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EP2477604A2 - Suspension d'acétate de dexaméthasone à usage oral composition masquant le goût de la dexaméthasone - Google Patents

Suspension d'acétate de dexaméthasone à usage oral composition masquant le goût de la dexaméthasone

Info

Publication number
EP2477604A2
EP2477604A2 EP10719774A EP10719774A EP2477604A2 EP 2477604 A2 EP2477604 A2 EP 2477604A2 EP 10719774 A EP10719774 A EP 10719774A EP 10719774 A EP10719774 A EP 10719774A EP 2477604 A2 EP2477604 A2 EP 2477604A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
dexamethasone
dexamethasone acetate
acetate
vehicle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10719774A
Other languages
German (de)
English (en)
Inventor
Angelos Kassotakis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Casso Pharmaceuticals Ltd
Original Assignee
Casso Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Casso Pharmaceuticals Ltd filed Critical Casso Pharmaceuticals Ltd
Publication of EP2477604A2 publication Critical patent/EP2477604A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • the invention related to a immediate release pharmaceutical formulation for oral administration comprising an effective amount of dexamethasone acetate in an aqueous ,pharmaceutically acceptable vehicle and a suspending agent
  • Dexamethasone a corticosteroid ,used in inflammatory and autoimmune disorders, usually formulated into tablets and liquid formulations for oral delivery.
  • Commercially available oral liquid formulations of dexamethasone comprising soluble salts of dexamethasone esters, for example dexamethasone sodium phosphate.
  • dexamethasone sodium phosphate.
  • the bad taste of these solutions .extensively described in the literature ,results in poor patient compliance .
  • the bad taste of dexamethasone and its soluble esters are dose dependent it is a considerable problem for the patient to comply especially in case of therapies require high doses of dexamethasone.
  • the problem is to create a palatable, stable, immediate release oral liquid dosage form of dexamethasone especially when high therapeutic doses of dexamethasone are needed
  • Dexamethasone acetate (the insoluble acetate ester of dexamethasone) has been previously used in formulations for local administration -including ophthalmic formulations-,as well as in parenteral ( intramuscular) formulations , but it has not been previously used in oral liquid formulations for immediate release dosage forms
  • dexamethasone acetate can be used for the preparation of a suspension of dexamethasone ,in which dexamethasone acetate has the attribute to mask the bad and exceptionally bitter taste of dexamethasone .
  • This attribute becomes perceptible particular when high doses of the said active ingredient are needed to be administered.
  • specific excipients that are known to the skilled person it can be prepared a immediate release ,stable formulation ,with components mutually compatible and stable during the shelf life of the product as it is determined from the rules governing the medicinal products for human use.
  • Dexamethasone acetate possess specific advantages compared to other dexamethasone esters for this specific purpose a) Immediate release of the active ingredient dexamethasone in the low pH of the gastric fluids (1-2), according to the literature b) Low solubility. Dexamethasone acetate does not dissolved in the aqueous conditions of the mouth cavity, and the interactions between the bitter molecule of dexamethasone and the taste buds of the tongue are prevented.
  • the formulation of the present invention is a palatable, oral aqueous suspension of dexamethasone in which dexamethasone is in the form of the its acetate ester and in concentration between about 0.4 mg/ml to about 40 mg/ml , more preferably between 0.4 mg/ml to about 10mg/ml,more preferably 4 mg/ml
  • the present invention is an aqueous suspension in which dexamethasone is dispersed in a medium-vehicle, that comprised mainly from water and may include propylene glycol and glycerin .
  • Dexamethasone acetate is evenly dispersed in the liquid aqueous vehicle.
  • the suspension has homogeneity so the active ingredient is uniformly dispersed, but undissolved in the vehicle-aqueous medium.
  • the medium can also comprise other pharmaceutical excipients that are mutually compatible at room temperature and they can form a pharmaceutically acceptable oral liquid preparation.
  • the aqueous vehicle serves as the external phase for the suspensions.
  • the vehicle may comprised of water ,glycerin , propylene glycol and mixtures there of.
  • the water comprising from about 30 to about 70% of the vehicle.
  • Glycerin may comprise up to 50 % of the vehicle.
  • the vehicle may also contain propylene glycol up to 20% of the vehicle.
  • Purified water that is the main ingredient of the vehicle component, comprising from about 30 to about 70% (w/w) of the formulation.
  • Water concentration is about 30% to 40% (w/w) in the final formulation
  • the particle size is very important for the bio availability of the product .
  • the active surface area is increased and the dissolution time is also increased .
  • the increased surface area may result in some agglomeration affecting the stability of the suspension or increase the oxidation and hydrolysis of the active compound resulting in faster degradation of dexamethasone.
  • Dexamethasone acetate of the inventive formulation has a median particle size of l ⁇ m to about 30 ⁇ m, more preferably about 3 ⁇ m to about 15 ⁇ m .
  • the particle size can be achieved using established methods well known to the skilled person like air jet milling, ball milling, mortal milling or any other approved method to decrease the particle size.
  • dexamethasone acetate particles of the disclose formulation were micronised using Jet Mil 50 (Jet Pharma S.A.)
  • the viscosity may be about 80 to about 2000 cps ,more preferably about 100 to about 500 cps,most preferably about 100 to 150cps.
  • the active ingredient particles maybe crystals that neither dissolve or grow substantially when the sample is heated to 45 0 C and cooled to room temperature repeatedly
  • the size of the particles may be measured using light scattering device ,sedimentation methods, or any other methods known to the skilled person .
  • Pharmaceutical excipients are pharmaceutically approved components of virtually all the pharmaceutical formulations. Excipients serve many different and wide purposes during the process of formulation as well as in the final formulation it self.
  • the inventive pharmaceutical suspension may comprise at least one of the additional component excipient selected form the following groups of excipients: surface active agents ,dispersing agents , sweetening agents, flavoring agents, coloring agents, buffers, salts, preservatives, oily vehicles, wetting agents, demulcents, spreading agents, stabilizers, antioxidants, antibiotic ,antifungal agents .
  • Poloxamer 188 found to be effective , in concentrations at about 0.05 to 0.5% without create excessive foaming and without alter the taste of the inventive composition .
  • Spreading agents like maltitol, mannitol, polyethylene glycol, and sorbitol can be added to the vehicle components in order to adjust the spreadability of the final suspension.
  • the present embodiment of the invention and due to the low concentration of Xantham Gum and the low viscosity of the suspension there is no need to adjust spreadability .Notwithstanding the use of such spreading agents cannot be excluded in other embodiments of the present invention where the higher viscosity could be higher.
  • sorbitol and mannitol also serve as an immediate on set sweetener and for this purpose used also in the present invention. In the present embodiment it has been used sorbitol solution 70% (w/w) in concentration less than 20% (w/w) ,even more less than 15%(w/w),to about 10 to 15% (w/w) of the final formulation
  • the suspension of the present invention may contain EDTA.
  • EDTA is a chelating agent that creates stable complexes with metals ions (alkaline earth , mainly Ca 2+ and Zn 2+ ) . The involvement of these metals in traces in catalyzing the auto oxidation, is an obvious possibility and has been reported in the literature.
  • EDTA is useful as an antioxidant, sequestering metal ions that otherwise catalyze autoxidation reactions. E.D.T.A. can also be serve as a preservative.
  • the stability of the suspension can be increased by the incorporation in the suspension a small amount of nitrogen- containing compound , such as niacinamide, creatinine and derivatives there of , like n-methylcreatinine .
  • nitrogen- containing compound such as niacinamide, creatinine and derivatives there of , like n-methylcreatinine .
  • antioxidants include , both inorganic and organic compounds .
  • Organic antioxidants such as Sodium Citrate penicillamine , pyridinesulfinic acid , thiourea and sodium formaldehyde sulfoxylate are acceptable .
  • Inorganic antioxidants such as sodium sulfite ,sodium metabisulf ⁇ te, sodium hypophosphite are acceptable.
  • inventive suspension contains sodium metabisulfite Suspending agents is another group of excipients.
  • the inventive formulation may contain xantham gum in a concentration from about 0.1% (w/w) at about 0.3% ,more preferably between 0.1 to 0.25 ,most preferably 0.17% (w/w).
  • a bacteriogical preservative for example , like sodium benzoate , methyl-paraben, propyl paraben, butyl-paraben , other antimicrobial agents can also be used in concentration and limits described in the pharmaceutical literature .
  • the inventive formulation may comprise sweeteners for making the inventive formulation even more palatable.
  • the present invention comprise at least one sweetener immediate onset and at least one sweetener delayed on set .
  • the present invention comprise aspartame and neohesperidin.
  • the present embodiment of the invention comprised of sorbitol solution (70%) in a concentration less than 20% (w/w) more preferably less than 15% (w/w),at about 10 to 15% of the final formulation.
  • organoleptic agents include coloring and flavoring agents and masking agents and can be incorporated to the inventive formulation for making it even more palatable.
  • the shelf life of the product may be six ,twelve, eighteen ,twenty four months, thirty or thirty six months as it can be determined by according to the regulatory stability testing of the final formulation and described by the rules governing the medicinal products for human use.
  • the dexamethasone acetate suspension contain the following ingredients TABLE 1
  • Mint Flavor (Tagasago Peppermint flavor 10324199) 0.11

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention concerne une composition pharmaceutiquement acceptable sous la forme d'une suspension d'acétate de dexaméthasone destinée à être administrée par voie orale. Dans ladite composition, le principe actif est dispersé de manière homogène dans un excipient-véhicule pharmaceutiquement acceptable. Cette invention concerne un procédé destiné à masquer le mauvais goût de la dexaméthasone, et une composition pharmaceutique comprenant un ester spécifique de dexaméthasone (acétate de dexaméthasone), en une quantité thérapeutiquement efficace dans un véhicule aqueux stable et compatible, et un agent de mise en suspension. La formulation selon l'invention comprend un acétate de dexaméthasone dispersé dans un véhicule aqueux compatible, à raison d'environ 0,4 à environ 40 mg/ml, de préférence, de 0,4 et environ 10 mg/ml, de préférence encore, de 4 mg/ml. Le véhicule aqueux peut, en outre, être constitué par du glycérol et du propylène glycol. La composition selon l'invention comprend plus d'un excipient pharmaceutique.
EP10719774A 2009-04-14 2010-04-14 Suspension d'acétate de dexaméthasone à usage oral composition masquant le goût de la dexaméthasone Withdrawn EP2477604A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20090100230A GR20090100230A (el) 2009-04-14 2009-04-14 Απο του στοματος εναιωρημα οξικης δεξαμεθανοζης-συνθεση καλυψης γευσης της δεξαμεθανοζης
PCT/GR2010/000018 WO2010119300A2 (fr) 2009-04-14 2010-04-14 Suspension d'acétate de dexaméthasone à usage oral – composition masquant le goût de la dexaméthasone

Publications (1)

Publication Number Publication Date
EP2477604A2 true EP2477604A2 (fr) 2012-07-25

Family

ID=42269791

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10719774A Withdrawn EP2477604A2 (fr) 2009-04-14 2010-04-14 Suspension d'acétate de dexaméthasone à usage oral composition masquant le goût de la dexaméthasone

Country Status (3)

Country Link
EP (1) EP2477604A2 (fr)
GR (1) GR20090100230A (fr)
WO (1) WO2010119300A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101368587B1 (ko) 2010-12-27 2014-03-05 주식회사 삼양바이오팜 오심 또는 구토 방지용 조성물
EP2875359A4 (fr) 2012-03-30 2015-08-19 Charles R Drew University Of Medicine And Science Compositions et procédés de traitement ou de prévention de troubles du syndrome métabolique
US20140271923A1 (en) 2013-03-14 2014-09-18 Christopher Brian Reid Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions
US10537585B2 (en) 2017-12-18 2020-01-21 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone

Family Cites Families (10)

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Publication number Priority date Publication date Assignee Title
FR2159195A1 (en) 1971-11-10 1973-06-22 Fabre Sa Pierre Compsns contg sorbitol and a corticoid or pyrazolone - - suppression of ulcerogenic effects
US3962430A (en) 1974-08-07 1976-06-08 Merck & Co., Inc. Sterilization of solid non-electrolyte medicinal agents employing sodium chloride
US6066292A (en) * 1997-12-19 2000-05-23 Bayer Corporation Sterilization process for pharmaceutical suspensions
NZ551336A (en) 2004-04-22 2010-04-30 Acucort Ab Pharmaceutical compositions for acute glucocorticoid therapy
LT2522365T (lt) 2004-11-24 2017-02-10 Meda Pharmaceuticals Inc. Kompozicijos, apimančios azelastiną, ir jų panaudojimo būdai
DE102005055385A1 (de) 2004-12-09 2006-06-14 Bayer Healthcare Ag Arzneimittel zur hygienischen Applikation im Ohr
JP5002462B2 (ja) 2004-12-09 2012-08-15 バイエル・アニマル・ヘルス・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング 酸によるグルココルチコイドエステルの安定化
US8468589B2 (en) 2006-01-13 2013-06-18 Fortinet, Inc. Computerized system and method for advanced network content processing
PT1795183E (pt) 2005-12-09 2009-08-21 Teva Pharma Dispersões aquosas e soluções de compostos difíceis de dissolver e métodos para a sua preparação
CN101190177B (zh) * 2006-11-24 2010-09-01 上海医药工业研究院 醋酸地塞米松局部成膜凝胶组合物及其应用

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Title
See references of WO2010119300A2 *

Also Published As

Publication number Publication date
GR20090100230A (el) 2010-11-18
WO2010119300A2 (fr) 2010-10-21
WO2010119300A9 (fr) 2011-07-28
WO2010119300A3 (fr) 2011-03-24

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