CROSS REFERENCE TO RELATED PATENT APPLICATIONS:

The present application claims the benefit of filing date of Indian Provisional Patent Application No. 202121046379 file don Oct 12, 2021 which is entirely incorporated herein by reference

TECHNICAL FIELD

The present invention relates to an improved and stable formulation of Pomalidomide and its methods.

BACKGROUND

Pomalidomide, an analogue of thalidomide, is an immunomodulatory antineoplastic agent.

Pomalidomide (INN, originally CC-4047 or 3-amino-thalidomide, trade name Pomalyst® [1] in the US and Imnovid® in EU) is a derivative of thalidomide marketed by Bristol-Myers Squibb Pharma EEIG. It is anti-angiogenic and also acts as an immunomodulator.

Pomalidomide is indicated for patients with multiple myeloma who have received at least two prior therapies including Lenalidomide and Bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approved formulation of Pomalidomide is Imnovid® and Pomalyst® capsules which is available in 1 mg, 2 mg, 3 mg and 4 mg capsules for oral administration. Each capsule contains Pomalidomide as the active ingredient and with inactive ingredients like mannitol, pregelatinized starch and sodium stearyl fumarate. Pomalidomide is a BCS class IV molecule, having low permeability and low solubility. Various excipients such as microcrystalline cellulose, sugar alcohols such as mannitol, starch, lactose has been studied.

US20070155791 discloses Pomalidomide compositions comprising mannitol or starch as a diluent.

EP2391355 and EP3199149 has disclosed Pomalidomide capsule formulation comprising mixture of mannitol and starch as a diluent or carrier or filler.

EP3900701 provides for a formulation comprising isomalt and starch as a diluent.

The prior art EP1845949B1 provides formulation studies using various sugar alcohols, wherein it is inferred that isomalt is suitable for chewable tablets.

Wijers et al., “Isomalt” p. 274 in: Alternative Sweeteners, ed. By L. O‘Brien Nabors (2001) provides use of isomalt in various formulations but not capsules.

WO2019185862 disclosed Pomalidomide formulation with Isomalt as a stabilizer in the concentration of 12.5% and in combination with a diluent microcrystalline cellulose, the example of which stated that the formulation could not achieve the desired dissolution for Pomalidomide.

The present invention provides for a stable formulation comprising only isomalt as a diluent.

Thus the prior art has suggested the use of isomalt for its organoleptic properties. The present invention has provided a formulation with isomalt as a diluent for capsules which has resulted in a stable formulation. More specifically the present invention discloses stable formulation of Pomalidomide with Isomalt present in a concentration of more than 50% of the total concentration. The dissolution pattern is better than the prior art.

The formulation of the present invention has also includes other excipients such as lubricant. SUMMARY OF INVENTION

The present invention therefore provides a stable formulation/composition containing Isomalt as a diluent.

In one aspect the formulation of the present invention is capsule.

In one aspect the present invention provides a stable formulation of Pomalidomide.

In one aspect, the present invention provides a formulation of Pomalidomide with isomalt as a diluent. In one preferred embodiment the present invention comprises of more than 50% of isomalt.

In another aspect of the present invention, formulation of Pomalidomide also comprises disintegrant at a concentration of about 5% to 30 % of the total weight of the composition. Preferred disintegrant is pregelatinized starch, sodium starch glycolate or croscarmellose sodium most preferably about 5% to 30% of croscarmellose sodium.

Other embodiments may include pharmaceutically acceptable excipients lubricant like sodium stearyl fumarate.

The present disclosure provides a combination of isomalt and croscarmellose sodium for a stable formulation of Pomalidomide for use in treatment of multiple myeloma.

BRIEF DESCRIPTION OF DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, the inventions of which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. Figure 1 : The dissolution profile of the formulation of the present invention as compared to Imnovid®

The details of one or more embodiments of the present invention are set forth in the description below

DETAILED DESCRIPTION OF THE INVENTION

Definitions and Preferred embodiments with scope:

As used herein, the term 'Pomalidomide' is used in broad sense to include not only the Pomalidomide per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.

In one preferred embodiment the polymorph form of Pomalidomide is Form A.

In one embodiment, the amount of Pomalidomide in the pharmaceutical composition is from about 0.1 to 25 mg, preferably from about 0.5 to about 10 mg, more preferably from about 0.5 mg to 5 mg.

As used herein, the term ‘formulation’ or ‘composition’ encompasses capsules, caplets, tablets pellets, granules. In another embodiment, the pharmaceutical composition is in the form of capsules, caplets, tablets pellets, granules, preferably capsules. In one embodiment, the composition of the present invention is preferably capsule.

As used herein, the term ‘capsule’ includes soft gelatin, hard gelatin, HPMC, polysaccharide or starch capsules as plugged, welded or glued capsules, of different size, colour, and water content. In one preferred embodiment, the present invention provides a stable formulation of hard gelatin capsules. In one embodiment, the capsules contain from about 50 to 500 mg of the pharmaceutical composition (i.e., active ingredient and excipient(s)). Capsules can be of any size. Examples of standard sizes include #000, #00, #0, #1, #2, #3, #4, and #5. The present invention provides a stable formulation in capsule size: #1, #2, #3 and #4

As used herein, the term ‘stable formulation’ or ‘stable composition’ means that the stability of active ingredient of formulation or composition comparable with that of Imnovid®.

As used herein, the term ‘diluent’ means carrier or filler. In one embodiment, the formulation is capsule comprising isomalt as a diluent. Preferable percentage of more than 50% of the total weight of the formulation. Different grades of isomalt can be used.

As used herein the term ‘Disintegrant’ includes, but are not limited to, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof. In one preferred embodiment the formulation comprises of croscarmellose sodium as a disintegrant. The amount of starch as a disintegrant in the formulation is about 5- 30% of the total weight of the formulation.

As used herein the term ‘Lubricant’ includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, corn starch, sodium stearyl fumarate, sodium benzoate, talc, and mixtures thereof. Preferred lubricant is sodium stearyl fumarate. The amount of the lubricant preferably Sodium stearyl fumarate is 0.5-2.0% of the total weight of the formulation.

It was noted that routine diluents such as microcrystalline cellulose, anhydrous lactose or mixture of both did not result in a formulation with comparable dissolution profile with Imnovid®. It was surprisingly noted that isomalt as a diluent resulted in a stable formulation. Although prior art suggests that isomalt is used for its organoleptic properties especially in chewable tablets, the use of isomalt as a diluent in capsules remained largely unexplored. The present invention also experimented the effect of various grades of Isomalt on the blend volumes and the dissolution profile. The bulk density of isomalt with 0.3 to 0.9 g/cm ³ was used, most preferably, the bulk density of about 0.4-0.6 g/cm ³ provided a stable formulation for Pomalidomide that are able to mimic the dissolution profile of the Imnovid® capsules.

EXAMPLES

The following Examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the Examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

EXAMPLE 1

The capsule strengths as per the present invention are dose proportional across the strengths i.e. uses common blends comprising the same excipients, varying in the proportion of drug substance and the three excipients pregelatinized starch, isomalt and sodium stearyl fumarate as per the strengths. The pharmaceutical composition according to the present invention requires just one single blend for all capsule strengths. The production process is simpler and the costs are reduced in case all capsule strengths are dose proportional.

In order to mimic the dissolution profile of the Imnovid® capsules, Pomalidomide in accordance with the present invention has a particle size distribution D90 equal to or less than 10 pm, most preferably less than 5 pm.

The formulation and its ingredients is tabulated below: TABLE 1

Process:

Pomalidomide, pregelatinized starch and Isomalt were sieved through a suitable mesh sieve and mixed in a suitable blender. Sodium stearyl fumarate was sieved through a suitable mesh sieve and added to the blender. The homogeneous blend was encapsulated using a dosator capsule filling machine.

Analysis:

The capsules thus prepared using present invention were tested for dissolution profile with approved formulation of Pomalidomide capsules (Imnovid®). The dissolution was carried out in USP Type-II (paddle) apparatus having 900 ml 0. IN HC1 as a dissolution medium at 50 RPM. The results of the tests are shown below in Figure 1. The dissolution profile of the formulation of the present invention given in example 1 as evident from Figure 1.

EXAMPLE 2

The capsule strengths as per the present invention are dose proportional across the strengths i.e. uses common blends comprising the same excipients, varying in the proportion of drug substance and the three excipients sodium starch glycolate, isomalt and sodium stearyl fumarate as per the strengths. The pharmaceutical composition according to the present invention requires just one single blend for all capsule strengths. The production process is simpler and the costs are reduced in case all capsule strengths are dose proportional.

The formulation and its ingredients is tabulated below: TABLE 2

Process:

Pomalidomide, Sodium starch glycolate and Isomalt were sieved through a suitable mesh sieve and mixed in a suitable blender. Sodium stearyl fumarate was sieved through a suitable mesh sieve and added to the blender. The homogeneous blend was encapsulated using a dosator capsule filling machine.

Analysis:

The capsules thus prepared using present invention were tested for dissolution profile with approved formulation of Pomalidomide capsules (Imnovid®). The dissolution profile of the formulation of the present invention given in example 2 as evident from Figure 2.

EXAMPLE 3

The capsule strengths as per the present invention are dose proportional across the strengths i.e. uses common blends comprising the same excipients, varying in the proportion of drug substance and the three excipients croscarmellose sodium, isomalt and sodium stearyl fumarate as per the strengths. The pharmaceutical composition according to the present invention requires just one single blend for all capsule strengths. The production process is simpler and the costs are reduced in case all capsule strengths are dose proportional.

The formulation and its ingredients is tabulated below: TABLE 3

Process:

Pomalidomide, croscarmellose sodium and Isomalt were sieved through a suitable mesh sieve and mixed in a suitable blender. Sodium stearyl fumarate was sieved through a suitable mesh sieve and added to the blender. The homogeneous blend was encapsulated using a dosator capsule filling machine.

Analysis:

The capsules thus prepared using present invention were tested for dissolution profile with approved formulation of Pomalidomide capsules (Imnovid). The dissolution profile of the formulation of the present invention was similar to the profile of Imnovid® as evident from Figure 3.

Thus, while we have described fundamental novel features of the invention, it will be understood that various omissions and substitutions and changes in the form and details may be possible without departing from the spirit of the invention. For example, it is expressly intended that all combinations of those elements and/or method steps, which perform substantially the same function in substantially the same way to achieve the same results, be within the scope of the invention.