Field of the Invention
The present invention relates to a novel controlled release pharmaceutical dosage form
comprising a therapeutically effective amount of ranolazine or pharmaceutically
acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or
more lipid(s) as release controlling agent(s) and one or more pharmaceutically acceptable
excipient(s).
Background of the invention
Ranolazine was first described in U.S. Pat. No. 4,567,264, the specification of which
discloses ranolazine, (±)-N- (2,6-dimethylphenyl)-4-[2-hydroxy-3- (2-methoxyphenoxy)-
propyl]-l- piperazineacetamide, and its pharmaceutically acceptable salts, and their use in
the treatment of cardiovascular diseases, including arrhythmias, variant and exercise
induced angina, and myocardial infarction.
U.S. Pat. No. 5,506,229 discloses the use of ranolazine and its pharmaceutically
acceptable salts and esters for the treatment of tissues experiencing a physical or
chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or
skeletal muscle or brain tissue, and for use in transplants. Conventional oral and
parenteral formulations are disclosed, including controlled release formulations. In
particular, Example 7D of U.S. Pat. No. 5,506,229 describes a controlled release
formulation in capsule form comprising microspheres of ranolazine and microcrystalline
cellulose coated with release controlling polymers.
U.S. Pat. No. 5,472,707 discloses a high-dose oral formulation employing supercooled
liquid ranolazine as a fill solution for a hard or soft gelatin capsule.
A study published in Circulation 90:726-734 (1994) demonstrated that ranolazine was
ineffective as an antianginal and anti-ischemic agent when administered as an IR
formulation. As set forth in literature, the initial trials of ranolazine on humans suffering

from angina were failures. The trials used an immediate release of ranolazine formulation
at a dose level of 120 mg taken three times daily. Based upon the initial experiments, it
was uncertain whether or not ranolazine could be given to humans in an amount and
mode that is effective against angina.
One problem with conventional oral dosage formulations is that they are not ideally
suited to ranolazine and its pharmaceutically acceptable salts, because the solubility of
ranolazine is relatively high at the low pH that occurs in the stomach. Furthermore
ranolazine also has a relatively short plasma half-life. The high acid solubility property of
ranolazine results in rapid drug absorption and clearance, causing large and undesirable
fluctuations in plasma concentration of ranolazine and a short duration of action, thus
necessitating frequent oral administration for adequate treatment.
There was therefore a need for a method for administering ranolazine in an oral dosage
form once or twice daily that provides therapeutically effective plasma concentrations of
ranolazine for the treatment of angina in humans.
Currently Ranolazine is marketed as modified release tablets at the dosage of 500mg and
lgm under the brand name Ranexa®.
U.S. Pat. No. 6,303,607 discloses a sustained release pharmaceutical dosage form
including at least 50% by weight ranolazine and an admixture of at least one pH-
dependent binder and at least one pH-independent binder, and wherein the peak to trough
plasma ranolazine level does not exceed 3:1 over a 24 hour period.
U.S. Pat. Application No. 20060177502A1 discloses a sustained release pharmaceutical
formulation comprising: less than 50% ranolazine, a pH dependent binder; a pH
independent binder and one or more pharmaceutically acceptable excipients.
However, there still exists a need to prepare novel controlled release dosage forms of
Ranolazine or pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s),

enantiomer(s) thereof which are simple to manufacture yet robust that provides
therapeutically effective plasma concentrations of ranolazine for the treatment of angina
in humans.
Objects Of The Invention
A novel controlled release pharmaceutical dosage form comprising a therapeutically
effective amount of ranolazine or pharmaceutically acceptable salt(s), polymorph(s),
solvate(s), hydrate(s), enantiomer(s) thereof, one or more lipid(s) as release controlling
agent(s) and one or more pharmaceutically acceptable excipient(s).
A novel controlled release pharmaceutical dosage form comprising a therapeutically
effective amount of ranolazine or pharmaceutically acceptable salt(s), polymorph(s),
solvate(s), hydrate(s), enantiomer(s), one or more lipid(s) as release controlling agent(s)
and one or more pharmaceutically acceptable excipient(s) wherein ranolazine is at least
about 20% w/w of the total formulation.
A process for preparing novel controlled release dosage form ranolazine or
pharmaceutically acceptable salt(s) or enantiomer(s) or polymorph(s) thereof, wherein the
process comprises the steps of blending ranolazine with one or more pharmaceutically
acceptable excipient(s), melting the lipid component and dispersing the blend of
ranolazine with the lipid component, cooling the blend, mixing with other excipient(s)
and then compressing the granules to form the solid oral dosage form.
A novel controlled release pharmaceutical dosage form comprising a therapeutically
effective amount of ranolazine or pharmaceutically acceptable salt(s), polymorph(s),
solvate(s), hydrate(s), enantiomer(s), one or more lipid(s) as release controlling agent(s)
and one or more pharmaceutically acceptable excipient(s) wherein about 0% to about
40% of said ranolazine is released after 2 hours; from about 40% to about 80% of said
ranolazine is released after 8 hours; not less than about 75% of said ranolazine is released
after 24 hours.

Detailed Description Of The Invention
The present invention relates to a novel controlled release pharmaceutical dosage form
comprising a therapeutically effective amount of ranolazine or pharmaceutically
acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or
more lipid(s) as release controlling agent(s) and one or more pharmaceutically acceptable
excipient(s).
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the ranolazine
wherein ranolazine is modified by reacting it with an acid or base as needed to form an
ionically bound pair. Examples of pharmaceutically acceptable salts include conventional
non- toxic salts or the quaternary ammonium salt of the parent compound formed, for
example, from non-toxic inorganic or organic acids. Suitable non-toxic salts include
those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,
phosphoric, nitric, and others known to those of ordinary skill in the art. The salts
prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl
acetic, benzoic, salicylic, sulfanilic, fumaric, oxalic, isethionic, and others known to those
of ordinarily skilled in the art.
Ranolazine is present in at least about 20% w/w of the total formulation.
The term "controlled release" as used herein in relation to the dosage form means which
is not immediate release and is taken to encompass controlled release, sustained release,
prolonged release, timed release, retarded release, extended release and delayed release.
Controlled release can be used interchangeably with prolonged release, programmed
release, timed release, extended release, sustained release and other such dosage forms.
By "pharmaceutically acceptable" is meant excipient(s) comprised of a material that is
not biologically or otherwise undesirable.
The release controlling polymers comprise of lipid such as fat(s), oil(s), wax(s) or
combinations thereof.

Fats are generally triesters of glycerol and fatty acids. Suitable fats and fatty substances
include but not limited to fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or
cetostearyl alcohol), fatty acids and derivatives, including but not limited to fatty acid
esters, fatty acid glycerides (mono-, di- and tri-glycerides), and hydrogenated fats. Fats
may be either solid or liquid at normal room temperature, depending on their structure
and composition. Although the words "oils", "fats", and "lipids" are all used to refer to
fats, "oils" is usually used to refer to fats that are liquids at normal room temperature,
while "fats" is usually used to refer to fats that are solids at normal room temperature.
"Lipids" is used to refer to both liquid and solid fats, along with other related substances
The fats include but not limited to oil, which is an animal (e.g., fatty acid esters), mineral
(e.g., paraffin oils), vegetable (e.g., vegetable oils), or synthethic hydrocarbons that are
liquid at room temperature, soluble in organic solvents, and substantially not soluble in
water. Examples of oils include but are not limited to: mineral oils such as paraffin oils;
synthetic hydrocarbons such as polybutene and polyisobutene; vegetable oils such as
castor oils, hydrogenated vegetable oil, sesame oils, and peanut oils; and animal oils and
fats such as triglycerides and butters. Partially hydrogenated vegetable oils are derived
from natural products and generally comprise a mixture of glycerides of C 14.20 fatty acids,
in particular palmitic and stearic acids. Suitable examples of partially hydrogenated
vegetable oils include partially hydrogenated cottonseed oil, soybean oil, corn oil, peanut
oil, palm oil, sunflower seed oil or mixtures thereof. Chemical equivalents of partially
hydrogenated vegetable oils include synthetically produced glycerides of C 14.20 fatty
acids having the same properties as the naturally derived products as hereinbefore
described.
Waxes are similar to oils, except that unlike oils, waxes are not liquid at room
temperature. Waxes include but not limited to animal waxes, plant waxes, mineral waxes,
and petroleum waxes. Examples of waxes include, but are not limited to, glyceryl
behenate, glyceryl monosterate, stearic acid, palmitic acid, lauric acid, carnauba wax,
cetyl alcohol, glyceryl stearate beeswax, paraffin wax, ozokerite, candelilla wax, cetyl
alcohol, stearyl alcohol, spermaceti, carnauba wax, baysberry wax, montan, ceresin, and
microcrystalline waxes.

Pharmaceutically acceptable excipient(s) include but are not limited to diluents,
lubricants, disintegrants, glidants and surface-active agents.
The amount of excipient employed will depend upon how much active agent is to be
used. One excipient can perform more than one function.
Fillers or diluents, which include, but are not limited to confectioner's sugar,
compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose,
starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate,
calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.
Lubricants may be selected from, but are not limited to, those conventionally known in
the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate,
mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium
silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of
ordinary skill in the art.
The present dosage forms may optionally contain disintegrants which include but are not
limited to starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-
linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL, cross-linked
sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOL from FMC;
and cross-linked calcium carboxymethylcellulose; and guar gum. Use of disintegrant
according to the present invention facilitates in the release of drug in the latter stage and
thereby completely releasing the drug from the dosage form.
The present dosage forms may optionally contain a surface-active agent. The preferred
agent is copolymers composed of a central hydrophobic chain of polyoxypropylene (poly
(propylene oxide)) and polyoxyethylene (poly (ethylene oxide)) that is well known as
poloxamer. However, other agents may also be employed such as dioctyl sodium
sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS), polyoxyethylene

sorbitan and poloxalkol derivatives, quaternary ammonium salts or other
pharmaceutically acceptable surface-active agents known to one ordinary skilled in the
art.
The dosage form according to the present invention include but is not limited to tablets,
pellets, beads, granules, capsules, microcapsules and tablets in capsules.
The pharmaceutical dosage forms of the invention may further be film coated.
The preferred film coating of this invention is comprised of a commercial film-coating
product designed for aqueous film coating containing the water-soluble, film-forming
resin, such a product is commercially available under the trade name Opadry White™
(Colorcon, West Point, Pa.).
These coating comprises one or more excipients selected from the group comprising
coating agents, opacifiers, fillers, plasticizers, polishing agents, colouring agents,
antitacking agents and the like.
The pharmaceutical dosage form of the invention can be formed by various methods
known in the art such as by dry granulation, wet granulation, melt granulation, direct
compression, double compression, extrusion spheronization, layering and the like.
Novel controlled release matrix tablet according to the present invention are
manufactured preferably as per the following procedure:
i) blend ranolazine and one or more pharmaceutically acceptable excipients,
ii) melt hydrogenated vegetable oil
iii) disperse step (i) with step (ii) under continuous and uniform stirring
conditions
iv) cool step (iii), pass it through suitable sieve, further mix it with other
excipient(s)
v) compressing step (iv) to form the solid oral dosage form.
vi) the dosage form is further coated.

The examples given below are illustrative embodiments of the invention and are merely
exemplary. A person skilled in the art may make variations and modifications without
deviating from the spirit and scope of the invention. All such modifications and variations
are intended to be included within the scope of the invention.
Examples:
Example 1:
Brief manufacturing procedure:
Hydrogenated vegetable oil was melted and Ranolazine was uniformly dispersed under
continuous and uniform stirring conditions and allowed to solidify. The material was
passed through a suitable sieve to form granules. The granules were blended with lactose,
colloidal silicon dioxide. This blend was lubricated with magnesium stearate and
compressed into tablets.



Brief manufacturing procedure:
Glyceryl behenate was melted and Ranolazine was uniformly dispersed under continuous
and uniform stirring conditions and allowed to solidify. The material was passed through
a suitable sieve to form granules. The granules were blended with lactose, colloidal
silicon dioxide. This blend was lubricated with magnesium stearate and compressed into
tablets.

Brief manufacturing procedure:
Glyceryl Monostearate was melted and Ranolazine was uniformly dispersed under
continuous and uniform stirring conditions and allowed to solidify. The material was
passed through a suitable sieve to form granules. The granules were blended with lactose,
colloidal silicon dioxide. This blend was lubricated with magnesium stearate and
compressed into tablets.



Brief manufacturing procedure:
Hydrogenated vegetable oil was melted and Ranolazine was uniformly dispersed under
continuous and uniform stirring conditions and allowed to solidify. The material was
passed through a suitable sieve to form granules. The granules were blended with lactose,
colloidal silicon dioxide. This blend was lubricated with magnesium stearate and
compressed into tablets.
In-vitro dissolution details
The formulations of the invention have a prolonged in vitro release rate. The in vitro test
used to measure release rate of the active agent from a formulation of the invention was
as follows. A solution of 900 ml of a 0.1N HC1 was placed in an apparatus capable of
agitation. The apparatus contained a paddle and rotated at a speed of 50 rpm. The tablet
formulation was placed in the apparatus and dissolution was periodically measured. The
in vitro dissolution studies of Example 1 is as follows


We Claims
1. A novel controlled release pharmaceutical dosage form comprising a
therapeutically effective amount of ranolazine or pharmaceutically acceptable
salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or more
lipid(s) as release controlling agent(s) and one or more pharmaceutically
acceptable excipient(s).
2. A novel controlled release pharmaceutical dosage form according to claim 1
wherein one or more lipid(s) consist of fat(s), oil(s) and wax(s).
3. A novel controlled release pharmaceutical dosage form according to claim 1
wherein pharmaceutically acceptable excipients are selected from the group
comprising diluents, lubricants, surfactants and glidants.
4. A novel controlled release pharmaceutical dosage form according to claim 1
wherein the dosages form includes tablets, capsules, pellets, granules, or mixtures
thereof.
5. A novel controlled release pharmaceutical dosage form comprising a
therapeutically effective amount of ranolazine or pharmaceutically acceptable
salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or more
lipid(s) as release controlling agent(s) and one or more pharmaceutically
acceptable excipient(s) wherein ranolazine is at least about 20% w/w of the total
formulation.
6. A process for preparing novel controlled release dosage form of ranolazine or
pharmaceutically acceptable salt(s) or enantiomer(s) or polymorph(s) thereof,
wherein the process comprises the steps of blending ranolazine with one or more
pharmaceutically acceptable excipient(s)s melting the lipid component and
dispersing the blend of ranolazine with the lipid component, cooling the blend,
sifting, mixing the granules with other excipient(s) and then compressing the
granules to form the solid oral dosage.

7. A novel controlled release pharmaceutical dosage form comprising a
therapeutically effective amount of ranolazine or pharmaceutically acceptable
salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or more
lipid(s) as release controlling agent(s) and one or more pharmaceutically
acceptable excipient(s) wherein about 0% to about 40% of said ranolazine is
released after 2 hours; from about 40% to about 80% of said ranolazine is released
after 8 hours; not less than about 75% of said ranolazine is released after 24 hours.

A novel controlled release pharmaceutical dosage form comprising a therapeutically effective amount of ranolazine or pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or more lipid(s) as release controlling agent(s) and one or more pharmaceutically acceptable excipient(s).