WO2018163199A1

WO2018163199A1 - "sustained release compositions of ranolazine"

Info

Publication number: WO2018163199A1
Application number: PCT/IN2018/050113
Authority: WO
Inventors: Venkata Nookaraju Sreedharala; Valluri GALIB SAHEB; Ravi Kumar P; Sridhar SADHULA; Varma Srinivasa Rajasekara RUDRARAJU
Original assignee: Aizant Drug Research Solutions Private Limited
Priority date: 2017-03-06
Filing date: 2018-03-03
Publication date: 2018-09-13

Abstract

The present invention relates to pharmaceutical compositions of Ranolazine or pharmaceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers thereof. In particular the present invention relates to sustained release dosage forms of Ranolazine comprising a combination of pH-independent binders and acids, and optionally one or more pharmaceutically acceptable excipients.

Description

"SUSTAINED RELEASE COMPOSITIONS OF RANOLAZINE

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of Ranolazine or pharmaceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers thereof. In particular the present invention relates to sustained release dosage forms of Ranolazine comprising a combination of pH-independent binders and acids, and optionally one or more pharmaceutically acceptable excipients. BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,567,264, the specification of which is incorporated herein by reference in its entirety, 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. In its dihydrochloride salt form, Ranolazine is represented by the formula:

This patent also discloses intravenous (IV) formulations of dihydrochloride Ranolazine further comprising propylene glycol, polyethylene glycol 400, Tween 80 and 0.9% saline.

U.S. Pat. No. 5,506,229, which is incorporated herein by reference in its entirety, 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. Oral and parenteral formulations are disclosed, including controlled release formulations. 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. This patent also discloses IV Ranolazine formulations which at the low end comprise 5 mg Ranolazine per milliliter of an IV solution containing about 5% by weight dextrose. And at the high end, there is disclosed an IV solution containing 200 mg Ranolazine per milliliter of an IV solution containing about 4% by weight dextrose.

The presently preferred route of administration for Ranolazine and its pharmaceutically acceptable salts and esters is oral. A typical oral dosage form is a compressed tablet, a hard gelatin capsule filled with a powder mix or granulate, or a soft gelatin capsule (softgel) filled with a solution or suspension. U.S. Pat. No. 5,472,707, the specification of which is incorporated herein by reference in its entirety, discloses a high-dose oral formulation employing supercooled liquid Ranolazine as a fill solution for a hard gelatin capsule or softgel. 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 is 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 500 mg and 1 gm 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.

US Pat No.20060177502Al 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.

US Pat No. 20120177729 discloses a sustained release dosage form of Ranolazine comprising a combination of at least two pH-dependent binders and optionally one or more pharmaceutically acceptable excipient(s).

However, there are alternate means by which a sustained release dosage form of Ranolazine, free of pH-dependent binders, can be designed. Surprisingly, it has been found that sustained release dosage forms of Ranolazine can be prepared using combination of pH-independent binders and acids, that are bioequivalent to the marketed formulation and provide the appropriate plasma levels of Ranolazine that are necessary for the treatment of angina and other cardiovascular diseases. SUMMARY OF THE INVENTION

An object of the present invention is to provide stable sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine.

Another object of the present invention is to provide sustained release pharmaceutical dosage forms, comprising a therapeutically effective amount of Ranolazine,free of pH-dependent polymers.

Yet another object of the invention is to provide sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients. Another object of the invention is to provide sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, characterized in that the sustained release pharmaceutical composition of invention is bioequivalent to marketed formulation.

Further, another object of the invention is to provide sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH- independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, wherein about 20% to about 40% of said Ranolazine is released after 2 hours; from about 45% to about 65% of said Ranolazine is released after 8 hours; not less than about 70% of said Ranolazine is released after 24 hours.

Yet another object of the invention is to provide simple and cost-effective method for preparation of asustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure- 1 is the comparative dissolution data for Example-3

Figure-2 is the comparative dissolution data for Example-4

Figure-3 is the comparative dissolution data for Example-5

Figure-4 is the comparative dissolution data for Example-6

Figure-5 is the comparative dissolution data for Example-7

Figure-6 is the comparative dissolution data for Example-8

DETAILED DESCRIPTION OF THE INVENTION

An present invention providesstable sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine. "Ranolazine" is (+-)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]-l- piperazine-acetamide, or its enantiomers (R)-(+)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2- methoxypheno-xy)-propyl]- -1-piperazineacetamide, and (S)-(-)-N-(2,6-dimethylphenyl)-4-[2- hydroxy-3-(2 -methoxyphenoxy)-propyl]-l-piperazineacetamide and their pharmaceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers and mixtures thereof.

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. The amount of Ranolazine present in the dosage form according to the present invention is in the range of 30 to 80%, more preferably 40 to 70%.

The term "stable" as used herein refers to physical stability and/or chemical stability of the active agent in a topical composition, wherein changes in the drug assay values and/or impurities content are less than about 10%, during stability study storage of the composition at 25° C. and 60% relative humidity (RH), or 30° C. and 65% RH, or 40° C. and 75% RH, for durations such as 3, 6, 12, 18, or 24 months.

The term "sustained release" as used herein in relation to the dosage form means which is not immediate release and is taken to encompass controlled release, prolonged release, timed release, retarded release, extended release and delayed release. Sustained release can be used interchangeably with prolonged release, programmed release, timed release, extended release, controlled release and other such dosage forms. The "dosage form" according to the present invention include but is not limited to tablets, pellets, beads, granules, capsules, microcapsules and tablets in capsules. "Therapeutically effective amount" means that the amount of active agent, which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition. A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden.

By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not biologically or otherwise undesirable.

An embodiment of the present invention provides sustained release pharmaceutical dosage forms, comprising a therapeutically effective amount of Ranolazine, free of pH-dependent polymers.

Another embodiment of the present invention provides sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH- independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients.

Ranolazine is relatively insoluble in aqueous solutions having a pH above about 6.5, while the solubility begins to increase dramatically below about pH 6, therefore it is very difficult to prepare a sustained release dosage form of Ranolazine wherein the drug is released throughout the gastrointestinal tract (GIT).

To provide a sustained release dosage form of Ranolazine, wherein the drug is released throughout the GIT, a combination of one or more pH-independent binders and one or more acids are chosen, to control the dissolution rate of the Ranolazine so that the dosage form releases Ranolazine slowly and continuously as it passes through the stomach and gastrointestinal tract. Proper selection and combination of pH-independent binder(s) and acid(s) in the dosage form helps in sustaining the release of Ranolazine throughout the GIT. Incorporating acids into the matrix system of the pH-independent binders partially neutralizes the acidic pH of the GIT, thereby enhancing the release profile of the drug. Accordingly, judicious selection of the type and the quantity of the pH-independent binder(s) and acid(s) is required to closely control the rate of dissolution of the Ranolazine from the formulation and to prevent dose-dumping. Accordingly, binders suitable for use in this invention are materials which include but not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, and the like. The pH-independent binders are present in the formulation of this invention in an amount ranging from about 5 to about 25 wt. %.

Further, acids suitable for use in this invention include but not limited to propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, maleic acid, malonic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, citric acid, 4-hydroxy benzoic acid, 2,5-dihydroxy benzoic acid, adipic acid, glycolic acid, decanoic acid, un-decanoic acid, cholic acid, dexo-cholic acid, mandelic acid, d-camphonic acid, benzoic acid, methansulphonic acid, ethanesulphonic acid, benzesulphonic acid, p-toluenesulphonic acid or combinations thereof. The acids are present in the formulation of this invention in an amount ranging from about 5 to about 25 wt. %. "Optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally pharmaceutical excipients" indicates that a formulation so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation so described includes instances in which the optional excipients are present and instances in which they are not.

In an embodiment, the pharmaceutical dosage forms of the present invention comprise additional pharmaceutically acceptable excipients selected from the group consisting diluents, lubricants, disintegrants, glidants, surface-active agents, antioxidants, thickeners, suspending agents, flavoring agents, sweeteners, and colorants. 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 compositions 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.

The present compositions 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. In an embodiment of the present invention the sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, such that when the composition tested in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8, about 20% to about 40% of said Ranolazine is released after 2 hours; from about 45% to about 65% of said Ranolazine is released after 8 hours; not less than about 70% of said Ranolazine is released after 24 hours.

Another object of the invention is to provide sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, characterized in that the sustained release pharmaceutical composition of invention is bioequivalent to marketed formulation.

In an embodiment of the present invention the sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, such that Maximum Plasma Concentration (C_max) and Area Under Curve (AUC) values of the compositions are within the limit of 80 % to 125 % of C_max and AUC of the marketed composition of Ranolazine modified release tablets (Ranexa ) respectively.

Another embodiment of the present invention provides a simple and cost-effective method for preparation of a sustained release pharmaceutical dosage form comprising a therapeutically effective amount of Ranolazine. The pharmaceutical composition 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.

Sustained release pharmaceutical dosage form according to the present invention are manufactured preferably as per the following procedure: i) Blending the active agent, pH-independent binder(s), acid (s) and one or more pharmaceutically acceptable excipient(s),

ii) Subjecting the blend to granulation,

iii) Drying and sieving the granulated blend to obtain granules,

iv) Blending the granules obtained in the above step with extragranular excipient(s),

v) Compressing the blend of step to form the solid oral dosage form.

The pharmaceutical dosage forms of the invention may further be coated. The coating may be a functional or non-functional coating. The preferred 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.

These coating comprises one or more excipients selected from the group comprising coating agents, opacifiers, fillers, polishing agents, colouring agents, antitacking agents and the like.

The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art. EXAMPLES

Example 1: Ranolazine sustained release composition

Ingredients %w/w

Ranolazine 65.79

MCC 101 1.75

HPMC K 100M 6.58

Tartaric acid 7.02

Sodium CMC 2.63

Citric acid 7.02

HPMC K 100M 6.58

Collodial silicon dioxide 1.32

Sodium stearyl fumarate 1.32

Purified water Q.S. Brief Manufacturing Process

1. Sifting: Ranolazine, MCC, HPMCK 100M and Sodium CMC was sifted through a specific mesh and mixed with the acids,

2. Granulating:The dry blend of above step was granulated with water to get granules of desired consistency,

3. Drying: The granules were dried in rapid drier,

4. Sizing and lubrication: The dried granules were passed through a particular mesh; mixed with the extragranular excipients and lubricated,

5. Compression: The lubricated blend of above step was compressed using appropriate tools to obtain the final solid oral dosage form.

Example 2: Ranolazine sustained release composition

Ingredients %w/w

Ranolazine 65.79

Lactose monohydrate 1.75

Eudragit RSPO 10.53

Ethylcellulose 7 cps 8.77

Tartaric acid 7.02

Sodium stearyl fumarate 1.75

Collodial silicon dioxide 1.75

HPMC E5 2.63

Purified water Q.s.

Brief Manufacturing Process

1. Sifting: Ranolazine, Lactose, EudragitRSPO and ethylcellulose was sifted through a specific mesh and mixed with tartaric acid,

2. Granulating: The dry blend of above step was granulated with aqueous solution of HPMC E5 to get granules of desired consistency,

3. Drying: The granules were dried in rapid drier,

4. Sizing and lubrication: The granules were then passed through a particular mesh; mixed with the extragranular excipients and lubricated, 5. Compression: The lubricated blend of above step was compressed using appropriate tools to obtain the final solid oral dosage form.

Example 3: Ranolazine sustained release composition

Ingredients %w/w

Ranolazine 64.10

Lactose monohydrate 1.71

HPMC K 100M 10.26

Tartaric acid 10.26

Citric acid 10.26

Colloidal silicon dioxide 2.56

Sodium stearyl fumarate 0.85

Brief Manufacturing Process

1. Sifting: Ranolazine, lactose and HPMCK 100M was sifted through a specific mesh and mixed with the acids,

2. Granulating: The dry blend of above step was granulated,

3. Sizing and lubrication: The granules were passed through a particular mesh; mixed with the extragranular excipients and lubricated,

4. Compression: The lubricated blend of above step was compressed using appropriate tools to obtain the final solid oral dosage form.

In- Vitro Dissolution Study:

Table- 1 given below shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 3 of the present invention (Test) & Ranexa^® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8. The release profile (cumulative % of drug released) is given in Table 1.

Table 1:

30 18 20

60 26 27

90 29 33

120 34 38

240 57 53

480 73 70

720 75 82

Example 4: Ranolazine sustained release composition

Ingredients % w/w

Ranolazine 52.45

Lactose monohydrate 3.50

HPMC K 100 M 8.40

Tartaric acid 12.59

Colloidal silicon dioxide 2.10

Citric acid 12.59

Polyethylene oxide 303 6.99

Magnesium stearate 1.40

Brief Manufacturing Process

1. Sifting: Ranolazine, Lactose monohydrate, HPMC K 100 M, tartaric acid and colloidal silicon dioxide was sifted through a specific mesh

2. Granulation: The blend of above step was granulated with Roller compaction.

3. Sizing and lubrication: The granules were then passed through a particular mesh; mixed with the extra granular excipients and lubricated,

In- Vitro Dissolution Study:

Table-2 given below shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 4 of the present invention (Test) & Ranexa^® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8. The release profile (cumulative % of drug released) is given in Table 2. Table 2:

Example 5: Ranolazine sustained release composition

Ingredients %w/w

Ranolazine 51.37

Lactose monohydrate 3.42

HPMC K 100M 8.22

citric acid 14.38

Tartaric acid 12.33

Colloidal silicon dioxide 2.05

Polyethylene oxide 6.85

Magnesium stearate 1.37

Brief Manufacturing Process

1. Sifting: Ranolazine, Lactose monohydrate, HPMC K 100 M, citric acid, tartaric acid and colloidal silicon dioxide was sifted through a specific mesh.

2. Granulation: The blend of above step was granulated with Roller compaction.

In- Vitro Dissolution Study: Table-3 given below shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 5 of the present invention (Test) & Ranexa^® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8. The release profile (cumulative % of drug released) is given in Table 3.

Table 3:

Example 6: Ranolazine sustained release composition

Ingredients %w/w

Ranolazine 47.32

Eudragit RSPO 12.62

Ethylcellulose 7 cps 12.62

Tartaric acid 7.57

Citric acid 6.31

Polyethylene oxide 303 10.09

Collodial silicon dioxide 0.63

Magnesium stearate 1.89

HPMC E5 0.95

Purified water Qs Brief Manufacturing Process

1. Sifting: Ranolazine, Eudragit RSPO and ethylcellulose was sifted through a specific mesh and mixed with the acids, 2. Granulating: The dry blend of above step was granulated with aqueous solution of HPMC E5 to get granules of desired consistency,

3. Drying: The granules were dried in rapid drier,

4. Sizing and lubrication: The granules were then passed through a particular mesh; mixed with the extragranular excipients and lubricated,

In- Vitro Dissolution Study:

Table-4 given below shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 6 of the present invention (Test) & Ranexa 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8. The release profile (cumulative % of drug released) is given in Table 4.

Table 4:

Example 7: Ranolazine sustained release tablet composition

Ingredients %w/w

Blend for compression layer 1

Ranolazine 43.80

Eudragit RSPO 13.02

Ethylcellulose 7cps 13.02

Tartaric acid 8.70 Citric acid 7.32

Hypromellose 1.06

Purified Water Q.S

Polyethylene oxide 303 10.14

Colloidal silicon dioxide 0.75

Magnesium stearate 2.19

Blend for compression layer 2

Ranolazine 69.44

Micro crystalline cellulose PH 101 14.79

Sodium starch glycolate 2.32

Povidone 3.72

Purified water Q.S

Hypromellose K 100 Premium LVCR 6.94

Colloidal silicon dioxide 0.97

Magnesium Stearate 1.81

Coating material

Opadry Pink 3.00

Purified water Q.S

Brief Manufacturing Process

Blend for compression layer 1 :

1. Sifting: Ranolazine, Eudragit RSPO, ethyl cellulose 7 cps, tartaric acid and citric acid was sifted through a specific mesh,

3. Drying: The granules were dried in rapid drier,

4. Sizing and lubrication: The granules were then passed through a particular mesh; mixed with the extra granular excipients and lubricated,

Blend for compression layer 2:

5. Sifting: Ranolazine, Microcrystalline cellulose PH 101 and sodium starch glycolate was sifted through a specific mesh,

6. Granulating: The dry blend of above step was granulated with aqueous solution of povidone to get granules of desired consistency,

7. Drying: The granules were dried in rapid drier, 8. Sizing and lubrication: The granules were then passed through a particular mesh; mixed with the extra granular excipients and lubricated,

9. Compression: The lubricated blends layer 1 and layer 2 were compressed into tablets using appropriate tools.

10. Coating: The compressed tablets were film-coated.

In- Vitro Dissolution Study:

Table-5 given below shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 7 of the present invention (Test) & Ranexa^® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8. The release profile (cumulative % of drug released) is given in Table 5.

Table 5:

Example 8: Ranolazine sustained release tablet composition

To execute a batch of Ranolazine Sustained release tablets with Extended Release layer and Immediate Release layer with proportional concentrations of polymer and to check it for dissolution.

% w/w

Ingredients

Blend for compression layer 1 Ranolazine 49.75

Eudragit RSPO 14.78

Ethyl cellulose 7cps 14.78

Tartaric acid 2.27

Citric acid 2.13

HPMC E5 1.42

Purified Water Q-S

Polyethylene oxide 303 11.51

Colloidal silicon dioxide 0.85

Magnesium stearate 2.49

Blend for compression layer 2

Ranolazine 69.44

Micro crystalline cellulose pH 101 14.79

Sodium starch glycolate 2.32

Povidone 3.72

Purified water Q-S

Hypromellose K 100 Premium LVCR 6.94

Colloidal silicon dioxide 0.97

Magnesium Stearate 1.81

Coating material

Opadry Pink 3.00

Purified water Q.S

Brief Manufacturing Process

Blend for compression layer 1 :

3. Drying: The granules were dried in rapid drier,

Blend for compression layer 2: 5. Sifting: Ranolazine, Microcrystalline cellulose PH 101 and sodium starch glycolate was sifted through a specific mesh,

7. Drying: The granules were dried in rapid drier,

8. Sizing and lubrication: The granules were then passed through a particular mesh; mixed with the extra granular excipients and lubricated,

10. Coating: The compressed tablets were film-coated.

In- Vitro Dissolution Study:

Table-6 given below shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 8 of the present invention (Test) & Ranexa^® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8. The release profile (cumulative % of drug released) is given in Table 6.

Table 6:

Example 9: Bioavailability Study - Fasted condition

A single dose, open-label, randomized, 2-period, 2-treatment, 2-way crossover bioavailability study was made with the Ranolazine Sustained release tablets of Example 5 under fasted conditions. Twenty Four healthy subjects were randomly assigned to a treatment sequence and received two separate single - dose administrations of study medication, one treatment per period, according to the randomized schedule. The subjects received Treatment T (test product of Example 5, Ranolazine Sustained release tablets) and Treatment R (reference product, Ranexa^® 1 Gm tablets) following an overnight fast of at least ten hours. Blood samples were collected, pre-dose and after administration of the dose, for 12 hours. The samples were analyzed for Ranolazine and pharmacokinetic parameters like Cmax, AUClast and AUCinf were calculated: The results, provided in the Table-7 below, indicate that the formulation of Example 8 exhibits a geometric mean ratio of Cmax, AUClast and AUCinf of within 80% to 125% limits for Ranolazine.

Table -7:

aGeometric Mean for the Test Formulation (Test) and Reference Product (Ref) based on Least Square Mean of log- transformed parameter values

bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)

c90% Confidence Interval

It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present inventions without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modification and variations of the invention provided they come within the scope of the appended claims and their equivalents.

Claims

We Claim

1. A sustained release pharmaceutical dosage form comprising Ranolazine, a pH- independent binder, an acid, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is free of pH-dependent binders.

2. A sustained release pharmaceutical dosage form as in claim 1 , wherein the pH- independent binder is selected from the group comprising hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, or mixtures thereof.

3. A sustained release pharmaceutical dosage form as in claim 1, wherein the acid is selected from the group comprising propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, maleic acid, malonic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, citric acid, 4- hydroxy benzoic acid, 2,5-dihydroxy benzoic acid, adipic acid, glycolic acid, decanoic acid, un-decanoic acid, cholic acid, dexo-cholic acid, mandelic acid, d-camphonic acid, benzoic acid, methansulphonic acid, ethanesulphonic acid, benzesulphonic acid, p- toluenesulphonic acid, or mixtures thereof.

4. A sustained release pharmaceutical dosage form as in claim 1 , wherein pharmaceutically acceptable excipients are selected from the group comprising diluents, lubricants and glidants.

5. A sustained release pharmaceutical dosage form as in claim 4, wherein the diluents are selected from the group comprising 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 mixtures thereof.

6. A sustained release pharmaceutical dosage form as in claim 4, wherein the lubricants are selected from the group comprising Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc, and mixtures thereof.

7. A sustained release pharmaceutical dosage form as in claim 4, wherein the glidants are selected from the group comprising silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel, and mixtures thereof.

8. A sustained release pharmaceutical dosage form as in claim 1 is wherein the dosage form is selected from group comprising tablets, pellets, beads, granules, capsules, microcapsules and tablets in capsules.

9. A sustained release pharmaceutical dosage form comprising Ranolazine, a pH- independent binder, an acid, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is free of pH-dependent binders; and characterized in that the sustained release pharmaceutical composition of invention is bioequivalent to marketed formulation.