WO2017103945A1

WO2017103945A1 - Pharmaceutical compositions

Info

Publication number: WO2017103945A1
Application number: PCT/IN2016/050443
Authority: WO
Inventors: Suresh Kumar THAMOTHARAN; Shubhrangshu Shekher SARKER; Srinivasan SERMADURAI; Selvakumar Ramalingam; Sampathkumar Devarajan
Original assignee: Strides Shasun Limited
Priority date: 2015-12-15
Filing date: 2016-12-15
Publication date: 2017-06-22

Abstract

The present invention discloses a pharmaceutical composition for oral dosage form of active substances with pH-dependent solubility characteristics and the pharmacologically acceptable salts thereof. The present invention particularly discloses pharmaceutical composition comprising a core containing uncoated tartaric acid, active substance layer and insulating layer that is free from water soluble polymers, which separates the core and active substance layer, for which the drug to be released in GIT.

Description

^'PHARMACEUTICAL COMPOSITIONS

FIELD OF THE INVENTION:

The present invention relates to a pharmaceutical composition for oral dosage form of active substances with pH-dependent solubility characteristics and the pharmacologically acceptable salts thereof. The present invention particularly relates to pharmaceutical composition comprising a core containing uncoated tartaric acid, active substance layer and insulating layer, free from water soluble polymers, which separates the core and active substance layer, for which the drug to be released in GIT.

BACKGROUND OF THE INVENTION:

The active substance of current invention is known from WO 98/37075 (corresponding to U.S. Pat. Nos.6,087,380; 6,469,039; 6,414,008; and 6,710,055, which are each hereby incorporated by reference), in which compounds with a thrombin- inhibiting and thrombin time- prolonging activity are disclosed, under the name Dabigatran etexilate. This active substance has the chemical formula (I).

(I)

The compound of formula (I) is a double prodrug of the compound of formula (II) i.e., the compound of formula (I) is only converted into the compound which is actually effective, namely the compound of formula (II), in the body. The main range of indications for the compound of chemical formula (I) is the postoperative prophylaxis of deep vein thrombosis.

US20100087488, U S 20060247278 and US20090042948 have disclosed various salts of dabigatran etexilate. US 20050234104, U S20060276513, US7932273 and US2010/0144796 describes various crystalline forms of dabigatran etexilate and its salts.

The solubility of dabigatran etexilate in water is 1.8 mg/mL and is dependent on the pH value. Although dabigatran etexilate is more soluble at lower pH, it is also less stable in acidic environment.

To increase the solubility of dabigatran, W 02003074056 suggests pharmaceutically acceptable salts of dabigatran etexilate with a water solubility of more than 1 g per 250 mL at 20eC. In addition, in W 02003074056 a pharmaceutical multi-particulate pellet composition is disclosed comprising a core comprising a pharmaceutically acceptable organic acid and a layer comprising dabigatran etexilate or a salt thereof, wherein the core and the layer comprising dabigatran etexilate are separated by an isolating layer comprising a water-soluble polymer. US20050107438 describes dabigatran etexilate formulations in a dispersed form in an encapsulated lipophilic, pharmaceutically acceptable carrier system, which are said to provide oral formulations that are chemically and physically stable and have good bioavailability.

US20050038077 describes a matrix tablet comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable organic acids and a pharmaceutically acceptable excipient or filler. However, due to the presence of an organic acid in a close contact with the active in a tablet composition without any special steps taken to separate the two from each other, can make the active highly susceptible to hydrolysis in the presence of humidity.

WO2009118321 discloses a process for the preparation of approximately spherical/ball-shaped tartaric acid pellets suitable for the manufacture of drug formulations containing active ingredients, the pellets so obtained as such, and the use thereof as a starting material for the production of drug formulations containing active ingredients. The process is characterized in that in a first step the tartaric acid pellets are produced by powder layering, which are sprayed in a second step with an ethanolic isolation suspension which comprises hydroxy propyl methyl eel I ul ose ( H P M C ) .

W 02009118322 describes a process characterized by a series of partial steps. First, the core is produced from a pharmaceutically acceptable organic acid, preferably tartaric acid by powder layering. The cores are then converted into so- called isolated tartaric acid cores by spraying on an isolating suspension. A dabigatran etexilate suspension prepared subsequently is sprayed onto these coated cores in one or more process steps by means of a coating process. Dabigatran etexilate methanesulfonate, as polymorph I, is suspended together with talc and hydroxy propyl cellulose in isopropanol, the preparation of the suspension being carried out at a temperature not exceeding 30.degree. C. Finally, the active substance pellets thus obtained are packed into suitable capsules.

WO2010007016 discloses a process for preparing a suspension 4 of the polymorph I of the methanesul phonic acid salt of dabigatran etexilate which is disclosed in WO2009118322 however is further characterized by that polymorph I of dabigatran etexilate methanesulfonate is being characterized by a melting point of Temperature 180e3.degree. C. as determined by DSC at a heating rate of 10eC/min is suspended together with talc and hydroxypropyl cellulose in isopropyl alcohol, the preparation of the suspension being carried out at a temperature not exceeding 30eC by the circulatory dispersal process. WO2010007016 also relates to the preferred particle size distribution of dabigatran etexilate is at an X ₉₀ of less than 14 1 m.

WO2011107427 discloses an oral pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof, and an inorganic acidic excipient that have a pH value in a 1 % aqueous solution of less than 6.

WO2012001156 discloses the process for the preparation of an oral dosage form comprising dabigatran etexilate or a salt thereof comprising a spherical core comprising tartaric acid coated with a layer comprising dabigatran etexilate and a dosage form obtainable by said process.

It is known that the solubility of weakly basic drugs, such as dabigatran and dabigatran etexilate, may be increased by the provision of an acidic environment. Hence, the provision of an acidic microenvironment at the intended site of drug release can increase the release rate from the dosage form. At the same time it is necessary to reduce the impact or the incompatibility of weakly basic drugs, such as dabigatran and dabigatran etexilate with the acids used to maintain the acidic environment. The above prior art attempts have only provided compositions of Dabigatran Etexilate Mesylate, which are either tedious or technologically demanding to prepare or are unlikely to remain stable over the shelf life of the product. A need therefore exists to prepare alternate compositions of dabigatran etexilate that are stable, easy or convenient to prepare, provide the desired in vitro release and bioavailability.

It is the object of the present invention to provide an improved solid dosage form of dabigatran etexilate and its pharmaceutically acceptable salts, preferably dabigatran etexilate methanesulfonate, that provide a fast dissolution of the drug at pH lower than 7 and/or improved and simplified technological/cost effective processes for the production thereof.

SU M MA RY OF T H E INV E NTION:

The present invention provides an improved solid oral dosage form of active ingredient with pH -dependent solubility characteristics and its pharmaceutically acceptable salts, solvates, hydrates thereof and to the process for its production thereof. The Dabigatran dosage form comprises tablets, mini tablets, capsules, granules or pellets consisting of organic acid pellets coated with isolating layer which are further coated with the said active ingredient layer. Optionally, an overcoat can also be applied to increase the abrasion resistance and shelf life of the finished product.

In an aspect, the isolating/insulating layer is essentially free of water soluble polymers that separate the acid sensitive pharmaceutically active ingredient from the organic acid layer.

In an aspect the present invention provides a compressed core for a pharmaceutical dosage form comprising at least one pharmaceutically acceptable organic acid which is uncoated, wherein the pharmaceutically acceptable organic acid is present in an amount of about 50-100% by weight of the core. The core can be used as a component of a multilayer pharmaceutical composition containing a drug having pH dependent solubility. In particular, upon dissolution of the pharmaceutical composition, the core provides an acidic microenvironment in order to facilitate the dissolution of the drug from the pharmaceutical composition.

In a preferred aspect the core is coated with an isolating layer; and the core coated with said isolating layer is further coated with a layer comprising the active substance.

The core comprises of sucrose, microcrystalline cellulose, starch or tartaric acid; preferably tartaric acid core, and the solid oral dosage form is particularly in pellet form.

In another aspect, the present invention provides a process for preparing the pharmaceutical composition comprising the compressed core, wherein the process comprises: (i) utilizing commercially available core comprising uncoated organic acid, (ii) applying a sub-coat layer or insulating layer over the core, (iii) applying a drug layer or active substance layer over the sub-coated core, and (iv) optionally applying a protective top coat an extended release coat or a delayed release coat over the drug layer.

DE TAIL E D DE SC RIPTION OF T H E INV E NT ION:

As used herein, unless otherwise indicated, the term "active substance having a pH dependent solubility" refers to a active substance that has increased solubility when present in acidic environment (i.e. pH<7). Typically, the drug has a pKa in the range of from about 7 to about 14, preferably the pKa is greater than 7 and less than 12, more preferably the pKa is greater than 7 and less than 10. As used herein, unless indicated otherwise, percentages refer to a weight percent. Weight percentages given in relation to the dosage form excludes the weight of any capsule shell.

As used herein, unless otherwise indicated, references to active substance/ active ingredient/ active agent include reference to active substance having a pH dependent solubility such as dabigatran, enantiomers or prodrugs of dabigatran, such as dabigatran etexilate, as well as pharmaceutically acceptable salts (preferably mesylate, hydrochloride, maleate, tartrate, salicylate, citrate and malate salts, and particularly the mesylate salt), as well as solvates and hydrates of dabigatran, its enantiomers or prodrugs.

The solubility of weakly basic active substances, such as dabigatran, dabigatran prodrugs such as dabigatran etexilate or pharmaceutically acceptable salts such as dabigatran etexilate mesylate, may be increased by the provision of an acidic environment. However, the weakly basic active substances such as dabigatran or its pharmaceutically acceptable salts are unstable in acidic environment. The prior arts disclose the use of water soluble polymers in the isolating layer between the drug layer and the tartaric acid core. The present inventors, however, observed that the use of water soluble polymers result in burst release of the active substance. To reduce the undesired impact of the contact of active substance with tartaric acid and increase the compatibility, stability and shelf life of the product the present invention provides an improvement wherein the requirements are met advantageously as provided in the specification.

In an embodiment, the present invention relates to a pharmaceutical composition comprising the core, wherein the core is coated with active ingredient layer comprising said active substance having a pH dependent solubility profile, wherein the solubility is greater at acidic pH (i.e. pH<7), and at least one pharmaceutically acceptable excipient and sub-coat or insulating layer, between the core containing pharmaceutically acceptable organic acid and the drug layer, that is essentially free of water soluble polymers.

The core of the pharmaceutical dosage form is comprised of sucrose, microcrystalline cellulose, starch or at least one pharmaceutically acceptable organic acid and is in particular in pellet form. Preferably, the compressed core for a pharmaceutical dosage form comprises at least one pharmaceutically acceptable organic acid such as tartaric acid.

In an embodiment of the present invention, the active ingredient layer comprises an active agent in combination with one or more pharmaceutically acceptable excipients, preferably wherein the one or more pharmaceutically acceptable excipients is selected from the group consisting of one or more binders, diluents, disintegrants, glidants, lubricants, plasticizers, separating agents, surfactants, colorants or pigments, flavorants, and anti-tacking (anti-adherant) agents, and mixtures thereof. Optionally, the active ingredient layer comprises an active agent in combination with one or more binders, plasticizers, and an anti-tacking agents. The active ingredient layer may comprise an active agent, in combination with one or more binders and one or more anti-tacking agents.

The active agent that can be used in the present invention is pH dependent. Such active agents are weak bases, and include: dabigatran, dabigatran prodrugs (preferably dabigatran etexilate) or pharmaceutically acceptable salts thereof (e.g. dabigatran etexilate mesylate), solvates or hydrates of dabigatran, dabigatran prodrugs and their pharmaceutically acceptable salts. The drug can also be selected from the group consisting of dipyridamole, aliskiren, fingolimod, and retigabin, and their pharmaceutically acceptable salts, as well as solvates and hydrates of these drugs or their pharmaceutically acceptable salts. In any of the embodiments of the invention, the drug is preferably dabigatran, dabigatran prodrugs (preferably dabigatran etexilate) or pharmaceutically acceptable salts thereof (e.g. dabigatran etexilate mesylate), solvates or hydrates of dabigatran. Dabigatran etexilate mesylate is a particularly preferred drug in the pharmaceutical compositions of any embodiment of the invention.

In a particularly preferred embodiment, the active ingredient layer comprises the active agent as described in any of the above embodiments which includes, dabigatran, its prodrugs, or pharmaceutically acceptable salts, solvates and hydrates thereof, such as dabigatran etexilate mesylate), in combination with one or more binders for example cellulose ethers such as ethyl cellulose, cellulose acetate phthalate, sodium ethyl cellulose sulfate, hydroxypropyl celluloses, hydroxyethyl eel I ul oses, hydroxypropyl methyl eel I ul oses, methyl eel I ul oses, hydroxyethyl celluloses, carboxymethyl celluloses, starch, starch derivatives, sugars, methacrylic acid copolymers, E udragit the polyvinylpyrrolidones, the copolymers of N -vinyl pyrrol i done, and vinyl acetate, zein, acrylic polymers, isomalt, sucrose, gelatin, pregelatinized starch, alginic acid, polyvinyl alcohol, polyethylene oxide, xanthum gum or a mixture thereof and one or more anti- tacking agents for example talc, magnesium stearate, and silica The active substance is present in an amount of atleast 10% wA/v of tplhe pharmaceutical composition.

The active ingredient layer may be applied to the insulated cores as described in any of the embodiments herein by any coating procedure, including by fluid- bed coater, by pan-coating or by spray coating. Preferably, the drug layer is applied by pan- coating or fluid- bed coating. Typically, the ingredients for the drug layer are mixed together in C-i-₃, alcohols such as ethanol, isopropanol, or mixtures thereof, and ketones such as acetone, dichloromethane and optionally in combination of alcohol with purified water to form a coating solution, which can be applied by the above coating methods. Since the cores are of uniform size, there is no need for a screening step following the drug-layer coating step in order to obtain uniform particles. Suitable excipients in the drug layer of the pharmaceutical composition of any embodiment of the present invention include excipients generally used for preparation of oral solid dosage forms. For example, one or more suitable binders are selected from the group consisting of cellulosic polymers (e.g., cellulose ethers such as ethyl cellulose, cellulose acetate phthalate, sodium ethyl cellulose sulfate and the like); hydroxypropyl celluloses, hydroxyethyl celluloses, hydroxypropyl methyl eel I ul oses, methyl eel I ul oses, hydroxyethyl eel I ul oses, carboxymethyl celluloses, starch, starch derivatives, sugars, the polyvinylpyrrolidones, the copolymers of N-vinyl pyrrol i done, and vinyl acetate, zein, acrylic polymers (e.g., methacrylic acid/methacrylic acid ester copolymers such as methacrylic acid/methyl methacrylate copolymers and the like), E udragits, isomalt; sucrose, gelatin, pregelatinized starch, alginic acid, polyvinyl alcohol, polyethylene oxide, and xanthum gum or a mixture thereof in an amount NMT 30%w/w.

In any embodiment of the present invention, an anti-tacking agent (anti-adherant) may be included. The anti-tacking agent can include magnesium stearate, magnesium carbonate, titanium dioxide, microcrystalline cellulose, polyethylene glycol, colloidal silica, corn starch and talc, or mixtures thereof.

In further embodiment, the diluent is selected from the group consisting of lactose, sucrose, fructose, dextrose, mannitol, sorbitol, xylitol, lactitol, silicon dioxide, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, talc, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof in an amount NMT 90%w/w.

Optionally di methyl polysi I oxane (dimethicone) or other antifoaming agents can be used to prevent foaming of the solution or suspension. In further embodiment, the disintegrant is selected from the group comprising of low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, polyvinyl pyrrolidine, cross-linked sodium carboxymethyl cellulose, cross-linked calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxy methyl cellulose, microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, ion-exchange resins, starch and modified starches including pregelatinized starch, formal in- casein, alginates, gums and combination thereof in an amount NMT 40%w/w.

In further embodiment, glidant is selected from the group comprising of talc, silicon dioxide, silicic acid, cornstarch, maize starch, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, colloidal silicon dioxide, starch, castor wax and combination thereof in an amount NMT 20%w/w.

In further embodiment, lubricant is selected from the group comprising of calcium stearate, glycerol behenate, sodium benzoate, magnesium stearate, silicon dioxide, silicic acid, colloidal silicon dioxide, zinc stearate, mineral oil, polyethylene glycol, sodium lauryl sulphate, fumaric acid, sodium stearyl fumarate, stearic acid, talc, vegetable oil, castor wax and combination thereof in an amount NMT 20%w/w.

The final pellets comprising the pharmaceutically active ingredient are preferably prepared by spraying an active substance suspension onto the isolated pellets. The active substance suspension is prepared using dabigatran etexilate or a pharmaceutically acceptable salt thereof, preferably dabigatran etexilate methanesulfonate.

Dabigatran etexilate methanesulfonate or for any other salts, the solvents to be used are chosen from the group of water or organic solvents, selected but not limited to the group of alcohols (ethyl alcohol, methyl alcohol, 2-propanol, dimethylformamide etc.), acetone and mixtures thereof and other pharmaceutically acceptable organic solvents optionally in combination with water. To the conditioned solvent active substance is added and stirred until dissolved or suspended. Then polymer or polyol is added and stirring is continued, after which optionally one or more anticaking agents, plasticizing agents, antifoaming agents and coloring agents are added. To prepare the final pellet the active substance suspension thus obtained is sprayed onto the isolated pellets. In certain embodiments of the pharmaceutical compositions of the present invention, it may be preferable to include a subcoat or isolating layer or insulating layer between the core containing the pharmaceutically acceptable acid and the drug layer. The inclusion of a subcoat layer is particularly useful for providing a physical barrier to protect certain active agents, including dabigatran, from undesirable interactions with the acid in the core.

The isolated pellets are preferably prepared by spraying an isolating suspension/solution onto the starter pellets obtained by the process described hereinabove. To prepare the isolating suspension the selected binder(s) are in particular dissolved or suspended in the solvent such as water or organic solvents, selected but not limited to the group of alcohols (ethyl alcohol, methyl alcohol, 2- propanol, di methyl formamide etc.), acetone and mixtures thereof and other pharmaceutically acceptable organic solvents. To the solution or suspension of the binder in the solvent optionally plasticizers, anticaking agents, antifoaming agents and coloring agents are added and the solution or suspension is sprayed onto the starter pellets.

The isolated pellets have a uniform and spherical geometry and practically no defects in the isolation caused by satellites. The so-called satellites are small particles adhering to the outside of the otherwise rounded pellets and detracting from the otherwise spherical geometry of the pellets.

Subcoat layer may comprise at least one pharmaceutically acceptable excipient selected from one or more of the group consisting of one or binders, anti -tacking agents, surfactants (emulsifier), dissolution enhancers and plasticizers. The subcoat layer preferably comprises one or more pharmaceutically acceptable excipients selected from the group consisting of binders, anti-tacking agents, surfactants (emulsifier), and plasticizers.

Suitable binders for the subcoat layer include cellulosic polymers (e.g., cellulose ethers such as ethyl cellulose, cellulose acetate phthalate, sodium ethyl cellulose sulfate and the like); hydroxypropyl celluloses, hydroxyethyl celluloses, hydroxypropyl methyl eel I ul oses, methyl eel I ul oses, hydroxyethyl eel I ul oses, carboxymethyl celluloses, starch, starch derivatives, sugars, the polyvinylpyrrolidones, the copolymers of N-vinyl pyrrol i done, and vinyl acetate, zein, acrylic polymers (e.g., methacrylic acid/methacrylic acid ester copolymers such as methacrylic acid/methylmethacrylate copolymers and the like), isomalf sucrose, gelatin, pregelatinized starch, alginic acid, polyvinyl alcohol, polyethylene oxide, and xanthum gum or a mixture thereof in an amount NMT 30%w/W.

Where present in the subcoat layer, the anti-tacking agent can be any of the anti- tacking agents employed in the drug layer. Thus, for example, the anti-tacking agent may include magnesium stearate, magnesium carbonate, titanium dioxide, microcrystalline cellulose, polyethylene glycol, colloidal silica, corn starch and talc or mixtures thereof.

The subcoat layer may further comprise a pore-forming material. The term "channeling agent" is in the art often synonymously used for the pore-forming material of the present invention. The pore-forming substances can be selected from inorganic substances, inorganic salts such as NaCI, KCI, Na₂S0₄ or organic substances, in particular organic substances being solid at 30 eC, such as Polyethylene glycol. The subcoat layer may be applied in a similar manner to the drug layer. For example the ingredients for the subcoat layer can be mixed together in, e.g. C_1-3 alcohols such as ethanol, isopropanol or 2-propanol, or mixtures thereof, and optionally in combinations of the alcohol with purified water, to form a coating solution, which can be applied by the various coating methods as discussed above for the drug layer (e.g. using fluid bed coater or wurster coater).

The final pellets as well as the isolated pellets may be prepared by the fluidized bed method comprising spraying phase solution or suspension to the cores or pellets.

By a fluidized method is meant that the product to be coated has a fluid, preferably air, flowing through it. The material put in is set in motion and kept in motion by this fluid, the nature of the movement being controlled by different equipment-specific inserts. Examples of suitable fluidized bed apparatus are GPCG (Glatt Particle Coater Granulator), Precision Coater (Aeromatic), K ugelcoater (Within) or carried out using the Aircoater (Innojet) or Wurster Coater.

Optionally, an overcoat can be applied to the final pellets to increase their abrasion resistance.

In any embodiment of the pharmaceutical compositions described herein, the drug layer may be provided with a further coating. This further coating may be a protective top coat or a top coat that provides particular release properties, e.g. an extended- release coat or delayed- release coat, as appropriate for the drug and dosage form to be released in the gastrointestinal track (GIT).

The protective top coat can include one or more binders, anti -tacking agents and plasticizers. Suitable binders, anti-tacking agents and plasticizers, include those described above for the subcoat layer. The binder(s) can be any of those mentioned including the preferred agents described above in relation to the drug layer or subcoat layer.

The top coat extended release coat and the delayed release coat can be applied by the coating procedures described above for the drug layer and the subcoat.

As the compressed cores can be made to a predetermined and uniform particle size, the cores are particularly suitable for the preparation of multiparticulate dosage forms of drugs having pH dependent solubility release as discussed above particularly in the form of capsules containing drug-coated minitablets.

Thus, in a further aspect the present invention provides a multiparticulate dosage forrn, comprising a plurality of coated cores as defined in any of the embodiments described above. The multiparticulate dosage form can be in the form of capsules filled with the coated cores.

In particular, in accordance with a further aspect of the present invention, there is provided a process for preparing a pharmaceutical dosage form comprising filling the pharmaceutical composition according to any embodiment of the invention (e.g. the minitablets), or a plurality thereof, into a capsule, preferably wherein the capsule is a hard gelatin capsule or hydroxypropy I methyl cellulose capsule.

Moreover, the present invention provides the coated cores containing the drug and the acid in a concentrated forrn, which enables the cores to be filled into smaller capsules whilst retaining the dosage size, which reduces the problem associated with large dosage forms (e.g. difficulty in swallowing, and hence poor patient compliance). EXAMPLES

Example 1:

Example 2:

Ingredients % wA/v

Core Pellet

Tartaric acid pellets

25-55

(100% uncoated Tartaric acid)

Seal Coating/Layer

Ethyl cellulose or Eudragit E 100 0.5-2.5

Colloidal silicon dioxide 0.3-3.0

Mannitol or lactose 0.5-5.0

Isopropyl alcohol Qs

Purified Water Qs

Drug Layer

D abi gatran E tex i I ate M esy I ate 30-50

H ydroxy propyl eel I ul ose or H ypromel I ose 5-15

Isopropyl alcohol Qs

Dichloromethane Qs

Protective Layer

H ypromel I ose or hydroxypropyl eel I ul ose 0.5-5.0

Talc 0.5-5.0 Polyethylene Glycol 0.1-2.0

Dimethicone 0.01-0.5

Isopropyl Alcohol Qs

Dichloromethane Qs

L ubrication

Talc 0.1-2.0

E xample 3:

Ingredients % wA/v

C ore Pellet

Tartaric acid pellets

41.03

(100% uncoated Tartaric acid)

Seal C oating/L ayer

Ethyl cellulose 1.23

Colloidal silicon dioxide 0.61

Mannitol 1.23

Isopropyl alcohol Qs

Purified Water Qs

Drug L ayer

D abi gatran E tex i I ate M esy I ate 42.51

Hydroxy propyl cellulose or

9.83 Hypromellose

Isopropyl alcohol Qs

Protective L ayer

Hypromellose 1.47

Talc 1.25

Polyethylene Glycol 0.22

Isopropyl Alcohol Qs Dichloromethane Qs

L ubrication

Talc 0.61 xample 4:

Ingredients % wA/v

C ore Pellet

Tartaric acid pellets

41.03

(100% uncoated Tartaric acid)

Seal C oating/L ayer

E udragit E 100 1.23

Colloidal silicon dioxide 0.61

Lactose monohydrate 1.23

Isopropyl alcohol Qs

Purified Water Qs

Drug L ayer

D abi gatran E tex i I ate M esy I ate 42.51

Hydroxy propyl cellulose or

9.83 Hypromellose

Isopropyl alcohol Qs

Dichloromethane Qs

Protective L ayer

Hydroxy propyl cellulose or

1.47 Hypromellose

Talc 1.25

Polyethylene Glycol 0.22

Isopropyl Alcohol Qs

Dichloromethane Qs

L ubrication

Talc 0.61 E xample 5:

E xample 6: Manufacturing Process

The process for the preparation dabigatran dosage form follows: Core was selected containing uncoated tartaric acid pellets. Ethyl cellulose or E udragit along with colloidal silicon dioxide, mannitol or lactose was mixed with suitable solvent in a suitable mixer. The solution or suspension was sprayed on to the cores forming seal layer or insulating layer. Active substance or A PI layer formed by mixing cellulose polymers or H PC or Hypromellose was added to isopropanol or Dichloromethane or mixtures thereof and stirred until dissolved. This was followed by addition of Dabigatran etexilate mesylate, stirred and the suspension was homogenized with a suitable device. The suspension was sprayed onto the cores with insulating or separating layer by a fluid bed coating system (type Wurster). Coating layer or protective layer was formed by mixing hypromellose or H PC in isopropyl alcohol or dichloromethane or combinations of solvents. In some formulations polyethylene glycol was added and stirred well. In some formulations dimethicone was added and stirred well. Talc was further added and stirred. The suspension or solution was sprayed onto the active substance layer by a fluid bed coating system (type Wurster). Finally the resulted particles or granules lubricated with talc and were filled in to capsule/sachet or compressed in to tablets/mini -tablet including other suitable dosage forms for oral administration.

Similar procedure was conducted to obtain the pharmaceutical granules of example 3, example 4 and example 5 respectively.

Any patents or publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. Further, these patents and publications are incorporated by reference herein to the same extent as if each individual publication was specifically and individually incorporated by reference. One skilled in the art will appreciate readily that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those ski I led in the art.

Claims

We claim,

1. A stable pharmaceutical composition for oral administration of active substance having a pH dependent solubility profile, wherein said composition provide a faster dissolution of the active substance at pH lower than 7 comprising;

(i) a core containing uncoated tartaric acid in an amount of 50-100% by weight of the core;

(ii) active substance layer coated on the core comprising active substance along with pharmaceutically acceptable excipients;

(iii) insulating layer separating core material and active substance layer, wherein insulating layer comprises one or more water-insoluble polymer; and

(iv) optionally a protective top coat, an extended release coat or a delayed release coat over the active substance layer and filled or compressed into suitable dosage f orm;

wherein the water- insoluble polymers of insulating layer reduces the undesired impact of the contact of active substance with tartaric acid and increases the compatibility, stability and shelf life of the product.

2. The stable pharmaceutical composition according to claim 1, wherein the active substance is selected from the group consisting of dabigatran, dabigatran prodrugs such as dabigatran etexilate or pharmaceutically acceptable salts such as dabigatran etexilate mesylate, solvates or hydrates thereof; Dipyridamole, Aliskiren, Fingolimod, and Retigabin, and their pharmaceutically acceptable salts, as well as solvates and hydrates thereof.

3. The stable pharmaceutical composition according to claim 1, wherein the active substance is selected from the group consisting of dabigatran, dabigatran prodrugs such as dabigatran etexilate or pharmaceutically acceptable salts such as dabigatran etexilate mesylate, solvates or hydrates thereof in amount of at least 10%w/w of the total composition.

4. A stable pharmaceutical composition for oral administration of active substance such as dabigatran etexilate mesylate, solvates or hydrates thereof having a pH dependent solubility profile, wherein said composition provide a faster dissolution of said active substance at pH lower than 7 comprising;

(ii) active substance layer coated on the core comprising said active substance along with pharmaceutically acceptable excipients;

5. The stable pharmaceutical composition according to claims 1 and 4, wherein water- insoluble polymer is selected from cellulose derivatives preferably ethyl cellulose, polyvinyl acetate, phthalate based polymers and copolymers, neutral copolymers based on ethyl acrylate and methyl methacry I ate, copolymers of acrylic and methacrylic acid esters, quaternary ammonium groups or mixtures thereof in amount of 0.5-2.5%w/w.

6. The stable pharmaceutical composition according to claims 1 and 4, wherein pharmaceutically acceptable excipients are selected from diluents/fillers, binders, disintegrants, glidants, lubricants, plasticizers, separating agents, surfactants, colorants or pigments, flavorants, anti-tacking agents alone or in combination thereof.

7. The stable pharmaceutical composition according to claim 6, wherein the diluent filler is selected from the group consisting of lactose, sucrose, fructose, dextrose, mannitol, sorbitol, xylitol, lactitol, silicon dioxide, starch, modified starches, dibasic calcium phosphate, tri basic calcium phosphate, magnesium carbonate, magnesium oxide, talc, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose or combination thereof in an amount of NMT 90%w/w.

8. The stable pharmaceutical composition according to claim 6, wherein the binder is selected from the group consisting of hydroxy propyl celluloses, hydroxyethyl eel I ul oses, hydroxypropyl methyl eel I ul oses, methyl eel I ul oses, hydroxyethyl celluloses, carboxymethyl celluloses, starch, starch derivatives, sugars, methacrylic acid copolymers, the polyvinylpyrrolidones, the copolymers of N-vinyl pyrrol i done, and vinyl acetate or combination thereof in an amount of NMT 30%w/w.

9. The stable pharmaceutical composition according to claim 6, wherein the disintegrant is selected from the group comprising of low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, polyvinyl pyrrolidine, cross-linked sodium carboxymethyl cellulose, cross-linked calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxy methyl cellulose, microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, ion-exchange resins, starch and modified starches including pregelatinized starch, formal in- casein, alginates, gums or combination thereof in an amount of NMT 40%w/w.

10. The stable pharmaceutical composition according to claim 6, wherein the glidant is selected from the group comprising of talc, silicon dioxide, silicic acid, cornstarch, maize starch, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, colloidal silicon dioxide, starch, castor wax or combination thereof in an amount of NMT 20%w/w.

11. The stable pharmaceutical composition according to claim 6, wherein the lubricant is selected from the group comprising of calcium stearate, glycerol behenate, sodium benzoate, magnesium stearate, silicon dioxide, silicic acid, colloidal silicon dioxide, zinc stearate, mineral oil, polyethylene glycol, sodium lauryl sulphate, fumaric acid, sodium stearyl fumarate, stearic acid, talc, vegetable

011. castor wax or combination thereof in an amount of NMT 20%w/w.

12. The stable pharmaceutical composition according to any of the preceding claims, wherein the solvent is selected from water or organic solvents, ethyl alcohol, methyl alcohol, 2-propanol, dichloromethane, di methyl formamide, acetone or mixtures thereof.

13. The stable pharmaceutical composition according to claim 1 and 4, wherei n the i nsul ati ng I ayer i s free from water sol ubl e polymers.

14. The stable pharmaceutical dosage form according to any of the preceding claims comprising tablets or pellets or granules or minitablets or powder of a pharmaceutically acceptable multilayer acid core and pellets or granules or minitablets or powder of dabigatran, dabigatran prodrugs such as dabigatran etexilate or pharmaceutically acceptable salts, esters, hydrates and solvates thereof.