herein.
DETAILED DESCRIPTION
[0010] The following description illustrates various embodiments of
the invention. It is to be understood that other embodiments of the
present invention are contemplated and may be made without
departing from the scope or spirit of the present invention. Thus,
the following description is not to be taken in a limiting
sense.
[0011] All scientific and technical terms used in this application
have meanings commonly used in the art unless otherwise specified.
The definitions provided herein are to facilitate understanding of
certain terms used frequently herein and are not meant to limit the
scope of the present disclosure.
[0012] In the context of the present invention, the terms "treat",
"therapy", and the like, as such terms refer to a disease, are
meant to include methods to alleviate, slow the progression,
prevent, attenuate, or cure the targeted disease.
[0013] As used herein, a heated injectable composition refers to a
composition that has been heated at some point. It will be
understood that a heated injectable composition may be essentially
at room temperature, or any other desired temperature, prior to
being injected into a subject.
[0014] As used herein, "injectable pharmaceutical composition"
means a composition that may be infused or injected into a subject,
which composition comprises a pharmaceutically active agent and is
sterile to a F.sub.0, or equivalent, suitable for administering to
a human patient via injection or infusion.
[0015] Embodiments of the present invention provide injectable
compositions comprising gabapentin. Injectable compositions
comprising gabapentin according to embodiments of the invention may
be used for any purpose for which study or use of gabapentin is
desired. For example, injectable compositions comprising gabapentin
may be used in studies to determine or elucidate (a) the effect of
gabapentin on a molecule, cell, tissue, organ, organism, or
combination thereof; (b) the mechanism of action of gabapentin, (c)
the properties of gabapentin, a solution comprising gabapentin, or
a combination thereof, and (d) the like. Injectable compositions
comprising gabapentin may also be used as therapy to treat a
disease or disorder responsive to gabapentin such as epilepsy,
pain, tinnitus, drug addiction, bipolar disorder, osteoarthritis,
migraine, and anxiety disorders including social phobia.
[0016] Injectable Composition
[0017] An embodiment of the invention provides an injectable
composition comprising gabapentin. As used herein, gabapentin
refers to 1-(aminomethyl)cyclohexane acetic acid and
pharmaceutically acceptable salts, solvates, hydrates, and
polymorphs thereof. 1-(aminomethyl)cyclohexane acetic acid is a
.gamma.-aminobutyric acid (GABA) analogue with a molecular formula
of C.sub.9H.sub.17NO.sub.2 and a molecular weight of 171.24.
1-(aminomethyl)cyclohexane acetic acid is freely soluble in water
and both in basic and acidic aqueous solutions.
1-(aminomethyl)cyclohexane acetic acid has the following structure:
##STR2##
[0018] Gabapentin may be obtained from a variety of commercial
sources, such as Shanghai Zhongxi International Trading Co.,
Shanghai, China; Hikal Limited, Bangalore, Karnaraka, India;
Erregierre S.p.A., San Paolo d'Argon (BG), Italy; MediChem, SA,
Sant Joan Despi (Barcelona), Spain; Ranbaxy Laboratories, New
Delhi, India; Procos S.p.A., Cameri, Italy; Zambon Group, Milan,
Italy; Hangzhuo Chiral Medicine Chemicals Co., Hangzhuo, China;
InterChem Corporation USA, Paramus, N.J.; SST Corporation, Clifton,
N.J.; Teva Pharmaceuticals USA, North Whales, Pa.; Plantex USA,
Hakensack, N.J.; and Sigma-Aldrich, St. Louis, Mo., or an
appropriate distributor. Alternatively, gabapentin may be
synthesized and/or prepared as known in the art.
[0019] Injectable compositions include solutions, suspensions,
dispersions, and the like. Injectable solutions, suspensions, or
dispersions may be formulated according to techniques well-known in
the art (see, for example, Remington's Pharmaceutical Sciences,
Chapter 43, 14th Ed., Mack Publishing Co., Easton, Pa.), using
suitable dispersing or wetting and suspending agents, such as
sterile oils, including synthetic mono- or diglycerides, and fatty
acids, including oleic acid.
[0020] Injectable compositions comprising gabapentin may be
prepared in water, saline, isotonic saline, phosphate-buffered
saline, citrate-buffered saline, and the like and may optionally
mixed with a nontoxic surfactant. Dispersions may also be prepared
in glycerol, liquid polyethylene, glycols, DNA, vegetable oils,
triacetin, and the like and mixtures thereof. Under ordinary
conditions of storage and use, these preparations may contain a
preservative to prevent the growth of microorganisms.
Pharmaceutical dosage forms suitable for injection or infusion
include sterile, aqueous solutions, suspensions, or dispersions or
sterile powders comprising an active ingredient which powders are
adapted for the extemporaneous preparation of sterile injectable or
infusible solutions or dispersions. Preferably, the ultimate dosage
form is a sterile fluid and stable under the conditions of
manufacture and storage. A liquid carrier or vehicle of the
solution, suspension or dispersion may be a diluent or solvent or
liquid dispersion medium comprising, for example, water, ethanol, a
polyol such as glycerol, propylene glycol, or liquid polyethylene
glycols and the like, vegetable oils, nontoxic glyceryl esters, and
suitable mixtures thereof. Proper fluidity of solutions,
suspensions or dispersions may be maintained, for example, by the
formation of liposomes, by the maintenance of the desired particle
size, in the case of dispersion, or by the use of nontoxic
surfactants. The prevention of the action of microorganisms can be
accomplished by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal,
and the like. In many cases, it will be desirable to include
isotonic agents, for example, sugars, buffers, or sodium chloride.
Prolonged absorption of the injectable compositions can be brought
about by the inclusion in the composition of agents delaying
absorption--for example, aluminum monosterate hydrogels and
gelatin. Excipients that increase solubility, such as cyclodextrin,
may be added.
[0021] In an embodiment, an injectable composition comprising
gabapentin is an injectable composition comprising an aqueous
solvent. The solvent may be water or saline. The saline may be,
e.g., 0.9% (w/v) sodium chloride or a solution where just enough
sodium chloride is added to make the final injectable composition
isotonic. The saline may be sterile saline.
[0022] Any concentration of gabapentin may be present in an
injectable composition according to various embodiments of the
invention. For example, gabapentin may be present in a solution,
suspension, or dispersion at a concentration between about 0.1
mg/mL and about 100 mg/mL. In an embodiment, gabapentin is present
in a solution, suspension, or dispersion at a concentration between
about 10 mg/mL and about 90 mg/mL. In an embodiment, gabapentin is
present in a solution, suspension, or dispersion at a concentration
between about 20 mg/mL and about 80 mg/mL. In an embodiment,
gabapentin is present in a solution, suspension, or dispersion at a
concentration between about 30 mg/mL and about 100 mg/mL. In an
embodiment, gabapentin is present in a solution, suspension, or
dispersion at a concentration of about 80 mg/mL. In an embodiment,
an injectable composition comprises between about 10 mg/ml and
about 50 mg/ml gababentin. For example, the composition may
comprise between about 20 mg/ml and 40 mg/ml, or about 30 mg/ml. An
injectable composition comprising gabapentin according to an
embodiment of the invention includes an amount of gabapentin
effective to treat a disease responsive to gabapentin. In an
embodiment, the amount of gabapentin is effective to treat a
gabapentin-responsive disease when administered intrathecally.
[0023] In an embodiment of the invention, an injectable composition
comprising gabapentin has a pH between about 4 and about 9, between
about 5 and about 7, between about 5.5 and about 6.5, or about 6.
The pH of an injectable gabapentin composition may be adjusted with
a pharmacologically acceptable acid, base, buffer or combination
thereof. In an embodiment, pH is adjusted with hydrochloric acid or
sodium hydroxide. The hydrochloric acid or sodium hydroxide may be
in any suitable form, such as a 1N solution.
[0024] In an embodiment, the invention provides an injectable
composition comprising gabapentin, where the composition is
substantially isotonic with a physiological fluid of a subject. For
example, the injectable solution may be isotonic with a subject's
blood or cerebrospinal fluid. Cerebrospinal fluid typically has a
tonicity of about 305 mOsm. Accordingly, an embodiment of the
invention provides an injectable gabapentin composition having a
tonicity of about 290 mOsm to about 320 mOsm. If an injectable
composition comprising gabapentin has a tonicity lower than about
290 mOsm to about 320 mOsm, the tonicity may be enhanced by adding
a tonicity enhancing agent, such as sodium chloride. As used
herein, "tonicity enhancing agent" means a compound or composition
that increases tonicity of a composition. However, such tonicities
of between about 290 mOsm to about 320 mOsm are not always
achievable with gabapentin compositions. For example, gabapentin
dissolved in water at a concentration of 80 mg/ml has a tonicity of
about 500 mOsm. When the concentration of gabapentin in an
injectable composition renders the composition hypertonic relative
to a subject's physiological fluid, it is preferred that little or
no amount of a tonicity enhancing agent be added to the
composition. However, it will be recognized that it may desirable
to add one or more additional compounds to the composition even
though the addition of the additional compound(s) will further
increase tonicity of an injectable gabapentin solution. For
example, it may be desirable to add to the composition an
additional therapeutic agent, stabilizing compound, preservative,
solubilizing agent, buffer, etc., even though tonicity will be
increased.
[0025] In an embodiment of the invention, an injectable gabapentin
composition is substantially free of preservatives, substantially
free of buffers, or substantially free of both preservatives and
buffers.
[0026] Sterile injectable composition comprising gabapentin may be
prepared by incorporating gabapentin in the desired amount in the
appropriate diluent or solvent with various other ingredients as
enumerated above and, as desired, followed by sterilization. Any
means for sterilization may be used. For example, sterilization may
be accomplished by heating, filtering, aseptic technique, and the
like, or a combination thereof. Heat for the purposes of
sterilization may be heat for terminal sterilization or may be heat
treatment associated with filtering and/or aseptic technique to
accomplish the desired level of sterilization. In an embodiment,
heating may be accomplished by autoclaving. As used herein
"autoclave", "autoclaving", "autoclaved", and the like is a type of
heating. Autoclaving is typically performed at 121.1.degree. C. and
15 psig. In some circumstances it may be desirable to obtain a
sterile powder for the preparation of sterile injectable solutions.
Such sterile powders may be prepared by vacuum drying and
freeze-drying techniques, which yield a powder of the active
ingredient plus any additional desired ingredient present in a
previously sterile-filtered solutions.
[0027] Heating as a Part of or to Accomplish Sterilization
[0028] In an embodiment of the invention, an injectable
compositions comprising gabapentin is heated. Heating may serve to
sterilize an injectable composition or may serve to assure
sterility of an aseptically prepared injectable composition.
Because increased temperature may result in increased conversion of
gabapentin to its corresponding lactam, which is generally
considered more toxic than gabapentin, it would be expected that
high temperatures should be avoided when preparing compositions
comprising gabapentin. Surprisingly, compositions comprising
gabapentin may be heat treated or sterilized by autoclaving to
provide suitable sterile injectable gabapentin compositions.
Heating, whether or not through autoclaving, may be performed at
any combination of temperature and time to sterilize a composition
comprising gabapentin or assure sterility of an aseptically
prepared composition. Heating may alone be sufficient to sterilize
an injectable composition. Alternatively, heat treatment may be
performed in conjunction with another form of sterilization and/or
aseptic technique. For example, heat treatment may follow
filtering. An injectable gabapentin composition may be filtered
through any filter capable of enhancing sterility of the
composition. For example, an injectable composition comprising
gabapentin may be filtered through a filter having a pore size of
about a 0.2 .mu.m or about 0.22 .mu.m. By way of non-limiting
example, a composition may be subjected to heat of greater than or
equal to about 105.degree. C. In a further example, a composition
may be subjected to heat for greater than or equal to about 2
minutes at a temperature of greater than or equal to about
105.degree. C. In further examples, an injectable composition
comprising gabapentin may be subjected to heat for about 2 minutes
to about 60 minutes at temperatures of about 105.degree. C. to
about 140.degree. C., for about 24 minutes at about 121.degree. C.,
for about 4 minutes at about 130.degree. C., for between about 6
minutes to about 8 minutes at about 121.degree. C. In an
embodiment, heating is performed at a temperature of about
121.degree. C. It will be recognized that with higher temperatures
and longer durations of application of heat, the likelihood of
gabapentin lactam formation will be increased. To prevent excess
formation of lactam, the time and temperature of heat application
may be adjusted to a combination that reduces lactam formation, yet
continues to provide a sterile injectable composition comprising
gabapentin. To achieve the appropriate level of sterilization, heat
may be applied in addition to filtering and/or aseptic
technique.
[0029] In various embodiments of the invention, a heated injectable
composition comprising gabapentin further comprises less than or
equal to about 10% gabapentin lactam (formula I), less than or
equal to about 5% gabapentin lactam, less than or equal to about 3%
gabapentin lactam, less than or equal to about 2% gabapentin
lactam, or less than or equal to about 1% gabapentin lactam. A
heated injectable composition comprising gabapentin may also
further comprise between about 0.5% and about 10% gabapentin
lactam, between about 0.5% and about 5% gabapentin lactam. between
about 0.5% and about 3% gabapentin lactam, between about 0.5% and
about 2% gabapentin lactam, or between about 0.5% and about 1%
gabapentin lactam. The above lactam levels are suitable for
injection into the CNS of a subject and thus are suitable for
pharmaceutical compositions. It will be recognized that gabapentin
lactam formation and other degradation products may form during
heating. As such, additional gabapentin may be added prior to
heating the composition to compensate for degradation. For example,
if an injectable composition comprising 80 mg/ml gabapentin is
desired and if it is know that about 3% of the gabapentin degrades
during heating, then 80 mg/ml plus and additional 3% may be present
in the injectable composition prior to heating.
[0030] In various embodiments of the invention, an injectable
composition comprising gabapentin is heated at an F.sub.0 of about
1 or greater, about 2 or greater, about 3 or greater, about 4 or
greater, about 5 or greater, about 6 or greater, about 7 or
greater, about 8 or greater, about 9 or greater, about 10 or
greater, about 12 or greater, about 18 or greater, or about 24 or
greater. F.sub.0 is a measure of efficiency of a specific heat
sterilization process, which uses time in minutes at 121.degree. C.
as a reference. For example, a heat sterilization process that
destroys organisms to the same extent as 8 minutes at 121.degree.
C. would have an F.sub.0 of 8. In other words, F.sub.0 is the
equivalent time at 121.degree. C. delivered to a container for the
purposes of sterilization. Conversions to F.sub.0 are within the
ability of one of skill in the art and may be performed as
described in Microbiology and Engineering of Sterilization
Processes, seventh edition 1990, Irving J. Pflug, Parenteral Drug
Association, Inc Technical Monograph 1 "Microbiology and
Engineering of Sterilization Processes" reprinted 2000, which
references are hereby incorporated herein by reference in their
entirety.
[0031] In an embodiment, the invention provides a process for
preparing an injectable composition comprising gabapentin. The
composition may be a composition suitable for pharmaceutical use.
The process comprises preparing an injectable composition
comprising gabapentin and heating the composition to sterilize the
composition or to assure the sterility of the composition. An
injectable composition may be prepared as having properties
described above. In an embodiment, gabapentin in a solid form, e.g.
a dry powder, is added to a diluent or solvent to form an
injectable composition. Additional excipeints may be added. The
injectable composition may be sterilized by, e.g., heating, filter
sterilization, and the like or combinations thereof. The sterilized
composition may be placed in a container. In an embodiment of the
invention, the sterilized composition is placed in the container in
an aseptic manner. The container may be any container capable of
housing an injectable composition. Preferably the container is
compatible with the injectable composition. In an embodiment, the
container is a vial, ampule, or the like. The vial, ampule, etc.
may be septum stoppered and capped with a flip-off seal. The
composition may be terminally heat sterilized by heating a
container housing the composition.
[0032] Administration
[0033] Injectable compositions, which have been subjected to heat,
according to the invention may be administered to a subject through
any pharmacologically acceptable route. For example, the
compositions may be administered intravenously, subcutaneously,
intramuscularly, intra-arterially, intra-articularly,
inthrathecally, epidurally, intraparenchymally, intraperitoneally,
intracerebroventricularly, etc., by infusion or injection.
[0034] In an embodiment of the invention, an injectable composition
comprising gabapentin is adapted for intrathecal administration.
Intrathecal administration of gabapentin provides a means for
achieving effective spinal concentrations of gabapentin by
bypassing the saturable L-amino acid active transport system and
blood-brain barrier, while reducing concomitant systemic or
supraspinal drug levels. Any effective amount of gabapentin may be
administered intrathecally. For example, gabapentin may be
administered intrathecally in a daily dose of between about 0.1 mg
and about 200 mg. It will be understood that daily dose
requirements may be adjusted to account for variability in CSF
volume, CSF production rates, and rate of clearance of gabapentin
from the CSF. One of skill in the art will understand that such
variability may be due in part to, e.g., gender and/or age.
[0035] The following patent applications are generally relevant to
injectable gabapentin and its use:
[0036] U.S. patent application Ser. No. 10/807,828, entitled
INTRATHECAL GABAPENTIN FOR TREATMENT OF PAIN, filed on Mar. 24,
2004, and having Attorney Docket No. P-20216.00;
[0037] U.S. patent application Ser. No. 10/808,127, entitled
INJECTABLE GABAPENTIN COMPOSITIONS, filed on Mar. 24, 2004, and
having Attorney Docket No. 20904.00;
[0038] U.S. patent application Ser. No. 10/807,827 entitled
INTRATHECAL GABAPENTIN FOR TREATMENT OF EPILEPSY, filed on Mar. 24,
2004, and having Attorney Docket No. P-20905.00; and
[0039] U.S. patent application Ser. No. 10/808,054, entitled PUMP
SYSTEMS INCLUDING INJECTABLE GABAPENTIN COMPOSITIONS, filed on Mar.
24, 2004, and having Attorney Docket No. P-20906.00.
[0040] All patents, patent applications, technical papers, and
other publications cited herein are hereby incorporated by
reference herein, each in its respective entirety. As those of
ordinary skill in the art will readily appreciate upon reading the
description herein, at least some of the compositions, devices and
methods disclosed in the patents and publications cited herein may
be modified advantageously in accordance with the teachings of the
present invention.
EXAMPLES
[0041] The following examples are provided to illustrate specific
embodiments of the invention, and should not be construed as
limiting the scope of the invention.
Example 1
Stability of Injectable Gabapentin Compositions Subjected to
Heating
[0042] Gabapentin was dissolved in sterile water for injection, USP
(lot 1), 50 mM sodium phosphate (lot 2), or 50 mM sodium citrate
(lot 3) at a concentration of 80 mg/ml. The pH of the resulting
solutions were adjusted to 6.0.+-.0.2 with 1N NaOH and/or 1N HCl.
4.5 ml of the resulting pH-adjusted solutions were placed in 3.5 ml
vials and subjected to autoclaving. Autoclaving occurred at
121.degree. C. and 15 psig for 12 min. (F.sub.0=12), 18 min
(F.sub.0=18), and 24 min (F.sub.0=24). Gabapentin and gabapentin
lactam concentrations of the autoclaved solutions were determined
by HPLC. The results are presented in Table 1. TABLE-US-00001 TABLE
1 Degradation of injectable gabapentin compositions by heating
Gabapentin % Gabapentin Lot F.sub.0 (% Target Level)* Lactam (w/v)
1 12 98.2 1.54 1 18 97.6 2.12 1 24 97.0 2.81 2 12 97.4 2.80 2 18
96.8 3.84 2 24 96.0 4.93 3 12 99.1 2.87 3 18 97.2 3.84 3 24 95.8
5.06 *% target level = [gabapentin concentration/(80 mg/ml)]
.times. 100
Example 2
Heated Injectable Gabapentin Compositions are not Toxic
[0043] Rats were infused intrathecally with solutions containing
varying concentrations of gabapentin. The solutions were subjected
to heat prior to administration, and no toxic effects attributable
to the infused solutions were observed.
[0044] Materials and Methods
[0045] Injectable solutions containing 80 mg/ml gabapentin were
prepared and sterilized by heating to F.sub.0=24 as described in
Example 1. The heat-sterilized 80 mg/ml gabapentin solutions were
diluted in sterile water for injection, USP (Abbott Laboratories;
North Chicago, Ill.) to prepare solutions at gabapentin
concentrations of 1.67, 4.17, and 37.5 mg/ml as shown in Table 2.
TABLE-US-00002 TABLE 2 Dilution of gabapentin solutions Desired
Conc. Volume of Volume of Vehicle Group (mg/ml) Gabapentin (ml)*
(ml)* 1 (Control) 0 0 40.0 2 (Low) 1.67 0.84 39.16 3 (Mid) 4.17
2.09 37.91 4 (High) 80.0 40.0 0 5 (Mid-High) 37.5 18.75 21.25 6
(Control) 0 0 40.0 *Volume of gabapentin (80 mg/ml) and vehicle
(sterile water for injection, USP) needed to make 40 ml.
[0046] Osmotic minipumps (ALZET.RTM. Model 2ML4) were filled with
approximately 2 ml of sterile water for Groups 1 and 6 or
approximately 2 ml of the appropriate test article preparation for
Groups 2 through 5. All dose preparations were filtered using a
0.22 .mu.m filter prior to filling the osmotic minipumps.
[0047] Male and female Crl:CD.RTM.(SD)IGS BR rats were assigned to
groups according to the study design shown in Table 3. The animals
were obtained from Charles River Laboratories; Raleigh, N.C. The
animals were cannulated by the supplier in the intrathecal space
overlying the lumbar vertebrae. The cannulae consisted of 1.3 cm
PE-10 tubing attached to a 7 cm piece of polyurethane tubing (0.025
ID.times.0.040 OD) with a total dead volume of approximately 23.5
.mu.l. On Day 1 (staggered based on sex), the animals were
anesthetized and one prefilled osmotic pump/animal was aseptically
inserted subcutaneously on the animal's dorsum. The cannula was
filled with sterile water or test article preparation, as
appropriate, and the pumps were connected to the intrathecal
cannulae. Beginning on Day 1, animals were dosed 24 hours/day at a
dose volume of approximately 60.96 .mu.l/day via intrathecal
infusion using the osmotic minipump through necropsy on Day 29. At
initiation of dosing, the animals were 8 to 9 weeks old, and their
body weights ranged from 264 g to 340 g for the males and 191 g to
264 g for the females. TABLE-US-00003 TABLE 3 Study design and
assignment of animals Approx. human Dose Dose dose No. of Animals
Level Concentration equivalent Group Male Female (mg/day) (mg/ml)
(mg/day) 1 (Control) 5 5 0 0 0 2 (Low) 5 5 0.10 1.67 8 3 (Mid) 5 5
0.25 4.17 20 4 (High) 5 5 4.8 80.0 384 5 (Mid-High) 5 5 2.25 37.5
180 6 (Control) 3 3 0 0 0
[0048] Assessment of toxicity was based on mortality, clinical
observations, ophthalmic examinations, body weights, food
consumption, clinical pathology, and anatomic pathology. Ophthalmic
examinations were performed prior to initiation of treatment and
during week 4. An indirect ophthalmoscopy examination was done to
include, but was not limited to, a cursory examination of the
adnexa and anterior structures of the globe (e.g., cornea, anterior
chamber, lens) and a detailed examination of the ocular fundus.
Body weights were taken prior to treatment, on Day 1, and weekly
thereafter. Food consumption was measured weekly. At scheduled
sacrifices, samples were taken for hematology, coagulation, and
clinical chemistry. When possible, blood was collected from animals
sacrificed at an unscheduled interval. Tissues were taken from each
animal in groups 1 and 4 and each animal sacrificed at an
unscheduled interval. Spinal cords were harvested from each animal
in Groups 2, 3, and 5. The tissues and spinal cords were processed
and examined microscopically. Macroscopic lesions were processed
and examined microscopically from animals in Groups 2, 3, and 5.
Sections of spinal cord from each animal in Groups 1 and 4 were
embedded in paraffin, sectioned, and stained with luxol fast blue,
and examined microscopically. Immunohistochemistry of spinal cord
sections in paraffin from each animal in Groups 1 and 4 were
sectioned, stained with anti-glial acidic fibrillary protein (Dako;
Carpinteria, Calif.); rabbit IgG from Vector Laboratories;
Burlingame, Calif. was used as a negative control), and
examined.
[0049] The following hematology tests were performed: red blood
cell (erythrocyte) count, hemoglobin, hematocrit, mean corpuscular
volume, mean corpuscular hemoglobin concentration, platelet count,
white blood cell (leukocyte) count, and differential blood cell
count. The following coagulation tests were performed: prothrombin
time and activated partial thromboplastin time. Clinical chemistry
data was obtained on the following: glucose, urea nitrogen,
creatinine, total protein, albumin, globulin, albumin/globulin
ratio, cholesterol, triglycerides, total bilirubin, alanine
aminotransferase, alkaline phosphatase, gamma glutamyl transferase,
asparate aminotransferase, calcium, inorganic phosphorous, sodium,
potassium, and chloride. The following tissues were weighed and
harvested at sacrifice: adrenal, brain, epididymis, heart, kidney,
liver, lung, ovary, pituitary gland, prostate, salivary gland
(mandibular), seminal vesicle, spleen, testis, thymus, thyroid with
parathyroid, and uterus. Paired organs; e.g., adrenal, epididymis,
kidney, ovary, etc., were weighed together. Organ-to-body weight
percentages and organ-to-brain weight ratios were calculated. The
following tissues were preserved in 10%-neutral-buffered-formalin:
adrenal, brain, cecum, colon, duodenum, epididymis, esophagus, eye,
femur with bone marrow (articular surface of the distal end),
Harderian gland, heart, ileum, infusion and catheterization sites
and pumps, jejunum, kidney, lacrimal gland (exorbital), lesions,
liver, lung with mainstem bronchi, lymph node (mesenteric), mammary
gland (females), optic nerve, ovary, pancreas, pituitary gland,
prostate, rectum, salivary gland (mandibular), sciatic nerve,
seminal vesicle, skeletal muscle, skin, spinal cord (cervical,
thoracic and lumbar), spleen, sternum with bone marrow, stomach,
testis, thymus, thyroid with parathyroid, tongue, trachea, urinary
bladder, uterus, and vagina.
[0050] Statistical analysis was performed as follows. Levene's test
was done to test for variance homogeneity. In the case of
heterogeneity of variance at p.ltoreq.0.05, transformations were
used to stabilize the variance. One way analysis of variance
(ANOVA) was used where applicable to analyze continuous clinical
pathology values, organ weight data, food consumption, and body
weight data. When significant, Dunnett's t-test was performed for
pairwise comparisons between treated and control groups. If ANOVA
showed significance for body weights at Week 1, one-way analysis of
covariance (ANCOVA) was used to analyze body weights, with initial
body weights as the covariate. If the ANCOVA was significant,
covariate-adjusted means was used for control versus treated group
comparisons. Group comparisons (Groups 2-5 versus Group 1) were
evaluated at the 5.0% two-tailed probability level. Only data
collected on or after the first day of treatment was analyzed
statistically. Evaluation of Group 6 data was limited to
calculation of mean and standard deviation.
[0051] Results
[0052] Insignificant or incidental differences between treated
groups (Groups 2-5) and control Group 1 were observed.
[0053] 1. Observations
[0054] On Day 11, one male given 4.8 mg/day was observed with
limited use of its hind limbs, the osmotic pump was exposed, and
the catheter did not appear to be connected; the animal was
sacrificed in moribund condition. On Day 17, one male given 2.25
mg/day was observed with limited use of its hind limbs; the animal
was sacrificed in moribund condition. On Days 20 and 21, one female
given sterile water (Group 6) was observed with black skin on the
right ventral abdominal region and a sore/scab on the right lateral
abdominal region; the animal was sacrificed on Day 21. All of these
unscheduled deaths were attributed to complications secondary to
the intrathecal infusion system. All other animals survived to
scheduled sacrifice.
[0055] Animals that survived to the scheduled sacrifice had no
significant observations related to test article administration. A
number of clinical observations were made, but these did not show
any dose relations and were considered incidental.
[0056] One female given 0.1 mg/day (Group 2) and one female given
4.8 mg/day (Group 4, left eye) were observed to have an opaque eye.
Upon further examination, these two individual animals were
confirmed to have corneal keratitis in the affected eye. One male
given 4.8 mg/day (Group 4, left eye) was diagnosed with corneal
keratitis and one female given 2.25 mg/day (Group 5, left eye) with
corneal ulceration. These few noted incidences of corneal keratitis
and one noted incidence of corneal ulceration were considered an
artifact of surgical procedures but not related to test article
administration.
[0057] Females given 2.25 mg/day (Group 5) had significantly lower
body weights for Weeks 1 to 3 as compared to Group 1 controls, but
the lower mean body weight did not appear to be different from the
concurrent controls (Group 6) and this was considered incidental as
the Group 5 animals had lower body weights at initiation compared
to animals in Group 1. There were no clear test article-related
effects on mean body weights, body weight changes, or food
consumption.
[0058] 2. Clinical and Anatomic Pathology
[0059] Administration of intrathecal gabapentin, terminally
sterilized by heat, had no obvious or adverse effect on clinical
pathology test results. The only statistically significant
differences for clinical pathology test results between the control
and treated animals (i.e., lower gamma glutamyltransferase for
males and females given 2.25 mg/day) were considered incidental, as
animals given 4.8 mg/day were not similarly affected. The most
prominent findings for three animals sacrificed at unscheduled
intervals because of poor health, including a control female from
Group 6, were increased absolute neutrophil count and globulin
concentration and decreased albumin concentration. These findings
were consistent with an inflammatory response and considered
incidental because there was no relationship to dose and animals
that survived to the scheduled sacrifice did not exhibit similar
findings.
[0060] The catheter tip was located between L3 and L6 of the
subarachnoid space in 48 animals; in 3 animals the catheter was
epidural. There were no test article-related organ weight
differences, macroscopic observations, or microscopic observations.
Several observations were related to the infusion apparatus and
catheter. In several animals, there was nerve degeneration in the
nerve roots in the region of catheter placement. Often gliosis
accompanied the degeneration. In the animals not surviving to the
scheduled sacrifice, inflammatory processes, including abscess and
pyogranulomas, were present at the infusion or catheter sites or
surrounding the infusion pump.
[0061] There was no significant variation in glial fibrillary
acidic protein immunostaining of spinal cord sections between the
control and high-dose group animals.
[0062] Discussion
[0063] Despite elevated gabapentin lactam concentrations due to
subjecting gabapentin compositions to heat, gabapentin delivered at
dose levels of 0, 0.10, 0.25, 2.25, and 4.8 mg/day was well
tolerated and non-toxic when administered intrathecally. No clear
effects were observed on clinical observations, body weights, body
weight changes, food consumption, ophthalmic observations, or
clinical or anatomic pathology observations.
* * * * *