WO2023031955A1

WO2023031955A1 - Oral pharmaceutical compositions of methylnaltrexone and salt thereof

Info

Publication number: WO2023031955A1
Application number: PCT/IN2022/050765
Authority: WO
Inventors: Vijayendrakumar Virendrakumar Ji REDASANI; Shantilal Prakashchand KHABIYA; Prajkta Vitthal BALAKSHE
Original assignee: Redasani Vijayendrakumar Virendrakumar Ji
Priority date: 2021-08-28
Filing date: 2022-08-29
Publication date: 2023-03-09

Abstract

The present invention relates to solid oral pharmaceutical compositions of methylnaltrexone and its salts. The compositions are free of an ion pairing agent and particularly free of sodium lauryl sulphate. The compositions contain a solid solubilizer and / or a semi-solid low melting solubilizer which enhances solubility of the compositions and thereby gastrointestinal absorption of such compositions.

Description

Oral Pharmaceutical Compositions Of Methylnaltrexone and Salt Thereof

Field Of The Invention

The present invention relates to solid oral pharmaceutical compositions of methylnaltrexone and its salts. The compositions are free of an ion pairing agent and particularly free of sodium lauryl sulphate. The compositions contain a solid solubilizer and / or a semi-solid low melting solubilizer which enhances solubility of the compositions and thereby gastrointestinal absorption of such compositions. Additionally, the solubilizer also acts a compression agent or compression aid and thereby reduces requirements of other ingredients for compression. This has enabled inventors to reduce unit weight substantially and also to combine 3 doses of 150 mg in a single unit dose which further provides better patient compliances. Additionally, compositions of the invention can be also consumed as suspensions before processing into tablets or alternatively, fast disintegrating tablets can be added to water to form a fine suspension which can be consumed.

Objects Of the Invention

A first object of the invention is to avoid use of an ion pairing agent in oral pharmaceutical compositions of methyl naltrexone or its salt methyl naltrexone bromide. Thus, the first object is to provide a solid oral pharmaceutical composition free of an ion pairing agent. Since marketed formulation of methyl naltrexone incorporates sodium lauryl sulphate as an ion pairing agent, the first object of the invention is to also provide solid oral compositions of methyl naltrexone free of sodium lauryl sulphate.

Second object is to add an alternative to an ion pairing agent to develop a quick release formulation of therapeutically effective amount of Methylnaltrexone to produce a soluble composition which can enhance gastrointestinal absorption. This alternative agent is a solid solubilizer and / or a semi- solid low melting solubilizer. The solid solubilizer also acts as a compression agent or compression aid and reduces requirement of ingredients which are added to impart compressibility. Currently available tablets of Methylnaltrexone bromide are of 150 mg and 3 tablets are given to administer a required dose of 450 mg. Because of use of an alternative agent which is not an ion pairing agent, it is possible to provide entire dose of 450 mg from a single dosage unit such as a capsule or a tablet. Thus, the third object of the invention is to combine multiple doses in a single unit such as in a single tablet or capsule. Under this object, invention provides a single unit of oral pharmaceutical composition having 450 mg of methyl naltrexone bromide. Reducing the frequency of dosing while administering daily dose in a single dosage form greatly enhances patient compliance.

Accordingly, one more and most important object is to provide a solid oral composition of methyl naltrexone or salt thereof for administering a complete dose of methyl naltrexone in a single unit of such composition. Under this object, the invention also covers a method of treating any disease which can be treated with Opioid receptor antagonist particularly, peripherally nonselective p opioid receptor antagonist by administering a single unit composition of methyl naltrexone or salt thereof containing an entire dose such as 450 mg.

Particularly, the invention provides a solid oral pharmaceutical composition containing 450 mg of methyl naltrexone bromide in a single unit dosage form for use in the treatment of any disease which can be treated with peripherally nonselective p opioid receptor antagonist.

Particularly, the invention provides a solid oral pharmaceutical composition containing 450 mg of methyl naltrexone bromide in a single unit dosage form for use in reversing one or more side effects of an opioid drug.

Yet another object is to provide various dosage forms of Methylnaltrexone or its salt. These include immediate release tablets and capsules, delayed release formulations, multiunit particulate system etc. Yet another object provides various processes to prepare oral pharmaceutical compositions of Methylnaltrexone or its bromide salt. Additionally, compositions of the invention can be also consumed as suspensions before processing into tablets or alternatively, fast disintegrating tablets can be added to water to form a fine suspension which can be consumed. Background Of The Invention

Opioids are narcotic medications that activate opioid receptors located in the central nervous system to relieve pain in certain conditions like cancer, surgery, severe injury, amputation etc. Cancer-related pain affects approximately 9 million people worldwide. As cancer progresses, an increasing fraction of patients require treatment with potent opioids, which may be administered via several routes.

Opioids, however, also react with receptors outside of the central nervous system, resulting in side effects including constipation, nausea, vomiting, urinary retention, and severe itching. Notable are the effects of opioids in the gastrointestinal (GI) tract where these drugs inhibit gastric emptying and peristalsis in the intestines, thereby decreasing the rate of intestinal transit and producing constipation. Constipation is the most commonly occurring adverse effect of chronic opioid therapy in patients with advanced cancer and almost inevitable consequence of opioid use in cancer and non-malignant disease states. Unlike other adverse effects of opioid therapy, constipation is one of the side effects of opioids to which tolerance rarely develops This may exacerbate bowel dysfunction, thereby delaying recovery of normal bowel function, prolonging hospital stays, and increasing medical care costs and more importantly the use of opioids in treating pain is often limited due to these undesired side effects, which can be debilitating and often cause patients to refuse the use of opioid analgesics (Becker G et al, 2007).

Opioid receptor antagonists, such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing the undesirable peripheral side effects of opioids. However, these agents not only act on peripheral opioid receptors but also on opioid receptors in the central nervous system, sometimes reversing the beneficial and desired analgesic effects of opioids or causing symptoms of opioid withdrawal. Methylnaltrexone a quaternary derivative of naltrexone, is a peripherally nonselective p opioid receptor antagonist which can provide causal treatment for opioid-induced constipation (OIC), yet not interfere with the analgesic effect (Li-Fang Yu et al, 2011). Having the general structure of a quaternary ammonium salt, Methylnaltrexone is a compound with greater polarity and lower lipid solubility. Therefore, Methylnaltrexone has restricted access to the bloodbrain barrier and decreases the constipating effects of opioid pain medications. Because these effects are mediated by peripherally located receptors, the analgesic effects, which are mediated at receptors in the central nervous system, are spared (Yuan, C.S, 2007) ³. However, as a hydrophilic compound, Methylnaltrexone has limited gastrointestinal absorption (Yuan, C.S et al, 1997 and Becker G et al, 2007). Methylnaltrexone is hydrophilic and quite soluble in aqueous solutions. The positive charge of the quaternary amine causes Methylnaltrexone to be poorly absorbed in the gastrointestinal tract. In general, less than about 5% of Methylnaltrexone is absorbed into the bloodstream when delivered orally.

This peripheral antagonist Methylnaltrexone has been studied since the late 1970s. It has been used in patients to reduce opioid-induced side effects such as constipation, pruritus, nausea, and urinary retention (see, e.g., U.S. Pat. Nos. 5,972,954, 5,102,887, 4,861,781, and 4,719,215; and Yuan et al., Drug and Alcohol Dependence 1998, 52, 161). The dosage form of Methylnaltrexone used most often in these studies has been a solution of Methylnaltrexone for intravenous injection. In U.S. Pat. No. 6,559,158, the dose of Methylnaltrexone for treating methadone maintenance patients was explored. Methylnaltrexone subcutaneous injection Relistor™ is available for the treatment of opioid induced constipation in patients with advanced illness receiving palliative care, when response to laxative therapy has not been sufficient.

U.S. Pat. No. 6,419,959, hereinafter US’959 patent discloses an oral dosage form that releases certain compounds “over the whole gastrointestinal tract.” According to the US”959 patent, opioid antagonists are not always suitable for administration in an immediate release form due to dose limiting side effects. In addition, opioid- induced constipation was believed to be a result from the direct and local effects of opioids on receptors across the entire gastrointestinal tract. To address these issues, the '959 patent suggests dosing certain opioid antagonists, including Methylnaltrexone, in a controlled-release dosage form, thereby delivering these antagonists at acceptable doses locally across the entire gastrointestinal tract. Data respecting Methylnaltrexone specifically, however, was not reported. In U.S. Pat. No. 6,274,591, it was demonstrated that an enteric coated Methylnaltrexone which released substantially no Methylnaltrexone in the stomach was more effective in antagonizing the oral-cecal delay caused by morphine than was an uncoated Methylnaltrexone. The '591 patent suggests and claims delivering effective amounts of Methylnaltrexone using an oral dosage that by-passes the stomach altogether. Data respecting taxation, however, was not reported. In U.S. Pat. No. 6,559,158, an oral dose of Methylnaltrexone was explored for treating constipation in methadone maintenance patients.

Relistor™ tablets 150 mg are available commercially. These are film-coated tablets containing 150 mg of Methylnaltrexone bromide (equivalent to 122.5 mg Methylnaltrexone). The reported composition from the label of Relistor™ tablets include silicified microcrystalline cellulose, microcrystalline cellulose (MCC), sodium lauryl sulfate, croscarmellose sodium (CCS), crospovidone, poloxamer 407, stearic acid (vegetable source), colloidal silicon dioxide, edetate calcium disodium, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

Significant patents related to Relistor™ tablets are US8524276, US8956651, US9314461, US 10307417, US 1037650 wherein an ion pair between the positively charged Methylnaltrexone and a negatively charged moiety was postulated to make a “pair” that is more hydrophobic than Methylnaltrexone bromide and thereby enhanced the absorption of Methylnaltrexone in the stomach. Ion pairing was done using Methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient particularly, sodium lauryl sulfate, which when dissolved in solution, in a solid dosage form together with a rapid-acting disintegrant (e.g., a carbon dioxidegenerating disintegrant) was effective to induce laxation.

There are many other possible approaches for increasing the absorption of Methylnaltrexone drug and subsequently its biovailability.

Summary Of the Invention

A first aspect of the invention is to avoid an ion pairing agent in oral pharmaceutical compositions of methyl naltrexone or its salt for example, methyl naltrexone bromide. Since marketed formulation of methyl naltrexone incorporates sodium lauryl sulphate as an ion pairing agent, the first aspect of the invention is to also provide solid oral compositions of methyl naltrexone free of sodium lauryl sulphate. Second aspect is to add an alternative to an ion pairing agent which produces a soluble composition with quick release of methyl naltrexone as well as its salt and such quick releasing soluble composition can enhance gastrointestinal absorption. The invention provides oral pharmaceutical compositions of methyl naltrexone or its salt for example, methyl naltrexone bromide for its safety reason employing a solid solubilizer preferably a solidified liquid solubilizer and / or a semi-solid low melting solubilizer which can be optionally solidified or adsorbed on suitable substrate / excipient to enhance solubility of the compositions and to quickly release methyl naltrexone ( or salt thereof) and thereby can enhance gastrointestinal absorption of such compositions..

The solid solubilizer is preferably a solidified liquid solubilizer. It has two components. The first component is a liquid surfactant / solubilizer which is adsorbed on the second component which is a solid support. The solid support is porous mineral carrier such as silicate preferably Magnesium Alumino metasilicate. The liquid surfactant / solubilizer is preferably Polyoxyethylene (20) sorbitan monooleate commonly known as polysorbate 80 or Polyoxyl 40 hydrogenated castor oil. The solid solubilizer formed from the two components is added in weight ratio of 1:0.1 to 1:10 preferably in a weight ratio of 1:0.2 to 1:10, more preferably in a weight ratio of 1 :0.5 to 1:10 and most preferably in a weight ratio of 1 : 1 to 1 : 10 with methyl naltrexone bromide. This solid solubilizer also acts as compression agent or aid. This has enabled inventors to reduce unit weight substantially and to combine 3 doses of 150mg in a single unit dose.

The solid solubilizer is also termed as “surfactant based solubilizer”.

Another preferred solubilizer is a semi-solid low melting solubilizer having a melting point of up to 100 °C, preferably up to 80°C, more preferably up to 60°C and most preferably up to 50°C. The most preferred solubilizer is D-a-Tocopherol polyethylene glycol 1000 succinate commonly known as vitamin E TPGS. It is added in weight ratio of from 1 :0.1 to 1 : 10 preferably in a weight ratio of from 1 :0.2 to 1:10, more preferably in a weight ratio of from 1 :0.5 to 1:10 and most preferably in a weight ratio of from 1:1 to 1:10 with methyl naltrexone bromide.

In preferred embodiment, ratio of solid solubilizer / low melting semi- solid solubilizer to methylnaltrexone or its salt is from 1:1 to 1:5, preferably from 1:2 to 1:5.

Preferably, the solid solubilizer is a solidified solubilizer where liquid surfactant / solubilizer is adsorbed on the solid support. The solid support is porous mineral carrier such as silicate preferably Magnesium Alumino metasilicate. The liquid surfactant / solubilizer is preferably Polyoxyethylene (20) sorbitan monooleate commonly known as polysorbate 80 or Polyoxyl 40 hydrogenated castor oil.

Such solid / solidified solubilizer employing Polyoxyethylene (20) sorbitan monooleate ( polysorbate 80) or Polyoxyl 40 hydrogenated castor oil adsorbed on the solid support Magnesium Alumino metasilicate are available under brand names SEPITRAP™ 80 and SEPITRAP™ 4000.

In embodiments, a weight ratio of around 1:3 of SEPITRAP™ 80 or SEPITRAP™ 4000 to methyl naltrexone or its salt have been successfully employed.

Additionally, few other solubilizer such as sorbitol can be employed.

In an embodiment, a weight ratio of around 1:3 of vitamin E TPGS to methyl naltrexone or its salt has been successfully employed.

The dose of Methylnaltrexone bromide is 450 mg. The currently available Relistor™ tablet contains 150 mg of methyl naltrexone bromide and weighs around 650 mg. Three such tablets are to be given to patient / consumed by the patient to administer a required dose of 450 mg. Third aspect of the invention is to combine multiple doses in a single unit such as in a single tablet or capsule. Under this aspect, invention provides a single unit of oral pharmaceutical composition having 450 mg of methyl naltrexone bromide. Weight of such single tablet having a dose of 450 mg preferably does not exceed 1.2 g, preferably 1.1 g and most preferably 1 g.

Reducing the frequency of dosing while administering daily dose in a single dosage form greatly enhances patient compliance.

Accordingly, one more and most important aspect is to provide a solid oral composition of methyl naltrexone or salt thereof for administering a complete dose of methyl naltrexone in a single unit of such composition. Under this aspect, the invention also covers a method of treating any disease which can be treated with an Opioid receptor antagonist particularly, peripherally nonselective p opioid receptor antagonist by administering a single unit composition of methyl naltrexone or salt thereof containing an entire dose / daily dose such as 450 mg.

More specifically, the invention also covers a method of reversing one or more side effects of an opioid drug by administering a single unit dosage form comprising entire dose / daily dose of 450 mg.

Yet other aspect provides various dosage forms of Methylnaltrexone or its salt. These include immediate release tablets and capsules, delayed release formulations, multiunit particulate system etc. Yet another aspect provides various processes to prepare oral pharmaceutical compositions of Methylnaltrexone or its bromide salt. These processes include direct compression, granulation, spheronization, extrusion and spheronization spray drying or melt extrusion, etc. Additionally, compositions of the invention can be also consumed as suspensions before processing into tablets or alternatively, fast disintegrating tablets can be added to water to form a fine suspension which can be consumed.

Detailed Description Of The Invention

The invention provides oral pharmaceutical compositions of Methylnaltrexone.

Most preferably, the invention provides oral pharmaceutical compositions of Methylnaltrexone bromide however other salts of Methylnaltrexone can also be employed.

Methylnaltrexone bromide is chemically (R)-N-(cyclopropylmethyl) noroxymorphone methobromide. The molecular formula is C2iH26NO4Br, and the molecular weight is 436.36.

The Methylnaltrexone for use in such compositions may be in any of a variety of forms like salts, prodrugs, polymorphs (i.e., crystal forms), co-crystals, hydrates, solvates, and the likes. All these forms are hereinafter referred as Methylnaltrexone or salt thereof.

The invention provides pharmaceutical compositions containing from 50 mg to 500 mg of Methylnaltrexone bromide. Preferably the invention provides pharmaceutical compositions containing from 150 mg to 450 mg of Methylnaltrexone bromide equivalent to 122.5 to 367.5 mg Methylnaltrexone.

Thus, whenever the term 150 mg or 450 mg of Methylnaltrexone or salt thereof is used, it is particularly applicable to methyl naltrexone bromide. For any other salt or derivative or for methyl naltrexone, an equivalent amount calculated on the basis of molecular weight may be employed.

The invention also provides method of treating any disease which can be treated with peripherally nonselective p opioid receptor antagonist by administering daily a single unit dosage form of the present invention containing 450 mg of methyl naltrexone or salt thereof.

Methyl naltrexone is available as methyl naltrexone bromide and has a quaternary ammonium group in its structure.

Methyl Naltrexone

This unique structure has greater polarity and lower lipid solubility and has restricted access to the blood-brain barrier and decreases the constipating effects of opioid pain medications. At the same time there is no compromise of opioid- mediated analgesia in the central nervous system.

Preparing compositions of methyl naltrexone is challenging. The compositions should be such that they shall improve gastrointestinal absorption. The present invention provides oral pharmaceutical compositions of methyl naltrexone particularly tablets and capsules of methylnaltrexone. The invention provides oral pharmaceutical compositions of methyl naltrexone bromide and a solubilizer which does not act as an ion pairing agent with methyl naltrexone but an alternative to such agent and still produces a soluble composition quickly releasing methyl naltrexone. The invention is about avoiding an ion pairing agent that forms more hydrophobic pair. The invention is about using an alternative to an ion pairing agent in the compositions of methyl naltrexone and its salts and still producing a quick releasing soluble composition that can achieve enhanced gastrointestinal absorption. The resulting compositions are fast disintegrating and fast dissolving releasing at least 80 % in 15 minutes and / or at least 90 % in 30 minutes. Preferably solid oral composition for example a tablet releases at least 80 % methyl naltrexone in 15 minutes, preferably at least 85 % methyl naltrexone in 15 minutes, and more preferably releasing at least 90 % methyl naltrexone in 15 minutes when tested using discriminatory dissolution method which employs dissolution apparatus type 2 (paddles) using dissolution media having 500 ml of 0.1N HC1 at 50rpm.

Particularly, the solubilizer is a solid solubilizer. More particularly, the solubilizer is a solidified liquid solubilizer. Most particularly, solubilizer is a micro- encapsulated solubilizer in powder form. The solidified liquid solubilizer has two components viz. a liquid surfactant / solubilizer adsorbed on the solid support. The solid support is porous mineral carrier such as silicate preferably Magnesium Alumino metasilicate. The liquid surfactant / solubilizer is preferably Polyoxyethylene (20) sorbitan monooleate commonly known as polysorbate 80 or Polyoxyl 40 hydrogenated castor oil.

Another suitable solubilizer that is employed to arrive at soluble compositions of methyl naltrexone and its salts without employing an ion pairing agent include low melting semi-solid solubilizer. These solubilizers melt below 100°C, preferably below 80°C and more preferably below 60°C or less.

The solid solubilizer and a semi-solid solubilizer employed in the present invention are summarized in table 1 below,

Table 1: Solid and semi-solid Solubilizers employed in the invention

Yet alternatively, both solid solubilizer wherein liquid surfactant is adsorbed on the solid support and a low melting semi-solid solubilizer are used to produce a soluble composition quickly releasing methyl naltrexone.

Preferably, when the semi-solid low melting solubilizer or both solid and semi-solid solubilizers are used to produce methyl naltrexone compositions, melt granulation is preferably adopted as method of preparation. Both solubilizers are low melting in nature and melt at a temperature below 100°C and therefore, a temperature of up to 100°C, preferably up to 80°C and most preferably up to 60°C or less is employed to cause melting of solubilizers. When semi-solid solubilizer is used alone, lower temperatures such as 60°C or less such as 50°C can be employed.

When both solid and semi- solid solubilizers are employed, they are employed in weight ratio of 1:0.2 to 1:5. Most preferred ratios are from 1:3 to 3:1. In an embodiment, 1:1 ratio of solid and semi-solid solubilizers are employed. In another embodiment, 1:2 ratio of solid and semi-solid solubilizers are used. In yet another embodiment, 3:1 ratio of solid and semi-solid solubilizers are used.

When tablet prepared in accordance with the present invention disintegrates, the surfactant which is adsorbed on the porous mineral carrier desorbs and form micelles to solubilize methyl naltrexone. These micelles are not in the nature of ion pair still they would enhance gastrointestinal absorption.

As reported earlier, marketed tablets of Methylnaltrexone viz. Relistor™ tablets 150 mg employ several ingredients which includes at least two disintegrants namely croscarmellose sodium and crospovidone and at least two surfactants including an ion pairing agent namely poloxamer and sodium lauryl sulphate which can pair with quaternary methyl naltrexone bromide to make a hydrophobic pair for enhancing gastrointestinal absorption. When dissolution testing is performed on Relistor™ tablets using various dissolution media, it is noted that the compositions are highly soluble releasing at least 80 % in 15 minutes and at least 90 % in 30 minutes.

The present invention contemplates ways and methods of enhancing gastrointestinal absorption of methyl naltrexone bromide. These methods preferably avoid few ingredients employed in Relistor™ tablets. The methods of the present invention preferably avoid use of an ion pairing excipient to enhance gastrointestinal absorption while ensuring fast and complete release or dissolution as achieved by Relistor™ tablets. Instead, the invention employs a solid solubilizer particularly solidified liquid solubilizer.

Thus, in the present invention, there is no need to calculate and add an ion pairing agent for methyl naltrexone bromide added.

Present invention employs an excipient which can produce a composition of methyl naltrexone bromide by a simple process.

The compositions of the present invention employ fewer ingredients as compared to Relistor™ tablets and are far less bulkier than the Relistor™ tablets. The weight of the tablets of the present invention is at least 25 mg, preferably at least 50 mg, more preferably at least 75 mg and most preferably at least 100 mg less than the Relistor™ tablets due to incorporation of solid solubilizer and fewer ingredients. The dose of Relistor™ tablets is 450 mg. The Relistor™ tablets are available as 150 mg tablets where each tablet weighs around 650 mg. Hence there is a need to take 3 tablets at a time. If an ion pairing agent is used in molar equivalent amount to that of methyl naltrexone bromide, 150 mg will require around 100 mg (96 mg) of sodium lauryl sulphate. The two ingredients together weigh around 250 mg. Around 400 mg of other ingredients are required to make a Relistor™ tablet of 650 mg.

If one attempts to make a single tablet of 450 mg of methyl naltrexone bromide, it requires 297.42 mg of sodium lauryl sulphate. The total of 450 mg of methyl naltrexone bromide and 297.42 mg of sodium lauryl sulphate is around 747 mg. This composition will additionally require ingredients such as diluent, disintegrant, lubricant, glidant etc. to compress it into a tablet. The total tentative composition will be very bulky and such larger tablet or capsule will not lead to a patient compliant composition.

By avoiding an ion pairing agent such as sodium lauryl sulphate and by using solid solubilizer or semi-solid solubilizer or both, the inventors of the present invention can arrive at a composition that can deliver a dose of 450 mg of methyl naltrexone bromide from a single unit dosage form such as tablet or capsule. Such compositions are provided in tables 9 and 10. Reducing the frequency of dosing while administering daily dose in a single dosage form greatly enhances patient compliance.

The solid solubilizer of the present invention in addition to serve as a solubilizer and bioavailability enhancer, also acts as a compression agent. This unique feature of the solid solubilizer serves multiple purposes. First, it can be added in required quantity without fearing for enhancing bulk of the tablet unlike an ion pairing agent and second it reduces requirement of other ingredients that aid in compression.

It is possible to use solid or semi-solid solubilizer in a weight-by-weight ratio of 1:0.1 to 1:10 preferably in a weight ratio of 1:0.2 to 1:10, more preferably in a weight ratio of 1 : 0.5 to 1 : 10 and mo st preferably in a weight ratio of 1 : 1 to 1 : 5 with methyl naltrexone bromide.

Preferably it is employed in a W/W ratio of 1:1 to 1:6 with methyl naltrexone bromide. Most preferably it is employed in a W/W ratio of 1:1 to 1:5 with methyl naltrexone bromide.

In an embodiment, weight ratio of Sepitrap®80 (solid solubilizer) to Methylnaltrexone is 1:2.4. In another embodiment, the ratio is 1:3. In yet another embodiment, the weight ratio of Sepitrap®80 (solid solubilizer) to Methylnaltrexone is 1:4.63.

In yet another embodiment, weight ratio of solid and semi- solid solubilizers to Methylnaltrexone is 1:1.5.

The compositions of the present invention preferably include tablet, dragee, capsule, caplet, orally-disintegrating tablet, film-coated tablet, enteric tablet, buccal tablet, sublingual tablet, chewable tablet, effervescent tablet, slow-release tablet, rapid-release tablet, modified-release tablet, delayed-release tablet, prolonged- release tablet, controlled-release tablet, sachet, granule, pilule, powder, pellet, , pastille and similar solid oral dosage forms.

Other excipients are chosen based on the composition to facilitate the physical formulation of various dosage forms. Pharmaceutical composition of the present inventions may comprise along with the active and a solubilizer, other pharmaceutically acceptable excipients like diluents / fillers, disintegrants, binders, lubricants, glidants, and the mixtures thereof, to facilitate the physical formulation of various dosage forms.

Binders can be selected from the group, but are not limited to methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, silicified microcrystalline cellulose(SMCC), polyvinyl pyrrolidone, gelatine, polyvinyl alcohol, acacia, tragacanth, guar, pectin, starch paste, pregelatinized starch, alginic acid, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, maltodextrin, guar gum, magnesium aluminium silicate, polymethacrylates, sorbitol and other materials known to one of ordinary skill in the art. A mixture of binders may also be used. The binder is preferably used in an amount of from about 2 to about 15% by weight.

Disintegrant can be selected from the group, but are not limited to a!ginic acid, carboxymethylcellulose calcium, carboxymethyl cellulose, carboxymethylcellulose sodium, cross-linked sodium carboxymethylcellulose, low substituted hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium (CCS), crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose (MCC), methyl cellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidones, polacrifin potassium, starch, pregelatinized starch, sodium alginate, sodium lauryl sulphate, sodium starch glycolate, crystalline cellulose, hydroxypropyl starch and other materials known to one of ordinary skill in the art. The combination of above-mentioned disintegrants can also be used.

Preferably, the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone and sodium starch glycolate. Disintegrant is preferably used in an amount of from about 1% to about 20% by weight of the tablet, more preferably in an amount of from about 2% to about 15% by weight and most preferably in an amount of from about 2% to about 10%.

In an embodiment, disintegrant is 3.2 % of the core tablet weight. In another embodiment, disintegrant is 4.6 % of the core tablet weight. In few embodiments, the disintegrant is from 5.5 to 5.7 % by weight of the tablet.

It is often required in the process to divide disintegrant into two portions / lots where there is a need to add disintegrant inside and outside granules or where there is a need to co-sift disintegrant with solubilizer or methyl naltrexone bromide. The two portions can be from 1:1 (exactly same portions) to 1:5 (one portion can be 20 % of the other portion).

Diluents or filler can be selected from the group consisting of calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, maltitol, microcrystalline cellulose, powdered cellulose, pregelatinized starch, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, and xylitol and other materials known to one of ordinary skill in the art.

Preferred diluents or fillers include lactose, fructose, starch, sucrose, mannitol, maltitol, sorbitol, xylitol and microcrystalline cellulose.

When semi-solid solubilizer is used, it is often adsorbed on diluent or part of diluent. Preferred diluents for the adsorption include microcrystalline cellulose, lactose, mannitol and starch.

If required in the process, where there is a need to add diluent inside and outside granules or in direct compression where there is a need to adsorb solubilizer particularly semi-solid solubilizer on part of diluent, diluent can be divided into two portions / lots. The two portions can be from 1 : 1 (exactly same portions) to 1 : 10(one portion can be 10 % of the other portion).

Binder can be selected from the group, but is not limited to methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, silicified microcrystalline cellulose(SMCC), polyvinyl pyrrolidone, gelatine, polyvinyl alcohol, acacia, tragacanth, guar, pectin, starch paste, pregelatinized starch, alginic acid, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, maltodextrin, guar gum, magnesium aluminium silicate, polymethacrylates, sorbitol and other materials known to one of ordinary skill in the art. A mixture of binders may also be used. The binder is preferably used in an amount of from about 1 to about 15% by weight, preferably from about 1 - 10 % by weight of the tablet. Lubricants can be selected from the group consisting of vegetable oils, such as hydrogenated vegetable oil or hydrogenated castor oil; polyethylene glycols, such as polyethylene glycol (PEG)-4000 and PEG-6000; stearic acid; derivatives of stearic acid, such as magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate and sodium stearyl fumarate; mineral salts, such as talc; inorganic salts; organic salts, such as sodium benzoate, sodium acetate, sodium chloride and sodium oleate; and polyvinyl alcohols, microcrystalline cellulose, sodium lauryl sulphate, silica, colloidal silica, corn-starch, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art.

The preferred lubricant is magnesium stearate or sodium stearyl fumarate. Preferably, lubricant is used in an amount from about 1 to about 5% by weight. Glidants can be selected from the group, but is not limited to colloidal silicon dioxide, colloidal silica, corn-starch, talc, calcium silicate, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicon, silicon hydrogel, powdered cellulose, silicon dioxide, talc, and other materials known to one of ordinary skill in the art.

Preferably, talc is used as a glidant. More preferably, colloidal silicon dioxide is used as a glidant. Most preferably, combination of talc and colloidal silicon dioxide is used as a glidant.

Glidants are used in an amount from about 0.5 to about 10 % by weight of the core tablet. Preferably, from about 1 to about 5 percent by weight of the tablet. Other ingredients include a chelating agent such as Edetate calcium disodium and and sodium carbonate, a stabilizer hereinafter named as alkalizer. When chelating agent such as Edetate calcium disodium is used alone for granulation of blend containing Methylnaltrexone bromide, it is also referred as a binder.

In yet another aspect, the invention provides simple and economical processes to prepare oral pharmaceutical compositions of Methylnaltrexone bromide. The compositions of the present invention can be prepared by various processes known to the person skilled in the art, such as, but not limited to direct compression, wet or dry granulation, slugging, hot melt granulation, extrusion-spheronization, hot melt extrusion, fluidized bed granulation, extrusion, spray drying, spray coating, and solvent evaporation and the like.

In one preferred embodiment, solid oral compositions of methyl naltrexone or salt thereof are prepared by direct compression. Methyl naltrexone is co-sifted with diluent, solid solubilizer and disintegrant and all ingredients are blended together to produce ready to process blend.

Additionally, this blend can be also consumed as suspensions or alternatively, fast disintegrating tablets can be added to water to form a fine suspension which can be consumed.

Additionally, one or more sweeteners and one or more flavours are added in the blend / fast disintegrating tablets when it is intended to be consumed as suspension. The above blend is often a lubricated blend which can be filled in capsule or compressed into a tablet.

A preferred embodiment employs direct compression process to prepare Methylnaltrexone bromide tablets. The solid solubilizer Sepitrap®80 is a compression agent and produces a directly compressible blend containing from 20 - 50 % of Methylnaltrexone preferably Methylnaltrexone bromide, preferably containing 25 -50 % of Methylnaltrexone.

In yet another embodiment, solid oral compositions of methyl naltrexone or salt thereof and semi-solid solubilizer are prepared by direct compression. Semi-solid solubilizer is melted and adsorbed on diluent or one part of diluent. Methyl naltrexone is co-sifted with part of diluent / entire diluent and / or diluent on which semi- solid solubilizer is adsorbed and disintegrant and all ingredients are blended together to produce ready to process blend. This blend is often a lubricated blend which can be filled in capsule or compressed into a tablet.

Thus, originally semi-solid solubilizer is co-processed with diluent to form a solid Solublizer. (Alternatively TPGS is dissolved in Purified water or Acetone and adsorb the same on Microcrystalline Cellulose 102 or any other suitable diluent, before using the blend for Hot Melt Extrusion). This process is provided under example 10.

In a preferred form of the embodiment, tablets are prepared by wet-granulation. In this process, each of diluent and disintegrant are preferably divided into two portions /lots. A first lot of each is added intragranularly before granulation while the second lot is added after granulation, wet milling, drying of milled granules etc. is performed. Granulation is done using a solution of a chelating agent which acts as a binder solution, and which is obtained by dissolving a chelating agent Edetate calcium disodium in water. After granulation, preferably the granules are wet milled and dried. Once dried, the granulation is milled to form a granular powder which is blended with extra granular excipients and blended with a suitable lubricant and pressed into tablets. In a preferred form of embodiment, a nonfunctional coating is applied to the tablets. A preferred form are tablets which are film-coated with a non-functional coating. In preferred embodiments, disintegrant s Croscarmellose sodium, diluent / filler is microcrystalline cellulose and solution of a chelating agent Edetate calcium disodium is employed as a binder solution. The wet granulation process comprises dividing each of Croscarmellose sodium and microcrystalline cellulose in two parts or lots. First part of each is blended with Methylnaltrexone bromide and granulated using the binder solution of Edetate calcium disodium. The granulate is wet milled, dried, dry milled to produce granules which are blended with the second remaining parts of disintegrant and diluent and further blended with glidant, lubricant etc. to produce blend of Methylnaltrexone that is compressed to produce tablets.

The solid solubilizer Sepitrap®80 can be added intragranularly or extragranularly or partly intragranularly and partly extragranularly. In one embodiment provided as batch 2, the entire amount of Sepitrap®80 is added before granulation and in the other embodiment provided as batch 4, the entire amount of Sepitrap®80 is added extragranularly. Tablets from both the embodiments are subjected to dissolution testing using a discriminating dissolution method and no difference is observed. Both the tablets are fast disintegrating and fast dissolving releasing more than 90 % of Methylnaltrexone in 5 minutes.

Apart from immediate release dosage form, other dosage forms including delayed release, extended release, modified release dosage forms can be prepared. Accordingly suitable matrixing agent, coating materials including polymers etc. can be employed. One dosage form can show dual release of methyl naltrexone in such a way that part of it is released immediately, and the other part is released over or after extended period. Such dosage form can be tablet in tablet, bilayered or multi-layered tablet, capsule having at least two types of minitablets or slugs releasing at different rates, and coated tablets having part of Methylnaltrexone in coating and part in core etc.

For example, tablets of batch 1, 2 or 3 can be subjected to enteric coating. A coating from 2 % to 25 % can be applied. Various polymers dissolve at slightly different pH, hence suitable polymer can be selected. Coating solution or suspension comprises enteric polymer, plasticizer and anti-tacking agent such as talc. Various polymers that can be employed include Cellulose acetate phthalate (CAP), Cellulose acetate trimellitate (CAT), Hydroxyl propyl methyl cellulose phthalate (HPMCP), Hydroxyl propyl methyl cellulose acetate succinate (HPMCAS), Polyvinyl acetate phthalate (PVAP) and methacrylic acid copolymers to name the few. Multiunit particulate system (MUPS) is another preferred form of administering formulations of the present invention. Wet granulated product can be subjected to spheronization or extrusion and spheronization to prepare multiunit particulate containing Methylnaltrexone or its salt. These Multiunit particulate system can be further coated with a film coating or a delayed release coating containing an enteric polymer described above. The

Multiunit particulate system which is coated with an enteric coating to provide delayed release can be further filled into a capsule or compressed into a tablet to provide solid oral unit dosage which can deliver Methylnaltrexone or its salt as desired.

Alternatively, an immediate release dosage form and modified / delayed / extended release dosage form can be separately administered together or sequentially at certain interval.

Before arriving at the present invention, the inventors in the present invention pondered upon the question whether it is possible to avoid an ion pairing agent in pharmaceutical compositions of the Methylnaltrexone or its salt. First, few experiments are carried out with and without sodium lauryl sulphate to ascertain its role in the compositions. Different molar ratios of sodium lauryl sulphate and methyl naltrexone bromide are considered including molar ratios between and including 1:4 and 2:1 to prepare Methylnaltrexone compositions. Compositions without sodium lauryl sulphate are also prepared. These are provided as comparative examples Batch A and Batch B.

Batch A has approximately 1:2 molar ratio of sodium lauryl sulphate and methyl naltrexone bromide; and Batch B is without sodium lauryl sulphate.

In Batch A is also added an additional surfactant to mimic the composition of RELISTOR ™ Tablets which has two surfactants. The detailed compositions and processes of Batches A and B are provided under comparative example 1.

Dissolution testing on Batches A and B are performed using discriminating dissolution method and compared with dissolution of RELISTOR ™ Tablets. This data is provided under comparative example 2.

It is noted that batch B without sodium lauryl sulphate did not exhibit a complete release of Methylnaltrexone bromide at the end of 30 mins, 45 mins and 60 mins. The release at 15 mins was not even 80 %. Batch A however exhibited around 90 - 95 % release in 10 - 15 minutes and around 100 % release at the end of 30 minutes. Several experiments finally led to a successful development of Methylnaltrexone bromide compositions which are fast disintegrating and fast dissolving and which have far better compressibility than Batch A composition. Moreover, the compositions of the present invention can be prepared by direct compression as well as wet granulation. This has been possible due to addition of a solid solubilizer in the composition which also acts as a compression agent or compression aid. Solid solubilizer is a solidified liquid solubilizer. Most particularly, solubilizer is a micro- encapsulated solubilizer in powder form. The solidified liquid solubilizer has two components viz. a liquid surfactant / solubilizer adsorbed on the solid support. The solid support is porous mineral carrier such as silicate preferably Magnesium Alumino metasilicate. The liquid surfactant / solubilizer is preferably Polyoxyethylene (20) sorbitan monooleate commonly known as polysorbate 80 or Polyoxyl 40 hydrogenated castor oil. Thus, solidified liquid solubilizer is Polysorbate 80 Co-processed with Magnesium aluminium metasilicate or Polyoxyl 40 hydrogenated castor oil co-processed with Magnesium aluminium metasilicate. Further, wet granulation trials are taken employing solid solubilizers Sepitrap® 80 and Sepitrap® 4000. Batches land 3 employ Sepitrap® 80 and batch 2 employs Sepitrap® 4000. Batches 1 and 2 employ solid solubilizer in dry blend before granulation. Batch 3 employs solid solubilizer after granulation. Compositions of batches and processes adopted are described under examples 3-5. The batches 1 and 3 are subjected to dissolution testing using discriminatory dissolution method. Both batches exhibited 100 % release in only 5 minutes providing faster and better release than RELISTOR ™ Tablets. Thus, solid solubilizer can be employed both intragranularly as well as extragranularly.

Since Sepitrap® 80 and Sepitrap® 4000 provided a blend with greater compressibility, it reduced requirement of other ingredients to impart compressibility. This led to two important developments. First, 150 mg tablet is compressed at a weight much less than RELISTOR ™ Tablets; and second, higher doses of Methylnaltrexone or salt can be incorporated in a single tablet or capsule which dispenses away administration of 3 tablets at a time to meet the dose.

Accordingly, preparation of two batches of compositions viz. batch 4 and 5 each having 450 mg of naltrexone bromide are provided in example 6. The tablet weight is from 900 - 1100 mg and such tablets can be administered with ease. Examples

Following examples describe the invention and do not limit the scope of the invention in any way. It is further possible to change all parameters one by one or simultaneously and make hundreds and thousands of formulations all of which will fall within the scope of the present invention.

Comparative Example 1:

Table 2 : Batch A with 1:2 molar ratio of SLS and methylnaltrexone bromide

Manufacturing procedure :

1. Weigh each ingredient separately.

2. Safely sieve each material through appropriate sieve.

3. Co-sift SLS, CCS (part A) and MCC (part A) through appropriate sieve in Appropriate sequence to attain uniformity.

4. Co-sift above blend of step 3 with methylnaltrexone bromide through appropriate sieve.

5. Mix the blend of step 4 in suitable sized blender for predetermined time at suitable RPM.

6. Transfer the blend of step 5 in equipment suitable for granulation.

7. Add and dissolve Polysorbate 80 and Edetate calcium disodium in required quantity of water (part A).

8. Add the binder solution of step 7 onto the powder blend of step 6 and granulate appropriately.

9. Pass the wet mass of step 8 through appropriate sieve.

10. Dry the wet mass of step 9 at suitable temperature to achieve desired LOD.

11. Pass the dried mass of step 10 through suitable sieve.

12. Mix the dried mass of step 11 in suitable sized blender for predetermined time at suitable RPM.

13. Co-sift Colloidal silica, CCS (part B), Sodium bicarbonate and

MCC (part B) through appropriate sieve in appropriate sequence to attain uniformity.

14. Add blend of step 13 in the dried blend of step 12 to mix for predetermined time at suitable RPM.

15. Add Talc and Magnesium stearate in the blend of Step 14 and mix for predetermined time at suitable RPM.

16. Compress the blend of step 15 using suitable shaped punches at preset parameters.

17. Add and disperse Opadry II in required quantity of water (part 2). Stir the solution for predetermined time at suitable RPM.

18. Using suitable coating equipment and at preset coating parameters, Coat the tablets of step 16 using coating solution of step 17 till a desired weight gain achieved.

Table 3: Batch B Composition without SLS

Manufacturing procedure:

1. Weigh each ingredient separately.

2. Safely sieve each material through appropriate sieve.

3. Co-sift CCS (part A) and MCC (part A) through appropriate sieve in

5 appropriate sequence to attain uniformity.

10 6. Transfer the blend of step 5 in equipment suitable for granulation.

7. Add and dissolve Edetate calcium disodium in required quantity of water (part A).

15 9. Pass the wet mass of step 8 through appropriate sieve.

10. Dry the wet mass of step 9 at suitable temperature to achieve desired LOD.

11. Pass the dried mass of step 10 through suitable sieve.

12. Mix the dried mass of step 11 in suitable sized blender for

20 predetermined time at suitable RPM.

13. Co-sift Colloidal silica, CCS (part B), Polysorbate 80 Co-processed with Magnesium aluminium metasilicate (Sepitrap® 80) , Sodium bicarbonate and MCC(part B) through appropriate sieve in appropriate sequence to attain uniformity.

2514. Add blend of step 13 in the dried blend of step 12 to mix for predetermined time at suitable RPM.

16. Compress the blend of step 15 using suitable shaped punches at preset

30 parameters. 17. Add and disperse Opadry II in required quantity of water (part 2). Stir the solution for predetermined time at suitable RPM.

Comparative Example 2:

Table 4: Dissolution Profile of Batch A (SLS) and Batch B (no SLS)

Example 3: Composition with intragranular Sepitrap®80 Table 5 : Composition of Batch 1 with intragranular Sepitrap®80

Manufacturing procedure:

1. Weigh each ingredient separately.

2. Safely sieve each material through appropriate sieve.

5 Co-sift CCS (part A), Polysorbate 80 Co-processed with Magnesium aluminium metasilicate (Sepitrap® 80) and MCC (part A) through appropriate sieve in appropriate sequence to attain uniformity.

4. Co-sift above blend of step 3 with methylnaltrexone bromide through appropriate sieve. fi) Mix the blend of step 4 in suitable sized blender for predetermined time at suitable RPM.

6. Transfer the blend of step 5 in equipment suitable for granulation.

8. Add the binder solution of step 7 onto the powder blend of step 6 and granulate

15 appropriately.

9. Pass the wet mass of step 8 through appropriate sieve.

10. Dry the wet mass of step 9 at suitable temperature to achieve desired LOD. 1. Pass the dried mass of step 10 through suitable sieve. 2. Mix the dried mass of step 11 in suitable sized blender for predetermined time at suitable RPM. 3. Co-sift Colloidal silica, CCS (part B), Sodium bicarbonate and MCC (part B)

5 through appropriate sieve in appropriate sequence to attain uniformity.4. Add blend of step 13 in the dried blend of step 12 to mix for predetermined time at suitable RPM.

15. Add Talc and Magnesium stearate in the blend of Step 14 and mix for predetermined time at suitable RPM. (16. Compress the blend of step 15 using suitable shaped punches at preset parameters.

17. Add and disperse Opadry II in required quantity of water (part 2).

18. Stir the solution for predetermined time at suitable RPM.

19. Using suitable coating equipment and at preset coating parameters, 5 Coat the tablets of step 16 using coating solution of step 17 till a desired weight gain achieved.

Example 4: Composition with intragranular Sepitrap®4000

Table 6: Composition for Batch 2 with intragranular Sepitrap®4000

Manufacturing Procedure: Weigh each ingredient separately. Safely sieve each material through appropriate sieve. Co-sift CCS (part A), Polyoxyl 40 hydrogenated castor oil co-processed with Magnesium aluminium metasilicate (Sepitrap® 4000) and MCC (part A) through appropriate sieve in appropriate sequence to attain uniformity. Co-sift above blend of step 3 with methylnaltrexone bromide through appropriate sieve. Mix the blend of step 4 in suitable sized blender for predetermined time at suitable RPM. Transfer the blend of step 5 in equipment suitable for granulation. 7. Add and dissolve Edetate calcium disodium in required quantity of water (part A).

£ Pass the wet mass of step 8 through appropriate sieve.

10. Dry the wet mass of step 9 at suitable temperature to achieve desired

LOD.

11. Pass the dried mass of step 10 through suitable sieve.

12. Mix the dried mass of step 11 in suitable sized blender for predetermined

10 time at suitable RPM.

13. Co-sift Colloidal silica, CCS (part B), Sodium bicarbonate and MCC (part B) through appropriate sieve in appropriate sequence to attain uniformity.

14. Add blend of step 13 in the dried blend of step 12 to mix for predetermined time at suitable RPM

US. Add Talc and Magnesium stearate in the blend of Step 14 and mix for predetermined time at suitable RPM

17. Add and disperse Opadry II in required quantity of water (part 2).

20 Stir the solution for predetermined time at suitable RPM.

Example 5: Composition with extragranular Sepitrap®80

Table 7: Composition of Batch 3 with extragranular Sepitrap®80

25

Manufacturing procedure:

1. Weigh each ingredient separately.

2. Safely sieve each material through appropriate sieve.

3. Co-sift CCS (part A) and MCC (part A) through appropriate sieve in

5 appropriate sequence to attain uniformity.

5. Mix the blend of step 4 in suitable sized blender for predetermined time at suitable RPM. (6. Transfer the blend of step 5 in equipment suitable for granulation.

7. Add and dissolve Edetate calcium disodium in required quantity of water (part A). 8. Add the binder solution of step 7 onto the powder blend of step 6 and granulate appropriately.

9. Pass the wet mass of step 8 through appropriate sieve.

10. Dry the wet mass of step 9 at suitable temperature to achieve desired

5 LOD.

11. Pass the dried mass of step 10 through suitable sieve.

13. Co-sift Colloidal silica, CCS (part B), Polysorbate 80 Co-processed with0 Magnesium aluminium metasilicate (Sepitrap® 80) , Sodium bicarbonate and MCC

(part B) through appropriate

Sieve in appropriate sequence to attain uniformity.

14. Add blend of step 13 in the dried blend of step 12 to mix for predetermined time at suitable RPM. J15. Add Talc and Magnesium stearate in the blend of Step 14 and mix for predetermined time at suitable RPM.

17. Add and disperse Opadry II in required quantity of water (part 2). Stir 0 the solution for predetermined time at suitable RPM.

18. Using suitable coating equipment and at preset coating parameters,

Coat the tablets of step 16 using coating solution of step 17 till a desired weight gain achieved. 5 Example 6: Dissolution testing of quick releasing methyl naltrexone tablets Table 8: Dissolution Testing of Batch 3 and 5 having intragranular and extragranular Sepitrap® 80 respectively using discriminatory dissolution method which employs dissolution apparatus type 2 (paddles) using dissolution media having 500 ml of 0.1N HC1 at 50rpm. 0

Conclusion: Solid solubilizer having surfactant adsorbed on porous mineral carrier can be added both intra as well as extra granularly to produce a soluble composition of methyl naltrexone or its salt. Example 7A: Higher dose in a single tablet

Table 9 : Tablets with 450 mg dose of methylnaltrexone bromide

Manufacturing process: Weigh each ingredient separately. Safely sieve each material through appropriate sieve. Co-sift CCS (part A), Polysorbate 80 Co-processed with Magnesium aluminium metasilicate (Sepitrap® 80) and MCC (part A) through appropriate sieve in appropriate sequence to attain uniformity. Co-sift above blend of step 3 with methylnaltrexone bromide through appropriate sieve. Mix the blend of step 4 in suitable sized blender for predetermined time at suitable RPM. Transfer the blend of step 5 in equipment suitable for granulation. Add and dissolve Edetate calcium disodium in required quantity of water (part A). Add the binder solution of step 7 onto the powder blend of step 6 and granulate appropriately. Pass the wet mass of step 8 through appropriate sieve. Dry the wet mass of step 9 at suitable temperature to achieve desired LOD. Pass the dried mass of step 10 through suitable sieve. 12. Mix the dried mass of step 11 in suitable sized blender for predetermined time at suitable RPM.

54. Add blend of step 13 in the dried blend of step 12 to mix for predetermined time at suitable RPM.

16. Compress the blend of step 15 using suitable shaped punches at preset parameters.(17. Add and disperse Opadry II in required quantity of water (part B). Stir the solution for predetermined time at suitable RPM.

18. Using suitable coating equipment and at preset coating parameters, Coat the tablets of step 16 using coating solution of step 17 till a desired weight gain achieved. 5 Example 7B: Higher dose in a single tablet

Table 9: Tablets with 450 mg dose in single unit

Manufacturing procedure: Weigh each ingredient separately. Safely sieve each material through appropriate sieve. Co-sift CCS (part A), Polysorbate 80 Co-processed with Magnesium aluminium metasilicate (Sepitrap® 80) and MCC (part A) through appropriate sieve in appropriate sequence to attain uniformity. Co-sift above blend of step 3 with methylnaltrexone bromide through appropriate sieve. Mix the blend of step 4 in suitable sized blender for predetermined time at suitable RPM. Transfer the blend of step 5 in equipment suitable for granulation. Add and dissolve Edetate calcium disodium in required quantity of water (part A). Add the binder solution of step 7 onto the powder blend of step 6 and granulate appropriately. Pass the wet mass of step 8 through appropriate sieve. Dry the wet mass of step 9 at suitable temperature to achieve desired LOD. Pass the dried mass of step 10 through suitable sieve. 12. Mix the dried mass of step 11 in suitable sized blender for predetermined time at suitable RPM.

514. Add blend of step 13 in the dried blend of step 12 to mix for predetermined time at suitable RPM.

16. Compress the blend of step 15 using suitable shaped punches at preset parameters. 1017. Add and disperse Opadry II in required quantity of water (part B). Stir the solution for predetermined time at suitable RPM.

15 Example 7C

Dissolution testing of quick releasing methyl naltrexone tablets containing entire dose of 450 mg.

Table 8: Dissolution Testing of examples 7A and 7B using discriminatory dissolution method which employs dissolution apparatus type 2 (paddles)

20 using dissolution media having 500 ml of 0.1N HC1 at 50rpm.

Conclusion: Tablets containing dose of 450 mg also exhibited quick release releasing at least 80 % in 15 minutes and / or at least 90 % in 30 minutes. Example 8A: Compositions having a combination of a solid solubilizer and a semi-solid solubilizer prepared by melt granulation / hot melt extrusion.

Table 10: Combination of a solid solubilizer and a semi-solid solubilizer

Manufacturing procedure:

I. Weigh each ingredient separately. . Safely sieve each material through appropriate sieve.

3. Co-sift CCS (part A), Polysorbate 80 Co-processed with Magnesium aluminium metasilicate (Sepitrap® 80) through ASTM 20 Mesh . Co-sift above blend of step 3 with MNB through ASTM 40 sieve.

6. Add Vitamin E TPGS in step 5 blend. . Transfer the blend of step 6 in hopper for hot melt granulation and granulate.

8. Collect the granules of step 7 and pass through co-mill to get 30 mesh granules.

9. Mix the mass of step 8 in suitable sized blender for predetermined time at suitable RPM.

10. Co-sift Disodium EDTA, Colloidal silica, CCS (part B), MCC through appropriate sieve and add to the blend of step 9 in appropriate sequence and mix to attain uniformity.

I I. Add sodium stearyl Fumarate in the blend of Step 10 and mix for predetermined time at suitable RPM.

12. Compress the blend of step 11 using suitable shaped punches at pre-set parameters.

13. Add and disperse coating pre-mix in required quantity of water (part B). Stir the solution for predetermined time at suitable RPM.

14. Using suitable coating equipment and at pre-set coating parameters, Coat the tablets of step 12 using coating solution of step 13 till a desired weight gain achieved. Example 8C

Dissolution testing of quick releasing methyl naltrexone tablets of example 8A and 8B containing 150 mg and entire dose of 450 mg.

Table 11: Dissolution Testing of examples 8 A using discriminatory dissolution method which employs dissolution apparatus type 2 (paddles) using dissolution media having 500 ml of 0.1N HC1 at 50rpm.

Conclusion: Tablets containing dose of 450 mg also exhibited quick release releasing at least 80 % in 15 minutes and / or at least 90 % in 30 minutes similar to 150 mg tablets.

Examples 9A and 9B: Compositions having a semi-solid solubilizer Table 12:

Manufacturing procedure:

1. Weigh each ingredient separately.

1. Safely sieve each material through appropriate sieve. 2. Co-sift CCS (part A), Polyethylene Glycol through ASTM 20 Mesh

3. Co-sift above blend of step 2 with MNB through ASTM 40 sieve.

4. Mix the blend of step 3 in suitable sized blender for predetermined time at suitable RPM.

5. Add Vitamin E TPGS in step 4 blend. 6. Transfer the blend of step 5 in hopper for hot melt granulation. 7. Collect the granules of step 6 and pass through co-mill to get 30 mesh granules.

8. Mix the mass of step 7 in suitable sized blender for predetermined time at suitable RPM.

9. Co-sift Disodium EDTA, Colloidal silica, CCS (part B), MCC (part B) through appropriate sieve and add to blend of step 8 in appropriate sequence and mix to attain uniformity.

10. Add sodium stearyl Fumarate in the blend of Step 9 and mix for predetermined time at suitable RPM.

11. Compress the blend of step 10 using suitable shaped punches at pre-set parameters.

12. Add and disperse coating pre-mix in required quantity of water (part B). Stir the solution for predetermined time at suitable RPM.

13. Using suitable coating equipment and at pre-set coating parameters, Coat the tablets of step 11 using coating solution of step 12 till a desired weight gain achieved.

Example 9C: Dissolution testing of quick releasing methyl naltrexone tablets of example 9A and 9B containing 150 mg and entire dose of 450 mg.

Table 13: Dissolution Testing of examples 9A using discriminatory dissolution method which employs dissolution apparatus type 2 (paddles) using dissolution media having 500 ml of 0.1N HC1 at 50rpm.

Conclusion: Tablets containing dose of 450 mg also exhibited quick release releasing at least 80 % in 15 minutes and / or at least 90 % in 30 minutes similar to 150 mg tablets. Example 10: Powder for oral suspension as well as Direct compression process with semi-solid solubilizer

Manufacturing procedure: Manufacturing of Co-processed TPGS: Mix Vitamin E TPGS and Microcrystalline Cellulose 102 and pass-through Hot melt Extrusion / Granulation at 45 - 60 Deg C. Mill the co-processed material through 30 mesh and used as coprocessed TPGS. Co-sift Sodium Carboxy Methyl Cellulose, Sorbitol through ASTM 20 Mesh Co-sift above blend of step 2 with MNB through ASTM 40 sieve. Mix the blend of step 3 in suitable sized blender for predetermined time at suitable RPM with step 1 co-processed material. Co-sift Disodium EDTA, Colloidal silica, through appropriate sieve and add in appropriate sequence in the blend of step 4 to attain uniformity. Add sodium stearyl Fumarate in the blend of Step 5 and mix for predetermined time at suitable RPM. Take this blend for filling as powder for oral suspension optionally mixing it with one or more sweeteners and one or more flavours or alternatively proceed for step 7. Compress the blend of step 6 using suitable shaped punches at pre-set parameters or fill in capsule / sachet at suitable weight accommodating 150 mg or 450 mg therapeutically effective amount. Optionally, add and disperse coating pre-mix I and II in required quantity of water (part B). Stir the solution for predetermined time at suitable RPM. Using suitable coating equipment and at pre-set coating parameters, Coat the tablets of step 7 using coating solution of step 8 till a desired weight gain achieved. References Becker G, Galandi D, Blum HE. Peripherally acting opioid antagonists in the treatment of opiate-related constipation: a systematic review. J Pain Symptom Manage. 2007; 34:547-565. Li-Fang Yu et al, Enhancing Oral Bioavailability of MethylnaltrexoneMethylnaltrexone Using an Emulsion Formulation. Letters in Drug Design & Discovery. 2011; 8:87-92 Yuan, C.S. MethylnaltrexoneMethylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann. Pharmacother., 2007, 41, 984-993 Yuan, C.S.; Foss J.F.; Osinski J.; Toledano A.; Roizen M.F.; Moss J. The safety and efficacy of oral methylnaltrexoneMethylnaltrexone in preventing morphine- induced delay in oral-cecal transit time. Clin. Pharmacol. Ther., 1997, 61, 467-475.

Claims

Claims: We claim

1. Solid oral pharmaceutical composition of methyl naltrexone or salt thereof comprising methyl naltrexone and additionally a solid solubilizer or a semisolid solubilizer or both.

2. The solid oral pharmaceutical composition as claimed in claim 1 exhibits quick release of methyl naltrexone or salt thereof wherein release is at least 85 % in 15 minutes and / or at least 90 % in 30 minutes.

3. The solid oral pharmaceutical composition as claimed in claim 2 exhibits quick release of methyl naltrexone or salt thereof wherein release is at least 60 % in 5 minutes.

4. The solid oral pharmaceutical composition as claimed in claim 1 wherein the solid solubilizer has a liquid surfactant adsorbed on the solid support and wherein semi- solid solubilizer is low melting solubilizer.

5. The solid oral pharmaceutical composition as claimed in claim 1 wherein the solid solubilizer is selected from Polysorbate 80 Co-processed with Magnesium aluminium metasilicate or Polyoxyl 40 hydrogenated castor oil co-processed with Magnesium aluminium metasilicate.

6. The solid oral pharmaceutical composition as claimed in claim 1 wherein the liquid surfactant of the solid solubilizer is polysorbate 80 or Polyoxyl 40 hydrogenated castor oil.

7. The solid oral pharmaceutical composition as claimed in claim 1 wherein the solid support of the solid solubilizer is Magnesium aluminium metasilicate.

8. The solid oral pharmaceutical composition as claimed in claim 1 wherein the semi-solid solubilizer is D-a-Tocopherol polyethylene glycol 1000 succinate.

47

9. The solid oral pharmaceutical composition as claimed in claim 1 wherein the composition is a granulated composition.

10. The solid oral pharmaceutical composition as claimed in claim 1 wherein the composition additionally comprises at least a diluent, a disintegrant, an alkalizer, a glidant, and a lubricant.

11. The solid oral pharmaceutical composition as claimed in claim 10 wherein the composition is a granulated composition and disintegrant is present inside the granules and outside the granules.

12. The solid oral pharmaceutical composition as claimed in claim 11 wherein the disintegrant is croscarmellose sodium.

13. The solid oral pharmaceutical composition as claimed in claim 1 wherein the alkalizer is sodium bicarbonate.

14. The solid oral pharmaceutical composition as claimed in claim 1 wherein the diluent is one or more of microcrystalline cellulose, lactose, mannitol and starch.

15. The solid oral pharmaceutical composition as claimed in claim 1 wherein the composition is free of an ion-pairing agent and sodium lauryl sulphate.

16. The solid oral pharmaceutical composition as claimed in claim 1 additionally comprising one or more sweeteners and one or more flavours.

17. The solid oral pharmaceutical composition as claimed in claim 16 for processing into a powder for oral suspension.

18. A solid oral pharmaceutical composition comprising 450 mg of methylnaltrexone bromide.

19. A process for preparing a solid oral pharmaceutical composition of methyl naltrexone or salt thereof comprising a. Dividing diluent and / or disintegrant into two lots; b. Co- sifting the first lot of diluent, the first lot of disintegrant and optionally a solid solubilizer;

48 c. Co-sifting blend of step b with methyl naltrexone or salt thereof; d. Mixing the blend of step c in a blender; e. Granulating the mixture of step d using binder solution comprising Edetate calcium disodium in water to produce wet granulated mass; f. Drying the wet mass; g. Sifting the dried mass of step f to produce granules; h. Co-sifting glidant, second lot of diluent, second lot of disintegrant, alkalizer and optionally a solid solubilizer if the solubilizer is not added in step b through a sieve; i. Adding co-sifted material of step h with granules of step g and adding further ingredients selected from glidant and lubricant; j. Compressing the blend of step i. k. Optionally preparing coating solution and coating tablets of step j.

20. A process for preparing a solid oral pharmaceutical composition of methyl naltrexone or salt thereof comprising a. Dividing disintegrant into two lots; b. Co-sifting the first lot of disintegrant, and optionally a solid solubilizer; c. Co-sifting blend of step b with methyl naltrexone or salt thereof; d. Mixing the blend of step c in a blender; e. Adding vitamin E TPGS to the blend of step d and transferring the blend for granulation; f. melt granulating or hot melt extruding the mixture of step e to produce granules; g. Optionally co-milling granules; h. mixing granules of step f or g in a blender; i. Co-sifting chelating agent, glidant, second lot of disintegrant, and diluent and mixing; f. Adding lubricant and mixing; g. Compressing the blend of step f.

49 k. Optionally preparing coating solution and coating tablets of step g.

21. A process for preparing a solid oral pharmaceutical composition of methyl naltrexone or salt thereof comprising a. Preparing co-processed Vitamin E TPGS by mixing Vitamin E TPGS and Microcrystalline Cellulose and passing the mixture through Hot melt Extrusion / Granulation at 45 - 60 Deg C. and optionally milling the co-processed material; b. Co- sifting the disintegrant and diluent; and optionally a solid solubilizer; c. Co-sifting blend of step b with methyl naltrexone or salt thereof; d. Mixing blend of step c with co-processed material of step a in a blender; e. Co-sifting a chelating agent and a glidant, and adding in the blend of step d; i. Adding a lubricant in the blend of step e and mixing; j. Optionally process the blend of step i for preparing powder for oral suspension by adding one or more sweeteners and one or more flavors; j. Compressing the blend of step i. k. Optionally preparing coating solution and coating tablets of step j.

22. A solid oral pharmaceutical composition containing 450 mg of methyl naltrexone bromide in a single unit dosage form for use in the treatment of any disease which can be treated with peripherally nonselective p opioid receptor antagonist.

23. A solid oral pharmaceutical composition containing 450 mg of methyl naltrexone bromide in a single unit dosage form for use in reversing one or more side effects of an opioid drug.

24. The solid oral pharmaceutical composition of claims 22 or 23 characterized in having a solid solubilizer or a semi- solid solubilizer or both wherein the

50 solid solubilizer has a liquid surfactant adsorbed on the solid support and wherein semi- solid solubilizer is low melting solubilizer.

25. Method of treating any disease which can be treated with peripherally nonselective p opioid receptor antagonist by administering a single unit composition containing a dose / daily dose of 450 mg methylnaltrexone bromide.

26. Method of reversing one or more side effects of an opioid drug by administering a single unit composition containing a dose / daily dose of 450 mg methylnaltrexone bromide.

27. The method as claimed in claims 25 or 26 wherein the composition is characterized in having a solid solubilizer or a semi- solid solubilizer or both wherein the solid solubilizer has a liquid surfactant adsorbed on the solid support and wherein semi- solid solubilizer is low melting solubilizer.