DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PHARMACEUTICAL COMPOSITION COMPRISING NALOXEGOL OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising Naloxegol or a pharmaceutically acceptable salt thereof as an active agent, process of preparation thereof and method of using the same.

This invention relates to a solid oral pharmaceutical composition which comprises Naloxegol or a pharmaceutically acceptable salt thereof, preferably Naloxegol oxalate salt, a process for preparation thereof. The invention also relates to the use of said formulation for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.

BACKGROUND OF THE INVENTION

Natural and synthetic alkaloids of opium (i.e., opioids) are useful as analgesics for the treatment of severe pain. Opioid Induced Constipation (OIC) is one of the most troublesome and the common side-effects of using opioids for a prolonged duration. It was observed that on using opioids for 8 weeks an average 4% of patients developed OIC. Various studies report constipation as a side effect in up to 40–95% of patients using opioids, which is potentially iatrogenic. Many drugs have been used with limited success for treating OIC, but the most specific among them were the peripherally acting µ opioid receptor antagonists.

Naloxegol oxalate Tablet; Oral 12.5mg and 25mg was first approved by USFDA on Sep 16, 2014 under the brand Movantik® to Astrazeneca Pharma and indicated for the treatment of OIC in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.

Naloxegol is a PEGylated derivative of naloxone. The chemical name of Naloxegol oxalate is (5a,6a)-17-allyl-6-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-4,5 epoxymorphinan-3,14-diol oxalate having chemical formula C34H53NO11.C2H2O4 and the molecular weight is 742, and its structural formula is:

U.S. Patent No. 7,786,133B discloses Naloxegol compound specifically. It also discloses a tablet formulation of Naloxegol oxalate containing pharmaceutically acceptable carrier materials.

U.S. Patent No. 8,617,530B discloses a method of treating constipation resulting from the administration of an opioid agonist.

U.S. Patent No. 9,012,469B discloses crystalline polymorph and oxalate salt of Naloxegol. It also discloses a tablet of Naloxegol oxalate containing carrier such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, etc.

U. S. patent publication 20180153879A discloses solid dispersion comprising, preferably consisting of, naloxegol salts in amorphous form and at least one pharmaceutically acceptable matrix compound.

Chinese publication 107802603A discloses a dispersion comprising naloxegol oxalate and hydroxypropyl methyl cellulose in a mass ratio of 1: 1 to 1:20.

PCT patent publication 2018096464A discloses a solid dispersion of Naloxegol oxalate and at least one pharmaceutically acceptable carrier such as polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropylcellulose, etc. in amorphous form.

The active substances in an amorphous form have better solubility and dissolve more rapidly than in a crystalline form and thus have better bioavailability. Hence, inventors of the present invention have developed pharmaceutical compositions comprising amorphous solid dispersion of Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone which exhibits excellent dissolution profile and storage stability and it is comparable to marketed reference product Movantik®.

Inventors of the present invention have developed a simple, reproducible, cost-effective pharmaceutical composition of Naloxegol or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a pharmaceutical compositions comprising Naloxegol or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s).

In another aspect, there is provided a pharmaceutical composition comprising:
a) Solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and suitable pharmaceutically acceptable polymers or carriers;
b) Pharmaceutically acceptable excipients comprising diluents, disintegrants, lubricants, glidants, antioxidants.

In another aspect, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
a) Solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) Pharmaceutically acceptable excipients comprising diluents, disintegrants, lubricants, glidants, antioxidants.
Wherein said solid dispersion contains naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone is in 1:1 w/w ratio.

In another aspect, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
a) Amorphous naloxegol or a pharmaceutically acceptable salt thereof;
b) Pharmaceutically acceptable excipients comprising diluents, disintegrants, lubricants, glidants, antioxidants.
Wherein said amorphous naloxegol or a pharmaceutically acceptable salt thereof is a solid dispersion of naloxegol oxalate and polyvinylpyrrolidone.

In another aspect, there is provided a pharmaceutical composition comprising:
a) 10 to 20% w/w of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 80 to 90% w/w of pharmaceutically acceptable excipients;
Wherein, said pharmaceutical composition is in the form of tablet or capsule.

In another aspect, there is provided a pharmaceutical composition comprising:
a) 10 to 20% w/w of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 30 to 60 % w/w of mannitol;
c) 15 to 40 % w/w of microcrystalline cellulose;
d) 2 to 6 % w/w of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, the ratio of Naloxegol oxalate to polyvinylpyrrolidone in a solid dispersion is between 0.5:2 w/w and 2:0.5 w/w.

In another aspect, there is provided a pharmaceutical composition comprising:
a) 20 to 70mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, said pharmaceutical composition is in the form of tablet or capsule and said pharmaceutical tablet having an oval shape with a thickness of from 2 mm to 8 mm and said tablet having the hardness from 5 kiloponds to 15 kiloponds and a disintegration time of 30 to 120 seconds.

In another aspect, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
a) 28.46mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 94mg of mannitol;
c) 40mg of microcrystalline cellulose;
d) 7.5mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein the 28.46mg of solid dispersion contains about 14.23mg of Naloxegol oxalate and about 14.23mg of polyvinylpyrrolidone.

In another aspect, there is provided a pharmaceutical composition comprising:
a) 28.46mg to 56.92mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, Naloxegol oxalate and polyvinylpyrrolidone are in 1:1 w/w ratio.

In another aspect, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
a) 28.46mg to 56.92mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, Naloxegol oxalate and polyvinylpyrrolidone are in 1:1 w/w ratio.

In another aspect, there is provided a pharmaceutical tablet composition comprising amorphous Naloxegol oxalate, wherein amorphous Naloxegol oxalate is premix of Naloxegol oxalate with polyvinylpyrrolidone. The content of Naloxegol oxalate in premix is from about 25% w/w to about 75% w/w, preferably from about 35% w/w to about 65% w/w, more preferably from about 45% w/w to about 55% w/w, specifically about 50% w/w.

In another aspect, there is provided a pharmaceutical composition comprising naloxegol oxalate and polyvinylpyrrolidone in a solid dispersion form wherein ratio of naloxegol oxalate to polyvinylpyrrolidone is 0.5:2 w/w to 2:0.5 w/w.

In another aspect, there is provided the process for preparation of a pharmaceutical tablet composition, wherein process comprises steps of:
a) Co-sifting active and excipients through appropriate mesh;
b) Milling of the materials of step (a) using co-mill;
c) Blending of the materials of step (b) in a suitable blender for pre-lubrication followed by lubrication;
d) Compressing the lubricated blend of step (c) in a suitable compression machine; and optionally
e) Coating of the compressed tablet of step (d).

In another aspect, there is provided the process for preparation of a pharmaceutical tablet composition, wherein process comprises steps of:
a) Co-sifting of Naloxegol Oxalate- polyvinylpyrrolidone Premix, colloidal silicon dioxide, Butylated Hydroxy Anisole, propyl gallate, microcrystalline cellulose and mannitol and passed through mesh;
b) Milling of materials of step (a) through co-mill;
c) Lubrication of materials of Step (b) with magnesium stearate;
d) Compression or filling of blend of step (c) to get suitable dosage form;
e) Optionally coating of tablets obtained in step (d).
Wherein, the obtained lubricated blend in step “c” has a bulk density of 0.40 to 0.55 g/ml, tapped density from about 0.50 to 0.70 g/ml and Hausner ratio of about 1.284 and compressibility index of about 22.115 (%).

In another aspect, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
Solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone; and pharmaceutically acceptable excipients.
Wherein, said composition exhibits a dissolution of at least 90% at about 30 minutes at a temperature of 37 ± 0.5°C using a paddle apparatus at a speed of about 50 rpm in 0.1N HCl dissolution medium and said composition does not contain more than 1.5% w/w of total impurity and not more than 2.5 % by weight of water content as measured by Karl Fischer titration method.

In another aspect, the present invention includes method of using pharmaceutical composition of Naloxegol or a pharmaceutically acceptable salt thereof in the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.

DETAILED DESCRIPTION OF THE INVENTION

By the term “pharmaceutical composition” or " solid oral pharmaceutical composition" or "composition" as used herein refers to a solid dosage form comprising Naloxegol or a pharmaceutically acceptable salt thereof suitable for administration such as a tablet, capsule, mini-tablets, pellets, granules, pills and the like.

The term “active ingredient” or “active agent” or “drug” used interchangeably, is defined to mean active drug i.e. Naloxegol that induce a desired pharmacological or physiological effect.

The term ‘‘stable’’ refers to formulations that substantially retain the labelled 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 term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response when administered to the patient.

The term “core” as used herein, refers to an interior compartment of a unit dosage form.

The term ‘‘w/w’’ refers to total weight of substance/excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.

The term “excipient” means a pharmacologically inactive component such as a solvent, diluent, disintegrant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, inert, non-toxic and are acceptable for human use.

The term “Naloxegol” includes all pharmaceutically acceptable salts, esters, isomers, stereo isomers, crystalline and amorphous forms, preferably Naloxegol oxalate. Naloxegol base in an amount of 12.5 mg equivalent to 14.23 mg of Naloxegol oxalate.

Pharmaceutically acceptable salts of Naloxegol includes but not limited to oxalate, phosphate or acid phosphate, hydrochloride, hydrobromide, sulphate, acetate, maleate, fumarate, lactate, tartrate, citrate, methanesulfonate, pamoate, tosylate, palmitate, and gluconate salts; most preferably used salt of naloxegol is oxalate salt.

Naloxegol or a pharmaceutically acceptable salt thereof exists mainly in crystalline and amorphous polymorphic forms. Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice; and amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice; most preferably used polymorph of naloxegol or a pharmaceutically acceptable salt thereof is amorphous polymorph.

The term “amorphous Naloxegol oxalate” is premix or dispersion/solid dispersion of Naloxegol oxalate with polyvinylpyrrolidone. The content of Naloxegol oxalate in premix is from about 25% w/w to about 75% w/w, preferably from about 35% w/w to about 65% w/w, more preferably from about 45% w/w to about 55% w/w, specifically about 50% w/w.

The ratio of Naloxegol oxalate to polyvinylpyrrolidone in a premix or dispersion/solid dispersion is about 1:0.5 to 2 w/w and 0.5 to 2:1 w/w. preferably in a 1:1 w/w ratio.

The term “dispersion or solid dispersion” is defined as dispersion or premix of one or more active ingredients in an inert carrier at solid state. Process for the preparation of dispersion of naloxegol oxalate comprises dissolving naloxegol oxalate in solvent to form a solution, adding pharmaceutically acceptable carriers like polyvinylpyrrolidone (povidone) and isolating amorphous solid dispersion of naloxegol oxalate. The isolation may be obtained by techniques known in the art such as freeze-drying (lyophilization), distillation, evaporation, oven drying, tray drying, spray drying, fluid bed drying, flash drying, spin flash drying and agitated thin film dryer (ATFD), hot melt extrusion and the like. Particularly, the solution is lyophilized to obtain amorphous solid dispersion.

“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient. Pharmaceutically acceptable excipient(s) includes, but not limited to, diluent, binder, disintegrant, lubricant/glidants, antioxidant, plasticizer, surfactants, solvent/vehicle, flavors or colorants, coating materials and any other excipient known to the art for making pharmaceutical composition of tablet.

Diluents according to the present invention are selected from, but not limited to, silicon dioxide, titanium dioxide, talc, powdered cellulose, microcrystalline cellulose, and as well as soluble materials such as mannitol, sorbitol or other sugar alcohols, sucrose, lactose, and the like used either alone or in combinations thereof and the most preferably used diluent is mannitol and microcrystalline cellulose.

Disintegrants according to the present invention are selected from, but not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, polacrilin potassium, microcrystalline cellulose, starches like used either alone or in combinations thereof and the most preferably used disintegrant is croscarmellose sodium. The disintegration test basically consists of placing a dosage form in an immersion medium under defined experimental conditions and measuring the time taken for the dosage form to disintegrate. The time in which the tablet or capsule should disintegrate is defined in the applicable monograph.

Lubricants according to the present invention are selected from, but not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, and the like used either alone or in combinations thereof and the most preferably used lubricant is magnesium stearate.

Glidants according to the present invention are selected from, but not limited to, colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, and the like used either alone or in combinations thereof and the most preferably used lubricant is colloidal silicon dioxide.

Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the preparation. Suitable antioxidants for use in the present invention include but not limited to propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof and the most preferably used antioxidant is propyl gallate or butylated hydroxyanisole alone or combination thereof.

‘‘Plasticizer’’ refers to an excipient that can impart flexibility and/or stretchability to a coat or membrane. Examples of plasticizers include but are not limited to medium chain triglycerides, phthalates, phosphates, glycerol, citrates, adipates, sebacates, succinates, glycolates, and the like used either alone or in combinations thereof.

‘‘Surfactant’’ refers to one or more excipients that may be added to the pharmaceutical composition to facilitate dissolution of poorly soluble excipients and/or to increase dissolution rate of composition or components thereof. Examples of surfactants include but are not limited to sodium lauryl sulphate, glycerol monostearate, sorbitan monolaurate, tween 60, tween 80 (polysorbate 80) etc.

A ‘‘Solvent/vehicle’’ is a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a solution. Examples include but not limited to purified water, alcoholic solvents methanol, ethanol; ketones such as acetone, propanone; esters such as ethyl acetate, n-propyl acetate, isopropylacetate and n-butyl acetate and the like; ethers such as dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, and dioxane.

‘‘Flavorants’’ refers to a substance that gives another substance flavor, altering the characteristics of the solute, causing it to become sweet, sour, etc. Pharmaceutically acceptable flavors includes but not limited to cherry, orange, vanilla.

‘‘Tablet coating’’ refers to the phenomenon of application of coating to the tablet which involves some coating agents like plasticizer, polymers, colorants and solvent.

Film coating refers to the process of polymeric solution to bring a uniform film. Examples include polyvinyl alcohol, GMCC Type 1 (Glyceryl mono-caprylate-caprate)/glycerol esters of fatty acids, hydroxypropyl cellulose, polyethylene glycol, oleic acid, ethyl cellulose, acrylate polymers, Opadry film coating is a one-step film coating system which combines polymer, plasticizer and pigment, as required, in a dry concentrate which result in attractive, elegant coatings on a tablet cores. Opadry systems can be easily dispersed in aqueous or organic solvent solutions.

‘‘Colorants’’ is a substance that is preferably added to the coating agent for coating of the tablet. Pharmaceutically acceptable colorants include but not limited to red iron oxide non-irradiated, iron oxide black, Ferrosoferric oxide, tartrazine, erythrosine, amaranth lake, opadry systems, titanium dioxide, and iron oxide yellow.

Suitable Pharmaceutically acceptable carriers that may be used to form dispersion/solid dispersion or premix with naloxegol oxalate includes but not limited to water soluble as well as water insoluble carriers. Typical water soluble carriers are polyvinylpyrrolidone (povidone), polyvinylpyrrolidone-vinyl acetate copolymer (copovidone), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus™), sugar and its derivatives, organic amines and similar. Typical water insoluble polymers are methylcellulose, ethylcellulose, microcrystalline celluloses, polymethacrylates, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate phthalate, carboxymethyl ethyl cellulose and crospovidone. Sugar and its derivatives mannitol, lactose, sorbitol, xylitol, dextrins and like. The preferable pharmaceutically acceptable carriers include but not limited to polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.

Karl Fisher Titration is a technique for the determination of water content. The technique was developed by a chemist named Karl Fischer. It is based on a reagent which reacts with water and converts the water into a non-conductive chemical. These water content of tablet according to the present invention between 1 – 5% w/w, preferably tablet having a water content not more than 5% w/w and more preferably tablet having a water content not more than 4% w/w, 3% w/w, 2.5% w/w, and 2% w/w.

Tablet hardness testing is used to test the breaking point and structural integrity of a tablet prior to storage, transportation, and handling before usage.
These hardness of tablet according to the present invention were tested for hardness (breaking force) under testing conditions performed in accordance with the standards of the pharmaceutical industry and found to have a hardness of between 5 and 15 kiloponds (Kp).

The thickness of tablets is critical to their therapeutic effectiveness. All tablets, where the active ingredient comprises a major part of the tablet are required to meet a weight variation test. It is assumed that providing the weight of the tablet is kept within defined limits that the amount of active drug available to the user will remain the same. These thickness of tablet according to the present invention between 1-10mm, preferably tablet having a thickness of 2-6mm, and more preferably 3-4mm.

The term “Bulk density” as used herein according to the present invention is defined as powder mass divided by its bulk volume without any tapping. Powder bulk density depends primarily on particle size distribution, particle shape, and the tendency of particles to adhere to each other. Some particles may pack loosely, leading to fluffy and light powder, while others may contain smaller particles that sift between larger particles to fill the void, leading to dense and heavy powder. Bulk density is often used to calculate the batch size for blender and granulator.
The bulk density of lubricated blend according to the present invention is from 0.30 g/mL to 0.70 g/mL, preferably from 40 g/mL to 60 g/mL, and more preferably 0.45 g/mL to 0.50 g/mL.

The term “Tapped density” as used herein according to the present invention is is measured after a powder sample is subjected to mechanically tapping. The measurement procedure for bulk density and tapped density can be found in the US Pharmacopeia. Bulk density and tapped density can be used to calculate compressibility index and Hausner ratio, which are measures of the propensity of a powder to flow and be compressed. The tapped density of lubricated blend according to the present invention is from is from 0.40 g/mL to 0.80 g/mL, preferably from 0.50 g/mL to 0.70 g/mL, and more preferably 0.58 g/mL to 0.63 g/mL.

The term “Hausner ratio (HR)” is a number that is correlated to the flowability of a powder or granular material. The Hausner ratio is determined by measurement of the tapped and untapped (or aerated) bulk density. The granules according to the present invention is having a Hausner ratio of about 1.284.
Hausner ratio formula = Tap density/Bulk density.

The Compressibility Index is measure of the propensity of a powder to be compressed as described above. As such it is measure of the powder’s ability to settle, and it permit an assessment of the relative importance of interparticulate interactions. The granules according to the present invention is having a Compressibility Index of about 2.115 %.
Compressibility Index formula = (Tap density-Bulk density)/Tap density x 100%.

In one general embodiment, there is provided a pharmaceutical compositions comprising Naloxegol or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s).

In another embodiment, there is provided a pharmaceutical composition comprising:
a) Solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and suitable pharmaceutically acceptable polymers or carriers;
b) Pharmaceutically acceptable excipients comprising diluents, disintegrants, lubricants, glidants, antioxidants.

In another embodiment, there is provided a pharmaceutical composition comprising:
a) Solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and water soluble and/or water insoluble polymers or carriers;
b) Pharmaceutically acceptable excipients comprising diluents, disintegrants, lubricants, glidants, antioxidants.
Wherein, said pharmaceutical composition is in the form of tablet or capsule.

In another embodiment, there is provided a pharmaceutical composition comprising:
a) Solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) Pharmaceutically acceptable excipients comprising diluents, disintegrants, lubricants, glidants, antioxidants.
Wherein, said pharmaceutical composition is in the form of tablet or capsule.

In another embodiment, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
a) Solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) Pharmaceutically acceptable excipients comprising diluents, disintegrants, lubricants, glidants, antioxidants.
Wherein said solid dispersion contains naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone is in 1:1 w/w ratio.

In another embodiment, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
a) Amorphous naloxegol or a pharmaceutically acceptable salt thereof;
b) Pharmaceutically acceptable excipients comprising diluents, disintegrants, lubricants, glidants, antioxidants.
Wherein said amorphous naloxegol or a pharmaceutically acceptable salt thereof is a solid dispersion and polyvinylpyrrolidone.

In another embodiment, there is provided a pharmaceutical composition comprising:
a) 10 to 20% w/w of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 80 to 90% w/w of pharmaceutically acceptable excipients;
Wherein, said pharmaceutical composition is in the form of tablet or capsule.

In another embodiment, there is provided a pharmaceutical composition comprising:
a) 10 to 20% w/w of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 30 to 60 % w/w of mannitol;
c) 15 to 40 % w/w of microcrystalline cellulose;
d) 2 to 6 % w/w of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, the ratio of Naloxegol oxalate to polyvinylpyrrolidone in a solid dispersion is between 0.5:2 w/w to 2:0.5 w/w.

In another embodiment, there is provided a pharmaceutical composition comprising:
a) 20 to 70mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, said pharmaceutical composition is in the form of tablet or capsule.

In another embodiment, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
a) 28.46mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 94mg of mannitol;
c) 40mg of microcrystalline cellulose;
d) 7.5mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein the 28.46mg of solid dispersion contains about 14.23mg of Naloxegol oxalate and about 14.23mg of polyvinylpyrrolidone.

In another embodiment, there is provided a pharmaceutical composition comprising:
a) 28.46mg to 56.92mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, Naloxegol oxalate and polyvinylpyrrolidone are in 1:1 w/w ratio.

In another embodiment, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
a) 28.46mg to 56.92mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, Naloxegol oxalate and polyvinylpyrrolidone are in 1:1 w/w ratio.

In another embodiment, there is provided a pharmaceutical tablet composition comprising amorphous Naloxegol oxalate, wherein amorphous Naloxegol oxalate is premix of Naloxegol oxalate with polyvinylpyrrolidone. The content of Naloxegol oxalate in premix is from about 25% w/w to about 75% w/w, preferably from about 35% w/w to about 65% w/w, more preferably from about 45% w/w to about 55% w/w, specifically about 50% w/w.

In another embodiment, there is provided a pharmaceutical composition comprising naloxegol oxalate and polyvinylpyrrolidone in a solid dispersion form wherein ratio of naloxegol oxalate to polyvinylpyrrolidone is 0.5:2 w/w to 2:0.5 w/w.

In another embodiment, there is provided the process for preparation of a pharmaceutical tablet composition, wherein process comprises steps of:
a) Co-sifting active and excipients through appropriate mesh;
b) Milling of the materials of step (a) using co-mill;
c) Blending of the materials of step (b) in a suitable blender for pre-lubrication followed by lubrication;
d) Compressing the lubricated blend of step (c) in a suitable compression machine; and optionally
e) Coating of the compressed tablet of step (d).

In another embodiment, there is provided the process for preparation of a pharmaceutical tablet composition, wherein process comprises steps of:
a) Co-sifting of Naloxegol Oxalate- polyvinylpyrrolidone Premix, colloidal silicon dioxide, Butylated Hydroxy Anisole, propyl gallate, microcrystalline cellulose and mannitol and passed through mesh;
b) Milling of materials of step (a) through co-mill;
c) Lubrication of materials of Step (b) with magnesium stearate;
d) Compression or filling of blend of step (c) to get suitable dosage form;
e) Optionally coating of tablets obtained in step (d).
Wherein, the obtained lubricated blend in step “c” has a bulk density of 0.40 to 0.55 g/ml, tapped density from about 0.50 to 0.70 g/ml and Hausner ratio of about 1.284 and compressibility index of about 22.11 (%).

In another embodiment, there is provided a pharmaceutical composition in the form of tablet dosage form comprising:
Solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof with polyvinylpyrrolidone; and pharmaceutically acceptable excipients.
Wherein, said composition exhibits a dissolution of at least 90% at about 30 minutes at a temperature of 37 ± 0.5°C using a paddle apparatus at a speed of about 50 rpm in 0.1N HCl dissolution medium.

In another embodiment, the present invention includes method of using pharmaceutical composition of Naloxegol or a pharmaceutically acceptable salt thereof in the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.

In another embodiment of the invention, the pharmaceutical composition is formulated into solid oral pharmaceutical dosage forms. Solid oral pharmaceutical dosage forms include, but are not limited to, tablets, capsules, powders, granules and sachets. Preferably, the solid oral pharmaceutical dosage form is a tablet.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention.
Table 1: Composition of Naloxegol Oxalate tablets (Examples: 1 - 3)

Sr. No. Ingredients Example- 1 Example- 2 Example- 3
(mg/tab) (% w/w) (mg/tab) (% w/w) (mg/tab) (% w/w)
Core tablets
1 Naloxegol oxalate: Polyvinylpyrrolidone# 28.46$ 15.64 28.46$ 15.64 28.46$ 15.64
2 Mannitol 72.30 39.73 93.38 51.31 95.30 52.36
3 Microcrystalline cellulose 60.00 32.97 40.00 21.98 37.00 20.33
4 Propyl gallate 1.10 0.60 1.00 0.55 1.10 0.60
5 Butylated hydroxyanisole 1.30 0.71 1.25 0.69 1.30 0.71
6 Croscarmellose sodium 7.70 4.23 7.50 4.12 7.70 4.23
7 Colloidal silicon dioxide 1.50 0.82 1.40 0.77 1.50 0.82
8 Magnesium stearate 2.10 1.15 2.00 1.10 2.10 1.15
Core tablet weight(mg) 174.46 95.86 174.99 96.15 174.46 95.86
9 Opadry system* (Film Coating)
[~30% overages considered] 9.10 5.00 9.10 5.00 9.10 5.00
10 Purified Water Quantity sufficient (Q.S) Quantity sufficient (Q.S) Quantity sufficient (Q.S)
Coated tablet weight (mg) 182 - 182 - 182 -
# Naloxegol Oxalate- polyvinylpyrrolidone Premix contains Naloxegol Oxalate: polyvinylpyrrolidone in ~1:1 w/w ratio.
$ Unit quantity of Naloxegol oxalate premix equivalents to 12.5mg of Naloxegol base or 14.23mg of Naloxegol oxalate.
*Opadry AMB II High performance Moisture Barrier Film coating 88A500004 Purple- contains Polyvinyl Alcohol, Titanium Dioxide, Glyceryl monocaprylocaprate, Talc, Red iron oxide non-irradiated, iron oxide black.
Manufacturing process:
a) Co-sifting: Co-sifting of Naloxegol Oxalate- polyvinylpyrrolidone Premix, colloidal silicon dioxide, Butylated Hydroxy Anisole, propyl gallate, microcrystalline cellulose and mannitol, and passed through mesh;
b) Milling: The materials of step (a) were sifted through co-mill;
c) Lubrication: Materials of Step (b) was loaded into blender for pre-lubrication and then lubricated with magnesium stearate;
d) Compression: Lubricated blend of step (c) was then compressed into tablet in multistation compression machine; and
e) Coating: Opadry system was dispersed in required quantity of purified water under stirring till it forms homogeneous dispersion, tablet of step (d) then loaded into a perforated pan coater.

Table 2: Composition of Naloxegol Oxalate tablets (Examples: 4 - 6)

Sr. No. Ingredients Example- 4 Example- 5 Example- 6
(mg/tab) (% w/w) (mg/tab) (% w/w) (mg/tab) (% w/w)
Core tablets
1 Naloxegol oxalate: Polyvinylpyrrolidone# 56.92$ 15.64 56.92$ 15.64 56.92$ 15.64
2 Mannitol 144.60 39.73 186.78 51.31 190.30 52.28
3 Microcrystalline cellulose 120.30 33.05 80.00 21.98 75.40 20.71
4 Propyl gallate 2.20 0.60 2.00 0.55 2.20 0.60
5 Butylated hydroxyanisole 2.60 0.71 2.50 0.69 2.60 0.71
6 Croscarmellose sodium 16.20 4.45 15.00 4.12 15.40 4.23
7 Colloidal silicon dioxide 3.00 0.82 2.80 0.77 3.00 0.82
8 Magnesium stearate 4.20 1.15 4.00 1.10 4.20 1.15
Core tablet weight(mg) 350.00 96.15 350.00 96.15 350.00 96.15
9 Opadry system* (Film Coating)
[~30% overages considered] 18.20 5.00 18.20 5.00 18.20 5.00
10 Purified Water Quantity sufficient (Q.S) Quantity sufficient (Q.S) Quantity sufficient (Q.S)
Coated tablet weight (mg) 364 - 364 - 364 -
# Naloxegol Oxalate- polyvinylpyrrolidone Premix contains Naloxegol Oxalate: polyvinylpyrrolidone in ~1:1 w/w ratio.
$ Unit quantity of Naloxegol oxalate premix equivalents to 25mg of Naloxegol base or 28.46mg of Naloxegol oxalate.
* Opadry AMB II High performance Moisture Barrier Film coating 88A500004 Purple- contains Polyvinyl Alcohol, Titanium Dioxide, Glyceryl monocaprylocaprate, Talc, Red iron oxide non-irradiated, iron oxide black.
Manufacturing process: Same as mentioned in examples 1 – 3.

Naloxegol oxalate blend obtained as per Example 1 has the following properties which is given in Table 3:
Table 3: Blend properties:
Parameter Results
Bulk Density 0.481 g/mL
Tapped Density 0.617 g/mL
Hausner Ratio 1.284
Compressibility index 22.115 %

Naloxegol oxalate tablets prepared as per Example 1 has the following properties which is given in Table 4:
Table 4: Compressed tablets properties:
Parameter Results
Thickness 3-4 mm
Hardness value 7-9.5 Kp
Disintegration time 50-65 sec.

Dissolution testing: The dissolution test is performed in accordance with general rules of USP for dissolution testing and results given in table 5.
The dissolution test parameters were: dissolution apparatus- USP II (paddle apparatus); dissolution media- 0.1N HCl; dissolution volume- 500mL; paddle rotation speed- 50 RPM; temperature- 37 ± 0.5°C.
Stability Study: Stability study conducted on compositions in order to ensure the stable composition for longer period of time and data is given in Table- 5 below:
Table 5: Dissolution, stability study results & impurity profile of example 1
Condition NA 40°C/75% RH
Pack HDPE Bottle with desiccant (Silica Gel)
Period Initial 3M 6M
Assay (of Naloxegol) 100.7 100.1 97.30
Dissolution 10 min 94 92 93
30 min 102 92 95.0
Water content (% w/w by KF) 1.50 1.52 2.01
Related Substances
Desallyl Naloxegol 0.02 0.06 Not Detected
Maximum unknown impurity 0.05 0.07 0.11
Total impurities 0.54 0.79 1.04

,CLAIMS:We Claim:

1. A pharmaceutical composition comprising:
a) 10 to 20 % w/w of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 80 to 90% w/w of pharmaceutically acceptable excipients;
Wherein, the ratio of Naloxegol oxalate to polyvinylpyrrolidone in a solid dispersion is between 0.5:2 w/w to 2:0.5 w/w.

2. A pharmaceutical composition comprising:
a) 10 to 20% w/w of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 30 to 60 % w/w of mannitol;
c) 15 to 40 % w/w of microcrystalline cellulose;
d) 2 to 6 % w/w of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, the ratio of Naloxegol oxalate to polyvinylpyrrolidone in a solid dispersion is between 0.5:2 w/w to 2:0.5 w/w.

3. A pharmaceutical composition comprising:
a) 20 to 70mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, said pharmaceutical composition is in the form of tablet or capsule and said pharmaceutical tablet having an oval shape with a thickness of from 2 mm to 8 mm and said tablet having the hardness from 5 kiloponds to 15 kiloponds and a disintegration time of 30 to 120 seconds.

4. A pharmaceutical composition comprising:
a) 28.46mg to 56.92mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, Naloxegol oxalate and polyvinylpyrrolidone in a solid dispersion are in 1:1 w/w ratio and said composition exhibits a dissolution of at least 90% at about 30 minutes at a temperature of 37 ± 0.5°C using a paddle apparatus at a speed of about 50 rpm in 0.1N HCl dissolution medium.

5. A pharmaceutical composition comprising:
a) 28.46mg to 56.92mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein, Naloxegol oxalate and polyvinylpyrrolidone in a solid dispersion are in 1:1 w/w ratio and the stability of the said composition is such that at least 95% amount of Naloxegol is present in the composition after storage for 6 months at 40°C and 75% relative humidity (RH).

6. A pharmaceutical composition comprising:
a) 28.46mg to 56.92mg of amorphous solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 60 to 200mg of mannitol;
c) 30 to 130mg of microcrystalline cellulose;
d) 5 to 20mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein the amorphous Naloxegol oxalate is solid dispersion of Naloxegol oxalate and polyvinylpyrrolidone and the content of Naloxegol oxalate in dispersion is from about 35% w/w to about 65% w/w.

7. A pharmaceutical composition in the form of tablet dosage form comprising:
a) 28.46mg of solid dispersion comprising Naloxegol or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone;
b) 94mg of mannitol;
c) 40mg of microcrystalline cellulose;
d) 7.5mg of croscarmellose sodium; and
e) Optionally other pharmaceutically acceptable excipients;
Wherein the 28.46mg of solid dispersion contains about 14.23mg of Naloxegol oxalate and about 14.23mg of polyvinylpyrrolidone.

8. The pharmaceutical composition according to claim 1-7, wherein the composition does not contain more than 1.5% w/w of total impurity.

9. The pharmaceutical composition according to claim 1-7, wherein the composition does not contain more than 2.5 % by weight of water content as measured by Karl Fischer titration method.

10. The method for preparing the pharmaceutical tablet of claim 7, comprising the steps: a) Co-sifting of Naloxegol Oxalate- polyvinylpyrrolidone Premix, colloidal silicon dioxide, Butylated Hydroxy Anisole, propyl gallate, microcrystalline cellulose and mannitol, and passed through mesh; b) the materials of step (a) were sifted through co-mill; c) materials of Step (b) was loaded into blender for pre-lubrication and then lubricated with magnesium stearate; d) lubricated blend of step (c) was then compressed into tablet in multistation compression machine; and e) coating with opadry system.

Wherein, the obtained lubricated blend in step “c” has a bulk density of 0.40 to 0.55 g/ml, tapped density from about 0.50 to 0.70 g/ml and Hausner ratio of about 1.284 and compressibility index of about 22.11 %.