WO2023187664A1 - A pharmaceutical composition for the treatment of immune system mediated diseases - Google Patents

A pharmaceutical composition for the treatment of immune system mediated diseases Download PDF

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Publication number
WO2023187664A1
WO2023187664A1 PCT/IB2023/053109 IB2023053109W WO2023187664A1 WO 2023187664 A1 WO2023187664 A1 WO 2023187664A1 IB 2023053109 W IB2023053109 W IB 2023053109W WO 2023187664 A1 WO2023187664 A1 WO 2023187664A1
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pharmaceutical composition
composition
salt
solvates
hydrates
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PCT/IB2023/053109
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French (fr)
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Mahesh Kandula
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Avaca Pharma Private Limited
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present disclosure generally relates to the field of pharmaceutical compositions.
  • the present disclosure provides a pharmaceutical composition comprising local anesthetic, corticosteroids and other agents in combination or as standalone.
  • the compositions of the present disclosure may find utility in treatment of allergic inflammatory conditions.
  • Eosinophilic esophagitis is an allergic inflammatory condition of the esophagus.
  • the esophagus In healthy individuals, the esophagus is typically devoid of eosinophils. Consumption of certain food triggers eosinophils migration to the esophagus in large numbers, leading to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartbum. EoE is not fully understood except that certain food and environmental allergens plays significant role.
  • EoE is poorly understood disease.
  • EoE is a chronic, T helper type 2 (Th2)-associated inflammatory disease characterized by predominant and marked eosinophilic inflammation of the esophagus.
  • EoE is characterized by a dense infiltrate of white blood cells of the eosinophil type into the epithelial lining of the esophagus. This may be due to an allergic reaction against ingested food, based on the important role eosinophils play in allergic reactions.
  • the eosinophils are recruited into the tissue in response to local production of eotaxin-3 by IL-13 stimulated esophageal epithelial cells.
  • Eosinophils are inflammatory cells that release a variety of chemical signals which inflame the surrounding esophageal tissue. The inflamed esophagus does not contract properly. It can get narrowed and develop rings or abscesses. This results in the signs and symptoms of pain.
  • Symptoms generally include difficulty in swallowing, food impaction, chest pain or heartburn, stomach pains, regurgitation or vomiting, decreased appetite and stunted growth or poor weight gain in children. It can happen at any age and affects both children and male adults.
  • Subjects with family history of EoE atopic dermatitis, asthma, or food or environmental allergies are more predisposed to developing EoE.
  • the commonly used treatment options may consist of avoiding known or suspected triggers and use of medication to suppress the immune response. In severe cases, it may be necessary to enlarge the esophagus with an endoscopy procedure.
  • the medication usually control the symptoms by decreasing the number of eosinophils in the esophagus and, subsequently, reducing the esophageal inflammation.
  • Management consists of dietary, pharmacological, and endoscopic treatment.
  • One of the objects of the present disclosure is to provide a pharmaceutical composition that may overcome the limitations associated with the conventional compositions.
  • Another object of the present disclosure is to provide a composition that exhibits superior storage stability, functional reciprocity and provide a composition that is easy to prepare and is economical.
  • composition that can be orally administered for targeted drug delivery.
  • composition that modifies the delivers of active ingredient: immediate release or modified release or local delivery formulation or to deliver at a specific rate, of different active agents so has to improves the local availability of the actives present in the composition.
  • Still another object of the present disclosure is to deliver the active agents either simultaneously or concurrently or concomitantly to a subject for treatment of an inflammatory disease.
  • the present disclosure generally relates to the field of pharmaceutical compositions.
  • the present disclosure provides a pharmaceutical composition comprising active agents which can target the pathophysiology of EoE.
  • the pharmaceutical composition comprises local anesthetic in combination with steroids, or their salt or hydrates or solvates thereof.
  • the pharmaceutical composition may comprise anti-inflammatory agents, or agents those that target key players in EoE inflammation pathways like IL-4, IL-5 or IL- 13 signaling or their salt or hydrates or solvates thereof.
  • the pharmaceutical composition may further comprise one or more other active agents such a melatonin or their salt or hydrates or solvates thereof.
  • local anesthetic or salt or hydrates or solvates thereof is present in an amount ranging from 25mg to 600 mg.
  • steroids or salt or hydrates or solvates thereof is present in an amount ranging from 0.005mg to 1000 mg.
  • melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg.
  • composition comprises lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 100 mg to 600 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
  • composition comprises lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 100 mg to 600 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with Melatonin or salt or hydrates or solvates thereof in an amount ranging from 1 mg to 100 mg.
  • composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25 mg to 100 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
  • composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25 mg to 100 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from 1 mg to 100 mg.
  • composition comprises ropivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg to 100 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
  • composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from Img to 100 mg.
  • the composition also includes a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is selected from any or a combination of: a diluent, an antioxidant, a preservative, an alkalizing agent, a buffering agent, a disintegrant, a binder, an antifoaming agent, a solvent, a glidant, a lubricant, a flavoring agent, a coating agent, a rate controlling polymer or non-polymer, a zinc salt, a fatty acid or derivative thereof, an amino acid or metabolites or derivative thereof, a bulking agent, an anti-tacking agent, an emulsifier, a surfactant, a plasticizer and a stabilizer and a film forming agents.
  • the fatty acid derivative includes any or a combination of: di glyceryl lauryl fumarate, di glyceryl lauryl succinate, and diglyceryl capryl succinate.
  • a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof and steroids or salt or hydrates or solvates thereof.
  • the composition comprises an intra-granular portion and an extra- granular portion, wherein the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient; in another aspect the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises and steroids or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient.
  • the intra-granular portion comprises steroid or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient
  • the extra-granular portion comprises and local anesthetic or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient
  • a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof and steroids or salt or hydrates or solvates thereof with melatonin or salt or hydrates or solvates thereof.
  • the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient or intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises melatonin or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient.
  • the composition is formulated to enhance drug delivery to specific regions in the GI tract.
  • the composition can be formulated into tablet, buccal tablet, sublingual tablet, lozenges film based, oral spray, or mucosal adhesive formulation for administering orally, topical and locally. Further the formulation is an modified release formulation which include, extended release, sustained release, delayed release or slow release.
  • the portions are compressed together to obtain any of: a tablet dosage form and an lozenge dosage form, and optionally coated with a seal coat.
  • the composition comprises local anesthetic in an amount of 100 mg to600 mg, steroid in an amount of 0.005 mg to 1000 mg and Melatonin in an amount of 1 mg to 100 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation or film based formulation.
  • the composition comprises local anesthetic in an amount of lOOmg to 600 mg and steroid in an amount of 0.005 mg to lOOOmg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation or film based formulation.
  • the composition is used in preparing the medicament for allergic inflammatory conditions such as Eosinophilic esophagitis (EoE) and asthma.
  • an oral pharmaceutical composition comprising: at least one local anesthetic in an amount of 25 mg to 600 mg, at least one steroid in an amount of 0.005 mg to 1000 mg, melatonin in an amount of 1 mg to 100 mg, and an excipient; or at least one local anesthetic in an amount of 25 mg to 600 mg, at least one steroid in an amount of 0.005 mg to 1000 mg and an excipient; or at least one local anesthetic in an amount of 25 mg to 600 mg, melatonin in an amount of 1 mg to 100 mg, and an excipient; or at least one steroid in an amount of 0.005 mg to 1000 mg, melatonin in an amount of 1 mg to 100 mg, and an excipient; or at least one steroid in an amount of 0.005 mg to 1000 mg, and an excipient.
  • the local anesthetic is selected from a group consisting of benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, amylocaine, oxybuprocain, articaine, bupivacaine, dibucaine, etidocaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, prilocaine, ropivacaine, sameridine, tonicaine and cinchocaine or their salt thereof.
  • the steroid are selected from a group consisting of hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone
  • the pharmaceutically acceptable excipient is selected from any or a combination of: disintegrant, binder, diluent, solvent, flavoring agent, glidant, lubricant, pH modifier, anti-foaming agent, fatty acid derivatives, antioxidant or a combination thereof.
  • the disintegrants is croscarmellose sodium or aerosil.
  • the binder is hypromellose.
  • the diluent is mannitol, xylitol, heavy magnesium oxide or calcium carbonate.
  • the solvent is alcohol, ethanol, or water.
  • the flavoring agent is organ or peppermint.
  • the glidants is colloidal silicon dioxide.
  • the lubricant is steric acid or zinc stearate.
  • the anti-foaming agent is simethicone 30% emulsion.
  • the pH modifier is L-Camosine
  • the antioxidant is citric acid, D-Panthenol, calcium D-Panthenol.
  • the fatty acid derivatives are selected from a group consisting of diglyceryl lauryl fumarate, diglyceryl lauryl succinate, diglyceryl capryl succinate, diglyceryl capryl fumarate or a combination thereof.
  • the oral pharmaceutical composition comprises of mometasone furoate, croscarmellose sodium, hypromellose, mannitol, xylitol, ethanol, peppermint flavor, colloidal silicon dioxide, and stearic acid.
  • the oral pharmaceutical composition comprises of bupivacaine hydrochloride, mometasone furoate, mannitol, xylitol, croscarmellose sodium, hypromellose, alcohol, colloidal silicon dioxide, peppermint flavor and stearic acid.
  • the oral pharmaceutical composition comprises of mannitol, 1- camosine, heavy magnesium oxide, calcium carbonate, croscarmellose sodium, calcium D- pantothenate, hypromellose, simethicone 30% emulsion, purified water, lidocaine hydrochloride monohydrate, melatonin, mannitol, colloidal silicon dioxide, zinc stearate, and peppermint flavor.
  • the oral composition is a lozenge.
  • the present disclosure generally relates to the field of pharmaceutical compositions.
  • an active agent or “an active ingredient” refers not only to a single active agent but also to a combination of two or more different active agents
  • a dosage form refers to a combination of dosage forms as well as to a single dosage form, and the like.
  • active agent or “therapeutic agent”, encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • combination therapy denotes any form of concurrent or concomitantly or co-administration of active agents for treating allergic inflammatory conditions affecting the oral and gastrointestinal tracts such as eosinophilic esophagitis (EoE), allergies, eczema, hives, psoriasis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, diseases of the esophagus, such as esophageal lichen planus, preferably eosinophilic esophagitis (EoE).
  • active agents for treating allergic inflammatory conditions affecting the oral and gastrointestinal tracts such as eosinophilic esophagitis (EoE), allergies, eczema, hives, psoriasis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, diseases of the esophagus, such as esophageal lichen planus, preferably eosinophilic es
  • treating and “treatment” as used herein refers to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage caused thereby.
  • “treating” a subject/patient as described herein encompasses treating oral, gastrointestinal and esophageal diseases such as eosinophilic esophagitis (EoE), asthma, gastric esophagitis and related diseases.
  • EoE eosinophilic esophagitis
  • asthma gastric esophagitis
  • drug form denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to elicit a desired therapeutic response.
  • controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate.
  • controlled release includes sustained release, non-immediate release, extended release, slow release and delayed release formulations.
  • sustained release (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time.
  • pharmaceutically acceptable means the material incorporated into a pharmaceutical composition that can be administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • pharmaceutically acceptable refers to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • “Pharmacologically active” as in a pharmacologically active derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
  • Pharmacologically active agents or API or active agents include local anesthetic agents, steroids, and melatonin. Further, it may further include anti-inflammatory agents specifically target key players in EoE inflammation pathways like IL-4, IL-5 or IL- 13 signaling.
  • the local anesthetic agents includes benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, amylocaine, oxybuprocain, articaine, bupivacaine, dibucaine, etidocaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, prilocaine, ropivacaine, sameridine, tonicaine and cinchocaine or their salt or hydrates or solvates thereof.
  • the steriod agents particularly corticosteroids includes hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone
  • IL4, IL5 and IL 13 inhibitors have been shown to reduce circulating eosinophil counts rapidly in humans with various disorders.
  • other agents which blocks IL4, IL5, IL13, TGF-beta and TSLP includes anrukinzumab, omalizumab, benralizumab, mepolizumab, reslizumab, lebrikizunab, lerdelimumab, metelimimab, rosiglitazone, tranilast, bimekizumab, brodalumab, cinqair, cosentyx, dupilumab, dupixent and tralokinumab.
  • Eosinophilic esophagitis is a multifactorial esophageal inflammation, with a genetic predisposition, which combines a deficient esophageal mucosal barrier, an abnormal immune reaction to environmental or food allergens mediated by Th2 interleukins, immediate esophageal lesions and dysmotility, with secondary remodeling and fibrosis.
  • Eosinophils are considered the main effector cells in fibrosis in a variety of hypereosinophilic syndromes and eosinophil-related allergic diseases including asthma and EoE. Thus it is important to target fibrosis reversal in treatment of EoE, but also underline the importance of eosinophils in tissue remodeling.
  • the mechanism of action of using steroid therapy in EoE is mainly based on the reduction of inflammatory cells and fibrosis with significant decrease of esophageal eosinophils, mast cells, T-cells and proinflammatory cytokines as well as restoration of epithelial barrier function and reduction of tissue remodeling. Most common side effect of steroid therapy is Candida esophagitis. Further, in EoE, the damage and inflammation, can cause pain and may lead to trouble swallowing. Children with EoE have frequent sleep complaints and several sleep disorders.
  • Present invention provides a fixed dose composition which address various pathophysiological aspect of EoE.
  • the composition comprises local anesthetics which can reduced the pain.
  • the steroid in the composition can reduces the inflammatory cells, restores the epithelial barrier function, reverse the fibrosis, decrease eosinophil numbers in the esophageal epithelium but also to reduce epithelial cell apoptosis and to decrease esophageal molecular remodeling. Steroid further downregulate the response of mast cells
  • Further melatonin used in the composition can address the sleep complaints in the subjects with EoE.
  • Present Fixed dose composition can be used in other inflammatory diseases such as allergies, eczema, hives, psoriasis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, preferably eosinophilic esophagitis (EoE).
  • inflammatory diseases such as allergies, eczema, hives, psoriasis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, preferably eosinophilic esophagitis (EoE).
  • local anesthetic or salt or hydrates or solvates thereof is present in an amount ranging from 25mg to 600 mg.
  • steroids or salt or hydrates or solvates thereof is present in an amount ranging from 0.005mg to 1000 mg.
  • melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg.
  • composition comprises lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from lOOmg to 600 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
  • composition comprises lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 1 OOmg to 600 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from 1 mg to 100 mg.
  • composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
  • composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from Img to 100 mg.
  • composition comprises ropivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
  • composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from Img to 100 mg.
  • the composition also includes a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is selected from any or a combination of: a diluent, an antioxidant, a preservative, an alkalizing agent, a buffering agent, a disintegrant, a binder, an antifoaming agent, a solvent, a glidant, a lubricant, a flavoring agent, a coating agent, a rate controlling polymer or non-polymer, a zinc salt, a fatty acid or derivative thereof, an amino acid or metabolites or derivative thereof, a bulking agent, an anti-tacking agent, an emulsifier, a surfactant, a plasticizer and a stabilizer and a film forming agents.
  • the fatty acid derivative includes any or a combination of: di glyceryl lauryl fumarate, di glyceryl lauryl succinate, and diglyceryl capryl succinate.
  • a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof and steroids or salt or hydrates or solvates thereof.
  • the composition comprises an intra-granular portion and an extra- granular portion, wherein the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient; in another aspect the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises and steroids or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient.
  • the intra-granular portion comprises steroid or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient
  • the extra-granular portion comprises and local anesthetic or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient
  • a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof and steroids or salt or hydrates or solvates thereof with melatonin or salt or hydrates or solvates thereof.
  • the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient or intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises melatonin or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient.
  • the composition is formulated to enhance drug delivery to specific regions in the GI tract.
  • the composition can be formulated into tablet, buccal tablet, sublingual tablet, film based, oral spray, orodispersible tablets or mucosal adhesive formulation for administering orally, topical and locally to target the GI tract.
  • the formulation is an modified release formulation which include, extended release, sustained release, delayed release or slow release.
  • the portions are compressed together to obtain any of: a tablet dosage form and a lozenge dosage form optionally coated with a seal coat.
  • the composition comprises local anesthetic in an amount of lOOmg to-600 mg, steroid in an amount of 0.005 mg to lOOOmg and melatonin in an amount of 3 mg- 100 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation or film based formulation.
  • the composition comprises local anesthetic in an amount of lOOmg to 600 mg and steroid in an amount of 0.005 mg to lOOOmg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation or film based formulation.
  • the composition is formulated to enhance drug delivery to specific regions in the GI tract.
  • the upper GI tract consists of the mouth, pharynx, esophagus, stomach, and the first part of the small intestine (duodenum), whereas the lower GI tract includes the other parts of the small intestine (jejunum and ileum) and the large intestine (cecum, colon, and rectum).
  • Manipulating the formulation can control the dissolution rate and where the drug is released in the GI tract for subsequent absorption. Their design is based on exploiting physiological conditions in the GI tract. By using modified formulations, it is possible to improve targeting the GI tract. Present composition ensures prolonged exposure of the active agent to esophageal mucosa.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising: local anesthetics or salt or hydrates or solvates thereof, steroid or salts or hydrate or solvates thereof and melatonin or salt or hydrates or solvates thereof.
  • the composition is a fixed dose combination.
  • the compositions of the present disclosure may find utility in treatment of inflammatory conditions affecting the GI tract particularly esophagus. It further, provides an fixed dose composition that significantly lower systemic bioavailability, with better safety profile and patient compliance.
  • lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 100 mg to 600 mg.
  • mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg-lOOOmg.
  • melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg.
  • lidocaine or salt or hydrates or solvates thereof is present in the composition in an amount of 100 mg to 600 mg.
  • Lidocaine or salt or hydrates or solvates thereof is present in an amount of 100 mg to 400 mg.
  • either of the three drug actives melatonin, mometasone or lidocaine are given simultaneously as individual formulations/compositions or three drug actives are given in a combination to a subject suffering from a disease.
  • either of the two drug actives mometasone or lidocaine are given simultaneously as individual formulations/compositions or two drug actives are given in a combination to a subject suffering from a disease.
  • bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25 mg to 100 mg.
  • mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
  • melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg.
  • either of the three drug actives melatonin, mometasone and bupivacaine are given simultaneously as individual formulations/compositions or three drug actives are given in a combination to a subject suffering from a disease.
  • either of the two drug actives mometasone and bupivacaine are given simultaneously as individual formulations/compositions or two drug actives are given in a combination to a subject suffering from a disease.
  • ropivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25 mg to 100 mg.
  • mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
  • melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg.
  • either of the three drug actives melatonin, mometasone or ropivacaine is given simultaneously as individual formulations/compositions or three drug actives are given in a combination to a subject suffering from a disease.
  • either of the two drug actives mometasone or ropivacaine is given simultaneously as individual formulations/compositions or two drug actives are given in a combination to a subject suffering from a disease.
  • local anesthetic, steroid and melatonin is formulated as individual formulations/compositions in titrated strengths or binary mixture compositions or a fixed dosage combination for the treatment of a disease/condition in a human subject.
  • the composition also includes a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient may be selected from any or a combination of: a diluent, an anti-oxidant, a preservative, an alkalizing agent, a buffering agent, a disintegrant, a binder, an anti -foaming agent, a solvent, a glidant, a lubricant, a flavoring agent, a sweetener, a coating agent, a rate controlling polymer or non-polymer, a zinc salt, a fatty acid or derivative thereof, an amino acid or metabolites or amino acid derivatives, a bulking agent, an anti-tacking agent, an emulsifier, a surfactant, a plasticizer, film forming agents, mucosal-adhesive agents and a stabilizer.
  • the pharmaceutically acceptable excipient may be selected disintegrant, binder, diluent, solvent, flavoring agent, glidant, lubricant, pH modifier, antifoaming agent and antioxidant.
  • the diluent(s) include(s), but not limited to, dicalcium phosphate dihydrate, calcium sulfate, calcium carbonate, heavy magnesium oxide, lactose, sucrose, mannitol, xylitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, and magnesium aluminum silicate and mixtures thereof.
  • the anti-oxidant(s) and preservative(s) include(s), but not limited to, L- Carnosine, vitamin A, vitamin E, vitamin C, D-Panthenol, Calcium D-Panthenol, retinyl palmitate, and selenium, citric acid, Citric acid anhydrous, sodium citrate, methyl paraben, propyl paraben, p-hydroxybenzoic acid esters, sorbic acid, benzoic acid, propionic acid or salts thereof; Alcohols such as benzyl alcohol, butanol or ethanol, isopropyl alcohol, and quaternary ammonium compounds such as benzalkonium chloride, sodium benzoate and mixtures thereof.
  • the alkalizing agent(s) include(s), but not limited to, ammonia solution NF, Ammonium Carbonate NF, Diethanolamine NF, monoethanolamine, Potassium Hydroxide NF, Sodium Bicarbonate USP, Sodium Borate NF, Sodium Carbonate NF, Sodium Hydroxide NF, sodium Phosphate Dibasic USP, trolamine NF, calcium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium trisilicate, aluminum hydroxide, aluminum carbonate, magnesium aluminium silicate hydrate, potassium bicarbonate, sodium bicarbonate, sodium citrate, potassium citrate, aluminum sulfate, calcium carbonate and mixtures thereof.
  • the buffering agent(s) include(s), but not limited to, a bicarbonate salt of alkali earth metal, amino acids, an acid salt of an amino acid, an alkali salt of an amino acid and mixture thereof.
  • the disintegrant(s) include(s), but not limited to Croscarmellose sodium, microcrystalline cellulose, Aerosil, low- substituted hydroxypropyl cellulose, alginic acid and alginates, modified starches, sodium starch glycolate, sodium carboxy methyl cellulose, carboxymethyl cellulose calcium, polyvinylpyrrolidone, docusate sodium, guar gum and mixtures thereof.
  • the binder(s) include(s), but not limited to, hypromellose (or hypromellose 5 cps), polyvinyl pyrrolidone, copolymers of vinyl pyrrolidone with other vinyl derivatives, hydroxypropyl cellulosic derivatives (such as methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose etc), polyacrylates (such as Carbopol, polycarbophil, etc), Povidone (all grades), Polyox of any molecular weight or grade, irradiated or not, maize starch, povidone, copovidone, corn starch, starch, polyvinylpyrrolidone (PVP), microcrystalline cellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates, starch, heavy magnesium oxide and mixtures thereof.
  • hypromellose or hypromellose 5
  • the anti-foaming agent(s) include(s), but not limited to, alcohols such as cetostearyl alcohol, insoluble oils such as castor oil, stearates, polydimethylsiloxanes and other silicones derivatives, ethers, paraffin oil, paraffin wax, glycols, simethicone (or simethicone 30% emulsion) and mixtures thereof.
  • alcohols such as cetostearyl alcohol
  • insoluble oils such as castor oil, stearates, polydimethylsiloxanes and other silicones derivatives
  • ethers such as paraffin oil, paraffin wax, glycols, simethicone (or simethicone 30% emulsion) and mixtures thereof.
  • solvent(s) include(s), but not limited to, methanol, ethanol, npropanol, isopropanol, hexane, heptane, petroleum ether, cyclohexane, diethyl ether, diisopropyl ether, ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone, 1,4- dioxane, toluene, ammonia solution, glacial acetic acid, ammonium hydroxide, sodium hydroxide, calcium hydroxide, calcium carbonate, potassium hydroxide, potassium carbonate, water and mixtures thereof.
  • the glidant(s) include(s), but are not limited to, colloidal silicon dioxide, stearic acid, talk, aluminum silicate and mixtures thereof.
  • the lubricant(s) include(s), but not limited to, stearic acid, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, zinc stearate, calcium stearate, silica, talc, polyethylene glycol, paraffin and mixtures thereof.
  • the flavoring agent(s) include(s), but not limited, cherry, maple, pineapple, orange, raspberry, banana-vanilla, peppermint, butterscotch, strawberry, vanilla, apricot, cinnamon, honey, lime, peach-orange, peach-rum, raspberry, wild cherry, mint and mixtures thereof.
  • coating agent(s) include(s), but not limited to, cellulosics, such as hydroxypropyl methyl cellulose (HPMC), methy ethylcellulose (MEC), carboxymethyl celluolose (CMC), carboxymethyl ethylcelluolose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hypromellose, povidone, copovidone, and ethyl cellulose (EC); vinyls, such as polyvinyl alcohol; acrylics, such as methacrylic acid / ethylacrylate copolymers (often used for enteric or delayed release coatings), natural derivatives, such as shellac or alginate and mixtures thereof.
  • cellulosics such as hydroxypropyl methyl
  • the rate controlling polymer(s) include(s), but not limited to, cellulose acetate, alkyl celluloses, hydroxyalkyl, acrylic polymers, copolymers dialkylphthalates, dibutyl phthalate, microcrystalline wax and mixtures thereof.
  • the rate controlling non-polymer(s) include(s), but not limited to, fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester and mixtures thereof.
  • zinc salt(s) include(s), but not limited to, zinc oxide, zinc stearate, zinc L-camosine, zinc acetate, zinc chloride, zinc bromide, zinc fluoride, zinc hexafluorosilicate, zinc iodide, zinc molybdate, zinc nitrate, zinc molybdite, zinc oxalate, zinc perchlorate, zinc tetrafluorob orate, zinc sulfate and mixtures thereof.
  • the fatty acid(s) or derivatives thereof include(s), but not limited to, fatty acids with Cl to C30 carbons, which includes long chain fatty acids; saturated or unsaturated fatty acids and derivatives thereof (monounsaturated fatty acids (MUFAs) C18: lnl2c, C16: ln-5, C16:4n-1 and the polyunsaturated fatty acids (PUFAs) C16:3n-4, C20:3n-3, C20:4n-6, C21 :5n-3 and C18:2n-9c,12t); hydrogenated fatty acids; fatty acid glycerides; polyoxyethylated oleic glycerides; monoglycerides and diglycerides; mono-, bi- or tri -substituted glycerides; glycerol mono-oleate esters; glycerol mono-caprate; glyceryl monocaprylate; dicaprylate; la
  • the fatty acid derivatives includes any or a combination of: di glyceryl lauryl fumarate (DGLF), diglyceryl lauryl succinate, diglyceryl capryl succinate, and diglyceryl capryl fumarate, and the same can be used in the composition to either delay disintegration and/or absorption and thereby provide sustained action over a longer period.
  • DGLF di glyceryl lauryl fumarate
  • diglyceryl lauryl succinate diglyceryl capryl succinate
  • diglyceryl capryl fumarate diglyceryl capryl fumarate
  • the amino acids or metabolites or amino acid derivatives include(s), but not limited to, glycine, glutamine, asparagine, arginine, lysine in biologically active enantiomeric forms, L-camosine, L-carnitine, choline, betaine, taurine, glycosaminoglycans including hyaluronic acid, chondroitin sulfate, glucosamine, L glucosamine, heparins and mixtures thereof.
  • the bulking agent(s) include(s), but not limited to, lactose USP, Starch 1500, mannitol, erythritol, sorbitol, maltodextrin, malitol or other non-reducing sugars; microcrystalline cellulose (e.g., Avicel), dibasic calcium phosphate (anhydrous or dihydrate), sucrose, etc. and mixtures thereof.
  • the anti -tacking agent(s) include(s), but not limited to, stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; sodium benzoate; sodium acetate and mixtures thereof.
  • the surfactant(s) and emulsifier(s) include(s), but not limited to, ionic or non-ionic surfactants and emulsifiers, poloxamers, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylated, hydrogenated castor oil and mixtures thereof.
  • the plasticizer(s) include(s), but are not limited to, diethyl phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, polyethylene glycol, dichloromethane, acetone, ethanol, methanol, isopropyl alcohol, water and mixtures thereof.
  • the stabilize ⁇ s) include(s), but not limited to, gums, agar, taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins and mixtures thereof.
  • the sweetener(s) include(s), but not limited to, mannitol, sorbitol, polyethylene glycol (PEG) 6000 and 8000, Emdex, Nu-tab, sweetrex, Mola-tab, Hony-tab, Sugartab, non-sugar sweetening agents such as aspartame, sorbitol, xylitol, isomalt, saccharin, sodium saccharin, calcium saccharin, sucralose, acesulfame-K, steviol, steviosin, mannitol, erythritol, lactitol, and sugar sweetening agents such as sucrose, fructose, dextrose and mixtures thereof.
  • the film forming agent(s) include(s), but not limited to, polymers such as ethylcellulose, hydroxypropylmethylcellulose (HPMC), Na-CMC, chitosan, Tween 80, PEG 400, cyclodextrin, gellan gum, xanthan gum, carbopol, Eudragit, Eudragit EPO, Eudragit E 100, Eudragit S 100, Eudragit RL 100, Eudragit RS 100, dermacryl, lutrol F-127, plasdone, Kollidon, polyvinyl alcohol, polyisobutylene, polyvinyl pyrrolidone, polymethacrylates and others.
  • polymers such as ethylcellulose, hydroxypropylmethylcellulose (HPMC), Na-CMC, chitosan, Tween 80, PEG 400, cyclodextrin, gellan gum, xanthan gum, carbopol, Eudragit, Eudragit EPO, Eudragit E 100, Eu
  • any other excipient known to or appreciated by a skilled person can also be used to realize the advantageous compositions of the present disclosure.
  • Examples of useful excipients which can optionally be added to the composition are described in the Handbook of Pharmaceutical Excipients, 3rd edition, Edited by A. H. Kibbe, Published by: American Pharmaceutical Association, Washington DC, ISBN: 0-917330-96-X, and in Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond C Rowe - Publisher: Science and Practice.
  • the pharmaceutical composition may be formulated as a solid, semi-solid or liquid dosage form.
  • dosage forms includes tablet, lozenge, capsule, caplet, modified release tablet or lozenge, subligual tablet, orally disintegrating tablets, orodispersible tablets, suspension, solution, emulsion, suppository, granules, pellets, beads, powder, aerosol sprays (oral, nasal), patches, pre-filled syringe, pre-filled pen, gel, tablet in tablet, bilayer tablet, trilayer tablet, inlay tablet, capsule in capsule, tablet(s) in capsule, granules and/or pellets in capsule, pellets and tablet in capsules and the likes.
  • a fixed dose pharmaceutical composition comprising local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof, and Melatonin or salt or hydrates or solvates thereof, wherein the composition is formulated into a chewy or hard or caramel based lozenge, pastilles, troches, soft lozenge, center or liquid filled lozenge, power based lozenge, compressed lozenge, syrup based lozenge, granulated lozenge, buccal and sublingual tablets.
  • the lozenge formulation of the present disclosure may increase bioavailability, and affords immediate relief from pain.
  • Lozenge dosage forms are easy to administer for geriatric and pediatric patients who can’t swallow tablets formulation. This formulation may help to keep the drug in contact to the oral cavity for longer time.
  • the lozenge may be formulated as a modified release formulation (modified release can be controlled release, immediate release, phased release, timed release, sustained release, delayed release or a combination of immediate or quick or fast and sustained or slow or extended release).
  • modified release can be controlled release, immediate release, phased release, timed release, sustained release, delayed release or a combination of immediate or quick or fast and sustained or slow or extended release.
  • the lozenge can be formulated as a bi-layer, tri-layer tablet or multi-layer tablet to facilitate the delivery of at least two or more active agents.
  • the carrier material for lozenge preparation includes sugar such as sucrose, dextrose, etc.
  • sugar such as sucrose, dextrose, etc.
  • sugar-free products including sugar-free medications.
  • Pharmaceutical manufacturers have attempted to find alternative carrier bases in order to provide sugar-free lozenges.
  • One such alternative carrier is a polyhydric alcohol such as xylitol.
  • Polyhydric alcohols are considered as a viable alternative because they provide a sweet taste will mask the bitter taste of many medicinal agents. Lozenges made from polyhydric alcohols do suffer from one serious disadvantage. They dissolve very rapidly when placed in the oral cavity.
  • a lozenge made from a xylitol based carrier will dissolve completely within approximately 3 minutes of administration.
  • Other polyhydric alcohols such as sorbitol or mannitol will also dissolve within 3 minutes of administration.
  • the medicinal agents are released so rapidly that a large percentage of the dose is washed into the patient’s alimentary canal rather than having an opportunity to come in contact with the tissues of the oral cavity, which are under treatment.
  • non-limiting examples of excipients for preparing a compressed powder lozenge or compressed granulated lozenge, cast lozenge includes at least one diluents, at least one fillers, at least one glidants, at least one lubricants, at least one binders, at least one preservatives, at least one artificial or natural sweeteners or and at least one aroma or flavoring compounds.
  • the lozenge may be formulated as a modified release formulation (modified can be controlled release, immediate release, phased release, timed release, sustained release, delayed release or a combination of immediate or quick or fast and sustained or slow or release).
  • modified can be controlled release, immediate release, phased release, timed release, sustained release, delayed release or a combination of immediate or quick or fast and sustained or slow or release.
  • the lozenge can be formulated as a bi-layer, tri-layer tablet or multi-layer tablet to facilitate the delivery of at least two or more active agents.
  • compositions are formulated as cast lozenges comprising at least one base selected from fructo-oligosaccharides, crystalline sugar, candy base, isomalt or stevia; at least one aromas selected from natural aroma, essential oils such as citrus, mint oils, terpenes and sesquiterpenes, organic acids, alcohols, aldehydes, liquorice powder, menthol, peppermint oil or any fruit flavors; at least one taste enhancing ingredient such as saccharose, glutamic acid, E621 monosodium glutamate, MSG, E622 monopotassium glutamate, E623 calcium diglutamate, E625 Magnesium diglutamate); guanylic acid (a ribonucleotide) and its salts (E626 guanylic acid, E627 disodium guanylate, sodium guanylate, E628 dipotassium guanylate, E629 calcium guanylate); E630 inosinic acid, E
  • a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof, wherein the composition is formulated into a tablet dosage form.
  • the tablet may be a monolayer tablet comprising local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof distributed uniformly.
  • the tablet may be a bilayer tablet comprising anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof in any of a first layer and a second layer.
  • the tablet may be a trilayer tablet comprising anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in any of a first layer, a second layer and a third layer.
  • the tablet may be a press-coated tablet, i.e. a small tablet and a granulation or a blend is compressed together to one large press-coated tablet. All types of the tablets mentioned hereinbefore may be without a coating or may have one or more coatings, in particular film coatings.
  • the tablet-in-tablet dosage form may be prepared by compressing active ingredients with one or more rate controlling polymer or non-polymer to form a core extended release tablet; and compressing active ingredients optionally along with one or more pharmaceutically acceptable excipient onto said core tablet to form compressed tablet that causes immediate release of the active ingredients.
  • the pharmaceutical composition is formulated as an inlay tablet.
  • Inlay tablets are tablets, wherein inner tablet is positioned within a comparatively larger outer tablet in such a way that at least one surface of the inner tablet is not in contact with outer tablet.
  • Inlay tablet dosage form includes: (a) an inner inlay ed tablet comprising active ingredients and excipient(s) that causes extended release; and (b) an outer tablet comprising active ingredients along with excipient(s) to cause immediate release.
  • the present disclosure embraces capsule-in-capsule formulations, wherein smaller size capsule is encapsulated into a larger capsule.
  • Capsule-in -capsule consists of an external capsule and internal capsule (inner capsule) located therein. It is preferred that smaller size capsule is filled with active ingredients and excipients so as to cause extended release while larger capsule is filled, optionally, with active ingredients along with excipients for immediate release.
  • the tablet of the present disclosure may be monolithic that means having a homogenous matrix of active ingredient and pharmaceutically acceptable excipients. Alternatively, the tablet may be formed as a bilayer, wherein the one layer is having active ingredients along with pharmaceutically acceptable excipients and other layer is having pharmaceutically acceptable excipients. Alternatively, both layers of bilayer tablet may contain active ingredients.
  • the composition can be made by different manufacturing processes such as by direct compression wet granulation, dry granulation, melt granulation, melt congealing process, extrusion and the likes.
  • the composition cores may be mono or multi-layer(s) and can be coated with appropriate overcoats as known in the art.
  • Wet granulation involves formation of granules using active ingredient and/or one or more pharmaceutically acceptable excipients and this portion can be termed as intra-granular portion. These granules are then lubricated with active ingredient and/or a blend of excipients comprising lubricant and this lubricant blend is then compressed to form a tablet. The portion outside the granules can be referred as extra-granular portion.
  • Direct compression on the other hand requires only that the active ingredient is blended with one or more pharmaceutically acceptable excipients before compression and then compressed into tablet.
  • a fixed dose pharmaceutical composition comprising local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient.
  • a fixed dose pharmaceutical composition comprising local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, and wherein the intra-granular portion comprises local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient.
  • Composition can be formulated with the active agent in the intra-granular and extra-granular portion along with pharmaceutically excipient agent as per the formulation art. Further the composition can include one or more other agents which can inhibit the inflammatory cells such as IL 4, IL 5, IL 13, TGF-beta, TSLP and agents which can reduced the eosinophil.
  • agents which can inhibit the inflammatory cells such as IL 4, IL 5, IL 13, TGF-beta, TSLP and agents which can reduced the eosinophil.
  • the portions are compressed together to obtain any of: a tablet dosage form and a Lozenge dosage form, optionally coated with a seal coat.
  • the seal coat is an aqueous seal coat.
  • All types of the tablets mentioned hereinabove may be without a coating or may have one or more coatings, in particular film-coatings.
  • a film coating is useful in limiting photolytic degradation and/or in limiting degradation of moisture sensitive materials.
  • the tablet may be coated to delay disintegration and absorption and thereby provide sustained action over a longer period.
  • film coating includes glyceryl monostearate or glyceryl distearate, polyvinyl alcohol based, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, plyethyelene glycol 4000 and cellulose acetate phthalate film coating.
  • the patient may receive the specific dosage over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years and the like.
  • the choice of appropriate dosages for the drugs used in combination therapy according to the present disclosure can be determined and optimized by the skilled artisan, e.g., by observation of the patient, including the patient's overall health, the response to the combination therapy, and the like. Optimization, for example, may be necessary if it is determined that a patient is not exhibiting the desired therapeutic effect or conversely, if the patient is experiencing undesirable or adverse side effects that are too many in number or are of a troublesome severity.
  • compositions of the present disclosure in unit dosage form for ease of administration and uniformity of dosage.
  • the specifications of the dosage unit forms of the present disclosure are dependent on the unique characteristics of the composition and the particular therapeutic effect to be achieved. Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients. Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.:
  • Step 1 Synthesis of 2-oxopropane- 1,3 -diyl dioctanoate (3): To an ice cold solution of l,3dihydroxypropan-2-one (1, 25.0 g, 0.277 mol) in dichloromethane (500 mL) was added 4dimethylaminopyridine (10.17 g, 0.083 mol) and pyridine (49.2 mL, 0.610 mol) and stirred for next 5 min. To the above mixture octanoyl chloride (2, 105.4 mL, 0.610 mol) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 16h.
  • reaction mixture was filtered; the solid was washed with di chloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HC1 solution (100 mL). Organic layer was separated and dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude.
  • the crude was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in hexanes to afford the desired product as white solid. Yield: 70.0 g, 73%.MS (ESI) m/z 343.19[M+1] + ; T H
  • Step 2 Synthesis of 2-hydroxypropane- 1,3 -diyl dioctanoate (4): To an ice cold solution of 2oxopropane- 1,3 -diyl dioctanoate (3, 70.0 g, 0.204 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL), followed by the portion wise addition of sodium cyanoborohydride (15.43 g, 0.245 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL).
  • Step 3 Synthesis of 4-((l,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (6): To a solution of 2-hydroxypropane- 1,3 -diyl dioctanoate (4, 50.0 g, 0.145 mol) in chloroform (200 mL), dihydrofuran-2, 5-dione (5, 17.44 g, 0.174 mol) and triethylamine (30.0 mL, 0.218 mol) were added at room temperature. The reaction mixture was stirred at 120 °C for 3h.
  • reaction mixture was diluted with water (200 mL) and extracted with 1,2 di chloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 10 to 15% ethyl acetate in hexanes to affored the desired product 6 as white solid.
  • Step 1 Synthesis of 2-oxopropane- 1,3 -diyl didodecanoate (3 A): To an ice cold solution of l,3-dihydroxypropan-2-one (1, 30.0 g, 0.33 mol) in dichloromethane (500 mL) was added 4dimethylaminopyridine (20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred for next 5 min. To the above mixture dodecanoyl chloride 2A (218.50 g, 1.167 mol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16h.
  • 4dimethylaminopyridine 20.30 g, 0.167 mol
  • pyridine 107 mL, 0.1.332 mol
  • reaction mixture was filtered; the solid was washed with di chloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HC1 solution (100 mL). Organic layer was separated and dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was triturated with diethyl ether to afford the desired product 3 A as white solid.
  • Step 2 Synthesis of 2-hydroxypropane- 1,3 -diyl didodecanoate (4A): To an ice cold solution of 2-oxopropane- 1,3 -diyl didodecanoate 3 A (75.0 g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium cyanoborohydride (12.41 g, 0.198 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL).
  • Step 3 Synthesis of 4-((l,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (6A): To a solution of 2 -hydroxypropane- 1,3 -diyl didodecanoate 4A (40.0 g, 0.087 mol) in chloroform (200 mL), dihydrofuran-2, 5-dione 5 (10.50 g, 0.105 mol) and triethylamine (18.50 mL, 0.131 mol) were added at room temperature. The reaction mixture was stirred at 120°C for 3h.
  • reaction mixture was diluted with water (200 mL) and extracted with 1,2 dichloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 25 to 30% ethyl acetate in hexanes to afford the desired product 6A as white solid. Yield: 20.0 g, 41%.
  • Step 1- Synthesis of 2-oxopropane- 1,3 -diyl didodecanoate (3*): To an ice cold solution of l,3dihydroxypropan-2-one (1, 30.0 g, 0.33 mol) in dichloromethane (500 mL) was added 4dimethylaminopyridine (20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred for next 5 min. To the above reaction mixture dodecanoyl chloride 2 (218.50 g, 1.167mol) was added dropwise at 0°C and the reaction mixture was stirred at room temperature for 16h.
  • reaction mixture was filtered, the solid was washed with dichloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HC1 solution (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was triturated with diethyl ether to afford the desired product 3 * as white solid. Yield: 78 g, 51%.
  • Step-2 Synthesis of 2-hydroxypropane- 1,3 -diyl didodecanoate (4*): To an ice cold solution of 2-oxopropane- 1,3 -diyl didodecanoate 3 (75.0 g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium cyanoborohydride (12.41 g, 0.198 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL).
  • Step-3 Synthesis of (E)-4-((l,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid (6*): To an ice-cold solution of 2-hydroxypropane- 1,3 -diyl didodecanoate 4 (10.0 g, 21.91 mmol) in THF (170 mL) was added fumaric acid 5 (2.54 g, 21.91 mmol), benzoyl chloride (2.5 mL, 21.91 mmol) and DMAP (0.67 g, 5.477 mmol). The resulting mixture was stirred at RT for 16h.
  • reaction mixture was concentrated under reduced pressure.
  • the crude was diluted with water (200 mL), adjust pH ⁇ 2-3 using 1N-HC1 and extracted with 1,2 di chloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 80% ethyl acetate in hexanes to afford the desired product 6* as white solid. Yield: 400 mg, 3.30% (un-optimized yield).
  • LC-MS m/z 553.64[M-1]; 97.27% purity.
  • Composition 4 Composition comprising Bupivacaine HC1 and Mometasone
  • step 4 Dried the wet mass of step 4 at 40°C for 1 hr
  • step 6 Add the extragranular material to step 6 and blend for 10 min.
  • Composition 5 Composition comprising Bupivacaine HC1 and Mometasone
  • API was mixed in geometric ratio with step 2 blend
  • Composition 6 Composition comprising Lidocaine and Melatonin
  • Composition 7 Composition comprising Lidocaine and Melatonin
  • Composition 8 Composition comprising Lidocaine and Melatonin
  • Composition 9 Composition comprising Lidocaine and Melatonin
  • Composition 10 Composition comprising Lidocaine and Melatonin
  • Composition 11 Composition comprising Lidocaine and Melatonin
  • Composition 12 Composition comprising Lidocaine and Melatonin
  • Composition 13 Composition comprising Lidocaine and Melatonin
  • Composition 14 Composition comprising Lidocaine and Melatonin
  • Composition 15 Composition comprising Lidocaine and Melatonin
  • Composition 16 Composition comprising Lidocaine and Melatonin
  • Composition 17 Composition comprising Lidocaine and Melatonin
  • Composition 18 Composition comprising Lidocaine and Melatonin.
  • Composition 19 Composition comprising Lidocaine and Melatonin.
  • Composition 20 Composition comprising Lidocaine and Melatonin.
  • Composition 21 Composition comprising Lidocaine and Melatonin.
  • Composition 22 Composition comprising Lidocaine and Melatonin.
  • Composition 23 Composition comprising Lidocaine and Melatonin.
  • composition 24 Composition comprising Lidocaine and Melatonin.
  • Composition 24 Composition comprising Lidocaine and Melatonin.
  • Composition 25 Composition comprising Lidocaine and Melatonin.
  • Composition 26 Composition comprising Lidocaine and Melatonin.
  • Composition 27 Composition comprising Lidocaine and Melatonin.
  • Step-1 Dispensed all the required raw materials using a calibrated weighing balance.
  • Step-2 Sifted Xylitol, L-Carnosine, Magnesium oxide, Diglyceryl lauryl fumarate, Calcium carbonate, L-Carnosine, Hypromellose, Croscarmellose sodium, simethicone powder and citric acid through ASTM #40 sieve.
  • Step 3 Dry mixed the sifted materials of step 2 for 10 min at 50 rpm
  • Step 4 Simethicone was added to step 3 mixed well.
  • Step 5 Dried the wet mass of step 4, at an inlet temperature of NMT 60°C until LOD of NMT 3.5% is obtained.
  • Step 6 Dried material of step 5 was passed through ASTM sieve no.40
  • Step 7 Granules of step 6 were blended with extra-granular materials (passed through ASTM 40 sieve) i.e., Lidocaine hydrochloride monohydrate, melatonin, Calcium D-Pantothenate, colloidal silicon dioxide and peppermint flavor and blended for 10 min.
  • extra-granular materials i.e., Lidocaine hydrochloride monohydrate, melatonin, Calcium D-Pantothenate, colloidal silicon dioxide and peppermint flavor and blended for 10 min.
  • Step 8 Blend of step 7 was lubricated with #60 passed zinc stearate for 5 min.
  • Step 9 Lubricated blend of step 8 was compressed with the following compression parameters
  • Step 10 40 tablets of step 9 were filled in 60cc HDPE bottle along with one 2g silica gel bag, induction sealed and closed with 33 mm CR closure.
  • Composition 28 Composition comprising Lidocaine and Melatonin.
  • composition 29 Composition comprising Lidocaine and Melatonin.
  • step 5 Granulate the material of step 3 using binder solution of step 4 6. Dry the wet mass of step no. 5 at inlet temperature of 50 ⁇ 5°C until LOD of granules reaches to NMT 2.0 %w/w at 105°C by auto mode using moisture analyzer.
  • Dispense the extra granular material i.e., Lidocaine hydrochloride monohydrate, Melatonin, Mannitol, Colloidal silicon dioxide, Peppermint flavor and zinc stearate.
  • Composition 30 Composition comprising Lidocaine and Mometasone.
  • Step 6 material was lubricated with exragranular materials (previously sifted through sieve #40) for 5min.
  • Composition 31 Composition comprising Lidocaine and Mometasone
  • Step 6 material was lubricated with exragranular materials (previously sifted through sieve #40) for 5min.
  • Composition 32 Composition comprising Lidocaine and Mometasone
  • Step 6 material was lubricated with exragranular materials (previously sifted through sieve #40) for
  • mometasone related impurity is found to be increase with mannitol, simethicone, magnesium oxide, zinc stearate and calcium carbonate.
  • Composition 33 Composition comprising Lidocaine and Mometasone
  • Composition 34 Composition comprising Lidocaine and Mometasone
  • Composition 35 Comprising Mometasone Lozenge 0.8 mg [0303] Manufacturing process:
  • API was sifted through sieve#60.
  • Composition 36 comprising Mometasone
  • step 2 Granulate step 2 sifted material with step 3 binder solution.

Abstract

The present disclosure provides a pharmaceutical composition comprising local anesthetics or salt or hydrates or solvates thereof, steroids or salt or hydrates or solvates thereof, and melatonin or salt or hydrates or solvates thereof delivered either as a standalone formulation or in any combination. The composition may include other active agents which can effectively inhibit the inflammation. The compositions of the present disclosure may find utility in treatment of inflammatory diseases affecting gastrointestinal tract.

Description

A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF IMMUNE SYSTEM MEDIATED DISEASES
FIELD OF THE INVENTION
[0001] The present disclosure generally relates to the field of pharmaceutical compositions. In particular, the present disclosure provides a pharmaceutical composition comprising local anesthetic, corticosteroids and other agents in combination or as standalone. The compositions of the present disclosure may find utility in treatment of allergic inflammatory conditions.
BACKGROUND OF THE INVENTION
[0002] Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus. In healthy individuals, the esophagus is typically devoid of eosinophils. Consumption of certain food triggers eosinophils migration to the esophagus in large numbers, leading to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartbum. EoE is not fully understood except that certain food and environmental allergens plays significant role.
[0003] EoE is poorly understood disease. EoE is a chronic, T helper type 2 (Th2)-associated inflammatory disease characterized by predominant and marked eosinophilic inflammation of the esophagus. EoE is characterized by a dense infiltrate of white blood cells of the eosinophil type into the epithelial lining of the esophagus. This may be due to an allergic reaction against ingested food, based on the important role eosinophils play in allergic reactions. The eosinophils are recruited into the tissue in response to local production of eotaxin-3 by IL-13 stimulated esophageal epithelial cells. Eosinophils are inflammatory cells that release a variety of chemical signals which inflame the surrounding esophageal tissue. The inflamed esophagus does not contract properly. It can get narrowed and develop rings or abscesses. This results in the signs and symptoms of pain.
[0004] Symptoms generally include difficulty in swallowing, food impaction, chest pain or heartburn, stomach pains, regurgitation or vomiting, decreased appetite and stunted growth or poor weight gain in children. It can happen at any age and affects both children and male adults. [0005] Subjects with family history of EoE atopic dermatitis, asthma, or food or environmental allergies are more predisposed to developing EoE.
[0006] The commonly used treatment options may consist of avoiding known or suspected triggers and use of medication to suppress the immune response. In severe cases, it may be necessary to enlarge the esophagus with an endoscopy procedure. The medication usually control the symptoms by decreasing the number of eosinophils in the esophagus and, subsequently, reducing the esophageal inflammation. Management consists of dietary, pharmacological, and endoscopic treatment.
[0007] In patients diagnosed with EoE, a trial of PPI as a first line therapy is a reasonable option. In patients with symptomatic improvement on using PPI, should repeat endoscopy with esophageal biopsy. If no eosinophils are present in the repeat biopsy, the diagnosis is either acid mediated GERD with eosinophilia or non GERD PPI responsive EoE with unknown mechanism. If both symptoms and eosinophils persist, the diagnosis is immune mediated EoE. Treatment for immune mediated EoE primarily involves using corticosteroids. Oral corticosteroids are shown to be effective in patients, but if the use of corticosteroids is discontinued patients see recurrence in symptoms.
[0008] Significant efforts have been put forth by the researchers to find products for treating EoE. However, none of the existing approaches seem to satisfy the existing needs. A need is also felt of improved the treatment using a pharmaceutical composition comprising a combination of active ingredients that are easy to administer and aids in improving patient compliance. The present disclosure satisfies the existing needs, at least in part, and overcomes one or more disadvantages of the conventional approaches.
OBJECTS OF THE INVENTION
[0009] One of the objects of the present disclosure is to provide a pharmaceutical composition that may overcome the limitations associated with the conventional compositions.
[0010] Another object of the present disclosure is to provide a composition that exhibits superior storage stability, functional reciprocity and provide a composition that is easy to prepare and is economical.
[0011] Further object of the present disclosure is to provide a composition that can be orally administered for targeted drug delivery. [0012] Yet another object of the present disclosure is to provide a pharmaceutical composition that modifies the delivers of active ingredient: immediate release or modified release or local delivery formulation or to deliver at a specific rate, of different active agents so has to improves the local availability of the actives present in the composition.
[0013] Targeted local delivery and sustained exposure of the bio-actives to modulate the inflammatory mediators, inflammation, and allergy.
[0014] Still another object of the present disclosure is to deliver the active agents either simultaneously or concurrently or concomitantly to a subject for treatment of an inflammatory disease.
SUMMARY OF THE INVENTION
[0015] The present disclosure generally relates to the field of pharmaceutical compositions. In particular, the present disclosure provides a pharmaceutical composition comprising active agents which can target the pathophysiology of EoE.
[0016] The pharmaceutical composition comprises local anesthetic in combination with steroids, or their salt or hydrates or solvates thereof.
[0017] The pharmaceutical composition may comprise anti-inflammatory agents, or agents those that target key players in EoE inflammation pathways like IL-4, IL-5 or IL- 13 signaling or their salt or hydrates or solvates thereof.
[0018] The pharmaceutical composition may further comprise one or more other active agents such a melatonin or their salt or hydrates or solvates thereof.
[0019] In embodiment, local anesthetic or salt or hydrates or solvates thereof is present in an amount ranging from 25mg to 600 mg.
[0020] In embodiment, steroids or salt or hydrates or solvates thereof is present in an amount ranging from 0.005mg to 1000 mg.
[0021] In an embodiment, melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg.
[0022] In an embodiment, composition comprises lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 100 mg to 600 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
[0023] In another embodiment, composition comprises lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 100 mg to 600 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with Melatonin or salt or hydrates or solvates thereof in an amount ranging from 1 mg to 100 mg.
[0024] In an embodiment, composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25 mg to 100 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
[0025] In an embodiment, composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25 mg to 100 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from 1 mg to 100 mg.
[0026] In an embodiment, composition comprises ropivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg to 100 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
[0027] In an embodiment, composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from Img to 100 mg.
[0028] The composition also includes a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is selected from any or a combination of: a diluent, an antioxidant, a preservative, an alkalizing agent, a buffering agent, a disintegrant, a binder, an antifoaming agent, a solvent, a glidant, a lubricant, a flavoring agent, a coating agent, a rate controlling polymer or non-polymer, a zinc salt, a fatty acid or derivative thereof, an amino acid or metabolites or derivative thereof, a bulking agent, an anti-tacking agent, an emulsifier, a surfactant, a plasticizer and a stabilizer and a film forming agents. In an embodiment, the fatty acid derivative includes any or a combination of: di glyceryl lauryl fumarate, di glyceryl lauryl succinate, and diglyceryl capryl succinate.
[0029] In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof and steroids or salt or hydrates or solvates thereof. In an embodiment, the composition comprises an intra-granular portion and an extra- granular portion, wherein the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient; in another aspect the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises and steroids or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient. In yet another aspect the intra-granular portion comprises steroid or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises and local anesthetic or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient.
[0030] In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof and steroids or salt or hydrates or solvates thereof with melatonin or salt or hydrates or solvates thereof. In an embodiment, the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient or intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises melatonin or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient.
[0031] In an embodiment, the composition is formulated to enhance drug delivery to specific regions in the GI tract. The composition can be formulated into tablet, buccal tablet, sublingual tablet, lozenges film based, oral spray, or mucosal adhesive formulation for administering orally, topical and locally. Further the formulation is an modified release formulation which include, extended release, sustained release, delayed release or slow release.
[0032] In an embodiment, the portions are compressed together to obtain any of: a tablet dosage form and an lozenge dosage form, and optionally coated with a seal coat.
[0033] In yet another embodiment, the composition comprises local anesthetic in an amount of 100 mg to600 mg, steroid in an amount of 0.005 mg to 1000 mg and Melatonin in an amount of 1 mg to 100 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation or film based formulation.
[0034] In yet another embodiment, the composition comprises local anesthetic in an amount of lOOmg to 600 mg and steroid in an amount of 0.005 mg to lOOOmg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation or film based formulation. [0035] In another embodiment, the composition is used in preparing the medicament for allergic inflammatory conditions such as Eosinophilic esophagitis (EoE) and asthma.
[0036] In an embodiment present invention provided an oral pharmaceutical composition, comprising: at least one local anesthetic in an amount of 25 mg to 600 mg, at least one steroid in an amount of 0.005 mg to 1000 mg, melatonin in an amount of 1 mg to 100 mg, and an excipient; or at least one local anesthetic in an amount of 25 mg to 600 mg, at least one steroid in an amount of 0.005 mg to 1000 mg and an excipient; or at least one local anesthetic in an amount of 25 mg to 600 mg, melatonin in an amount of 1 mg to 100 mg, and an excipient; or at least one steroid in an amount of 0.005 mg to 1000 mg, melatonin in an amount of 1 mg to 100 mg, and an excipient; or at least one steroid in an amount of 0.005 mg to 1000 mg, and an excipient.
[0037] In another embodiment, the local anesthetic is selected from a group consisting of benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, amylocaine, oxybuprocain, articaine, bupivacaine, dibucaine, etidocaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, prilocaine, ropivacaine, sameridine, tonicaine and cinchocaine or their salt thereof.
[0038] In another embodiment, the steroid are selected from a group consisting of hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, tixocortol pivalate or their salt thereof.
[0039] In another embodiment, the pharmaceutically acceptable excipient is selected from any or a combination of: disintegrant, binder, diluent, solvent, flavoring agent, glidant, lubricant, pH modifier, anti-foaming agent, fatty acid derivatives, antioxidant or a combination thereof.
[0040] In another embodiment, the disintegrants is croscarmellose sodium or aerosil.
[0041] In another embodiment, the binder is hypromellose.
[0042] In another embodiment, the diluent is mannitol, xylitol, heavy magnesium oxide or calcium carbonate.
[0043] In another embodiment, the solvent is alcohol, ethanol, or water. [0044] In another embodiment, the flavoring agent is organ or peppermint.
[0045] In another embodiment, the glidants is colloidal silicon dioxide.
[0046] In another embodiment, the lubricant is steric acid or zinc stearate.
[0047] In another embodiment, the anti-foaming agent is simethicone 30% emulsion.
[0048] In another embodiment, the pH modifier is L-Camosine
[0049] In another embodiment, the antioxidant is citric acid, D-Panthenol, calcium D-Panthenol. [0050] In another embodiment, the fatty acid derivatives are selected from a group consisting of diglyceryl lauryl fumarate, diglyceryl lauryl succinate, diglyceryl capryl succinate, diglyceryl capryl fumarate or a combination thereof.
[0051] In another embodiment, the oral pharmaceutical composition comprises of mometasone furoate, croscarmellose sodium, hypromellose, mannitol, xylitol, ethanol, peppermint flavor, colloidal silicon dioxide, and stearic acid.
[0052] In another embodiment, the oral pharmaceutical composition comprises of bupivacaine hydrochloride, mometasone furoate, mannitol, xylitol, croscarmellose sodium, hypromellose, alcohol, colloidal silicon dioxide, peppermint flavor and stearic acid.
[0053] In another embodiment, the oral pharmaceutical composition comprises of mannitol, 1- camosine, heavy magnesium oxide, calcium carbonate, croscarmellose sodium, calcium D- pantothenate, hypromellose, simethicone 30% emulsion, purified water, lidocaine hydrochloride monohydrate, melatonin, mannitol, colloidal silicon dioxide, zinc stearate, and peppermint flavor. [0054] In an embodiment the oral composition is a lozenge.
DETAILED DESCRIPTION OF THE INVENTION
[0055] The present disclosure generally relates to the field of pharmaceutical compositions.
[0056] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
[0057] It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, “an active agent” or “an active ingredient” refers not only to a single active agent but also to a combination of two or more different active agents, “a dosage form” refers to a combination of dosage forms as well as to a single dosage form, and the like.
[0058] The term “active agent” or “therapeutic agent”, encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
[0059] The term “combination therapy" or "combined treatment" or "in combination" as used herein denotes any form of concurrent or concomitantly or co-administration of active agents for treating allergic inflammatory conditions affecting the oral and gastrointestinal tracts such as eosinophilic esophagitis (EoE), allergies, eczema, hives, psoriasis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, diseases of the esophagus, such as esophageal lichen planus, preferably eosinophilic esophagitis (EoE).
[0060] The terms “treating” and “treatment” as used herein refers to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage caused thereby. Thus, “treating” a subject/patient as described herein encompasses treating oral, gastrointestinal and esophageal diseases such as eosinophilic esophagitis (EoE), asthma, gastric esophagitis and related diseases.
[0061] The term “dosage form” denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to elicit a desired therapeutic response.
[0062] The term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate. The term “controlled release” as used herein includes sustained release, non-immediate release, extended release, slow release and delayed release formulations.
[0063] The term “sustained release” (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time.
[0064] The term “pharmaceutically acceptable” means the material incorporated into a pharmaceutical composition that can be administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
[0065] “Pharmacologically active” (or simply “active”) as in a pharmacologically active derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
[0066] Pharmacologically active agents or API or active agents include local anesthetic agents, steroids, and melatonin. Further, it may further include anti-inflammatory agents specifically target key players in EoE inflammation pathways like IL-4, IL-5 or IL- 13 signaling.
[0067] In an embodiment the local anesthetic agents includes benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, amylocaine, oxybuprocain, articaine, bupivacaine, dibucaine, etidocaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, prilocaine, ropivacaine, sameridine, tonicaine and cinchocaine or their salt or hydrates or solvates thereof.
[0068] In an embodiment the steriod agents particularly corticosteroids includes hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, and tixocortol pivalate or their salt or hydrates or solvates thereof.
[0069] The IL4, IL5 and IL 13 inhibitors have been shown to reduce circulating eosinophil counts rapidly in humans with various disorders. In an embodiment other agents which blocks IL4, IL5, IL13, TGF-beta and TSLP includes anrukinzumab, omalizumab, benralizumab, mepolizumab, reslizumab, lebrikizunab, lerdelimumab, metelimimab, rosiglitazone, tranilast, bimekizumab, brodalumab, cinqair, cosentyx, dupilumab, dupixent and tralokinumab.
[0070] Eosinophilic esophagitis (EoE) is a multifactorial esophageal inflammation, with a genetic predisposition, which combines a deficient esophageal mucosal barrier, an abnormal immune reaction to environmental or food allergens mediated by Th2 interleukins, immediate esophageal lesions and dysmotility, with secondary remodeling and fibrosis.
[0071] Eosinophils are considered the main effector cells in fibrosis in a variety of hypereosinophilic syndromes and eosinophil-related allergic diseases including asthma and EoE. Thus it is important to target fibrosis reversal in treatment of EoE, but also underline the importance of eosinophils in tissue remodeling. The mechanism of action of using steroid therapy in EoE is mainly based on the reduction of inflammatory cells and fibrosis with significant decrease of esophageal eosinophils, mast cells, T-cells and proinflammatory cytokines as well as restoration of epithelial barrier function and reduction of tissue remodeling. Most common side effect of steroid therapy is Candida esophagitis. Further, in EoE, the damage and inflammation, can cause pain and may lead to trouble swallowing. Children with EoE have frequent sleep complaints and several sleep disorders.
[0072] Present invention provides a fixed dose composition which address various pathophysiological aspect of EoE. The composition comprises local anesthetics which can reduced the pain. The steroid in the composition can reduces the inflammatory cells, restores the epithelial barrier function, reverse the fibrosis, decrease eosinophil numbers in the esophageal epithelium but also to reduce epithelial cell apoptosis and to decrease esophageal molecular remodeling. Steroid further downregulate the response of mast cells
[0073] Further melatonin used in the composition can address the sleep complaints in the subjects with EoE.
[0074] Present Fixed dose composition can be used in other inflammatory diseases such as allergies, eczema, hives, psoriasis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, preferably eosinophilic esophagitis (EoE).
[0075] In embodiment, local anesthetic or salt or hydrates or solvates thereof is present in an amount ranging from 25mg to 600 mg.
[0076] In embodiment, steroids or salt or hydrates or solvates thereof is present in an amount ranging from 0.005mg to 1000 mg.
[0077] In an embodiment, melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg.
[0078] In an embodiment, composition comprises lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from lOOmg to 600 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
[0079] In another embodiment, composition comprises lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 1 OOmg to 600 mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from 1 mg to 100 mg. [0080] In an embodiment, composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
[0081] In an embodiment, composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from Img to 100 mg.
[0082] In an embodiment, composition comprises ropivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg.
[0083] In an embodiment, composition comprises bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25mg tolOO mg and mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg with melatonin or salt or hydrates or solvates thereof in an amount ranging from Img to 100 mg.
[0084] The composition also includes a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is selected from any or a combination of: a diluent, an antioxidant, a preservative, an alkalizing agent, a buffering agent, a disintegrant, a binder, an antifoaming agent, a solvent, a glidant, a lubricant, a flavoring agent, a coating agent, a rate controlling polymer or non-polymer, a zinc salt, a fatty acid or derivative thereof, an amino acid or metabolites or derivative thereof, a bulking agent, an anti-tacking agent, an emulsifier, a surfactant, a plasticizer and a stabilizer and a film forming agents. In an embodiment, the fatty acid derivative includes any or a combination of: di glyceryl lauryl fumarate, di glyceryl lauryl succinate, and diglyceryl capryl succinate.
[0085] In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof and steroids or salt or hydrates or solvates thereof. In an embodiment, the composition comprises an intra-granular portion and an extra- granular portion, wherein the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient; in another aspect the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises and steroids or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient. In yet another aspect the intra-granular portion comprises steroid or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises and local anesthetic or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient.
[0086] In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof and steroids or salt or hydrates or solvates thereof with melatonin or salt or hydrates or solvates thereof. In an embodiment, the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient or intra-granular portion comprises local anesthetic or salt or hydrates or solvates thereof, and steroids or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises melatonin or salt or hydrates or solvates thereof with pharmaceutically acceptable excipient.
[0087] In an embodiment, the composition is formulated to enhance drug delivery to specific regions in the GI tract. The composition can be formulated into tablet, buccal tablet, sublingual tablet, film based, oral spray, orodispersible tablets or mucosal adhesive formulation for administering orally, topical and locally to target the GI tract. Further the formulation is an modified release formulation which include, extended release, sustained release, delayed release or slow release.
[0088] In an embodiment, the portions are compressed together to obtain any of: a tablet dosage form and a lozenge dosage form optionally coated with a seal coat.
[0089] In yet another embodiment, the composition comprises local anesthetic in an amount of lOOmg to-600 mg, steroid in an amount of 0.005 mg to lOOOmg and melatonin in an amount of 3 mg- 100 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation or film based formulation.
[0090] In yet another embodiment, the composition comprises local anesthetic in an amount of lOOmg to 600 mg and steroid in an amount of 0.005 mg to lOOOmg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation or film based formulation. [0091] In an embodiment, the composition is formulated to enhance drug delivery to specific regions in the GI tract. The upper GI tract consists of the mouth, pharynx, esophagus, stomach, and the first part of the small intestine (duodenum), whereas the lower GI tract includes the other parts of the small intestine (jejunum and ileum) and the large intestine (cecum, colon, and rectum). Manipulating the formulation can control the dissolution rate and where the drug is released in the GI tract for subsequent absorption. Their design is based on exploiting physiological conditions in the GI tract. By using modified formulations, it is possible to improve targeting the GI tract. Present composition ensures prolonged exposure of the active agent to esophageal mucosa.
[0092] The present disclosure provides a pharmaceutical composition comprising: local anesthetics or salt or hydrates or solvates thereof, steroid or salts or hydrate or solvates thereof and melatonin or salt or hydrates or solvates thereof. In an embodiment, the composition is a fixed dose combination. The compositions of the present disclosure may find utility in treatment of inflammatory conditions affecting the GI tract particularly esophagus. It further, provides an fixed dose composition that significantly lower systemic bioavailability, with better safety profile and patient compliance.
[0093] In embodiment, lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 100 mg to 600 mg. In embodiment, mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg-lOOOmg. In an embodiment, melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg.
[0094] In an embodiment, lidocaine or salt or hydrates or solvates thereof is present in the composition in an amount of 100 mg to 600 mg. Alternatively, Lidocaine or salt or hydrates or solvates thereof is present in an amount of 100 mg to 400 mg.
[0095] In an embodiment, either of the three drug actives melatonin, mometasone or lidocaine are given simultaneously as individual formulations/compositions or three drug actives are given in a combination to a subject suffering from a disease.
[0096] In an embodiment, either of the two drug actives mometasone or lidocaine are given simultaneously as individual formulations/compositions or two drug actives are given in a combination to a subject suffering from a disease.
[0097] In embodiment, bupivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25 mg to 100 mg. In embodiment, mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg. In an embodiment, melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg. [0098] In an embodiment, either of the three drug actives melatonin, mometasone and bupivacaine are given simultaneously as individual formulations/compositions or three drug actives are given in a combination to a subject suffering from a disease.
[0099] In an embodiment, either of the two drug actives mometasone and bupivacaine are given simultaneously as individual formulations/compositions or two drug actives are given in a combination to a subject suffering from a disease.
[0100] In embodiment, ropivacaine or salt or hydrates or solvates thereof is present in an amount ranging from 25 mg to 100 mg. In embodiment, mometasone or salt or hydrates or solvates thereof is present in an amount ranging from 0.005 mg to 1000 mg. In an embodiment, melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 100 mg.
[0101] In an embodiment, either of the three drug actives melatonin, mometasone or ropivacaine is given simultaneously as individual formulations/compositions or three drug actives are given in a combination to a subject suffering from a disease.
[0102] In an embodiment, either of the two drug actives mometasone or ropivacaine is given simultaneously as individual formulations/compositions or two drug actives are given in a combination to a subject suffering from a disease.
[0103] In another embodiment, local anesthetic, steroid and melatonin is formulated as individual formulations/compositions in titrated strengths or binary mixture compositions or a fixed dosage combination for the treatment of a disease/condition in a human subject.
[0104] The composition also includes a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be selected from any or a combination of: a diluent, an anti-oxidant, a preservative, an alkalizing agent, a buffering agent, a disintegrant, a binder, an anti -foaming agent, a solvent, a glidant, a lubricant, a flavoring agent, a sweetener, a coating agent, a rate controlling polymer or non-polymer, a zinc salt, a fatty acid or derivative thereof, an amino acid or metabolites or amino acid derivatives, a bulking agent, an anti-tacking agent, an emulsifier, a surfactant, a plasticizer, film forming agents, mucosal-adhesive agents and a stabilizer.
[0105] In a preferred embodiment, the pharmaceutically acceptable excipient may be selected disintegrant, binder, diluent, solvent, flavoring agent, glidant, lubricant, pH modifier, antifoaming agent and antioxidant.
[0106] In an embodiment, the diluent(s) include(s), but not limited to, dicalcium phosphate dihydrate, calcium sulfate, calcium carbonate, heavy magnesium oxide, lactose, sucrose, mannitol, xylitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, and magnesium aluminum silicate and mixtures thereof.
[0107] In an embodiment, the anti-oxidant(s) and preservative(s) include(s), but not limited to, L- Carnosine, vitamin A, vitamin E, vitamin C, D-Panthenol, Calcium D-Panthenol, retinyl palmitate, and selenium, citric acid, Citric acid anhydrous, sodium citrate, methyl paraben, propyl paraben, p-hydroxybenzoic acid esters, sorbic acid, benzoic acid, propionic acid or salts thereof; Alcohols such as benzyl alcohol, butanol or ethanol, isopropyl alcohol, and quaternary ammonium compounds such as benzalkonium chloride, sodium benzoate and mixtures thereof.
[0108] In an embodiment, the alkalizing agent(s) include(s), but not limited to, ammonia solution NF, Ammonium Carbonate NF, Diethanolamine NF, monoethanolamine, Potassium Hydroxide NF, Sodium Bicarbonate USP, Sodium Borate NF, Sodium Carbonate NF, Sodium Hydroxide NF, sodium Phosphate Dibasic USP, trolamine NF, calcium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium trisilicate, aluminum hydroxide, aluminum carbonate, magnesium aluminium silicate hydrate, potassium bicarbonate, sodium bicarbonate, sodium citrate, potassium citrate, aluminum sulfate, calcium carbonate and mixtures thereof.
[0109] In an embodiment, the buffering agent(s) include(s), but not limited to, a bicarbonate salt of alkali earth metal, amino acids, an acid salt of an amino acid, an alkali salt of an amino acid and mixture thereof.
[0110] In an embodiment, the disintegrant(s) include(s), but not limited to Croscarmellose sodium, microcrystalline cellulose, Aerosil, low- substituted hydroxypropyl cellulose, alginic acid and alginates, modified starches, sodium starch glycolate, sodium carboxy methyl cellulose, carboxymethyl cellulose calcium, polyvinylpyrrolidone, docusate sodium, guar gum and mixtures thereof.
[oni] In an embodiment the binder(s) include(s), but not limited to, hypromellose (or hypromellose 5 cps), polyvinyl pyrrolidone, copolymers of vinyl pyrrolidone with other vinyl derivatives, hydroxypropyl cellulosic derivatives (such as methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose etc), polyacrylates (such as Carbopol, polycarbophil, etc), Povidone (all grades), Polyox of any molecular weight or grade, irradiated or not, maize starch, povidone, copovidone, corn starch, starch, polyvinylpyrrolidone (PVP), microcrystalline cellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates, starch, heavy magnesium oxide and mixtures thereof. [0112] In an embodiment the anti-foaming agent(s) include(s), but not limited to, alcohols such as cetostearyl alcohol, insoluble oils such as castor oil, stearates, polydimethylsiloxanes and other silicones derivatives, ethers, paraffin oil, paraffin wax, glycols, simethicone (or simethicone 30% emulsion) and mixtures thereof.
[0113] In an embodiment, solvent(s) include(s), but not limited to, methanol, ethanol, npropanol, isopropanol, hexane, heptane, petroleum ether, cyclohexane, diethyl ether, diisopropyl ether, ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone, 1,4- dioxane, toluene, ammonia solution, glacial acetic acid, ammonium hydroxide, sodium hydroxide, calcium hydroxide, calcium carbonate, potassium hydroxide, potassium carbonate, water and mixtures thereof.
[0114] In an embodiment, the glidant(s) include(s), but are not limited to, colloidal silicon dioxide, stearic acid, talk, aluminum silicate and mixtures thereof.
[0115] In an embodiment, the lubricant(s) include(s), but not limited to, stearic acid, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, zinc stearate, calcium stearate, silica, talc, polyethylene glycol, paraffin and mixtures thereof.
[0116] In an embodiment, the flavoring agent(s) include(s), but not limited, cherry, maple, pineapple, orange, raspberry, banana-vanilla, peppermint, butterscotch, strawberry, vanilla, apricot, cinnamon, honey, lime, peach-orange, peach-rum, raspberry, wild cherry, mint and mixtures thereof.
[0117] In an embodiment, coating agent(s) include(s), but not limited to, cellulosics, such as hydroxypropyl methyl cellulose (HPMC), methy ethylcellulose (MEC), carboxymethyl celluolose (CMC), carboxymethyl ethylcelluolose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hypromellose, povidone, copovidone, and ethyl cellulose (EC); vinyls, such as polyvinyl alcohol; acrylics, such as methacrylic acid / ethylacrylate copolymers (often used for enteric or delayed release coatings), natural derivatives, such as shellac or alginate and mixtures thereof.
[0118] In an embodiment, the rate controlling polymer(s) include(s), but not limited to, cellulose acetate, alkyl celluloses, hydroxyalkyl, acrylic polymers, copolymers dialkylphthalates, dibutyl phthalate, microcrystalline wax and mixtures thereof. [0119] In an embodiment, the rate controlling non-polymer(s) include(s), but not limited to, fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester and mixtures thereof. [0120] In an embodiment, zinc salt(s) include(s), but not limited to, zinc oxide, zinc stearate, zinc L-camosine, zinc acetate, zinc chloride, zinc bromide, zinc fluoride, zinc hexafluorosilicate, zinc iodide, zinc molybdate, zinc nitrate, zinc molybdite, zinc oxalate, zinc perchlorate, zinc tetrafluorob orate, zinc sulfate and mixtures thereof.
[0121] In an embodiment, the fatty acid(s) or derivatives thereof include(s), but not limited to, fatty acids with Cl to C30 carbons, which includes long chain fatty acids; saturated or unsaturated fatty acids and derivatives thereof (monounsaturated fatty acids (MUFAs) C18: lnl2c, C16: ln-5, C16:4n-1 and the polyunsaturated fatty acids (PUFAs) C16:3n-4, C20:3n-3, C20:4n-6, C21 :5n-3 and C18:2n-9c,12t); hydrogenated fatty acids; fatty acid glycerides; polyoxyethylated oleic glycerides; monoglycerides and diglycerides; mono-, bi- or tri -substituted glycerides; glycerol mono-oleate esters; glycerol mono-caprate; glyceryl monocaprylate; dicaprylate; laurate, monolaurate; glyceryl palmitostearate; glyceryl behenate; diethyleneglycol palmitostearate; polyethyleneglycol stearate; polyoxyethyleneglycol palmitostearate; glyceryl mono palmitostearate; cetyl palmitate; polyethyleneglycol palmitostearate; dimethylpolysiloxane; mono- or di-glyceryl behenate; fatty acid derivatives such as diglyceryl lauryl fumarate (DGLF), diglyceryl lauryl succinate, diglyceryl capryl succinate, diglyceryl capryl fumarate; fatty alcohols associated with polyethoxylate fatty alcohols; cetyl alcohol; octyl dodecanol; myristyl alcohol; isopropyl myristate, isopropyl palmitate, stearic acid, lauric acid, EP A, DHA, linoleic acid, linolenic acid, stearyl alcohol and mixture thereof.
[0122] In an embodiment, the fatty acid derivatives includes any or a combination of: di glyceryl lauryl fumarate (DGLF), diglyceryl lauryl succinate, diglyceryl capryl succinate, and diglyceryl capryl fumarate, and the same can be used in the composition to either delay disintegration and/or absorption and thereby provide sustained action over a longer period.
[0123] In an embodiment, the amino acids or metabolites or amino acid derivatives include(s), but not limited to, glycine, glutamine, asparagine, arginine, lysine in biologically active enantiomeric forms, L-camosine, L-carnitine, choline, betaine, taurine, glycosaminoglycans including hyaluronic acid, chondroitin sulfate, glucosamine, L glucosamine, heparins and mixtures thereof.
[0124] In an embodiment, the bulking agent(s) include(s), but not limited to, lactose USP, Starch 1500, mannitol, erythritol, sorbitol, maltodextrin, malitol or other non-reducing sugars; microcrystalline cellulose (e.g., Avicel), dibasic calcium phosphate (anhydrous or dihydrate), sucrose, etc. and mixtures thereof.
[0125] In an embodiment, the anti -tacking agent(s) include(s), but not limited to, stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; sodium benzoate; sodium acetate and mixtures thereof.
[0126] In an embodiment, the surfactant(s) and emulsifier(s) include(s), but not limited to, ionic or non-ionic surfactants and emulsifiers, poloxamers, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylated, hydrogenated castor oil and mixtures thereof.
[0127] In an embodiment, the plasticizer(s) include(s), but are not limited to, diethyl phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, polyethylene glycol, dichloromethane, acetone, ethanol, methanol, isopropyl alcohol, water and mixtures thereof.
[0128] In an embodiment, the stabilize^ s) include(s), but not limited to, gums, agar, taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins and mixtures thereof.
[0129] In an embodiment, the sweetener(s) include(s), but not limited to, mannitol, sorbitol, polyethylene glycol (PEG) 6000 and 8000, Emdex, Nu-tab, sweetrex, Mola-tab, Hony-tab, Sugartab, non-sugar sweetening agents such as aspartame, sorbitol, xylitol, isomalt, saccharin, sodium saccharin, calcium saccharin, sucralose, acesulfame-K, steviol, steviosin, mannitol, erythritol, lactitol, and sugar sweetening agents such as sucrose, fructose, dextrose and mixtures thereof.
[0130] In an embodiment, the film forming agent(s) include(s), but not limited to, polymers such as ethylcellulose, hydroxypropylmethylcellulose (HPMC), Na-CMC, chitosan, Tween 80, PEG 400, cyclodextrin, gellan gum, xanthan gum, carbopol, Eudragit, Eudragit EPO, Eudragit E 100, Eudragit S 100, Eudragit RL 100, Eudragit RS 100, dermacryl, lutrol F-127, plasdone, Kollidon, polyvinyl alcohol, polyisobutylene, polyvinyl pyrrolidone, polymethacrylates and others.
[0131] Although several embodiments of the present disclosure names few of the commonly used excipients, any other excipient known to or appreciated by a skilled person can also be used to realize the advantageous compositions of the present disclosure. Examples of useful excipients which can optionally be added to the composition are described in the Handbook of Pharmaceutical Excipients, 3rd edition, Edited by A. H. Kibbe, Published by: American Pharmaceutical Association, Washington DC, ISBN: 0-917330-96-X, and in Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond C Rowe - Publisher: Science and Practice.
[0132] Depending on the intended mode of administration, the pharmaceutical composition may be formulated as a solid, semi-solid or liquid dosage form. Non-limiting examples of dosage forms includes tablet, lozenge, capsule, caplet, modified release tablet or lozenge, subligual tablet, orally disintegrating tablets, orodispersible tablets, suspension, solution, emulsion, suppository, granules, pellets, beads, powder, aerosol sprays (oral, nasal), patches, pre-filled syringe, pre-filled pen, gel, tablet in tablet, bilayer tablet, trilayer tablet, inlay tablet, capsule in capsule, tablet(s) in capsule, granules and/or pellets in capsule, pellets and tablet in capsules and the likes.
[0133] In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof, and Melatonin or salt or hydrates or solvates thereof, wherein the composition is formulated into a chewy or hard or caramel based lozenge, pastilles, troches, soft lozenge, center or liquid filled lozenge, power based lozenge, compressed lozenge, syrup based lozenge, granulated lozenge, buccal and sublingual tablets. The lozenge formulation of the present disclosure may increase bioavailability, and affords immediate relief from pain. Lozenge dosage forms are easy to administer for geriatric and pediatric patients who can’t swallow tablets formulation. This formulation may help to keep the drug in contact to the oral cavity for longer time. The lozenge may be formulated as a modified release formulation (modified release can be controlled release, immediate release, phased release, timed release, sustained release, delayed release or a combination of immediate or quick or fast and sustained or slow or extended release). The lozenge can be formulated as a bi-layer, tri-layer tablet or multi-layer tablet to facilitate the delivery of at least two or more active agents.
[0134] Typically, the carrier material for lozenge preparation includes sugar such as sucrose, dextrose, etc. Recently consumers have become concerned about the excessive levels of sugar contained within their diets. This concern has caused a demand for sugar-free products, including sugar-free medications. Pharmaceutical manufacturers have attempted to find alternative carrier bases in order to provide sugar-free lozenges. One such alternative carrier is a polyhydric alcohol such as xylitol. Polyhydric alcohols are considered as a viable alternative because they provide a sweet taste will mask the bitter taste of many medicinal agents. Lozenges made from polyhydric alcohols do suffer from one serious disadvantage. They dissolve very rapidly when placed in the oral cavity. For example, a lozenge made from a xylitol based carrier will dissolve completely within approximately 3 minutes of administration. Other polyhydric alcohols such as sorbitol or mannitol will also dissolve within 3 minutes of administration. Thus the medicinal agents are released so rapidly that a large percentage of the dose is washed into the patient’s alimentary canal rather than having an opportunity to come in contact with the tissues of the oral cavity, which are under treatment. Thus, it would be a valuable contribution to the art to produce polyhydric alcohol based lozenges having slower rates of dissolution within the oral cavity.
[0135] In an embodiment, non-limiting examples of excipients for preparing a compressed powder lozenge or compressed granulated lozenge, cast lozenge includes at least one diluents, at least one fillers, at least one glidants, at least one lubricants, at least one binders, at least one preservatives, at least one artificial or natural sweeteners or and at least one aroma or flavoring compounds.
[0136] The lozenge may be formulated as a modified release formulation (modified can be controlled release, immediate release, phased release, timed release, sustained release, delayed release or a combination of immediate or quick or fast and sustained or slow or release). The lozenge can be formulated as a bi-layer, tri-layer tablet or multi-layer tablet to facilitate the delivery of at least two or more active agents.
[0137] In some embodiments, the compositions are formulated as cast lozenges comprising at least one base selected from fructo-oligosaccharides, crystalline sugar, candy base, isomalt or stevia; at least one aromas selected from natural aroma, essential oils such as citrus, mint oils, terpenes and sesquiterpenes, organic acids, alcohols, aldehydes, liquorice powder, menthol, peppermint oil or any fruit flavors; at least one taste enhancing ingredient such as saccharose, glutamic acid, E621 monosodium glutamate, MSG, E622 monopotassium glutamate, E623 calcium diglutamate, E625 Magnesium diglutamate); guanylic acid (a ribonucleotide) and its salts (E626 guanylic acid, E627 disodium guanylate, sodium guanylate, E628 dipotassium guanylate, E629 calcium guanylate); E630 inosinic acid, E631 disodium inosinate, E632 dipotassium inosinate, E633 calcium inosinate), E634 calcium 5'-ribonucleotides, E635 disodium 5'- ribonucleotides; E636 maltol, E637 ethyl maltol, E640 glycine andE641 L-leucine.
[0138] The advantages of drugs administration by the buccal route is the drug is not damaged by acidic media of the stomach, and the achievement of therapeutic serum concentrations of the drug more rapidly. The sublingual route gives greater permeability and has rich blood supply leading to more rapid absorption than other routes. [0139] In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising local anesthetic or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof, wherein the composition is formulated into a tablet dosage form. The tablet may be a monolayer tablet comprising local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof distributed uniformly. The tablet may be a bilayer tablet comprising anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof in any of a first layer and a second layer. Alternatively, the tablet may be a trilayer tablet comprising anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in any of a first layer, a second layer and a third layer. Alternatively, the tablet may be a press-coated tablet, i.e. a small tablet and a granulation or a blend is compressed together to one large press-coated tablet. All types of the tablets mentioned hereinbefore may be without a coating or may have one or more coatings, in particular film coatings.
[0140] The tablet-in-tablet dosage form may be prepared by compressing active ingredients with one or more rate controlling polymer or non-polymer to form a core extended release tablet; and compressing active ingredients optionally along with one or more pharmaceutically acceptable excipient onto said core tablet to form compressed tablet that causes immediate release of the active ingredients.
[0141] In another embodiment of the present invention, the pharmaceutical composition is formulated as an inlay tablet. Inlay tablets are tablets, wherein inner tablet is positioned within a comparatively larger outer tablet in such a way that at least one surface of the inner tablet is not in contact with outer tablet. Inlay tablet dosage form includes: (a) an inner inlay ed tablet comprising active ingredients and excipient(s) that causes extended release; and (b) an outer tablet comprising active ingredients along with excipient(s) to cause immediate release.
[0142] In another embodiment, the present disclosure embraces capsule-in-capsule formulations, wherein smaller size capsule is encapsulated into a larger capsule. Capsule-in -capsule consists of an external capsule and internal capsule (inner capsule) located therein. It is preferred that smaller size capsule is filled with active ingredients and excipients so as to cause extended release while larger capsule is filled, optionally, with active ingredients along with excipients for immediate release. [0143] The tablet of the present disclosure may be monolithic that means having a homogenous matrix of active ingredient and pharmaceutically acceptable excipients. Alternatively, the tablet may be formed as a bilayer, wherein the one layer is having active ingredients along with pharmaceutically acceptable excipients and other layer is having pharmaceutically acceptable excipients. Alternatively, both layers of bilayer tablet may contain active ingredients.
[0144] The composition can be made by different manufacturing processes such as by direct compression wet granulation, dry granulation, melt granulation, melt congealing process, extrusion and the likes. The composition cores may be mono or multi-layer(s) and can be coated with appropriate overcoats as known in the art. Wet granulation involves formation of granules using active ingredient and/or one or more pharmaceutically acceptable excipients and this portion can be termed as intra-granular portion. These granules are then lubricated with active ingredient and/or a blend of excipients comprising lubricant and this lubricant blend is then compressed to form a tablet. The portion outside the granules can be referred as extra-granular portion. Direct compression on the other hand requires only that the active ingredient is blended with one or more pharmaceutically acceptable excipients before compression and then compressed into tablet.
[0145] In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient.
[0146] In another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, and wherein the intra-granular portion comprises local anesthetics or salt or hydrates or solvates thereof, steroid or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient. Composition can be formulated with the active agent in the intra-granular and extra-granular portion along with pharmaceutically excipient agent as per the formulation art. Further the composition can include one or more other agents which can inhibit the inflammatory cells such as IL 4, IL 5, IL 13, TGF-beta, TSLP and agents which can reduced the eosinophil.
[0147] In an embodiment, the portions are compressed together to obtain any of: a tablet dosage form and a Lozenge dosage form, optionally coated with a seal coat. In an embodiment, the seal coat is an aqueous seal coat.
[0148] All types of the tablets mentioned hereinabove may be without a coating or may have one or more coatings, in particular film-coatings. A film coating is useful in limiting photolytic degradation and/or in limiting degradation of moisture sensitive materials.
[0149] In one embodiment, the tablet may be coated to delay disintegration and absorption and thereby provide sustained action over a longer period. The non-limiting examples of film coating includes glyceryl monostearate or glyceryl distearate, polyvinyl alcohol based, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, plyethyelene glycol 4000 and cellulose acetate phthalate film coating.
[0150] Further, the patient may receive the specific dosage over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years and the like.
[0151] The choice of appropriate dosages for the drugs used in combination therapy according to the present disclosure can be determined and optimized by the skilled artisan, e.g., by observation of the patient, including the patient's overall health, the response to the combination therapy, and the like. Optimization, for example, may be necessary if it is determined that a patient is not exhibiting the desired therapeutic effect or conversely, if the patient is experiencing undesirable or adverse side effects that are too many in number or are of a troublesome severity.
[0152] It is especially advantageous to formulate compositions of the present disclosure in unit dosage form for ease of administration and uniformity of dosage. The specifications of the dosage unit forms of the present disclosure are dependent on the unique characteristics of the composition and the particular therapeutic effect to be achieved. Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients. Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.:
Mack Publishing Co., 1995). EXAMPLES
[0153] Fatty acid derivatives
[0154] General Schema:
The general scheme of synthesis of compounds of Formula I is described and can be used for the synthesis of various compounds of formula I with fatty acids with carbon chains length from 1 to 30 with the reagents, catalysts, solvents and reaction conditions as described.
[0155] Example I
Figure imgf000025_0001
[0156] Example II: Methods of Synthesis
Figure imgf000025_0002
[0157] Scheme I: Synthesis of 4-((E3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid
(di glyceryl capryl succinate):
Figure imgf000025_0003
SCHEME 1
[0158] Step 1 : Synthesis of 2-oxopropane- 1,3 -diyl dioctanoate (3): To an ice cold solution of l,3dihydroxypropan-2-one (1, 25.0 g, 0.277 mol) in dichloromethane (500 mL) was added 4dimethylaminopyridine (10.17 g, 0.083 mol) and pyridine (49.2 mL, 0.610 mol) and stirred for next 5 min. To the above mixture octanoyl chloride (2, 105.4 mL, 0.610 mol) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was filtered; the solid was washed with di chloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HC1 solution (100 mL). Organic layer was separated and dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in hexanes to afford the desired product as white solid. Yield: 70.0 g, 73%.MS (ESI) m/z 343.19[M+1]+; TH
NMR (400 MHz, DMSO-d6); 8 4.84 (s, 4H), 2.37 (t, J = 7.2 Hz, 4H), 1.45-1.62 (m, 4H), 1.151.35 (m, 16H), 0.78-0.92 (m, 6H).
[0159] Step 2: Synthesis of 2-hydroxypropane- 1,3 -diyl dioctanoate (4): To an ice cold solution of 2oxopropane- 1,3 -diyl dioctanoate (3, 70.0 g, 0.204 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL), followed by the portion wise addition of sodium cyanoborohydride (15.43 g, 0.245 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 12 to 15% ethyl acetate in hexanes to afford the desired product 4 as yellow liquid. Yield: 50.0 g, 71%.MS (ESI)- m/z 345.29[M+1]+; 'H NMR (400 MHz, DMSO- d6); 8 5.25 (d, J = 5.2 Hz, 1H), 3.92-4.03 (m, 4H), 3.81-3.90 (m, 1H), 2.29 (t, J =
7.6 Hz, 4H), 1.45-1.59 (m, 4H), 1.12-1.35 (m, 16H), 0.85 (t, J = 6.8 Hz, 6H).
[0160] Step 3: Synthesis of 4-((l,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (6): To a solution of 2-hydroxypropane- 1,3 -diyl dioctanoate (4, 50.0 g, 0.145 mol) in chloroform (200 mL), dihydrofuran-2, 5-dione (5, 17.44 g, 0.174 mol) and triethylamine (30.0 mL, 0.218 mol) were added at room temperature. The reaction mixture was stirred at 120 °C for 3h. After completion, reaction mixture was diluted with water (200 mL) and extracted with 1,2 di chloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 10 to 15% ethyl acetate in hexanes to affored the desired product 6 as white solid. Yield: 47.0 g, 72%.MS (ESI)- m/z 443.2[M-1];1H NMR (400 MHz, DMSO-d6): 8 12.22 (s, 1H), 5.12-5.22 (m, 1H), 4.18-4.25 (m, 2H), 4.09-4.17 (m, 2H), 2.42-2.50 (m, 4H), 2.29 (t, J = 7.24 Hz, 4H), 1.44-1.55 (m, 4H), 1.15-1.31 (m, 16H), 0.79-0.90 (m, 6H).
[0161] Scheme II: Synthesis of 4-((L3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (diglyceryl lauryl succinate):
Figure imgf000027_0001
SCHEME II
[0162] Step 1 : Synthesis of 2-oxopropane- 1,3 -diyl didodecanoate (3 A): To an ice cold solution of l,3-dihydroxypropan-2-one (1, 30.0 g, 0.33 mol) in dichloromethane (500 mL) was added 4dimethylaminopyridine (20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred for next 5 min. To the above mixture dodecanoyl chloride 2A (218.50 g, 1.167 mol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was filtered; the solid was washed with di chloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HC1 solution (100 mL). Organic layer was separated and dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was triturated with diethyl ether to afford the desired product 3 A as white solid. Yield: 78 g, 51%.MS (ESI)m/z 455.37[M+1]+;1H NMR (400 MHz, DMSO-d6) - 84.74 (s, 4H), 2.43 (m, 4H), 1.64 (m, 4H), 1.55- 1.25 (m, 32H), 0.87 (m, 6H).
[0163] Step 2: Synthesis of 2-hydroxypropane- 1,3 -diyl didodecanoate (4A): To an ice cold solution of 2-oxopropane- 1,3 -diyl didodecanoate 3 A (75.0 g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium cyanoborohydride (12.41 g, 0.198 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude was triturated with diethyl ether to afford the desired product 4A as white solid. Yield: 60.0 g, 80%. MS (ESI); m/z 457.48[M+1]+;1H NMR (400 MHz, DMSO-d6) - 8 5.26 (d, J = 5.2 Hz, 1H), 3.92-3.98 (m, 4H), 2.28 (m, 4H), 1.50 (m, 4H), 1.23 (m, 33H), 0.83 (m, 6H).
Step 3: Synthesis of 4-((l,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (6A): To a solution of 2 -hydroxypropane- 1,3 -diyl didodecanoate 4A (40.0 g, 0.087 mol) in chloroform (200 mL), dihydrofuran-2, 5-dione 5 (10.50 g, 0.105 mol) and triethylamine (18.50 mL, 0.131 mol) were added at room temperature. The reaction mixture was stirred at 120°C for 3h. After completion, reaction mixture was diluted with water (200 mL) and extracted with 1,2 dichloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 25 to 30% ethyl acetate in hexanes to afford the desired product 6A as white solid. Yield: 20.0 g, 41%. MS (ESI)m/z 555.40^4-1];^ NMR (400 MHz, DMSO-d6)8 12.30 (s, 1H), 5.17 (m, 1H), 4.18-4.25 (m, 4H), 2.50-2.47 (m, 8H), 1.23-1.25 (m, 36H), 0.83 (m, 6H).
[0164] Scheme III: Synthesis of (E)-4-((L3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2- enoic acid(diglyceryl lauryl fumarate):
Figure imgf000028_0001
[0165] Step 1- Synthesis of 2-oxopropane- 1,3 -diyl didodecanoate (3*): To an ice cold solution of l,3dihydroxypropan-2-one (1, 30.0 g, 0.33 mol) in dichloromethane (500 mL) was added 4dimethylaminopyridine (20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred for next 5 min. To the above reaction mixture dodecanoyl chloride 2 (218.50 g, 1.167mol) was added dropwise at 0°C and the reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was filtered, the solid was washed with dichloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HC1 solution (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was triturated with diethyl ether to afford the desired product 3 * as white solid. Yield: 78 g, 51%. MS (ESI) m/z 455.37[M+1]+; 1HNMR (400 MHz, DMSO-d6): 84.74 (s, 4H), 2.43 (m, 4H), 1.64 (m, 4H), 1.55- 1.25 (m, 32H), 0.87 (m, 6H).
[0166] Step-2: Synthesis of 2-hydroxypropane- 1,3 -diyl didodecanoate (4*): To an ice cold solution of 2-oxopropane- 1,3 -diyl didodecanoate 3 (75.0 g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium cyanoborohydride (12.41 g, 0.198 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude was triturated with diethyl ether to afford the desired product 4* as white solid. Yield: 60.0 g, 80%. MS (ESI) m/z 457.48[M+1]+; 1HNMR (400 MHz, DMSO-d6): 8 5.26 (d, J = 5.2 Hz, 1H), 3.92-3.98 (m, 4H), 2.28 (m, 4H), 1.50 (m, 4H), 1.23 (m, 33H) and 0.83 (m, 6H).
[0167] Step-3: Synthesis of (E)-4-((l,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid (6*): To an ice-cold solution of 2-hydroxypropane- 1,3 -diyl didodecanoate 4 (10.0 g, 21.91 mmol) in THF (170 mL) was added fumaric acid 5 (2.54 g, 21.91 mmol), benzoyl chloride (2.5 mL, 21.91 mmol) and DMAP (0.67 g, 5.477 mmol). The resulting mixture was stirred at RT for 16h. After completion of reaction (TLC monitoring), reaction mixture was concentrated under reduced pressure. The crude was diluted with water (200 mL), adjust pH ~2-3 using 1N-HC1 and extracted with 1,2 di chloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 80% ethyl acetate in hexanes to afford the desired product 6* as white solid. Yield: 400 mg, 3.30% (un-optimized yield). LC-MS: m/z 553.64[M-1]; 97.27% purity. 1HNMR (400 MHz, DMSO-d6): 8 13.26 (br s, 1H), 5.17 (d, J = 15.8 Hz, 2H), 5.29 (m, 1H), 4.30-4.33 (m, 2H), 4.19-4.23 (m, 2H), 2.28 (m, 4H), 1.48 (m, 4H), 1.22 (m, 32H) and 0.83 (m, 6H).
[0168] Non-Limiting Examples:
Prototype Composition 1:
Figure imgf000029_0001
Figure imgf000030_0001
Prototype Composition 2:
Figure imgf000030_0002
Prototype Composition 3:
Figure imgf000030_0003
Figure imgf000031_0001
[0169] Bupivacaine HC1 and mometasone Lozenge 25 mg & 0.4 mg
[0170] Objective: To take a batch by wet granulation process and to check physical properties and loaded for stability study.
[0171] Composition 4: Composition comprising Bupivacaine HC1 and Mometasone
Figure imgf000031_0002
[0172] Manufacturing process:
1. Dispense all ingredients as per batch composition.
2. Sift the intragranular material through sieve 30 and manually blend for 10 min.
3. Dissolve mometasone furoate in alcohol to obtain clear homogenous solution
4. Granulate step 2 blend with solution of step 3
5. Dried the wet mass of step 4 at 40°C for 1 hr
6. Sift the dried granules of step 5 through sieve#30
7. Add the extragranular material to step 6 and blend for 10 min.
8. Lubricated step 7 with #60 passed stearic acid
9. Compressed the blend of step 8 with below parameters
[0173] Compression parameters; Batch No.: ACGCP200620011:
Figure imgf000032_0001
[0174] Observation: The flow of the blend was found to be good. The drug product were loaded for stability in HDPE bottles.
[0175] Objective: To take a batch by direct compression process and to check physical properties and loaded for stability study.
[0176] Composition 5: Composition comprising Bupivacaine HC1 and Mometasone
Figure imgf000032_0002
[0177] Manufacturing process:
1. Dispense all ingredients as per batch composition.
2. Sift step-1 material through sieve 30 and manually blend for 10 min.
3. API was mixed in geometric ratio with step 2 blend
4. Sift stearic acid through sieve#60
5. Lubricated step2 with step3
6. Compressed the step 5 with below parameters
[0178] Compression parameters; Batch No.: ACGCP200620012:
Figure imgf000032_0003
[0179] Observation: The flow of the blend was found to be good. The drug product were loaded for stability in HDPE bottles. [0180] Lidocaine and Melatonin Lozenges lOOmg + 10mg/ lOOmg + 3mg & 200mg + 3mg
[0181] Objective: Aqueous granulation with xylitol as diluent and lidocaine, melatonin added extragr anular
[0182] Composition 6: Composition comprising Lidocaine and Melatonin
Figure imgf000033_0001
[0183] Compression parameters; Batch No. ACGCP300220007B:
Figure imgf000033_0002
[0184] Dissolution of tablets in pH 6.8 Phosphate buffer; Batch No.: ACGCP300220007B
Figure imgf000033_0003
Figure imgf000034_0001
[0185] Objective: Reproducible batch to #07B
[0186] Composition 7: Composition comprising Lidocaine and Melatonin
Figure imgf000034_0002
[0187] Objective: Batch similar to #07B where citric acid used as stabilizing agent and D- Panthenol added in binder solution and extragranular addition of lidocaine.
[0188] Composition 8: Composition comprising Lidocaine and Melatonin
Figure imgf000034_0003
Figure imgf000035_0001
[0189] Objective: Batch similar to #07B by DC process where citric acid used as stabilizing agent and inclusion of calcium d-pantothenate.
[0190] Composition 9: Composition comprising Lidocaine and Melatonin
Figure imgf000035_0002
Figure imgf000036_0001
[0191] Compression parameters; Batch No.ACGCP300220010B:
Figure imgf000036_0002
[0192] Objective: Batch similar to #010B by DC process and inclusion of N-Acetyl cysteine
[0193] Composition 10: Composition comprising Lidocaine and Melatonin
Figure imgf000036_0003
[0194] Compression parameters; Batch No.ACGCP30022001 IB:
Figure imgf000037_0001
[0195] Objective: Batch similar to #01 IB by DC process by reducing disintegrant concentration
[0196] Composition 11: Composition comprising Lidocaine and Melatonin
Figure imgf000037_0002
[0197] Compression parameters; Batch No. AC GCP300220012B:
Figure imgf000037_0003
[0198] Objective: Batch similar to #01 IB by DC process and increasing concentration of binder;
HPMC E5.
[0199] Composition 12: Composition comprising Lidocaine and Melatonin
Figure imgf000038_0001
[0200] Compression parameters; Batch No. AC GCP300220013B:
Figure imgf000038_0002
[0201] Objective: Batch similar to #01 IB by DC process and using binder of higher viscosity grade; Hypromellose El 5
[0202] Composition 13: Composition comprising Lidocaine and Melatonin
Figure imgf000038_0003
Figure imgf000039_0001
[0203] Compression parameters; Batch No.ACGCP300220014B:
Figure imgf000039_0002
[0204] Objective: Repeat batch for #014B
[0205] Composition 14: Composition comprising Lidocaine and Melatonin
Figure imgf000039_0003
Figure imgf000040_0001
[0206] Compression parameters; Batch No.: AC GCP300220015B:
Figure imgf000040_0002
[0207] Objective: Batch similar to #01 IB by DC process and using binder of higher viscosity grade; Hypromellose E50
[0208] Composition 15: Composition comprising Lidocaine and Melatonin
Figure imgf000040_0003
[0209] Compression parameters; Batch No.:ACGCP300220016Bl :
Figure imgf000040_0004
Figure imgf000041_0001
[0210] Objective: Batch similar to #O16B1 by DC process without disintegrants.
[0211] Composition 16: Composition comprising Lidocaine and Melatonin
Figure imgf000041_0002
[0212] Compression parameters; Batch No.ACGCP300220016B2:
Figure imgf000041_0003
[0213] Objective: Batch similar to #01 IB by DC process and using binder of higher viscosity grade; HPMC K4M
[0214] Composition 17: Composition comprising Lidocaine and Melatonin
Figure imgf000041_0004
Figure imgf000042_0001
[0215] Compression parameters; Batch No. AC GCP300220017B:
Figure imgf000042_0002
[0216] Objective: Batch similar to #01 IB by DC process and including DGLF.
[0217] Composition 18: Composition comprising Lidocaine and Melatonin.
Figure imgf000042_0003
Figure imgf000043_0001
[0218] Compression parameters; Batch No. AC GCP30022018B:
Figure imgf000043_0002
[0219] Dissolution of tablets in pH 6.8 Phosphate buffer; Batch No. AC GCP30022018B
Figure imgf000043_0003
[0220] Objective: Batch similar to #010B by DC process and inclusion of DGLF.
[0221] Composition 19: Composition comprising Lidocaine and Melatonin.
Figure imgf000043_0004
Figure imgf000044_0001
[0222] Compression parameters; Batch No. AC GCP30022019B:
Figure imgf000044_0002
[0223] Physico-chemical properties of tablets; Batch No. AC GCP30022019B
Figure imgf000044_0003
Figure imgf000045_0001
[0224] Objective: Batch similar to #019B by DC process with melatonin 3 mg.
[0225] Composition 20: Composition comprising Lidocaine and Melatonin.
Figure imgf000045_0002
[0226] Compression parameters; Batch No. ACGCP30022020B:
Figure imgf000045_0003
Figure imgf000046_0001
[0227] Dissolution of tablets in pH 6.8 Phosphate buffer; Batch No. ACGCP30022020B
Figure imgf000046_0002
[0228] Objective: Batch similar to #019B without DGLF by DC process with melatonin 3 mg.
[0229] Composition 21 : Composition comprising Lidocaine and Melatonin.
Figure imgf000046_0003
[0230] Compression parameters; Batch No.: ACGCP300220021B:
Figure imgf000046_0004
Figure imgf000047_0001
[0231] Dissolution of tablets in pH 6.8 Phosphate buffer; Batch No. ACGCP3002202 IB
Figure imgf000047_0002
[0232] Objective: Repeat batch of #020 for stability initiation
[0233] Composition 22: Composition comprising Lidocaine and Melatonin.
Figure imgf000047_0003
[0234] Compression parameters; Batch No. ACGCP300220022B:
Figure imgf000048_0001
[0235] Physico-chemical parameters of tablets; Batch No. ACGCP30022022B
Figure imgf000048_0002
[0236] Objective: Repeat batch of #021 for stability initiation
[0237] Composition 23: Composition comprising Lidocaine and Melatonin.
Figure imgf000048_0003
Figure imgf000049_0001
[0238] Compression parameters; Batch No. ACGCP300220023B:
Figure imgf000049_0002
[0239] Physico-chemical parameters of tablets; Batch No. ACGCP30022023B
Figure imgf000049_0003
[0240] Objective: Batch similar to #019B without DGLF by DC process with melatonin 3mg [0241] Composition 24: Composition comprising Lidocaine and Melatonin.
Figure imgf000049_0004
Figure imgf000050_0001
[0242] Compression parameters; Batch No.ACGCP300220024B:
Figure imgf000050_0002
[0243] Dissolution of tablets in pH 6.8 Phosphate buffer; Batch No. ACGCP30022024B
Figure imgf000050_0003
[0244] Objective: Batch without DGLF by DC process with 200 mg of lidocaine and melatonin 3 mg
[0245] Composition 24: Composition comprising Lidocaine and Melatonin.
Figure imgf000050_0004
Figure imgf000051_0001
Compression parameters; Batch No. ACGCP200420001A:
Figure imgf000051_0002
Dissolution of tablets in pH 6.8 Phosphate buffer; Batch No. ACGCP200420001 A
Figure imgf000051_0003
[0246] Objective: Batch with DGLF by DC process with 200 mg of lidocaine and melatonin 3 mg [0247] Composition 25: Composition comprising Lidocaine and Melatonin.
Figure imgf000051_0004
Figure imgf000052_0001
[0248] Compression parameters; Batch No. ACGCP200420002A:
Figure imgf000052_0002
[0249] Dissolution of tablets in pH 6.8 Phosphate buffer; Batch No. ACGCP200420002A
Figure imgf000052_0003
[0250] Objective: Batch similar to #001 A without DGLF by DC process with 100 mg of lidocaine and melatonin 3 mg.
[0251] Composition 26: Composition comprising Lidocaine and Melatonin.
Figure imgf000052_0004
Figure imgf000053_0001
[0252] Compression parameters; Batch Ao. ACGCP200420003B:
Figure imgf000053_0002
[0253] Dissolution of tablets in pH 6.8 Phosphate buffer; Batch No. ACGCP200420003B
Figure imgf000053_0003
[0254] Objective: Batch similar to #002 A by DC process with 2 mg sodium hyaluronate, 100 mg of lidocaine and melatonin 3 mg.
[0255] Composition 27: Composition comprising Lidocaine and Melatonin.
Figure imgf000054_0001
[0256] Compression parameters; Batch No. ACGCP200420004B:
Figure imgf000054_0002
[0257] Dissolution of tablets in pH 6.8 Phosphate buffer; Batch No. ACGCP200420004B
Figure imgf000054_0003
[0258] Description of the Manufacturing Process [0259] Dispensing:
Step-1 : Dispensed all the required raw materials using a calibrated weighing balance.
[0260] Dry mixing:
Step-2: Sifted Xylitol, L-Carnosine, Magnesium oxide, Diglyceryl lauryl fumarate, Calcium carbonate, L-Carnosine, Hypromellose, Croscarmellose sodium, simethicone powder and citric acid through ASTM #40 sieve.
Step 3: Dry mixed the sifted materials of step 2 for 10 min at 50 rpm
Step 4: Simethicone was added to step 3 mixed well.
[0261] Drying:
Step 5: Dried the wet mass of step 4, at an inlet temperature of NMT 60°C until LOD of NMT 3.5% is obtained.
[0262] Sizing:
Step 6: Dried material of step 5 was passed through ASTM sieve no.40
[0263] Pre-Lubrication:
Step 7: Granules of step 6 were blended with extra-granular materials (passed through ASTM 40 sieve) i.e., Lidocaine hydrochloride monohydrate, melatonin, Calcium D-Pantothenate, colloidal silicon dioxide and peppermint flavor and blended for 10 min.
[0264] Lubrication:
Step 8: Blend of step 7 was lubricated with #60 passed zinc stearate for 5 min.
[0265] Compression:
Step 9: Lubricated blend of step 8 was compressed with the following compression parameters
[0266] Compression parameters:
Figure imgf000055_0001
[0267] Packaging: Step 10: 40 tablets of step 9 were filled in 60cc HDPE bottle along with one 2g silica gel bag, induction sealed and closed with 33 mm CR closure.
Batch Formula for ACGCP200420010A
[0268] Objective: Batch with granulation process with 200 mg of lidocaine and melatonin 3 mg.
Composition 28: Composition comprising Lidocaine and Melatonin.
Figure imgf000056_0001
[0269] Objective: Batch with granulation process with 100 mg of lidocaine and melatonin 3 mg. Composition 29: Composition comprising Lidocaine and Melatonin.
Figure imgf000056_0002
Figure imgf000057_0001
[0270] Manufacturing procedure:
1. Dispense Mannitol, L-Carnosine, Heavy Magnesium oxide, Calcium carbonate, Croscarmellose sodium, Calcium D-Panthenol, Hypromellose, Simethicone emulsion.
2. Sift Mannitol, L-Camosine, Heavy Magnesium oxide, Calcium carbonate, Croscarmellose sodium and Calcium D-Pantothenate through #30 ASTM sieve.
3. Dry mix the material of step 2 for 10 minutes
[0271] Preparation of binder solution:
4. Add Hypromellose and Simethicone to weighed quantity of purified water under stirring and mix well to obtain clear solution.
5. Granulate the material of step 3 using binder solution of step 4 6. Dry the wet mass of step no. 5 at inlet temperature of 50±5°C until LOD of granules reaches to NMT 2.0 %w/w at 105°C by auto mode using moisture analyzer.
7. Sift the dried granules of step no. 6 through mesh #30 (600p)
8. Dispense the extra granular material i.e., Lidocaine hydrochloride monohydrate, Melatonin, Mannitol, Colloidal silicon dioxide, Peppermint flavor and zinc stearate.
9. Sift the Lidocaine hydrochloride monohydrate, Melatonin, Mannitol, Colloidal silicon dioxide and Peppermint flavor of step 8 through #30 ASTM sieve.
10. Sift zinc stearate through #60 ASTM sieve separately.
11. Blend the material of step 7 and 9 for 15 minutes
12. Lubricate the blend of step 11 with sifted zinc stearate of step no. 10
13. Compress the lubricated blend of step no. 12 with the following compression parameters.
[0272] Compression parameters:
Figure imgf000058_0001
[0273] Pack the tablets of step no. 13 in 60cc HDPE with 40’s count, 2g silica gel bag and 1g absorbent cotton and seal with 33mm CR closure with induction sealing liner wadExamples of compositions comprising Lidocaine and Mometasone Lozenge 200/0.8 mg
[0274] Objective: To take a trial with lidocaine (200 mg/tab) and Momentasone furoate (0.8 mg/tab) by wet granulation process to check physico-chemical properties and to submit samples for method development.
[0275] Composition 30: Composition comprising Lidocaine and Mometasone.
Figure imgf000058_0002
Figure imgf000059_0001
[0276] Manufacturing procedure:
1. Dispense all ingredients as per batch composition.
2. Sift mannitol, magnesium oxide, calcium carbonate, Croscarmellose sodium, Hypromellose and Lidocaine HC1 through sieve 30 and collected in a polybag.
3. Manually blend step-2 sifted material for 10 min.
4. Dissolve API in required quantity of alcohol and used as binder solution.
5. Granulate step 3 material with step 4 binder solution.
6. Dry the wet mass step 5 in an oven at 50°C for 2 hrs and sift the dried granules through #30 mesh.
7. Step 6 material was lubricated with exragranular materials (previously sifted through sieve #40) for 5min.
8. Compress the blend with following parameters
[0277] Compression parameters; Batch No.: ACGCP200620002.
Figure imgf000059_0002
[0278] Observation and conclusion: Moisture was pickup by blend during compression and sticking also observed.
[0279] Objective: To take a batch similar to #002 with extragranular addition of lidocaine to check physico-chemical properties.
[0280] Composition 31: Composition comprising Lidocaine and Mometasone
Figure imgf000059_0003
Figure imgf000060_0001
[0281] Manufacturing process:
1. Dispense all ingredients as per batch composition.
2. Sift mannitol, magnesium oxide, calcium carbonate, Croscarmellose sodium and Hypromellose through sieve 30 and collected in a polybag.
3. Manually blend step-2 sifted material for 10 min.
4. Dissolve mometasone in required quantity of alcohol and used as binder solution.
5. Granulate step 3 material with step 4 binder solution.
6. Dry the wet mass step 5 in oven at 50°C for 2 hrs and sift the dried granules through #30 mesh.
7. Step 6 material was lubricated with exragranular materials (previously sifted through sieve #40) for 5min.
8. Compress the blend with following parameters
[0282] Compression parameters; Batch No.: ACGCP200620003:
Figure imgf000060_0002
[0283] Observation and conclusion: Flow of blend is good. Batch submitted for method development.
[0284] Objective: To take a batch similar to #003 with 0.4 mg of Momatasone furoate (Lower strength) to check physico-chemical properties and to submit samples for analysis.
[0285] Composition 32: Composition comprising Lidocaine and Mometasone
Figure imgf000060_0003
Figure imgf000061_0001
[0286] Manufacturing procedure:
1. Dispense all ingredients as per batch composition.
2. Sift mannitol, magnesium oxide, calcium carbonate, CCS and HPMC through sieve 30 and collected in a polybag.
3. Manually blend step-2 sifted material for 10 min.
4. Dissolve CLX-GEN-G024-C01 in required quantity of alcohol and used as binder solution.
5. Granulate step 3 material with step 4 binder solution.
6. Dry the wet mass step 5 in oven at 50°C for 2 hrs and sift the dried granules through #30 mesh.
7. Step 6 material was lubricated with exragranular materials (previously sifted through sieve #40) for
5min.
8. Compress the blend with following parameters
[0287] Compression parameters; Batch No.: ACGCP200620004:
Figure imgf000061_0002
[0288] Observation and conclusion: Flow of blend is good. Batch submitted for analytical method development. [0289] Objective: To carry-out drug-excipient compatibility study to check RS.
[0290] Drug-excipient compatibility study to check RS
Figure imgf000062_0001
[0291] Analytical data:
Figure imgf000062_0002
Figure imgf000063_0001
[0292] Observation and conclusion: Based on stability data, mometasone related impurity is found to be increase with mannitol, simethicone, magnesium oxide, zinc stearate and calcium carbonate.
[0293] Objective: To take a batch with different excipients and to check its impact on RS.
[0294] Composition 33 Composition comprising Lidocaine and Mometasone
Figure imgf000063_0002
[0295] Manufacturing process:
1. Dispense all ingredients as per batch composition.
2. Sift intragranular material through sieve 30 and collected in a polybag.
3. Manually blend step-2 sifted material for 10 min.
4. Dissolve Mometasone in required quantity of alcohol and used as binder solution.
5. Granulate step 3 material with step 4 binder solution.
6. Dry the wet mass step 5 in oven at 50°C for 2 hrs and sift the dried granules through #30 mesh.
7. Lubricated the granules as per batch composition.
8. Blend filled in HDPE containers and kept for stress study at 60°C [0296] Observation and conclusion: Different combinations of mixtures loaded for stress study to check RS. RS was found to be increased in all the mixtures. (More than 2%)
[0297] Objective: To take a batch with different combination of excipients by DC process and to check RS.
[0298] Composition 34: Composition comprising Lidocaine and Mometasone
Figure imgf000064_0001
[0299] Manufacturing process:
1. Dispense all ingredients as per batch composition.
2. Sift step-1 material through sieve 30 and manually blend for 10 min.
3. Blend filled in HDPE containers and kept for stress study at 60°C
[0300] Observation and conclusion: Different combinations of mixtures prepared and loaded in stress study. RS was found to be increased in all the mixtures. (More than 2%). API-API interaction was observed during stress study.
[0301] Objective: To take a batch with DC process and to check physical properties and loaded for stability study.
[0302] Composition 35: Comprising Mometasone Lozenge 0.8 mg
Figure imgf000064_0002
[0303] Manufacturing process:
1. Dispense all ingredients as per batch composition.
2. Sift step-1 material through sieve 30 and manually blend for 10 min.
3. Sift stearic acid through sieve#60.
4. Lubricated step2 with step3.
5. API was sifted through sieve#60.
6. API was geometric mix with step 4.
7. Compressed the step6 with below parameters.
[0304] Compression parameters; Batch No.: ACGCP200620009:
Figure imgf000065_0001
[0305] Analytical data; Batch No.: ACGCP200620009:
Figure imgf000065_0002
[0306] Observation and conclusion: Flow of blend is good. Based on content uniformity data, there is a unit-to-unit variation and also fails to meet the acceptance criteria.
[0307] Objective: To take a batch by wet granulation process and to check physical properties and loaded for stability study.
[0308] Composition 36: comprising Mometasone
Figure imgf000066_0001
[0309] Manufacturing process:
1. Dispense all ingredients as per batch composition.
2. Sift intragranular material through sieve 30 and manually blend for 10 min.
[0310] Binder solution
3. Mometasone dissolved in required quantity of ethanol and used as binder.
4. Granulate step 2 sifted material with step 3 binder solution.
5. Dried the wet mass at 40°C for 2 hrs.
6. Sift the dried granules through sieve # 30 and lubricated with extra granular material (Sifted through sieve#60).
7. Compressed the step 6 with below parameters
[0311] Compression parameters
Figure imgf000066_0002
[0312] BIOLOGY MODELS TO DETERMINE THE USE OF THE INVENTION WITH THE ACTIVES IN THE COMPOSITION OF THE INSTANT INVENTION
[0313] Nonmalignant immortalized esophageal epithelial cell lines, cell types, and immortalization techniques.
[0314] Reduction of eosinophils and mast cells, which demonstrate changes in the expression of numerous signaling molecules, including IL-4, IL-5, IL-13, TGF-beta and TSLP, in reaction to allergens.
[0315] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
INCORPORATION BY REFERENCE
[0316] All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Claims

: An oral pharmaceutical composition comprising: at least one local anesthetic in an amount of 25 mg to 600 mg; at least one steroid in an amount of 0.005 mg to 1000 mg; melatonin in an amount of 1 mg to 100 mg; and a pharmaceutically acceptable excipient; or at least one local anesthetic in an amount of 25 mg to 600 mg; at least one steroid in an amount of 0.005 mg to 1000 mg; and a pharmaceutically acceptable excipient; or at least one local anesthetic in an amount of 25 mg to 600 mg; melatonin in an amount of 1 mg to 100 mg; and a pharmaceutically acceptable excipient; or at least one local anesthetic in an amount of 25 mg to 600 mg; melatonin in an amount of 1 mg to 100 mg; and a pharmaceutically acceptable excipient; or at least one steroid in an amount of 0.005 mg to 1000 mg and a pharmaceutically acceptable excipient; or at least one steroid in an amount of 0.005 mg to 1000 mg; and a pharmaceutically acceptable excipient delivered as a lozenge formulation. The oral pharmaceutical composition of claim 1, wherein the local anesthetic are selected from a group consisting of benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, amylocaine, oxybuprocaine, articaine, bupivacaine, dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, sameridine, tonicaine, cinchocaine or their salt thereof. The oral pharmaceutical composition of claim 1, wherein the steroid are selected from a group consisting of hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, predni carb ate, tixocortol pivalate or their salt thereof. The oral pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from any or a combination of: disintegrant, binder, diluent, solvent, flavoring agent, glidant, lubricant, pH modifier, anti-foaming agent, fatty acid derivatives and antioxidant or a combination thereof. The oral pharmaceutical composition of claim 4, wherein the disintegrants is croscarmellose sodium or aerosil. The oral pharmaceutical composition of claim 4, the binder is hypromellose. The pharmaceutical composition of claim 4, the diluent is mannitol, xylitol, heavy magnesium oxide or calcium carbonate. The oral pharmaceutical composition of claim 4, the solvent is alcohol, ethanol, or water The oral pharmaceutical composition of claim 4, the flavoring agent is organ or peppermint. The oral pharmaceutical composition of claim 4, the glidants is colloidal silicon dioxide. The oral pharmaceutical composition of claim 4, the lubricant is steric acid or zinc stearate. The oral pharmaceutical composition of claim 4, anti-foaming agent is simethicone 30% emulsion. The oral pharmaceutical composition of claim 4, wherein the pH modifier is L-Camosine The oral pharmaceutical composition of claim 4, wherein the antioxidant is citric acid, D- Panthenol, or Calcium D-Pantothenate. The oral pharmaceutical composition of claim 4, wherein the fatty acid derivatives are selected from a group consisting of diglyceryl lauryl fumarate, diglyceryl lauryl succinate, diglyceryl capryl succinate, diglyceryl capryl fumarate or a combination thereof. The oral pharmaceutical composition of claim 1 wherein the composition comprises of mometasone furoate, croscarmellose sodium, hypromellose, mannitol, xylitol, ethanol, peppermint flavor, colloidal silicon dioxide, and stearic acid. The oral pharmaceutical composition, of claim 1 wherein the composition comprises of bupivacaine hydrochloride, mometasone furoate, mannitol, xylitol, croscarmellose sodium, hypromellose, alcohol, colloidal silicon dioxide, peppermint flavor and stearic acid. The oral pharmaceutical composition, of claim 1 wherein the composition comprises of lidocaine hydrochloride monohydrate, mometasone furoate, mannitol, 1-carnosine, heavy magnesium oxide, calcium carbonate, croscarmellose sodium, calcium D-pantothenate, hypromellose, simethicone 30% emulsion, purified water, mannitol, colloidal silicon dioxide, zinc stearate, and peppermint flavor. The oral pharmaceutical composition, of claim 1, wherein the composition is formulated as dosage forms tablet, oral gel, mouth wash, buccal tablet, sublingual tablet, lozenges, film based, oral spray, or mucosal adhesive formulation.
PCT/IB2023/053109 2022-03-30 2023-03-29 A pharmaceutical composition for the treatment of immune system mediated diseases WO2023187664A1 (en)

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WO2019219145A1 (en) * 2018-05-17 2019-11-21 Fertin Pharma A/S An oral tablet suitable for fast release of active pharmaceutical ingredients
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WO2001030288A1 (en) * 1999-10-27 2001-05-03 Anesta Corporation Oral transmucosal drug dosage using solid solution
US20090123390A1 (en) * 2007-11-13 2009-05-14 Meritage Pharma, Inc. Compositions for the treatment of gastrointestinal inflammation
AU2016213816A1 (en) * 2009-10-01 2016-09-01 Adare Pharmaceuticals, Inc. Orally administered corticosteroid compositions
US20140296293A1 (en) * 2011-04-29 2014-10-02 Oracain Ii Aps Pharmaceutical compositions comprising a local anaesthetic such as bupivacaine for local administration to the mouth or throat
US20160361320A1 (en) * 2015-06-15 2016-12-15 Banner Life Sciences Llc Soft lozenges comprising corticosteroids
WO2019219149A1 (en) * 2018-05-17 2019-11-21 Fertin Pharma A/S An oral tablet for delivery of active ingredients to the gastrointestinal tract
WO2019219145A1 (en) * 2018-05-17 2019-11-21 Fertin Pharma A/S An oral tablet suitable for fast release of active pharmaceutical ingredients
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