FIELD OF THE INVENTION
The present invention relates to a novel, sustained release formulations of ranolazine dihydrochloride and methods for making the sustained release formulations of ranolazine dihydrochloride and methods for using the sustained release formulations of ranolazine hydrochloride to treat patients suffering from cardiovascular diseases are provided.
BACKGROUND OF THE INVENTION
Ranolazine is a calcium channel-blocking agent that is approved for treatment of cardiovascular diseases such as myocardial infarction, congestive heart failure, angina and arrhythmia. US patent 4567264 discloses the use of ranolazine i.e.,.+-.N-(2,6-dimethylphenyl)-4- [2-hydroxy-3-(2-methoxyphenoxy) propyl]-1-piperazine acetamide or 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl) aminocarbonylmethyljpiperazine, and its pharmaceutically acceptable salts and esters in treating such cardiovascular conditions.
U.S.Pat.No. 5,209,933 discloses sustained release pharmaceutical composition for dihydropyridine calcium channel blockers using a pH dependent binder that is less soluble below about pH 4.5 and more soluble above about pH 5.5.
U.S. Pat. No. 5,472,707 discloses high-dose oral formulation employing super cooled liquid ranolazine as a fill solution for a hard gelatin capsule or softgel. The prior art discloses the necessity for sustained release of the active as the immediate release dosage forms proved inadequate in achieving the therapeutic benefit.
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 quadriplegia, hypoxic or reperfusion injury to cardiac

or skeletal muscle or brain tissue, and for use in transplants. The patent 5,506,229 also describes a controlled release formulation in capsule form comprising microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers.
U.S.Pat.No. 5,906,988 discloses the use of ranolazine and other piperazine derivatives of stated formula and their salts for the treatment of tissues experiencing physical or chemical insult.
U.S.Pat Nos. 6303607, 6369062. 6503511, 6525057, 6562826, 6617328, 6620814, 6852724 and 6864258 from the prior art disclose sustained release ranolazine formulation containing an intimate mixture of ranolazine and a partially neutralized pH-dependent binder to form a film that is mostly insoluble in aqueous media below pH 4.5 and soluble in aqueous media above pH 4.5. The formulation disclosed is suitable for twice daily administration of ranolazine and is useful for controlling the rate of dissolution of ranolazine, and to maintain human plasma ranolazine levels at defined level where in the peak to trough human patient ranolazine levels is less than 2:1 over a 24 hour time period as described in U.S.Pat Nos. 6303607 and 6479496.
Examples of prior art formulations use insoluble ranolazine base to achieve sustained release of the active. The formulation comprises 50% to 95% of ranolazine base along with pH dependant binders selected from methacrylic acid copolymers, hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinylpyrrolidone phthalate. Among the mentioned, the preferable composition is the one containing methacrylic acid copolymer Type C in the concentration of 5% to 12%. The disclosed composition includes hydroxypropyl methylcellulose as pH independent binder in the concentration of 1% to 3.0%.
Prior art primarily achieves control on the dissolution of ranolazine by using pH dependant binder that remains insoluble in the pH range below 4.5 thus

preventing the drug release in the acidic environment of the stomach. In the alkaline environment, the drug release is facilitated by the dissolution of the polymer. However, insoluble nature of the drug in the alkaline environment is a limitation of this approach and may result in inadequate drug release in the intestinal environment. Prior art also claims that viscosity enhancing agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, and the like, do not themselves provide the required dissolution control provided by the identified pH-dependent binders.
Examples cited in the prior art that use ranolazine dihydrochloride are immediate release dosage forms filled in capsules that are used for comparison of the release profile with the sustained release formulation.
SUMMARY OF THE INVENTION
Accordingly, one aspect of the present invention to provide a sustained release composition for treating cardiovascular diseases comprising,an active pharmaceutical compound ranolazine dihydrochloride, matrix forming polymer including nonionic hydrogen forming polymer, matrix forming polymer an anionic polymer and pharmaceutically acceptable excipients.
Another aspect of the present invention is to provide a the pharmaceutically active compound is a dihydrochloride salt of ranolazine present in the composition between 40% and 85%, more preferably between 50% and 80%, and most preferably between 65% and 75%.
Yet another aspect of the present invention is to provide the matrix forming polymer includes a nonionic hydrogen forming polymer for sustaining the release of the active compound in the acidic environment of the gastric fluids.

Further aspect of the present invention is to provide the matrix forming polymer includes a anionic polymer for sustaining the release of the active compound in the basic environment of the intestinal fluids.
Still another aspect of the present invention is to provide an anionic polymer is selected from carbomers.
Another aspect of the present invention is to provide the composition is preferably a matrix tablet prepared using techniques of direct compression or wet granulation.
Further aspect of the present invention is to provide sustained release medicament such as tablet, capsule etc wherein the said tablet is coated or uncoated and the said medicament releases the active pharmaceutical compound in a near zero order release fashion for a period of at least 12 hours.
a composition for sustained release of ranolazine. The other aspect of invention is to utilize ranolazine dihydrochloride to achieve sustained release of the active. The polymers that may be used to achieve the objective of sustained release of the active are nonionic gel forming polymers such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose and anionic polymers that are polymers of acrylic acid cross linked with allyl ethers of sugars popularly known as carbomers. The polymers may be used either alone or in combination to achieve sustained release of ranolazine. The drug in the composition may be embedded in a matrix tablet prepared using standard compression techniques. Such compositions may be coated using standard coating techniques to improve the appearance and /stability of the product.
It is also an objective of the present invention to provide and test the developed composition for its sustained release of ranolazine for at least a duration of 12 hours at a near zero order release rate to maintain therapeutic levels of the active. The testing will be in the simulated gastric and intestinal fluids in

comparison with the prior art formulation that is commercially available with the trade name of Arena®.
Other aspect of the invention is to test for the stability of the provided composition as per the standard ICH and USP guidelines.
Brief description of drawing:
The following drawings disclose various embodiments of the present invention for purposes of illustration only and are not intended to limit the scope of the invention. For purposes of clarity, not every component may be labeled in every figure. In the figures:
Figure 1 illustrates % Dissolution of ranolazine vs time
Figure 2 illustrates % Dissolution of ranolazine vs time
Figure 3 illustrates % Dissolution of ranolazine vs time
Figure 4 illustrates % dissolution of ranolazine vs time
Figure 5 illustrates % dissolution of ranolazine vs time
Figure 6 illustrates % Dissolution of ranolazine vs time
Figure 7 illustrates % dissolution of ranolazine vs time
DETAILED DESCRIPTION OF THE PREFERRED EVIBODIMENTS
The invention provides sustained-release formulations that are an alternative to the prior art formulations for sustained release of an anti-angina drug, ranolazine. The prior art formulations typically require use of ranolazine base to sustain the release of the active in the acidic environment of the gastric fluid. A pH dependant binder such as methacrylic acid copolymer facilitates the release of the drug in the relatively alkaline intestinal fluid. However, in view of the poor

solubility of the active at alkaline pH, the drug release that ensues from use of the base form of the active may result in poor release characteristics especially in the intestinal environment.
An embodiment of the present invention provides for a stable sustained release ranolazine dihydrochioride formulation for twice daily dosing without the need for using ranolazine base. Unlike the prior art, the present invention provides a composition for oral administration of ranolazine dihydrochioride that provides a near zero order drug release of the active for a period of at least 12 hours.
The present invention is a composition that controls the release of the active from a matrix tablet. The amount of ranolazine dihydrochioride in the matrix is between 40% and 85%, more preferably between 50% and 80%, and most preferably between 65% and 75% or 585 mg, equivalent to about 500 mg ofranolazine.
The nonionic polymer of the present invention is hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC), preferably HPMC. The composition generally contains about 10% to 30% of the nonionic polymer, more preferably about 10 % to 20%. The anionic polymer of the composition is acrylic acid polymer cross linked with allyl ethers of sugars known as carbomers (available commercially as carpools), more preferably allyl ethers of pentaerythritol present in concentrations of about 3% to 20%. More preferably the composition contains about 5% to 10% of the polymer. Different viscosity or molecular weight grades of the above mentioned polymers may be used alone or in combination.
When in contact with water, HPMC hydrates rapidly and forms a gelatinous barrier layer or hydrogen around the tablet. At the pH of the gastric fluid, the gelatinous barrier layer that also forms the erosion front releases the initial quantity of the drug while preventing further hydration of the internal layers of the matrix and disintegration of the tablet that may lead to dose dumping.

The anionic polymer, carbomer holds the matrix further in the acidic pH of the gastric fluids. In the absence of channels, drug does not diffuse through the inner layers of the matrix, thus effectively controlling the release of ranolazine dihydrochloride in the gastric environment.
The alkaline environment of the intestinal fluids results in swelling of the anionic carbomer. The channels thus formed allow hydration of HPMC forming microgel structures through out the matrix. The localized acidic environment created by the dihydrochloride salt of ranolazine allows drug dissolution in adequate amounts ensuring drug release in a near zero order fashion.
An effective amount of any generally accepted filler such as dicalcium phosphate or a binding agent such as polyvinylpyrrolidone may also be added to improve the compressibility of the tablet. The composition also contains pharmaceutical lubricants such as glyceryl monostearate, magnesium stearate, calcium stearate or stearic acid to prevent the tablets from sticking during processing on a high-speed rotary press.
A glidants or anti-caking agent such as colloidal silicon dioxide or talc also may be employed. Other excipients known to those skilled in the art, such as sucrose, dextrose, lactose, microcrystalline cellulose, mannitol, polyethylene glycol, sorbitol, citric acid and mixtures thereof also may be used.
The tablets are prepared by direct compression or wet granulation techniques, the process of which is known to those skilled in the art.
The tablet cores are coated further to improve the aesthetics or stability of the formulation. The coatings employed aqueous or non-aqueous, preferably aqueous HPMC based. The employed coating composition may be the one readily available for commercial use or a composition that is prepared as per compositions known to those skilled in the art of coating.

The stability of ranolazine dihydrochloride tablets prepared according to the present invention are tested in accordance with the ICH guidelines for storage, i.e., three months at about 40° C and 75% relative humidity. Formulations of the present invention stored under these conditions retain at least about 90% of the ranolazine dihydrochloride present in the composition during the time of storage. Standard procedures such as HPLC or UV spectroscopic methods are used to determine the amount of active ingredient remaining after storage. Shelf life assay for the formulation limit between 90% and 110% of the labeled amount of the tablet are applied and found the potency of the drug well within the limit. The design of the stability studies was in compliance with the general requirements suggested by the FDA stability guidelines.
The coated and uncoated tablets were subjected to dissolution for a period of 12 hours. 2 hours in 0.1 N HCI and 10 hours in pH 7.4 phosphate buffer.
The rate release polymers are a combination of both nonionic and anionic polymers. The non-ionic polymer controls the release in the acidic environment of stomach where as the anionic polymer controls it in the alkaline environment of the intestine. The perceived miechanism of sustained release is as follows:
"When in contact with water, HPMC hydrates rapidly and forms a gelatinous barrier layer or hydrogen around the tablet. At the pH of the gastric fluid, the gelatinous barrier layer that also forms the erosion front releases the initial quantity of the drug while preventing further hydration of the internal layers of the matrix and disintegration of the tablet that may lead to dose dumping.
The anionic polymer, carbomer holds the matrix further in the acidic pH of the gastric fluids. In the absence of channels, drug does not diffuse through the inner layers of the matrix, thus effectively controlling the release of ranolazine dihydrochloride in the gastric environment.
The alkaline environment of the intestinal fluids results in swelling of the anionic carbomer. The channels thus formed allow hydration of HPMC forming microgel

structures through out the matrix. The localized acidic environment created by the dihydrochloride salt of ranolazine allows drug dissolution in adequate amounts ensuring drug release in a near zero order fashion.
The following examples illustrate the present invention and are not intended to limit the scope of the present invention.
EXAMPLE 1
The formulation contained the following ingredients in the following amounts:
Ingredient Weight (mg)/Tablet % (Wt.)

Ranolazine dihydrochloride Carbopol971P
Hydroxypropyl methylcellulose
Dicalcium phosphate
Magnesium stearate ., ,
TOTAL

585.34 70.2
58.5 7.0
120.375 14.4
60.0 7.2
10.0 1.2
834.2 100

Ranolazine dihydrochloride, carbopol, hydroxypropylmethylcellulose and dicalcium phosphate were weighed and sifted through a 36 mesh screen. The sifted ingredients were blended with isopropyl alcohol to form wet granules. The wet granules were dried in an oven at 50°C for 2 hours. After mixing with magnesium stearate (sifted through a 100 mesh screen), the blend was compressed into tablets using oval shaped, concave tooling. The punched tablets were aqueous film coated using a commercially available HPMC based coating composition by standard techniques.

The coated tablets were subjected to dissolution for a period of 12 hours (2 hours in 0.1N HCI and 10 hours in pH 7.4 phosphate buffer). The % dissolution of ranolazine vs. time is presented in Figure 1.
EXAMPLE 2
The formulation contained the following ingredients in the following amounts:
Ingredient Weight (mg)/Tablet % (Wt.)
Ranolazine dihydrochloride 583.0 70.1
Carbopol971P 58.3 7.0
Hydroxypropyl methylcellulose 120.375 14.5
Dicalcium phosphate 60.0 7.2
Magnesium stearate 10.0 1.2
TOTAL 831.7 100
Ranolazine dihydrochloride, carbopol, hydroxypropylmethylcellulose and dicalcium phosphate were weighed and sifted through a 36 mesh screen. The sifted ingredients were blended with isopropyl alcohol to form wet granules. The wet granules were dried in an oven at SOX for 2 hours. After mixing with magnesium stearate (sifted through a 100 mesh screen), the blend was compressed into tablets using oval shaped, concave tooling.
The uncoated tablets were subjected to dissolution for a period of 12 hours. The % dissolution of ranolazine with time is presented in Figure 2.

EXAMPLE 3
The formulation contained the following ingredients in the following amounts:
Ingredient Weight (mg)yTablet % (Wt.)
Ranolazine dihydrochloride 583.0 60.0
Carbop9l 940 58.5 6.0
Hydroxypropyl methylcellulose 120.375 12.4
Dicalcium phosphate 120.375 12.4
Magnesium stearate 20.0 2.1
Talc 10.0 1.0
Colloidal silicon dioxide 10.0 1.0
Polyvinylpyrrolidine 50.0 5.1
TOTAL 972.25 100.0
Ranolazine dihydrochloride, carbopol, hydroxypropylmethylceliulose, dicalcium phosphate, magnesium stearate, talc, colloidal silicon dioxide, polyvinylpyrrolidine were weighed and sifted through a 60 mesh screen. The sifted ingredients were blended thoroughly. The blend was compressed into tablets using caplet shaped, concave tooling.
The punched tablets were subjected to dissolution for a period of 12 hours. The % dissolution of ranolazine with time is presented in Figure 3.

EXAMPLE 4
The formulation contained the following ingredients in the following amounts:
Ingredient Weight (mg)/Tablet % (Wt.)
Ranolazine dihydrochloride 583.0 50.9
Carbopol 940 58.5 5.1
Microcrystalline cellulose 120.375 10.5
Dicalcium phosphate 120.375 10.5
Magnesium stearate 20.0 1.7
Talc 10.0 0.9
Colloidal silicon dioxide 10.0 0.9
Polyvinylpyrrolidine 50.0 4.4
Citric acid 174.08 15.2
TOTAL 1146.33 100.1
Ranolazine dihydrochloride, carbopol, microcrystalline cellulose, dicalcium phosphate, citric acid, magnesium stearate, talc, colloidal silicon dioxide, polyvinylpyrrolidine were weighed and sifted through a 60 mesh screen. The sifted ingredients were blended thoroughly. The blend was compressed into tablets using caplet shaped, concave tooling.
The punched tablets were subjected to dissolution for a period of 12 hours. The % dissolution of ranolazine with time is presented in Figure 4.

EXAMPLE 5
The formulation contained the following ingredients in the following amounts:
Ingredient Weight (mg)yTablet % (Wt.)
Ranoiazine dihydrochloride 583.0 65.64
Carbopol971P 58.5 6.6
Hydroxypropyl methylcellulose 87.45 9.8
Dicalcium phosphate 60.0 6.8
Polyethylene glycol 6000 29.15 3.3
Magnesium stearate 20.0 2.3
Polyvinylpyrrolidine 50.0 5.6
TOTAL 888.1 100.04
Ranoiazine dihydrochloride, hydroxypropylmethylcellulose and dicalcium phosphate were weighed and sifted through a 60 mesh screen. The sifted ingredients were then blended thoroughly. Polyethylene glycol and polyvinylpyrrolidine were dissolved in IPA and water mixture and was used for granulation. The wet granules were dried in an oven at 50°C for 2 hours. After mixing with carbopol and magnesium stearate (sifted through a 100 mesh screen), the blend was compressed into tablets using caplet shaped concave, tooling.
The punched tablets were subjected to dissolution for a period of 12 hours. The % dissolution of ranoiazine with time is presented in Figure 5.

EXAMPLE 6
The formulation contained the following ingredients in the following amounts:
Ingredient Weight (mg)/Tablet % (Wt.)
Ranolazine dihydrochloride 583.0 67.9
Carbopol971P 58.5 6.8
Hydroxypropyl methylcellulose 87.45 10.2
Dicalcium phosphate 60.0 7.0
Magnesium stearate 20.0 2.3
Polyvinylpyrrolidine 50.0 5.8
TOTAL 858.95 100.0
Ranolazine dihydrochloride, hydroxypropylmethylcellulose, polyvinylpyrrolidine and dicalcium phosphate were weighed and sifted through a 60 mesh screen. The sifted ingredients were blended thoroughly and were granulated using IPA. The wet granules were dried in an oven at 50°C for 2 hours. After mixing with carbopol and magnesium stearate (sifted through a 100 mesh screen), the blend was compressed into tablets using caplet shaped concave, tooling.
The punched tablets were subjected to dissolution for a period of 12 hours. The % dissolution of ranolazine with time is presented in Figure 6.

EXAMPLE 7
The formulation contained the following ingredients in the following amounts:
Ingredient Weight (mg)yTablet % (Wt.)
Ranolazine dihydrochloride 583.0 71.2
Carbopol971P 34.98 4.3
Hydroxypropyl! methylcellulose 2208 120.375 14.71
Dicalcium phosphate 60.0 7.3
Magnesium stearate 20.0 2.4
TOTAL 818.4 99.91
Ranolazine dihydrochloride, carbopol, hydroxypropylmethylcellulose and dicalcium phosphate were weighed and sifted through a 36 mesh screen. The sifted ingredients were blended with isopropyl alcohol to form wet granules. The wet granules were dried in an oven at 50°C for 2 hours. After mixing with magnesium stearate (sifted through a 100 mesh screen), the blend was compressed into tablets using oval shaped, concave tooling. The punched tablets were aqueous film coated using standard techniques.
The coated tablets were subjected to dissolution for a period of 12 hours. The % dissolution of ranolazine with time is presented in Figure 7.

We Claim:
1. A sustained release composition for treating cardiovascular diseases
comprising;
(a) a active pharmaceutical compound ranolazine dihydrochloride
(b) matrix forming polymer including nonionic hydrogen forming polymer
(c) matrix forming polymer an anionic polymer and
(d) pharmaceutically acceptable excipients.

2. A composition as claimed in claim 1, wherein the pharmaceutically active compound is a dihydrochloride salt of ranolazine present in the composition between 40% and 85%, more preferably between 50% and 80%, and most preferably between 65% and 75%.
3. A composition as claimed in claim 1, wherein the matrix forming polymer includes a nonionic hydrogel forming polymer for sustaining the release of the active compound in the acidic environment of the gastric fluids,
4. A composition as claimed in claim 1, wherein the nonionic gel forming polymer having different viscosity and molecular weight and is selected from hydroxypropyl cellulose and hydroxypropylmethyl cellulose, more preferably hydroxypropylmethyl cellulose.
5. A composition as claimed in claim 1, wherein the nonionic gel forming polymer present in the composition between 10% and 30%, more preferably about 10% to 20%.
6. A composition as claimed in claim 1, wherein an anionic polymer is selected from carbomers.

7. A composition as claimed in claim 6, wherein the carbomers including acrylic acid cross linked with allyl ethers of pentaerythritol.
8. A composition as claimed in claim 6, wherein the carbomer present in the composition is between 3% and 20%, more preferably between 5% and
10%.
9. A composition as claimed in claim 1, wherein the said nonionic and anionic polymers are used in the composition alone or in combination thereof.
10. A composition as claimed in claim 1, wherein the polymers used for making the composition selected from different viscosity and/or molecular weight grades.
11. A composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from group such as binding agents, diluents, lubricants, glidants etc.
12. A composition as claimed in claim 1, wherein the composition is used for preparing a medicament such as tablet, capsule etc.
13. A composition as claimed in claim 12, wherein the tablet is coated or uncoated.
14. A process for the preparation of sustained release composition for treating cardiovascular diseases comprising mixing an active pharmaceutical compound ranolazine dihydrochloride in a mixture of matrix forming polymer including nonionic hydrogel forming polymer and matrix forming polymer an anionic polymer and pharmaceutically acceptable excipients.

15. A process wherein the active releases the drug in a near zero order
release fashion for a period of at least 12 hours.
16. A process and a composition wherein the composition retains 90% of its
initial potency when tested for stability as per standard guidelines.