WO2023062647A1 - Formulation de pomalidomide - Google Patents

Formulation de pomalidomide Download PDF

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Publication number
WO2023062647A1
WO2023062647A1 PCT/IN2022/050907 IN2022050907W WO2023062647A1 WO 2023062647 A1 WO2023062647 A1 WO 2023062647A1 IN 2022050907 W IN2022050907 W IN 2022050907W WO 2023062647 A1 WO2023062647 A1 WO 2023062647A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
pomalidomide
isomalt
present
composition
Prior art date
Application number
PCT/IN2022/050907
Other languages
English (en)
Inventor
Prasanna Kumar Sreenivasa Reddy Gari JONNALA
Deepti DHANAVADE
Deepak Deshpande
Original Assignee
Reliance Life Sciences Pvt.Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Reliance Life Sciences Pvt.Ltd. filed Critical Reliance Life Sciences Pvt.Ltd.
Publication of WO2023062647A1 publication Critical patent/WO2023062647A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to an improved and stable formulation of Pomalidomide and its methods.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention therefore provides a stable formulation/composition containing Isomalt as a diluent.
  • the formulation of the present invention is capsule.
  • the present invention provides a stable formulation of Pomalidomide.
  • 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.
  • 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.
  • inventions 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.
  • 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.
  • polymorph form of Pomalidomide is Form A.
  • 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.
  • formulation encompasses capsules, caplets, tablets pellets, granules.
  • pharmaceutical composition is in the form of capsules, caplets, tablets pellets, granules, preferably capsules.
  • the composition of the present invention is preferably capsule.
  • 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.
  • the present invention provides a stable formulation of hard gelatin capsules.
  • 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
  • stable formulation or ‘stable composition’ means that the stability of active ingredient of formulation or composition comparable with that of Imnovid®.
  • the term ‘diluent’ means carrier or filler.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une formulation comprenant plus de 50 % d'isomalt comme diluant. De façon plus spécifique, la présente Invention concerne une formulation en capsule stable de pomalidomide avec de l'isomalt et ses procédés de préparation.
PCT/IN2022/050907 2021-10-12 2022-10-10 Formulation de pomalidomide WO2023062647A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202121046379 2021-10-12
IN202121046379 2021-10-12

Publications (1)

Publication Number Publication Date
WO2023062647A1 true WO2023062647A1 (fr) 2023-04-20

Family

ID=85987563

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2022/050907 WO2023062647A1 (fr) 2021-10-12 2022-10-10 Formulation de pomalidomide

Country Status (1)

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WO (1) WO2023062647A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010135396A2 (fr) * 2009-05-19 2010-11-25 Celgene Corporation Préparations de 4-amino-2-(2,6-dioxopipéridine-3-yl)isoindoline-1,3-dione
EP3545949A1 (fr) * 2018-03-29 2019-10-02 Midas Pharma GmbH Formes posologiques orales comprenant une forme cristalline a de pomalidomide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010135396A2 (fr) * 2009-05-19 2010-11-25 Celgene Corporation Préparations de 4-amino-2-(2,6-dioxopipéridine-3-yl)isoindoline-1,3-dione
EP3545949A1 (fr) * 2018-03-29 2019-10-02 Midas Pharma GmbH Formes posologiques orales comprenant une forme cristalline a de pomalidomide

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