DESC:FIELD OF THE INVENTION:
The present invention relates to novel stable pharmaceutical oral solid composition comprising, Relugolix or a pharmaceutically acceptable salt thereof. The present invention, more particularly, relates to a stable oral tablet composition comprising, relugolix or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, and their use in medical therapy. Furthermore, the present invention provides enhanced dissolution profile of Relugolix oral solid dosage form.

BACKGROUND OF THE INVENTION:
Relugolix (RGX; RVT-601; TAK-385) is sold under the brand names Orgovyx® and Relumina® among others, is a gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) medication which is used in the treatment of prostate cancer in men and uterine fibroids in women. It is also under development for use in the treatment of endometriosis.

Relugolix is chemically known as 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d] pyrimidin-6-yl]phenyl]-3-methoxyurea and is structurally represented as below:

Relugolix film-coated tablets for oral administration marketed under Orgovyx® was first disclosed in US7709517. Each tablet contains 120 mg of relugolix. The inactive ingredients are mannitol, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hypromellose, titanium dioxide, ferric oxide red, and carnauba wax. The recommended dose of relugolix is 12 mg, a loading dose of 360mg on the first day of treatment followed by 120mg taken orally once daily, at approximately the same time each day.

WO 2004/067535 discloses compound A and a salt thereof together with the method of manufacturing the compound. The compound A having superior gonadotropic hormone-releasing hormone antagonistic action can be used, for example, as a prophylactic or therapeutic agent for hormone dependent diseases.

WO2010/026993 discloses a preparation of the compound and a salt thereof, which contains an organic acid and shows improved oral absorbability.

WO2016136849 relates to a solid preparation (e.g., tablet) showing improved stability of relugolix and a salt thereof in the solid preparation, and a method of stabilizing the same. Low-melting fat and oil-like substance from polyethylene glycol, glycerol monostearate, and triethyl citrate are added for stabilizing relugolix or a salt of relugolix in a tablet. The fat and oil-like substance has a low melting point and an average molecular weight of about 6000 to 120000.

WO2021239917A1 claims a combination solid oral dosage form comprising about 18% to 22% w/w of relugolix or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.3% to 0.7% w/w of estradiol; about 0.1% to 0.4% w/w of norethindrone acetate; about 24% to 28% w/w of mannitol; about 2% to 6% w/w of a starch selected from the group consisting of sodium starch glycolate, pregelatinized starch, and a combination of the foregoing; about 0.5% to 3% w/w of hydroxypropyl cellulose; about 0.5% to 3% w/w of magnesium stearate; about 38% to 42% w/w of lactose monohydrate; and about 1% and 5% w/w of a film coating.

Delivery of the active pharmaceutical ingredient (API) is aided by formulating into dosage forms such as tablets, capsules, injections and creams. However, a major role is played by the excipients for the accurate administration of the API. Depending on the dosage form, the excipients perform various functions and the mode of action required. Excipients have an effect on the method and rate of delivery of the API to the patient. Another aspect of pharmaceutical formulations that affects the rate of delivery or the bioavailability of the pharmaceutically active substance is the particle size. This relationship between particle size and bioavailability is well known. While dissolution and bioavailability can be achieved through use of excipients, undesired interaction between the excipients and active substance is a huge risk. Poor bioavailability is a critical problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water.
Relugolix is classified as a BCS-4 drug (low solubility/low permeability). Coarser particles of Relugolix affect the drug release and resulting in incomplete dissolution. Controlling the particle size of relugolix tablet is critical during the formulation. There is an unmet need in the prior art to develop a patient compliant oral solid pharmaceutical formulation having enhanced dissolution of relugolix tablet.

The inventors of the present invention have arrived at an invention comprising micronized particle of relugolix that increases the solubility of relugolix and provides better dissolution profile. The present invention has further achieved higher stability of relugolix. The solubility and stability of the patient compliant relugolix formulation, prepared as per the present invention, is proven higher when compared to prior art inventions.

OBJECTIVE OF THE INVENTION
The primary object of the present invention is to provide to novel stable oral solid pharmaceutical formulation of relugolix or a pharmaceutically acceptable salt thereof. A solid pharmaceutical formulation comprising Relugolix in ranges from about 25mg to 500mg. by weight of the total composition. In certain embodiments, the Relugolix is present in a concentration of 120 mg to 360 mg per unit dose.

Another object of the present invention is to provide a novel stable oral solid pharmaceutical formulation of relugolix or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Yet another object of the present invention is to provide to oral solid formulation of relugolix or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Dosage forms include solid dosage forms like tablets, capsules, caplets, pellets, beads, granules, or powder.

Another object of the present invention is to provide oral solid dosage form, preferably a tablet dosage form that is bioequivalent.

Yet another object of the present invention is to provide a pharmaceutical composition of Relugolix wherein, Relugolix is in micronized form having a particle size distribution D90 about 1µm to 30µm, preferably from 5µm to 25µm, and more preferably from 10µm to 20µm.

Yet another object of the present invention is to provide a pharmaceutical composition of Relugolix or a pharmaceutically acceptable salt thereof having excellent dissolution profile and higher stability with minimum use of excipients.

Yet another object of the present invention is to provide a novel process for preparation of oral solid dosage pharmaceutical composition of Relugolix or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparation of oral solid dosage formulation of Relugolix by process but not limited to direct compression, wet granulation, dry granulation, top spray granulation or hot melt granulation techniques.

SUMMARY OF THE INVENTION:
The present invention relates to a novel oral solid pharmaceutical formulation comprising Relugolix as the active pharmaceutical ingredient (API) along with pharmaceutically acceptable excipients and process for preparation thereof. The formulation can be in the form of tablets, capsules, caplets, pellets, beads, granules, or powder, preferably oral tablet, and it is designed to enhance drug release and dissolution.

The invention also discloses the pharmaceutical formulation may include relugolix as an active ingredient with one or more selected from pharmaceutically acceptable excipients like diluent, disintegrants, binder, lubricants, granulating fluid and the like within the IIG level.

Another aspect of the invention is the solid pharmaceutical formulation comprising Relugolix in ranges from about 25mg to 500mg. by weight of the total composition. In certain embodiments, the Relugolix is present in a concentration of 120 mg to 360 mg per unit dose.

Another aspect of the invention is the use of micronized Relugolix with a particle size distribution D90 ranging from 1 to 30µm, ensuring improved drug dissolution and bioavailability. The formulation is developed using economical and advanced manufacturing techniques, making it more stable, efficient, and suitable for large-scale production with minimal excipients and reduced side effects.

In another aspect of the invention relates to various formulation methods, including but not limited to direct compression, wet granulation, dry granulation, top spray granulation, and hot melt granulation. A preferred method involves sifting, mixing, granulating, drying, milling, blending, lubrication, compression, and coating to obtain the final oral solid dosage form.

This novel formulation provides a fixed oral solid dose of Relugolix with improved drug release characteristics, making it a superior alternative to existing dosage forms.

In general aspect, pharmaceutical formulation as per the present invention is in the form of an oral solid dose comprising:
(a) Sifting and dry mixing of Relugolix API and other excipients
(b) Binder solution preparation with granulating fluid.
(c) Dry mixture of the blend prepared in step (a), is blended in rapid mixer granulator (RMG) to form wet mass.
(d) Drying the wet granules till loss on drying (LOD) is less than 2%.
(e) Sifting and milling the dried granules are blended along with disintegrant.
(f) Lubricant is added in the blend for lubrication.
(g) Lubricated blend is compressed to core tablet.
(h) Coating of core tablets to form a coated tablet.

The details of one or more embodiments of the invention are set forth in the description below. Other features of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.

References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.

The term "drug" or “active ingredient” or “active pharmaceutical ingredient (API)” herein refers to relugolix or a pharmaceutically acceptable salt thereof.

The term "relugolix" as used herein according to the present invention includes, relugolix in the form of free base, a pharmaceutically acceptable salt thereof, amorphous, crystalline, any isomer, derivative, hydrate, solvate or prodrug or a combination thereof.

The term "drug solution" as used herein according to the present invention includes solution obtained by dissolving relugolix or its pharmaceutically acceptable salt thereof in solvent and (or) mixture of solvents.

In accordance with the present invention, an oral solid pharmaceutical formulation of relugolix comprising of relugolix as an active ingredient with pharmaceutically acceptable excipients in oral solid dosage forms, preferably herein present invention in form of a tablet, capsule, caplet, pellets, beads, granules or powder.

In accordance with the present invention, an oral solid pharmaceutical formulation of relugolix comprising of relugolix as an active ingredient with pharmaceutically acceptable excipients.

Excipients used in pharmaceutical formulation for oral administration of pharmaceutically acceptable excipients in pharmaceutical formulations are physiologically inert compounds that are included in the formulation to facilitate the administration of the dosage form, e.g., pourability, palatability, to protect the formulation from issues regarding physical and chemical stability and to enhance the solubility of the therapeutic agent. Pharmaceutical formulation commonly contains a wide range of excipients, the details of which are provided below.

The term "pharmaceutically acceptable excipients" as used herein, refers to excipients those are routinely used in pharmaceutical formulations. The pharmaceutically acceptable excipients may comprise of diluent, disintegrants, binder, lubricants, granulating fluid and combinations thereof.

One embodiment further comprises a novel oral solid pharmaceutical formulation comprising Relugolix as the active pharmaceutical ingredient (API) along with pharmaceutically acceptable excipients and process for preparation thereof. A solid pharmaceutical formulation comprising Relugolix in ranges from about 25mg to 500mg. by weight of the total composition. In certain embodiments, the Relugolix is present in a concentration of 120 mg to 360 mg per unit dose.

In another embodiment, the pharmaceutical formulation may include relugolix as an active ingredient with one or more selected from pharmaceutically acceptable excipients like diluent, disintegrants, binder, lubricants, granulating fluid and the like within the IIG level.

In another embodiment, suitable binders may include but are not limited to one or more from of hydroxyl propyl methyl cellulose (HPMC or hypromellose), polyvinyl pyrrolidone (povidone), polyvinyl pyrrolidine, hydroxyl propyl cellulose, polyvinyl alcohol, methyl cellulose, ethyl cellulose, gum arabic, alginic acid, polyethylene glycol (PEG), pregelatinized starch (PGS) and combination thereof.

In yet another embodiment, suitable binder in a tablet dosage comprises, about 0.5 % to about 5.0% weight/ weight to total weight of tablet. Specifically, about 1.0 % to about 4.5 % weight/ weight to total weight of tablet.

In another embodiment, suitable diluents may include but are not limited to one or more of sugars such as lactose, sucrose glucose, fructose, dextrose, galactose, starch; cellulose derivatives such as microcrystalline cellulose; carbonates like calcium carbonate; sugar alcohols such as mannitol, sorbitol, erythritol; magnesium carbonate, calcium phosphates kaolin, magnesium oxide, magnesium hydroxide; and cellulose derivative such as Avicel CL-611 (Microcrystalline cellulose and Carboxymethylcellulose sodium and the like.

In yet another embodiment diluents may be selected from the group consisting of dextrates, dextrin, dextrose, fructose, 1-O-a-D-glucopyranosyl- mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, lactose monohydrate, maltitol, mannitol, maltodextrin, maltose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents.

In yet another embodiment, suitable diluents in a tablet dosage comprises, about 30% to about 90% weight/ weight to total weight of tablet. Specifically, about 40% to about 80% weight/ weight to total weight of tablet.

In another embodiment, suitable disintegrants may include but are not limited to one or more from crospovidone, croscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and the like.

In yet another embodiment, suitable disintegrants in a tablet dosage comprises, about 0.01% to about 9.0% weight/ weight to total weight of tablet. Specifically, about 1% to about 8%, weight/ weight to total weight of tablet.

In another embodiment, suitable lubricants may include but are not limited to one or more from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; and and mixtures thereof.

In yet another embodiment, suitable lubricants in a tablet dosage comprises, about 0.01% to about 5.0% weight/ weight to total weight of tablet. Specifically, about 0.5% to about 4.5%, weight/ weight to total weight of tablet.

In another embodiment, suitable solvents for preparing binding solution may include one or more from water, organic solvents such as ethanol, isopropyl alcohol (IPA), acetone, propylene glycol, glycerin and the like.

In another embodiment, the excipients used as listed above; however, it is not limited to the said excipients only.

In another embodiment, active ingredient Relugolix have a particle size distribution D90 with ranging from 1µm to 30µm. It has been observed by present inventors that various composition discussed in prior art suffer a disadvantage of coarser Relugolix that affects the drug release and gives incomplete dissolution. The present invention thus provides a pharmaceutical composition comprising Relugolix wherein the particle size provides better dissolution profile and solubility of the drug. The present invention comprises Relugolix API having particle size D90 ranging from 1µm to 30µm.

The present invention provides economical aqueous coating as an advantage over non-uniform and difficult which may result as blistering, chipping, picking, blushing, cracking (splitting) or the like.

The pharmaceutical composition comprising Relugolix according to the present invention is administered orally through the solid dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units), MUPS (multiple unit pellet systems), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates, sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like.

Preferably, the pharmaceutical composition comprising Relugolix according to the present invention may be administered in a solid oral dosage form of a tablet including film coated tablet, sugar coated tablet, chewable tablet, delayed release tablet, multiple compressed tablet, enteric coated tablets, effervescent tablet, dispensing tablet.

In another embodiment, an oral solid pharmaceutical formulation as per the present invention may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet granulation, dry granulation, top spray granulation or hot melt extrusion. Preferably, direct compression or wet granulation method.

In general embodiment, pharmaceutical formulation as per the present invention is in the form of an oral solid dose comprising:
(a) Sifting and dry mixing of Relugolix API and other excipients
(b) Binder solution preparation with granulating fluid.
(c) Dry mixture of the blend prepared in step (a), is blended in rapid mixer granulator (RMG) to form wet mass.
(d) Drying the wet granules till loss on drying (LOD) is less than 2%.
(e) Sifting and milling the dried granules are blended along with disintegrant.
(f) Lubricant is added in the blend for lubrication.
(g) Lubricated blend is compressed to core tablet.
(h) Coating of core tablets to form a coated tablet.

In another embodiment, an oral solid pharmaceutical formulation as per the present invention, comprising coating agent applied to the surface of the tablet.

Inventors of the present invention have surprisingly arrived at better intact property of composition and improvement in release profile. The dissolution profile was similar to reference product i.e., 120mg was found comparable and bioequivalent to the 120mg. More than 85% drug release was observed in 15 minutes.

The term "oral" administration means that the active agent is in a formulation designed to be ingested, i.e. designed to be delivered to the gastrointestinal system for absorption.

The term "solid oral composition" comprises capsule, tablet (film coated tablet, controlled release tablet, modified release tablet, extended release, delayed release, immediate release etc.), micro tablet, powder, granule and pellets. Capsules used as oral dosage form can be soft or hard capsules, though oral dosage form of the present invention is tablet.

The term "% w/w" refers to the relative value to total weight of granules or to total weight of pharmaceutical composition and “%v/v” refer to volume by total volume percentage.

The pharmaceutical composition of the present specification is stable at 9 months accelerated storage conditions and throughout the shelf life when subjected to accelerated and long-term stability studies. The present invention complies with the ICH (Q3B).

The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The scope of the invention is in no manner limited by the disclosed example.

Example 1: Relugolix tablets
Sr. No. Ingredients %w/w Role
Intra-granular material
1 Relugolix 20 - 50 API
2 Mannitol 30 - 60 Diluent
3 Microcrystalline cellulose 15 - 30 Diluent
4 Croscarmellose sodium 0.5 to 4 Disintegrant
Binder -
5 Hydroxy propyl cellulose 1 to 5 Binder
6 Purified water Q. S vehicle
Extra-granular material -
7 Croscarmellose sodium 1 to 5 Disintegrant
Stage B: Lubrication
8 Magnesium Stearate 0.05 to 2 Lubricant
Total Weight of Core Tablet 100.00 -
9 Opadry Brown 03F565212 NA Coating agent
10 Purified water Q. S Coating vehicle

Example 2: Relugolix tablets
Sr. No Ingredients % w/w
1. Relugolix 27.27
2. Mannitol 45.73
3. Crystalline cellulose (MCC) 18.87
4. Polyvinyl pyrrolidine or HPMC 0.0 to 3.0
5. Hydroxy propyl cellulose 0.0 to 3.0
6. Croscarmellose sodium 4.53
7. Sodium starch glycolate or Crosspovidone 0.0 to 3.0
8. Magnesium stearate 0.85 to 0.88
Total weight of Core Tablet (mg) 100
B. Film Coating Composition
9 Film Coating Composition containing (Hypromellose,
Titanium Dioxide, Ferric oxide red) NA
10 Purified water
Total weight of Coated Tablet (mg) 456

Example 3: Relugolix Tablets 120mg
Sr. No Ingredients mg/Tab % w/w
1 Relugolix 120.00 26.67
2 Mannitol 185.00 41.11
3 Crystalline cellulose 110 to 115 23 to 26
4 Hydroxy propyl cellulose 15.00 3.33
5 Croscarmellose sodium 12.00 2.66
6 Magnesium stearate 6.73 1.50
Total weight of Core Tablet (mg) 450.00 100.00
B. Film Coating Composition.
7 Film Coating Composition (Hypromellose, Titanium Dioxide, Ferric oxide red) 16.00 NA
8 Purified water Q.S. -
Total weight of Coated Tablet (mg) 466.00 -

General manufacturing process for Example 1 to 3 (Wet Granulation- RMG Technique)
(a) Sifting and dry mixing of Relugolix API and other excipients
(b) Binder solution preparation with granulating fluid.
(c) Dry mixture of the blend prepared in step (a), is blended in rapid mixer granulator (RMG) to form wet mass.
(d) Drying the wet granules till loss on drying (LOD) is less than 2%.
(e) Sifting and milling the dried granules are blended along with disintegrant.
(f) Lubricant is added in the blend for lubrication.
(g) Lubricated blend is compressed to core tablet.
(h) Coating of core tablets to form a coated tablet.

DISSOLUTION STUDY
Dissolution rate is a critical property that is prerequisite for final dosage form. The comparative dissolution profile of the product of present invention with a reference product was studied. It was found that dissolution of present invention vis-à-vis reference product was comparable. Complete release and hence, enhanced solubility was achieved.

Dissolution study of the pharmaceutical dosage of the present invention was carried out by HPLC. The dissolution method employed in the present invention is USP Apparatus Il with sinker at 50 RPM in 900 mL of citrate buffer pH 5.5, paddle at (37 ± 0.5)ºC. Samples were taken at 5, 10, 15, 20, 30 and 45 minutes. The sample was filtered through a 0.45µm syringe filter, transferred to HPLC vials and analyzed by HPLC. Table 1 depicts the comparative dissolution data of the Relugolix tablet of reference product vis-à-vis the product of the present invention.

Table 1: Comparative dissolution study of Enzalutamide tablet of present invention with reference product
Product Relugolix Tablets 120mg
Media / Condition 50 mM citrate buffer pH 5.5, 900 mL, in apparatus paddle, at speed 50 RPM
Lot No. /Batch No. % Drug released
Orgovyx® (Relugolix) Tablets 120 mg Lot No. W07035A Relugolix Tablets 120mg (Batch No. POV24024A)
Time point (Min) Mean % RSD Mean % RSD
5 63 11.96 66.76 16.23
10 94 1.97 97.18 3.49
15 97 0.84 100.92 0.62
20 97 0.99 101.85 0.52
30 97 0.84 101.43 1.14
45 97 0.75 102.43 0.70
Drug release > 85%

Observation and Conclusion: The inventors of the present invention have surprisingly found that the Relugolix tablets of the present invention underwent rapid and complete dissolution compared to reference product.

STABILITY STUDY
The inventors of the present invention have surprisingly found that the Relugolix tablets of the present invention underwent rapid and complete dissolution initially compare to reference product. The Relugolix tablets of the present invention underwent rapid and complete dissolution even after 9 months when tested using the USP Apparatus (II) in comparison with the reference product of the innovator. An increase in the solubility and dissolution rates leads to consistent and uniform improvement in the bioavailability of the drug.

The composition in accordance with the present invention was subjected to stability studies under stability analysis condition of 25°C±2°C and relative humidity 60%±5%. Relugolix tablets of present invention are adequately stable, as per general stability requirement under conditions. Additionally, Relugolix tablets of present invention are also stable in accelerated stability conditions.

Table 2: Stability study under 9 months accelerated storage condition
Stability station Initial 3 Month 6 Month 9 Month
Condition Initial 25°C/60%RH 25°C/60%RH 25°C/60%RH
Assay (%) 100. 1% 102 .9% 103 .7'% 99.68%
Related Substances by HPLC
Stage 04 0.04% 0.06% 0.09% 0. 10%
Urea impurity 0.01% 0.01% 0.01% 0.01%
Des methyl impurity 0.06% 0 10% 0.11% 0.13%
Amide impurity ND ND ND ND
4-Nitrophenol ND ND ND ND
Any unspecified degradation product 0.06% 0.06% 0.09% 0.11%
Total
(NMT 0.85%) 0.39% 0.52% 0.50% 0.57%
Dissolution
pH 5.5, 900 ml, Paddle, 50 RPM, USP-Il 105.7% 102.9% 102.8% 101.3%
*ND = Not detected

As indicated in above table, the result of the stability study establishes that Relugolix composition in accordance with the present invention exhibits excellent storage stability.

IMPACT OF PARTICLE SIZE OF API ON DISSOLUTION DATA OF DRUG PRODUCT
The particle size of the API impacts the dissolution profile of the Relugolix tablets. Two different particle size of the API were tested and their impact on the dissolution profile of the Relugolix tablets in OGD conditions were studied. The data are shown in below table.

Table 3: Dissolution data of Relugolix Tablets 120 mg with different particle size (Batch no.: TQI- R01-018 and TQI-R01-005)
Dissolution Media: 50 Mm Citrate buffer pH 5.5, volume: 900 mL, Paddle, 50 RPM
Batch No.: Orgovyx Tablets 120mg
Lot No. W07035A TQI-R01-018 TQI-R01-005
CMA Particle size of API
D10:
D50:
D90: NA 1.52 µm
7.19 µm
22.9 µm 1.31 µm
2.46 µm
4.56 µm
Time point (Min) % Drug released
Mean % RSD Mean % RSD Mean % RSD
05 63 11.94 40.2 0.65 52.3 10.3
10 94 1.98 54.6 1.28 97.3 1.52
15 97 0.83 58.4 0.60 102.5 0.65
30 97 0.86 72.5 1.19 105.7 0.88
45 97 0.74 78.9 0.23 105.1 1.13
Specification NLT 75% (Q) at 15min and 85% (Q) in 30min

Observation and Conclusion: Significant difference was observed in dissolution data in batches manufactured with different particle size of drug substance for Relugolix Tablet 120mg at Q time point i.e., 15 min as well as 30 minutes. Data show that higher particle size batch having lesser drug release at Q time points i.e., 15 min as well as 30 minutes while batch which having micronized particle size gives completed release at Q time points i.e., 15 min as well as 30 minutes.

SELECTION OF EXCIPIENTS
During the selection of excipients, the excipients are not only required to be compatible but must also meet the IIG limits. Incorporating different excipient or even varying the amount of excipient may result in incompatibility between excipient/excipient or excipient/drug and in turn impact the activity of a drug.

Table 4: Drug-Excipient Compatibility Study Results (Related Substances) at 40°C±2°C/75%RH±5%RH (Open)
Sample Details Drug Excipients Batch No Initial stage 40°C±2°C/75%RH±5%RH
30 Days (open)
Stage 04
(RRT 0.93) Urea impurity
(RRT 0.87) Des methyl
(RRT 0.79) Amide Imp.
(RRT 1.66) 4-Nitrophenol (RRT 0.69) Single max unk impurity Total Imp Stage 04
(RRT 0.93) Urea impurity
(RRT 0.87) Des methyl
(RRT 0.79) Amide Imp.
(RRT 1.66) 4-Nitrophenol (RRT 0.69) Single max unk impurity Total Imp
Specification Limit
(Release Specification) NA NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 1.0% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 1.0%
Relugolix (API) TQI-R01-019A 0.046 0.006 0.071 0.007 0.000 0.061 0.410 0.080 0.010 0.094 0.034 0.000 0.080 0.542
Relugolix + Mannitol TQI-R01-019B 0.049 0.007 0.066 0.012 0.000 0.058 0.399 0.079 0.007 0.096 0.015 0.000 0.083 0.522
Relugolix + Microcrystalline cellulose TQI-R01-019C 0.050 0.008 0.069 0.013 0.000 0.059 0.410 0.083 0.007 0.094 0.014 0.000 0.074 0.514
Relugolix + Croscarmellose sodium TQI-R01-019D 0.037 0.004 0.058 0.012 0.000 0.047 0.350 0.065 0.005 0.081 0.014 0.000 0.057 0.436
Relugolix + Hydroxy propyl cellulose TQI-R01-019E 0.046 0.006 0.068 0.013 0.000 0.067 0.419 0.076 0.006 0.091 0.021 0.000 0.081 0.542
Relugolix + Magnesium stearate TQI-R01-019F 0.045 0.007 0.071 0.013 0.000 0.063 0.407 0.079 0.006 0.095 0.015 0.000 0.074 0.528
Relugolix + Opadry Brown 03F565212 TQI-R01-019G 0.044 0.006 0.064 0.012 0.000 0.063 0.390 0.066 0.008 0.083 0.011 0.000 0.063 0.503

Table 5: Drug-Excipient Compatibility Study Results (Related Substances) at 25°C±2°C/60%RH±5%RH (Close)

Sample Details Drug Excipients Batch No Initial stage 25°C±2°C/60%RH±5%RH
30 Days (Close)
Stage 04
(RRT 0.93) Urea impurity
(RRT 0.87) Des methyl
(RRT 0.79) Amide Imp.
(RRT 1.66) 4-Nitrophenol (RRT 0.69) Single max unk impurity Total Imp Stage 04
(RRT 0.93) Urea impurity
(RRT 0.87) Des methyl
(RRT 0.79) Amide Imp.
(RRT 1.66) 4-Nitrophenol (RRT 0.69) Single max unk impurity Total Imp
Specification Limit
(Release Specification) NA NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 1.0% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.2% NMT 1.0%
Relugolix (API) TQI-R01-019A 0.046 0.006 0.071 0.007 0.000 0.061 0.410 0.045 0.006 0.072 0.017 0.000 0.062 0.381
Relugolix + Mannitol TQI-R01-019B 0.049 0.007 0.066 0.012 0.000 0.058 0.399 0.046 0.005 0.071 0.018 0.000 0.066 0.412
Relugolix + Microcrystalline cellulose TQI-R01-019C 0.050 0.008 0.069 0.013 0.000 0.059 0.410 0.048 0.006 0.070 0.015 0.000 0.064 0.413
Relugolix + Croscarmellose sodium TQI-R01-019D 0.037 0.004 0.058 0.012 0.000 0.047 0.350 0.038 0.004 0.058 0.015 0.000 0.048 0.351
Relugolix + Hydroxy propyl cellulose TQI-R01-019E 0.046 0.006 0.068 0.013 0.000 0.067 0.419 0.048 0.006 0.073 0.016 0.000 0.077 0.419
Relugolix + Magnesium stearate TQI-R01-019F 0.045 0.007 0.071 0.013 0.000 0.063 0.407 0.050 0.008 0.074 0.011 0.000 0.057 0.413
Relugolix + Opadry Brown 03F565212 TQI-R01-019G 0.044 0.006 0.064 0.012 0.000 0.063 0.390 0.049 0.007 0.073 0.013 0.000 0.059 0.435

Observation and Conclusion: The Drug-Excipient compatibility study results established that Related Substances were within the permitted limits.

Table 5: Maximum daily limits per IIG database
Sr. No. Ingredients Qty. /tab. Maximum daily intake as per Maximum daily dose i.e., 360mg Maximum daily exposure as per IIG database
120mg
1. Relugolix 122.07 366.21 -
2. Mannitol 185.00 555.00 2309 mg
3. Microcrystalline cellulose 111.27 333.81 5117 mg
4. Croscarmellose sodium 12.00 36.00 736 mg
5. Hydroxy propyl cellulose 15.00 45.00 128 mg
6. Magnesium Stearate 6.73 20.19 980 mg
7. Hypromellose 7.03 21.09 1127 mg
8. Macrogol/PEG 1.41 4.23 52 mg
9. Titanium dioxide 2.40 7.20 120 mg
10. Ferric oxide red 0.42 1.26 8 mg

Observation and Conclusion: Considering the maximum daily dose, quantity of excipients used in the present invention is within the IIG level.

The invention will be further described with respect to the examples. However, the scope of the invention is not limited thereby. All percentages stated in this specification are by weight, unless otherwise specified. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
,CLAIMS:We claim:
1. A stable solid oral composition comprising relugolix or pharmaceutically acceptable salt thereof and at least one or more pharmaceutically acceptable excipients.

2. The solid oral composition as claimed in claim 1 comprising
a) 20 - 50 % w/w of Relugolix,
b) 15 - 90 % w/w of diluent or a mixture thereof,
c) 0.01 - 10 % w/w of disintegrant or a mixture thereof,
d) 0.5 - 5 % w/w of binder or a mixture thereof,
e) 0.01 - 5 % w/w of lubricant or a mixture thereof,
f) granulating vehicle or a mixture thereof, and optionally other excipients.

3. The solid oral composition as claimed in claim 1, wherein the total amount of relugolix in the composition is in the range of from 25mg to 500mg.

4. The solid oral composition as claimed in claim 1, comprising relugolix in micronized form having a particle size distribution D90 about 1µm to 30µm, preferably from 5µm to 25µm, and more preferably from 10µm to 20µm.

5. The solid oral composition as claimed in claim 1, wherein the diluent is selected from microcrystalline cellulose, mannitol or a mixture thereof preferably 15% to 90% w/w by weight of the total weight of the pharmaceutical composition.

6. The solid oral composition as claimed in claim 1, wherein the disintegrant is selected from crospovidone, croscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and mixture thereof preferably 0.01 to 9% by weight of the total weight of the pharmaceutical composition.

7. The solid oral composition as claimed in claim 1, wherein the binder is selected from hydroxyl propyl methyl cellulose (HPMC or hypromellose), polyvinyl pyrrolidone (povidone), polyvinyl pyrrolidine hydroxyl propyl cellulose, polyvinyl alcohol, methyl cellulose, ethyl cellulose, gum arabic, alginic acid, polyethylene glycol (PEG), pregelatinized starch (PGS) preferably 0.5 to 5% by weight of the total weight of the pharmaceutical composition.

8. The solid oral composition as claimed in claim 1, wherein the lubricant is selected from magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate and talc or a mixture thereof preferably 0.01 to 5% by weight of the total weight of the pharmaceutical composition.

9. The solid oral composition as claimed in claim 1, wherein the granulating vehicle is selected from acetone, acetone and dichloromethane, methanol and dichloromethane, acetone and water, acetone and methanol, acetone and ethanol, dichloromethane and ethanol or ethanol and water or a mixture thereof.