Field of the Invention:
The present invention is directed to an extended release formulation of anti-parkinsonism
drug comprising pramipexole or pharmaceutically acceptable salts; derivatives; solvates;
and isomers thereof, a weak acid and an extended release polymer.
Background of the Invention:
Parkinson's disease is a movement disorder of increasing occurrence in aging populations.
It is a progressive neurodegenerative disorder affecting the mobility and control of the
skeletal muscular system. The disease is associated with the depletion of dopamine from
cells in the corpus striatum. Parkinson's disease is a common disabling disease of old age
affecting about one percent of the population over the age of 60 in the United States. The
incidence of parkinson's disease increases with age and the cumulative lifetime risk of an
individual developing the disease is about 1 in 40. Symptoms include pronounced tremor of
the extremities, bradykinesia, rigidity and postural change. A perceived pathophysiological
cause of Parkinson's disease is progressive destruction of dopamine-producing cells in the
basal ganglia which comprise the pars compartum of the substantia nigra, basal nuclei
located in the brain stem. Loss of dopamineric neurons results in a relative excess of
acetylcholine. Parkinson's disease often begins with mild limb stiffness and infrequent
tremors and progresses over a period of ten or more years to frequent tremors and memory
impairment, to uncontrollable tremors and dementia.
Based on the mechanism the anti-parkinson's drugs can be classified as dopamine
precursors or prodrugs, dopamine receptor agonists, monoamine oxidase-B inhibitors,
catechol-O-methyl transferase inhibitors, aromatic L-amino acid decarboxylase inhibitors,
anticholinergics, N-methyl D-aspartate receptor inhibitors etc.
Drugs such as etilevodopa; droxidopa; levodopa; melevodopa; aplindore; apomorphine
bromocriptine; cabergoline; dihydroergocryptine; Iisuride; pardoprunox; pergolide; piribedil;
pramipexole; ropinarole; rotigotine; ladostigil lazabemide; mofegiline; pargyline; rasagiline;
selegiline; entacapone; tolcapone; benserazide; carbidopa; methyldopa; benzatropine;
biperiden; bornaprine; chlorphenxamine; cynmlne; dexetimide; dimenhydrinate;
diphenylhydramine; etanautine; etybenzatropine; mazaticol; metixene; orphenadrine;
phenglutarimide; piroheptine; procyclidine; profenamine; trihexyphenidyl; tropatepine;
2
amantadine; budipine; memantine; rimantadine and the like are used for the treatment of
parkinson's disease.
Most common adverse events in early parkinson's disease without levodopa were
somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle
spasms, and peripheral edema.
Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full
intrinsic activity at the O2 subfamily of dopamine receptor, binding with higher affinity to 03
than O2 or 04 subtypes. The precise mechanism of action of pramipexole as a treatment for
parkinson's disease is unknown, although it is believed to be related to its ability to stimulate
dopamine receptors in the striatum. This conclusion is supported by electrophysiologic
studies in animals that have demonstrated that pramipexole influences striatal neuronal
firing rates via activation of dopamine receptors in the striatum an the substantia nigra, the
site of neurons that send projections to the striatum. The relevance of 03
receptor binding in
parkinson's disease is unknown.
The pramipexole is a basic drug and its chemical name is (S)-2-amino-4,5,6,7-tetrahydro-6-
(propylamino) benzothiazole. Its empirical formula is C10H17N3S. The salt form commonly
used is pramipexole dihydrochloride monohydrate.
The pramipexole as its dihydrochloride monohydrate salt is approved in United States as
MIRAPEX®(immediate release tablets) and as MIRAPEX®ER(extended release tablets) for
the treatment of early as well as advanced idiopathic parkinson's disease. MIRAPEX® is
also approved for the treatment of moderate-to-severe primary restless legs syndrome
(RLS). MIRAPEX®ERtablets are taken orally once daily. US 4,886,812 discloses tetrahdrobenzthiazole compounds (pramipexole). US6, 001,861 & US 6,194,445 disclose use of
pramipexole for the treatment of restless legs syndrome.
The starting dose of pramipexole is 0.375 mg/day. Based on efficacy and tolerability,
dosages may be increased gradually, not more frequently than every 5 to 7 days, first to
0.75 mg/day and then by 0.75mg increments up to a maximum recommended dose of 4.5
mg/day.
3
As is commonly known, extended release of active ingredient(s) allows simplification of the
patient's administration scheme by reducing the amount of recommended daily intakes,
improves patient's compliance, and attenuates adverse events, e.g., related to high plasma
peaks. Extended release pharmaceutical preparations regUlate the release of the
incorporated active ingredient or ingredients over time and comprise formulations with
controlled, prolonged, sustained, delayed, slow or an extended release, so they accomplish
therapeutic or convenience objectives not offered by conventional dosage forms such as
solutions or promptly dissolving dosage forms.
There are a number of approaches described in prior art to provide extended release tablet
compositions of pramipexole.
US 7,695,734 discloses an extended release tablet formulation comprising pramipexole or a
pharmaceutically acceptable salt thereof in a matrix comprising at least two water swelling
hydrophilic polymers other than pregelatinized starch, and wherein at least one of the at
least two polymers is an anionic polymer and the other is a substantially neutral polymer.
US 2005/0175691 discloses the orally deliverable pharmaceutical once daily sustained
release composition comprising a therapeutically effective amount of pramipexole or a
pharmaceutically acceptable salt thereof , a starch preferably pregelatinized starch, a
hydrophilic polymer such as hydroxypropylmethyl cellulose and at least one
pharmaceutically acceptable excipient.
US 2005/0226926 discloses a sustained-release pharmaceutical composition in a form of an
orally deliverable tablet comprises a water soluble salt of pramipexole dispersed in a matrix
comprising a hydrophilic polymer and a starch having a tensile strength of at least about
0.15 kN cm-2
at a solid fraction representative of the tablet.
US 2009/0281153 discloses an extended release tablet formulation comprising pramipexole
or a pharmaceutically acceptable salt thereof in a matrix comprising at least one water
swelling polymer other than pregelatinized starch.
US 2009/0182024 discloses an extended release tablet formulation comprising pramipexole
or a pharmaceutically acceptable salt thereof in a matrix, the matrix comprising at least two
4
water swelling polymers, wherein one of the polymers is pregelatinized starch, and wherein
another one of the polymers is an anionic polymer.
US 2009/0130197 disclose an extended release pellet comprlsmg an active ingredient
selected from pramipexole and the pharmaceutically acceptable salts thereof, and at least
one release-modifying excipient.
US 2008/0254117 disclose a process for preparing tablets of pramipexole dihydrochloride
wherein the tablets exhibit enhanced stability properties.
WO 2007/090882 discloses an extended release composition which comprises the active
compound pramipexole and provides a selected release profile. Preferably, the composition
does not exhibit a lag phase of more than 1 hour. The composition is for suitable for oral
administration. It also discloses a method for achieving a 5 selected release profile,
optionally by combining an extended release dose fraction and an immediate release dose
fraction.
US 2003/0133982 discloses zero-order sustained release solid dosage forms suitable for
administration of a wide range of therapeutically active medicaments, especially those that
are water-soluble comprises (a) a matrix core comprising ethylcellulose and the active agent
and (b) a hydrophobic polymer coating encasing the entire matrix core.
US 2008/0248107 discloses a controlled release formulation comprising an therapeutically
effective amount of pharmacologically active substance haVing high water solubility, at least
one non-polymeric release retardant, and at least one pH independent non-swelling release
retarding polymer. The said dosage form provides controlled release of the active agent with
reduced initial burst release.
US 2006/0110454 discloses an extended release composition of Pramipexole or a
pharmaceutical acceptable salt thereof, wherein the active agent is coated on a non pareil
inert core, the drug loaded core is further coated with a polymeric layer which enables the
release of the active agent over an extended period and optionally the extended release
pellets being further blended with suitable excipients and compressed into a multi unit tablet
and processes for the preparation of the said composition.
5
we 2008/068778 discloses an extended release pharmaceutical composition comprising
pramipexole having an extended release profile such that not less than 25% of the total
amount of pramipexole or a pharmaceutically acceptable salt thereof in the composition is
released within one hour no, significant release of the drug takes place over the subsequent
one hour and not less than 80% of the total amount of pramipexole or a pharmaceutically
acceptable salt thereof in the composition is released over a period of about 24 hours.
US 2009/0304794 disclose a controlled release pharmaceutical formulation of pramipexole
for once-a-day administration comprising a therapeutically effective amount of pramipexole,
and an osmotic agent, wherein pramipexole is released from the formulation along a predetermined release profile. The controlled release formulation of the invention is osmotic
formulation
US 2009/0110728 discloses the solid dosage form for delivery of water soluble
pharmaceutical agents comprises a matrix core containing the pharmaceutical agent and a
hydrophobic material, and a coating containing a hydrophilic pore-forming agent and a
hydrophobic polymer. The dosage form exhibits a zero-order release profile upon
dissolution.
US 2009/0053310 discloses novel sustained release dosage form comprising an active
agent and a combination of a non-swelling pH dependent release retardant and a non
swelling pH independent release retardant polymer which provides pH-independent drug
release for a considerable period of time after administration.
we 2007/002518 disclose delayed-release (DR) pramipexole pharmaceutical composition
in an once - daily orally deliverable form, comprising an enteric coating, a pramipexole core,
and pharmaceutically acceptable carriers and excipients, wherein the enteric coating
substantially eliminates the release and/or absorption of pramipexole in the upper
gastrointestinal (GI) tract.
US 2004/0228915 disclose an extended release multiparticulate formulation of a therapeutic
agent, wherein coated core multiparticulate particles of the therapeutic agent are overcoated
with a binder-dispersing agent, such as povidone or cross-povidone. The binder-dispersing
6
agent in the formulations of the present invention ensure that compressed tablets formed
therefrom will remain intact through oral administration, and dissolve shortly thereafter,
enabling the multi particulates to release the therapeutic agent contained therein over an
extended period of time.
Although number of approaches has already been developed for extended release of
pramipexole, we have found that the presence of weak acid in the formulation provides a pH
independent release profile for pramipexole dihydrochloride monohydrate.
Pramipexole is a basic drug. The presence of two or more basic centres in pramipexole and
2-aminobenzothiazole structure is the reason for the strong basic character of this drug.
Basic and acidic drugs exhibit pH-dependent solubility profiles varying by more than 2
orders of magnitude in the physiological pH range. A basic drug's solubility decreases as it
proceeds distally towards the large intestine (pH 8.0) while it is soluble in the stomach and
the upper or proximal region of the small intestine. Thus, a poorly soluble basic drug will
lead to less drug being available for absorption in the lower or distal intestine .. While not
intending to be bound by any particular theory, it is believed that the formulation with the
weak acid creates a microenvironment of low pH to enhance the solubility of the drug within
the dosage form as it moves down the GI tract.
Thus the oral extended release formulations comprise of pramipexole or pharmaceutically
acceptable salts; derivatives; solvates; and isomers thereof, a weak acid and an extended
release polymer would provide an extended release of pramipexole. The release profile is
found to be pH independent.
Objects of the Invention:
An extended release formulation comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer.
An extended release formulation comprising
7
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer,
wherein the extended release formulation exhibits a pH independent release profile.
Summary of the Invention:
One embodiment disclose an extended release formulation comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer.
Other embodiment disclose an extended release formulation comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer, providing therapeutically effective concentration of
pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof for a period of at least 8 hrs.
Another embodiment disclose an extended release formulation comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer, wherein the extended release formulation exhibits a
pH independent release profile.
Another embodiment disclose an extended release formulation comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer, wherein the extended release formulation is
gastroretentive.
8
Another embodiment disclose an extended release formulation comprising
(i) Core comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer, and
(ii) Coating.
Another embodiment disclose an extended release formulation comprising
(i) Core comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer, and
(ii) Coating, wherein the extended release formulation is gastroretentive.
Brief Description of the Drawing:
FIG. 01 depicts the in vitro dissolution profile of pramipexole dihydrochloride monohydrate
tablets of Example 01 in 0.1 N HCI, pH 4.5 acetate buffers and pH 6.8 phosphate buffers.
Detailed Description of the Invention:
The present invention provides an extended release formulation of anti-parkinson drug
preferably pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and
isomers thereof, a weak acid and an extended release polymer.
As used herein, the term "pramipexole" is understood as covering all forms of pramipexole,
the free base as well as pharmaceutically acceptable salts; derivatives; solvates; and
isomers thereof. The most preferred form is pramipexole dihydrochloride monohydrate.
The term "therapeutically effective concentration" or "therapeutically effective amount" is
used throughout the specification to describe concentrations or amounts of compounds
according to the present invention which are therapeutically effective in treating diseases.
9
The extended release formulation would release drug at substantially constant rate over an
extended period of time or a substantially constant amount of drug will be released
incrementally over an extended period of time.
The term extended release formulation may also used synonymously with prolonged release
formulation, programmed release formulation, timed release formulation, modified release
formulation, site specific release formulation, sustained release formulation, controlled
release formulation, slow release formulation, delayed release formulation, osmotic dosage
form, bioadhesive formulation, orally disintegrating modified release formulation,
gastroretentive formulation and other such dosage forms.
The term "pH independent release" means the release profile which does not vary much
with changes in pH.
The term "pharmaceutically-acceptable excipients" as used herein includes any
physiologically inert, pharmacologically inactive material known to one skilled in the art,
which is compatible with the physical and chemical characteristics of the particular
pramipexole active ingredient selected for use.
The extended release formulation includes tablets, coated tablets, layered tablets, particles,
granules, pellets, powders, microparticles, capsules which may be hard gelatin or soft
gelatin, caplets, sachets, pellets, spheroids, mini-tablets, beads, microcapsules, lozenges
and pills.
One of the embodiments disclose an extended release formulation comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer.
The weak acid may be selected from organic acids, inorganic acids or combination thereof.
The organic acids may include, but are not limited to, citric acid, fumaric acid, malic acid,
maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, mandelic acid, glutaric
acid, and glutamic acid.
10
The inorganic acids may include, but are not limited to, hydrochloric acid, phosphoric acid,
nitric acid, and sulfuric acid.
The preferred weak acid is organic acid and the preferred organic acid is fumaric acid.
Weak acid provides acidic microenvironment and may avoid degradation of pramipexole
when exposed to alkaline media. The weak acid used may also act as anti-oxidant to
prevent oxidation of pramipexole at alkaline pH.
In another embodiment, the extended release formulation comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer, providing therapeutically effective concentration of
pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof for a period of at least 8 hrs.
The extended release polymer used in the present invention may be selected from water
soluble polymer, water insoluble polymer, waxy material or combination thereof. The
extended release polymer may be added in the formulation in the range of about 1 to about
90%.
The water soluble polymer may be selected from the group consisting of alkyl celluloses
such as methyl cellulose; pseudo ethylcellulose; hydroxyalkyl celluloses, for example,
hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl
cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and
hydroxypropyl methyl cellulose (hypromellose); carboxyalkyl cellulose esters; other natural,
semi-synthetic, or synthetic di-, oligo-, and polysaccharides such as galactomannans,
tragacanth, agar, guar gum, and polyfructans; methacrylate copolymers; polyvinyl alcohol;
polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of
polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene
oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.
11
Water insoluble polymer may be selected from the group consisting of cellulose acylate;
cellulose ethyl ether; cellulose diacylate; cellulose triacylate; cellulose acetate; cellulose
diacetate; cellulose triacetate; mono-, di- and tricellulose alkan, mono-, di- and tricellulose
aroyl; ethyl cellulose; cellulose acetate; cellulose acetate butyrate; cellulose acetate
phthalate; cellulose acetate trimellitate; cellulose acetate succinate; polyvinylacetate
phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate
succinate; poly(alkyl methacrylate); poly vinyl alcohols; polyacrylamide derivatives poly (vinyl
acetate); polyvinylacetatephthalate, polyvinylbutyrate acetate, vinyl acetate-maleic
anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic
acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, pH-independent
acrylates such as ammonio methacrylate copolymer and the like; ethyl cellulose, crosslinked
polymers such as styrene-divinylbenzene copolymer, polysaccharides having hydroxyl
groups such as dextran, cellulose derivatives which are treated with bifunctional crosslinking
agents such as epichlorohydrin, dichlorohydrin, 1, 2-, 3, 4-diepoxybutane and the like.
Waxy material may be selected from carnauba wax; beeswax; chinese wax; spermaceti;
lanolin; bayberry wax; candelilla wax; castor wax; esparto wax; Japan wax; jojoba oil;
ouricury wax; rice bran wax; ceresin waxes; montan wax; ozocerite; peat waxes; paraffin
wax; polyethylene waxes; polyglycerol fatty acid esters; fatty alcohols; glyceryl esters of fatty
acids; and mineral or vegitable oil.
The extended release formulation of the present invention may further contain
pharmaceutically acceptable excipients such as binders; diluents; lubricants; disintegrating
agents; glidants; stabilizers; osmotic agents and surface active agents.
The binders may include, but are not limited to, potato starch; modified starch; gelatin; wheat
starch; corn starch; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose,
hydroxyethyl cellulose, hydroxypropylmethyl cellulose (hypromellose), ethyl cellulose and
sodium carboxy methyl cellulose; natural gums such as acacia, alginic acid and guar gum;
liquid glucose; dextrin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; poly vinyl
alcohol; poly-N-vinyl amide; polyethylene glycol; gelatin; poly propylene glycol; tragacanth;
hydrogenated vegetable oil; castor oil; paraffin; higher aliphatic alcohols; higher alphatic
acids; long chain fatty acids; fatty acid esters; and wax-like materials such as fatty alcohols,
fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, waxes, stearic acid
12
and stearyl alcohol. The amount of binder present can vary from about 0.1% to about 25%
by weight of the tablet dry weight, preferably about 0.5% to about 10%.
The diluents may include, but are not limited to, pharmaceutically acceptable inert fillers
such as microcrystalline cellulose; lactose; dibasic or tribasic calcium phosphate;
saccharides confectioner's sugar; compressible sugar; dextrates; dextrin; dextrose; fructose;
lactitol; mannitol; sucrose; starch (Le. corn starch); xylitol; sorbitol; talc; calcium carbonate;
and calcium sulphate. The diluent is preferably used in an amount of about 10 to 90% by
weight.
The disintegrating agents may include, but are not limited to, cross-linked polymers such as
crospovidone; starch or modified starch such as sodium starch glycolate; clays such as
bentonite or veegum; celluloses or cellulose derivatives; and crosslinked cellulose such as
croscarmellose sodium resins such as polacrillin potassium.
The lubricants may include, but are not limited to, Mg, AI or Ca or Zn stearate; polyethylene
glycol; glyceryl behenate; glyceryl monosterate; mineral oil; sodium stearyl fumarate; stearic
acid; hydrogenated vegetable oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine;
polyethylene glycol; ethylene oxide polymers; and colloidal silica.
The glidants may include, but are not limited to, magnesium trisilicate; powdered cellulose;
starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; colloidal silicon
dioxide; and silicon hydrogel.
The extended release formulation may optionally contain a surface active agent. The
surface active agents may include, but are not limited to, fatty acid; olefin; alkylcarbonyl;
silicon elastomer; sulfate ester; petty alcohol sulfate; sulfate pete and oil; sulfonic acid-base;
fat sulfonate; alkylaryl sulfonate; ligmin sulfonate; phosphoric acid ester; polyoxyethylene;
polyoxyethylene caster oil; polyglycerol; polyol; imidazol; altanolamine; hetamine;
sulfobecamine; phosphotide; polyoxyethylene-sorbitan fat acid ester; and sorbitan ester.
The osmotic agents may include, but are not limited to sodium chloride; potassium chloride;
magnesium sulfate; magnesium chloride; sodium sulfate; lithium sulfate; urea; inositol;
13
sucrose; lactose; glucose; sorbitol; fructose; mannitol; dextrose; magnesium succinate; and
potassium acid phosphate.
One embodiment disclose an extended release formulation comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer
wherein the extended release formulation exhibits a pH independent release profile.
One embodiment disclose an extended release formulation comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer, wherein the extended release formulation is
gastroretentive.
Gastroretentive means a formulation which is remained in the stomach or upper part of the
small intestine. The size of the extended release formulation will determine whether the
formulation is gastroretentive.
Other embodiment disclose an extended release formulation comprising
(i) Core comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer, and
(ii) Coating.
The coating may be functional, multifunctional or non-functional coating. It includes moisture
barrier coatings; enteric polymeric coatings; extended release coating; sustained release
coating; controlled release coating; and the like.
14
The functional coating comprise of extended release polymer which may affect the release
of pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof from the extended release formulation.
The non-functional coatings have no affect on the release of pramipexole from the extended
release formulation.
The coating composition may further include other pharmaceutically acceptable excipients
such as plasticizer, pore forming agent or channeling agent, solvent system (Le., water), a
colorant and the like to provide elegance and product distinction. Color may be added to the
solution of the therapeutically active agent instead, or in addition to the overcoat. Suitable
ingredients for providing color to the formulation include titanium dioxide and color pigments,
such as iron oxide pigments. The incorporation of pigments, may, however, increase the
retard effect of the coating. Alternatively, any suitable method of providing color to the
formulations of the present invention may be used.
The plasticizer may include, but not limited to polyethylene glycol; triethyl citrate; triacetin;
diethyl phthalate; dibutyl stearate; dibutyl sebacate; oleic acid; alcohol; mineral oil; castor oil;
lanolin; petrolatum; propylene glycol; glycerol; acetylated monoglyceride; rape oil; olive oil;
sesame oil; acetyltributylcitrate; acetyltriethylcitrate; glycerin sorbitol; diethyloxalate;
diethylmalate; diethylfumarate; dibutylsuccinate; diethylmalonate; dioctylphthalate;
dibutylsebacate; triethylcitrate; tributylcitrate; glyceroltributyrate; and the like.
The pore forming agent which may be used are lactose, sodium chloride, sodium carbonate,
polyethylene glycol etc.
Another embodiment disclose an extended release formulation comprising
(i) core comprising
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer, and
(ii) coating, wherein the extended release formulation is gastroretentive.
15
The extended release formulation of the present invention may be manufactured by various
methods known in the art such as by dry granulation, wet granulation, fluidized bed
granulation, melt granulation, direct compression, double compression, extrusion
spheronization, layering and the like. Compaction of the blend into coprimate may be carried
out using a slugging technique or roller compaction. The milling of the granules may be
carried out according to conventional milling methods. Aqueous and/or non-aqueous
solvents may be used for granulation.
The wet granulation process comprises the admixing of the active ingredient with diluent(s)
and/or extended release polymer, and granulation of the blend with the binder mass to form
the wet mass followed by drying and sizing. The binder may optionally be admixed with the
dry blend and granulation performed with aqueous or non-aqueous solvent. The solvent for
the non-aqueous granulation is selected from methanol, ethanol, isopropyl alcohol and
dichloromethane.
Alternatively pramipexole may also be dissolved in solvent and then used as granulating
solution.
The present invention is not to be limited in scope by the specific embodiments described
herein. Indeed, various modifications of the invention in addition to those described herein
will become apparent to those skilled in the art from the foregoing description. Such
modifications are intended to fall within the scope of the appended claims.
Examples:
Formula:
Sr. %wlw
No. Ingredients Example 01 Example Example 03 Example 04
02
1 Pramipaxole
dihydrochloride 1.5 2 3 5 monohydrate ::
Pramipexole
2 Microcrystalline cellulose 26 54 53 29
3 Hvpromellose 55 30 20 50
4 Fumaric acid 0.5 2 7 4
5 Povidone 15 10 14 10
6 Methanol: Water mixture as as as as
16
1 1.0 1.5 1.0
1 1.0 1.5 1.0
Procedure:
Microcrystalline cellulose, hypromellose & fumaric acid were sifted and mixed. This mixture
was granulated with solution of pramipexole dihydrochloride monohydrate & povidone in
methanol and water mixture. The granules were dried for desired loss on drying. The dried
granules were sifted, lubricated and compressed into tablets.
Dissolution study for pramipexole dihydrochloride monohydrate tablets of Example
01:
The dissolution profile of the pramipexole dihydrochloride monohydrate tablets of Example
01 was carried out in type 1 dissolution apparatus, basket, at 100rpm, at a temperature of
about 37±0.5'C, in 500ml of 0.1 N HCI, pH 4.5 acetate buffer and pH 6.8 phosphate buffer
which may release not more than about 25% of pramipexole dihydrochloride monohydrate
within 1 hour, from about 30% to about 70% of pramipexole dihydrochloride monohydrate is
released within 4 hour and not less than about 75 % of pramipexole is released within 12
hours. The results of the in vitro dissolution profile are set forth in Table: 01 and illustrated
in Figure 01.
Table: 01
Dissolution profile of pramipexole dihydrochloride monohydrate tablets of
Example 01
% Drug Release
Time (Hrs) In 0.1 N HCI In pH 4.5 In pH 6.8
Acetate Buffer Phosphate Buffer
1 22.9 17.3 18.0
2 34.0 26.6 28.6
4 49.7 42.5 41.7
8 71.1 61.6 60.9
12 84.7 77.3 75.5
14 90.9 85.3 80.8
16 93.6 90.7 84.9
18 97.2 100.4 89.6
20 99.7 102.1 94.0

We Claim:
1. An extended release formulation comprising:
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer.
2. The extended release formulation as defined in claim 1, wherein the weak acid is
organic acid, inorganic acid or combination thereof.
3. The extended release formulation as defined in claim 2, wherein the organic acid is
citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid,
aspartic acid, mandelic acid, glutaric acid or glutamic acid.
4. The extended release formulation as defined in claim 2, wherein the inorganic acid is
hydrochloric acid, phosphoric acid, nitric acid or sulfuric acid.
5. The extended release formulation as defined in claim 2, wherein the organic acid is
fumaric acid.
6. The extended release formulation as defined in claim 1, wherein the extended release
polymer is water soluble polymer, water insoluble polymer, waxy material or combination
thereof.
7. The extended release formulation as defined in claim 6, wherein the water soluble
polymer is selected from the group consisting of methyl cellulose, hydroxymethyl
cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose,
hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxyalkyl cellulose
esters, galactomannans, tragacanth, agar, guar gum, polyfructans, methacrylate
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copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone
with vinyl acetate, polyethylene oxide and copolymers of ethylene oxide and propylene
oxide.
8. The extended release formulation as defined in claim 6, wherein the water insoluble
polymer is selected from the group consisting of cellulose acylate, cellulose ethyl ether,
cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose
triacetate, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate
phthalate, cellulose acetate trimellitate, cellulose acetate succinate, polyvinylacetate
phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate,
ethylhydroxycellulose phthalate, polyvinylacetatephthalate, polyvinylbutyrate acetate,
vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl
acrylate-methacrylic acid copolymer, ammonio methacrylate copolymer, methacrylatemethacrylic acid-octyl acrylate copolymer, ethyl cellulose, styrene-divinylbenzene
copolymer, dextran, epichlorohydrin, dichlorohydrin, 1,2-,3,4-diepoxybutane
hydroxypropylmethylcellulose acetate succinate, poly (vinyl acetate), poly vinyl alcohols
and polyacrylamide derivatives.
9. The extended release formulation as defined in claim 6, wherein the waxy material is
selected from the group consisting of carnauba wax, beeswax, chinese wax, spermaceti,
lanolin, bayberry wax, candelilla wax, castor wax, esparto wax, Japan wax, jojoba oil,
ouricury wax, rice bran wax, ceresin waxes, montan wax, ozocerite, peat waxes, paraffin
wax, polyethylene waxes, and polyglycerol fatty acid esters.
10.An extended release formulation comprising:
(a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers
thereof;
(b) a weak acid; and
(c) an extended release polymer,
wherein the extended release formulation exhibits a pH independent release profile.
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11. The extended release formulation as defined in claim 10, wherein the extended release
formulation of pramipexole releases not more than about 25% of pramipexole within 1
hour, from about 30% to about 70% of pramipexole within 4 hour and not less than about
75% of pramipexole within 12 hours when tested according to USP type 1 dissolution
apparatus at 100rpm and 37±0.5'C temperature in 500ml of 0.1 N HCI.