EP2477604A2 - Oral suspension of dexamethasone acetate -taste masking composition of dexamethasone - Google Patents

Oral suspension of dexamethasone acetate -taste masking composition of dexamethasone

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Withdrawn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)
French (fr)
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/en
Withdrawn legal-status Critical Current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)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (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

The present invention is a pharmaceutically acceptable composition in the form of suspension for the oral delivery of dexamethasone acetate in which the active ingredient is homogenously dispersed in a pharmaceutically acceptable aqueous carrier -vehicle. The present invention relates to a method for taste masking the bad taste of dexamethasone, provide a pharmaceutical composition comprising a specific ester of dexamethasone (dexamethasone acetate), in a therapeutically effective amount in a aqueous, compatible, stable media vehicle and a suspending agent The inventive formulation comprising dexamethasone acetate dispersed in an aqueous, compatible, 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 aqueous vehicle may further consist of glycerin and propylene glycol. The inventive composition, comprises more than one pharmaceutical excipients.

Description

ORAL SUSPENSION OF DEXAMETHASONE ACETATE -TASTE
MASKING COMPOSITION OF DEXAMETHASONE
DESCRIPTION
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. However the bad taste of these solutions .extensively described in the literature ,results in poor patient compliance . Provided that 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.
Furthermore the bad (bitter ) taste and aftertaste of these liquid oral dosage forms is difficult to be masked , without alter the release rate of the active ingredient and using the already known taste masking techniques , that can be found in the literature and are known to the skilled person.
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
After many experiments we surprisingly found that 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.. Moreover by the use of 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. In our case and as it is previously described , 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. In the present embodiment 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 .In case of smaller particle size the active surface area is increased and the dissolution time is also increased .On the other hand 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 lμm to about 30 μm, more preferably about 3 μm to about 15 μm . 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. For example 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. In the inventive formulation there is no crystalline growth during a heat cool study for three days at a temperature range of 80C to about 45°C.The active ingredient particles maybe crystals that neither dissolve or grow substantially when the sample is heated to 45 0C 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 .For example Matersizer 2000 manufactured by Malvern instruments Ltd ,Malvern U.K. the maybe used to measure the particle size. 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 .
In the present formulation , due to the insoluble nature of dexamethasone acetate a wetting agent was necessary in order to ensure the homogenously dispersion of the active ingredient in the aqueous based vehicle. 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. In 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. Especially 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 Ca2+ and Zn2+ ) .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 .These compounds usually act as stabilizers for the ester and prevents the precipitates for long period of time
In addition to these stabilizers and since a certain proportion of any decomposition evidenced is due to oxidative degradation , it is desirable to include to these formulations , a small amount of antioxidant .Suitable 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 metabisulfϊte, sodium hypophosphite are acceptable. In the present embodiment the inventive suspension contains sodium metabisulfite Suspending agents is another group of excipients. These agents usually added for obtain the desired viscosity and flow to the formulation. As thickening can be used a group of different compounds like xantham gum or carbomers. This depends on the desired viscosity of the final formulation. Xantham gum is active and keep its properties in a wide range of pH, thus it appears more advantageous than other suspending agents. 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).
Even though it is well described in the literature that the acetate ester of dexamethasone is more stable in low pH values (acidic conditions) there is a further need to determine with more accuracy the pH values in which the suspension remain stable ,avoiding the ester degradation and further interactions between suspension components. For these reasons we proceed in one month accelerated stability studies. A sample of the suspension that is described in the present embodiment of the invention divided in 6 amber glass vials of 100ml volume. pH was adjusted with NaOH. Finally it was prepared six suspension of the said formulation with pH values of 3.8, 4.0 ,4.2, 4.6, 5.0 ,5.2 ,5.4 και 5.6.Dexamethasone acetate was measured by HPLC (High Pressure Liquid Chromatography)Measurements showed that the optimal pH is 4 9 (percentage of degradation less than 1%)
In addition to those stabilizers and antioxidants other substances can be included to the present formulation .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.
Other organoleptic agents include coloring and flavoring agents and masking agents and can be incorporated to the inventive formulation for making it even more palatable.
As it is previously mentioned the components are pharmaceutically compatible, that means that do not interact or separate in the preparation ,keep their properties and are stable during the shelf life of the product as it is determined by the regulatory storage stability testing of the preparation ( as indicated by accelerated 3 month intervals stability studies in stress conditions Θ=40°C,RH=75%)
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 following examples further illustrate the invention, but should not be construed as limiting the invention by any manner.
In describing embodiments of the present invention has been used specific terminology common and well known to the skilled of the art person. However this invention is not intended to be limited of, the specific terminology. Each specific element includes all the technical equivalents which operates in a similar manner to accomplish a similar purpose. The above described embodiments of the invention may be modified or varied, and elements added or omitted, without changing the teaching of the invention, as it is well understood from the skilled in the art person.
EXAMPLE 1
[0037]The dexamethasone acetate suspension contain the following ingredients TABLE 1
Composition of oral dexamethasone acetate suspension
INGREDIENTS 4mg/ml
Dexamethasone acetate 0.38
Poloxamer 188. 0.13
Glycerine 43.7
Propylene Glycol 4.48
Edetate disodium 0.17
Aspartame 0.09
Mint Flavor (Tagasago Peppermint flavor 10324199) 0.11
Xantham Gum 0.17
Sodium Metabisulfite 0.17
Sorbitol solution 70 % 11.25
Creatinine 0.17
Neohesperidin dihydrochalcone 0.02
Purified water 38.90
Citric acid q.s. pH = 3.80 - 4.20 (about 3.60 mg for pH = 4.00) [0038] A small sample of volunteers( 5 volunteers) evaluate the dexamethasone formulation for taste and flavour Sensory Perception in different samples of Dexamethasone formulation
Product Description Initial Taste After Taste
Dex/ne acetate suspension Sweet, Mint Flavor No bitterness 4 mg/ml perceived
Dexamethasone Sodium
Phosphate Sol 4mg/ml Sweet, Mint Flavour Delayed bitter taste, CASSO Persistent for long time

Claims

I .A pharmaceutical composition for the oral delivery comprising a effective amount of dexamethasone acetate .
2. A pharmaceutical composition of the claim 1 for taste masking the bitter taste and after taste of dexamethasone .
3. The pharmaceutical composition of the claim 1 where in the dexamethasone acetate is suspended.
4. The pharmaceutical composition of the claim 3 further comprising a pharmaceutically acceptable vehicle and a suspending agent 5. The composition of the claim 1 containing dexamethasone acetate between 0.4 mg/ml to about 40 mg/ml of dexamethasone acetate.
6. The pharmaceutical composition of the claim 1 wherein the dexamethasone acetate has a particle size between 1 to 30μm, more preferably between 3 to 15 μm
7. The pharmaceutical composition of the claim 4 where the suspending agent is xantham gum .
8. The pharmaceutical composition of the claim 4 where the vehicle is water, glycerine or propylene glycol and mixtures there of.
9. The pharmaceutical composition of the claim 3 where further comprising pharmaceutical excipients. 10. The pharmaceutical composition of the claim 8 further comprising a wetting agent
I 1 .The pharmaceutical composition of the claim 8 further comprising a spreading agent 12. The pharmaceutical composition of the claim 8 further comprising a stabilizer
13. The pharmaceutical composition of the claim 8 further comprising a preservative
14. The pharmaceutical composition of the claim 8 further comprising a sweetener 15. The pharmaceutical composition of the claim 8 further comprising a delay on set sweetener
16. The pharmaceutical composition of the claim 8 further comprising a flavouring agent
17. The pharmaceutical composition of the claim 3 having pH between 3.8 to 6, more preferably 4 to 5
18. The pharmaceutical composition of the for oral delivery comprising from about O.lto about 10 mg/ml of dexamethasone acetate ,about 30-70 % water (w/w) ,up to 50% glycerin ,up to 10% propylene glycol, up to 20% sorbitol, up to about 3% surfactant, up to about 15% surfactant (poloxamer 188) and up to about 1% of a suspending agent (Xantham gum)
19.A pharmaceutical composition for oral delivery comprising: a. 0.38 (w/w) dexamethasone acetate b. 0.13% (w/w) Poloxamer 188 c. 43.7 (w/w) Glycerin d. 4.48 % (w/w) Propylene glycol e. 0.17 % (w/w) EDTA f. 0.09% (w/w)Aspartame g. 0.17% (w/w) Xantham gum h. 11.25% (w/w) Sorbitol sol. 70% i. 0.17% (w/w) Sodium Metabisulfite j. 0.17% (w/w) Creatinine k. 0.02% (w/w) Neohesperidin dihydrochalcone 1. 0.11% (w/w) Mint Flavor (Mint Flavor-Tagasago Peppermint Flavor
10324199) m. 38.90% (w/w) Purified Water n. Citric acid q.s. pH = 3.80 - 4.20
20. The pharmaceutical composition of the claim 18,where the pH is between 3.8 and 6.
EP10719774A 2009-04-14 2010-04-14 Oral suspension of dexamethasone acetate -taste masking composition of dexamethasone Withdrawn EP2477604A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20090100230A GR20090100230A (en) 2009-04-14 2009-04-14 Oral suspension of dexamethasone acetate and composition masking the bad taste thereof
PCT/GR2010/000018 WO2010119300A2 (en) 2009-04-14 2010-04-14 Oral suspension of dexamethasone acetate -taste masking composition of dexamethasone

Publications (1)

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

Family

ID=42269791

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10719774A Withdrawn EP2477604A2 (en) 2009-04-14 2010-04-14 Oral suspension of dexamethasone acetate -taste masking composition of dexamethasone

Country Status (3)

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

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101368587B1 (en) * 2010-12-27 2014-03-05 주식회사 삼양바이오팜 Composition for prevention of nausea or vomiting
US9682093B2 (en) 2012-03-30 2017-06-20 Charles R. Drew University Of Medicine And Science Compositions and methods for treating or preventing metabolic syndrome disorders
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)

* Cited by examiner, † Cited by third party
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
WO2005102287A2 (en) 2004-04-22 2005-11-03 Duocort Ab Pharmaceutical compositions for acute glucocorticoid therapy
NZ555501A (en) 2004-11-24 2010-01-29 Medpointe Healthcare Inc Compositions comprising azelastine and methods of use thereof
EP1827498A2 (en) 2004-12-09 2007-09-05 Bayer HealthCare AG Stabilisation of glucocorticoid esters with acids
DE102005055385A1 (en) 2004-12-09 2006-06-14 Bayer Healthcare Ag Medicines for hygienic application in the ear
US8468589B2 (en) 2006-01-13 2013-06-18 Fortinet, Inc. Computerized system and method for advanced network content processing
WO2007067208A1 (en) 2005-12-09 2007-06-14 Teva Pharmaceutical Industries Ltd. Aqueous dispersions and solutions of difficult to dissolve compounds and methods of their preparation
CN101190177B (en) * 2006-11-24 2010-09-01 上海医药工业研究院 Dectancyl partial film forming gel composition and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010119300A2 *

Also Published As

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

Similar Documents

Publication Publication Date Title
US7799331B2 (en) Oral suspension of prednisolone acetate
US20100029714A1 (en) Aqueous pharmaceutical suspensions containing rebamipide and manufacturing process thereof
EP2838510B1 (en) Atomoxetine solution
WO2012001093A2 (en) Liquid formulations of rupatadine fumarate
KR100841893B1 (en) Pregabalin Composition
EP2477604A2 (en) Oral suspension of dexamethasone acetate -taste masking composition of dexamethasone
WO2013024373A1 (en) Pharmaceutical composition comprising cefuroxime
ES2968899T3 (en) Formulation of the oral solution
WO2006129160A2 (en) Stable aqueous oral solution of risperidone
US20230255885A1 (en) Chemotherapeutic pharmaceutical suspension for oral dosage
DK2662093T3 (en) tobramycin
JP5009707B2 (en) Solution for oral administration of quinolone antibacterial agent masked with unpleasant taste
WO2012150607A2 (en) Oral liquid composition comprising divalproex sodium and process for preparing thereof
KR102556874B1 (en) A pharmaceutical composition comprising bisphosphonate and cholecalciferol, and its manufacturing method
AU2017317523B2 (en) Pharmaceutical solution of Asenapine for sublingual or buccal use
JP4248795B2 (en) Liquid for internal use
GR1009513B (en) Drinkable pharmaceutical carbocysteine-containing solutions
AU2022240348B2 (en) Liquid preparation of l-serine or pharmaceutically acceptable salt thereof and method for preparing same
GR1009462B (en) Drinkable pharmaceutical solution with dissimulated taste
WO2017025930A1 (en) Oral solution of aripiprazole
EP2656857A1 (en) Oral liquid formulation
CN116133643A (en) Liquid composition
WO2018002738A1 (en) Taste masked liquid pharmaceutical composition of (rs)-4-(ethyl[1-(4-methoxyphenyl)propan-2-yl]amino)butyl 3,4-dimethoxybenzoate or pharmaceutically acceptable salts thereof
NZ614970B2 (en) A pharmaceutical composition for treating a disease in the oral cavity comprising rebamipide

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20120330

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

17Q First examination report despatched

Effective date: 20130313

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20151101