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WO2025150072A1 - Formulation de pro-dispersion orale stable et ses mises en œuvre - Google Patents

Formulation de pro-dispersion orale stable et ses mises en œuvre

Info

Publication number
WO2025150072A1
WO2025150072A1 PCT/IN2025/050034 IN2025050034W WO2025150072A1 WO 2025150072 A1 WO2025150072 A1 WO 2025150072A1 IN 2025050034 W IN2025050034 W IN 2025050034W WO 2025150072 A1 WO2025150072 A1 WO 2025150072A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
api
weight
present disclosure
capsule
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/IN2025/050034
Other languages
English (en)
Inventor
Naga Hemanth Kumar PARVATHABHATLA
Gopinath DEVARAJ
Rambhau Devraj
Krishna Kaushik CHINTABHATLA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pulse Pharmaceuticals Pvt Ltd
Original Assignee
Pulse Pharmaceuticals 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 Pulse Pharmaceuticals Pvt Ltd filed Critical Pulse Pharmaceuticals Pvt Ltd
Publication of WO2025150072A1 publication Critical patent/WO2025150072A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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 Biopharmaceutical Classification System is a critical tool for understanding and predicting the bioavailability of drugs (API). It classifies compounds into four categories (Class 1, 2, 3, and 4) based on their solubility and permeability profiles, which are key factors in determining how well a drug is absorbed in the body after oral administration.
  • BCS Class 1 drugs have high solubility and high permeability, hence are typically well absorbed and have predictable bioavailability.
  • BCS Class 2 drugs with low solubility but high permeability are often absorbed well when they are dissolved, but their poor solubility in aqueous environments, like the gastrointestinal tract, limits their bioavailability.
  • BCS Class 3 drugs with high solubility but low permeability can dissolve well in the body but face difficulties in crossing the biological membranes to reach systemic circulation.
  • BCS Class 4 drugs have both low solubility and low permeability, thus are the most challenging in terms of bioavailability since they struggle both to dissolve in the gastrointestinal tract and to permeate cell membranes.
  • Solubilized systems aim to increase the solubility of poorly soluble drugs by formulating with surfactants, cyclodextrins, or other solubilizers that can help dissolve the drug into a more bioavailable form.
  • surfactants cyclodextrins
  • solubilizers that can help dissolve the drug into a more bioavailable form.
  • These systems are typically employed in soft gelatin capsules or liquid formulations, as they can facilitate the drug's dissolution before it reaches the gastrointestinal tract, thus improving absorption.
  • other factors such as drug stability, enzymatic degradation, and gastrointestinal motility, can still impede the drug’s effectiveness.
  • Solubilised systems in the form of selfemulsifying drug delivery systems have also been proposed, which are defined as isotropic mixtures of one or more hydrophilic solvents, cosolvents and surfactants that are capable of forming fine oil-in-water (O/W) emulsions upon mild agitation and dilution in gastrointestinal fluids; various types of emulsions or suspensions.
  • SEDDS selfemulsifying drug delivery systems
  • Lipid-Lock technologies involve incorporating the drug into a lipid -based formulation, typically in soft-gel capsules. This encapsulation in lipids protects API from the harsh environment of the gastrointestinal tract and facilitates its absorption via the lymphatic system or lipid digestion pathways. While lipid-lock technology can enhance absorption for some drugs, it has limitations as well.
  • US4690823A discloses an ibuprofen-containing soft gelatin capsule containing a solution of ibuprofen wherein ibuprofen is dissolved in a polyoxyethylene-polyoxypropylene polymer or in a mixture of a polyalkylene glycol and a surfactant at a temperature of from 45 °C to 65 °C and will remain in solution upon cooling to room temperature.
  • US6221391B1 discloses a clear ibuprofen solution, said solution consisting essentially of a polyoxyethylene derivative of castor oil, polyvinylpyrrolidone, and ibuprofen.
  • US6251426B 1 discloses a liquid soft gel fill formulation consisting essentially of ibuprofen in free acid form in solution; polyethylene glycol; a weight of polyvinylpyrrolidone; and a surfactant.
  • GB2331458B mentions solubilizing systems for difficult pharmaceutical actives by preparing concentrated stable solutions for encapsulation into soft gelatin, wherein a nanoparticle formulation of Ibuprofen having a surface modifier adsorbed on the surface is disclosed.
  • the existing formulations are based on drug solubilization, which increases absorption while decreasing gastrointestinal tract (GIT) side effects, gastrointestinal tract (GIT) side effects were reduced but not eliminated completely.
  • GIT gastrointestinal tract
  • the bioavailability may still be affected by factors such as drug crystallization, degradation of the drug in the digestive tract, or insufficient digestion of the lipids, which can impair absorption.
  • lipid digestion is required for absorption, variability in lipid metabolism among patients can lead to inconsistent drug absorption and therapeutic outcomes.
  • a capsule comprising the formulation as disclosed herein.
  • a stable oral pro-dispersion formulation comprising (i) 2 to 10% by weight of an active pharmaceutical ingredient (API), wherein the API is an antitussive, preferably dextromethorphan, its derivatives, salts or solvates thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 5 to 58% by weight of a surfactant; and (v) 5 to 80% by weight of a solvent.
  • API active pharmaceutical ingredient
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising (i) 2 to 10 % by weight of an active pharmaceutical ingredient (API), wherein the API is an analgesic, preferably tapentadol, its derivatives, salts or solvates thereof; (ii) 0.5 to 15% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 10 to 58% by weight of a lipid; (iv) 10 to 55% by weight of a surfactant; and (v) 12 to 63% by weight of a solvent.
  • API active pharmaceutical ingredient
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation as disclosed herein, wherein the API is a factor Xa inhibitor, selected from apixaban, rivaroxaban, edoxaban, betrixaban, fondaparinux, idraparinux, otamixaban, letaxaban, darexaban, antithrombin alfa, or their derivatives, or combinations thereof.
  • the API is a factor Xa inhibitor, preferably apixaban.
  • stable oral a formulation comprising (i) 1 to 8% by weight of an active pharmaceutical ingredient (API), wherein the API is a factor Xa inhibitor, preferably apixaban, its derivatives, salts or solvates thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) a lipid; (iv) a surfactant; and (v) a solvent.
  • API active pharmaceutical ingredient
  • SPIM specialised polymeric interfacial modifier
  • stable oral a formulation comprising (i) 1 to 8% by weight of an active pharmaceutical ingredient (API), wherein the API is a factor Xa inhibitor, preferably apixaban, its derivatives, salts or solvates thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 5 to 58% by weight of a surfactant; and (v) 5 to 80% by weight of a solvent.
  • API active pharmaceutical ingredient
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising (i) 1 to 10% by weight of an active pharmaceutical ingredient (API), wherein the API is a vitamin, preferably vitamin D3, its derivatives, salts or solvates thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) a lipid; (iv) a surfactant; and (v) a solvent.
  • API active pharmaceutical ingredient
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising (i) 1 to 10% by weight of an active pharmaceutical ingredient (API), wherein the API is a vitamin, preferably vitamin D3, its derivatives, salts or solvates thereof; (ii) 1 to 7% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 10 to 58% by weight of a surfactant; and (v) 10 to 40% by weight of a solvent.
  • API active pharmaceutical ingredient
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation as disclosed herein, wherein the SPIM is selected from poloxamers, polyvinyl compounds, polyvinylpyrrolidones or its derivatives, polyethylene glycol derivatives having molecular weight greater than 350 g/mol, phospholipids, polyoxyethylene fatty acid esters, sucrose esters, phosphatidylcholines or its derivatives thereof, tocopherol esters, D-a-tocopheryl polyethylene glycol succinate (TPGS) or derivatives thereof, ascorbic acid esters, pegylated compounds, pegylated lipids, or combinations thereof.
  • the SPIM is selected from poloxamers, polyvinyl compounds, polyvinylpyrrolidones or its derivatives, polyethylene glycol derivatives having molecular weight greater than 350 g/mol, phospholipids, polyoxyethylene fatty acid esters, sucrose esters, phosphatidylcholines or its derivatives thereof, tocopherol esters, D-a
  • a stable oral formulation as disclosed herein wherein the API and the SPIM are in a weight ratio range of 1:0.02 to 1:4.6.
  • the API and the SPIM are in a weight ratio range of 1:0.02 to 1:1.8; and the API is NSAID preferably ibuprofen.
  • the API and the SPIM are in a weight ratio range of 1:0.05 to 1:1.7; and the API is antitussive preferably dextromethorphan.
  • the API and the SPIM are in a weight ratio range of 1 :0.02 to 1:4.6; and the API is other drug, preferably selected from atorvastatin, rosuvastatin, aspirin and diclofenac.
  • lipid is selected from fats, cholesterol, long chain triglycerides, medium-chain triglycerides, fatty acids, fatty alcohols, fatty acid esters of glycerol, glyceryl stearate, oils, propylene glycol laurate, or combinations thereof.
  • lipid is present in a weight range of 4 to 62% by weight, with respect to the formulation.
  • a prodispersion formulation wherein the formulation comprises 4 to 62% by weight a lipid selected from fats, cholesterol, long chain triglycerides, medium-chain triglycerides, fatty acids, fatty alcohols, fatty acid esters of glycerol, glyceryl stearate, oils, propylene glycol laurate, or combinations thereof.
  • a lipid selected from fats, cholesterol, long chain triglycerides, medium-chain triglycerides, fatty acids, fatty alcohols, fatty acid esters of glycerol, glyceryl stearate, oils, propylene glycol laurate, or combinations thereof.
  • a stable oral formulation as disclosed herein wherein the API and the lipid are in a weight ratio range of 1:0.4 to 1: 30.8.
  • the API and the lipid are in a weight ratio range of 1:0.4 to 1:2; and the API is NSAID preferably ibuprofen.
  • the API and the lipid are in a weight ratio range of 1:0.5 to 1: 17; and the API is antitussive preferably dextromethorphan.
  • a stable oral formulation as disclosed herein wherein the surfactant is selected fatty acid esters of sorbitan, polyoxyl hydrogenated castor oil, polyoxyethylene esters/polysorbates, fatty acid esters, polyglycerol esters, propylene glycol fatty acid esters, sulfate- based surfactants, sulfonate -based surfactants, or combinations thereof.
  • the surfactant is selected fatty acid esters of sorbitan, polyoxyl hydrogenated castor oil, polyoxyethylene esters/polysorbates, fatty acid esters, polyglycerol esters, propylene glycol fatty acid esters, sulfate- based surfactants, sulfonate -based surfactants, or combinations thereof.
  • a stable oral pro-dispersion formulation as disclosed herein, wherein the surfactant is present in a weight range of 5 to 58% by weight, with respect to the formulation.
  • a stable oral pro-dispersion formulation as disclosed herein, wherein the formulation comprises 5 to 58% by weight of a surfactant selected from fatty acid esters of sorbitan, polyoxyl hydrogenated castor oil, polyoxyethylene esters/polysorbates, fatty acid esters, polyglycerol esters, propylene glycol fatty acid esters, sulfate-based surfactants, sulfonate-based surfactants, or combinations thereof.
  • a surfactant selected from fatty acid esters of sorbitan, polyoxyl hydrogenated castor oil, polyoxyethylene esters/polysorbates, fatty acid esters, polyglycerol esters, propylene glycol fatty acid esters, sulfate-based surfactants, sulfonate-based surfactants, or combinations thereof.
  • a stable oral pro-dispersion formulation as disclosed herein, wherein the API and the surfactant are in the weight ratio range of 1:0.5 to 1:27.5.
  • the API and the surfactant are in a weight ratio range of 1:0.5 to 1:6; and the API is NS AID preferably ibuprofen.
  • the API and the surfactant are in a weight ratio range of 1:1 to 1:23; and the API is antitussive preferably dextromethorphan.
  • the API and the surfactant are in a weight ratio range of 1:1 to 1: 17; and the API is analgesic, preferably tapentadol.
  • the API and the surfactant are in a weight ratio range of 1: 1 to 1:27.5; and the API is vitamin, preferably vitamin D3.
  • the API and the surfactant are in a weight ratio range of 1:0.5 to 1:21; and the API is factor Xa inhibitor, preferably apixaban.
  • the API and the surfactant are in a weight ratio range of 1:0.5 to 1:27.5; and the API is other drug, preferably selected from atorvastatin, rosuvastatin, aspirin and diclofenac.
  • a stable oral pro-dispersion formulation as disclosed herein, wherein the API and the solvent are in a weight ratio range of 1:0.2 to 1:34.1.
  • the API and the solvent are in a weight ratio range of 1:0.2 to 1:1; and the API is NS AID preferably ibuprofen.
  • the API and the solvent are in a weight ratio range of 1:2 to 1:14; and the API is antitussive preferably dextromethorphan.
  • the API and the solvent are in a weight ratio range of 1:3 to 1:8; and the API is analgesic, preferably tapentadol.
  • the API and the solvent are in a weight ratio range of 1:3 to 1:17; and the API is vitamin, preferably vitamin D3.
  • the API and the solvent are in a weight ratio range of 1:10 to 1:34.1; and the API is factor Xa inhibitor, preferably apixaban.
  • the API and the solvent are in a weight ratio range of 1:0.2 to 1:34.1; and the API is other drug, preferably selected from atorvastatin, rosuvastatin, aspirin and diclofenac.
  • a prodispersion formulation comprising: (i) 1 to 30% by weight of an active pharmaceutical ingredient (API) selected from non-steroidal anti-inflammatory drugs (NSAIDs), antitussives, analgesics, factor Xa inhibitors, vitamins, derivatives, or combinations thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 5 to 58% by weight of a surfactant; and (v) 5 to 80% by weight of a solvent, with a proviso that if API is NSAID preferably ibuprofen, in a weight range of 10 to 30% (w/w), then the SPIM is in a weight range of 0.4 to 27%(w/w), the lipid is in a weight range of 10 to 45% (w/w), the surfactant is in a weight range of 15 to 55%(w
  • API active pharmaceutical ingredient
  • SPIM non-steroidal anti
  • a stable oral pro-dispersion formulation comprising: (i) 20 to 22% by weight of a NSAID, preferably ibuprofen; (ii) 10 to 17% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 25 to 29% by weight of a lipid; (iv) 33 to 35% by weight of a surfactant; and (v) 5 to 10% by weight of a solvent.
  • a NSAID preferably ibuprofen
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising: (i) 1 to 30% by weight of an active pharmaceutical ingredient (API) selected from non-steroidal anti-inflammatory drugs (NSAIDs), antitussives, analgesics, factor Xa inhibitors, vitamins, other drugs, derivatives, or combinations thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 5 to 58% by weight of a surfactant; and (v) 5 to 80% by weight of a solvent, with a proviso that if API is antitussive preferably dextromethorphan, in a weight range of 2 to 10%(w/w), then the SPIM is in a weight range of 0.1 to 10%(w/w), the lipid is in a weight range of 5 to 60%(w/w), the surfactant is in a weight range of
  • API active pharmaceutical ingredient
  • SPIM non-steroidal anti
  • a stable oral pro-dispersion formulation comprising: (i) an active pharmaceutical ingredient (API) selected from non-steroidal anti-inflammatory drugs (NSAIDs), antitussives, analgesics, factor Xa inhibitors, vitamins, other drugs, derivatives, or combinations thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) a lipid; (iv) a surfactant; and (v) a solvent, with a proviso that if API is antitussive preferably dextromethorphan, in a weight range of 2 to 10%(w/w), then the SPIM is in a weight range of 0.1 to 10%(w/w), the lipid is in a weight range of 5 to 60%(w/w), the surfactant is in a weight range of 15 to 58%(w/w), the solvent is in weight range of 14 to 60%(w/w), with respect to
  • API active pharmaceutical ingredient
  • SPIM non-steroidal anti
  • a stable oral pro-dispersion formulation comprising: (i) 2 to 10% by weight of an antitussive, preferably dextromethorphan; (ii) 0.1 to 10% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 5 to 60% by weight of a lipid; (iv) 15 to 58% by weight of a surfactant; and (v) 14 to 60% by weight of a solvent, wherein the API and the solvent are in a weight ratio range of 1 :2 to 1:14; the API and the surfactant are in a weight ratio range of 1 : 1 to 1:23; the API and the lipid are in a weight ratio range of 1:0.5 to 1:17; and the API and the SPIM are in a weight ratio range of 1:0.05 to 1:1.7.
  • SPIM polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising: (i) 2 to 4% by weight of an antitussive, preferably dextromethorphan; (ii) 2 to 5% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 29 to 31% by weight of a lipid; (iv) 38 to 43% by weight of a surfactant; and (v) 20 to 22% by weight of a solvent, with respect to the formulation.
  • SPIM polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising: (i) 1 to 30% by weight of an active pharmaceutical ingredient (API) selected from non-steroidal anti-inflammatory drugs (NSAIDs), antitussives, analgesics, factor Xa inhibitors, vitamins, other drugs, derivatives, or combinations thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 5 to 58% by weight of a surfactant; and (v) 5 to 80% by weight of a solvent, with a proviso that if API is an analgesic preferably tapentadol, in a weight range of 2 to 10%(w/w), then the SPIM is in a weight range of 0.5 to 15%(w/w), the lipid is in a weight range of 10 to 58%(w/w), the surfactant is in a weight range
  • API active pharmaceutical ingredient
  • SPIM non-steroidal anti
  • a stable oral pro-dispersion formulation comprising: (i) an active pharmaceutical ingredient (API) selected from non-steroidal anti-inflammatory drugs (NSAIDs), antitussives, analgesics, factor Xa inhibitors, vitamins, other drugs, derivatives, or combinations thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) a lipid; (iv) a surfactant; and (v) a solvent, with a proviso that if API is an analgesic preferably tapentadol, in a weight range of 2 to 10%(w/w), then the SPIM is in a weight range of 0.5 to 15%(w/w), the lipid is in a weight range of 10 to 58%(w/w), the surfactant is in a weight range of 10 to 55%(w/w), the solvent is in weight range of 12 to 63%(w/w), with
  • API active pharmaceutical ingredient
  • SPIM non-steroidal anti
  • a stable oral pro-dispersion formulation comprising: (i) 2 to 10% by weight of an analgesic, preferably tapentadol; (ii) 0.5 to 15% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 10 to 58% by weight of a lipid; (iv) 10 to 55% by weight of a surfactant; and (v) 12 to 63% by weight of a solvent, wherein the API and the solvent are in a weight ratio range of 1:3 to 1:8; the API and the lipid are in a weight ratio range of 1:1 to 1:21; the API and the surfactant are in a weight ratio range of 1:1 to 1:17; the API and the SPIM are in a weight ratio range of 1:0.2 to 1:2.
  • an analgesic preferably tapentadol
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising: (i) 2 to 10% by weight of an analgesic, preferably tapentadol; (ii) 5 to 15% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 15 to 20% by weight of a lipid; (iv) 11 to 14% by weight of a surfactant; and (v) 45 to 57% by weight of a solvent, with respect to the formulation.
  • an analgesic preferably tapentadol
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising: (i) 1 to 30% by weight of an active pharmaceutical ingredient (API) selected from non-steroidal anti-inflammatory drugs (NSAIDs), antitussives, analgesics, factor Xa inhibitors, vitamins, other drugs, derivatives, or combinations thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 5 to 58% by weight of a surfactant; and (v) 5 to 80% by weight of a solvent, with a proviso that if API is vitamin, in a weight range of 1 to 10%(w/w), then the SPIM is in a weight range of 1 to 7%(w/w), the lipid is in a weight range of 4 to 62%(w/w), the surfactant is in a weight range of 10 to 58%(w/w), the solvent
  • API active pharmaceutical ingredient
  • SPIM non-steroidal anti
  • a stable oral pro-dispersion formulation comprising: (i) 1 to 10% by weight of a vitamin, preferably cholecalciferol or vitamin D3; (ii) 1 to 7% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 10 to 58% by weight of a surfactant; and (v) 10 to 40% by weight of a solvent, wherein the API and the solvent are in a weight ratio range of 1:3 to 1:17; the API and the surfactant are in a weight ratio range of 1:1 to 1:27.5; the API and the lipid are in a weight ratio range of 1:0.4 to 1:30.8; and the API and the SPIM are in a weight ratio range of 1:0.3 to 1:2.
  • SPIM polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising: (i) 2 to 6% by weight of a vitamin, preferably cholecalciferol or vitamin D3; (ii) 1 to 3% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 49 to 62% by weight of a lipid; (iv) 20 to 24% by weight of a surfactant; and (v) 10 to 19% by weight of a solvent, with respect to the formulation.
  • a vitamin preferably cholecalciferol or vitamin D3
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising: (i) 1 to 30% by weight of an active pharmaceutical ingredient (API) selected from non-steroidal anti-inflammatory drugs (NSAIDs), antitussives, analgesics, factor Xa inhibitors, vitamins, other drugs, derivatives, or combinations thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 5 to 58% by weight of a surfactant; and (v) 5 to 80% by weight of a solvent, with a proviso that if API is factor Xa inhibitor preferably apixaban, in a weight range of 1 to 8%(w/w), then the SPIM is in a weight range of 1 to 10%(w/w), the lipid is in a weight range of 5 to 30%(w/w), the surfactant is in a weight range of 5
  • API active pharmaceutical ingredient
  • SPIM non-steroidal anti
  • a stable oral pro-dispersion formulation comprising: (i) 2 to 4% by weight of a Factor Xa inhibitors, preferably apixaban; (ii) 2 to 4% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 9 to 15% by weight of a lipid; (iv) 5 to 8% by weight of a surfactant; and (v) 70 to 76% by weight of a solvent.
  • a Factor Xa inhibitors preferably apixaban
  • SPIM specialised polymeric interfacial modifier
  • a stable oral pro-dispersion formulation comprising: (i) 1 to 30% by weight of an active pharmaceutical ingredient (API) selected from non-steroidal anti-inflammatory drugs (NSAIDs), antitussives, analgesics, factor Xa inhibitors, vitamins, other drugs, derivatives, or combinations thereof; (ii) 0.1 to 30% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 4 to 62% by weight of a lipid; (iv) 5 to 58% by weight of a surfactant; and (v) 5 to 80% by weight of a solvent, with a proviso that if API is selected from other drugs preferably atorvastatin, Rosuvastatin, aspirin, or diclofenac, in a weight range of 2 to 25%(w/w), then the SPIM is in a weight range of 1 to 12%(w/w), the lipid is in a weight range of 5 to 45%
  • API active pharmaceutical ingredient
  • SPIM non-steroidal anti
  • a stable oral pro-dispersion formulation comprising 2 to 25% by weight of API selected from other drugs preferably atorvastatin, Rosuvastatin, aspirin, or diclofenac; (ii) 1 to 12% by weight of a specialised polymeric interfacial modifier (SPIM); (iii) 5 to 45% by weight of a lipid; (iv) 5 to 58% by weight of a surfactant; and (v) 5 to 35% by weight of a solvent, wherein the API and the solvent are in a weight ratio range of 1:0.2 to 1:34.1; the API and the surfactant are in a weight ratio range of 1:0.5 to 1:27.5; the API and the lipid are in a weight ratio range of 1:0.4 to 1:30.8; and the API and the SPIM are in a weight ratio range of 1:0.02 to 1:4.6.
  • API selected from other drugs preferably atorvastatin, Rosuvastatin, aspirin, or diclofenac
  • SPIM specialised poly
  • a process of preparing the formulation as disclosed herein comprising the steps of: (i) adding one or more SPIM, one or more lipids, one or more solvent with an API and optionally adding at least one pharmaceutically acceptable excipient selected from biodegradable polymer, stabilizers, or combinations thereof, and mixing thoroughly to obtain a clear solution of a first mixture; and (ii) adding one or more surfactants to the first mixture and optionally at least one pharmaceutically acceptable excipient selected from biodegradable polymer, stabilizers, or combinations thereof and processing to form the formulation.
  • a capsule comprising the pro-dispersion formulation as disclosed herein, wherein the capsule is a shell made of a material selected from gelatin, hydroxypropyl methylcellulose, acrylic polymer, acid resistant polymer, natural polymer, vegan or vegetarian shell, or combinations thereof.
  • shell materials also include but not limited to modified starches, carrageenans, pullulans, pectins, and behenates.
  • a capsule wherein the capsule has a moisture content in a weight range of 1 to 10%(w/w), with respect to total weight of the capsule.
  • a capsule wherein the carrier particle entrapping the API has a particle size in the range of 5 nm to 10 pm.
  • the carrier particle entrapping the API has an entrapment efficiency of 50% to 90%.
  • a capsule wherein the carrier particle entrapping the API is physically stable for a time period in the range of 3h to 6h in a simulated gastric/GIT pH conditions.
  • a process of preparing the capsule as disclosed herein comprising filling the prodispersion formulation as disclosed herein into a shell to obtain the capsule.
  • condition refers to any illness, disorder, disease, or injury that affects the normal functioning of the body or mind.
  • a method of treatment or management of a condition in a subject in need thereof comprising treating with the pro-dispersion formulation as disclosed herein or the capsule as disclosed herein.
  • a method of treatment or management of a condition in a subject in need thereof wherein the condition is selected from acute pain, chronic pain, fever, inflammatory conditions, osteoarthritis, rheumatoid arthritis, musculoskeletal pain, diabetic neuropathy, cough, common cold, flu, depression, major depressive disorder, thromboembolism, atrial fibrillation, venous thromboembolism, acute coronary syndrome, arterial thrombosis, coronary and peripheral artery disease, cardiovascular risk reduction prophylaxis, treatment of deep vein thrombosis after abdominal, hip replacement, knee joint replacement surgery, or vitamin deficiency.
  • the condition is selected from acute pain, chronic pain, fever, inflammatory conditions, osteoarthritis, rheumatoid arthritis, musculoskeletal pain, diabetic neuropathy, cough, common cold, flu, depression, major depressive disorder, thromboembolism, atrial fibrillation, venous thromboembolism, acute coronary syndrome, arterial thrombosis, coronary
  • a method of treatment or management of a condition in a subject in need thereof wherein the formulation or the capsule is administered once or twice a day for treating or managing the condition.
  • the condition is selected from pain (acute and chronic), fever, and inflammatory conditions, which include osteoarthritis and rheumatoid arthritis, provided the API in the formulation or capsule as disclosed herein is NSAID, preferably ibuprofen.
  • a method of treatment or management of a condition in a subject in need thereof wherein the condition is selected from cough caused by common cold, flu, depression or major depressive disorder, provided the API in the formulation or capsule as disclosed herein is antitussive, preferably dextromethorphan.
  • a method of treatment or management of a condition in a subject in need thereof wherein the condition is selected from common cold, flu or other related conditions, provided the API in the formulation or capsule as disclosed herein is analgesic, preferably tapentadol.
  • a method of treatment or management of a condition in a subject in need thereof wherein the condition is selected from acute pain, chronic pain, fever, inflammatory conditions, osteoarthritis, rheumatoid arthritis, musculoskeletal pain, diabetic neuropathy, cough, common cold, flu, depression, major depressive disorder, thromboembolism, atrial fibrillation, venous thromboembolism, acute coronary syndrome, arterial thrombosis, coronary and peripheral artery disease, cardiovascular risk reduction prophylaxis, treatment of deep vein thrombosis after abdominal, hip replacement, knee joint replacement surgery, or vitamin deficiency, provided the API in the formulation or capsule as disclosed herein is selected from other drugs, preferably selected from atorvastatin, rosuvastatin, aspirin, or diclofenac.
  • EXAMPLE 1.1 Preparation of the pro-dispersion formulation: [00181]
  • the pro-dispersion formulation was prepared by adding one or more specialised polymeric interfacial modifier (SPIM), one or more lipids, one or more solvent with an API and optionally adding at least one pharmaceutically acceptable excipient selected from biodegradable polymer, stabilizers, or combinations thereof, followed by thorough mixing to obtain a clear solution of a first mixture.
  • SPIM polymeric interfacial modifier
  • lipids one or more solvent with an API
  • optionally adding at least one pharmaceutically acceptable excipient selected from biodegradable polymer, stabilizers, or combinations thereof followed by thorough mixing to obtain a clear solution of a first mixture.
  • surfactants and optionally a pharmaceutically acceptable excipients were added and mixed with high shear processor to obtain the pro-dispersion formulation.
  • EXAMPLE 2 PREPARATION OF A PRO-DISPERSION FORMULATION COMPRISING IBUPROFEN, NSAID AS AN API
  • Alpha tocopherol (stabilizer), polyoxyl-40-hydrogenated castor oil and polysorbate 80 (surfactants) were added to the first mixture and mixed with high shear processor to obtain the pro-dispersion formulation comprising Ibuprofen.
  • Table 1.1 depicts the composition of the pro-dispersion formulation, Eg. 1 to 10 comprising Ibuprofen, NSAID as an API and mentioned components in said weight percentages, prepared using the method described in Example 2.1.
  • Table 1.1 Composition of the pro-dispersion formulation comprising Ibuprofen,
  • SPIM phospholipid and TPGS
  • API Ibuprofen
  • MCT lipid
  • surfactants were added to the first mixture and mixed with high shear processor to obtain the pro-dispersion formulation comprising
  • Ibuprofen, NSAID as an API.
  • Table 1.2 depicts the composition of the prodispersion formulation, Eg. 11 to 18 comprising Ibuprofen, NSAID as an API prepared using the method described in Example 2.2.
  • Table 1.2 Composition of the pro-dispersion formulation comprising Ibuprofen, NSAID as an API prepared using the method described in Example 2.2
  • Example 2.3 Preparation Method 3 (Eg. 19 to Eg. 23) [00185] BHT (stabilizer) was added to benzyl alcohol (solvent) and PEG 600 (SPIM) and mixed thoroughly to obtain a clear solution. To the clear solution, Ibuprofen and MCT (lipid) were added and mixed continuously under controlled conditions until a clear solution of a first mixture was obtained. Alpha tocopherol (stabilizer), polyoxyl-40-hydrogenated castor oil and polysorbate 80 (surfactants) were added to the first mixture and mixed with high shear processor to obtain the pro-dispersion formulation comprising Ibuprofen, NSAID as an API. Table 1.3 depicts the composition of the pro-dispersion formulation, Eg.
  • BHT stabilizer
  • cetostearyl alcohol(lipid) and lecithin ascorbyl palmitate
  • TPGS polyvinylpyrrolidone
  • SPIM polyvinylpyrrolidone
  • Polyoxyl 40 hydrogenated castor oil and polysorbate 80 surfactants were added to the first mixture and mixed with high shear processor to obtain the prodispersion formulation comprising dextromethorphan, antitussive as an API.
  • Table 2.1 depicts the composition of the pro-dispersion formulation, Eg. 24 to 32 comprising dextromethorphan, antitussive as an API prepared using the method described in Example 3.1.
  • Table 2.1 Composition of the pro-dispersion formulation comprising dextromethorphan, antitussive as an API prepared using the method described in Example 3.1
  • Example 3.2 Preparation Method 2 (Eg. 33 to Eg. 40) [00187] BHT(stabilizer), poloxamer (SPIM), phospholipid (lipid), were added to benzyl alcohol, PEG 200 (solvents) (mixture of solvents) and mixed until dissolved completely to obtain a clear solution. To the clear solution, dextromethorphan (API), oleic acid and MCT (lipids) were added and mixed continuously under controlled conditions until a clear solution of a first mixture was obtained.
  • Alpha tocopherol (stabilizer), polyoxyl 40 hydrogenated castor oil and polysorbate 80 (surfactants) were added to the first mixture and mixed with high shear processor to obtain the pro-dispersion formulation comprising dextromethorphan, antitussive as an API.
  • Table 2.2 depicts the composition of the pro-dispersion formulation, Eg. 33 to 40 comprising dextromethorphan, antitussive as an API prepared using the method described in Example 3.2.
  • Table 2.2 Composition of the pro-dispersion formulation comprising dextromethorphan, antitussive as an API prepared using the method described in Example 3.2
  • EXAMPLE 4 PREPARATION OF A PRO-DISPERSION FORMULATION COMPRISING TAPENTADOL, ANALGESIC AS AN API: (Eg. 41 to Eg.
  • Polyoxyl-40-hydrogenated castor oil and polysorbate 80 were added to the first mixture and mixed with high shear processor to obtain the pro-dispersion formulation comprising tapentadol, analgesic as an API.
  • Table 3 depicts the composition of the pro-dispersion formulation, Eg. 41 to 50 comprising tapentadol, analgesic as an API prepared using the method described in Example 4.
  • Table 3 Composition of the pro-dispersion formulation comprising tapentadol, analgesic as an API prepared using the method described in Example 4.
  • EXAMPLE 5 PREPARATION OF A PRO-DISPERSION FORMULATION COMPRISING STATINS, ASPIRIN, AND DICLOFENAC, ANALGESIC AS AN API: (Eg. 51 to Eg. 55)
  • Alpha Tocopherol, BHT (stabilizers), cetostearyl alcohol and cholesterol (lipids) were added to benzyl alcohol, polyethylene glycol 200, ethanol, and propylene glycol (solvents), polyvinyl pyrrolidone (SPIM), and methoxy polyethylene glycol 2000 (SPIM), and mixed until dissolved, followed by addition of lecithin(SPIM) or phospholipid (lipid) and poloxamer (SPIM) and mixed continuously until dissolved to obtain a clear solution.
  • Table 4 Composition of the pro-dispersion formulation comprising atorvastatin, rosuvastatin, aspirin, diclofenac sodium, analgesic as an API prepared using the method described in Example 5
  • EXAMPLE 6 PREPARATION OF A PRO-DISPERSION FORMULATION COMPRISING VITAMIN D3 AS AN API: (Eg. 56 to Eg. 62)
  • BHT stabilizer
  • poloxamer poloxamer
  • SPIM polyvinylpyrrolidone
  • SPIM polyvinylpyrrolidone
  • Table 5 depicts the composition of the pro-dispersion formulations, Eg. 56 to 62 comprising vitamin D3 as an API prepared using the method described in Example 6.
  • Table 5 Composition of the pro-dispersion formulation comprising vitamin D3, as an API prepared using the method described in Example 6.
  • Table 6.1 Composition of the pro-dispersion formulation comprising apixaban, factor Xa inhibitor as an API prepared using the method described in Example 7.1
  • BHT stabilizer
  • poloxamer poloxamer
  • sucrose palmitate sucrose acetate isobutyrate
  • SPIM sucrose acetate isobutyrate
  • API apixaban
  • Polyoxyl 40 hydrogenated castor oil, polyoxyl 35 hydrogenated castor oil and polysorbate 80 (surfactants) were added to the first mixture and mixed with high shear processor to obtain the pro-dispersion formulation comprising apixaban, factor Xa inhibitor as an API.
  • EXAMPLE 8 ANALYSIS OF THE FORMULATIONS (Eg. 1 to 73)
  • the prepared formulations were tested for their stability under five different conditions of temperature and pH: i) At room temperature (RT): The freshly prepared formulations kept at RT were evaluated. ii) Simulated gastric condition: The formulations were contacted with 0.1N HC1, simulating a gastric pH for a time period of up to 6h. iii) Simulated gastrointestinal tract condition: The formulations were contacted with buffers having a pH of 6.2 and 7.4 for a time period of up to 6h. iv) Accelerated conditions as per ICH guidelines'. The formulations were exposed to a temperature of 40°C and 75% relative humidity for a time period of up to 6 months. v) Long term stability as per ICH guidelines'. The formulations were exposed to a temperature of 30°C and 75% relative humidity for a time period of up to 24 months.
  • the stability of the formulations was assessed by evaluating both the particle size distribution and the polydispersity index (PDI) under five different conditions. These two factors are commonly used to gauge the stability of particlebased formulations, especially in the context of dispersions or emulsions containing active pharmaceutical ingredients (APIs).
  • PDI polydispersity index
  • Particle Size Distribution The distribution of particle sizes within a formulation is crucial for understanding its physical stability. If the particle sizes remained consistent over time, it indicated that the formulation is stable, as there was no significant aggregation or growth of particles. In this study, the particle size distribution of the formulation remained unaltered across the five conditions, suggesting that the formulation was stable under those conditions. A stable particle size distribution means that the formulation is less likely to undergo changes such as particle coalescence or precipitation, which could negatively affect the API's performance or delivery.
  • Poly dispersity Index (PDI): The PDI is a measure of the width of the particle size distribution and is a critical indicator of homogeneity. A PDI value ranges from 0 to 1, where a lower PDI indicated a more uniform particle size distribution, and a higher PDI indicated a broader range of particle sizes. A PDI value approaching zero suggested that the particles were more monodisperse (uniform in size), which was desirable for maintaining formulation stability. In this study, as the PDI value stayed closer to zero, it indicated that the particle size of the formulation remained consistent over time. This consistency in particle size is important because it suggested that the particles were not aggregating, which would otherwise lead to a shift in particle size distribution. The PDI can be determined using instruments that use Dynamic Light Scattering or photon correlation spectroscopy or determined through electron microscopy.
  • a key implication of maintaining a constant particle size distribution and a low PDI is that the formulation is likely free from crystallization. Crystallization of the API would lead to the growth of larger particles, which could change the overall particle size distribution and disrupt the formulation. In the context of pharmaceutical formulations, crystallization of the API reduced bioavailability or compromised the stability and effectiveness of the drug. The fact that the particle size remained constant and the PDI remained low under the tested conditions strongly suggested that the API did not undergo crystallization, further confirming the enhanced stability of the formulation.
  • formulations exposed to the condition (i) to (iv), were subjected to physical observations under microscope to check for drug crystallization if any and depicted in Figures 1 to 6 and 8 to 22.
  • the formulations were hydrated with appropriate amount of purified water, for particle size testing, for Transmission Electron Microscopic analysis and the formulation as such was used for assay test and other chemical testing.
  • the entrapment efficiency of the loaded API was calculated for each formulation.
  • the pro-dispersion formulation PDF was first diluted with 0.22pm filtered deionized water to create a particulate dispersion (PD), which was then used to evaluate drug entrapment efficiency.
  • PD particulate dispersion
  • TFF Tangential Flow Filtration
  • the diluted dispersion was passed through the TFF capsule, and a fixed volume of filtrate was collected, while the remaining retentate was separated. This process was repeated if necessary, and the pooled samples were collected.
  • Both the filtrate and retentate were analyzed using HPLC (with a validated fit-for-purpose method) to determine the amounts of entrapped and un-entrapped drug, and a mass balance was calculated to confirm the method's validity.
  • the retentate contained the entrapped drug within the carrier particles, while the free drug remained in the filtrate. Additionally, a total-drug assay of the formulation was conducted using a validated HPLC method. The entrapment efficiency of the particulate dispersion was then calculated using a specific formula.
  • the assay percentage for each formulation referred to the measurement of the actual amount of the active pharmaceutical ingredient (API) present in a formulation compared to the theoretical or expected amount. It is an important quality control test that helped to determine the content uniformity, potency, and consistency of the drug formulation. To evaluate the assay percentage validated HPLC method for the specific drug was used.
  • Example 8.1 Analysis of the properties of the formulations comprising Ibupro en as an API (Eg. 1 to 23)
  • FIG. 9 showed no crystals for over six months at RT, and Eg. 2 showed no crystals for up to two years at RT and under long-term ICH conditions (30°C/75%RH), as shown in Figure 3.
  • Figure 24A depicts transmission electron microscopy (TEM) images of formed nanoparticles when ibuprofen pro-dispersion formulation (Eg. 2) was hydrated with purified water.
  • TEM transmission electron microscopy
  • Table 7.2 Stability of the prepared formulation comprising Ibuprofen (Eg. 2) as an API, exposed to long term (30°C/75%RH) up to 24 Months and Accelerated Conditions (40°C/75%RH) up to 6 Months:
  • Table 7.4 Stability of the prepared formulation comprising Ibuprofen (Eg. 2) as an API exposed to GIT pH conditions (pH 6.2 & pH 7.4 buffers) up to 6 hours.
  • Example 8.2 Analysis of the properties of the formulations comprising Dextromethorphan as an API (Eg. 24 to 40)
  • Table 8.1 Stability of the prepared formulation comprising dextromethorphan (Eg. 24 and 25) as an API exposed accelerated conditions (40°C/75%RH) for up to 6 months
  • Table 8.2 Stability of the prepared formulation comprising dextromethorphan (Eg. 26) as an API exposed to long term (30°C/75%RH) up to 18M and at Accelerated Conditions (40°C/75%RH) up to 6 Months
  • Table 9.4 Stability of the formulation comprising Tapentadol as an API (Eg. 41 ) exposed to GIT pH 6.2 & 7.4 buffers up to 6 hours
  • Table 9.5 Particle size distribution of the formulations comprising Tapentadol as an API (Eg. 44) at RT
  • Table 12.1 Stability of the prepared formulation comprising Apixaban as an API (Eg. 63) exposed to Accelerated conditions (40°C/75%RH) for up to 6 Months and Long-term conditions 30°C/75%RH & 25°C/60%RH for up to 18 Months
  • Table 12.3 Stability of the prepared formulation comprising Apixaban as an API (Eg. 63) exposed to 0.1N HCl I Gastric acid/Stomach acid (Gastric pH) for up to 6 Hrs
  • Table 12.4 Stability of the prepared formulation comprising Apixaban as an API (Eg. 63) exposed to GIT pH (pH 6.2 buffer and pH 7.4 buffer) for upto 6 hours
  • Table 12.5 Particle size distribution of the formulation comprising Apixaban as an API (Eg. 65, 66, 68 to 72) at RT
  • zeta potential ZP
  • electrokinetic potential zeta potential is the potential difference between the dispersion medium and the stationary layer of fluid attached to the dispersed particle. Zeta potential measures charge on the surface of the particle and surface charge density which is amount of charge per unit area on surface of particle.
  • Zeta potential is a measure of charge density or surface charge on the particles, generally strong electrical repulsion between particles prevent them from aggregation.
  • Table 13 Estimated zeta potential for the formulations Eg. 9, 26, 57, and 64
  • Table 14 Estimated zeta potential for the formulations Eg. 14 to 18 with respect to varying SP1M concentration.
  • EXAMPLE 10 EVALUATION OF GASTRIC ULCEROGENIC POTENTIAL ACTIVITY OF FORMULATION COMPRISING IBUPROFEN (Eg. 2) IN RATS
  • NSAIDs like Ibuprofen
  • GI gastrointestinal
  • gastric ulcers gastritis, bleeding, and perforation
  • the risk is higher in older individuals, those with poor health, smokers, heavy alcohol drinkers, and people with pre-existing GI conditions.
  • an ulcerogenic potential study was conducted in small animals, such as rats.
  • the present disclosure provides a stable oral pro-dispersion formulation with the following advantages:
  • API crystallization Physical Stability: preventing crystallization, ensures that the API remains in a stable state, which is indicated by a low Polydispersity Index (PDI) and uniform particle size throughout the shelf-life.
  • PDI Polydispersity Index
  • the formulations exhibit desirable technical attributes like shelf-stability, GIT- stability, sustained action, better absorption, and minimal gastro-intestinal toxicity.

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Abstract

La présente divulgation concerne une formulation de pro-dispersion orale stable, comprenant (i) un ingrédient pharmaceutique actif (API) ; (ii) un modificateur interfacial polymère spécialisé (SPIM) ; (iii) un lipide ; (iv) un tensioactif ; et (v) un solvant, et son procédé de préparation. La présente divulgation concerne en outre une capsule comprenant la formulation de pro-dispersion, son procédé de préparation et une méthode de traitement d'une affection à l'aide de la formulation ou de la capsule.
PCT/IN2025/050034 2024-01-13 2025-01-13 Formulation de pro-dispersion orale stable et ses mises en œuvre Pending WO2025150072A1 (fr)

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CN120585770A (zh) * 2025-08-11 2025-09-05 成都药宜立康医药科技有限公司 一种含有稳定剂的苯磺酸美洛加巴林片剂及其制备方法
CN120938940A (zh) * 2025-10-15 2025-11-14 成都药宜立康医药科技有限公司 一种苯磺酸美洛加巴林药物组合物及其制备方法

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WO2008031782A1 (fr) * 2006-09-12 2008-03-20 Glaxo Group Limited Composition pharmaceutique comprenant une pluralité de mini-comprimés contenant un inhibiteur du facteur xa

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US4690823A (en) * 1984-10-13 1987-09-01 Dolorgiet Beteiligungs-Gmbh Ibuprofen-containing soft gelatin capsules and process for preparing same
US6251426B1 (en) * 1999-09-02 2001-06-26 Banner Pharmacaps, Inc. Ibuprofen-containing softgels
WO2008031782A1 (fr) * 2006-09-12 2008-03-20 Glaxo Group Limited Composition pharmaceutique comprenant une pluralité de mini-comprimés contenant un inhibiteur du facteur xa

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120585770A (zh) * 2025-08-11 2025-09-05 成都药宜立康医药科技有限公司 一种含有稳定剂的苯磺酸美洛加巴林片剂及其制备方法
CN120938940A (zh) * 2025-10-15 2025-11-14 成都药宜立康医药科技有限公司 一种苯磺酸美洛加巴林药物组合物及其制备方法

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