Field of The Invention

The invention relates to high dosed Dexamethasone Compositions that are highly concentrated compositions of Dexamethasone having from 20 % - 40 % Dexamethasone, more preferably from 25 - 40 % of Dexamethasone. Dexamethasone herein also includes any derivative, salt, hydrate solvate etc. of Dexamethasone. The preferred compositions include tablets, granules or powder for oral solution / suspension / for filling into capsules etc. High dosed compositions preferably contain 40 mg dose of Dexamethasone in not than 200 mg preferably not more than 180 mg and more preferably not more than 160 mg of a tablet and 20 mg dose of Dexamethasone in not more than 100 mg preferably not more than 80 mg of a tablet. The high dosed tablet can be split to deliver smaller doses. Also granules formulation can be titrated to obtain lower doses such as 20 mg and 10 mg doses. High dosed compositions are high dissolving compositions which provide Dexamethasone in soluble form and exhibit satisfactory release of Dexamethasone in media of all pH.

Objects of the Invention

A first object of the invention is to provide high dosed highly concentrated compositions of Dexamethasone. Preferably, the invention provides a dose of 40 mg of dexamethasone in not more than 200 mg of a tablet. The tablet can be split to provide lower doses.

Earlier dexamethasone was only available in lower strengths such as 4 mg tablet or lower and one needed to take 10 tablets at a time to achieve a dose of 40 mg. Recently, another brand Hemady is introduced which provides a maximum of 20 mg in a single tablet. Thus, one has to take 2 tablets at a time to achieve a dose of No one has achieved accommodating a dose of 40 mg of Dexamethasone in unit dosage form so far. The present invention achieves the same and enables the patient to take a single tablet.

Second object is to achieve soluble composition of Dexamethasone which can solubilize a high dose in a highly concentrated form.

Third object is to retain this solubility of soluble composition on shelf and stability. Thus, third object deals with stable compositions without drop in dissolution on shelf and stability. Sometimes tablets exhibit solubility in the beginning but significant drop is solubility is observed after a few months. This object ensures that dexamethasone solubility does not drop with time.

Fourth object of the invention is to achieve soluble composition of Dexamethasone which exhibits a pH independent In Vitro release of Dexamethasone. For this, high dosed Dexamethasone compositions are subjected to different dissolution media of various pH and it is found that high dosed compositions provide rapid to very rapid release of dexamethasone in a media of pH from 1.2 to 6.8. Rapid and very rapid release means at least 85 % release in 15 - 30 mins.

Fifth object is to provide a sturdy method with low variability to produce soluble compositions of a high dose Dexamethasone in a highly concentrated form.

Summary of the Invention

Under the first aspect the invention provides a high dosed highly concentrated compositions of Dexamethasone. Preferably, the invention provides a dose of 40 mg of dexamethasone in a single unit dosage form which is provided for the first time ever. Also, this high dose is provided in a highly concentrated form wherein the amount of Dexamethasone in such unit dosage form is from 20 - 40 %, preferably, from 25 - 40 %.

This enables client to consume entire dose by consuming a single unit dosage form. Also, it is taken care that such high dose does not amount to increase in the weight of the unit dosage form. Thus, a tablet not more than 200 mg, preferably not more than 160 mg effectively contains 40 mg of dose. The tablet can be split to provide lower doses. Thus, a single tablet incorporating 40 mg of Dexamethasone can efficiently deliver 10 mg or 20 mg.

No one has achieved accommodating a dose of 40 mg of Dexamethasone in unit dosage form so far. The present invention achieves the same and enables the patient to take a single tablet.

Second aspect is to achieve soluble composition of Dexamethasone which can solubilize a high dose in a highly concentrated form. This has been achieved by employing a method of hot melt extrusion. Additionally, solubilizers or solubility enhancers and buffering agents are added.

Dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO) has been found preferably suitable. It plays multiple roles such as plasticizer, solubility enhancer, stability enhancer and also as a carrier to disperse Dexamethasone preferably in crystalline form. Another advantage is that it melts or softens well at a temperature of 70°C and above which is above its glass transition temperature (40-48°C) and aids in hot melt extrusion.

Another solubility enhancer which has been particularly found useful in preparing compositions of the present invention is a solid solubilizer and compression agent with a brand name SepitrapTM80. This solid solubilizer has polysorbate 80 (45- 65%) adsorbed on the porous mineral carrier Magnesium Aluminometasilicate (35- 55%). Another type SEPITRAP™ 4000 can also be employed which has Polyoxyl 40 hydrogenated castor oil (55-75%) adsorbed on the porous mineral carrier Magnesium Aluminometasilicate (25-45%).

The buffering agents such as citric acid and other acids such as tartaric acid, benzoic acid, lactic acid, malic acid, maleic acid are also employed.

Hydroxy propyl beta cyclodextrins are also preferably employed for their ability to enhance solubility as well as stability.

Third aspect is to retain the solubility of soluble composition on shelf and stability. Thus, third aspect deals with stable compositions without drop in dissolution on shelf and stability. Sometimes tablets may exhibit solubility in the beginning but significant drop in solubility is observed after a few months. This object ensures that dexamethasone solubility does not drop with time. Also, in general, stable compositions are produced with can retain stability on shelf and when subjected to accelerated conditions such as 40°C/75%RH for 6 months. Impurities A, C, D, E,

F, G, J and K are below 0.5 % and preferably below 0.3 %. Single maximum unknown impurity is below 0.1 % and total impurities are below 1.0 %.

In Vitro release profile of Dexamethasone tablets prepared in accordance with the present invention at Initial time point, after 1 month storage at 40°C / 75 % RH and after 6 months storage at 40°C / 75 % RH. There is no drop in the dissolution.

Under the fourth aspect, the invention provides soluble composition of Dexamethasone which exhibits a pH independent solubility. The In Vitro release of Dexamethasone in various media such as 0.1 N HC1 (OGD media), acetate buffer of pH 4.5 are as below. The pH shift media is also employed which exposes Dexamethasone tablet to acidic pH for first 15 mins and a pH of 6.8 for next 45 minutes.

Table A Fifth aspect provides a sturdy method with low variability to produce soluble composition of a high dose Dexamethasone in a highly concentrated form. The method employed is such that it causes melting of one or more excipients to produce extrudates which are milled to produce granules. This solventless process removes variability which is associated with non-uniform wetting during wet granulation especially when the active ingredient is extremely insoluble.

The present invention employs hot melt extrusion to provide high dosed compositions of dexamethasone which are fast dissolving and contain at least one soluble excipient / which melts at a temperature substantially lower than melting point of dexamethasone. The dry blend containing dexamethasone is continuously and uniformly subjected to same temperatures to cause melting of one or more excipient ingredient from the composition. The difference in the melting points of Dexamethasone and soluble ingredient is at least 10-20°C, preferably at least 30 °C, more preferably at least 40°C and most preferably at least 50°C. The soluble ingredient employed include any one or more of polyethylene glycol, mannitol, lactose, sorbitol, fructose, sucrose, polyvinyl pyrrolidone, etc. Generally melting temperature of soluble ingredient is from 50 - 250°C. Preferably, the melting temperature is from 70 - 210°C. More preferably, the melting temperature is from 110°C to 210°C. Most preferably, the melting temperature is from 110°C to 180°C. Since Dexamethasone is not subjected to its melting temperature, it retains its polymorphic form. Hence dexamethasone does not get converted into any other crystal form or amorphous form.

This process thus leads to solid dispersion wherein Dexamethasone at least substantially in crystal form is suspended in soluble, hydrophilic matrix without getting converted into amorphous form. This is referred as “Solid Crystal Suspension”. Figure 1 provides process steps in preparing the same.

Finally, even if the present invention adopts a different method to obtain high dosed highly concentrated compositions of Dexamethasone, the aim is to have same In Vitro release profile in media of all pH. Background of the Invention

Dexamethasone is a synthetic steroidal glucocorticoid that was approved in 1958 under the brand name Decadron (NDA 011664). Decadron was available in five strengths: 0.5, 0.75 1.5, 4 and 6 mg (withdrawn from the market in 2007).

Dexamethasone is highly insoluble in nature. To develop a soluble composition of Dexamethasone poses challenges. Therefore, it was never available in higher strengths but was only available in lower strengths such as 4 mg tablet or lower and one needed to take 10 tablets at a time to achieve a dose of 40 mg.

In 2019, for the first time a brand Hemady was approved having strength of 20 mg. Hemady provides a maximum of 20 mg in a single tablet. One has to take 2 tablets at a time to achieve a dose of 40 mg. HEMADY enables patients to take 1 or 2 oral tablets instead of 5 - 10 tablets to achieve the dose of 20 mg or 40 mg and is frequently used together with other anti-myeloma treatments.

Dexamethasone Immediate Release Tablets, 20 mg is indicated for the treatment of patients with multiple myeloma (MM), as part of combination regimens with antimyeloma drugs. Dexamethasone is approved for the palliative management of leukemias and lymphomas. The recommended dosing regimen for Dexamethasone Tablets is 20 or 40 mg orally, once daily, on specific days of the treatment cycle depending on the treatment protocol.

Dexamethasone is a small chiral molecule. It is a white to practically white non- hygroscopic crystalline solid that is practically insoluble in water, sparingly soluble in acetone, ethanol, and methanol; and slightly soluble in dichloromethane. Dexamethasone exhibits polymorphic behaviour.

Drug release is usually the rate limiting process for absorption of a Biopharmaceutics Classification System (BCS) Class II compound like Dexamethasone due to its low solubility. Therefore, the dissolution of the brand tablets was thoroughly evaluated. Initially, the dissolution method recommended in the FDA dissolution methods database for this product was utilized (500 mL of 0.1 N HC1 using USP apparatus 2 (paddle) at 50 rpm). The temperature of the dissolution medium was maintained at 37 ± 0.5 C and the drug concentration was determined using HPLC analysis. The drug release of brand tablets was also obtained at different strengths (20 mg and 40 mg (20 mg+20 mg) As shown in Figure 1, RLD tablets exhibited a very rapid dissolution using the FDA- recommended method. Later dissolution is also tested and compared in other media such as acetate buffer of pH 4.5 and pH shift media viz. 0.1N HC1 for 15 mins and phosphate buffer of pH 6.8 for next 45 mins.

US patent no. US1053785B2 covers a high-dose immediate release dexamethasone tablet or caplet containing 20 mg of Dexamethasone in 100 mg tablet or capsule. It employs wet granulation process which is a variable process for highly insoluble medicines such as Dexamethasone.

US patent application no. US20200147106A1 covers similar composition having up to 25 % of dexamethasone. It has binder from 10 - 30 % and at least 45 % filler. The compositions therein are also prepared by wet granulation process which is a variable process for highly insoluble medicines such as Dexamethasone.

Brief Description of figures

Figure 1 describes process steps of conventional manufacturing and the solid crystal suspension of the present invention.

Figure 2 describes comparative dissolution profiles of RLD, Batch F0106C (20 mg) and Batch F0106C (40 mg), in 500 mL of medium (strengths as shown) using USP apparatus 2 at 50 rpm.

Figure 3A describes comparative dissolution profiles of RLD and Batch F0106I, in 500 mL of medium in pH 4.5 acetate buffer using USP apparatus 2 at 50 rpm.

Figure 3B describes comparative dissolution profiles of Batch F0106C and Batch F0106I, in 500 mL of medium in pH 4.5 acetate buffer using USP apparatus 2 at 50 rpm. Figure 4 describes comparative dissolution profiles of Batch F0106C and Batch F0116C, in 500 mL of medium in 0.1N HC1 using USP apparatus 2 at 50 rpm.

Figure 5A describes Multimedia dissolution profiles of Batch F0113A in 500 mL of medium (different pH as shown) using USP apparatus 2 at 50 rpm Figure 5B describes comparative dissolution profiles of Batch F0113A and Batch F0113B, in 500 mL of medium in 0.1N HC1 using USP apparatus 2 at 50 rpm

Figure 6 describes comparative dissolution profiles of F0106C and Batch F0106G, in 500 mL of medium in pH 4.5 acetate buffer using USP apparatus 2 at 50 rpm.

Definitions:

Brand product and reference listed drug or RLD are used synonymously.

Softening of Eudragit EPO above glass transition temperature is also termed as melting of Eudragit EPO.

Detailed Description of the Invention

Under the first aspect, the present invention provides high dosed and highly concentrated dexamethasone compositions. Preferably, the invention provides high dosed solid oral compositions of dexamethasone. More preferably, the compositions of the present invention contain at least 20 %, preferably at least 25 % and more preferably at least 28 % of dexamethasone. Most preferably, the compositions of the present invention contain from around 28 % to around 40 % of Dexamethasone.

High dosed compositions of the present invention contain around 20 mg or around 40 mg dose of dexamethasone or can be given in as 10 mg or 20 mg or 40 mg dose. High dosed compositions of the present invention are also high dissolving compositions. Some of the compositions are fast disintegrating or dispersible compositions.

Preferably the compositions are tablets of Dexamethasone. Another preferred form is capsules of dexamethasone. Yet another preferred form is dispersible or fast disintegrating tablets. One more preferred form is powder for oral suspension or powder for solution.

High dosed tablets of dexamethasone of the present invention are preferably with a dose of 20 mg - 40 mg. More preferably they are with a break line or a score line that can divide tablets into two or four parts delivering from 5 mg, 10 mg, 20 mg, and 40 mg of dose.

In an embodiment, dexamethasone is present in an amount of 40 mg in a tablet of 100 mg. In few embodiments, dexamethasone is present in an amount of 40 mg in tablets weighing 120 mg, 132 mg, 138 mg and 140 mg. Therefore % dose of these high dosed formulation varies from about 28 % to about 40 %.

In an embodiment, dexamethasone is present in an amount of 20 mg in a tablet of 50 mg. In few embodiments, dexamethasone is present in an amount of 20 mg in tablets weighing 60 mg, 66 mg, 69 mg and 70 mg. Therefore % dose of these high dosed formulation varies from about 28 % to about 40 %.

Powder for oral suspension prepared in accordance with the present invention has a dose of 20 mg or 40 mg of dexamethasone.

Dispersible or fast disintegrating tablets prepared in accordance with the present invention have a dose of 20 mg or 40 mg of dexamethasone.

Highly concentrated high dosed compositions of Dexamethasone provide 40 mg dose in a relatively smaller tablet. This enables client to consume entire dose by consuming a single unit dosage form. Also, it is taken care that such high dose does not amount to increase in the weight of the unit dosage form. Thus, a tablet not more than 200 mg, preferably not more than 160 mg effectively contains 40 mg of dose. The tablet can be split to provide lower doses. Thus, a single tablet incorporating 40 mg of Dexamethasone can efficiently deliver 10 mg or 20 mg.

No one has achieved accommodating a dose of 40 mg of Dexamethasone in unit dosage form so far. The present invention achieves the same and enables the patient to take a single tablet.

High dosed compositions of dexamethasone of the present invention preferably contain at least one ingredient which exists in substantial amount and which melts at a temperature lower than melting point of dexamethasone. The substantial amount is at least about 5 %, preferably at least about 10 % and more preferably, at least about 15 % of the composition. This ingredient is preferably a soluble ingredient forming soluble part of the composition. Melting of the soluble ingredient in the blend containing Dexamethasone produces granulate of dexamethasone without affecting crystal form of dexamethasone making the composition fast dissolving. The process employed that achieves partial or complete melting of soluble ingredient is known as hot melt extrusion but is unique process in the present case because active ingredient is not subjected to melting as in other cases of melt extrusion.

This process thus leads to solid dispersion wherein Dexamethasone at least substantially in crystal form is suspended in soluble, hydrophilic matrix without getting converted into amorphous form. This is referred as “Solid Crystal Suspension”. Figure 1 provides process steps in preparing the same.

During hot melt extrusion, the soluble ingredient, dexamethasone and optionally any other excipient / ingredient are subjected to a first elevated temperature zone. The soluble ingredient optionally with any other ingredient is blended with dexamethasone at first elevated temperature zone to form a blend which is subjected to a second elevated temperature zone higher than the first elevated temperature zone. The second elevated temperature zone is same as or close to melting temperature of the said soluble ingredient at which dexamethasone does not melt but the soluble ingredient melts partially or fully / completely. The blend is kneaded at this second elevated temperature zone and partial or complete melting of soluble ingredient and kneading together cause granulation of Dexamethasone blend. The granulate is then subjected to a third elevated temperature zone at same or lower temperature than the second elevated temperature zone to cause solidification of molten soluble ingredient. Further they are taken to another zone of a temperature preferably lower than third zone to cause further solidification and drying and taken out of die as dried extrudates. These extrudates can be like granules or can be optionally subjected to milling/ crushing/ sizing / sifting etc. to obtain granules of desired size ranges.

Dexamethasone compositions of the present invention are soluble and fast dissolving in spite of having high dose of dexamethasone which is insoluble in water. Preferably at least 30 % of the high dosed composition has soluble portion containing soluble excipient / ingredient. More preferably, at least 40 % of the composition has soluble portion containing soluble ingredient. Most preferably at least 50 % of the composition has soluble portion containing soluble ingredient.

The soluble or hydrophilic excipient / ingredient can be partially / completely melted or softened to prepare granulate of Dexamethasone containing soluble mass. The granulate is prepared by a unique process of partial / complete melting of soluble / hydrophilic ingredient and provides a rapidly dissolving composition of the present invention.

Soluble ingredient is selected from one or more of sugars, sugar alcohols, saccharides, polyols and polymers. Soluble ingredient is selected such that its melting point is less than melting point of dexamethasone. Soluble ingredient can be more than one ingredient wherein at least one of them has melting point lower than melting point of dexamethasone. Optionally and additionally, insoluble ingredients can be present in the granulate of Dexamethasone.

In an embodiment, a soluble excipient which is subjected to partial / complete melting is a sugar alcohol. In another embodiment, a soluble excipient which is subjected to partial / complete melting is a sugar. In yet another embodiment, a soluble excipient which is subjected to partial / complete melting is a polymer.

In an embodiment sugar alcohol is mannitol. In another embodiment, polyol is polyethylene glycol. In yet other embodiments polymer is polyvinyl pyrrolidone.

In an embodiment, combination of at least two ingredients selected from sugars, sugar alcohols, saccharides, polyols and polymers are employed as soluble excipients. In an embodiment, a combination of mannitol and polyvinyl pyrrolidone are used as soluble excipients. In another embodiment, combination of mannitol and polyethylene glycol are used as soluble excipients added in granulation. In yet another embodiment, combination of mannitol, polyvinyl pyrrolidone and polyethylene glycol are used as soluble excipients added in granulation.

The present invention provides high dosed compositions of dexamethasone which are fast dissolving and contain at least one soluble excipient which melts at a temperature substantially lower than melting point of dexamethasone. The difference in the melting points of Dexamethasone and soluble ingredient is at least 10-20°C, preferably at least 30 °C, more preferably at least 40°C and most preferably at least 50°C. The soluble ingredient employed include any one or more of polyethylene glycol, mannitol, sorbitol, fructose, sucrose, polyvinyl pyrrolidone, etc. Generally melting temperature of soluble ingredient is from 50 - 250°C. Preferably, the melting temperature is from 70 - 210°C. More preferably, the melting temperature is from 110°C to 180°C. Since Dexamethasone is not subjected to its melting temperature, it retains its polymorphic form. Hence dexamethasone does not get converted into any other crystal form or amorphous form.

The granulate produced due to melting of soluble ingredient is subjected to a third temperature zone at elevated temperature but lower than that of second elevated temperature zone to cause solidification of molten soluble excipient. This process of melt extrusion employed in a unique way in the present invention provides granules after solidification of said granulate. Such granules can be mixed with one or more extragranular materials if needed and further converted into various dosage forms such as tablets, capsules, fast disintegrating or dispersible tablets, powder for oral suspension or solution etc.

Once dexamethasone granules containing dexamethasone, soluble excipient which is subjected to partial / complete melting and optionally one or more other excipients are prepared, they are blended with one or more extra-granular excipients selected from filler, disintegrant, surfactant, glidant and lubricant and the blend is ready for compression into a tablet composition or filled in a capsule.

In few embodiments, two soluble ingredients having melting temperatures lower than dexamethasone are employed. The first soluble ingredient is mannitol. The second soluble ingredient is either polyvinyl pyrrolidone and polyethylene glycol such as PEG 4000 or both polyvinyl pyrrolidone and polyethylene glycol.

Batch Fl employs mannitol as soluble and intragranular excipient which melts at around 160-170°C which is substantially lower than melting point of Dexamethasone (melting point about 262°C). Batch F2 employs two soluble excipients viz. mannitol and PVP K30. Batch F7 employs three soluble excipients viz. mannitol, PVP K30 and PEG 400.

A non-soluble excipient is also added along with the soluble ingredient / excipient in melt extrusion process. This non-soluble excipient may or may not melt at a second elevated temperature zone or at any temperature substantially lower than melting point of Dexamethasone. In an embodiment, microcrystalline cellulose is added as a non-soluble excipient.

Batch F6 employs around 14.28 % of microcrystalline cellulose.

Additionally, one or more solubilizers or solubility enhancers, carriers / diluents, protective agents are added. These agents are added in an amount of from about 1 % to about 50 %, preferably from about 1 % to about 40 %, more preferably from about 2 % to about 30 % of the total weight of the composition.

In addition to or alternative to soluble excipient such as mannitol, a hydrophilic ingredient can be employed. Eudragit EPO is one such ingredient. Dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO), a terpolymer based on N,N-dimethylaminoethyl methacrylate with methylmethacrylate and butylmethacrylate commonly known by brand name as Eudragit®EPO is found particularly beneficial. It has reportedly glass transition temperatures (Tg) at 48°C and 56°C. Temperature higher than Tg such as 70°C and above are employed to soften Eudragit EPO. This softening of Eudragit EPO is termed as melting of Eudragit EPO.

Eudragit®EPO when added during granulation plays multiple roles. It acts as a protective agent as well as solubility enhancer. It plays multiple roles such as plasticizer, solubility enhancer, stability enhancer and also as a carrier to disperse Dexamethasone preferably in crystalline form. Another advantage is that it melts or softens well at a temperature of 70°C and above which is above its glass transition temperature (40-48 °C) and aids in hot melt extrusion.

Therefore, when Eudragit EPO is added, it is possible to avoid melting of mannitol. Eudragit EPO melts or sufficiently softens at a temperature of 70°C and above and it is possible to conduct hot melt extrusion at a lower temperature such as from 110°C to 160°C and preferably, from 120°C to 150°C and most preferably at 140°C + 10°C . In a batch of Dexamethasone, mannitol and Eudragit EPO, one can employ a temperature of 170°C to 180°C and cause melting / softening of both mannitol and Eudragit EPO while keeping dexamethasone in crystalline form or one can employ a temperature of from 120°C to 150°C and most preferably at 140°C + 10°C to cause melting / softening of only Eudragit EPO.

It is always preferred to cause melting and granulation at lower temperatures. Although dexamethasone is stable, it is still preferred to employ temperature just sufficient to cause melting / softening of intragranular mass to produce extrudates.

If mannitol is not melted in the process, it will add to increase in the % torque generated. Melting of major portion of intragranular mass produces lower % torque such as up to 40 % whereas melting of lesser portion of intragranular mass wherein major portion is in powder or solid crystalline form enhances % torque.

Therefore, a balance is needed between melting at lower temperature and % torque generated.

In best mode batches, the temperature of 140°C + 10°C to cause melting / softening of only Eudragit EPO has been employed (Batch No. F0106C). For lower temperature melting i..e melting / softening at 140°C + 10°C or below, there must be sufficient intragranular melting component which can melt at this temperature to avoid generation of higher torque. Thus, quantity of Eudragit EPO is important when it is the only melting component at applied temperatures. The quantity of Eudragit EPO must be at least 25 % of intragranular mass, preferably at least 30 % and most preferably from 30 - 60 % of intragranular mass.

In an embodiment, Eudragit®EPO is added in an amount of about 1 - 5 %.

In an embodiment, Eudragit®EPO is added in an amount of from 10-30 %.

In other few preferred embodiments, Eudragit EPO is at least 25 % of intragranular mass or preferably at least 30 % and more preferably, from 30 % to 60 % of intragranular mass. In an embodiment, Eudragit EPO is 30 % of intragranular mass (F0109C). In another embodiment, Eudragit EPO is 36 % of intragranular mass (F0116C). In yet another embodiment, Eudragit EPO is 40 % of intragranular mass (F0106C). In one more embodiment, Eudragit EPO is 60 % of intragranular mass (F0108C).

However batch with 40 % Dexamethasone and 60 % Eudragit EPO although could be produced successfully with desired torque resulted in tablets with high friability. This friability is not due to addition of 60 % Eudragit EPO but due to removal of mannitol completely. This batch however is processed successfully as granules for oral suspension.

Thus, depending on the melting temperature, Eudragit EPO quantity can be varied. When it is the only melting component such as when lower melting temperatures are employed, its amount shall be at least 25 % of intragranular mass. Batch No. F0107C with 20 % intragranular EPO could not be processed as torque raised to 100 % due to non-melting component reaching 80 % of intragranular mass.

Torque up to 70 - 75 % is acceptable. When non-melting component of intragranular mass is 70 % as in case of batch F0109C, torque of 60 % was observed and acceptable.

If lower than 25 % of intragranular Eudragit EPO is desired, temperature should be raised to at least 160- 165 °C to cause melting of mannitol to avoid escalation in % torque.

Tablets of Batches F9 and F10 have Eudragit®EPO in an amount of about 28.5 %. Powder for oral suspension of Batch F14 has Eudragit®EPO in an amount of about 18 %. Dispersible tablets of Batch F12 have Eudragit®EPO in an amount of about 2.85 %. All compositions containing Eudragit®EPO exhibited at least 85 % release in 15 minutes when tested using 500 ml of 0.1N HC1 using USP type II Dissolution apparatus when used at 50 RPM.

Another solubility enhancer which has been particularly found useful in preparing compositions of the present invention is a solid solubilizer and compression agent with a brand name Sepitrap™80. This solid solubilizer has polysorbate 80 (45- 65%) adsorbed on the porous mineral carrier Magnesium Aluminometasilicate (35- 55%). Another type SEPITRAP™ 4000 can also be employed which has Polyoxyl 40 hydrogenated castor oil (55-75%) adsorbed on the porous mineral carrier Magnesium Aluminometasilicate (25-45%).

Tablets of batch F13 have around 11.4 % of Sepitrap™80 added during granulation. Solubility enhancers can be added during granulation or in extragranular blend or both during granulation and in extragranular blend.

In an embodiment, mannitol is used as a soluble excipient. In a melt extrusion process, a mixture of mannitol and dexamethasone is blended at first elevated temperature and then subjected to a temperature of around 160 - 170°C to cause partial or complete melting of mannitol. Optionally one or more additional pharmaceutically acceptable excipients are added. Melting and kneading are done at second elevated temperature to prepare granulate. Granulate is subjected to a third elevated temperature lower than second elevated temperature allowing granulate to solidify and form extrudates. Extrudates are optionally subjected to milling/ crushing/ sizing / sifting if required and granules obtained are further blended with one or more extra-granular excipients selected from filler, disintegrant, surfactant, glidant and lubricant and the blend is ready for compression into a tablet composition or filled in a capsule.

In another embodiment, fast dissolving granules prepared by hot melt extrusion containing dexamethasone and mannitol are blended with extragranular diluent, disintegrant and lubricant to form a lubricated blend which is further compressed into tablets.

Under a second aspect there is provided a unique process to carry out hot melt extrusion of dexamethasone containing blend. The process of hot melt extrusion is carried out using Pharma 11 Twin-screw Extruder by Thermo Scientific™. The extruder has multiple conveying zones which can be maintained at varying temperatures zones. At least 3 zones of varying temperatures can be employed in the extruder. At the first zone elevated temperature can be used for blending. In Second zone, temperature can be used for kneading. This temperature is same as melting temperature of the soluble ingredient or close to its melting point. With Third zone, temperature which may be lower than or similar to the second zone temperature, is used for solidifying the molten soluble ingredient.

Before subjecting dexamethasone to blending, dexamethasone, soluble ingredient optionally with one or more other ingredient are subjected to conveying zone which is also maintained at a higher temperature lower than first elevated temperature. Similarly, after extrudes are formed due to solidifying of soluble ingredient, the extrudes are exposed to another higher temperature lower than third elevated temperature zone for further solidification / cooling/ drying etc.

This unique process gradually exposes dexamethasone, soluble and / or hydrophilic ingredient and optionally one or more other ingredient to increasing temperature till partial / complete melting of soluble / hydrophilic ingredient and similarly gradually expose granulate to decreasing temperatures till granulate solidify fully and granules are formed.

As a result of this unique process, dexamethasone high dosed fast dissolving granules are formed which can be further processed into fast dissolving high dosed compositions of dexamethasone.

High Dosed Highly Concentrated Tablet Compositions with split.

The present invention provides high dosed compositions having a dose of 40 mg and additionally of 20 mg or 10 mg. Preferred compression weights are 140 mg for 40 mg, 70 mg for 20 mg and 35 mg for 10 mg.

Each composition which is compressed into tablet are compressed into split tablets having one or two breaklines. Such split tablets can be easily cut with tablet cutters. Thus, 40 mg tablet with a single breakline can give 20 mg dose upon splitting and 40 mg tablet with two breaklines can give 10 mg dose upon splitting. Once split, the unconsumed portion of the tablet can be stored in the same container or in a separate pharmacy bottle / dispensing bottle.

Dissolution studies / In Vitro Release profiles Even if the present invention adopts a different method to obtain high dosed highly concentrated compositions of Dexamethasone, the aim is to have same In Vitro release profile in media of all pH of that of Brand product Hemady.

Hence comparison of In Vitro release profile with this Brand product is also provided in various dissolution media.

Office Of Generic Drugs (OGD), United States has recommended following dissolution conditions for Dexamethasone Tablets.

Table B OGD recommended dissolution medium:

Three way release criteria is set as follows:

Three-way release criteria in OGD media is set for in-house trials as follows:

Table C Fast dissolving compositions of the present invention release at least 70 % dose of Dexamethasone in 15 mins in 500 ml of 0.1N HC1 using USP type II Dissolution apparatus when used at 50 RPM. Preferably, fast dissolving compositions release at least 75 % of the high dose of dexamethasone in 15 mins. More preferably, fast dissolving compositions release at least 85 % of the high dose of dexamethasone in 15 mins.

An embodiment provided in table 5 releases around 88 % of the dose of Dexamethasone in 15 mins when tested in 0.1 N HC1 using USP type II Dissolution apparatus when used at 50 RPM. Another embodiment releases around 94 % of the dose of Dexamethasone in 15 mins using same test conditions.

It has been noted that all hot melt granulation batches exhibited excellent Cumulative release profile when tested in 500 ml of 0.1N HC1 using USP type II dissolution apparatus at 50 RPM (OGD dissolution conditions). Each batch irrespective of composition type exhibited at least 85 % release of the dose of Dexamethasone in 15 minutes which matched the % release of reference product Hemady (Dexel Pharma) having dose of 20 mg Dexamethasone.

The In Vitro release profile of Dexamethasone high dosed highly concentrated compositions of the present invention has been tested in various media such as 0.1 N HC1 (OGD media), acetate buffer and in the pH shift media is studied. Acetate buffer of pH 4.5 was able to show better discrimination between the batches.

The pH shift media is one which exposes Dexamethasone tablet to acidic pH for first 15 mins and a pH of 6.8 for next 45 - 60 minutes.

The speed 50 RPM paddles and volume 500 ml is kept same for acetate buffer. The speed 50 RPM paddles is kept same for pH shift media but volume is increased to 900 ml because 400 ml of phosphate buffer with sufficient sodium hydroxide which upon addition in 500 ml of 0.1N HC1 exhibits pH of 6.8 was necessary. This led to increase in volume. If volume is reduced, granules would get disturbed. Hence 6.8 phosphate buffer with sufficient sodium hydroxide maintained at 37°C is cautiously added in volume of 400 ml to OGD media of 500 ml which readily provides pH of 6.8. has been employed.

In-house pH-shift dissolution protocol is prepared to check dissolution of optimized batch by subjecting it to 0.1N HC1 for first 15 mins and then to 6.8 pH phosphate buffer for next 45 - 60 minutes. The conditions are as follows:

Table D

Stability studies

Optimized batch F0106 is subjected to accelerated stability conditions at 40°C and 75 % RH. There is no drop in release of Dexamethasone even after storage at 40°C and 75 % RH for 6 months. Example 8 A provides the detailed results of the same. Impurity profiling of initial sample and sample stored at 40°C and 75 % RH for 3 months is also done and tablets are found to be stable meeting criteria of stability by ICH.

Failed batches - Examples 9, 10, 11

Batches F16 -F20 prepared with hot melt extrusion failed in In Vitro release profile. None of the batches could release 85 % in 15 mins. Batches 16 and 18 - 20 exhibited incomplete release even at the end of 60 mins in OGD medium. Example 10 provides that batch F0107C could not be processed due to high torque when melting component of intragranular mass is 20 %.

Example 10 also provides that batch F0108C with 60 % of melting component Eudragit EPO of intragranular mass although passed in % torque led to tablets with high friability due to complete removal of mannitol.

Observations and Conclusions

Hot melt granulation / hot melt extrusion is essential to enhance solubility of high dosed highly concentrated dexamethasone compositions.

At least one ingredient which is either soluble excipient like mannitol or hydrophilic excipient like Eudragit EPO or both are essential for obtaining desired in vitro release profiles.

The soluble and / or hydrophilic component should melt / soften to produce extrudes / extrudates at a temperature lower than melting point of Dexamethasone.

Dexamethasone remains dispersed at least substantially in crystal form in soluble and / or hydrophilic carrier thus leading to solid crystal suspension.

During hot melt granulation, melting component shall be at least 25 % of the intragranular mass, preferably from 30 - 60 % of intragranular mass.

Melting temperature in the process shall be selected based on selection of ingredients. For melting of mannitol, a temperature of at least 160°C, preferably up to 180°C is preferred. For melting of Eudraagit EPO, a temperature of from 110°C - 160°C, preferably from 120°C to 150°C and most preferably from 140°C + 10°C is preferred.

Following examples illustrate the invention but do not limit the scope of the invention in any way.

Example 1: Batches with one or two intragranular excipients

Table 1:

Process

1. Dexamethasone, mannitol / mannitol and PVP K30 are added in the conveying zone of a Twin-screw Extruder which is at a temperature of around 70- 80°C;

2. The above ingredients are taken to a mixing / blending zone maintained at around 110°C (first elevated temperature) and blended together;

3. The blend from step 2 is taken to a kneading and mixing zone maintained at 170°C (second elevated temperature) and kneaded during which melting of mannitol starts and further kneading commences granulation;

4. Granulate from step 3 is taken to another zone maintained at 110°C (third elevated temperature) where molten mannitol starts solidification and mixing in this zone produces cooled flakes/ rods/ granulate;

5. Cooled granulate from step 4 is taken to a conveying zone maintained at 80°C to cause further cooling / solidification of molten mass and taken out of a die as extrudates or flakes or rods or dried granules.

6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to required sizes. These granules are then blended with extragranular materials such as diluent, disintegrant, glidant and lubricant to produce high dissolving granules which are compressed into tablets.

Example 2: Batches with at least two intragranular excipients Table 2:

Process 1. Dexamethasone, mannitol and PEG / mannitol and PVP K30 / mannitol and

PVP K30 and microcrystalline cellulose /mannitol and PVP K30 and PEG / mannitol and PVP K30 and EudragitOEPO are added in the conveying zone of a Twin-screw Extruder which is at a temperature of around 70-80°C;

2. The above ingredients are taken to a mixing / blending zone maintained at around 110 °C (first elevated temperature) and blended together;

3. The blend from step 2 is taken to a kneading and mixing zone maintained at 170°C (second elevated temperature) and kneaded during which melting of mannitol starts and further kneading commences granulation;

4. Granulate from step 3 is taken to another zone maintained at 110°C (third elevated temperature) where molten mannitol solidifies and mixing in this zone produced dried granulate; 5. Dried granulate from step 4 is taken to a conveying zone maintained at 80°C to cause further drying / solidification of molten mass and taken out of a die as dried extrudates or dried granules.

6. Dried granules are blended with extragranular materials such as diluent, disintegrant, glidant and lubricant to produce high dissolving granules which are compressed into tablets.

7. Batch F9 was compressed using standard concave punches of diameter 5.5 mm and batch F5-F8 and batch F10 was compressed using standard concave punches of diameter 7 mm. Hardness of tablets of batch F9 is from 4 - 5 kp and that of tablets of batches F5-F8 and batch F10 is from 7 - 8 kp. Disintegration time for tablets of batch F9 is 4 - 5 minutes and that of tablets of batches F5-F8 and batch F10 is less than 3 minutes.

Example 3: Batches with solubility enhancers

Table 3:

Process 1. Dexamethasone, mannitol and Eudragit EPO or Dexamethasone, mannitol andSepitrap-80are added in the conveying zone of a Twin-screw Extruder which is at a temperature of around 70-80°C;

2. The above ingredients are taken to a mixing / blending zone maintained at around 110°C (first elevated temperature) and blended together; 3. The blend from step 2 is taken to a kneading and mixing zone maintained at

170°C (second elevated temperature) and kneaded during which melting of mannitol starts and further kneading commences granulation;

4. Granulate from step 3 is taken to another zone maintained at 110°C (third elevated temperature) where molten mannitol solidifies and mixing in this zone produced dried granulate;

5. Dried granulate from step 4 is taken to a conveying zone maintained at 80°C to cause further drying / solidification of molten mass and taken out of a die as dried extrudates or dried granules. 6. Dried granules are blended with extragranular materials such as diluent, disintegrant and lubricant to produce high dissolving granules which are compressed into tablets.

Dispersible tablets of batch F12 have hardness of about 4-5kp and disintegration time of less than a minute, preferably less than 30 seconds and more preferably less than 15 seconds.

Example 4: % Cumulative Release in OGD media

Table 4:

Example 5: Best Mode Batches having 40 % melting component Eudragit EPO

Table 5:

Process

1. Dexamethasone, mannitol and Eudragit EPO are added in the conveying zone of a Twin-screw Extruder which is at a temperature of around 70-80°C;

2. The above ingredients are taken to a mixing / blending zone maintained at around 110°C (first elevated temperature) and blended together;

3. The blend from step 2 is taken to a kneading and mixing zone maintained at 140°C (second elevated temperature) and kneaded during which melting /softening of Eudragit EPO starts and further kneading commences granulation;

4. Granulate from step 3 is taken to another zone maintained at 110°C (third elevated temperature) where molten Eudragit EPO starts solidification and mixing in this zone produces cooled flakes/ rods/ granulate;

5. Cooled granulate from step 4 is taken to a conveying zone maintained at 80°C to cause further cooling / solidification of molten mass and taken out of a die as extrudates or flakes or rods or dried granules.

6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to required sizes. These granules are then blended with extragranular materials such as diluent (lactose in batch F0106C and mannitol in batch F0106I), disintegrant, glidant and lubricant to produce high dissolving granules which are compressed into tablets.

Example 5A: Comparison of In Vitro Release profile of optimized batches with extragranular lactose (F0106C ) and mannitol (F0106I) in acetate buffer of pH

4.5.

Table 5A

Example 5B: Comparison of In Vitro Release profile of optimized batch F0106C and brand product Hemady in OGD medium.

Table 5B:

Example 5C: pH-shift dissolution data of brand product and F0106C Table 5C

Example 6A: Optimization trials with and without buffering agent citric acid

Table 6A

Process

1. Dexamethasone, mannitol, Eudragit EPO and optionally citric acid monohydrate (batch F0116C) are added in the conveying zone of a Twin-screw Extruder which is at a temperature of around 70-80°C;

2. The above ingredients are taken to a mixing / blending zone maintained at around 110°C (first elevated temperature) and blended together;

3. The blend from step 2 is taken to a kneading and mixing zone maintained at 140°C (second elevated temperature) and kneaded during which melting /softening of Eudragit EPO starts and further kneading commences granulation; 4. Granulate from step 3 is taken to another zone maintained at 110°C (third elevated temperature) where molten Eudragit EPO starts solidification and mixing in this zone produces cooled flakes/ rods/ granulate;

5. Cooled granulate from step 4 is taken to a conveying zone maintained at 80°C to cause further cooling / solidification of molten mass and taken out of a die as extrudates or flakes or rods or dried granules.

6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to required sizes. These granules are then blended with extragranular materials such as diluent, disintegrant, glidant and lubricant to produce high dissolving granules which are compressed into tablets.

Example 6B - In vitro release profile of batch with citric acid and comparison with best mode batch F0106C.

Table 6B

Batch F0116C which has citric acid does not enhance in vitro release profile over optimized batch F0106C. Example 7A: Optimization batches with additional solubilizing and stabilizing agent Hydroxy propyl beta Cyclodextrin in addition to citric acid.

Table 7A

Process

1. Dexamethasone, mannitol, Eudragit EPO, and citric acid monohydrate are added in the conveying zone of a Twin-screw Extruder which is at a temperature of around 70-80°C;

2. The above ingredients are taken to a mixing / blending zone maintained at around 110°C (first elevated temperature) and blended together;

3. The blend from step 2 is taken to a kneading and mixing zone maintained at 140°C (second elevated temperature) and kneaded during which melting /softening of Eudragit EPO starts and further kneading commences granulation;

4. Granulate from step 3 is taken to another zone maintained at 110°C (third elevated temperature) where molten Eudragit EPO starts solidification and mixing in this zone produces cooled flakes/ rods/ granulate;

5. Cooled granulate from step 4 is taken to a conveying zone maintained at 80°C to cause further cooling / solidification of molten mass and taken out of a die as extrudates or flakes or rods or dried granules.

6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to required sizes. These granules are then blended with extragranular materials such as disintegrant, glidant, lubricant and hydroxy propyl beta cyclodextrin (batch F0113B) to produce high dissolving granules which are compressed into tablets.

Example 7B Since tablets F0113C exhibited disintegration time higher than desired (desired DT <_5 mins), granules for suspension 113A were directly subjected to In Vitro release profile in 0.1 N HC1 (OGD medium) and phosphate buffer of pH 6.8.

Table 7B

Example 7C

Table 7C

These granules did not release 85 % in 15 mins although release is 74 % in 15 mins and hence comply with the first release criteria.

When granules of batch F0113A are blended with another solubility enhancer hydroxy propyl beta cyclodextrin, sodium starch glycolate and magnesium stearate, such batch F0113B exhibited better release releasing about 5 - 15 % higher than release of granules of batch F0113 A at each time point. Example 7C provides such enhanced release. Example 8A: Stability studies - In vitro release profile

Best mode batch F0106C was subjected to accelerated stability studies at 40°C and 75 % RH (accelerated conditions).

Samples initial, 1 month and 6 months accelerated conditions exhibited same in vitro release profile in ODG medium as below: Table 8A

Example 8B: Stability studies - Impurity profile Impurities profiling of the F0106C batch Table 8B

Failed batches

Following batches are not part of the invention namely examples 9, 10 and 11.

Example 9A: Comparative batches not part of invention - batches without holt melt extrusion Table 9A

Process:

1. All ingredients except magnesium stearate are blended together in a blender to prepare a blend.

2. The blend is blended with magnesium stearate to prepare lubricated blend.

3. Tablets are compressed at an avg wt. of 70 mg.

Example 9 B: % Cumulative release in 0.1N HC1 (500 ml) using paddles (50 RPM) for batches without hot melt extrusion

Table 9B

Batches 16 -20 prepared without hot melt extrusion failed in In Vitro release profile. None of the batches could release 85 % in 15 mins. Batches 16 and 18 - 20 exhibited incomplete release even at the end of 60 mins in OGD medium.

Example 10 : Batches with i) melting component 20 % of intragranular mass; and ii) with 60 % melting component but without mannitol and without sufficient binding.

Table 10

Process

1. Dexamethasone, mannitol, Eudragit EPO, and citric acid monohydrate are added in the conveying zone of a Twin-screw Extruder which is at a temperature of around 70-80°C;

2. The above ingredients are taken to a mixing / blending zone maintained at around 110°C (first elevated temperature) and blended together;

3. The blend from step 2 is taken to a kneading and mixing zone maintained at 140°C (second elevated temperature) and kneaded during which melting /softening of Eudragit EPO starts and further kneading commences granulation; 4. Granulate from step 3 is taken to another zone maintained at 110°C (third elevated temperature) where molten Eudragit EPO starts solidification and mixing in this zone produces cooled flakes/ rods/ granulate;

5. Cooled granulate from step 4 is taken to a conveying zone maintained at 80°C to cause further cooling / solidification of molten mass and taken out of a die as extrudates or flakes or rods or dried granules.

6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to required sizes. These granules are then blended with extragranular materials such as disintegrant, glidant, lubricant and hydroxy propyl beta cyclodextrin (batch F0113B) to produce high dissolving granules which are compressed into tablets.

Example 11A: Comparative batches with high amount of Eudragit EPO but without holt melt extrusion

Table 11A

Process:

1. Dexamethasone, mannitol and Eudragit EPO are blended. 2. Lactose, Ac-di-sol are added and blended again

3. Magnesium stearate is added and blended again.

Example 11B: Comparison of dissolution profile in acetate buffer of pH 4.5 of F0106C (best mode batch 1) and Comparative example batch F0106G (without hot melt extrusion).

Table 11B Example 12: Marketed Product Evaluation / RLD evaluation

Marketed product Hemady by Dexcel Pharma Technologies is procured and subjected to various testing including in vitro release profile and to compare it with development batches of Dexamethasone.

The dissolution conditions requirement by Office of Generic Drugs (OGD) are as follows:

Table 12A

OGD recommended dissolution medium:

Table 12B

Marketed / Brand product was evaluated for release profile in OGD media