SUSTAINED RELEASE ORAL LIQUID SUSPENSION DOSAGE FORM
FIELD OF THE INVENTION
The present invention relates to a stable, sustained release oral liquid suspension
dosage form of pharmaceutical active ingredients, which is easy to administer and
particularly beneficial for the pediatric and geriatric patients. This invention particularly
relates to a sustained release oral liquid suspension dosage form which is a ready-to-use and
does not require reconstitution before oral administration. Present invention also relates to a
process for preparing said dosage form.
BACKGROUND
Oral route is the most convenient and preferred route for the drug administration and
there are various conventional dosage forms available for the oral administration of the drug
such as tablets, capsules, solutions, emulsions or suspensions. However, for the pediatric and
geriatric patients solid oral dosage formulations especially large tablets or capsules are very
difficult to swallow, hence for such patients liquid formulations are most preferred dosage
forms and patients may be more inclined to comply with their medication instructions if the
dosages are easier to ingest.
However, the problem with the use of conventional oral dosage forms like tablets,
capsules and solution is the fluctuation in the blood concentrations within each interval
between dosing. Moreover, certain drugs, especially those exhibiting a short half-life
necessitate frequent dosing, are too rapidly absorbed and sometimes result in peak serum
levels that are excessively high. Such fluctuating serum drug levels often result in the
development of adverse symptoms. Thus the pharmaceutical scientists have developed
formulations to prolong the residence time of drug molecules in the body by controlling the
release rate of the drug from the formulation to enhance convenience of the regimen, improve
patient compliance and reduce frequency of side effects due to fluctuations in blood
concentration. Further, by controlling the release of the active substance it is possible to
influence the extent of absorption and the duration of action.
For many drugs sustained release solid dosage forms are available in the market such
as extended release tablets of Levetiracetam (Keppra®), Metformin (Fortamet®), Metoprolol
(Toprol-XL®), Desvenlafaxine (Pristiq®), and Venlafaxine (Effexor XR®). However such
controlled release solid formulations requires large amounts of excipients which can retard
the drug release in the formulation such as polymers, waxes as matrixing agents and
increases the size of the final formulation which reduces patient compliance especially for
the pediatric and geriatric patients. Therefore an alternative approach to administer sustained
release dosage form will be an oral liquid dosage form. Among the liquid dosage form, the
suspension formulation against the solution can provide sustained drug release by controlling
the drug release. Such formulations are particularly suitable for pediatric, geriatric patients
and for those who can not swallow the tablet dosage form. However, there are different
challenges in preparation of such dosage form and thus there are very few sustained release
suspension dosage form products available commercially in the market. The major challenge
with suspension of sustained release dosage form would be to maintain the stability of
suspension throughout the shelf life because in case of failure, irregular blood concentration
may be achieved and can be sometimes sub therapeutic or toxic.
The inventors of the present inventions have discovered a stable, taste masked oral
sustained release dosage form.
Various approaches are disclosed for oral sustained release dosage form in the
literature. US5296236 discloses liquid- controlled release suspension of the drug containing
micro granules coated with series of successive polymer having alternate hydrophobic and
hydrophilic coatings. US 4999189 disclose sustained release oral suspensions wherein drugresin
particle coated with a first inner coating of water-insoluble wax and a second outer
coating of a pharmaceutically acceptable water-insoluble polymer. WO2006093838 discloses
method of preparing controlled release suspension of drug microbeads in thixotropic
solution. US5 156842 discloses oral sustained release suspension of the antibiotics, the
antibiotic of said microparticles being coated with, distributed through or adsorbed onto the
non-toxic polymer and finally such coated microparticles are suspended in of non-aqueous
vehicles. EP07 17992 discloses aqueous pharmaceutical suspensions containing a high
amount of acetaminophen embedded in a polymer to impart controlled release properties.
US20091 11872 discloses stabilized pharmaceutical suspension of carisbamate using
hypromellose. US20030108575 mentions oral suspension formulation for the drug of low
water solubility using wetting agent, thixotropic thickening agent and suspending agent.
WO2003053403 discloses use of water-soluble or swellable nonsurfactant polymer along
with the suspending agents for the poorly water soluble drug for the suspension formulation.
US7300670 discloses an aqueous suspension of the particulate drug containing suspending
agent in a liquid phase. WO2008 122993 discloses drug containing microparticles with first
pH independent polymer coating and second pH dependent polymer coating layer. US
6156340 disclose drug liquid sprayed on to inert core and such drug coated particles were
further coated with two layers of the polymer having increasing permeability for the water.
SUMMARY OF THE INVENTION
The present invention relates to a stable, sustained release oral liquid suspension
dosage form of pharmaceutical active ingredients.
The present invention is to provide a sustained release oral liquid suspension dosage
form of pharmaceutically active ingredients, which is ready to use and does not require
reconstitution before oral administration.
An another aspect of the present invention is to provide a -sustained release oral liquid
suspension dosage form of active ingredients which can be administered as once-daily or
twice-daily.
Another aspect of the present invention is to provide a sustained release oral liquid
suspension dosage form of high solubility active ingredients, which can be administered as
once-daily or twice-daily.
Another aspect of the present invention is to provide a sustained release oral liquid
suspension dosage form of active ingredients, which is stable during storage period and does
not leach out in suspending media during storage period.
Further aspect of the present invention is to provide a sustained release oral liquid
suspension dosage form of active ingredients, which is particularly convenient for the
pediatric and geriatric patient population.
Another aspect of the present invention is to provide a process for the preparation of
sustained release oral liquid suspension dosage form of active ingredients.
Another aspect of the present invention is to provide a sustained release liquid
suspension dosage form of active ingredients which comprises of the pharmaceutically
acceptable additives like that of fillers, binders, lubricants, glidants, rate controlling
polymers, suspension stabilizers, buffering agents, sweeteners, antioxidants, flavoring agents,
viscosity modifying agent, surfactants, preservatives, plasticizing agent etc.
DETAIL DESCRIPTION OF THE INVENTION
Sustained release oral liquid suspension dosage form for once daily or twice daily
administration, preferably once daily administration of present invention in general
comprises active ingredient in particles, granules, pellets, beads or micro particles which
would be additionally mixed with appropriate additives such as viscosity modifying agents
that provide suspending properties in the liquid dosage form, sweetening agents which would
mask undesirable taste and feel of active ingredient, glidants which provides flow properties
and also prevents caking when present in liquid composition, and also other additives such
as buffering agents, lubricants, surfactants etc.
"Sustained-release dosage forms" as used in the present invention to define a release
profile of an active agent over an extended period of time. The terms "modified-release",
controlled-release", "prolonged-release", "extended-release", "sustained-release" and
"delayed release" are used interchangeably herein.
In an embodiment of the present invention the sustained release liquid oral suspension
dosage form comprises of inert pellet, active ingredient, rate controlling polymer and other
pharmaceutically acceptable excipients.
In an embodiment of the present invention the sustained release liquid oral suspension
dosage form comprises of inert pellet, high solublity active ingredient, rate controlling
polymer and other pharmaceutically acceptable excipients.
In further embodiments of the present invention, the seal coated inert pellets are
loaded with active ingredient along with pharmaceutically acceptable additives, and these
drug loaded pellets are further coated with rate controlling polymers to yield sustained
release pellets of the active ingredient.
In another embodiment of the present invention the seal coated inert pellets are coated
by drug coating. The drug coated pellets are further coated with rate controlling polymer
coating. Optionally the sustained release pellets obtained can be further coated with drugbinder
solution. The pellets so obtained may be coated with alkali soluble coating and/or with
an acid soluble polymer coating.
In a preferred aspect the present invention provides a ready to use, stable sustained
release liquid oral suspension dosage form comprises: sustained release pellets, which
comprises:
a) Inert pellets, surrounded by seal coating,
b) Drug layer surrounding the seal coated inert pellets comprises pharmaceutically
active ingredient with one or more pharmaceutically acceptable excipient,
c) Coating layer surrounding the drug layer comprises rate controlling polymer,
Wherein the sustained release pellets are suspended with viscosity modifying agent or
suspending agent or thickening agent or suspension stabilizers in addition to other
pharmaceutically acceptable excipients in a suspending media at a suitable pH which
is maintained with or without buffer,
Wherein the sustained release liquid oral suspension does not required reconstitution
before oral administration.
In another preferred aspect, the sustained release pellets so obtained are further
surrounded by protective coating.
In another preferred aspect the protective coating is applied to surround a coating
layer having rate controlling polymers and/or secondry drug coating or any other suitable
step in process according to the present invention.
In another preferred embodiment of the present invention the seal coated inert pellets
are coated by drug resin complex.
The sustained release pellets so obtained are suspended with viscosity modifying
agent or suspending agent or thickening agent along with sweetener, flavoring agent,
buffering agent, preservative, humectant etc in addition to other pharmaceutically acceptable
excipients. The ready to use suspension can be prepared in aqueous or non-aqueous media at
adequate pH which can be maintained with or without buffer. The preferred pH of such
suspension would be in a range of 6 to 7.5.
The dosage form can be prepared as per the therapeutic dosage requirement of
particular active ingredient and to be converted in to mg/ml basis.
"Seal coated inert pellet" according to the present invention are inert pellets coated
with a polymer, for eg. ethylcellulose. The seal coating provides a film over the pellets,
which improves the strength of pellets. So, during the coating/layering process the pellet does
not get deformed or distorted.
"Drug-binder solution" according to the present invention is a solution of drug and
one or more binding agent.
"High solubility active ingredient" according to the present invention is an active
agent that from less than 1 part to 30 parts of water will be required to dissolve 1 part of
active ingredient.
The "pharmaceutically active ingredient" "active ingredient" or "drug substances" or
"drugs" according to the present invention is selected from the group of analgesic; anti¬
allergic; anti-anginal; antibacterial; anticonvulsant; antipsychotic; antidepressant;
antidiabetic; anti-epileptic; hypolipidemic; antihyperlipidemic; hypocholesterolemic;
antihypertensive; vasoconstrictor; vasodilator; anti-inflammatory; antineoplastic,
antiparasitic; antiproliferative; antisecretory; antithrombotic; anti-ulcerative; antiviral;
appetite suppressant; diagnostic aid; diuretic; glucocorticoid; immunizing agent;
immunomodulator; immunoregulator; immunostimulant; immunosuppressant;
neuroprotective; NMDA antagonist; radioactive agent; sedative; sedative-hypnotic; steroid;
tranquilizer; cerebral ischemia agent; wound healing agent; xanthine oxidase inhibitor and
the like.
The active ingredient, which can be used in the present invention is selected from but
not limited to aspirin, paracetamol, diclofenac, naproxen, oxycodone, hydrocodone,
diamorphine, carbamazepine, topiramate, lamotrigine, Levetiracetam, Brivaracetam,
seletracetam, primidone, clonazepam, diazepam, oxcarbazepine, zonisamide, pregabalin,
ethosuximide, lorazepam, nitrazepam, midazolam, lorazepam, tolbutamide, acetohexamide,
tolazamide, chlorpropamide, metoprolol, metformin, phenformin, buformin, rosiglitazone,
pioglitazone,troglitazone, miglitol, acarbose, alogliptin, vildagliptin, sitagliptin, saxagliptin,
glipizide, glimeperide, glyburide, repaglinide, nateglinide, Chlorpromazine, Fluphenazine,
Perphenazine, Prochlorperazine, Thioridazine, Trifluoperazine, Mesoridazine, Periciazine,
Promazine, Triflupromazine, Levomepromazine, Promethazine, Pimozide chlorprothixene,
clopenthixol, flupenthixol, thithixene, Zuclopenthixol, Clozapine, Olanzapine, Risperidone,
Paliperidone, Quetiqpine, Ziprasidone, Amisulpride, Asenapine, Iloperidone, Zotepine,
Sertindole, Lurasidone, Aripiprazole, alprazolam, Zolpidem, bupropion, duloxetine,
milnacipran, tolterodine, diltiazem, Oxybutinin, venlafaxine, desvenlafaxine, tramadol,
tapentadol or there pharmaceutical acceptable salts and a combination thereof.
The term "inert core" or "inert cores" or "inert particles" or "inert pellets" herein
refers to inert particles made from sugar spheres also known as non-peril seeds or other
equivalents conventionally used for the preparation of dosage form like microcrystalline
cellulose, dibasic calcium phosphate, mannitol or other suitable polyols or glass beads and
the like.
The use of the terms "a" and "an" and "the" and similar referents in the context of
describing the invention (especially in the context of the following claims) are to be
construed to cover both the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context.
The "rate controlling polymer" according to the present invention can be selected
from hydrophilic polymer, hydrophobic polymer or the mixture thereof. The rate controlling
polymer can be used as a matrixing agent or as a coating agent. Hydrophilic polymer that can
be used in the present invention can be exemplified as hydroxyethyl cellulose, hydroxypropyl
cellulose, sodium alginate, carbomer, sodium carboxymethyl cellulose, xanthan gum, guar
gum, locust bean gum, polyvinyl alcohol and hydroxypropyl methylcellulose. The preferred
hydrophilic rate controlling polymer that can be used in the present invention is
hydroxypropyl cellulose. The matrix forming polymer comprises from about 1% to about
70%, preferably from about 5% to about 50% and most preferably from 15% to 50% by
weight of the coated sustained release composition. The hydrophilic polymer described
above can also be used as a constituent of the coating layer.
Hydrophobic polymer that can be used in the present invention are selected from the
group comprising of cellulose ether such as ethyl cellulose, cellulose acetate, polyvinyl
acetate, methacrylic acid esters neutral polymer, polyvinyl alcohol-maleic anhydride
copolymers, hydroxypropyl methyl cellulose phthalate, EUDRAGIT ® RSPO, EUDRAGIT®
S 100, hydrogenated castor oil, waxes and the like. Even the commercially available
dispersion of film formers namely, EUDRAGIT® L-30D, EUDRAGIT ® NE 30D,
AQUACOAT® ECD-30, SURELEASE ® E-7, EUDRAGIT ® RS 30D, EUDRAGIT® RL
30D, etc. may be used for the purpose of providing sustained release composition. Preferably
the hydrophobic polymer that can be used in the present invention is ethyl cellulose,
hydroxypropyl methyl cellulose phthalate, EUDRAGIT ® RSPO, EUDRAGIT® S 1 0 and
hydrogenated castor oil.
Acid soluble polymer that can be used in the present invention is selected from the
group of EUDRAGIT ® E 100, EUDRAGIT® E 12, 5 and EUDRAGIT ® EPO. Preferably
EUDRAGIT® E 100 is used as the acid soluble polymer. These polymers also provide pH
dependent drug release, protection of sensitive active ingredient, taste and odor masking,
moisture protection etc. Preferably EUDRAGIT® E 100 is used as the acid soluble polymer.
Alkali-soluble polymers which can be used in the present invention are selected from
EUDRAGIT® S or L, EUDRAGIT ®- SI00, EUDRAGIT ® LI00, EUDRAGIT® L 00-55
EUDRAGIT® L30D, hydroxypropyl methyl cellulose phthalate etc. Preferably EUDRAGIT®
LI00-55 is used as the alkali soluble polymer.
The polymers described above may also be used as a constituent of protective
coating, which protects drug leaching. The protective coating may be applied as one or more
layer based on characteristic of active ingredient. Preferred protective coating in the present
invention is EUDRAGIT ® E 100 or EUDRAGIT® RSPO or EUDRAGIT ® L100-55.
The other pharmaceutically acceptable excipients that can be used in the present
invention may be selected from filler, binder, lubricant, glidant, viscosity modifying agent,
plasticizer, stabilizer, ion exchange resin, preservative, buffering agent, sweetener, flavoring
agent or a mixture thereof.
Filler which can be used in the present invention is selected from the group
comprising of cellulose and cellulose derivatives like microcrystalline cellulose, calcium
carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium
carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol,
lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol,
starch, sucrose, sugar, and xylitol and other materials known to one of ordinary skill in the art
or mixture thereof. The filler may be present in an amount from about 1% to about 50%,
preferably from about 10% to about 50% by weight of the sustained release composition.
Binder or binding agent that can be used in the present invention is selected from the
group comprising of polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl
methylcellulose (low viscosity grade), methyl cellulose, ethyl cellulose, starch, pregelatinized
starch, modified corn starch, polyacryl amide, poly-N-vinyl amide, sodium carboxymethyl
cellulose, polyethylene glycol, gelatin, polyethylene oxide, poly propylene glycol,
tragacanth, alginic acid, and other materials known to one of ordinary skill in the art or
mixture there of. The binder may be present in an amount from about 0.1% to about 20%,
preferably from about 1% to about 10% by weight of the sustained release composition.
Lubricant or glidant that can be used in the present invention is exemplified by
magnesium stearate, calcium stearate, glyceryl stearate, zinc stearate, talc, polyethylene
glycols, hydrogenated vegetable oil, mineral oil, stearic acid, glyceryl behenate, cornstarch,
calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel, sodium
stearyl fumarate, glyceryl palmitostearate, stearic acid, and other materials known to one of
ordinary skill in the art or mixture thereof. The glidant, lubricant and anti adherent are
individually present in the range from about 0.01% to about 20%w/w by weight of the
sustained release composition.
Plasticizers are used in the present formulation for providing flexibility to the
sustained release polymer coating layer. Different kinds of plasticizers that can be used in the
present formulation are selected from low molecular weight polymers, oligomers,
copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic
hydroxyls, ester-type plasticizers, glycol ethers, polypropylene glycol, multi-block polymers,
single block polymers, lo molecular weight poly(ethylene glycol), citrate ester-type
plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can also include
ethylene glycol, 1 ,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol,
triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds,
monopropylene glycol, monoisopropyl ether, propylene glycol monoethyl ether, ethylene
glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate,
butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltributylcitrate, triethyl citrate, acetyl
triethyl citrate, tributyl citrate and allyl glycolate. Also the combination of the plasticizers
can be used in the present composition. The composition in the present embodiment
preferably comprises up to 1- 25 % of plasticizer by the total weight of the composition.
"Viscosity modifying agent" or "thickening agent" or "suspending agent" are one of
the most important constituent of liquid sustained release dosage form. These agents are also
called as suspension stabilizers and they are intended to ensure that the individual doses
removed have constant active ingredient content. A large variety of agents can be used for
the above purpose like colloidal silicates having a high aluminum and magnesium content,
such as bentonite, Veegum or Gel White; colloidal silica, for example Aerosil (Degussa),
Cabosil (Cabot); organic stabilizers, for example swelling agents, such as alginates, sodium
alginate, calcium alginate or propylene glycol alginate, gum arabic, tragacanth, karaya gum,
sterculia gum, carrageen, guar gum, xanthan gum or agar; synthetic or semi synthetic
swelling agents, for example 1,2-epoxide; polymers, in particular ethylene oxide
homopolymer having a degree of polymerization of about 2,000-100,000, which are known,
for example, under the trade name Polyox (Union Carbide), preferably swellable cellulose
ethers, for example methyl- or ethyl cellulose, hydroxy ethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, methyl- or ethylhydroxyethyl cellulose,
carboxymethyl cellulose or an alkali metal salt thereof, or microcrystalline cellulose, or
water-soluble polyvinyl compounds, such as polyvinyl acetate, polyvinyl alcohol or
polyvinylpyrrolidone or combination thereof. Preferably xanthan gum is used as the
suspension stabilizers.
Suspension stabilizers are advantageously present in an amount which ranges up to 1-
25% by weight of the composition, preferably about 1 to about 5 % by weight.
Ion-exchange resin that can be used in the present invention is selected from cationic
and anionic ion-exchange resins. Ion exchange resins useful in the practice of the present
invention include cationic resins such as: AMBERLITE® IRP-64 (a porous copolymers of
methacrylic acid crosslinked with divinylbenzene), and AMBERLITE® IRP-69 (Sodium
polystyrene sulfonate USP). AMBERLITE® IRP 69 is preferred resin. The DOWEX® resins,
available from the Dow Chemical Company, Midland, MI are also included in the practice of
the present invention. Said DOWEX® resins are strong cationic exchangers based upon
polystyrenesulphonic acid with variable crosslinking (1-12% divinylbenzene) in a variety of
particle sizes.
Further, said AMBERLITE® IRP 69 (sodium polystyrenesulfonate) is available
commercially as a sodium salt. However, it is within the scope of the present invention to
convert the sodium salt to other salt forms including, but not limited to, K and Li. The ion
exchange resin useful in the practice of the present invention comprise from % to 60% by
weight of the pharmaceutical compositions of the present invention. More preferably, the ion
exchange resins useful in the practice of the present invention comprise from about 5% to
40% by weight of the pharmaceutical compositions of the present invention.
In an embodiment of the present invention the sustained release granules or particles
prepared according to any of the above described embodiments is suspended along with other
additives in an aqueous or non-aqueous solvent or solution or dispersing agent or suspending
media.
According to the present invention aqueous solvent or non-aqueous solvent dispersing
agent or suspending media which can be used are selected from water, alcohols, oils or
mixtures thereof. Edible oils that can be used in the present invention are selected from
edible oils of animal or plant origin, such as but not limited to mono, di, and triglycerides,
acetylated monoglycerides, pharmaceutically acceptable esters of aliphatic hydroxyacids,
fatty acids; tocopherol and tocopherol esters, glycol esters, squalane, squalene, corn oil,
limonene, crill oil, oregano oil and lipid soluble vitamins and the like.
A common problem associated with liquid pharmaceutical dosage forms is the often
disagreeable taste which may manifest itself when the drug is administered in a liquid dosage
form. For example, Levetiracetam is a drug with an undesirable taste. This taste may be
overcome by the addition of sweeteners or flavoring agents to the formulation which mask
the bitter or unpleasant taste of the drugs.
Sweeteners are used to mask the bitter taste of the active ingredients or to impart
sweetness to the liquid dosage form. Sweeteners that can be used in accordance with the
present invention are selected from sugar such as monosaccharide or disaccharides, for
example D-glucose, D-fructose, D-xylose, maltose or sucrose; polyols, such as glycerol,
dulcitol, mannitol, sorbitol or xylitol, or artificial sweeteners, such as saccharine or the
corresponding sodium, potassium or calcium salt, cyclamate or the corresponding sodium or
calcium salt, aspartame, or acesulfame or the potassium salt thereof, furthermore Dulcin or
ammonium glycyrrhizinate. Generally sweeteners are present in higher percentage in the
suspension dosage form. Sweeteners used in the present formulation ranges from 2 to 60 %
of the weight of the dosage form, preferably 5 to 50 %, more preferably 5-30% weight of the
composition.
Flavouring agents that can be used in the present invention are selected from without
any limitation peppermint flavour, mint flavour, orange flavour, lemon flavour, grape flavor
etc. Flavouring agents can be used in the range of 0.01 to 5% of the dosage form.
The term "buffering agent," as used herein, refers to an agent or a mixture of agents
that can maintain the original acidity or basicity of a composition. Representative buffering
agents include, but are not limited to, citric acid, sodium citrate, sodium phosphate,
potassium citrate, and mixtures thereof. A preferred buffering agent of the present invention
is a mixture of citric acid and sodium citrate. Buffering agent that can be used in the present
invention ranges from 0.01 to 20%, preferably 1 to 10% by weight of the composition.
The term "preservative," as used herein, refers to an agent or mixture of agents that is
used to protect a composition against antimicrobial (e.g., yeast, mold, bacteria) activity.
Representative preservatives include, but are not limited to, sodium benzoate, benzoic acid,
ethylenediaminetetraacetic acid, sorbic acid, benzethonium chloride, benzalkonium chloride,
bronopol, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, thiomersal, sodium
propionate, chlorhexidine, chlorobutanol, chlorocresol, cresol, imidurea, phenol,
phenylmercuric salts, potassium sorbate, propylene glycol, and mixtures thereof. A preferred
preservative of the present invention is the combination of methyl paraben and propyl
paraben. Preservatives that can be used in the present invention ranges from 0.01% to 5%.
A humectant is a hygroscopic substance. It is often a molecule with several
hydrophilic groups, most often hydroxyl groups, but amines and carboxyl groups, sometimes
esterified, can be encountered as well. Humectants maintain the water content of the liquid
dosage form. Examples of humectants include glycerin, propylene glycol and glyceryl
triacetate. Others can be polyols like sorbitol, xylitol and maltitol, polymeric polyols like
polydextrose, or natural extracts like quillaia, lactic acid or urea. Preferably maltitol and
glycerin is used as humectant in the present invention. The amount of preservatives that can
be used in the present invention ranges from 0.01% to 5%.
In an another embodiment of the present invention, the sustained release oral
suspension can be prepared by the following process;
a) Suitable fillers are coated with a binder solution to obtain seal coated inert
pellets.
b) Seal coated inert pellets obtained from the above step are further coated with a
drug -binder solution or drug-binder resin complex to form drug layering,
c) Drug layered pellets so obtained from step b) are further coated with a rate
controlling polymer with one or more pharmaceutically acceptable excipient
to form coated layer.
d) Optionally, the pellets so obtained in step c) are further coated by drug binder
solution or drug resin complex
e) The pellets so obtained either from step c) or d) are further coated with
protective coating using suitable polymer.
f) Sustained release pellets so obtained are suspended with viscosity modifying
agent or suspending agent or thickening agent or suspension stabilizers along
with sweeteners, flavoring agent, buffering agent, preservative, humectants in
addition to other pharmaceutically acceptable excipients in aqueous or non
aqueous media at a pH which can be maintained with or without buffer.
In one of the preferred embodiment of the present invention, the sustained release oral
suspension can be prepared by the following process;
a) Suitable fillers are coated with a binder solution to obtain seal coated inert pellets.
b) Seal coated inert pellets obtained from the above step are further coated with a drug -
binder solution or drug-binder resin complex to form drug layering.
c) Drug layered pellets so obtained from step b) are further coated with a rate controlling
polymer with one or more pharmaceutically acceptable excipient to form coated
layer.
d) Optionally, the pellets so obtained in step c) are further coated by drug binder
solution or drug resin complex.
e) The pellets so obtained from step c) or d) are further coated with protective coating.
f) The pellets so obtained either from step e) are optionally coated using acid soluble
or/and alkali soluble polymer.
g) Sustained release pellets so obtained are suspended with viscosity modifying agent or
suspending agent or thickening agent or suspension stabilizers along with sweeteners,
flavoring agent, buffering agent, preservative, humectants in addition to other
pharmaceutically acceptable excipients in aqueous OR non aqueous media at a pH
which can be maintained with or without buffer.
The invention will be further illustrated by the following Examples, however, without
restricting its scope to these embodiments.
EXAMPLES:
Example 1
Levetiracetam sustained release suspension for 100 mg/ml
Ingredients Qty in mg
Seal Coating
Sugar Spheres (#60-80) 45.45
Ethyl Cellulose 10 cps 3.64
Purified Talc 0.91
Methyl Alcohol q.s.
DCM q.s.
Levetiracetam Drug Coating
Seal coated pellets 50
Levetiracetam 100
HPMC 6 cps 18.8
Talc 6.2
Methanol q.s.
Extended release coating
Drug coated pellets 175.00
Ethyl Cellulose 45 cps 45.29
HPMC 2910 6 cps 4.53
DEP 4.53
TEC 2.26
Talc 4.53
Ferric oxide yellow 0.1 1
Methanol q.s.
DCM q.s.
Protective Coating
EC coated pellets 236.25
Eudragit RSPO 47.25
DEP 4.725
Talc 18.9
Acetone q.s
Isopropyl alcohol q.s
Preparation of Corn Oi suspension
Eudragit RSPO coated pellets 307.13
Corn Oil 523.35
Methyl Paraben 0.54
Propyl Paraben 0.54
Hydrogenated Castor Oil 1.08
Aerosil 2.74
Sucralose 2.70
Propyl gallate 1.08
Lake of Panceau 0.27
Strawberry 2.70 .
Suspension with pellets 842.12
Table 1: Composition of Levetiracetam sustained release suspension 00 mg / ml
Procedure:
1 Sea coating: Sifted the sugar pellets through the 60/80 mesh. Ethylcellulose (EC) and talc
are dispersed in a blend of Methanol/Dichloromethane (DCM). This dispersion was coated
on spheres using FBC bottom spray to get seal coated pellets.
2 Drug layering: Dissolved HPMC 6 cps in methanol then added Levetiracetam and Talc to
this dispersion, stirred the dispersion to get homogeneous suspension. Seal coated pellets
were coated with this suspension using FBC bottom spray to get drug loaded pellets.
3 Extended release layering: Dispersed Diethyl phthatate (DEP), Triethyl citrate (TEC),
HPMC 6 cps and Ethyl cellulose (EC) 45 cps in methanol with stirring to get uniform
dispersion. Methylene chloride was added to this dispersion to solubilize all dispersed
material by stirring. Talc and Ferric oxide yellow are mixed with stirring. Drug loaded pellets
were coated with this suspension using FBC bottom spray to get extended release drug
pellets.
4 Protective layering: Eudragit RSPO and DEP were dissolved in a blend of Acetone/
Isopropyl alcohol with stirring. Finally talc was dispersd in this solution with stirring.
Extended release drug pellets were coated with this solution using FBP bottom spray.
5 Suspension vehicle preparation: Hydrogenated castor oil, aerosil with corn oil was milled
in colloid mill. Continue the milling and added propyl gallate, methyl paraben, propyl
paraben and sucralose. Finally the color (Lake of Panceau) and flavors (strawberry) are
milled. Filter this milled suspension through # 40 sieve.
6. Preparation of Suspension: Mixed the drug pellets of step 4 in suspension vehicle of step
5 with stirring.
The dissolution data (Table 2) for levetiracetam suspension at the initial shows that, the
suspension provided a sustained release up to 12 hrs as compared with Keppra®.
Procedure: Weighed accurately about eq. to 500 mg of Levetiracetam in 100 ml beaker from
the bottle (the bottle should be well shaken). Washed this suspension with 20ml n-Hexane for
3-4 times and discarded n-hexane. Allowed to stand the pellets for drying at room
temperature for 1 hr. Transfer these pellets in dissolution vessel without loosing any pellets.
Time (Hrs) Levetiracetam Oil based suspension Keppra (500 mg)
Dissolution (% Release)
1 16 3 1
2 47 47
3 62 59
4 74 69
6 86 83
8 90 9 1
10 92 95
12 93 97
Table 2
(Dissolution in hours pH 6.8 phosphate buffer, 900ml, 50 RPM, Paddle)
The assay (Table 3) for levetiracetam suspension at different time periods shows that
the suspension provided an assay without a significant change.
Table 3
The dissolution data (Table 4) for levetiracetam sustained release suspension at
different time periods shows that there is no significant change in dissolution of
40°C/75%RH, 1, 2, 3 Months as compared to the initial data.
Time (Hrs) Dissolution (% Release)
Initial 1M 2 M 3 M
40°C/75%RH 40°C/75%RH 40°C/75%RH
1 16 18 18 15
2 47 36 36 4 1
3 62 57 57 58
4 74 68 68 68
6 86 80 80 78
8 90 86 86 84
10 92 90 90 88
12 93 93 93 90
Table 4
(Dissolution in hours pH 6.8 phosphate buffer, 900ml, 50 RPM, Paddle)
Example 2
Levetiracetam sustained release suspension for 100 mg/ml
Ingredients Qty in mg
Seal Coating
Sugar Spheres (#60-80) 45.45
Ethyl Cellulose 1 cps 3.64
Purified Talc 0.91
Methyl Alcohol q.s.
MDC q.s.
Levetiracetam Drug Coating
Seal coated pellets 50
Levetiracetam 100
HPMC 6 cps 18.8
Talc 6.2
Methanol q.s.
Extended release coating
Drug coated pellets 175.00
Ethyl Cellulose 45 cps 45.29
HPMC 2910 6 cps 4.53
DEP 4.53
TEC 2.26
Talc 4.53
Ferric oxide yellow 0.1 1
Methanol q.s.
Methylene chloride q.s.
Acid soluble Coating
EC coated pellets 236.25
Eudragit E-100 25.74
PEG 6000 5.15
Talc 12.87
Purified water q.s.
IPA q.s.
Acetone q.s.
Preparation of Aqueous suspension
Eudragit E-100 coated pellets 280.00
Purified Water 456.08
Xanthum Gum 4.26
Methyl Paraben 0.61
Propyl Paraben 0.61
Hydrogenated Castor Oil 1.22
Aerosil 6.08
Aspartame 12.16
Sucrose 121.62
Propyl gallate 1.22
Lake of Panceau 1.22
Strawberry 3.04
Suspension with pellets 888.1 1
1 Seal coating: Sifted the sugar pellets through the 60/80 mesh ethylcellulose (EC) and talc
are dispersed in a blend of Methanol/Dichloromethane (DCM). This dispersion was coated
on spheres using FBC bottom spray to get seal coated pellets.
2 Drug layering: Dissolved HPMC 6 cps in methanol then added Levetiracetam and Talc to
this dispersion, stirred the dispersion to get homogeneous suspension. Seal coated pellets
were coated with this suspension using FBC bottom spray to get drug loaded pellets.
3 Extended release layering: Dispersed Diethyl phthatate (DEP), Triethyl citrate (TEC),
HPMC 6 cps and Ethyl cellulose (EC) 45 cps in methanol with stirring to get uniform
dispersion. Methylene chloride was added to this dispersion to solubilize all dispersed
material by stirring. Talc and Ferric oxide yellow are mixed with stirring. Drug loaded pellets
were coated with this suspension using FBC bottom spray to get extended release drug
pellets.
4 Protective layering: Eudragit and PEG were dissolved in a blend of Purified
water/Acetone/ Isopropyl alcohol with stirring. Finally talc was dispersd in this solution with
stirring. Extended release drug pellets were coated with this solution using FBP bottom
spray.
5 Suspension vehicle preparation: Hydrogenated castor oil, aerosol,xanthan gum with
purified water was milled in colloid mill. Continue the milling and added propyl gallate,
methyl paraben, propyl paraben and sucrose/asparmate. Finally the color (Lake of Panceau)
and flavors (strawberry) are milled. Filter this milled suspension through # 40 sieve.
6. Preparation of Suspension: Mixed the drug pellets of step 4 in suspension vehicle of step
5 with stirring.
Example 3
Ingredients Qty in mg
Seal Coating
Microcrystalline cellulose pellets (#70- 140) 714.285
Ethyl cellulose STD 45 CPS 35.715
Methanol qs
Methylene chloride qs
Drug Loading
Microcrystalline cellulose pellets ( # 60- 100) 750.00
Levetiracetam 500.00
HPMC 6 CPS 62.50
Talc 30.625
Purified water qs
Sustained Release Coating
Drug loaded pellets of Levetiracetam 1343.125
Ethyl cellulose STD 45 CPS 155.80
Diethyl Phthalate 32.20
Talc 9.92
Methanol qs
Methylene chloride qs
Protective coating
Ethyl Cellulose coated Levetiracetam pellets 1541.045
Eudragit E 100 124.277
Diethyl Phthalate 22.968
Talc 71.71
Isopropyl alcohol qs
Acetone qs
Total 1760.00
Suspension
Levetiracetam extended release granules 1760.00
Sucralose 100.00
Propylene Glycol 13.28
Glycerin 1.33
Sorbitol Soln (Non crystalliziing) 2.66
Citric acid monohydrate 1.5
Sodium bicarbonate 50.00
Methyl Paraban 5.0
Propyl Paraban 1.0
Selecta Banana Flavour (844439) 1.1
Purified Water q.s
Total 1934.87
Manufacturing Process
Drug loading
1. Ethyl cellulose is dissolved in the mixture of methanol and methylene chloride and
sprayed upon microcrystalline cellulose to obtain seal coated pellets.
2. Drug binder dispersion is prepared by adding levetiracetam with mixtures of HPMC,
talc in water and coated over the seal-coated pellets and further dried.
3. Drug loaded pellets are coated with dispersion of ethyl cellulose obtained by adding
ethyl cellulose, diethyl phthalate and talc in mixtures of methanol and methylene
chloride.
Protective coating
4. Sustained release pellets obtained as above are again coated with the dispersion
obtained by adding Eudragit E 100, talc, diethyl phthalate in a mixture of isopropyl
alcohol and acetone.
5. Above pellets are suspended in purified water along with Sucralose, Propylene
Glycol, Glycerin, Sorbitol soln (Non crystallizing), Citric acid monohydrate, Sodium
bicarbonate, Methyl Paraben, Propyl Paraben, Selecta Banana Flavour (844439) and
filled in bottle for ready to use suspension.
Example 4: Sustained release suspension of Levetiracetam by hydrogenated castor oil.
Ingredients Qty in g
Seal Coating
Microcrystalline Cellulose 714.285
Ethyl cellulose STD 45 CPS 35.715
Methanol qs
Methylene chloride qs
Drug Coating
Seal coated Microcrystalline cellulose pellets 750.00
Levetiracetam 500.00
HPMC 6 CPS 62.50
Talc 30.625
Purified water qs
Polymer Coating
Drug loaded pellets of Levetiracetam 1343.125
Ethyl cellulose STD 45 CPS 155.80
Diethyl Phthalate 32.20
Talc 9.92
Methanol qs
Methylene chloride qs
Hydrophobic Coating
Ethyl Cellulose coated Levetiracetam pellets 1541.045
Hydrogenated castor oil 124.277
Diethyl Phthalate 22.968
Talc 71.71
Isopropyl alcohol qs
Acetone qs
Acid soluble Coating
Ethyl Cellulose coated Levetiracetam pellets 1760.00
Eudragit E 100 124.277
Diethyl Phthalate 22.968
Talc 71.71
Isopropyl alcohol qs
Acetone qs
Total 1978.955
Manufacturing Process:
Drug loading:
1. Ethyl cellulose is dissolved in the mixture of methanol and methylene chloride and
sprayed upon microcrystalline cellulose to obtain seal coated pellets.
2. Drug binder dispersion is prepared by adding levetiracetam with mixtures of HPMC,
talc in water and coated over the seal-coated pellets and further dried.
3. Drug loaded pellets are coated with dispersion of ethyl cellulose obtained by adding
ethyl cellulose, diethyl phthalate and talc in mixtures of methanol and methylene
chloride.
4. Ethyl cellulose pellets are further coated with hydrogenated castor oil.
Acid soluble Coating:
5. Further the pellets obtained from the above step are coated with alkaline soluble
polymer Eudragit E 100.
The pellets thus obtained are suspended in an aqueous or oily based dispersing
agents containing other additives such as sweeteners, flavors, stabilizers, pH modifiers and
suspending agent.
Example -5: Sustained release liquid dosage form having alkali soluble coating and acid
soluble coating.
Ingredients Qty in mg
Seal Coating
Microcrystalline Cellulose pellets 714.285
Ethyl cellulose STD 45 CPS 35.715
Methanol qs
Methylene chloride qs
Drug Coating
Seal coated Microcrystalline cellulose pellets 750.00
Levetiracetam 500.00
HPMC 6 CPS 62.50
Talc 30.625
Purified water qs
Polymer coating
Drug loaded pellets of Levetiracetam 1343.125
Eudragit RSPO 255.80
Diethyl Phthalate 32.20
Talc 9.92
Methanol qs
Methylene chloride qs
Alkali Soluble Coating
Eudragit RSPO coated Levetiracetam pellets 1641.045
Eudragit L 100 -55 124.277
Diethyl Phthalate 22÷968
Talc 71.71
Isopropyl alcohol qs
Acetone qs
Acid Soluble Coating
Ethyl Cellulose coated Levetiracetam pellets 1860.0
Eudragit E 100 124.277
Diethyl Phthalate 22.968
Talc 71.71
Isopropyl alcohol qs
Acetone qs
Total 2078.955
Drug loading:
1. Ethyl cellulose is dissolved in the mixture of methanol and methylene chloride and
sprayed upon microcrystalline cellulose to obtain seal coated pellets.
2. Drug binder dispersion is prepared by adding levetiracetam with mixtures of HPMC,
talc in water and coated over the seal-coated pellets and further dried.
3. Drug loaded pellets are coated with dispersion of Eudragit RSPO obtained by adding
ethyl cellulose, diethyl phthalate and talc in mixtures of methanol and methylene
chloride.
Alkali and Acid soluble Coating:
4. Eudragit RSPO pellets are further coated with an alkaline soluble coating comprising
of Eudragit L 100-55.
5. Further the pellets obtained from the above step are coated with acid soluble polymer
Eudragit E 100.
The pellets thus obtained are suspended in an aqueous or oily based dispersing
agents containing other additives such as sweeteners, flavors, stabilizers, pH modifiers and
suspending agent.
Example -6: Sustained release liquid suspension having dual drug release.
Ingredients Qty in g
Seal Coating
Microcrystalline Cellulose pellets 714.285
Ethyl cellulose STD 45 CPS 35.715
Methanol qs
Methylene chloride qs
Drug Coating
Seal coated Microctystalline cellulose pellets 750.00
Levetiracetam 400.00
HPMC 6 CPS 62.50
Talc 30.625
Purified water q
Polymer Coating
Drug loaded pellets of Levetiracetam 1243.125
Ethyl cellulose STD 45 CPS 155.80
Diethyl Phthalate 32.20
Talc 9.92
Methanol qs
Methylene chloride qs
Second Drug Coating
Ethyl cellulose coated pellets . 1441.045
Levetiracetam 100.00
HPMC 6 CPS 20.0
Talc 30.0
Purified water qs.
Alkali Soluble Coating
Ethyl Cellulose followed by drug coated pellets 1591.045
Eudragit L 100 -55 124.277
Diethyl Phthalate 22.968
Talc 71.71
Isopropyl alcohol qs
Acetone qs
Acid Soluble Coating
Eudragit L 100 -55 coated Levetiracetam pellets . 1810.00
Eudragit E lOO 124.277
Diethyl Phthalate 22.968
Talc 71.71
Isopropyl alcohol qs
Acetone qs
Manufacturing Process:
Drug loading:
1. Ethyl cellulose is dissolved in the mixture of methanol and methylene chloride and
sprayed upon microcrystalline cellulose to obtain seal coated pellets.
2. Drug binder dispersion is prepared by adding levetiracetam with mixtures of HPMC,
talc in water and coated over the seal-coated pellets and further dried.
3. Drug loaded pellets are coated with dispersion of ethyl cellulose obtained by adding
ethyl cellulose, diethyl phthalate and talc in mixtures of methanol and methylene
chloride.
Drug Coating:
4. Drug-binder solution obtained by dissolving levetiracetam, HPMC, talc in purified
water is sprayed upon the sustained release pellets obtained above.
5. Further the pellets obtained from the above step are coated with alkaline soluble
polymer Eudragit L 100-55.
6. The pellets obtained above are further coated with acid-soluble coating comprising of
Eudragit E 100.
The pellets thus obtained are suspended in an aqueous or oily based dispersing
agents containing other additives such as sweeteners, flavors, stabilizers, pH modifiers and
suspending agent.
Example -7: Sustained release suspension prepared by ion-exchange resin
complexation.
Ingredients Qty in mg
Sea Coating
Microcrystalline Cellulose pellets 714.285
Ethyl cellulose STD 45 CPS 35.715
Methanol qs
Methylene chloride qs
Drug-Resin Complex Formation
Seal coated Microcrystalline cellulose pellets 750.00
Levetiracetam 500.00
Sodium polystyrene sulphonate (Amberlite IR69) 200.00
HPMC 6 CPS 62.50
Talc 30.625
Purified water QS
Polymer coating
Drug - resign loaded pellets of Levetiracetam 1543.125
Ethyl cellulose STD 45 CPS 55.80
Diethyl Phthalate 32.20
Talc 9.92
Methanol qs
Methylene chloride qs
Protective coating
Ethyl Cellulose coated Levetiracetam pellets 1641.045
Eudragit E 100 124.277
Diethyl Phthalate 22.968
Talc 71.71
Isopropyl alcohol qs
Acetone qs
Manufacturing Process:
Drug loading:
. Ethyl cellulose is dissolved in the mixture of methanol and methylene chloride and
sprayed upon microcrystalline cellulose to obtain seal coated pellets.
2. Drug-resin complex solution is prepared by dissolving levetiracetam, ion-exchange
resin, talc and HPMC in purified water. The drug-resin complex binder dispersion
was sprayed upon the seal coated pellets.
3. Drug loaded pellets are coated with dispersion of ethyl cellulose obtained by adding
ethyl cellulose, diethyl phthalate and talc in mixtures of methanol and methylene
chloride.
Protective coating:
4. The pellets obtained above are further coated with acid-soluble protective coating
comprising of Eudragit E 00.
The pellets thus obtained can be suspended in an aqueous or oily based dispersing
agents containing other additives such as sweeteners, flavors, stabilizers, pH modifiers and
suspending agent.
CLAIMS
1. A ready to use, stable sustained release liquid oral suspension dosage form
comprising: sustained release pellets, said sustained release pellets comprising:
a) Inert pellets, surrounded by seal coating,
b) Drug layer comprising pharmaceutically active ingredient with one or more
pharmaceutically acceptable excipients surrounding said seal coated inert pellets,
c) Coating layer comprising rate controlling polymer surrounding said drug layer,
such that the sustained release pellets are suspended with suitable suspending agent,
in addition to other pharmaceutically acceptable excipients in a suspending media at
a suitable pH.
2. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in claim , wherein the Sustained release pellets are further surrounded by
drug-binder solution.
3. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in claim 1 or 2, wherein the Sustained release pellets are further surrounded
by protective coating.
4. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in any of preceding claim, wherein the suspending media is an aqueous
media.
5. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in any of preceding claim, wherein the suspending media is a non-aqueous
media.
6. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in any of preceding claim, has a pH in a range of 6 to 7.5.
7. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in claim 1, wherein the drug layer comprises drug resin complex with one
or more pharmaceutically acceptable excipient
8. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in claim 1, wherein the pharmaceutically active ingredient is a high
solubility active ingredient.
9. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in claim 1, wherein the pharmaceutically active ingredient is selected from
the group comprising of analgesic; anti-allergic; anti-anginal; antibacterial;
anticonvulsant; antipsychotic; antidepressant; antidiabetic; anti-epileptic;
hypolipidemic; antihyperlipidemic; hypocholesterolemic; antihypertensive;
vasoconstrictor; vasodilator; anti-inflammatory; antineoplastic, antiparasitic;
antiproliferative; antisecretory; antithrombotic; anti-ulcerative; antiviral; appetite
suppressant; diagnostic aid; diuretic; glucocorticoid; immunizing agent;
immunomodulator; immunoregulator; immunostimulant; immunosuppressant;
neuroprotective; NMDA antagonist; radioactive agent; sedative; sedative-hypnotic;
steroid; tranquilizer; cerebral ischemia agent; wound healing agent and xanthine
oxidase inhibitor.
10. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in claim 1, wherein the pharmaceutically active ingredient is selected from
to the group comprising of aspirin, paracetamol, diclofenac, naproxen, oxycodone,
hydrocodone, diamorphine, carbamazepine, topiramate, lamotrigine, Levetiracetam,
Brivaracetam, seletracetam, primidone, clonazepam, diazepam, oxcarbazepine,
zonisamide, pregabalin, ethosuximide, lorazepam, nitrazepam, midazolam,
lorazepam, tolbutamide, acetohexamide, tolazamide, chlo ropa , metoprolol,
metformin, phenformin, buformin, rosiglitazone, pioglitazone,troglitazone, miglitol,
acarbose, alogliptin, vildagliptin, sitagliptin, saxagliptin, glipizide, glimeperide,
glyburide, repaglinide, nateglinide, Fluphenazine ,Perphenazine,
, Thioridazine, Trifluoperazine, Mesoridazine, Periciazine,
Promazine, Triflupromazine, Levomepromazine, Promethazine, Pimozide
chlorprothixene, clopenthixol, flupenthixol, thithixene, Zuclopenthixol, Clozapine,
Olanzapine, Risperidone, Paliperidone, Quetiqpine, Ziprasidone, Amisulpride,
Asenapine, Iloperidone, Zotepine, Sertindole, Lurasidone, Aripiprazole, alprazolam,
Zolpidem, bupropion, duloxetine, milnacipran, tolterodine, diltiazem, Oxybutinin,
Tramadol, Tapentadol, venlafaxine, desvenlafaxine or there pharmaceutical
acceptable salts and a combination thereof.
1 1. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in claim , wherein the pharmaceutically active ingredient is
levetiracetam.
12. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected
from the group of fillers, binders, lubricants, glidants, rate controlling polymers,
suspension stabilizers, buffering agents, sweeteners, antioxidants, flavoring agents,
viscosity modifying agent, surfactants, preservatives, humectants, plasticizers and
resins.
13. A ready to use, stable sustained release liquid oral suspension dosage form as
claimed in any of preceding claim, wherein it does not require reconstitution before
oral administration.
14.A process for preparation of ready to use, stable sustained release liquid oral
suspension dosage form comprising the steps:
a) coating suitable fillers with a binder solution to obtain seal coated inert
pellets;
b) further coating said seal coated inert pellets obtained from step a) with a drugbinder
solution or drug-binder resin complex;
c) further coating drug coated pellets so obtained from step b) with a rate
controlling polymer with one or more pharmaceutically acceptable excipients;
d) Optionally, further coating the pellets so obtained in step c with drug binder
solution or drug resin complex;
e) Applying the protective coating to the the pellets so obtained in step c) or d)
using suitable polymer
f) forming suspension of the sustained release pellets so obtained using suitable
suspending agent along with sweeteners, flavoring agent, buffering agent,
preservative, humectants in addition to other pharmaceutically acceptable
excipients in aqueous or non aqueous media at a pH being maintained with or
without buffer.