WO2022180612A1

WO2022180612A1 - Orodispersible formulation of hypolipidemic agent

Info

Publication number: WO2022180612A1
Application number: PCT/IB2022/051711
Authority: WO
Inventors: M. E. Kannan; Mukul Jain; Ritu Laddha; Mukesh Ukawala; Jitendra Patel; Arpit Jain
Original assignee: Cadila Healthcare Limited
Priority date: 2021-02-26
Filing date: 2022-02-26
Publication date: 2022-09-01

Abstract

Present invention relates to orodispersible formulation of suitable hypolipidemic agent. Preferably, the present invention discloses novel orodispersible formulation of the compound of formula (I), or its pharmaceutically acceptable salts and preparation of such stable pharmaceutical formulations.

Description

ORODISPERSIBLE FORMULATION OF HYPOLIPIDEMIC AGENT

FIELD OF THE INVENTION:

BACKGROUND OF THE INVENTION

For the past one decade, there has been an enhanced demand for more patient-friendly and compliant dosage forms. As a result, the demand for developing new technologies has been increasing annually (1). Since the development cost of a new drug molecule is very high, efforts are now being made by pharmaceutical companies to focus on the development of new drug dosage forms for existing drugs with improved safety and efficacy together with reduced dosing frequency, and the production of more cost effective dosage forms. For most therapeutic agents used to produce systemic effects, the oral route still represents the preferred way of administration, owing to its several advantages and high patient compliance compared to many other routes (2). Tablets and hard gelatin capsules constitute a major portion of drug delivery systems that are currently available. However, many patient groups such as the elderly, children, and patients who are mentally retarded, uncooperative, nauseated, or on reduced liquid-intake/diets have difficulties swallowing these dosage forms. Those who are traveling or have little access to water are similarly affected (3-5). To fulfill these medical needs, pharmaceutical technologists have developed a novel oral dosage form known as Orally Disintegrating Tablets (ODTs) which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take it with water. Drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be significantly greater than those observed from conventional dosage forms (6-8).

Several factors must be considered when selecting drug candidates for delivery as ODT dosage forms. In general, an ODT is formulated as a bioequivalent line extension of an existing oral dosage form. Under this circumstance, it is assumed that the absorption of a drug molecule from the ODT occurs in the postgastric GIT segments, similar to the conventional oral dosage form. But this scenario may not always be the case. An ODT may have varying degrees of pregastric absorption and thus, the pharmacokinetic profiles may vary (9). Therefore, the ODT may not be bioequivalent to the conventional oral dosage form. There are various examples of ODT formulations which have significantly different pharmacokinetic profiles compared with the same dose administered in a conventional dosage form. For example ODT formulations of selegiline, apomorphine, buspirone, orodispersible tablet of Carvidilol (Drug Design, Development and Therapy 2015:9 1379- 1392), Orodispersible tablet of Nebivolol (Journal of Pharmaceutical Investigation:

December 2014) have significantly different pharmacokinetic profiles compared with the same dose administered in a conventional dosage form (10,11).

The compound of Formula (I) are useful to prevent or reduce the risk of developing atherosclerosis, which leads to disease and condition selected from arteriosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular disease, peripheral vessel diseases and related disorders.

Various compounds as hypolipidaemic and hypocholesterolemic compounds are disclosed in PCT application no. W001053257 and W003009841 as well as processes for their preparation. WO 03009841 discloses compounds of the following general formula:

Saroglitazar of formula (I) disclosed in WIPO patent application no. WO 03009841.

Formula (I) Saroglitazar magnesium of compound of Formula (I-a) and its use in lipodystrophy is described in WO 201210486; the contents of which are incorporated herein by reference. The compound of Formula (I-a) are useful in the treatment of diabetes mellitus type 2, and/or non-alcoholic steatohepatitis and/or Non-alcoholic fatty lever diseases (NAFLD) and/or Primary biliary cholangitis (PBC).

Formula (I-a)

WO 2018104916 disclosed a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in treating primary biliary cholangitis.

WO 2015011730 disclosed a stable pharmaceutical composition of Saroglitazar of compound of formula (I) or its pharmaceutically acceptable salts comprising compounds of formula (I) or its pharmaceutically acceptable salts, wherein the pH of the formulation is maintained above 7.

In order to obtain marketing approval for a new drug product, manufacturers must submit to the regulatory authority evidence that the product is acceptable for administration to humans. Such a submission must include impurity profile of the product to demonstrate that the impurities are either absent, or present in a negligible amount. Different regulatory authorities have promulgated guidelines requiring applicants to identify the impurities present in the product and also disclose their concentration in the product. They also provide the axi um level of impurities allowable in the product. Thus for e.g. USFDA (United States Food and Drug Administration) recommends that drug applicants identify all the impurities having concentration of 0.1 % or greater in the active ingredient. Therefore, there is a need to check impurity profile and identify the impurities and also their concentration in the active ingredient or in finish drug product.

Some of the impurities of the compound of formula (I) or its pharmaceutically acceptable salts have been disclosed in WIPO patent application no. WO2017064635 and Indian Patent application no. IN 201921010391. The handling and storage particularly in the bulk form of pharmaceutically active ingredients which are sensitive to oxidation is difficult. Special handling is necessary and often the oxidation-sensitive ingredient is stored in airtight packaging under protective gas. The compounds of formula (I) or its pharmaceutically acceptable salts are susceptible to oxidation, alkaline & acid hydrolysis and stress degradation during synthesis and purification of the drug substance or when formulated as a dosage form.

Accordingly, there is a need to develop alternate formulation which can stabilize the compound of formula (I) or its pharmaceutically acceptable salts with desirable PK and bulk physical properties. The orodispersible tablets of the present invention show rapid disintegration in the buccal cavity upon contact with saliva without chewing, have a pleasant taste and palatability and thus better patient convenience and acceptance due to ease of administration and ingestion.

SUMMARY OF THE INVENTION

The present invention describes a orodispersible formulation of compounds of formula (I) or its pharmaceutically acceptable salts. Preferably, the present invention describes a stable orodispersible formulation of Saroglitazar magnesium of compound of formula (I-a).

The present invention further describes a stable orodispersible formulation of compounds of formula (I) or it’s pharmaceutically acceptable salts comprise one or more pharmaceutical excipients. EMBODIMENTS OF THE PRESENT INVENTION

In an embodiment, there is provided an orodispersible formulation comprising Saroglitazar compound of formula (I) or its pharmaceutically acceptable salts.

In another embodiment, there is provided an orodispersible formulation comprising compound of formula (I) Saroglitazar or its pharmaceutically acceptable salts and pharmaceutically acceptable excipient.

In a preferred embodiment, there is provided an orodispersible formulation comprising compound of formula (I)

Formula (I) or its pharmaceutically acceptable salt comprising,

(i) a diluent or filler, wherein the diluent or filler is mannitol where 10 % of particles should not be more than 315 μm and 90 % of particles should not be less than 75 μm;

(ii) a disintegrating agent;

(iii) a soluble excipients component part more than 50%w/w.

(iv) and one or more pharmaceutically acceptable excipient.

In a further embodiment, there is provided a stable orodispersible tablet formulation which disintegrates rapidly by the action of saliva in the oral cavity. In an embodiment, the orodispersible tablet of the present invention disintegrates in less than 60 seconds, preferably in less than 40 seconds.

In yet another embodiment, there is provided a process for the preparation of stable orodispersible tablet formulation of compound of formula (I) or its pharmaceutically acceptable salts preferably compound of formula (I-a).

In yet another embodiment the invention further provides a stable orodispersible tablet formulation of compound of formula (I) or its pharmaceutically acceptable salts preferably compound of formula (I-a) suitable for treatment of primary biliary cholangitis (PBC). In a further embodiment, there is provided a use of stable orodispersible tablet formulation of compound of formula (I) or its pharmaceutically acceptable salts preferably compound of formula (I-a) for treating diseases or disorders associated with primary biliary cholangitis (PBC).

DETAILED DESCRIPTION OF THE INVENTION: The term “rapidly disintegrating tablet in the buccal cavity ” in the present invention shall mean a tablet that can rapidly and completely disintegrate in the oral cavity only by saliva without water. The term “orodispersible tablet” or “ODT” refer to a solid dosage form of the present invention, which disintegrates rapidly in the oral cavity of a patient after administration, without chewing. The rate of disintegration can vary, but faster than the rate of disintegration of conventional solid dosage forms or chewable solid dosage forms which are intended to be swallowed immediately after administration.

The term “about” as used herein is intended to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%.

The term “ method of treatment ” as used herein, means any treatment of a disease or disorder in a mammal, including: preventing or protecting against the disease or disorder, that is, causing the clinical symptoms not to develop; inhibiting the disease or disorder, that is, arresting or suppressing the development of clinical symptoms; and/or relieving the disease or disorder, that is, causing the regression of clinical symptoms.

The term “C_max ” as used herein refers to maximum plasma concentration.

The term “(AUC_0-t) ^" used herein refers to area under theconcentration-time curve fromtime zero to time t.

The term “T_max ” as used herein refers to time to maximum concentration.

The term "pharmaceutically acceptable" indicates that the material does not have properties that would cause one of skill in the art to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. Further, the material is considered to be safe for administration in humans or animals.

" Patient " includes both human and animals. "Mammal" means humans and other mammalian animals.

The term "excipient(s)" or " pharmaceutically acceptable excipient(s)" refers to pharmacologically inactive substances that are added to a pharmaceutical preparation in addition to the active pharmaceutical ingredient. Excipients may take the function of vehicles, diluents/fillers, disintegration or dissolution modifying agents, absorption enhancers, stabilizers or a manufacturing aid among others. Excipients may include fillers, diluents/fillers, binders, disintegrating agents, lubricants, stabilizers and glidants. Examples of excipients classes frequently used are listed below.

As used herein, the term "binders" is intended to mean substances used to cause adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other similar material known to those of ordinary skill in the art.

When needed, other binders may also be included in the present invention. Exemplary binders include starch, poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC F68, PLURONIC F127), collagen, albumin, celluloses in nonaqueous solvents, and the like or their suitable combinations. Other binders which may be included may be, for example, poly(propylene glycol), polyoxyethylene - polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.

As used herein, the term "diluent" or "filler" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, lactose, mannitol, maltodextrin, fructose, maltitol, xylitol, sucrose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, pregelantized starch, hydrated sodium sulfoaluminate combinations thereof and other such materials known to those of ordinary skill in the art.

As used herein, the term "glidant" is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, corn starch, talc, ascorbil palmitate, calcium palmitate, combinations thereof and other such materials known to those of ordinary skill in the art.

As used herein, the term "lubricant" is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, sodium stearate, sodium steryl fumarate, talc, sodium lauryl sulfate, mineral oil, stearic acid, zinc stearate, suitable combinations thereof and other such materials known to those of ordinary skill in the art.

As used herein, the term "disintegrant" is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as com starch, potato starch, pre-gelatinized and modified starch (Starch 1500) thereof, sweeteners, clays, such as bentonite, croscarmellose sodium, microcrystalline cellulose (e.g. Avicel™.), crospovidone, polacrilin potassium, methyl cellulose sodium CMC, calcium CMC, HPMC, alginates, alginic acid, low substituted HPC, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.

As used herein, the term stabilizers are the compound that maintain the pH of the formulation used according to the present invention include, but are not limited to attapulgite, bentonite, calcium carbonate, calcium phosphate, calcium sulphate, mono ethanolamine, tri ethanolamine, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium benzoate, sodium hydroxide, sodium citrate, sodium sulfite, sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, mono basic potassium phosphate, dicalcium phosphate, meglumine, light or heavy magnesium oxide and other similar excipients and their suitable combinations and other materials known to those of ordinary skill in the art.

As used herein, the term "carrier polymer" is intended to mean substances used to act as carrier to form complex with API and enhance solubility. Such compounds include, by way of example and without limitation, alkylcellulose such as methylcellulose; hydroxyalkylcellulose such as hydroxyethylcellulose and hydroxypropylcellulose; hydroxyalkylalkylcellulose such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; hypromellose acetate succinate, methylcellulose phthalate, cellulose acetate phthalate, polyethylene glycol, ethylcellulose, pyroxylin, polyethylene oxide, polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol, hydroxypropyl methylcellulose phthalate, hydroxybutylcellulose, carboxymethylcellulose, 60:40 copolymer of N-vinyl-2-pyrrolidone and vinylacetate, sodium carboxymethylcellulose, carboxymethyl- ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymers polyvinyl alcohol; polyvinyl pyrrolidone and combinations thereof. Of these, polyvinyl pyrrolidone is particularly preferable.

The sweetener in the formulations of the present invention selected from a group comprising isomalt, sorbitol, acesulfame, aspartame, alitame, fructose, maltitol, lactitol, xylitol, erythritol, saccharin, sodium cyclamate, sucralose, sucrose, neotame, neohespiridine dihydrochalcone, glycyrrhizin, stevloside, thaumatin, tagatose or suitable combination thereof.

The flavouring agent in the formulations of the present invention selected from a group comprising levomenthol, menthol, anethole, methyl salicylate, eucalyptol, cinnamon, mint, mango, almond, anise, celery, cassia, nutmeg rosemary, savory, basil, sweet marjoram, wintergreen, peppermint, 1-methyl acetate, sage, eugenol, oxanone, lemon, orange, strawberry, blackberry, raspberry, banana, butterscotch, coconut-custard, cinnamon , grinatidine, portwine, gaulterial, peppermint, clove, berry, aniseed, eucalyptus, thyme oil, cedar leaf oil, walnut oil, sage oil, bitter almonds, vanilla, citrus oil, including grape, lime and grapefruit, and fruit essences, including apple, pear, peach, raspberry, cherry, maple, plum, pineapple, apricot or combinations thereof.

As used herein, the term "solvents" is intended to mean a compound or mixture of more than one used to dissolve the API and the carrier polymer in one phase. Examples of the solvent may include, without limitation, water, methanol, ethanol, methylene chloride, acetone, methyl acetate, ethyl acetate, chlorinated solvents, N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) or dimethylacetamide (DMAc), n-propanol, isopropanol, butanol, methyl ethyl ketone and methyl isobutyl ketone, ethyl acetate and propylacetate, acetonitrile, toluene, 1,1,1-trichloroethane or suitable combinations thereof.

Suitable coloring agents include, one or more natural and/or artificial colorants such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, and the like. In one aspect, the present invention provides a stable orodispersible formulation of compounds of formula (I)

Formula (I) or its pharmaceutically acceptable salts.

Preferably, the present invention provides a stable orodispersible tablet formulation of saroglitazar magnesium of compound of formula (I-a).

Formula (I-a) The present invention further describes a stable orodispersible formulation of compounds of formula (I) or its pharmaceutically acceptable salts preferably a compound of formula (I-a), comprising one or more pharmaceutical excipients.

In a preferred embodiment, the orodispersible formulation of compound of formula (I) or its pharmaceutically acceptable salts, preferably a compound of formula (I-a) of the present invention essentially comprises of

(i) a diluent or filler , wherein the diluent or filler is mannitol where 10 % of particles should not be more than 315 μm and 90 % of particles should not be less than 75 μm;

(ii) a disintegrating agent; (iii) a soluble excipients component part more than 50%w/w. (iv) and one or more pharmaceutically acceptable excipient.

Suitable disintegrating agent in the formulations of the present invention selected from a group comprising croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate or low-substituted hydroxypropyl cellulose.

Soluble excipients component part is selected from mannitol, lactose, aspartame or mixture thereof.

The other pharmaceutical excipients according to the present invention can be selected from stabilizers, binders, lubricants, glidants, sweeteners, carrier polymer, solvents, flavoring agents and colors and the like as known in the art.

Any conventional gelling matrix forming agent may be used for purposes of the present disclosure. Suitable gelling matrix forming agents include, without limitation, gelling gelatin, carageenan gums, hyaluronic acid, pectins, sodium pectate, starches, carboxymethyl cellulose sodium, agar, gellan gum, xanthan gum, guar gum, tragacanthan gum, hydroxypropyl cellulose, hydroxyethyl cellulose hydroxypropyl methylcellulose, methylcellulose, carbopols, carbomers, poloxamer, polyacrylic acid, polyvinyl alcohol, alginates and poly(glycolic acid) or suitable combinations thereof. Any of excipients may have more than one role in formulation for example starch used as both binder and glidant in formulation.

In one embodiment of the above aspects, orodispersible formulation according to the present invention comprises from about 0.5 % to about 10 % w/w compound of Formula (I-a).

In one embodiment, the present invention provides a stable orodispersible tablet formulation which disintegrates rapidly by the action of saliva in the oral cavity. In an embodiment, the orodispersible tablet of the present invention disintegrates in less than 60 seconds, preferably in less than 40 seconds.

In one embodiment, the orodispersible tablet formulation of the present invention comprises compound of formula (I) or its pharmaceutically acceptable salts, preferably compound of formula (I-a) having particle size (D90) of is less than 200 μm, preferably less than 100 μm, more preferably less than 75μm.

The orodidpersable formulation of the present invention comprise orodispersable tablet formulation of compound of formula (I) or its pharmaceutically acceptable salts, preferably compound of formula (I-a) with good disintegration characteristics and pharmacokinetics, which provide improved compliance for patients in need thereof.

In one embodiment, the orodispersible tablet formulation of the present invention may further comprise one or more known impurities and if present their individual limit should not be more than 1.5 %.

In a further embodiment, the orodispersible tablet formulation of the present invention may further comprise one or more unknown impurities and if present their individual limit should not be more than 0.5%.

In a further another embodiment, the orodispersible tablet formulation comprising a therapeutically effective amount of compound of formula (I) or its pharmaceutically acceptable salt preferably compound of formula (I-a) and a pharmaceutically acceptable excipient, wherein the composition provides a serum or plasma profile comprising a mean of C_max of from about 19.50 ng/ml to about 850 ng/ml, when administered to the patient in need thereof. In one embodiment, the pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or its pharmaceutically acceptable salt preferably compound of formula (I-a) and a pharmaceutically acceptable excipient, wherein the composition provides a serum or plasma profile comprising a mean of AUC_last of from about 46.50 hr*ng/ml to about 2050 hr*ng/ml, when administered to the patient in need thereof.

In one embodiment, the pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or its pharmaceutically acceptable salt preferably compound of formula (I-a) and a pharmaceutically acceptable excipient, wherein the composition provides a serum or plasma profile comprising a T_max of from about 0.25 hr to about 2.0 hr, when administered to the patient in need thereof.

In one embodiment, the orodispersible tablet formulation of the present invention may be packed in suitable size HDPE bottle pack or Blister pack or Blister in pouch pack using appropriate desiccant and/or oxygen scavenger and/or packaging component under nitrogen environment. This may help to stabilize the drug product to control the moisture and oxygen sensitive impurities.

Orodispersible formulation according to the present invention may be in the form of a tablet or capsule or a powder or a suspension in a liquid or an aerosol formulation or solutions, preferably in the form of a tablet.

In one of the embodiment, the orodispersible formulations prepared according to the present invention comprise Saroglitazar magnesium in the range of about 0.5% to about 8 % (w/w), disintegrant in the range of about 1% to about 10 % (w/w), binder in the range of about 0.1 % to about 15 %, diluent in the range of about 5 % to about 90% (w/w), wetting agent in the range of about 2 % to about 20%, alkanilizer agent in the range of about 1% to about 16% (w/w), glidant in the range of about 0.1% to about 2.0 % (w/w), sweetener in the range of about 0.1% to about 50% (w/w), antioxidant in the range of about 0.1 % to about 10 %, gelling matrix forming agent in the range of about 0.1% to about 20%, carrier polymer in the range of about 0.5% to about 50%, solvents in the range of about 2% to about 90%, flavoring agent in the range of about 0.1% to about 8 % (w/w) and lubricant in the range of about 0.1% to about 4% (w/w) in proportion to total weight of unit dose. In a preferred embodiment, the orodispersible formulation prepared according to the present invention as disclosed in example 1-7.

The orodispersible formulation may be made by direct compression, wet granulation, dry granulation, lyophilization, solid dispersion or top spray granulation methods by techniques known to persons skilled in the art. Thus, for example,

In wet granulation process, the drug is mixed with one or more pharmaceutical excipients and granulated with suitable binding solution as described earlier, to form wet granules; the wet granules are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.

In direct compression process, the drug is mixed with all the pharmaceutical excipients required and then is compressed into tablets.

In dry granulation process the drug is mixed with one or more pharmaceutical excipients and compressed into slugs and these slugs are passed through required size of sieve. The sieved granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.

In lyophilization process the drug is suspended in water with one or more suitable pharmaceutical excipients with or without help of homogenization. The resultant suspension is accurate filled in suitable aluminum blister and lyophilized. The lyophilized tablets are sealed in the blister pack.

In solid dispersion process the drug and a suitable polymer are dissolved in a common solvent or mixture of solvents to form drug polymer complex. The remaining excipients are passed through required size of sieve and granulated with the drug polymer solution under controlled process. The wet granules are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets.

In top spray granulation process the drug is dissolved in a suitable solvent or mixture of solvents. The bulk of one or more excipients are passed through appropriate size of sieve and granulated with the drug solution under controlled process. The wet granules are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets. In another aspect of the present invention, provides processes for the preparation of a stable pharmaceutical composition of compounds of formula (I), preferably a compound of formula (I-a).

Manufacturing process comprises following techniques: 1. Wet Granulation

2. Direct compression

3. Dry-granulation

4. Lyophilization

5. Solid dispersion 6. Top spray granulation

The invention is further exemplified by the following non-limiting example, which is illustrative representing the preferred modes of carrying out the invention. The invention’s scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge that are within the general understanding of a person skilled in the art.

Example 1

Example 2

Example 3

Example 4

Example 5

Brief manufacturing Process of ODT (Direct Compression)

1. All excipients and compound of formula (I-a) are weighed accurately.

2. Compound of formula (I-a) is mixed with part quantity of mannitol and sifted through sieve #30.

3. Magnesium oxide light is mixed with remaining quantity of mannitol and sifted through sieve #30.

4. Half material of step 3 and complete material of step 2 and then remaining half material of step 3 are added in conta blender and blended for 5 min at 18 RPM. 5. Iron oxide red is sifted with of microcrystalline cellulose through sieve #40 and kept aside.

6. Remaining microcrystalline cellulose, crospovidone, colloidal silicon dioxide, peppermint and aspartame are sifted through sieve #40 with material of step 5 and added them to blender and blended for 15 min at 18 RPM.

7. Magnesium stearate is sifted through #60 and added into step 6 and blend is lubricated for 5 min at 18 RPM.

8. Final lubricated blend is compressed in to tablets.

Example 6

Brief manufacturing Process of ODT (Lyophilization)

1. Mannitol and gelatin are dissolved in purified water heated at 60°C under stirring.

2. Once clear solution obtained, magnesium oxide and compound of formula (I-a) are suspended in to it under stirring.

3. The suspension of step 2 is homogenized using high speed homogenizer.

4. The resultant suspension is accurately filled by specified weight in to pockets of aluminum blister and lyophilized.

5. The prepared tablets are packed in the blisters pack.

Example 7

*Does not remain in the final product

Brief manufacturing Process of ODT (Solid dispersion)

1. Compound of formula (I-a) and polyvinylpyrrolidone are dissolved in dichloromethane system under stirring.

2. Intragranular excipients (magnesium oxide light, mannitol, crospovidone and microcrystalline cellulose) are weighed accurately and mixed properly in suitable granulator.

3. To the dry blend of step 2, API polymer solution is added and the blend is granulated.

4. The wet mass of step 3 is passed through # 10 and the wet granules are dried in fluid bed dryer at temperature below 35°C.

5. The dried granules of step 4 are milled to get uniform granules.

6. Colloidal silicon dioxide, peppermint flavor and aspartame are weighed and passed along with the milled granules of step 5 through # 30.

7. The above blend is mixed in the conta blender

8. Talc and magnesium stearate are added and mixed.

9. The final blend is compressed to make the tablet dosage form.

Example 8

*Does not remain in the final product

Brief manufacturing process (Top spray granulation)

1. Compound of formula (I-a) are dissolved in suitable solvent or solvent system under stirring.

2. Intragranular excipients (magnesium oxide light, mannitol, crospovidone and microcrystalline cellulose) are weighed accurately and mixed and loaded in to fluidized bed granulator.

3. The dry blend is granulated using the API solution using top spray granulation technique.

4. The wet granules of step 3 are dried in fluid bed dryer at temperature below 35°C.

5. The dried granules of step 4 are milled to get uniform granules.

7. The above blend is mixed in the conta blender.

8. Talc and magnesium stearate are added and mixed.

9. The final blend is compressed to make the tablet dosage form.

1.0. Wet Granulation

Suitable intragranular excipients and compound of formula (I- a) are weighed accurately and mixed properly in suitable granulator. To the dry blend, IPA is added and the blend is granulated. The wet mass is passed through # 10 and the wet granules are dried in fluid bed dryer at temperature below 60°C. The dried granules are milled to get uniform granules. Colloidal silicon dioxide, peppermint flavor and aspartame are weighed and passed along with the dried granules through # 30. The above blend is mixed with the granules in the conta blender and to the dried mass; talc and magnesium stearate are added and mixed. The final blend is compressed to make the tablet dosage form. 2.0 Dry granulation

Suitable excipients and compound of formula (I-a) are mixed and passed through a roller compactor. Obtained compressed powder/slug is then subjected to milling to get uniform particle size granules which are further lubricated and compressed to make tablet dosage form. Table 1 given below shows stability data of stable orodispersible tablet formulation of Example- 1 as exemplified above.

Table 1

Tables 2, 3 and 4 given below show analytical data of orodispersible tablet formulation of Example-6, Example-7 and Example-8 respectively as exemplified above.

Table 2

Table 3

Table 4

Table 5 given below shows stability data of stable orodispersible tablet formulation of Example-4 as exemplified above.

Table 5

Saroglitazar magnesium ODT dosage form have better advantage over conventional immediate release (IR) dosage form, where disintegration time is observed less than 60 seconds. Saroglitazar magnesium ODT having higher soluble fraction of excipients (more than 70%) as well as sweetner and flavoring agents which make ODT formulation more patient compliant. The higher soluble fraction of excipient along with sweetner and flavoring agent renders pleasant mouth feeling.

IR formulation of Saroglitazar as mentioned here can be prepared according to the US patent No. US 10098868 B2. Table 6 given below shows comparative data of stable orodispersible tablet formulation and IR formulation of Compound of formula (I) or its pharmaceutically salts, preferably Compound of formula (I- a).

Table 6

Table 7 given below shows comparative In-vitro dissolution data of stable ODT formulation and IR formulation. Despite of change in the formulation composition of Saroglitazar magnesium ODT formulation, the dissolution profile of Saroglitazar magnesium ODT formulation found comparable to conventional IR formulation.

Table 7

Pharmacokinetic study of Saroglitazar magnesium: Immediate release Tablets ( IR) vs

Orodispersible Tablets (OPT)

Objective:

To assess the bioequivalence of Saroglitazar magnesium OD Tablets 2 mg in healthy, adult, human subjects under fasting conditions.

Test Product: Saroglitazar magnesium OD tablet 2 mg

Reference Product: Saroglitazar magnesium IR tablet 2 mg

Design of Study:

An Open-label, balanced, randomized, two-treatment, two-sequence, two-period, crossover, single dose, oral bioequivalence study in 13 healthy, adult, human subjects under fasting conditions were carried out to assess the bioequivalence of Saroglitazar magnesium OD Tablets 2 mg in healthy, adult, human subjects under fasting conditions against Saroglitazar magnesium Immediate release Tablets 2 mg.

Procedure of Test and Reference Product administration:

Test Product: After an overnight fasting of at least 10 hours, subjects were administered a single 2 mg oral dose of Test Product in a sitting posture without drinking water as per randomization schedule. Subjects were required to place the Test Product on the tongue without crushing or breaking the tablet with teeth till it completely dispersed in saliva and then subjects were allowed to swallow the content without administration of water. Subjects were allowed to wet the mouth by swallowing 20 ml of 20% Glucose solution 10 min before placing the ODT on the tongue.

Reference Product: After an overnight fasting of at least 10 hours, subjects were administered a single 2 mg oral dose of Reference Product in a sitting posture with about 240 ± 2 mL of 20% Glucose solution at ambient temperature as per randomization schedule.

Summary Results:

The summary of Pharmacokinetic results is detailed below. Table 1: Summary of Pharmacokinetic results (N=13)

^Median Tmax

Based on the pharmacokinetic results, it is observed that Cmax, AUC_0-t and AUC_0-I value of Saroglitazar magnesium OD Tablets 2 mg are comparable to Saroglitazar magnesium immediate release tablets 2 mg.

References:

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Claims

We claim:

1. An orodispersible formulation comprising compound of formula (I)

Formula (I) or its pharmaceutically acceptable salt comprising,

(ii) a disintegrating agent;

(iii) a soluble excipients component part more than 50%w/w.

(iv) and one or more pharmaceutically acceptable excipient.

2. The orodispersible formulation as claimed in claim 1, wherein the pharmaceutically acceptable salt is Mg salt.

3. The orodispersible formulation as claimed in claim 2, having particle size distribution having D₉₀ value of less than 200 μm, preferably less than 100 μm, more preferably less than 75μm.

4. The orodispersible formulation as claimed in any preceding claim of claims 1 to 3 is in the form of a tablet or a caplet or a capsule or a powder or a suspension in a liquid or an aerosol formulation or solutions, preferably in the form of a tablet.

5. The orodispersible formulation as claimed in claim 4, wherein the orodispersible tablet is able to disintegrate in the buccal cavity upon contact with saliva by formation of an easy-to-swallow suspension, in less than 60 seconds, more preferably less than

40 seconds.

6. The orodispersible formulation as claimed in claim 1, wherein the soluble excipients component part is selected from mannitol, lactose, aspartame or mixture thereof.

7. The orodispersible formulation as claimed in claim 1, wherein the pharmaceutical excipient is selected from stabilizers, diluent or filler, lubricants, glidants, sweeteners, flavoring agents and colors or suitable combination thereof.

8. The orodispersible formulation as claimed in claim 1, wherein the disintegrating agent is selected from croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate or low-substituted hydroxypropyl cellulose.

9. The orodispersible formulation as claimed in claim 1 or 7, wherein the disintegrating agent is present in 1 to 10% by weight, based on the weight of the tablet.

10. The orodispersible formulation as claimed in claim 1, wherein the diluent or filler is present in 5 to 90% by weight, based on the weight of the tablet.

11. The orodispersible formulation as claimed in claim 6, wherein the sweetener is present in 0.1 to 50% by weight, based on the weight of the tablet.

12. The orodispersible formulation as claimed in claim 6, wherein the flavoring agent is present in 0.1 to 8% by weight, based on the weight of the tablet.

13. The orodispersible formulation as claimed in claim 6, wherein the glidant is present in 0.1 to 2% by weight, based on the weight of the tablet.

14. The orodispersible formulation as claimed in claim 6, wherein the lubricant is present in 0.1 to 4% by weight, based on the weight of the tablet.

15. The orodispersible formulation as claimed in claim 6, wherein the flavoring agents is selected from levomenthol, menthol, anethole, methyl salicylate, eucalyptol, cinnamon, mint, mango, almond, anise, celery, cassia, nutmeg rosemary, savory, basil, sweet marjoram, wintergreen, peppermint, 1-methyl acetate, sage, eugenol, oxanone, lemon, orange, strawberry, blackberry, raspberry, banana, butterscotch, coconut-custard, cinnamon, grinatidine, portwine, gaulterial, peppermint, clove, berry, aniseed, eucalyptus, thyme oil, cedar leaf oil, walnut oil, sage oil, bitter almonds, vanilla, citrus oil, including grape, lime and grapefruit, and fruit essences, including apple, pear, peach, raspberry, cherry, maple, plum, pineapple, apricot or combinations thereof.

16. An orodispersible formulation comprising a therapeutically effective amount of Saroglitazar or its pharmaceutically acceptable salt preferably Saroglitazar magnesium and a pharmaceutically acceptable excipient, wherein the formulation provides a serum or plasma profile comprising a mean of C_max of from about 19.50 ng/ml to about 850 ng/ml, when administered to the patient in need thereof.

17. An orodispersible formulation comprising a therapeutically effective amount of Saroglitazar or its pharmaceutically acceptable salt preferably Saroglitazar magnesium and a pharmaceutically acceptable excipient, wherein the formulation provides a serum or plasma profile comprising a mean of AUQast of from about 46.50 hr.ng/ml to about 2050 hr.ng/ml, when administered to the patient in need thereof.

18. An orodispersible formulation comprising a therapeutically effective amount of or its pharmaceutically acceptable salt preferably Saroglitazar magnesium and a pharmaceutically acceptable excipient, wherein the formulation provides a serum or plasma profile comprising a T_max (median) of from about 0.25 hr to about 2.0 hr, when administered to the patient in need thereof.

19. A pharmaceutical composition comprising:

(i) from 0.5 to 10 % by weight of Saroglitazar or its pharmaceutically acceptable salt; more prefarably between 0.5 to 5%.

(ii) from 1 to 10 % by weight of a disintegrant selected from croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate or low-substituted hydroxypropyl cellulose; more preferably crospovidone.

(v) Having soluble fraction of excipients more than 50%w/w

(iii) from 5 to 90 % by weight of a diluent selected from microcrystalline cellulose, lactose, starch or mannitol; more preferably mannitol and microcrystalline cellulose

(iv) from 1 to 16 % by weight of an stabilizing agent selected from meglumine, light or heavy magnesium oxide; more preferably magnesium oxide light

(v) from 0.1 to 50 % by weight of a sweetner selected from aspartame, sucralose, neotame, sacharrine; more preferably aspartame

(vi) from 0.1 to 8 % by weight of a flavouring agent selected from peppermint flavour, vanilla flavour; more preferably peppermint

(vii) from 0.1 to 15 % by weight of a glidant selected from colloidal silicon dioxide, calcium silicate and magnesium silicate; more preferably colloidal silicon dioxide

(vii) from 0.1 to 4 % by weight of a lubricant from calcium stearate, magnesium stearate, sodium stearate, stearic acid and sodium steryl fumarate; more preferably magnesium stearate

20. A method of treatment for primary biliary cholangitis (PBC) in a patient comprising administering to a patient in need thereof the pharmaceutical composition as claimed in claim 1.

21. A method of treatment for primary biliary cholangitis (PBC) in a patient comprising administering to a patient in need thereof the pharmaceutical composition as claimed in claim 19.