Technical Field
The subject matter relates to a controlled release gabapentin composition and process
for preparing the same.
Background
Gabapentin [1-(aminomethyl) cyclohexaneacetic acid] is a y-amino acid analogue
effective in the treatment of epilepsy. Gabapentin is an antiepileptic drug indicated as an
adjuvant therapy in the treatment of partial seizure with and without secondary
generalization in adults with epilepsy. It has also been approved for neuropathic pain in
few countries.
Gabapentin has an intense bitter taste (US 6488964) and exists in a crystalline form,
exhibiting poor compressibility and compactability. It has been reported to convert to a
lactam compound (Impurity A) during preparation and storage.
Gabapentin (structure I) degrades via intramolecular cyclization to form a y-lactam (3,3-
pentamethylene-y-butyrolactam) indicated as structure 11. This degradation product is a
white, crystalline, solid, which melts at approximately 85OC (Gabapentin M.P. is 165OC).
This lactam has been shown to cause adverse pharmacological activity (seizures) in a
pre-clinical animal model focusing greater attention on the need to monitor the lactam
degradant in gabapentin pharmaceutical products. (Journal of Pharmaceutical and
Biomedical Analysis 43 (2007) 1647-1653). The lactam has a toxicity that exceeds that
of Gabapentin itself. The lethal dose (LD50) of Gabapentin in mice has been reported to
be 8000mg/kg while that of the corresponding lactam is 300mg/kg. (WO 2005/020978
Al).
Gabapentin exhibits chemical and physical incompatibility with wide range of excipients
commonly used in pharmaceutical formulation. The chemical instability is due to the
Lactam Formation. The possible causes of Lactam formation are:
(i) Catalytic effects of excipients used in the formulation (WO 2005/020978).
(ii) API - degrades in aqueous solution to give a lactam-type degradation
product by intramolecular cyclization. (US 6488964)
(iii) Impact of heat on long term storage.
Majority of the epileptic patients require taking medication for their entire life whereas
others may require taking it for relatively shorter period. Gabapentin having a shorter
half life (i.e. 5 - 7 hrs) in a conventional dosage form may require multiple dosing which
is inconvenient and would lower the patient compliance. Moreover, shorter half life of
Gabapentin can lead to substantial fluctuation in its plasma concentration hence
frequent dosing is necessary to maintain the steady plasma concentration. The
therapeutic dose for Gabapentin is 900 mg to 1800 mg per day, in divided dose.
Gabapentin is typically absorbed from the upper intestine by active transport through a
large neutral amino acid transporter located in the upper small intestine, having limited
transport capacity. This limited capacity leads to its saturation when drug concentration
is high. Therefore, the plasma level of drug is not dose proportional. Conventional
dosage forms release most of the gabapentin in the stomach at very short time resulting
in poor or incomplete drug absorption from the upper region of small intestine.
The problem of poor compressibility and compactability may be overcome by use of
additional compression aid materials or using wet granulation methods. However,
inclusion of a large no, or large amount of excipient in gabapentin formulation may lead
to stability problems. A large amount of excipient is reported to be incompatible with
gabapentin. Lactam is the main degradant, which lowers the potency and is toxic to
humans. It is generally accepted that the tablets should have lactam less than or upto
0.4% w/w.
WO 02/26263, discloses stable compositions of gabapentin containing a stabilizer
comprising a compound (which reduces the ionic strength) and at least 20 ppm of one
anion of mineral acid.
However, these methods are not entirely satisfactory for stabilizing gabapentin
composition and require moisture protective or total moisture barrier packaging.
US 6294198, discloses a spray coating method in which a binder is dissolved in a solvent
to form a binder solution which is then spray coated on the drug particles. By using this
method the entire solvent is evaporated, leaving a film of binder around the drug
particles. This process is conducted at or below room temperature. This utilizes a
cumbersome technique of spray coating which is tedious, requires sophisticated
equipments and is time consuming.
IE 3089/90, discloses a process for stabilizing pharmaceutical compositions containing
gabapentin in solid form. The process describes hydrolyzing Gabapentin with a semiconcentrated
mineral acid and then converting Gabapentin into a solid pharmaceutical
composition containing hydroxyl propyl methyl cellulose, polyvinyl pyrrolidone, cross
povidone , maize starch, cyclodextrin , talcum, co-polymer of dimethylaminomethacrylic
acid and/or neutral methacrylic acid ester.This additional hydrolyzing step is tedious and
time consuming.
US 6488964 62, discloses a process for manufacturing coated particles of y-amino
butyric acid analogue, whose lactam content by weight relative to the weight of y-amino
butyric analogue is less than 0.5O/0. The process is characterized in that a coating
solution of at least one polymer in an organic solvent is sprayed onto the particles of yamino
butyric acid analogue.This utilizes a cumbersome technique of spray coating
which is tedious and requires sophisticated equipments.
US 5955103 discloses an osmotic dosage form for sustained release of anti-epileptic
drugs. The dosage form includes an outer wall and an inner membrane in contact with
the outer wall. Inside the dosage form, there are two layers, an expandable polymeric
layer and a drug layer in contact with the expandable polymeric layer. There is an exact
orifice in the outer wall and the membrane from which the drug release takes place. The
outer wall maintains the integrity of the dosage form and protects the inner membrane
and the enclosed layers from the variable pH environment of the gastro-intestinal tract.
Once inside the stomach, water penetrates the dosage form and the expandable
polymeric layer absorbs water and swells, thereby pushing the drug coat through the
orifice to the outer side of dosage form. However the osmotic dosage form preparation
requires specialized equipments and a lot of precision to produce the product
commercially.
From the above it can be concluded that there is a need for development of a stable
composition of gabapentin.
Object and Summary
The principal object of the subject matter is to provide a controlled release gabapentin
pharmaceutical composition.
Another object of the subject matter is to provide a process for the preparation of a
controlled release gabapentin pharmaceutical composition.
Yet another object of the subject matter is to provide a controlled release gabapentin
pharmaceutical composition with reduced lactam content.
Still another object of the subject matter is to provide a process for the preparation of a
controlled release gabapentin pharmaceutical composition which is cost effective.
The subject matter relates to a controlled release gabapentin pharmaceutical
composition which includes the following:
- gabapentin and pharmaceutically acceptable salts or hydrate thereof
- 1:0.05 to 1:l by weight of heat sealable and moisture protective agent;
- rate controlling polymer;
- 1:0.05 to 1:l by weight of at least one alkalizing agent;
- 1:0.02 to 1:l by weight of at least one amino acid; and
- conventional excipients.
The subject matter also relates to a process for the preparation of the controlled release
gabapentin pharmaceutical composition which includes the following steps:
i. encapsulating gabapentin with heat sealable and moisture protective
agent;
ii. mixing said gabapentin with rate controlling polymer and higher aliphatic
alcohol to obtain a matrix composition;
iii. stabilizing said matrix composition at relative humidity not exceeding
60% by mixing the same with at least one alkalizing agent, at least one
weak amino acid and at least one conventional exicipients to obtain a
controlled release gabapentin pharmaceutical composition.
The subject matter will now be described in detail with reference to accompanying
examples.
Description
The subject matter provides a controlled release gabapentin pharmaceutical composition
having the following constituents:
- gabapentin and pharmaceutically acceptable salts or hydrate thereof
- 1:0.05 to 1:l by weight of heat sealable and moisture protective agent;
- rate controlling polymer;
- 1:0.05 to 1:l by weight of at least one alkalizing agent;
- 1:0.02 to 1:l by weight of at least one amino acid; and
- conventional excipients.
A suitably designed stable controlled release gabapentin tablet is prepared by
encapsulating the gabapentin with suitable moisture protective and heat sealable agent
in combination with one or more rate-controlling polymer; at least one alkalizing agent;
at least one or more weak amino acids; at least one or more other conventional
excipients and further coated with suitable moisture protective and heat sealable agent.
Thus the controlled release gabapentin pharmaceutical composition is prepared as
follows:
i. encapsulating gabapentln with heat sealable and moisture protective
agent;
ii. mixing said gabapentin with rate controlling polymer and higher aliphatic
alcohol to obtain a matrix composition;
iii. stabilizing said matrix composition at relative humidity not exceeding
60°/o by mixing the same with at least one alkalizing agent, at least one
weak amino acid and at least one conventional exicipients to obtain a
controlled release gabapentin pharmaceutical composition.
In accordance with the subject matter, the encapsulated gabapentin particles produce
good flowability, good compressibility, good compactable and stable composition in
combination with one or more rate-controlling polymer; at least one alkalizing agent; at
least one or more weak amino acids; at least one or more other conventional excipients
and further coated with suitable moisture protective and heat sealable agent.
The subject matter highlights stability of gabapentin raw material, which otherwise
when stored at 80°C for 72 hours shows increase in the lactam impurity upto 9.57% by
weight level, thus indicating its instability. This is due to intramolecular cyclization of
Gabapentin to form a y-lactam (3,3-pentamethylene-y-butyrolactam). This Lactam has
been shown to cause adverse pharmacological activity (seizures). Moisture can also play
a vital role in the formation of lactam impurity on long-term storage. To combat the
lactam formation and provide product stability, the inventor discloses a method, where
gabapentin raw material is encapsulated with moisture protective and heat sealable
agent in a ratio of 1 to 5% w/w of gabapentin. The encapsulation of gabapentin is
carried out by using moisture protective and heat sealable agent, dissolved in non
aqueous solvent preferably isopropyl alcohol and then it is evaporated at room
temperature. The dried encapsulated gabapentin granules stabilized its lactam impurity
below 2.2% w/w, when stored at 80°C for 72 hours and below 1.5 O/O w/w, and when is
stored at 50°C or 60°C for 1 month.
The process of the subject matter developed a stable controlled release dosage form of
gabapentin by using above encapsulated gabapentin granules with suitable ratecontrolling
polymer and higher aliphatic alcohol to form a matrix composition. This
polymeric matrix controlled the release of gabapentin up to 12 hours. The in-vitro drug
release of these stabilized controlled release tablet is not less than 80% in twelve hours
time interval.
In the presence of gastric fluids, matrix erode by imbibing water and controlling the
release of gabapentin by a combination of both erosion and diffusion mechanism. First,
there is an erosion of matrix from the swollen matrix to the surrounding fluids. Second,
slow or controlled dissolution or diffusion of gabapentin from the surface of erodeable
matrix.
The subject matter further stabilize the controlled gabapentin granules by incorporating
at least one alkalizing agent; at least one or more weak amino acids; at least one or
more other conventional excipients and compressing the granules into tablets. The
controlled release tablets are further coated with suitable moisture protective and heat
sealable agent to improve the stability or reduce the lactam content in the composition.
The moisture protective and heat sealable agent generally include hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone
and higher aliphatic alcohol/ waxes or a combination thereof.
The rate-controlling polymer is either a hydrophilic or a hydrophobic or a combination
thereof; particularly suitable polymer that erode in aqueous media and results in slow or
controlled diffusion of drug. The amount of polymer in the tablet with respect to
gabapentin depends upon the rate of drug release required, the type, the viscosity and
the molecular weight of the polymer. Examples of suitable rate-controlling polymers
include hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethyl cellulose, methyl
cellulose and higher aliphatic alcohol; vinylacetate copolymers; polysaccharides, such as
xanthan gum, alginates, guar gum; starch and starch based polymers; polyethylene
oxide, methacrylic acid copolymers; maleic anhydride; methyl vinyl ether copolymers
and derivatives and a combination thereof.
The stable controlled release gabapentin composition further includes alkalizing agent
which is selected from a group comprising of calcium or sodium salts, like calcium
sulfate, calcium carbonate, calcium stearate, tribasic calcium phosphate or a
combination thereof. Examples of sodium salt include sodium sulphate, sodium
phosphate, sodium carbonate and combination thereof. This alkalizing agent maintains a
basic environment surrounding the gabapentin molecules and reduces the lactam
formation.
Suitable weak amino acids, which can also be incorporated along with the above
combination, is selected from a group of glycine, phenylglycine, hydroxyphenylglycine,
dihydroxyphenylglycine, L-alanine, hydroxy-L-alanine, L-leucine, hydroxy-L-leucine,
dihydroxy-L-leucine, L-norleucine, methylene-L-norleucine, L-ketonorleucine, Lisoleucine,
hydroxy-L-isoleucine, dihydroxy-L-isoleucine, L-valine, hydroxy-L-valine, Lisovaline,
L-norvatine, hydroxy-L-norvaline, hydroxy-L-ketonorvaline, L-methionine, Lhomomethionine,
L-ethionine, L-threonine, acetyl-L-threonine, L-tryptophan, hydroxy-Ltryptophan,
methyl-L-tryptophan, L-tyrosine, hydroxy-L-tyrosine, methyl-L-tyrosine,
brorno-L-tyrosine, dibromo-L-tyrosine, 3,5-diiodo-L-tyrosine, acetyt-L-tyrosine, chloro-Ltyrosine,
L-m-tyrosine, L-levodopa, L-methyldopa, L-thyroxine, L-serine, acetyl-L-serine,
L-homoserine, acetyl-L-homoserine, ethyl-L-homoserine, propyl-L-homoserine, butyl-Lhomoserine,
L-cystine, L-homocystine, methyl-L-cysteine, allyl-L-cysteine, propyl-Lcysteine,
L-phenylalanine, dihydro-L-phenylalanine, hydroxymethyl-L-phenylalanine, Laminobutyric
acid, L-aminoisobutyric acid, L-ketoaminobutyric acid, dichJoro-Laminobutyric
acid, dihydroxy-L-aminobutyric acid, phenyl-L-aminobutyric acid, Laminovaleric
acid, L-aminohydroxyvaleric acid, dihydroxy-L-aminovaleric acid, Laminoisovaleric
acid, L-aminohexanoic acid, methyl-L-aminohexanoic acid, Laminoheptanoic
acid, L-aminooctanoic acid and citrulline and the D- and DL-forms
thereof, This weak amino acid is self oxidized and prevents oxidation of gabapentin to
produce lactam content.
The higher aliphatic alcohol used in the process for preparing the gabapentin
composition has a Clo - C18 long carbon chain. Said alcohol can be selected from the
group of cetyl alcohol, stearyl alcohol, cetostearyl alcohol and combination thereof.
The stable controlled release gabapentin composition further include other convention
excipients such as binders, diluents, lubricants, glidants, colorants, etc.
Suitable coating agent include, but are not restricted to hydroxypropyl cellulose and/or
polyvinyl acetate or a combination thereof. For example, OpadryB a ready mix coating
preparation (commercially available from M/s Colorcon) for film coating. The above said
ready mix coating material contains suitable excipient like pigments, dyes, titanium
dioxide, iron oxide and talc. The preparation is suitable for aqueous film coating.
The Lactam content of the stable controlled release gabapentin tablet of present
invention after three months of storage at 40°C and 75% RH does not exceed 0.3% by
weight of gabapentin, when packed in clear polyvinylidene chloride coated Polyvinyl
chloride (PVdC/PVC) film blister pack or better moisture barrier suitable packaging. The
composition maintains the lactam level less than 0.4% w/w after six months of storage
under accelerated stability conditions humidity.
The following examples are given for the purpose of illustrating the present subject
matter and are not intended to limit the scope of the subject matter.
Examples
Composition
The compositions for example 1 and 2 are given in table 1.
Table - 1
I
2 1 Hydroxypropyl cellulose
I (Klucel LF)
~xam~le-2-
Qtyltab (mg)
900.00
I
3 1 Hydroxypropyl methyl
Example-1
Qtyltab (mg)
900.00
S.
NO.
1
Ingredients
Gabapentin
I
4
I
Cetostearyl alcohol
5
I
Microcrystaliine Cellulose
6
I
The compositions for examples 3, 4 and 5 are given in Tabie -2
Calcium Carbonate
7
I
Glycine
8 Magnesium Stearate
Table-2
5
(HPMC K 100 LV)
Hydroxypropyl 66.7 66.7 66.7
(1 methyl cellulose in
6
7
8
The compositions of examples 6 and 7 along with their physical parameters and 6
months accelerated stability data for are described in the following Table-3.
(HPMC K 100 M)
Cetostearyl alcohol
Microcrystalline
Cellulose
Calcium Carbonate
I
Ingredients
12.0
26.7
9
Example - 6
33.3
18.0
33.3
Glycine
Example - 7
-
33.3
18.0
33.3
12.0
10 1 Magnesium Stearate 26.7
B. Size 2500
Tablets
12.0
26.7
B. Size 5000
Tablets
Gabapentin
I I
600.0
LF)
Hydroxypropyl methyl cellulose
Microcrystalline Cellulose
Calcium Carbonate
600.0
Hydroxypropyl cellulose (Klucel 30.0
(HPMC K 100 M)
Cetostearyl alcohol
30.0
66.7 66.7
33.3
Glycine
Magnesium Stearate
33.3
12.0
26.7
12.0
26.7
(Hydroxypropyl cellulose based
Tablets
Parameters Tablet dimension
(mm)
Tablet Shape
Average weight (mg)
Hardness (Kp)
Thickness (mm)
Accelerated Stability Results
ssay Value (%)
Initial
lfter 1 month at 40°C/75%RH
lfter 3 month at 40°C/75%RH
ifter 6 month at 40°C/75%RH
.actam Impurity (%)
nitial
ifter 1 month at 4O0C/7S0/0RH
ifter 3 month at 40°C/75%RH
ifter 6 month at 40°C/75%RH
18.5x9.1
Caplet,
biconvex
867.0
10-15
5.7 - 5.9
18.5x9.1
aplet, biconve:
867.0
10 - 15
5.7 - 5.9
Example 1
Hydroxypropyl cellulose is dissolved in isopropyl alcohol under stirring, to form a clear
solution. Gabapentin is encapsulated with above solution in a rapid mixer granulator and
dried in fluid bed dryer on Air. The dried granules are suitably sized. These encapsulated
dried granules are than mixed with hydroxypropyl methyl cellulose which are further
layered with molten cetostearyl alcohol in a rapid mixer granulator and allowed to cool
and conditioned at lower temperature around 20°C. The conditioned granules are
further suitably sized using oscillating granulator or suitable equipment. The
encapsulated and layered granules are mixed in geometrical fashion with calcium
carbonate and glycine. The blend is then finally lubricated with magnesium stearate in
low shear blender for 15 minutes and compressed into tablets using rotary tablet
compression machine and tooling.
Example 2
Hydroxypropyi cellulose is dissolved in isopropyl alcohol under stirring, to form a clear
solution. Gabapentin is encapsulated with above solution in a rapid mixer granulator and
dried in fluid bed dryer on Air. The dried granules are suitably sized. These encapsulated
dried granules are than mixed with hydroxypropyl methyl cellulose which are further
layered with molten cetostearyl alcohol in a rapid mixer granulator and allowed to cool
and conditioned at lower temperature around 20°C. The conditioned granules are
further suitably sized using oscillating granulator or suitable equipment. The blend is
then finally lubricated with magnesium stearate in low shear blender for 15 minutes and
compressed into tablets using rotary tablet compression machine and tooling.
The tablets made as per the above examples were subjected to stress studies, in amber
glass bottle, for one month at 50°C. The samples were tested for Lactam contents.
Example -1 yielded the encapsulated granules showing better stability in the stress
conditions. The observed stability data is shown in the Table -4.
I Examples [-I
Example 3
Hydroxypropyl cellulose is dissolved in isopropyl alcohol under stirring, to form a clear
solution. Gabapentin is encapsulated with above solution in a rapid mixer granulator and
dried in fluid bed dryer on Air. The dried granules are suitably sized. These encapsulated
dried granules are than mixed with hydroxypropyl methyl cellulose which are further
layered with molten cetostearyl alcohol in a rapid mixer granulator and allowed to cool
and conditioned at lower temperature around 20°C. The conditioned granules are
further suitably sized using oscillating granulator or suitable equipment. The
encapsulated and layered granules are mixed in geometrical fashion with calcium
carbonate and glycine. The blend is then finally lubricated with magnesium stearate in
low shear blender for 15 minutes and compressed into tablets using rotary tablet
compression machine and tooling.
Example 4
Povidone (K30) is dissolved in isopropyl alcohol under stirring, to form a clear solution.
Gabapentin is encapsulated with above solution in a rapid mixer granulator and dried in
fluid bed dryer on Air. The dried granules are suitably sized. These encapsulated dried
granules are than mixed with hydroxypropyl methyl cellulose which are further layered
with molten cetostearyl alcohol in a rapid mixer granulator and allowed to cool and
conditioned at lower temperature around 20°C. The conditioned granules are further
suitably sized using oscillating granulator or suitable equipment. The encapsulated and
layered granules are mixed in geometrical fashion with calcium carbonate and glycine.
The blend is then finally lubricated with magnesium stearate in low shear blender for 15
minutes and compressed into tablets using rotary tablet compression machine and
tooling.
Example 5
Hydroxypropyl methyl cellulose is dissolved in isopropyl alcohol under stirring, to form a
clear solution. Gabapentin is encapsulated with above solution in a rapid mixer
granulator and dried in fluid bed dryer on Air. The dried granules are suitably sized.
These encapsulated dried granules are than mixed with hydroxypropyl methyl cellulose
which are further layered with molten cetostearyl alcohol in a rapid mixer granulator
and allowed to cool and conditioned at lower temperature around 20°C. The conditioned
granules are further suitably sized using oscillating granulator or suitable equipment.
The encapsulated and layered granules are mixed in geometrical fashion with calcium
carbonate and glycine. The blend is then finally lubricated with magnesium stearate in
low shear blender for 15 minutes and compressed into tablets using rotary tablet
compression machine and tooling.
The tablets made as per the above examples (example -3, example -4, and example -5)
are coated with the heat sealable or moisture protective polymer i.e. hydroxypropyl
cellulose (5% -6% by weight of tablet) in an aqueous composition.
The tablets made as per the above examples (example -3, example -4, and example -5)
were subjected to accelerated studies for 3 month at 40°C and 75OIoRH clear PVdC 90
gsm/ PVC blister pack; the stability data is shown in the Table-5.
Table-5
Examples
Example-3
Example-4
Example-5
Lactam content
(O/ow/w)
After 3 Month at
40°C/750/o RH
0.09 O/O
0.07 O h
0.08 O/O
From the above examples, example 3 is selected for further study and different trials.
The compositions for Examples 6 and Example 7 are processed using the similar
manufacturing process described for example 3. Their physical parameters and 6
months accelerated stability data are described in the following Table-6.
Table - 6
Example - 7
Qt~/tab(m g)
8. Size 5000
Tablets
600.0
30.0
66.7
Parameters Tablet dimension
Average weight (mg)
Example - 6
Qt~/tab(m g)
8. Size 2500
Tablets
600.0
30.0
66.7
S. No.
1
2
3
Ingredients
Gabapentin
Hydroxypropyl cellulose (Klucel
LF)
Hydroxypropyl methyl cellulose
(HPMC K 100 M)
Stability ~esults
ssay Value (%)
After 1 month at 40°C/75%RH
After 3 month at 40°C/75%RH
After 6 month at 40°C/75%RH
Lactam Impurity (%)
Initial r- After 1 month at 4O0C/75%RH
After 3 month at 40°C/75%RH
After 6 month at 40°C/75%RH
Also, a comparative in-vitro dissolution profile is performed with a reference product
NEUPENTTM AF 900, NEUPENTTM AF 600, NEUPENTA~F~ 450 mg tablet (Manufactured
by: Ranbaxy; India) and GABAPIN SR - 900 mg Tablet (Manufactured by: Intas
Pharmaceutical Ltd.; India) using USP type I1 dissolution apparatus, in 900 ml of Purified
water medium, at stirring speed of paddle at 50 rpm and a temperature of 37OCrt0.5.
The observations are tabulated in Table-7.
Table - 7
Time Duration
After 1" hour
Dissolution Results(% Drug Release)
-Example -
7
22.1
Example
6
20.1
Reference Product
SR-900
18.8
AF 900
17.8
NEUPENTNEUPEN~NEUPEN~GABAPIN
AF 600
21.6
AF 450
21.3
Pharmacokinetic (PK) Parameter under Fastinq condition:
Study was conducted on 16 healthy subjects, with 2 treatment, 2 period, 2 sequence,
randomized crossover design under non- fed with 7 days washout period between
dosing.
The observed results are summarized in Table-8
36.2
55.5
82.2
96.7
Table- 8
After 2" hours
After 4th hours
After ath hours
After 12'~ hours
34.3
53.7
81.5
96.4
Pharmacokinetic (PK) Parameter under Fed condition:
29.1
46.3
72.6
90.5
Study was conducted on 16 healthy subjects, with 2 treatment, 2 period, 2 sequence,
randomized crossover design under fed with 7 days washout period between dosing.
The observed results are summarized in Table-9
32.8
52.8
82.1
97.2
337
51.8
78.7
94.8
% Ratio of
(Test /
Reference)
Pharmacokinetic
Parameter
(Gabapentin)
Table- 9
34.0
53.7
80.5
98.0
Geometric Mean
Reference
Product
Test Product
~eometicM ean
Pharmacokinetic
O/O Ratio of
Test Product (Test /
(Gabapentin)
Reference)
The various embodiments described above can be combined to provide further
embodiments. All of the U.S. patents and WO applications, referred to in this
specification are incorporated herein by reference, in their entirety. Aspects of the
embodiments can be modified, if necessary to employ concepts of the various patents to
provide yet further embodiments.
The subject matter is not intended to be restricted to any particular form or
arrangement, or any specific embodiment, or any specific use, disclosed herein, since
the same may be modified in various particulars or relations without departing from the
spirit of the invention.
We Claim:
1. A controlled release gabapentin pharmaceutical composition comprising:
- gabapentin and pharmaceutically acceptable salts or hydrate thereof
- 1:0.05 to 1:l by weight of heat sealable and moisture protective agent;
- rate controlling polymer;
- 1:0.05 to 1:l by weight of at least one alkalizing agent;
- 1:0.02 to 1:l by weight of at least one weak amino acid; and
- conventional excipients.
2. The controlled release gabapentin pharmaceutical composition as claimed in
claim 1, wherein said moisture protective and heat sealable agent is selected
from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl
cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, waxes and combination
thereof.
3. The controlled release gabapentin pharmaceutical composition as claimed in
claim 1, wherein said rate-controlling polymer is selected from the group
consisting of cellulosic polymer, vinylacetate copolymers, polyvinylpyrrolidone,
alginates, xanthan gum, guar gum, starch, polyethylene oxide, methacrylic acid
copolymers, ethyl cellulose, cellulosic acetates, hydroxypropyl methyl cellulose,
hydrogenated castor oil, waxes, methacrylates, acrylic acid polymers, polyvinyl
alcohols and combination thereof.
4. The controlled release gabapentin pharmaceutical composition as claimed in
claim 1, wherein said alkalizing agent is selected from the group consisting of
calcium, sodium salts and combination thereof.
5. The controlled release gabapentin composition as claimed in claim 4, wherein
said calcium salt is selected from the group consisting of calcium sulfate, calcium
carbonate, calcium stearate, tribasic calcium phosphate and combination thereof.
6. The controlled release gabapentin composition as claimed in claim 4, wherein
said sodium salt is selected from the group consisting of sodium sulphate,
sodium phosphate, sodium carbonate and combination thereof.
7. The controlled release gabapentin pharmaceutical composition as claimed in
claim 1, wherein said weak amino acid is selected from the group consisting of
glycine, phenylglycine, hydroxyphenylglycine, dihydroxyphenylglycine, L-alanine,
hydroxy-L-alanine, L-leucine, hydroxy-L-leucine, dihydroxy-L-leucine, Lnorleucine,
methylene-L-norleucine, L-ketonorleucine, L-isoleucine, hydroxy-Lisoleucine,
dihydroxy-L-isoleucine, L-valine, hydroxy-L-vaiine, L-isovaline, Lnorvaline,
hydroxy-L-norvaline, hydroxy-L-ketonorvaline, L-methionine, Lhomomethionine,
L-ethionine, L-threonine, acetyl-L-threonine, L-tryptophan,
hydroxy-L-tryptophan, methyl-L-tryptophan, L-tyrosine, hydroxy-L-tyrosine,
methyl-L-tyrosine, bromo-L-tyrosine, dibromo-L-tyrosine, 3,5-diiodo-L-tyrosine,
acetyt-L-tyrosine, chloro-L-tyrosine, L-m-tyrosine, L-levodopa, L-methyldopa, Lthyroxine,
L-serine, acetyl-L-serine, L-homoserine, acetyl-L-homoserine, ethyl-Lhomoserine,
propyl-L-homoserine, butyl-L-homoserine, L-cystine, L-homocystine,
methyl-L-cysteine, allyl-L-cysteine, propyl-L-cysteine, L-phenylalanine, dihydro-Lphenylalanine,
hydroxymethyl-L-phenylalanine, L-aminobutyric acid, Laminoisobutyric
acid, L-ketoaminobutyric acid, dichJoro-L-aminobutyric acid,
dihydroxy-L-aminobutyric acid, phenyl-L-aminobutyric acid, L-aminovaleric acid,
L-aminohydroxyvaleric acid, dihydroxy-L-aminovaleric acid, L-aminoisovaleric
acid, L-aminohexanoic acid, methyl-L-aminohexanoic acid, L-aminoheptanoic
acid, L-aminooctanoic acid and citrulline, the D- and DL-forms and combination
thereof.
8. The controlled release gabapentin pharmaceutical composition as claimed in
claim 1, wherein said conventional excipient is selected from the group consisting
of diluents, a lubricant, a glidant and combination thereof.
9. The controlled release gabapentin pharmaceutical composition as claimed in
claim 1, wherein said composition optionally comprises a further coating of
moisture protective or heat sealable polymer selected from the group consisting
of hydroxypropyl cellulose and/or polyvinyl acetate, pigment, dyes, titanium
dioxide, iron oxide, and talc and combination thereof.
10.The controlled release gabapentin pharmaceutical composition as claimed in
claim 1, wherein said composition maintains the lactam level less than 0.4% w/w
after six months of storage under accelerated stability conditions humidity.
11.A process for the preparation of the controlled release gabapentin
pharmaceutical composition comprising the steps of:
i. encapsulating gabapentin with heat sealabie and moisture protective
agent;
ii. mixing said gabapentin with rate controlling polymer and higher aliphatic
alcohol to obtain a matrix composition;
iii, stabilizing said matrix composition at relative humidity not exceeding
60% by mixing the same with at least one alkalizing agent, at least one
weak amino acid and at least one conventional exicipients to obtain a
controlled release gabapentin pharmaceutical composition.
12. The process as claimed in claim 11, optionally comprising the step of further
coating the controlled release gabapentin pharmaceutical composition with heat
sealable and moisture protective agent.
13. The process as claimed in claim 11, wherein said moisture protective and heat
sealable agent is selected from the group consisting of hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone and
waxes and combination thereof.
14. The process as claimed in claim 11, wherein said rate-controlling polymer is
selected from the group consisting of cellulosic polymer, vinylacetate copolymers,
polyvinylpyrrolidone, alginates, xanthan gum, guar gum, starch, polyethylene
oxide, methacrylic acid copolymers, ethyl cellulose, cellulosic acetates,
hydroxypropyl methyl cellulose, hydrogenated castor oil, waxes, methacrylates,
acrylic acid polymers, polyvinyl alcohols and combination thereof.
15. The process as claimed in claim 11, wherein said higher aliphatic alcohol has a
Clo - C18 long carbon chain.
16.The process as claimed in claim 15, wherein said higher aliphatic alcohol is
selected from the group consisting of cetyl alcohol, stearyl alcohol, cetostearyl
alcohol and combination thereof.
17. The process as claimed in claim 11, wherein said alkalizing agent is selected from
the group consisting of calcium, sodium salts and combination thereof.
18. The process as claimed in claim 17, wherein said sodium salt is selected from the
group consisting of sodium sulphate, sodium phosphate, sodium carbonate and
combination thereof.
19. The process as claimed in claim 17, wherein said calcium salt is selected from
the group consisting of calcium sulfate, calcium carbonate, calcium stearate,
tribasic calcium phosphate and combination thereof.
20. The process as claimed in claim 11, wherein said weak amino acid is selected
from a group consisting of glycine, phenylglycine, hydroxyphenylglycine,
dihydroxyphenylglycine, L-alanine, hydroxy-L-alanine, L-leucine, hydroxy-lleucine,
dihydroxy-L-leucine, L-norleucine, methylene-L-norleucine, Lketonorleucine,
L-isoleucine, hydroxy-L-isoleucine, dihydroxy-L-isoleucine, Lvaline,
hydroxy-L-valine, L-isovaline, L-norvaline, hydroxy-L-norvaline, hydroxy-Lketonorvaline,
L-methionine, L-homomethionine, L-ethionine, L-threonine, acetyl-
L-threonine, L-tryptophan, hydroxy-L-tryptophan, methyl-L-tryptophan, Ltyrosine,
hydroxy-L-tyrosine, methyl-L-tyrosine, bromo-L-tyrosine, dibromo-Ltyrosine,
3,5-diiodo-L-tyrosine, acetyt-L-tyrosine, chloro-L-tyrosine, L-m-tyrosine,
L-levodopa, L-methyldopa, L-thyroxine, L-serine, acetyl-L-serine, L-homoserine,
acetyl-L-homoserine, ethyl-L-homoserine, propyl-L-homoserine, butyl-Lhomoserine,
L-cystine, L-homocystine, methyl-L-cysteine, allyl-L-cysteine, propyl-
L-cysteine, L-phenylalanine, dihydro-L-phenylalanine, hydroxymethyl-Lphenylalanine,
L-aminobutyric acid, L-aminoisobutyric acid, L-ketoaminobutyric
acid, dichJoro-L-aminobutyric acid, dihydroxy-L-aminobutyric acid, phenyl-Laminobutyric
acid, L-aminovaleric acid, L-aminohydroxyvaleric acid, dihydroxy-Laminovaleric
acid, L-aminoisovaleric acid, L-aminohexanoic acid, methyl-laminohexanoic
acid, L-aminoheptanoic acid, L-aminooctanoic acid and citrulline
and the D- and DL-forms thereof.
21.The process as claimed in claim 11, wherein said conventional excipient is
selected from the group consisting of a diluent, a lubricant, a glidant and
combination thereof.
22. The process as claimed in claim 11, wherein said composition maintains the
lactam level less than 0.4% w/w after six months of storage under accelerated
stability conditions.