Ranolazine multiple compressed tablets

This application claims the benefit of the following patent applications: TW 105120746 (filed on June 30th, 2016); EP16206070.0 (filed on December 22th, 2016), EP16206067.7 (filed on December 22th, 2016), and EP17152643.7 (filed on January 23rd, 2017).

Filed of the Invention

The present invention is in the field of drug delivery, more specifically in the field of extended release drug delivery, and deals with ranolazine extended release delivery using multiple compressed tablets or using a monolithic tablet comprising pharmaceutically acceptable acid and at least one or more of the following: a release retardant agent and a thickening agent.

Background of the invention

Ranolazine is marketed as Ranexa® in 375, 500, 750 and 1000 mg extended release tablets as antianginal agent and was first disclosed in EP0126449 A1 , has the systematic name N-(2,6- dimethylphenyl)-2-(4-(2-hydroxy-3-(2-methoxyphenoxy)propyl)p iperazin-1 -yl)acetamide and the following chemical structure:

The solubility of ranolazine is pH dependent and according to WO03086401 A1 the solubility of ranolazine is as follows:

Solution pH Solubility (mg/mL) USP Solubility Class

4.81 161 Freely Soluble

4.89 73.8 Soluble

4.90 76.4 Soluble

5.04 49.4 Soluble

5.35 16.7 Sparingly Soluble

5.82 5.48 Slightly soluble

6.46 1.63 Slightly soluble

6.73 0.83 Very slightly soluble

7.08 0.39 Very slightly soluble

7.59 (unbuffered water) 0.24 Very slightly soluble

7.79 0.17 Very slightly soluble

12.66 0.18 Very slightly soluble

As shown in the previous table, ranolazine is much more soluble at acidic pH than in neutral or basic pH. The rate at which a 100% ranolazine tablet dissolves at different pH values is shown in Figure 1 , where it is clearly observed that at pH 1 in less than 30 minutes all the ranolazine is dissolved, while at pH 6.8 in 30 minutes only around 63% of the ranolazine is dissolved and in 12 hours ranolazine is not yet fully dissolved.

According to WO0166093 A2: "[o]ne 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". Therefore, the preferred method of administration of ranolazine is as an extended release formulation. Thus, several ranolazine extended release formulations have been disclosed based on different technologies.

The use of pH dependent polymers is disclosed in WO03099281 , CN101637442, WO0013686, WO0013687, WO0166093, CN101066253, W011036677, W012152440 or TR201203341.

The use of acids is disclosed in JP2000336032.

The use of lipid compounds is disclosed in W010137040, US2013022676 or W011107750.

The use of pellets coated only with pH independent binders is disclosed in CN102125523, CN101066254, CN102125523, CN103751112, CN101176723, IN02204MU2009 and WO06074398.

CN1891218 discloses extended release formulations (providing a sustained release of drug for 12 hours) of ranolazine dihydrochloride which has a much higher solubility than ranolazine free base. According to CN1891218 the solubility of ranolazine dihydrochloride at 37°C in water is as follows:

Solution pH Solubility (g/mL) USP Solubility Class

HCI 0.1 M >1.5 Very soluble

pH 5.8 >1.1 Very soluble

pH 6.8 >1.0 Very soluble

Unbuffered water >1.2 Very soluble

The use of a release mechanism based on the pH of the medium (pH dependent polymers and acids) is convenient because in the digestive system different values of pH can be found: acidic in the stomach and neutral/basic in the bowel. However, the inventors of the present invention have found that, with this kind of release mechanism, ranolazine formulations show a high inter-subject variability due to inter-subject variations in stomach pH and transit time variability, which results in high inter- subject bioavailability variability. This issue can be amplified in conditions such as gastroparesis, hyperchlorhydria or achlorhydria. Ranexa® marketed composition is based on pH dependent binders. Figure 2 shows that the dissolution of ranolazine in Ranexa® is heavily dependent on the pH of the medium.

The alternative of using coated granules was found not desirable either, because when coated granules are compressed into tablets the coating may be damaged irregularly and will result in increasing variability between tablets due to the irregularly damaged coating. This can be solved by using capsules, but this is not desirable in the case of high dosage drugs (such as ranolazine, which is administered up to 1000 mg) because, since the capsule content is not compressed, it is very bulky and occupies a large volume; thus, requiring large capsules (which are hard to swallow). Not only that, but capsules are also usually difficult to fill accurately and their preparation is lengthier and costlier than that of tablets.

A part form the previously mentioned problems, the preparation of coated granules has many drawbacks, such as variability in granule size and form or coating thickness and the long times required to coat the granules. Since the coating is functional, variability in its thickness may result in increased variability in the release rate depending on the thickness of the coating.

The alternative of using lipid compounds such as fats, oils or waxes to obtain the extended release is not desirable either, because such excipients are difficult to handle due to their viscosity and sticky properties and results in a high variability in the drug content within the manufactured dosage forms. Not only that, but fats, oils or waxes may also have different behaviour when taken with or without food.

Therefore, there is a need to provide new ranolazine extended release pharmaceutical compositions which overcome the previous problems including the variability (inter-subject, interaction with food, content uniformity...) and that can be easily modified to obtain different dissolution profiles in time as desired. Summary of the Invention

One aspect of the invention is a multiple compressed tablet obtainable by a process comprising at least two compression cycles, wherein

- in each of the compression cycles a pharmaceutical composition, comprising one or more pharmaceutically acceptable excipients, is used,

- at least one of such pharmaceutical compositions comprises one or more release retardant agents,

- at least two of such pharmaceutical compositions comprise ranolazine and have a different quantitative and/or qualitative composition. wherein:

I. the one or more release retardant agents comprises at least one polyalkylene oxide and/or

II. at least one of such pharmaceutical compositions comprises at least one thickening agent.

A second aspect of the invention is a process for the preparation of the multiple compressed tablet according to the invention comprising:

a) independently mixing all the components of all the pharmaceutical compositions,

b) optionally tableting one or more pharmaceutical compositions,

c) either

i. charging and optionally precompressing a pharmaceutical composition different from the one used in the previous cycle on the result of the previous cycle, or ii. placing a tablet of step b), prepared using a pharmaceutical composition different from the one used in the previous cycle, on the result of the previous cycle, d) repeating step c) at least one time,

e) compressing the result of the previous step.

A third aspect of the invention is a ranolazine extended release monolithic tablet which comprises one or more pharmaceutically acceptable acid and one or more of the following:

- one or more release retardant agent

- one or more thickening agent

Another aspect of the invention is a ranolazine extended release monolithic tablet according to the invention for use in the treatment of angina pectoris.

A fourth aspect of the invention is a process for the preparation of the ranolazine extended release monolithic tablet according to the third aspect of the invention comprising:

a) mix all the components of the intragranular fraction,

b) dry or wet granulate,

c) add the extragranular fraction,

d) compress the resulting mixtures.

A fifth aspect of the invention is a process for the preparation of the ranolazine extended release monolithic tablet according to the third aspect of the invention comprising:

a) mix all the components,

b) compress the resulting mixtures.

A sixth aspect of the invention is a multiple compressed tablet according to the invention for use in the treatment of angina pectoris.

A seventh aspect of the invention is a ranolazine monolithic tablet according to the invention for use in the treatment of angina pectoris.

The ranolazine used in the present invention is ranolazine free base.

Definitions

A pharmaceutically acceptable excipient is a component of a pharmaceutical composition or formulation which has one or more functions and is suitable to be administered to any animal including mammals and humans. Some of the functions that the excipient may perform are: release retardant agent, thickener, diluent, binder, disintegrant, glidant, lubricant, coating, colorant, flavouring agent, sweetener and the like.

A release retardant agent is a pharmaceutical acceptable excipient that, when incorporated in a pharmaceutical composition, reduces the rate at which a drug is released from the pharmaceutical composition.

A pH dependent release retardant agent is a release retardant agent that, when incorporated in a pharmaceutical composition, makes the rate at which the drug is released dependent on the pH of the dissolution media.

A pH independent release retardant agent is a release retardant agent that, when incorporated in a pharmaceutical composition, makes the rate at which the drug is released substantially independent of the pH of the dissolution media. Suitable pH independent release retardant agents are pH independent polymers and pH independent binders.

A pH independent polymer is a polymeric pH independent release retardant agent. Examples of pH independent polymers are: hydroxypropyl methylcellulose (also known as hypromellose or HPMC), hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone (also known as povidone or PVP), neutral poly(meth)acrylate esters, poly(meth)acrylate esters with functional group, polyalkylene oxides (also known as macrogols, high molecular mass) and the like. The pH independent polymers are preferably used as solids, not as solutions, because the inventors have found that results in much better binding properties when a binder is used.

Suitable polyalkylene oxides have an average molecular weight (Mw) of from 900000 to 15000000 and include polymethylene oxide, polyethylene oxide, polypropylene oxide, polyisopropylene oxide and polyisobutylene oxide, copolymers and mixtures thereof.

Polyethylene oxide having an average molecular weight (Mw) of from 900000 to 15000000 can be used in the present invention, e.g. 900000, 1000000, 2000000, 4000000, 5000000 or 7000000. Commercial examples of polyethylene oxide include Polyox® in grades WSR 1105, WSR N-12K, WSR N-60K, WSR 301 , WSR Coagulant or WSR 303.

Polyisopropylene oxide having an average molecular weight (Mw) of from 900000 to 15000000 can be used in the present invention, e.g. 1000000 or 5000000. Commercial example of polyisopropylene oxide includes Oppanol® in grades B100 or B200.

A thickening agent is a product that, when added to a mixture, increases its viscosity without substantially modifying its other properties. Suitable thickening agents are: polyvinyl acetate, ethylcellulose, hydroxyethyl cellulose or hydroxyethylmethyl cellulose.

The preferred polyvinyl acetate is a polyvinyl acetate with a Mw of 200000 to 650000, preferably from 400000 to 500000.

The preferred ethylcellulose is an ethylcellulose with a viscosity measured at 25°C using 5% w/v ethylcellulose dissolved in a solvent blend of 80% toluene 20% ethanol (w/w) of 40 to 400 mPa-s, more preferably of 150 to 350 mPa-s. Suitable marketed ethylcellulose include: Ethocel Std 45P Premium, Ethocel Med 50P Premium, Ethocel Med 70P Premium, Ethocel Std 100FP Premium, Ethocel Std 100P Premium, Ethocel Std 100P Industrial, Ethocel Std 200P Premium or Ethocel Std 300P Premium

The preferred hydroxyethyl cellulose is a hydroxyethyl cellulose with a viscosity measured in a 2% w/v aqueous solution of 5000 to 30000 mPa-s, more preferably of 14000-22000 mPa-s. Suitable marketed hydroxyethyl cellulose include: Cellosize QP10000, Cellosize QP15000 or Natrosol 250 HHR.

The preferred hydroxyethylmethyl cellulose is hydroxyethylmethyl cellulose with a viscosity measured in a 2% w/v aqueous solution at 20°C of 5 to 15 mPa-s.

A diluent is an inert pharmaceutically acceptable excipient that provides bulk to the pharmaceutical composition, facilitates the manufacturing process of the dosage form as well as improves the uniformity of content of the active ingredient in the composition. Suitable examples of diluents are: microcrystalline cellulose, lactose (including but not limited to lactose USP, anhydrous lactose USP and spray-dried lactose USP), starch (including but not limited to maize starch, dry starch and directly compressible starch and hydrolysed starch (including but not limited to Celutab®)), mannitol, sorbitol, inositol, sucrose-based diluents (including but not limited to sucrose, confectioner's sugar and sugar spheres NF), dextrose (including but not limited to Cerelose® and dextrose monohydrate), dicalcium phosphate (including but not limited to dicalcium phosphate trihydrate), monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate (including but not limited to calcium lactate trihydrate granular NF), calcium carbonate, dextrates (e. g., Emdex®), hydrolysed cereal solids (including but not limited to Matron products and Mor-Rex), amylose, Recel, powdered cellulose (including but not limited to Elcema®), glycine, bentonite and the like.

A binder is a pharmaceutically acceptable excipient that holds the components of a pharmaceutical composition together. Suitable binders are: polyvinylpyrrolidone (preferably a grade with viscosity between 1.5 to 8.5 and more preferable with viscosity 3.5 to 5.5 mPa-s), starch (including but not limited to maize starch and pregelatinized starch), copovidone, gum acacia, gum arabica, gelatine, cellulose and derivatives thereof (including but not limited to cellulose esters, cellulose ethers and hydroxypropylcellulose), xylitol, sorbitol, maltitol, polyethylene glycol and the like.

A disintegrant is a pharmaceutically acceptable excipient that included in solid pharmaceutical forms, such as tablets or granules, facilitate its break up or disintegration in an aqueous environment. Suitable disintegrants are starches (including but not limited to sodium starch glycolate, corn starch, potato starch, maize starch, modified starches and pregelatinized corn starches (including but not limited to National 1551 and National 1550)), crospovidone, clays (including but not limited to bentonite, bentonite magma, purified bentonite, kaolin, ball clay, common clay, magnesium aluminium silicate, magnesium trisilicate and shale, and fire clay), celluloses (including but not limited to purified cellulose, methylcellulose and carmellose sodium (also known as sodium carboxymethylcellulose), cross-linked celluloses, such as cross-linked carmellose (croscarmellose) and its salts, including sodium croscarmellose), alginates, gums (such as agar, guar, locust bean, karaya, pectin, and tragacanth gums) and the like.

A glidant is a pharmaceutically acceptable excipient that eases powder flow of pharmaceutical mixtures. Suitable glidants are anhydrous colloidal silica (a.k.a. silicon dioxide), talc, magnesium carbonate, glyceryl behenate (including but not limited to Compritol® 888), hydrogenated vegetable oils (including but not limited to Sterotex®), waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycols (including but not limited to Carbowax® 4000 and Carbowax® 6000), sodium oleate and the like.

A lubricant is pharmaceutical excipient that prevents the ingredients from sticking to the tablet dies and punches. Suitable lubricants are sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, magnesium lauryl sulfate, talc, silica, and the like.

A pharmaceutically acceptable acid is substance that when dissolves in water decreases the pH of the solution. Suitable pharmaceutically acceptable acids can be selected form tartaric acid, citric acid, gluconic acid, D-lactic acid (including D-, L- and D/L-), oxalic acid, ascorbic acid, boric acid, phosphoric acid (including anhydrous and hemihydrate), malic acid, maleic acid, malonic acid, succinic acid, glutaric acid, glutamic acid, aspartic acid, NaH2P0 ₄ , fumaric acid and the like.

A coating is defined here as a layer of a given thickness that surrounds the entire tablet surface.

A film coating is a thin layer (of about 0.02-0.5 mm) that surrounds a dosage form, here a tablet. The coating may perform different functions: aesthetic, ease swallowing, modify the release of the drug (e.g. enteric coating, sustained release, etc.). Suitable coatings include coatings based on hydroxypropylmethylcellulose (HPMC) or polyvinyl alcohol) (PVA). Commercial examples are Opadry®, Opadry® 200, Opadry® amb II, Opadry® fx™, Opadry® II, Opalux®.

Sugar coating involves the deposition from an aqueous solution of coatings based on sugars, typically sucrose.

A colorant is a product that provides colour to the pharmaceutical composition. Suitable colorants are: C.I. Pigment White 6, C.I. Natural Brown 10, C.I. Food Red 12, C.I. Food Red 17, C.I. Food Red 9, C.I. Food Red 3, C.I. Food Orange 8, C.I. Natural Red 4, C.I. Red 87, C.I. Food Red 14, C.I. Pigment Red 101 & 102, C.I. Food Red 7, C.I. Food Red 10, C.I. Food Orange 5, C.I. Food Orange 6, C.I. Natural Yellow 3, C.I. Food Yellow 13, C.I. Pigment Yellow 42 & 43, C.I. Food Yellow 13, C.I. Food Yellow 3, C.I. Food Yellow 4, C.I. Natural Green 3, C.I. Natural Green 3, C.I. Food Green 3, C.I. Food Green 4, C.I. Food Blue 2, C.I. Food Blue 1 , C.I. Food Blue 5, C.I. Food Black 1 , C.I. Pigment Black 11 , C.I. Food Black 3 and the like.

A flavouring agent is a product that provides flavour to the pharmaceutical composition. Suitable flavouring agents are strawberry flavour, cherry flavour, banana flavour, mint flavour, orange, lemon, vanillin, peppermint, grape and the like.

A sweetener is an excipient that provides sweet taste to the pharmaceutical composition. Suitable sweeteners are preferably selected from the group consisting of sugars (such as sucrose, fructose, glucose and the like), artificial sweeteners (such as saccharin or its pharmaceutically acceptable salts (such as saccharin sodium), cyclamate or its pharmaceutically acceptable salts (such as cyclamate sodium), aspartame, acesulphame or its pharmaceutically acceptable salts (such as acesulphame potassium), sucralose, neohespiridin dihydrochalcone, naringin dihydrochalcone and the like), and mixtures thereof.

Further suitable excipients and its role can be found on Handbook of Pharmaceutical Excipients, APhA Publications 5 ^th edition 2005, edited by Raymond C. Rowe, Paul J. Sheskey, Sian C. Owen, ISBN-10: 1582120587. In this reference synonyms of the excipients cited here and further examples of specific types of excipients discussed here can be found.

pH values lower than 7 mean acidic medium, pH=7 is neutral and pH values higher than 7 mean basic medium. According to Remington: The Science and Practice of Pharmacy, 21 ^st edition, 2006, page 890, multiple compressed tablets are compressed tablets made by more than one compression cycle. This definition includes layered tablets (bilayer tablets, trilayer tablets and, more generally, multilayer tablets) as well as press-coated tablets and inlay tablet.

A multilayer tablet is a tablet prepared by at least precompressing one or more additional pharmaceutical compositions on a previously at least precompressed pharmaceutical composition.

A bilayer tablet is a multilayer tablet which is prepared with only one additional pharmaceutical composition and resulting in a tablet with two layers.

A trilayer tablet is a multilayer tablet which is prepared with one or two additional pharmaceutical compositions and results in a tablet with three layers. Only one additional pharmaceutical composition is required if after forming a bilayer tablet, the same composition of the first layer is used.

A press-coated tablet is a tablet prepared by compressing a pharmaceutical composition around a previously formed tablet. The press-coated tablets are also referred as dry coated tablet, tablet-into- tablet or tablet-within-a-tablet.

An inlay tablet is a tablet prepared by compressing a pharmaceutical composition around a previously formed tablet, but wherein the inner tablet is not completely surrounded by this pharmaceutical composition and thus one of the surfaces of the inner tablet is exposed.

A compression cycle in the context of the present invention is a step that includes the compression or precompression of a pharmaceutical composition.

Precompressing is applying force to a mixture, being that force lower than that required for compressing a mixture into a tablet. Typically, the force applied in precompression ranges from 0.2 kN to 5.0 kN, most commonly from 0.5 kN to 2 kN.

Compressing is applying enough force to a mixture to compress that mixture into a tablet. This is sometimes referred as tabletting. Typically, the force applied in compression ranges from 5 kN to 100 kN, most commonly from 5 kN to 75 kN and most commonly, from 10 kN to 30 kN.

A drug is a chemical substance used in the treatment, cure, prevention or diagnosis of a disease or used to otherwise enhance physical or mental well-being of a mammal including humans and when present in a tablet is in an amount enough to produce such effect.

Outer pharmaceutical compositions are the pharmaceutical compositions present in the trilayer, multilayer, press-coated or inlay tablets which contain the point further away from the geometrical centre of the tablet.

Inner pharmaceutical compositions are the pharmaceutical compositions present in the press- coated or inlay tablets which are totally or partially surrounded by the outer pharmaceutical compositions.

Intermediate pharmaceutical compositions in the trilayer and multilayer tablets are the pharmaceutical compositions found between the two outer pharmaceutical compositions.

In bilayer tablets the inner and outer layers of pharmaceutical compositions are named arbitrarily. Charging a pharmaceutical composition in a die means placing the powder or granules in the die prior to precompression or compression.

Unless otherwise stated, aqueous dissolution media is deionized water wherein, optionally, the pH is adjusted as described or as known in the art. Description of figures

Figure 1 shows the % of dissolution in time of 500 mg ranolazine compressed into tablets in 900 mL of two aqueous dissolution media at pH values of 1.0 (0.1 M HCI) and 6.8 (0.05 M KH ₂ P0 ₄ /Na ₂ HP0 ₄ buffer adjusting to the desired pH using 85% H ₃ P0 ₄ or 2.0 M NaOH) using paddle stirred at 100 rpm.

Figure 2 shows the dissolution of 1000 mg Ranexa® tablets at pH values of 1.0, 4.5 and 6.8. The 1000 mg Ranexa® tablets are dissolved in 900 mL of aqueous dissolution media using paddle stirring at 50 rpm. The pH 1.0 is obtained using 0.1 M HCI. The pH 4.5 is obtained using 0.2 M acetic acid sodium acetate buffer and adjusting to the desired pH using glacial acetic acid or 2.0 M NaOH. The pH 6.8 is obtained using 0.05 M KH2P0 ₄ /Na2HP0 ₄ buffer and adjusting to the desired pH using 85% H ₃ PO ₄ or 2.0 M NaOH.

Figure 3 shows cross-sectional views of representative kinds of tablets. The drawings are based on round tablets which have flat surfaces. The different pharmaceutical composition of the different layers or regions is shown graphically. The invention is not in any way limited to round tablets which have flat surfaces.

Figure 3A shows a tablet with two layers, each prepared using different pharmaceutical compositions. This is commonly known as a bilayer tablet.

Figure 3B shows a tablet with three layers, the outer and inner fractions are prepared using different pharmaceutical compositions. The two outer pharmaceutical compositions can be the same or different. This is commonly known as a trilayer tablet.

Figure 3C shows a tablet which is made of an inner tablet fully surrounded by an outer pharmaceutical composition, wherein the outer and the inner fractions have a different pharmaceutical composition. This is commonly known as a press-coated tablet.

Figure 3D shows a tablet surrounded by another pharmaceutical composition on one base and on the entire lateral surface, wherein the other base is exposed to the dissolution media. This is commonly known as an inlay tablet.

Figure 3E shows a tablet made of different layers of different pharmaceutical compositions. Some or all of the non-touching layers may have the same pharmaceutical composition as shown in the figure or not. This is commonly known as a multilayer tablet.

Figure 4 shows different shapes of tablet bases.

Figure 4A represents a round tablet.

Figure 4B represents an oblong tablet.

Figure 4C represents an oval tablet.

Figure 4D represents a square tablet.

Figure 4E represents a rectangle tablet.

Figure 4F represents a diamond tablet.

Figure 4G represents a 3-sided tablet.

Figure 4H represents a 5-sided tablet.

Figure 4I represents a 6-sided tablet.

Figure 4J represents a 7-sided tablet

Figure 4K represents an 8-sided tablet.

Figures 5A to 5J show the dissolution profile of several example compositions using the following dissolution method: the tablets to be measured are placed in a vessel with 800 mL of 0.1 M HCI aqueous solution stirred with paddles at 100 rpm, the concentration of ranolazine in the aqueous solution is measured at different times until 1 h. Afterwards 100 mL of 0.51 M Na3P0 ₄ solution are added and the pH is adjusted to pH 6.8 using 2.0 M HCI or 2.0 M NaOH. The samples are taken at different times and the ranolazine content is measured using the area obtained with a HPLC apparatus with UV detector and compared to a reference.

The reference is prepared by dissolving the full amount of ranolazine present in the tablet to be measured in the same amount of aqueous dissolution media of the sample. If it is desired, the reference can be prepared by using the same ranolazine to aqueous dissolution media ratio found in the measurement vessel.

Figure 5A shows the dissolution profile of the marketed 1000 mg Ranexa® tablets.

Figure 5B shows the dissolution profile of the composition obtained in Example 31

Figure 5C shows the dissolution profile of the composition obtained in Example 33

Figure 5D shows the dissolution profile of the composition obtained in Example 35

Figure 5E shows the dissolution profile of the composition obtained in Example 37 Figure 5F shows the dissolution profile of the composition obtained in Example 44

Figure 5G shows the dissolution profile of the composition obtained in Example 48

Figure 5H shows the dissolution profile of the composition obtained in Example 55

Figure 51 shows the dissolution profile of the composition obtained in Example 61

Figure 5J is the combination of figures 5A to 5I.

Figure 6 shows the dissolution profiles of Examples 107, 110, 111 , 112, 113, 114, 115, 116, 117, 118, 119 and a tablet of Ranexa® 750 mg using the same methodology used in example 5.

Detailed description of the invention

The inventors have found that the present invention allows preparing extended release tablets showing different ranolazine release rates thanks to the possible modulation by means of the relative amount of ranolazine and the content of release retardant agent in each of the pharmaceutical compositions used in the different compression cycles. For instance, when the fraction with more release retardant agent represents a larger portion of the tablet, greater extended release effect is found.

Tablets can have different shapes, which are determined by the shapes of the die and punches. In Figure 4 different shapes for the bases of the tablets are depicted, but any other shape may be suitable for the present invention. Some embodiments of the invention are depicted in Figure 3, for such embodiments round shape for the tablet bases has been selected, but any other form (among the ones of Figure 4 or any other) may be used within the scope of the invention.

The bases and lateral surface of the embodiments in Figure 3 are flat, but may have different form such as curved, convex, concave, wavy or any other or combinations thereof.

It is known by the skilled in the art that the dissolution of a drug in a tablet depends on the surface to volume ratio and that shapes with a higher surface to volume ratio tend to increase the dissolution rate, while shapes with lower surface to volume ratio tend to decrease it. For instance, an oblong tablet has a higher surface to volume ratio than a round tablet. Depending of the desired dissolution rate one specific tablet shape would be preferred.

The viscosity is measured according to the European Pharmacopeia 8 ^th edition 2015 (8.5).

Embodiment 1 is a multiple compressed tablet obtainable by a process comprising at least two compression cycles, wherein

- in each of the compression cycles a pharmaceutical composition, comprising one or more pharmaceutically acceptable excipients, is used,

- at least one of such pharmaceutical compositions comprises one or more release retardant agents,

- at least two of such pharmaceutical compositions comprise ranolazine and have a different quantitative and/or qualitative composition,

wherein:

I. the one or more release retardant agents comprises at least one polyalkylene oxide and/or

II. at least one of such pharmaceutical compositions comprises at least one thickening agent.

Embodiment 2 is the multiple compressed tablet according to embodiment 1 , wherein at least one release retardant agent is a pH independent release retardant agent.

Embodiment 3 is the multiple compressed tablet according to embodiment 2, wherein all of the release retardant agents are pH independent release retardant agents.

Embodiment 4 is the multiple compressed tablet according to any of the preceding embodiments, which is substantially free from pH dependent release retardant agents.

Embodiment 5 is the multiple compressed tablet according to any of the preceding embodiments, wherein the release retardant agent is a pH independent release retardant polymer.

Embodiment 6 is the multiple compressed tablet according to embodiment 5, wherein the pH independent release retardant polymer is selected from: hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, poly(meth)acrylate esters with functional group, polyalkylene oxide and mixtures thereof.

Embodiment 7 is the multiple compressed tablet according to embodiment 5, wherein the pH independent release retardant polymer is selected from: hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone poly(meth)acrylate esters with functional group, and neutral poly(meth)acrylate esters.

Embodiment 8 is the multiple compressed tablet according to embodiment 6, wherein the pH independent release retardant polymer is selected from hydroxypropyl methylcellulose, polyalkylene oxide and mixtures thereof.

Embodiment 9 is the multiple compressed tablet according to embodiment 8, wherein the pH independent release retardant polymer is polyalkylene oxide.

Embodiment 10 is the multiple compressed tablet according to embodiment 8, wherein the pH independent release retardant polymer is hydroxypropyl methylcellulose.

Embodiment 11 is the multiple compressed tablet according to embodiment 7 wherein the pH independent release retardant polymer is a poly(meth)acrylate esters with functional group is preferably Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) such as commercially available Eudragits RS 100, RL 100 or RSPO.

Embodiment 12 is the multiple compressed tablet according to embodiments 6 to 8 or 10, wherein the pH independent release retardant polymer has a viscosity between 20000 and 300000 mPa-s at 20 °C measured in a 2% (w/v) aqueous solution of the pH independent release retardant polymer.

Embodiment 13 is the multiple compressed tablet according to embodiment 12, wherein the pH independent release retardant polymer has a viscosity between 30000 and 150000 mPa-s at 20 °C measured in a 2% (w/v) aqueous solution of the pH independent release retardant polymer.

Embodiment 14 is the multiple compressed tablet according to embodiment 13, wherein the pH independent release retardant polymer has a viscosity between 75000 and 140000 mPa-s at 20 °C measured in a 2% (w/v) aqueous solution of the pH independent release retardant polymer.

Embodiment 15 is the multiple compressed tablet according to embodiments 6 to 9, wherein the pH independent release retardant polymer includes a polyalkylene oxide selected from polyethylene oxide, polypropylene oxide, polyisopropylene oxide and polyisobutylene oxide, the copolymers and mixtures thereof.

Embodiment 16 is the multiple compressed tablet according to embodiment 15, wherein the polyalkylene oxide has an average molecular weight (Mw) of from 900000 to 15000000.

Embodiment 17 is the multiple compressed tablet according to embodiment 16, wherein the polyalkylene oxides has an average molecular weight (Mw) selected form 900000, 1000000, 2000000, 4000000, 5000000 or 7000000.

Embodiment 18 is the multiple compressed tablet according to any of the embodiments 15 to 17, wherein the polyalkylene oxide is polyethylene oxide.

Embodiment 19 is the multiple compressed tablet according to embodiment 6, wherein the pH independent release retardant polymer includes hydroxypropyl cellulose having a molecular weight between 850000 and 1150000.

Embodiment 20 is the multiple compressed tablet according to embodiment 6, wherein the pH independent release retardant polymer includes methylcellulose with a viscosity between 1000 mPa-s measured in a 2% w/v aqueous solution.

Embodiment 21 is the multiple compressed tablet according to embodiment 6, wherein the pH independent release retardant polymer includes polyvinylpyrrolidone having a dynamic viscosity higher than 3.0 mPa-s and lower than 60.0 mPa-s measured in a 5% w/v solution in ethanol (95%).

Embodiment 22 is the multiple compressed tablet according to embodiment 6, wherein the pH independent release retardant polymer includes neutral poly(meth)acrylate esters which is poly(ethyl acrylate, methyl methacrylate) 2:1.

Embodiment 23 is the multiple compressed tablet according to any of the preceding embodiments, wherein at least one of the pharmaceutical compositions which comprise ranolazine used in the compression cycles comprises at least one release retardant agent.

Embodiment 24 is the multiple compressed tablet according to any of the preceding embodiments, wherein ranolazine is the only drug.

Embodiment 25 is the multiple compressed tablet according to any of the preceding embodiments, wherein the total ranolazine content is higher than 50% with respect to the total weight of the tablet.

Embodiment 26 is the multiple compressed tablet according to any of the preceding embodiments, wherein the total ranolazine content is higher than 65% with respect to the total weight of the tablet.

Embodiment 27 is the multiple compressed tablet according to any of the preceding embodiments, wherein the total ranolazine content is higher than 70% with respect to the total weight of the tablet.

Embodiment 28 is the multiple compressed tablet according to any of the preceding embodiments, wherein at least one of the pharmaceutical compositions used in the compression cycles is used in more than one compression cycle.

Embodiment 29 is the multiple compressed tablet according to embodiment 28, in which only two different pharmaceutical compositions are used in the compression cycles.

Embodiment 30 is the multiple compressed tablet according to any of the previous embodiments which is a bilayer tablet, a trilayer tablet, a press-coated tablet, an inlay tablet or a multilayer tablet.

Embodiment 31 is the multiple compressed tablet according to embodiment 30, which is a bilayer tablet.

Embodiment 32 is the multiple compressed tablet according to embodiment 30, which is a trilayer tablet.

Embodiment 33 is the trilayer tablet according to embodiment 32, wherein the two outer layers are obtained using the same pharmaceutical composition

Embodiment 34 is the trilayer tablet according to embodiments 32 or 33, wherein in the preparation of the two outer layers, substantially the same amount of a pharmaceutical composition is used in the two layers.

Embodiment 35 is the multiple compressed tablet according to embodiment 30, which is a press- coated tablet. Embodiment 36 is the press-coated tablet according to embodiment 35, wherein in the compression cycles used to prepare the two outer parts, the same pharmaceutical composition is used in each compression cycle.

Embodiment 37 is the press-coated tablet according to embodiments 35 or 36, wherein in the compression cycles used to prepare the two outer parts, substantially the same amount of a pharmaceutical composition is used in each compression cycle.

Embodiment 38 is the multiple compressed tablet according to embodiment 30, which is an inlay tablet.

Embodiment 39 is the multiple compressed tablet according to embodiment 30, which is a multilayer tablet.

Embodiment 40 is the multiple compressed tablet according to any of embodiments 30 to 39 wherein at least one of the outer pharmaceutical compositions comprises at least one release retardant agent.

Embodiment 41 is the multiple compressed tablet according to embodiment 30 which is a trilayer tablet wherein the outer pharmaceutical composition or compositions comprises at least one release retardant agent.

Embodiment 44 is the press-coated tablet according to any of the embodiments embodiment 36 or 37 wherein the outer pharmaceutical composition comprises at least one release retardant agent.

Embodiment 43 is the inlay tablet according to embodiment 38 wherein the outer pharmaceutical composition comprises at least one release retardant agent.

Embodiment 44 is the multiple compressed tablet according to any of the embodiments 30 to 43, wherein the inner or intermediate pharmaceutical composition comprises less than 50% of the total ranolazine content.

Embodiment 45 is the multiple compressed tablet according to any of embodiments 30 to 44 wherein at least one of the outer pharmaceutical compositions comprises at least one release retardant agent and at least part of the ranolazine content.

Embodiment 46 is the multiple compressed tablet according to any of embodiments 30 or 45, wherein the inner pharmaceutical composition is film-coated or sugar coated.

Embodiment 47 is the multiple compressed tablet according to any of the preceding embodiments, wherein the tablet is film-coated or sugar coated.

Embodiment 48 is a multiple compressed tablet according to any of the preceding embodiments for use in the treatment of angina pectoris.

Embodiment 49 is the multiple compressed tablet according to any of the embodiments 1 to 48, which has been prepared at room temperature, except for the optional drying steps.

Embodiment 50 is the multiple compressed tablet according to the embodiment 49, wherein the temperature is between 15 and 30°C.

Embodiment 51 is the multiple compressed tablet according to the embodiment 50, wherein the temperature is between 18 and 24°C.

Embodiment 52 is the multiple compressed tablet according to any of the previous embodiments wherein the thickening agent is selected from polyvinyl acetate, ethylcellulose, hydroxyethyl cellulose or hydroxyethylmethyl cellulose.

Embodiment 53 is the multiple compressed tablet according to any of the previous embodiments wherein at least one pharmaceutical composition further comprises a pharmaceutically acceptable acid.

Embodiment 54 is the multiple compressed tablet according to Embodiment 53 wherein the pharmaceutically acceptable acids is selected from tartaric acid, citric acid, gluconic acid, D-lactic acid (including D-, L- and D/L-), oxalic acid, ascorbic acid, boric acid, phosphoric acid (including anhydrous and hemihydrate), malic acid, maleic acid, malonic acid, succinic acid, glutaric acid, glutamic acid, aspartic acid, NaH2P0 ₄ and fumaric acid.

Embodiment 55 is the multiple compressed tablet according to any of the previous embodiments which comprises at least one polyalkylene oxide.

Embodiment 56 is the multiple compressed tablet according to any of the previous embodiments which comprises at least one thickening agent.

Embodiment 57 is the multiple compressed tablet according to any of the previous embodiments which comprises at least one polyalkylene oxide and at least one thickening agent.

Embodiment 58 is a process for the preparation of the multiple compressed tablet according to any of the preceding embodiments comprising:

a) independently mixing all the components of all the pharmaceutical compositions,

b) optionally tableting one or more pharmaceutical compositions,

c) either

charging and optionally precompressing a pharmaceutical composition different from the one used in the previous cycle on the result of the previous cycle, or ii. placing a tablet of step b), prepared using a pharmaceutical composition different from the one used in the previous cycle, on the result of the previous cycle, d) repeating step c) at least one time,

e) compressing the result of the previous step. Embodiment 59 is the process according to embodiment 58 for the preparation of a bilayer tablet according to embodiment 31 , comprising:

a) independently mixing all the components of two pharmaceutical compositions,

b) charging and at least precompressing one pharmaceutical composition in the die of a tabletting machine,

c) charging the other pharmaceutical composition on the result of step b), and

d) compressing the result of step c).

Embodiment 60 is the process according to embodiment 58 for the preparation of trilayer tablets according to any of the embodiments 32 to 34comprising:

a) independently mixing all the components of all the pharmaceutical compositions,

b) charging and at least precompressing one pharmaceutical composition in the die of a tabletting machine,

c) charging and at least precompressing another pharmaceutical composition on the result of step b),

d) charging

i. the pharmaceutical composition used in step b), or

ii. a pharmaceutical composition different from the one used in steps b) and c) on the result of step c), and

e) compressing the result of step d).

Embodiment 61 is the process according to embodiment 58 for the preparation of a press-coated tablet according to any of the embodiments 35 to 37 comprising:

a) independently mixing all the components of all the pharmaceutical compositions,

b) tableting one pharmaceutical composition,

c) charging and at least precompressing another pharmaceutical composition in the die of a tabletting machine,

d) placing the tablet of step b) on the result of step c),

e) charging

i. the pharmaceutical composition used in step c), or

ii. a pharmaceutical composition different from the one used in steps b) or c)

on the result of step d), and

f) compressing the result of step e).

Embodiment 62 is the process according to embodiment 58 for the preparation of an inlay tablet according to embodiment 38 comprising: a) independently mixing all the components of two pharmaceutical compositions,

b) tableting one pharmaceutical composition,

c) charging and at least precompressing the other pharmaceutical composition in the die of a tabletting machine,

d) placing the tablet of step b) on the result of step c), and

e) compressing the result of step d).

Embodiment 63 is the process according to embodiment 58 for the preparation of an inlay tablet according to embodiment 38 comprising:

a) independently mixing all the components of two pharmaceutical compositions,

b) tableting one pharmaceutical composition,

c) placing the tablet of step b) on the die of a tabletting machine,

d) charging the other pharmaceutical composition in the result of step c), and

e) compressing the result of step d).

Embodiment 64 is the process according to embodiment 58 for the preparation of a multilayer tablet according to embodiment 38 comprising:

a) independently mixing all the components of all the pharmaceutical compositions,

b) charging and at least precompressing one pharmaceutical composition in the die of a tabletting machine,

c) charging and at least precompressing a pharmaceutical composition different from that used in the previous cycle on the result of the previous cycle,

d) repeating step c) as many times as desired, and

e) compressing the result of step d).

Embodiment 65 is the process according to any of the embodiments 58 to 64 further comprising a film coating or a sugar coating step.

Embodiment 66 is the process according to any of the embodiments 58 to 65, wherein all the steps, except for the optional drying, are performed at room temperature.

Embodiment 67 is the process according to the embodiment 66, wherein all the steps, except for the optional drying, are performed between 15 and 30°C.

Embodiment 68 is the process according to the embodiment 67 wherein all the steps, except for the optional drying, are performed between 18 and 24°C.

Embodiment 69 is the multiple compressed tablet according to any of the claims 1 to 57 wherein the excipients are used in solid form until the optional water is added.

Embodiment 70 is the multiple compressed tablet according to any of the claims 1 to 57 or 69 which comprise 375, 500, 750 or 1000 mg ranolazine.

The inventors have also found that the present invention allows preparing extended release tablets showing different ranolazine release rates thanks to the possible modulation by means of the relative amount of ranolazine and the content of the pharmaceutically acceptable acid, the release retardant agent and the thickening agent.

Embodiment 71 is a ranolazine extended release monolithic tablet which comprises one or more pharmaceutically acceptable acid and one or more of the following:

- one or more release retardant agent

- one or more thickening agent

Embodiment 72 is the ranolazine extended release monolithic tablet according to embodiment 71 , wherein the release retardant agent is a pH independent release retardant agent.

Embodiment 73 is the ranolazine extended release monolithic tablet according to embodiment 72, wherein all of the release retardant agents are pH independent release retardant agents.

Embodiment 74 is the ranolazine extended release monolithic tablet according to any of the preceding embodiments, which is substantially free from pH dependent release retardant agents.

Embodiment 75 is the ranolazine extended release monolithic tablet according to any of the preceding embodiments, wherein the release retardant agent is a pH independent release retardant polymer.

Embodiment 76 is the ranolazine extended release monolithic tablet according to embodiment 75, wherein the pH independent release retardant polymer is selected from: hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, poly(meth)acrylate esters with functional group, polyalkylene oxide and mixtures thereof.

Embodiment 77 is the ranolazine extended release monolithic tablet according to embodiment 75, wherein the pH independent release retardant polymer is selected from: hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone poly(meth)acrylate esters with functional group, and neutral poly(meth)acrylate esters.

Embodiment 78 is the ranolazine extended release monolithic tablet according to embodiment 76, wherein the pH independent release retardant polymer is selected from hydroxypropyl methylcellulose, polyalkylene oxide and mixtures thereof.

Embodiment 79 is the ranolazine extended release monolithic tablet according to embodiment 78, wherein the pH independent release retardant polymer is polyalkylene oxide.

Embodiment 80 is the ranolazine extended release monolithic tablet according to embodiment 78, wherein the pH independent release retardant polymer is hydroxypropyl methylcellulose.

Embodiment 81 is the ranolazine extended release monolithic tablet according to embodiment 77 wherein the pH independent release retardant polymer is a poly(meth)acrylate esters with functional group, is preferably Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) such as commercially available Eudragits RS 100, RL 100 or RSPO.

Embodiment 82 is the ranolazine extended release monolithic tablet according to embodiments 6 to 78 or 80, wherein the pH independent release retardant polymer has a viscosity between 20000 and 300000 mPa-s at 20 °C measured in a 2% (w/v) aqueous solution of the pH independent release retardant polymer.

Embodiment 83 is the ranolazine extended release monolithic tablet according to embodiment 82, wherein the pH independent release retardant polymer has a viscosity between 30000 and 150000 mPa-s at 20 °C measured in a 2% (w/v) aqueous solution of the pH independent release retardant polymer.

Embodiment 84 is the ranolazine extended release monolithic tablet according to embodiment 83, wherein the pH independent release retardant polymer has a viscosity between 75000 and 140000 mPa-s at 20 °C measured in a 2% (w/v) aqueous solution of the pH independent release retardant polymer.

Embodiment 85 is the ranolazine extended release monolithic tablet according to embodiments 76 to 79, wherein the pH independent release retardant polymer includes a polyalkylene oxide selected from polyethylene oxide, polypropylene oxide, polyisopropylene oxide and polyisobutylene oxide, the copolymers and mixtures thereof.

Embodiment 86 is the ranolazine extended release monolithic tablet according to embodiment 85, wherein the polyalkylene oxide has an average molecular weight (Mw) of from 900000 to 15000000.

Embodiment 87 is the ranolazine extended release monolithic tablet according to embodiment 86, wherein the polyalkylene oxides has an average molecular weight (Mw) selected form 900000, 1000000, 2000000, 4000000, 5000000 or 7000000.

Embodiment 88 is the ranolazine extended release monolithic tablet according to any of the embodiments 85 to 87, wherein the polyalkylene oxide is polyethylene oxide.

Embodiment 89 is the ranolazine extended release monolithic tablet according to embodiment 76, wherein the pH independent release retardant polymer includes hydroxypropyl cellulose having a molecular weight between 850000 and 1150000.

Embodiment 90 is the ranolazine extended release monolithic tablet according to embodiment 76, wherein the pH independent release retardant polymer includes methylcellulose with a viscosity between 1000 mPa-s measured in a 2% w/v aqueous solution.

Embodiment 91 is the ranolazine extended release monolithic tablet according to embodiment 76, wherein the pH independent release retardant polymer includes polyvinylpyrrolidone having a dynamic viscosity higher than 3.0 mPa-s and lower than 60.0 mPa-s measured in a 5% w/v solution in ethanol (95%).

Embodiment 92 is the ranolazine extended release monolithic tablet according to embodiment 76, wherein the pH independent release retardant polymer includes neutral poly(meth)acrylate esters which is poly(ethyl acrylate, methyl methacrylate) 2:1.

Embodiment 93 is the ranolazine extended release monolithic tablet according to any of the preceding embodiments, wherein ranolazine is the only drug.

Embodiment 94 is the ranolazine extended release monolithic tablet according to any of the preceding embodiments, wherein the total ranolazine content is higher than 50% with respect to the total weight of the tablet.

Embodiment 95 is the ranolazine extended release monolithic tablet according to any of the preceding embodiments, wherein the total ranolazine content is higher than 65% with respect to the total weight of the tablet.

Embodiment 96 is the ranolazine extended release monolithic tablet according to any of the preceding embodiments, wherein the total ranolazine content is higher than 70% with respect to the total weight of the tablet.

Embodiment 97 is the ranolazine extended release monolithic tablet according to any of the preceding embodiments, wherein the tablet is film-coated or sugar coated.

Embodiment 98 is a ranolazine extended release monolithic tablet to any of the preceding embodiments for use in the treatment of angina pectoris.

Embodiment 99 is the ranolazine extended release monolithic tablet according to any of the preceding embodiments which has been prepared at room temperature, except for the optional drying steps.

Embodiment 100 is the ranolazine extended release monolithic tablet according to the embodiment 49, wherein the temperature is between 15 and 30°C.

Embodiment 101 is the ranolazine extended release monolithic tablet according to the embodiment 50, wherein the temperature is between 18 and 24°C.

Embodiment 102 is the ranolazine extended release monolithic tablet according to any of the previous embodiments wherein the thickening agent is selected from polyvinyl acetate, ethylcellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose or poloxamers. Embodiment 103 is the ranolazine extended release monolithic tablet according to any of the previous claims wherein the pharmaceutically acceptable acids is selected from tartaric acid, citric acid, gluconic acid, D-lactic acid (including D-, L- and D/L-), oxalic acid, ascorbic acid, boric acid, phosphoric acid (including anhydrous and hemihydrate), malic acid, maleic acid, malonic acid, succinic acid, glutaric acid, glutamic acid, aspartic acid, NaH2P0 ₄ and fumaric acid.

Embodiment 104 is a process for the preparation of the ranolazine extended release monolithic tablet according to the invention comprising:

a) mix all the components of the intragranular fraction,

b) dry or wet granulate,

c) add the extragranular fraction,

d) compress the resulting mixtures.

Embodiment 105 is a process for the preparation of the ranolazine extended release monolithic tablet according to the invention comprising:

a) mix all the components,

b) compress the resulting mixtures.

Embodiment 106 is the process according to any of the embodiments 104 or 105 further comprising a film coating or a sugar coating step.

Embodiment 107 is the process according to any of the embodiments 104 to 106, wherein all the steps, except for the optional drying, are performed at room temperature.

Embodiment 108 is the process according to the embodiment 107, wherein all the steps, except for the optional drying, are performed between 15 and 30°C.

Embodiment 109 is the process according to the embodiment 108 wherein all the steps, except for the optional drying, are performed between 18 and 24°C.

Embodiment 110 is the ranolazine extended release monolithic tablet according to any of the Embodiments 1 to 103 which includes one or more release retardant agents selected from:

- a polyalkylene oxide selected from polyethylene oxide, polypropylene oxide, polyisopropylene oxide and polyisobutylene oxide, the copolymers and mixtures thereof and/or

- a poly(meth)acrylate esters with functional group which is Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) such as commercially available Eudragits RS 100, RL 100 or RSPO.

The following examples are illustrative and are not considered to limit the scope of the invention. Examples

Examples of multiple compressed tablets Manufacturing process examples

Manufacturing of the inner (11 to 110), intermediate (11 to 110) and outer (01 to 015) pharmaceutical compositions

All the components of the inner, intermediate or outer pharmaceutical compositions listed above water in the following tables (the intra-granular components) are mixed and granulated with binder aqueous solution (i.e. a solution of the binder in the required amount of water) in a high shear mixer granulator. The resulting granules are dried in a fluid bed dryer and the components listed below water in the following tables (the extra-granular components) are added to the mixture of granules and mixed in a blender to obtain the corresponding fraction.

Alternatively, the inner and/or the outer pharmaceutical compositions can be prepared using compactation, dry granulation or can be compressed directly.

Except for the drying, all the steps are performed at room temperature (18-24°C).

Example M1 (bilaver)

The desired amount of the inner pharmaceutical compositions is charged inside of the die of a bi- layer rotary tabletting machine and precompressed with a force of 1.0 kN. Then the desired amount of the outer pharmaceutical compositions is charged inside of the die on the previous composition, precompressed with a force of 1.0 kN and finally compressed with a force of 18 kN. Example M2 (trilaver)

Part of the desired amount of the outer pharmaceutical compositions is charged inside of the die of a three-layer rotary tabletting machine and precompressed with a force of 0.5 kN. Then the desired amount of the intermediate pharmaceutical compositions is charged inside of the die on the previous composition and precompressed with a force of 1.0 kN. Finally, the remaining part of the outer pharmaceutical compositions is charged inside of the die on the previous composition and compressed with a force of 18 kN.

In the present example, the amount of the outer pharmaceutical composition is divided in two equal parts and used to prepare the first and third layer in the tablet. Example M3 (multilayer tablets)

Part of the desired amount of the outer pharmaceutical compositions is charged inside of the die of a multil-layer rotary tabletting machine and precompressed with a force of 0.5 kN. Then part of the desired amount of the inner pharmaceutical compositions is charged inside of the die and precompressed with a force of 1.0 kN on the previous composition. The process is repeated as many times as layers desired. Finally, the mixture is compressed with a force of 18 kN.

In the specific examples that refer to Example M3 5-layer tablets are prepared with the following pattern: outer, intermediate, outer, intermediate and outer pharmaceutical compositions. Only one intermediate and one outer pharmaceutical composition were used in the present examples.

Example M4 (press coated tablet)

The desired amount of the inner pharmaceutical compositions is tabletted in the desired manner.

Part of the desired amount of the outer pharmaceutical compositions is charged inside of the die of a rotary tabletting machine and precompressed with a force of 0.5 kN. The inner tablet is placed partially sunken in the previously placed outer pharmaceutical compositions and precompressed with a force of 0.5 kN. Then the rest of the outer pharmaceutical compositions is charged inside of the die and then compressed with a force from 18 kN.

In the present example, the amount of the outer pharmaceutical composition is divided in two equal parts that are charged in the die in the two compression cycles wherein an outer pharmaceutical composition is charged.

Example M5 (inlay tablet)

The desired amount of the inner pharmaceutical compositions is tabletted in the desired manner.

The desired amount of the outer pharmaceutical compositions is charged inside of the die of a rotary tabletting machine and precompressed with a force of 0.5 kN. The inner tablet is partially sunken in the previously placed outer pharmaceutical compositions and precompressed with a force of 0.5 kN. Finally, the mixture is compressed with a force of 18 kN .

In any of the Examples M1 to M5, the tablets obtained might optionally be film or sugar coated.

In the following examples, inner, intermediate and outer pharmaceutical compositions have been obtained by wet granulation as described above, except for the cases wherein no water is indicated in the quantitative composition. In these later cases mixing and direct compression was carried out. Where the compositions include a coating (such as Opadry pink or Opadry AMB white), this coating has been applied to the tablet by a conventional coating process using the amounts of water specified in the following table. Quantitative outer pharmaceutical compositions examples:

Ingredient 01(%) 02(%) 03(%) 04(%) 05(%) 06(%) 07(%) 08(%) 09(%) O10(%) 011(%) 012(%) 013(%) 014(%) 01

Ranolazine 78.00 69.00 73.00 85.00 77.00 69.50 43.64 43.80 43.71 78.21 85.37 70.67 69.26 70.05 7

Hypromellose K100M Premium 3.35 5.75 6.10 2.00 3.35 5.70 3.35 2.07 5.87 5.76 5.82

Hypromellose K100 LVCR 3.35 5.75 6.10 2.00 2.35 5.70 3.35 2.07 5.87 5.76 5.82

Hypromellose 2910 E5 - - - - - - 1.09 1.06 1.08 2.23 2.44 2.36 2.31 2.34

Carmellose Sodium 9.92 9.72 9.83

Eudragit RSPO** - - - - - - 13.09 13.02 13.11 - - - - -

Polyvinyl acetate 2.49 - - - 2.50 - - - - - - - - -

Ethylcellulose Std 100P Premium - 12.34 - - - 10.00 13.09 13.02 13.11 - - - - -

Hydroxyethyl cellulose QP 15000 10.41

Hydroxyethylmethyl cellulose

2.98

(Culminal MHEC 8000)

Citric acid 2.90 7.27 7.32 7.26

Tartaric acid 1.94 5.82 5.82 5.78

Water* 0.26 0.48 0.33 0.26 0.25 0.48 QS QS QS 0.26 0.26 0.48 0.48 0.48

Polyethylene oxide WSR-303 8.90 3.00 4.00 8.00 3.00 10.18 10.14 10.15 8.94 4.02 1.06 3.03 1.93

Tartaric acid 2.91 2.88 2.89

Aerosil 200** 1.12 1.39 1.46 1.22 1.11 1.39 0.73 0.75 0.74 1.12 1.22 1.41 1.39 1.40

Sodium stearyl fumarate 2.79 2.77 2.93 2.80 2.79 2.77 2.79 2.80 2.83 2.77 2.80

Magnesium stearate 2.18 2.19 2.15

* mg(water)/mg(ranolazine); ** Hydrophilic fumed silica with specific surface area of 200 m ² /g. ** ethyl acrylate, methyl methacrylate and trimethylammonioet methacrylate copolymer in an aproximate ratio of. 1 :2:0.1.

Quantitative inner or intermediate pharmaceutical compositions examples:

11 I2 I3 I4 I5 I6 I7 I8 I9 no 111 112 113 114 115 116 1

Ingredient

(%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (

Ranolazine 69.69 69.69 69.69 69.69 69.69 69.69 67.87 67.57 67.57 67.50 69.70 69.70 69.70 69.77 69.44 6

Microcrystalline cellulose 102 14.29 14.29 12.29 12.29 11.29 12.29 85.00 12.22 13.85 13.85 11.00 12.47 11.00 12.00 14.42 14.79 1

Hypromellose K100M Premium 2.00 2.00 3.00 2.00 4.07

Sodium starch glycolate 2.44 2.44 2.44 2.44 2.44 2.44 14.00 2.38 2.36 2.36 5.60 2.36 2.40 2.33 2.33 2.32

Polyvinylpyrrolidone K25 3.83 3.72

Polyvinylpyrrolidone K30 0.00 3.83 3.83 3.83 3.83 3.83 3.73 3.72 3.80 3.80 3.80 3.80 3.72 3.72

Polyvinyl acetate 2.00

Ethylcellulose Std 100P Premium 3.43

Hydroxyethyl cellulose QP 15000 2.50

Water* 0.50 0.50 0.50 0.40 0.40 0.50 0.40 0.40 0.40 0.50 0.40 0.40 0.50 0.67 0.67

Hypromellose K100 LVCR 6.97 6.97 6.97 6.97 6.97 6.97 - 6.79 6.76 6.76 6.90 6.90 6.90 6.90 6.98 6.94

Polyethylene oxide WSR-303 3.04 3.04 2.43

Aerosil 200** 0.93 0.92 0.92 0.92 0.92 0.92 0.90 0.90 0.90 0.92 0.92 0.92 0.92 0.93 0.97

Sodium stearyl fumarate 1.86 1.86 1.86 1.86 1.86 1.86 1.00 2.04 1.80 1.80 0.92 0.92 0.92 0.92

Magnesium stearate - - - - - - - - - - - - - - 1.86 1.81

* mg(water)/mg(ranolazine); ** Hydrophilic fumed silica with specific surface area of 200 m ² /g.

Tablet examples (amounts in mg/tablet):

Inner/intermediate pharmaceutical

Outer pharmaceutical compositions manufacturing

Ex compositions

process amount example ranolazine amount example ranolazine

1 724.64 02 500.00 358.68 112 250.00 M3

2 769.23 01 600.00 222.22 111 150.00 M3

3 324.68 05 250.00 358.68 113 250.00 M2

4 416.67 01 325.00 251.08 112 175.00 M5

5 1159.42 02 800.00 296.30 111 200.00 M1

6 273.97 03 200.00 251.08 112 175.00 M1

7 684.93 03 500.00 180.00 I7 0.00 M4

8 543.48 02 375.00 179.34 114 125.00 M2

9 512.82 01 400.00 148.15 111 100.00 M4

10 719.42 06 500.00 358.68 113 250.00 M2

11 384.62 01 300.00 111.11 111 75.00 M5

12 821.92 03 600.00 573.89 112 400.00 M4

13 779.22 05 600.00 215.21 112 150.00 M3

14 724.64 02 500.00 370.37 111 250.00 M4

15 320.51 01 250.00 370.37 111 250.00 M1

16 470.59 04 400.00 143.47 114 100.00 M1

17 431.65 06 300.00 107.60 114 75.00 M2

18 688.41 02 475.00 35.87 112 25.00 M2

19 647.06 04 550.00 286.94 113 200.00 M1

20 769.23 01 600.00 222.22 111 150.00 M4

21 384.62 01 300.00 286.94 114 200.00 M3

22 382.35 04 325.00 251.08 113 175.00 M5

23 519.48 05 400.00 502.15 113 350.00 M4*

24 617.65 04 525.00 322.81 113 225.00 M3**

25 616.44 03 450.00 430.42 112 300.00 M4 ^#

26 1375.00 07 600.00 215.00 115 150.00 M1

27 1598.00 08 700.00 72.00 116 50.00 M1

28 1487.00 09 650.00 143.00 117 100.00 M1

29 1598.00 08 700.00 72.50 117 50.00 M1

30 1487.00 09 650.00 216.00 116 150.00 M1

31 895.00 O10 700.00 442.00 I8 300.00 M2

32 895.00 O10 700.00 442.00 I8 300.00 M1

33 820.00 011 700.00 442.00 I8 300.00 M2

34 820.00 011 700.00 442.00 I8 300.00 M1

35 1132.00 012 800.00 296.00 I9 200.00 M1

36 1132.00 012 800.00 296.00 I9 200.00 M2

37 1155.00 013 800.00 296.00 I9 200.00 M1

* The tablets are further coated with 42.00 mg of Opadry pink using 238.00 mg of water per tablet.

** The tablets are further coated with 141.00 mg of Opadry AMB white using 800 mg of water per tablet The tablets are further coated with 43.00 mg of Opadry pink using 240.00 mg of water per tablet. Inner/intermediate pharmaceutical

Outer pharmaceutical compositions manufactur

Ex compositions

ing process amount example ranolazine amount example ranolazine

38 1155.00 013 800.00 296.00 I9 200.00 M2

39 895.00 O10 700.00 442.00 I8 300.00 M4

40 999.80 015 700.00 442.00 I8 300.00 M5

41 857.00 015 600.00 589.33 I8 400.00 M4

42 831.07 O10 650.00 515.67 I8 350.00 M5

43 351.43 011 300.00 110.50 I8 75.00 M1

44* 857.00 015 600.00 222.00 I9 300.00 M1

45 499.90 015 350.00 222.00 I9 150.00 M5

46 778.25 012 550.00 296.00 I9 200.00 M4

47 1082.81 013 750.00 370.00 I9 250.00 M1

48 1142.00 014 800.00 296.00 110 200.00 M2

49 ^# 1022.86 O10 800.00 287.00 I2 200.00 M4

50** 1142.00 014 800.00 287.00 I5 200.00 M2

51 395.36 011 337.50 53.81 I4 37.50 M5

52 321.4 015 225.00 222.00 I9 150.00 M1

53 856.50 014 600.00 573.97 I4 400.00 M3

54 495.25 012 350.00 215.24 I6 150.00 M3

55* 849.00 012 600.00 222.00 11 150.00 M1

56 974.53 013 675.00 107.62 I6 75.00 M3

57 575.36 O10 450.00 71.75 I6 50.00 M1

58 321.19 014 225.00 222.00 I9 150.00 M3

59 263.57 011 225.00 215.24 I6 150.00 M5

60* 1155.00 013 800.00 287.00 I2 200.00 M2

61* 866.25 013 600.00 222.00 I9 150.00 M4

62 767.14 O10 600.00 215.25 I2 150.00 M4

63 1427.50 014 1000.00 200.00 I7 0.00 M2

64 937.14 011 800.00 287.00 I3 200.00 M2

65 937.14 011 800.00 287.00 I2 200.00 M4

66 1833.18 07 800.00 287.23 117 200.00 M3

67 684.93 08 300.00 107.50 115 75.00 M5

68 916.59 07 400.00 143.33 115 100.00 M2

69 1601.46 09 700.00 432.03 116 300.00 M4

70 627.85 08 275.00 144.01 116 100.00 M2

71 1541 ,10 08 675,00 107,50 115 75,00 M3

72 1031 ,16 07 450,00 72,00 116 50,00 M1

73 513,70 08 225,00 215,42 117 150,00 M2

74 513,70 08 225,00 216,01 116 150,00 M1

75 1830,24 09 800,00 286,66 115 200,00 M1

* The tablets are further coated with 42.00 mg of Opadry pink using 238.00 mg of water per tablet.

The tablets are further coated with 43.00 mg of Opadry pink using 240.00 mg of water per tablet.

M The tablets are further coated with 44.00 mg of Opadry pink using 241.00 mg of water per tablet.

* The tablets are further coated with 32.00 mg of Opadry pink using 180.00 mg of water per tablet. Examples of monolithic tablets

All the components of the pharmaceutical, except if explicitly stated, composition listed above water in the following tables (the intra-granular components) are mixed and granulated with binder aqueous solution (i.e. a solution of the binder in the required amount of water) in a high shear mixer granulator.

The resulting granules are dried in a fluid bed dryer and the components listed below water in the following tables (the extra-granular components) are added to the mixture of granules and mixed in a blender to obtain the corresponding fraction.

Alternatively, the pharmaceutical composition can be prepared using compactation, dry granulation or can be compressed directly. Examples 109, 110, 112, 115 and 117 are prepared using dry granulation.

Except for the drying, all the steps are performed at room temperature (18-24°C).

In the following examples the pharmaceutical compositions have been obtained by wet granulation as described above, except for the cases wherein no water is indicated in the quantitative composition. In these later cases mixing and direct compression was carried out.

Where the compositions include a coating (such as Opadry pink or Opadry AMB white), this coating has been applied to the tablet by a conventional coating process using the amounts of water specified in the following table:

Composition Examples for monolithic tablets:

Ingredient E1(%) E2(%) E3(%) E4(%) E5(%) E6(%) E7(%) E8(%)

Ranolazine 68.11 69.02 70.05 67.06 69.50 65.22 68.18 68.18

Hypromellose K100M Premium 3.35 5.75 6.19 6.11 5.70 13.04 18.18 18.18

Hypromellose K100 LVCR 6.19 5.55 5.70

Hypromellose E5 2.61 2.73 2.73

Polyvinyl acetate 2.49

Ethylcellulose Std 100P Premium 12.34 10.00

Hydroxyethyl cellulose QP 15000 10.41

Hydroxyethylmethyl cellulose

4.51

(Culminal MHEC 8000)

Citric acid 3.33 2.77 1.04 3.64

Tartaric acid 2.98 3.11 1.94 3.48 3.64

Microcrystalline cellulose 102 2.61 2.73 2.73

Sodium starch glycolate 5.00

Polyvinylpyrrolidone K30 5.00

Sodium carboxymethylcellulose 2.35 6.96 1.82 1.82

Water* 0.26 0.48 0.33 0.48 0.48 0.48 0.48

Polyethylene oxide WSR-303 8.81 5.75 - 6.25 3.00 3.48 - -

Aerosil 200** 1.12 1.39 1.46 1.22 1.39 1.30 1.36 1.36

Sodium stearyl fumarate 2.79 2.77 2.93 2.80 2.77 1.30 1.36 1.36

* mg(water)/mg(ranolazine); ** Hydrophilic fumed silica with specific surface area of 200 m ² /g Ingredient E9(%) I≡10(%) l≡11(%) l≡12(%) 1≡13(%) I≡14(%) [≡15(%) E≡16(%) E≡17(%) E≡18(%) E≡19(%) [ Ξ20(%) 1≡21(%) E≡22(%)

Ranolazine 65.79 59.76 60.73 64.66 61.48 59.29 57.25 54.15 51.90 52.45 49.18 51.37 47.32 45.05

Microcrystalline cellulose 101

Lactose monohydrate 1.75 1.72 1.64 3.82 1.40 2.05

Eudragit RSPO 10.53 11.95 12.15 - - 11.86 - 14.44 13.84 - 13.11 - 12.62 16.22

Ethylcellulose 7cps 8.77 9.56 12.15 11.86 14.44 13.84 13.11 12.62 16.22

Hypromellose K100M Premium 5.17 4.92 1.58 4.58 4.20 4.11

Tartaric acid 7.02 7.97 6.48 10.34 9.84 6.32 11.45 7.22 4.15 12.59 5.25 12.33 5.05 4.80

Citric acid 6.37 4.05 4.74 5.78 5.54 6.56 2.05 6.31 6.01

Sodium carboxymethylcellullose

Aerosil 200** 0.86 0.82 0.76 0.70 0.68

Hypromellose E5 2.63 1.20 1.21 1.19 1.08 1.04 0.98 0.95 0.90

Water* QS QS QS QS QS QS QS QS QS

Citric Acid 5.17 9.84 11.45 12.59 12.33

Tartaric Acid 2.77 2.62 2.52 2.40

Hypromellose K100M Premium 5.17 4.92 4.58 4.20 4.11

Polyethylene Oxyde WR-303 3.45 3.28 3.05 4.15 6.99 6.56 6.85 10.09 6.01

Aerosil 200** 1.75 0.80 0.81 1.72 1.64 0.79 1.53 0.72 0.69 1.40 0.66 1.37 0.63 0.60

Lactose monohydrate 2.10 1.37

Sodium Stearyl Fumarate 1.75

Magnesium stearate 2.39 2.43 1.72 1.64 2.37 1.53 2.17 2.08 1.40 1.97 1.37 1.89 1.80

* mg(water)/mg(ranolazine); ** Hydrophilic fumed silica with specific surface area of 200 m ² /g. QS: Quantity Sufficient.

Monolithic Tablet Examples:

Example ranolazine amount Tablet weight Composition example

76 750 1087 E2

77 750 1100 E8*

78 500 719 E5

79 500 733 E7

80 1000 1449

81 375 535 E3

82 500 767 E6

83 500 733 E7 ^#

84 500 734 E1

85 750 1100 E7##

86 375 550 E7

87 1000 1467 E8

88 750 1150 E6*

89 750 1101 E1

90 500 733 E7##

91 500 714 E3

92 375 540 E5

93 500 714 E3*

94 750 1100 E8

95 750 1100 E7*

96 500 733 E8

97 500 714 E3 ^#

98 750 1100 E7

99 750 1118 E4

100 750 1100 E8

101 750 1150 E6*

102 750 1100

103 750 1100 _E8 ##

104 1000 1439 E5

105 1000 1449 E2

* The tablets are further coated with 42.00 mg of Opadry pink using 238.00 mg of water per tablet.

** The tablets are further coated with 141.00 mg of Opadry AMB white using 800 mg of water per tablet

^# The tablets are further coated with 43.00 mg of Opadry pink using 240.00 mg of water per tablet. ^m The tablets are further coated with 44.00 mg of Opadry pink using 241.00 mg of water per tablet, t The tablets are further coated with 32.00 mg of Opadry pink using 180.00 mg of water per tablet. Example ranolazine amount Tablet weight Composition example

106 750,00 1140,00 E9

107 750,00 1255,00 E10

108 750,00 1235,00 E11

109 750,00 1160,00 E12

110 750,00 1220,00 E13

111 750,00 1265,00 E14

112 750,00 1310,00 E15

113 750,00 1385,00 E16

114 750,00 1445,00 E17

115 750,00 1430,00 E18

116 750,00 1525,00 E19

117 750,00 1460,00 E20

118 750,00 1585,00 E21

119 750,00 1665,00 E22