DESC:FORM 2
THE PATENTS ACT 1970
(39 OF 1970)

COMPLETE SPECIFICATION
(Section 10, rule 13)

“ORAL PHARMACEUTICAL COMPOSITION OF OBETICHOLIC ACID”
OPTIMUS PHARMA PRIVATE LIMITED,
SY NO. 37/A & 37/P, PLOT NO. 6P, 2nd FLOOR
SIGNATURE TOWERS, KOTHAGUDA, KONDAPUR, HYDERABAD
TELANGANA, INDIA 500084
A company incorporated under Indian Company Act, 1956

The following specification particularly describes the nature of this invention and the manner in which it is to be performed.
TITLE OF THE INVENTION:
“ORAL PHARMACEUTICAL COMPOSITION OF OBETICHOLIC ACID”
FIELD OF THE INVENTION:
The present invention relates to an oral pharmaceutical composition comprising solid dosage form of Obeticholic acid tablets. The composition is also suitable for use in the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.
BACKGROUND OF THE INVENTION:
Obeticholic acid is a semi-synthetic bile acid analogue which has the chemical name as 6a-ethyl-chenodeoxycholic acid. It is used as a drug to treat primary biliary cholangitis (PBC), and is undergoing development for several other liver diseases and related disorders. It is an analog of the naturally occurring bile acid chenodeoxycholic acid (CDCA) and agonist of the farnesoid X receptor.

Obeticholic acid was first approved by the U.S. Food and Drug Administration (FDA) on May 27, 2016 and then approved by European Medicine Agency (EMA) on Dec 12, 2016. It was developed and marketed as Ocaliva® by Intercept Pharms Inc, in the U.S. Obeticholic acid is available as tablet for oral use, containing 5 mg and 10 mg strength. Other names of Obeticholic acid is INT-747 and OCA.

OBETICHOLIC ACID

US10052337 B2 disclosure relates to a method for preparing an Obeticholic acid tablet composition comprising Obeticholic acid is in the form of particles at least d50 is 200 micrometer or less.
WO2017170858 A1 discloses oral preparation containing Obeticholic acid tablet and a water-soluble excipient, (ii) a disintegrant, and (iii) a water-soluble polymer binder.
WO2017170854 A1 discloses film-coated tablet comprising obeticholic acid, b) Film base and is substantially free of plasticizers.
CN106822005 A disclosure relates to an obeticholic acid composition comprises obeticholic acid, micro carrier and pharmaceutically acceptable accessories for an oral solid preparation.
Obeticholic acid is a BCS Class II compound which has low solubility and soluble in the organic solvents like ethanol, methanol, acetone and ethyl acetate.
The above attempts only provided compositions of Obeticholic acid, which are either tedious, expensive or technologically demanding to prepare or are unlikely to remain stable over the shelf life of the product. Therefore, it need exists to prepare alternate compositions of Obeticholic acid that are stable, cost effective and it also provides the desired in vitro release and bioavailability.
Obeticholic acid is a BCS Class II compound which has low solubility and soluble in the organic solvents like ethanol, methanol, acetone and ethyl acetate.
When compositions containing a high concentration of a poorly water-soluble drug are produced, usually, powders are tableted by direct compression or granules are produced by dry or wet granulation methods. However, tableting by direct compression and granulation are largely affected by the physical properties of the drug and often have great weight variations and poor content uniformity at the time of tableting, resulting in poor manufacturability in consideration of productivity. Moreover, these approaches can provide a drug product with poor dissolution.
In order to solve the above problems, the present inventors have developed a composition, which provides stable product, cost effective product, as well as improved drug bioavailability.
SUMMARY OF THE INVENTION:
The present invention relates to obeticholic acid solid dosage form and a preparation method by dry granulation technique.
In one aspect of the present invention provides process for the preparation of stable oral pharmaceutical compositions, wherein the method of manufacturing comprises the following steps:
1. Intragranular composition comprising Obeticholic acid and/or diluent sifting through 600µm mesh (ASTM, #30 sieve) and blended.
2. Compacted with roll compactor and milled until all the granules passes through 30# mesh.
3. Extra granular portion composition comprising Diluent and/or disintegrant and/or glidant sifted through 600µm mesh (ASTM, #30 sieve) and blended intragranular components.
4. Obtained granules were blended with magnesium stearate which is passed through 60# mesh.
5. Finally Compressed into tablets and Film coated.
In another aspect of the present invention, the solid dosage form comprising obeticholic acid, diluent, disintegrating agent, lubricants, solvents and water soluble polymers and/or water insoluble polymers.
The above said method is prepared by dry granulation technique by using roll compaction method.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to stable oral pharmaceutical composition comprising Obeticholic acid, diluents and pharmaceutical acceptable excipients.
In one embodiment of the present invention, the stable pharmaceutical composition of Obeticholic acid comprising:
a) an intra granular portion with Obeticholic acid and a diluent; and
b) an extra granular portion with pharmaceutically acceptable excipients.
Another embodiment of the present invention provides process for the preparation of stable oral pharmaceutical compositions, wherein the process comprises of the following steps:
1. Intragranular composition comprising Obeticholic acid and/or diluent sifting through 600µm mesh (ASTM, #30 sieve) and blended.
2. Compacted with roll compactor and milled until all the granules passes through 30# mesh.
3. Extra granular portion composition comprising Diluent and/or disintegrant and/or glidant sifted through 600µm mesh (ASTM, #30 sieve) and blended intragranular components.
4. Obtained granules were blended with magnesium stearate which is passed through 60# mesh.
5. Finally Compressed into tablets and Film coated.
The term “composition” or “pharmaceutical composition” or “dosage form” as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
The term ‘excipient’ means a pharmacologically inactive component such as diluent, disintegrant, carrier, filler, lubricant, binder, and solvent, coating agent or the like. These are generally safe, nontoxic. Reference to an excipient includes both one and more than one such excipient.
The term ‘stable’ refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.
Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", “having”, “containing” "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
According to the embodiments of the present invention diluent includes, but are not limited to, Micro crystalline cellulose, starch, pregelatinized starch, calcium carbonate, dibasic, tribasic calcium phosphate, calcium phosphate, lactose, dextrose, calcium phosphate, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, maltodextrin and mixtures thereof.
According to the embodiments of the present invention disintegrant includes, but are not limited to, starches, croscarmellose sodium, carmellose, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate, low-substituted hydroxypropylcellulose , crospovidone and mixtures thereof.
According to the embodiments of the present invention lubricant includes, but are not limited to, anti-tacking agent, sodium lauryl sulphate, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glycerylpalmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearylfumarate, sodium benzoate, mineral oil, glycerine fumarate and mixtures thereof.
According to the embodiments of the present invention film coating agents includes, but are not limited talc, polyvinyl alcohol (part hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350) and iron oxide and the solvents includes, but are not limited to acetone, isopropyl alcohol, purified water, ethanol, polyol (for example, propylene glycol , glycerol and liquid polyethylene glycol and the like.
In yet another embodiment of the present invention, the composition comprising Obeticholic acid having at least 50 % of particles with diameter more than about 200 micrometers and each tablet comprising 5mg or 10mg of Obeticholic acid.
The details of the present invention are given in the below description with other features and advantages.
According to embodiment of the present invention, the composition will provide stable product, cost effective one as well as improved drug bioavailability. Moreover, inventors here using simple method in comparative to above said prior art methods.
In yet another embodiment of the present invention, the composition will provide stable product as well as improved drug bioavailability as shown in the comparative dissolution data in Table 01.

Table.01
Dissolution in 900 mL of 0.08% polysorbate 80 in 50mM sodium phosphate dibasic buffer, pH 6.8 using USP apparatus II (paddle) at 75 rpm (OGD Condition)
Batch Number Test Product Reference Product
Time Point (min) % Drug Release
05 81 86
10 86 92
15 89 93
20 90 94
30 93 94
45 92 93

Figure. 01

The present invention is used for method of treating a condition selected from the group consisting of primary sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis and liver fibrosis in a patient in need thereof.
The method of preparing a composition is provided in the example given below, which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Examples-1
Table 02

S.No. Ingredients Qty per Unit (mg)
5 mg % w/w 10 mg % w/w
Intragranular Portion
1. Obeticholic acid 5.00 2.50 10.00 5.00
2. Microcrystalline cellulose 105.00 52.5 100.00 50.00
Extragranular Portion
3. Microcrystalline cellulose 76.00 38.00 76.00 38.00
4. Sodium starch glycolate 12.00 6.00 12.00 6.00
5. Magnesium stearate 2.00 1.00 2.00 1.00
Uncoated Tablet weight (mg) 200.00 100.00 100.00 100.00
Film Coating
6. Opadry II Yellow 6.00 -- 6.00 --
7. Purified water QS -- QS --
Coated Tablet Weight (mg) 206.00 -- 206.00 --

$ Opadry Yellow contains Hypromellose, Polyethylene Glycol 3350, Talc, Yellow Iron oxide Non-IRR and Titanium Dioxide.

BRIEF MANUFACTURING PROCESS:
Sifting
i. Co-sift Obeticholic acid and microcrystalline cellulose through sieve # 30 ASTM.
ii. Re-sift material of step-i through sieve #30 ASTM.
Pre Mixing
iii. Load the sifted material of step-ii into the blender and mix for 20 minutes.
Dry granulation
iv. Compact the blend from step iii using Roller Compactor using suitable parameters.
v. Sift the compacts of step v through sieve # 40 ASTM and mill the oversize material through co-mill fitted with 0.5 mm screen at medium speed and pass the materials through sieve # 40 ASTM.
Sifting of extra-granular material
vi. Sift microcrystalline cellulose, sodium starch glycolate through sieve #40 ASTM.
vii. Sift magnesium stearate through sieve #60 ASTM (250 µm).
Blending and Lubrication
viii. Load the granules of step-v and step-vi materials in blender and mix for 20 minutes.
ix. Add pre-sifted magnesium stearate of step-vii to above material and mix for 5 minutes at slow speed.
Compression
x. Compress the lubricated blend of step-ix using Tablets compression machine
Film Coating:
xi. Disperse Opadry II in purified water (15% w/w solids) under stirring and continue stirring for 45 minutes to form uniform dispersion.
xii. Load the uncoated tablets of step-x in coating pan and coat the tablets with Opadry II solution of step xi with suitable parameters till it reaches weight gain of 3.0 ± 1.0% w/w. After achieving the desired weight gain, dry the coated tablets for 15 minutes with low inlet temperature.
,CLAIMS:WE CLAIM:

1. A stable pharmaceutical composition of Obeticholic acid comprising:
a) an intra granular portion with Obeticholic acid and a diluent; and
b) an extra granular portion with pharmaceutically acceptable excipients.
2. The pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of tablet.
3. The pharmaceutical composition as claimed in claim 1, comprising a tablet of 5mg or 10mg of Obeticholic acid.
4. The pharmaceutical composition as claimed in claim 1, comprising Obeticholic acid having at least 50 % of particles with diameter more than about 200 micrometers.
5. The pharmaceutical composition as claimed in claim 1, wherein the intra granular composition comprising diluents selected from Micro crystalline cellulose, starch, pregelatinized starch, calcium carbonate, dibasic, tribasic calcium phosphate, calcium phosphate, lactose, dextrose, calcium phosphate, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, maltodextrin.
6. The pharmaceutical composition as claimed in claim 1, wherein extra granular portion comprising pharmaceutically acceptable excipients are selected from diluents, disintegrants, film coating agents, lubricants and solvents.
7. The pharmaceutical composition as claimed in claim 6, wherein diluents are selected from Micro crystalline cellulose, starch, pregelatinized starch, calcium carbonate, dibasic, tribasic calcium phosphate, calcium phosphate, lactose, dextrose, calcium phosphate, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, maltodextrin.

6. The pharmaceutical composition as claimed in claim 6, wherein disintegrants are selected from one or more of starches, croscarmellose sodium, carmellose, low-substituted hydroxypropyl cellulose , crospovidone.
7. The pharmaceutical composition as claimed in claim 6, wherein film coating agents are selected from talc, polyvinyl alcohol (part hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350) and iron oxide.
8. The pharmaceutical composition as claimed in claim 6, wherein lubricants are selected from magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil and glycerine fumarate.
9. The pharmaceutical composition as claimed in claim 6, wherein solvents are selected from ethanol, water, polyol (for example, propylene glycol, glycerol, and liquid polyethylene glycol, and the like) and suitable mixtures thereof.

Dated this fifth (5th ) day of February, 2020