This application takes priority from Indian Complete Application 201721028736 filed on August 11, 2017 and is incorporated herein in its entirety.

FIELD OF INVENTION

The present invention relates to a direct compressible (DC) pharmaceutical composition in the form of granules or tablets. The present composition is directed for water-soluble Active Pharmaceutical Ingredients (APIs) to achieve immediate release (IR) and extended release (ER) drugs releasing profiles simultaneously which comprises APIs:excipient ratio and method of preparation thereof.

DESCRIPTION OF THE RELATED ART

Pharmaceutical tablets are the most popular dosage form in administering drugs to patients. Formulation development of a drug comprises numerous excipients viz- binder, disintegrant, diluents, polymer coating etc. Tablets are formulated by compressing dry powder blends and active pharmaceutical agents (APIs) for different therapeutics. Towards this, pharmaceutical technology is in quest to improve the patient compliance, reduce manufacturing processes, and achieve desired drug release profiles.

The majority of commercially available solid dosage formulations are in the form of tablets, and their method to manufacture involves processes namely, granulation, blending, compression and coating. The selection of appropriate pharmaceutical excipient(s) is foremost critical component to achieve desired release profiles. Towards this, selecting combination of excipients, is a difficult task and requires a balance between cost and production process performance.

Oral administration of drugs has been the most common and preferred route for delivery of most therapeutic agents. The acceptance of the oral route is due, ease of administration, accurate dosing, cost-effective manufacturing methods, and improved shelf-life of the product. The conventional immediate release (IR)formulations provide satisfactory clinical performance with an appropriate balance of efficacy and safety. On the other hand, controlled release systems (CRS) are generally in the form of tablets and capsules. These formulations are often called as novel drug delivery systems (NDSS). The NDDS formulations vary drug releasing ability in GIT with different drug release profiles and orders of release. For example, they can be of extended release, sustained release, controlled release, pulsatile release and delayed release profiles. The NDDS formulations control drug's exposure over time, assists drug in crossing physiological barriers, shield's drug from premature elimination, and drive drug to the desired site of action while minimizing drug exposure elsewhere in the body.

Further, the rationale for development of an extended-release formulation of a drug is to enhance its therapeutic benefits, minimizing its side effects while improving the management of the diseased condition. For example, a highly water-soluble compounds viz- metformin

hydrochloride, dissolution and absorption usually are complete within few hours. For these compounds with high water solubility, short half-lives, repeated dosing may be required to maintain in vivo drug concentrations within therapeutically relevant levels (C _max ). In these cases, extended release (ER) or sustained release (SR) dosage forms are suitable to overcome the frequent dosing problem, leading to better patient compliance.

Various pharmaceutical technological rationale have been designed to achieve extended release profiles in solid dosage forms. A typical matrix formulation consists of a drug, one or more water-swellable hydrophilic polymers, excipients such as fillers or binders, a flow aid (glidant) and a lubricant. Other functional ingredients, such as buffering agents, stabilizers, solubilizers and surfactants, may also be included to improve or optimize the release and/or stability performance of the formulation system( Pharmacy Pharmacol. 2005; 57; 533-546; Int J Pharm.2006; 316; 14-20). The physico-chemical properties of API's are very critical in establishing the release profiles and co-relating it with desired bioequivalence and therapeutic activity thereafter. However addition of the pharmaceutical excipients with API increases mass of solid dosage forms and therefore reduces patient compliances. This is true when the APIs dose is higher than 500 mg to 1000 mgs. The challenge is in reducing the excipient amount and formulating the solid dosage forms with least possible weight. This also could reduce the cost and increase patient compliance including easy swallow-ability especially for pediatric use and dysphagia. This is highly essential especially in rational drug combinations where there is increased mass of tablets further. In addition, it is envisioned to design the formulation with drug combinations having different release profiles.

US6117451relates to new direct compression metformin hydrochloride tablets, a process for the preparation thereof, and to new metformin hydrochloride formulations in the form of a tableting powder, capable of being directly compressed into the metformin hydrochloride tablets. Also, EP2498758 and EP 1948149 disclose bilayer tablet formulations comprising metformin extended release (ER) or reduced mass metformin ER formulation as the first layer, a SGLT2 inhibitor formulation as the second layer, and optionally a film coating and an invention refers to a formulation comprising a dipeptidylpeptidase IV (DPP-IV) inhibitor preferably vildagliptin and metformin, to tablets comprising such formulations and to processes for the preparation thereofrespectively. Further, WO2004110422 discloses invention related to ER unit dosage formulations of metformin or its pharmaceutically acceptable salt thereof and the process for their preparation.

In general, there are multiple excipients processed in unit dosage form which increases the tablet mass and size thereby, leading to difficulty in swallowing in children and patients with dysphagia.

Following are the shortfalls of conventional unit dose tableting systems:

1. Due to multiple components in a formulation, the release/ profile can vary.

2. Inability to control the delivery rate of either single or two different APIs in the

formulation.

3. Difficulty in separation of incompatible (APIs) from each other, and to control the release of API from one layer by utilizing the functional property of the other layer.

4. An increased number of excipients, there are increased number of manufacturing process which affect both- time as well as cost. SUMMARY

It is an objective of the invention to formulate the dual drug releasing granuleswhich can be directly compressed into a tablet or bilayer tablets. It is a further object of the invention to provide a process of preparing direct compressible dual release granules or its tablets as dosage form to achieve varied combinations of drug release profiles, e.g. one as immediate release and other as extended release, in a single tablet form. The present invention of DC dual releasing granules or their tablets are composed of single polymer as drug release controlling excipient and APIs, the composition is exemplified by APIs, acotiamide and proton pump inhibitor such as, esomeprazole, metformin and DPP-IV inhibitor, aspirin and platelet aggregation inhibitor or HMG CoA reductase inhibitor.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1. Dissolution profile of direct compressible dual release tablet of acotiamide (ER) and Esomeprazole (IR).

Figure 2. Dissolution profile of direct compressible dual release tablet of aspirin (ER) and clopidogrel (IR).

Figure 3. Dissolution profile of direct compressible dual release tablet of Metformin (ER) and teneligliptin (IR).

DETAILED DESCRIPTION

The present invention provides a direct compressible (DC) dual release formulation comprising DC- dual release tablet or bilayer tablets composed of only single hydrophilic polymer and two active ingredients as a combination formulation for therapeutic use.

Further, present invention refers to the simplest and most cost-effective method of modulating dual release tablet as solid oral dosage form.

A pharmaceutical process for preparation of direct compressible pharmaceutical formulation of dual release tablet or granules or bilayer tablet containing two different active pharmaceutical ingredients (API), one having an extended release profile and the other having an immediate release profile, in a single tablet form is also provided. The said process comprises the following steps:

a) preparation of polymer by dissolving in cyclohexane at 60°-70°C;

b) mixing the polymer of (a) to the first API that imparts extended release profile to the formulation and lowering the temperature to 30-35°C;

c) removal of cyclohexane from the mixture of (b) and washing the resultant granules with insoluble solvents and drying the granules at a temperature of 30-35 °C;

d) mixing the second API that imparts immediate release profile to the formulation, to the granules obtained from (c) and compressing them to obtain granules, tablets or bilayer tablets. The polymer of the invention is a hydrophilic polymer selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose (HPC), and hydroxyl propyl methyl cellulose (HPMC) or its salts thereof. Ethyl cellulose is the preferred hydrophilic polymer.

The polymer is prepared by dissolving it in cyclohexane, pentane, methyl t-butyl ether or acetonitrile. Preferably the polymer is dissolved in cyclohexane.

The insoluble solvents of the invention is selected from the group consisting of n-hexane, heptane, octane and mixtures thereof. The preferred insoluble solvent is n-hexane.

The API imparting immediate release profile to the direct compressible pharmaceutical formulation is with or without a pharmaceutical excipient. Herein, Applicants propose that such direct compressible dual release tablet is composed of a single hydrophilic polymer and a combination of any two APIs, one with ER profile and the other with IR profile. These dual release tablet may be exemplified by, but not limited to, acotiamide (ER) with proton pump inhibitors (PPIs, IR), metformin (ER) with

dipeptidylpeptidase IV (DPP-IV) inhibitors , and aspirin (ER) in combination with oral platelets aggregation inhibitors or HMG CoA reductase inhibitors (IR) for relevant disorders or conditions as appropriate. These combinations, are explained in detail as examples to better understand the invention.

This brings minimal (< 2) tableting operation/s with dual release platform (tablet as a solid dosage form) for therapeutic efficacy to release of drug/bioactives at specific time to the site of action which benefits manufacturer as well as patient. The rate of release of APIs is achieved through IR and ER profiles in a unit dosage.

Functional dyspepsia (FD) is a gastro-duodenal disorder that presents as postprandial fullness, early satiation, or epigastric burning despite no evidence of a structural disease (Ailment Pharmacol Ther. 2012; 36; 3-15). Proton pump inhibitors (PPIs) are often the first choice for treating FD (J Dig Dis. 2013; 14; 623-625). Due to different symptom subtypes, patients need additional medication alongwith first-line treatment (Tohoku J Exp Med.2014;234; 237-240). The combination of PPIs and novel agents such as acotiamide (Drugs.2013;73; 1377-1383) that enhances acetylcholine release in the enteric nervous system via muscarinic receptor antagonism and acetycholinesterase inhibition (Expert Opin Emerg Drugs.2015; 20; 221-33), is the promising combination. Therefore, combination therapy of acotiamide and PPI is effective in selected FD patients with insufficient improvement with an initial PPI.

This unmet need is fulfilled for these patients by a combination of acotiamide and PPI such as esomeprazole, lansoprazole, pantoprazole and rabeprazole sodium with a single hydrophilic polymer. This has more beneficial effect which gives dual- IR and ER profiles with ease of accurate dosing and administration of a single tablet than changing their medication. Simplicity in handling, least cost, ease as well as speed of production are advantages with direct compressible tablet among pharmaceutical manufacturers.

In one embodiment, the unit dosage form as granule or tablet or as bilayer tablet provides dual release of APIs to the gastrointestinal tract of a subject for the treatment of gastrointestinal motility disorders.

In one aspect, a method for treating a subject suffering from a GI motility disorder comprising orally administering esomeprazole for IR and acotiamide for ER in tablet as dosage form is provided.

In another aspect, the invention provides a DC-dual release tablet dosage form comprising active agents viz- acotiamide (ER) coated with only one swellable hydrophilic polymer (for ER) and any one of above-mentioned PPI without coating (for IR) which administered to a subject suffering from or diagnosed with a GI motility disorder.

This DC dual release tablet is used to elevate therapeutic efficacy of an initial esomeprazole followed by combination therapy with esomeprazole and acotiamide in FD patients with residual symptoms after an initial PPI.

In yet another aspect, DC-dual release tablet or bilayer tablet dosage form comprising active agents viz- metformin in combination with dipeptidylpeptidase IV (DPP-IV) inhibitors or sulfonylureas or thiazohdinedionesor a-glucosidase inhibitors is designed. The pathophysiology of Type 2 diabetes mellitus (T2DM) is characterised by deficient insulin activity arising from decreased insulin secretion secondary to β-cell failure, and/or compromised insulin action in peripheral target tissues (insulin resistance). This abnormal metabolic state is exacerbated by excess hepatic glucose production and altered metabolism of proteins and lipids, which along with hyperglycaemia, contribute to microvascular and macrovascular complications. The recommended first line treatment is metformin, which restrains hepatic glucose production and decreases peripheral insulin resistance. Although being efficient in attenuating

hyperglycaemia, this treatment has more or less serious side effects and there is a need for development of efficient formulation in combination of drugs without metabolic or other side effects.

The suggested treatment of type 2 diabetes mellitus is a dual oral therapy. A fixed-dose combination tablet from the class of dipeptidylpeptidase IV (DPP-IV) inhibitors such as vildagliptin, linagliptin, sitagliptin, teneligliptin or sulfonylureas class viz- glimepiride, gliclazide or thiazolidinedione class viz- pioglitazone or a-glucosidase inhibitorv z.voglibose or optionally a pharmaceutically acceptable salt thereof as immediate release (IR) and metformin as extended release (ER) is expected to be more convenient for the patient and hence lead to better compliance and improved glycemic control. Especially, in such dual drug combinations, metformin is preferred as extended release formulation, while glimepiride, sitagliptin, and gliclazide are provided as immediate release APIs.

This invention relates to a direct compressible (DC) dual release formulation comprising either a dipeptidylpeptidase IV (DPP-IV) inhibitors such as vildagliptin, linagliptin, sitagliptin, teneligliptin or sulfonylureas class viz- glimepiride or thiazolidinedione classv z. pioglitazone or a-glucosidase inhibitorv z.voglibose as immediate release and metformin as extended release compressed to form granules or tablet or bilayer tablet. The present invention also provides a method of producing the said tablet.

In yet another aspect of invention, DC-dual release tablet dosage form comprising active agent viz- aspirin in combination with oral platelets aggregation inhibitors or HMG CoA reductase inhibitors is proposed.

Aspirin or acetylsalicylic acid is used as an analgesic agent. Also, aspirin is used for reducing non-fatal myocardial infarction risk and ischemic attack risk in patients with unstable angina. WO97029753 provides a combination of clopidogrel and aspirin which is set to exhibit a synergistic effect.

The combination formulation of the present invention is designed for dual release profiles in such a manner that aspirin is allowed to work as extended release and clopidogrel is allowed to work as an immediate release profiles. In a preferred embodiment, the direct compressible pharmaceutical composition which is in the form of granules or tablets or as bilayer tablets for achieving dual drug release profiles as extended release and immediate release comprises between <10 to 98%, between 20 to 98%, between 30 to 98%, between 40 to 98%, between 50 to 98%, between 60 to 98%, between 70 to 98% or 80 to 98% by weight on a dry weight basis of active ingredients, wherein the active ingredients consist of acotiamide and any one of proton pump inhibitors such as esomeprazole, lansoprazole, pantoprazole and rabeprazole or optionally in any case a pharmaceutically acceptable salt thereof. The present invention also provides a method of producing said tablet.

In yet another preferred embodiment, the direct compressible pharmaceutical composition which is in the form of granules or tablets for achieving dual drug release profiles as extended release and immediate release comprises between <10 to 98%, between 20 to 98%, between 30 to 98%, between 40 to 98%, between 50 to 98%, between 60 to 98%, between 70 to 98% or 80 to 98% by weight on a dry weight basis of active ingredients,wherein the active ingredients consist of metformin and any one from the class of dipeptidylpeptidase IV (DPP-IV) inhibitors such as vildagliptin, linagliptin, sitagliptin, teneligliptin or sulfonylureas class viz- glimepiride or thiazolidinedione class viz- pioglitazone or a-glucosidase inhibitorv z.vogliboseor optionally in any case a pharmaceutically acceptable salt thereof. The present invention also provides a method of producing said tablet.

In another embodiment, the invention relates to a direct compressible (DC) dual release formulation comprising either oral platelets aggregation inhibitors viz- clopidogrel, HMG CoA reductase inhibitorsv z. atorvastatin, lovastatin, pravastatin, pitavastatin, cerivastatin, fluvastatin, simvastatin or optionally in any case a pharmaceutically acceptable salt thereof and aspirin, to granules or tablet comprising such formulations and to processes for the preparation thereof. The present invention also provides a method of producing said tablet.

The invention also provides that a direct compressible pharmaceutical composition in the form of granules or tablet wherein the active agents acotiamide or metformin or aspirin is in the form of embryo capsules or microcapsules or granules or pellets. The present invention provides a direct compressible pharmaceutical composition or granules or tablet comprising between 1 to 28% , between 1 to 14% or between 1 to 7%, by weight on a dry weight basis of a pharmaceutically acceptable polymer.

Uses

The drug combinations of the present invention are important as it increase patient compliance and there is better control of disease as two drugs may effect on different targets. In addition having a combination of drugs complement and or synergize each other's activity. Conclusively, dual release oral tablet with immediate (IR) and extended release (ER) formulation with various features simultaneously provide successful drug delivery with minimal tableting processes. This can be primary option to avoid chemical incompatibilities between APIs by physical separation and to enable the development of different drug release profiles viz. IR and ER. Dual release is suitable for sequential release of two drugs in combination of tablet in which one API can achieve immediate release as loading dose and second layer is extended release as maintenance dose. So use of dual release tablet is a very different aspect for anti-diabetic, anti-inflammatory and analgesic drugs where combination therapy is often practiced.

The examples provided here are for understanding the operability of the invention and in no way to be construed as limiting the scope of the invention. EXPERIMENATAL

Direct compressible dual drug release pharmaceutical composition of the present invention is prepared by a process comprising: (a) active ingredients consist of acotiamide and proton pump inhibitor such as esomeprazole, lansoprazole, pantoprazole and rabeprazole or optionally in any case a pharmaceutically acceptable salt thereof OR (b) active ingredients consist of aspirin and any one or the oral platelets aggregation inhibitors viz- clopidogrel, HMG CoA reductase inhibitors viz- Atorvastatin, lovastatin, pravastatin, pitavastatin, cerivastatin, fluvastatin, simvastatin or optionally in any case a pharmaceutically acceptable salt thereof OR (c) active ingredients consist of metformin and any one from the class of dipeptidylpeptidase IV (DPP-IV) inhibitors such as vildagliptin, linagliptin, sitagliptin, teneligliptin or sulfonylureas class viz- glimepiride or thiazolidinedione class viz- pioglitazone or a-glucosidase inhibitor v z.voglibose or optionally in any case a pharmaceutically acceptable salt thereof. Example 1. Direct compressible dual drug release pharmaceutical composition of the present invention can be prepared by a process comprising: (a) active ingredients consist of acotiamide and any one of proton pump inhibitors such as esomeprazole, lansoprazole, pantoprazole and rabeprazole or optionally in any case a pharmaceutically acceptable salt thereof OR (b) active ingredients consist of aspirin and any one or the oral platelets aggregation inhibitors viz.

clopidogrel, HMG CoA reductase inhibitors viz. Atorvastatin, lovastatin, pravastatin, pitavastatin, cerivastatin, fluvastatin, simvastatin or optionally in any case a pharmaceutically acceptable salt thereof OR (c) active ingredients consist of metformin and any one from the class of dipeptidylpeptidase IV (DPP-IV) inhibitors such as vildagliptin, linagliptin, sitagliptin, teneligliptin or sulfonylureas class viz. glimepiride or thiazolidinedione class viz. pioglitazone or a-glucosidase inhibitor viz. voglibose or optionally in any case a pharmaceutically acceptable salt thereof. Example 2. The required quantity of cyclohexane to the reaction vessel was stirred with a speed of about 200-500 rpm and heat to 60-70°C. An adequate amount of hydrophobic polymers e.g. ethyl cellulose between 0.1 to 28% in respect of the ratio of core to wall to the heated cyclohexane was added with the rate lOgm/min and raised the temperature to 70-74°C over lOmin with stirring speed of 500 rpm. Core material, API viz. acotiamide or aspirin or metformin was added to the solution of heated in cyclohexane. After being maintained at this temperature, stirring was continued for lhour at 70-74°C.

The temperature was cooled down slowly to 30-35°C over IHr. and allowed to sediment at room temperature. Decant excess cyclohexane and product of microcapsules was obtained and they are washed with other insoluble solvents. Finally, microcapsules were dried under 35°C.

Further, these granules of acotiamide or aspirin or metformin were compressed along with bare API viz. (a) any one of proton pump inhibitors such as esomeprazole, lansoprazole, pantoprazole and rabeprazole or optionally in any case a pharmaceutically acceptable salt thereof (b) any one or the oral platelets aggregation inhibitors viz. clopidogrel, HMG CoA reductase inhibitors viz. atorvastatin, lovastatin, pravastatin, pitavastatin, cerivastatin, fluvastatin, simvastatin or optionally in any case a pharmaceutically acceptable salt thereof (c) any one from the class of dipeptidylpeptidase IV (DPP-IV) inhibitors such as vildagliptin, linagliptin, sitagliptin, teneligliptin or sulfonylureas class viz. glimepiride or thiazolidinedione class viz. pioglitazone or a-glucosidase inhibitor viz. voglibose or optionally in any case a pharmaceutically acceptable salt thereof respectively into tablets using a rotary tablet press in a controlled environment.

Compression of dual drug release tablet at appropriate compression weight using round, concave punches produced desired hardness, disintegrating ability, and acceptable dissolution

characteristics. In addition, the direct compressible dual drug release provides competitive unit production cost, eliminates heat and moisture, allows for prime particle dissociation, physical stability, and ensures particle size uniformity.

The direct compressible dual drug release tablets produced provide an unit dosage form having an acceptable dissolution profile as shown in Figure 1, 2 and 3 as well as acceptable degrees of hardness and resistance to chipping, as well as a short disintegration time.

Example 3. Dissolution for dual release of drug/s was studied by reported USP method which comply USP limits for respective dual release tablet using following parameters:

Dissolution method for metformin (ER) tablet:

Medium: pH 6.8 phosphate buffer (6.8 g of monobasic potassium phosphate in 1000 mL of water; adjust with 0.2 N sodium hydroxide to a pH of 6.8 ± 0.1);

1000 mL

Apparatus 2: 100 rpm for Tablets labeled to contain 500

Times: 1, 3, and 10 h

Detector: UV 232 nm

Standard solution USP Metformin Hydrochloride RS in medium

Sample solution: Pass a portion of the solution under test through a suitable hydrophilic polyethylene filter of 0.45-μπι pore size. Dilute, if necessary, with

Medium to a concentration similar to the Standard solution.

Analysis: Calculate the percentage of C ₄ H ₁₁ N ₅ · HC1.

Tolerances: The percentages of the labeled amount of C ₄ H ₁₁ N ₅ HCI dissolved at the times specified conform to Acceptance