WO2006093493A1 - Composition pharmaceutique liquide aqueuse stable a temperature ambiante - Google Patents

Composition pharmaceutique liquide aqueuse stable a temperature ambiante Download PDF

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Publication number
WO2006093493A1
WO2006093493A1 PCT/US2005/006576 US2005006576W WO2006093493A1 WO 2006093493 A1 WO2006093493 A1 WO 2006093493A1 US 2005006576 W US2005006576 W US 2005006576W WO 2006093493 A1 WO2006093493 A1 WO 2006093493A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
liquid pharmaceutical
composition according
polyol
polyols
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PCT/US2005/006576
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English (en)
Inventor
Emmett Clemente
Bhiku Patel
Kuljit Bhatia
Frank L. Sorgi
Emil D. Kakkis
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Biomarin Pharmaceutical Inc.
Medicis Pediatrics, Inc.
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Application filed by Biomarin Pharmaceutical Inc., Medicis Pediatrics, Inc. filed Critical Biomarin Pharmaceutical Inc.
Priority to JP2007557006A priority Critical patent/JP2008531556A/ja
Priority to MX2007010163A priority patent/MX2007010163A/es
Priority to EP05724171A priority patent/EP1850854A1/fr
Priority to AU2005328349A priority patent/AU2005328349A1/en
Priority to PCT/US2005/006576 priority patent/WO2006093493A1/fr
Priority to CA002597155A priority patent/CA2597155A1/fr
Publication of WO2006093493A1 publication Critical patent/WO2006093493A1/fr

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates to a liquid drug composition, and more particularly to a room temperature-stable, microbially-protected, pleasant-tasting (due to the use of debittering agents and taste-masking technologies) aqueous liquid pharmaceutical composition of a steroidal drug, specifically, prednisolone sodium phosphate.
  • bitter tasting drugs have a bitter taste or are unstable when dissolved in liquid form.
  • Bitter-tasting or potentially unstable drugs are consequently usually formulated for oral administration as coated tablets or capsules or as a powder or liquid within a capsule so that the bitter tasting medicament does not contact the tongue during oral administration.
  • U.S. Patent No. 5,455,049 illustrates one technique that was successful in overcoming the bitter taste problem associated with orally- administered terfenadine.
  • U.S. Patents No. 5,763,449 and No. 5,962,461 describe a pleasant-tasting aqueous liquid composition that can contain prednisolone sodium phosphate (PSP) as the active ingredient.
  • PSP prednisolone sodium phosphate
  • the disclosure that follows illustrates specific resolution to the problems of bitter taste and oral administration of PSP.
  • PSP compositions are particularly suitable to adults and children that have difficulty swallowing or cannot swallow tablets, capsules and the like.
  • the drug is formulated as an aqueous composition that can be stored at ambient room temperature while providing stability to the active ingredient and minimizing microbial attack at an acceptable level (i.e., conforms to the USP antimicrobial effectiveness test).
  • the present invention provides disclosure of a liquid pharmaceutical composition.
  • That composition is a liquid pharmaceutical composition comprising a pharmaceutically effective amount of a steroid or other bitter-tasting drug such as prednisolone sodium phosphate (PSP) dissolved or dispersed in an aqueous medium.
  • a steroid or other bitter-tasting drug such as prednisolone sodium phosphate (PSP) dissolved or dispersed in an aqueous medium.
  • the aqueous medium comprises water, optionally about 3% to about 10% weight/volume (% w/v) polyvinylpyrrolidone (PVP), about 60% to about 75% w/v of a C 3 -C 6 polyol that includes at least 55% w/v of the total composition of a non-reducing disaccharide or trisaccharide such as sucrose, and optionally, about 0.01 to about 5.0% w/v, and more preferably, 0.01 to about 0.5% w/v of glycyrrhetic acid, a glycyrrhizinate derivative such as an ester, amide or thioester of glycyrrhetic acid, or a salt thereof and one or more flavorants.
  • PVP polyvinylpyrrolidone
  • the liquid composition contemplated herein is transparent and may have a pleasant taste when orally administered; i.e., it is substantially free from having a bitter taste that would otherwise be associated with the bitter-tasting active ingredient such as PSP.
  • a contemplated composition is designed for storage at ambient room temperature; i.e., typically at about 20-35°C.
  • the drug is present in an amount of less than about 0.5% w/v of the total weight of the composition.
  • the composition is such that the C 3 -C 6 polyol is present as a mixture of C 3 polyol and C 6 polyol, that the mixture of C 3 polyol and C 6 polyol being present in an amount of about 60% to about 75% w/v, and that the weight ratio of the C 3 polyol to the C 6 polyol be about 1 :6 to about 1 :70.
  • the polyvinylpyrolidone (PVP) is preferably present at about 3% to about 7% w/v.
  • the invention contemplates compositions that are stable with respect to the active pharmaceutical ingredient (API) and can be stored at ambient room temperature without degradation of the API.
  • the drug interacts with ammonium glycyrrhizinate (a glycyrrhetic acid derivative), sucrose and preservatives to enhance the stability of the formulation comprising the drug.
  • ammonium glycyrrhizinate a glycyrrhetic acid derivative
  • sucrose glycyrrhetic acid derivative
  • preservatives to enhance the stability of the formulation comprising the drug.
  • the invention further contemplates compositions that are well-preserved and less prone to microbial contamination as compared to prior art preparations of the same.
  • the contemplated compositions have a pleasant taste that permits them to be administered to children without the usually observed reluctance of children to take the bitter tasting drug.
  • the compositions are particularly useful for administration to children and the elderly as the compositions are substantially free of ethanol or other alcohols.
  • exemplary contemplated compositions are homogeneously dispersed and non-settling so that one need not resuspend the medication within the composition prior to each administration and each dose contains a desired amount of the medicament.
  • Oral administration of pharmaceutically active agents is a particularly convenient form of administration of a medicament.
  • Active agents can be given to the patient orally as liquid solutions, oral dispersions (emulsions, suspensions, colloids, liposomes, micelles and the like) or in solid form such as capsules or tablets. Infants, children, the elderly and many other persons often have difficulty in swallowing tablets or bitter-tasting solutions.
  • the present invention is designed to alleviate these problems and provides orally- administrable formulations of bitter-tasting and/or unstable medicaments which are preferably stable at room temperature.
  • the compositions of the present invention may readily be prepared using any bitter-tasting drug.
  • Exemplary such drugs include, but are not limited to acetaminophen, terfenadine, guaifenesin, dexamethasone, triamcinolone, trimethoprim, prednisolone, ibuprofen, prednisolone sodium phosphate, methacholine, neostigmine, epinephrine, albuterol, pseudoephedrine hydrochloride, diphenhydramine, chlorpheniramine maleate, phenothiazine, chlorpromazine, chlordiazepoxide, amitriptyline, barbiturates, steroids, prednisone, diphenylhydantoin, caffeine, morphine, demerol, codeine, diphenoxylate, opiate derivatives, benzodiazepines, lidocaine, antidepressants, opioids, prostaglandine analogs (e.g.
  • misoprostol glucocorticosteroids
  • cytostatics methotrexate, cimetidine, ranitidine, pantoprazole, omeprazole, lansoprazole, furosemide, penicillamine, sulfasalazine, auranorfin, salicylic acid, fluticasone propionate, sulfonamides, salbutamol, formoterol, salmeterol, terbutaline, beclometasone dipropionate, flunisolide, budesonide, chloroquine, pregnanes, desogestrel, allylestrenol, ethylestrenol, lynestrenol, ca ⁇ ipramine, clomipramine, desipramine, imipramine, imipraminoxide, imipramine pamoate, lofepramine, metapramine, opipramol, quinupramine, trimipramine, amitrip
  • the bitter-tasting drug is prednisolone sodium phosphate (PSP) or prednisolone base.
  • PSP prednisolone sodium phosphate
  • concentrations of PSP include 2% w/v or less, 1% w/v or less, or 0.5% w/v or less.
  • This drug is used herein in the following descriptions by way of example.
  • any of the foregoing or, indeed, any other bitter- tasting drug may be formulated using the teachings provided with PSP as an example.
  • a contemplated composition is stable at room temperature, and may have at least a pleasant taste when administered orally.
  • the PSP is dissolved or dispersed in an aqueous medium. That is, the composition of drug and ingredients other than the flavorant, even if not forming a true solution, is not cloudy or milky in the aqueous medium. It is presently not known if the aqueous medium containing the drug and other ingredients is a true solution or a non-settling dispersion, but the composition containing its various constituents discussed hereinafter is preferably transparent as would be a true solution or a colloidal dispersion.
  • a contemplated pharmaceutical composition may be essentially free of ethanol (ethyl alcohol). Ethanol is often used in aqueous medicinal compositions as a solvent for the active medicament.
  • ethanol is not utilized in a preferred composition, or, if used, is present in an amount of about ten percent by volume or less. Preferably, the ethanol, if present, is present at less than five percent.
  • a contemplated composition is referred to as having an aqueous medium in that water is present as a major liquid ingredient.
  • Water is a major liquid component of a contemplated composition, but water does not constitute a majority of the composition.
  • a pharmaceutically effective amount of prednisolone sodium phosphate is present in the contemplated composition as the active ingredient.
  • PSP prednisolone sodium phosphate
  • a pharmaceutically effective amount of PSP, or any drug is the concentration of the drug at which a desired volume of the composition includes a therapeutic amount of the medicament.
  • a contemplated amount of PSP can differ where compositions formulated for children and adults are contemplated, as well as when different amount of composition are contemplated for administration.
  • Therapeutic dosages of PSP and other contemplated drugs are well-known and are available from the above-noted texts as well as from the Physicians' Desk Reference, Medical Economics Company, Inc., Oradell, NJ, Goodman and Gilman's The
  • Exemplary amounts of active PSP are present at about 0.1% to about 2% w/v. Preferably, PSP is present in an amount of less than about 0.5% w/v of the contemplated composition.
  • composition makeup of a formulation There are several standard ways in which to represent the composition makeup of a formulation. Both percent weight/volume (% w/v) and percent weight/weight (% w/w) are used frequently by those of skill in the art. Herein, the measurements presented are in units of % w/v, unless otherwise indicated. Percent weight/volume is defined to be the weight in grams of a component expressed as if the total volume of the formulation was 100 ml (i.e., number of grams per 100 ml). Percent weight/weight, however, is the weight in grams of a component expressed as if the total weight of the formulation was 100 grams (i.e., number of grams per 100 grams).
  • a contemplated composition also contains about 60% to about 75% and more preferably about 60 to about 70 % w/v (as solids or non- volatile liquids) of a C 3 -C 6 polyol.
  • C 3 -C 6 polyol refers to the number of carbons in the basic polyol unit.
  • C 3 -C 6 polyol is meant to include multiple such C 3 -C 6 polyol units linked together into an oligmer.
  • sucrose is a disaccharide that is comprised of two C 6 polyols linked together.
  • non-reducing disaccharide at least 55% w/v, and preferably about 60% w/v, of the total pharmaceutical composition is a non-reducing disaccharide, trisaccharide, or tetrasaccharide.
  • non-reducing refers to a saccharide (e.g., a disaccharide, trisaccharide or tetrasaccharide) that does not reduce Fehling's solution.
  • exemplary non-reducing polyols used in the compositions contemplated herein include, but are not limited to sucrose, trehalose, melezitose, planteose, and raffinose. In particularly preferred compositions, the non-reducing polyol is sucrose.
  • the substantially higher concentration of total C 3 -C 6 polyol and the significant minimum amount of non- reducing disaccharide, trisaccharide, or tetrasaccharide such as sucrose required herein compared to the total C 3 -C 6 polyol contemplated in a PSP composition of U.S. Patent No. 5,763,449 or No. 5,962,461 are a major contributing factor to solving the problems related to PSP stability and taste.
  • the minimum amount of non-reducing sugar required in the formulations is greater than the maximum amount of C 3 -C 6 polyol permitted in either of the above patents. This increase in required C 3 -C 6 polyol, and more specifically, in the higher percentage of non-reducing saccharide, lends to the increased stability of the active ingredient at ambient temperatures, allowing for shelf-stability of the formulation.
  • sucrose in combination with the preservatives may stabilize PSP through the ordering of molecules.
  • surfactants may stabilize PSP through the ordering of molecules.
  • One possible explanation is that the molecules are becoming ordered due to preferred alignments around polar and non-polar regions of the molecule. This ordering of molecules are facilitated by the presence of surfactants.
  • Surfactants contain regions of polar groups and regions of nonpolar groups and serve to bridge the interaction between immiscible or poorly miscible components (oil and water, for example).
  • Glycyrrhetic acid or a derivative thereof contains a steroid-like multi-ring region (nonpolar, hydrophobic) connected to a sugar-like region (polar, hydrophilic), and can be represented as A-B where A represents the nonpolar region of the molecule and B represents the polar (water-loving) region of the molecule.
  • PSP is relatively nonpolar and can be represented as (A) while sucrose is very polar and also represented as (B).
  • the first ordered structure will resemble a micelle or sphere-like structure.
  • a sphere will form with all the sugar regions (B) being on the outside of the sphere and the ring structures (A) pointing to the inside of the sphere.
  • This structure forms spontaneously in an effort to find the lowest energy state for the ordered structure.
  • This description would be representative of oil droplets in water. If the continuous phase were polar, then the ring structures (A) would be on the outside of the sphere with the sugar regions (B) remaining on the inside of the sphere. This description would be representative of water droplets in oil.
  • Micelles or solid spheres) occur when the molecular structures are wedge or pie-shaped, thereby facilitating a sphere-like structure.
  • the second structure occurs when the molecules are roughly the same size and align more are sticks in a row, rather than wedges in a pie. Again, in an effort to minimize contact of an unfavored molecule with the continuous phase (in an effort to find the lowest energy state), the molecules will form a sheet of A-B or B-A with similar regions near each other. However, in this second situation, a bilayer will form whereby a sheet will be aligned with another sheet in a common molecular manner. An example of this would be a bilayer comprised of A-B:B-A or B-A: A-B, the alignment being dictated by the polarity of the continuous phase. In the present invention, the continuous phase is polar (B) so a B-ArA-B structure would be preferred. This ordered bilayer may remain as a sheet, or as a multi- stacked sheet or may form a liposome-like structure whereby a hollow sphere will form with the continuous phase being contained both inside and outside of the sphere.
  • PSP would be either contained within the core of the micelle or within the middle of the bilayer with minimal to no contact with the continuous (sucrose solution) phase. This is significant as PSP degrades in water that would be present in the continuous phase. Ordered structures would form to specifically exclude water coming in contact with PSP. The result of such an ordered structure excluding water from contacting PSP is that the source of degradation would be removed and the PSP formulation would be imparted with an unexpected stability.
  • the formation of micelles and bilayer/liposome ordered structures is well known and they are often used in an effort to protect a molecule from the environment present in the continuous phase.
  • exemplary other C 3 -C 6 polyols that can be present in a contemplated composition include propylene glycol, glycerin (glycerol), threose, threitol, erythrose, erythritol, ribose, arabinose, lyxose, maltitol, sorbitol, sorbose, glucose, mannose, mannitol, levulose, dextrose, maltose, fructose, xylitol, inositol, galactose, xylose, fructose, sucrose, 1,2,6-hexanetriol and the like.
  • glycerin glycerol
  • threose threitol
  • erythrose erythritol
  • ribose arabinose
  • lyxose maltitol
  • sorbitol sorbos
  • reducing sugars such as fructose, maltose or galactose
  • those polyols oxidize more readily than do non-reducing sugars, and that oxidation is believed to lead to acidification of the composition and decomposition of the PSP.
  • Maltitol is another molecule containing two linked C 6 polyols that is deemed therefore to be a C 6 polyol.
  • a C 3 -C 6 polyol serves several functions in the compositions of the invention, including acting as a solvent for the system, contributing to the stability of the active compound at room temperature, as well as being a masking agent for bitter flavors.
  • One or more C 6 reducing sugar oligosaccharide polyols such as sorbitol USP, maltitol NF at 75 percent solids, liquid fructose (an ⁇ -hydroxyketose that is a reducing sugar) such as that available under the mark KRYSTARTM, from A.E. Staley Mfg. Co., Decatur, IL that is sold as an aqueous liquid, about 77 weight percent of which is fructose, as well as sugars such as glucose, xylitol and the like can also be present.
  • C 6 reducing sugar oligosaccharide polyols such as sorbitol USP, maltitol NF at 75 percent solids, liquid fructose (an ⁇ -hydroxyketose that is a reducing sugar) such as that available under the mark KRYSTARTM, from A.E. Staley Mfg. Co., Decatur, IL that is sold as an aqueous liquid, about 77
  • a mixture of two or more C 3 -C 6 polyols is utilized.
  • Such a mixture utilizes a C 3 polyol such as glycerin or 1,3-propanediol (propylene glycol), with both of those C 3 polyols being preferred for use.
  • This C 3 and C 6 polyol mixture when utilized, is typically present at a weight ratio of 1 :6 C 3 :C 6 polyol to about 1 :70 C 3 :C 6 polyol, as non-volatiles, provided that the total polyol weight percentage in the composition is between 55% and 75%.
  • polyols other than a C 6 polyol i.e. C 3 , C 4 , and C 5 polyols
  • the composition of the invention also may comprise about 3% to about 10% w/v polyvinylpyrrolidone (PVP), and more preferably about 3% to about 7% w/v PVP.
  • PVP commercially (BASF) known as Povodone
  • BASF BASF
  • Povodone is commercially available from a number of suppliers under a number of designations with molecular weights ranging from 10,000 to 1,500,000 Da.
  • PVP is dissolved or dispersed in the water of the aqueous medium and serves to assist in dissolving or dispersing the bitter-tasting drug in that medium, as well as stabilizing the compound and masking the flavor of the bitter-tasting drug.
  • the disclosures of Volker B ⁇ hler's book, Kollidon, BASF Aktiengesellshaft, Ludwigshafen, Germany (1992) teach the use of PVP as both a solubilization aid for several drugs as well as for masking the bitter taste of acetaminophen.
  • An exemplary formulation for an oral PVP- and acetaminophen-containing composition is provided at page 113, Table 81 of the above B ⁇ hler text. PVP has been used as a thickening agent (U.S.
  • Other agents can be used as a thickener, texture modifier or binder similar to PVP and include but are not limited to colloidal cellulose, hydrated silica, polyethylene glycol, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, guar gum or xanthan gum, and hydroxypropyl methylcellulose.
  • liquid pharmaceutical composition comprising a pharmaceutically effective amount of a drug dissolved or dispersed in an aqueous medium that is preferably free of ethanol, said aqueous medium comprising water, about 3% to about 10% w/v polyvinylpyrrolidone (PVP), about 60% to about 75% w/v of C 3 - C 6 polyol and including more than 55% w/v of the total composition of a non-reducing disaccharide, trisaccharide, or tetrasaccharide wherein the composition is stable at room temperature.
  • PVP polyvinylpyrrolidone
  • C 3 -C 6 polyols with the PVP are effective in stabilizing the active ingredient in a room temperature formulation. Therefore, what is contemplated is a combined formulation of polyols, PVP and an active ingredient that is stable at room temperature as an aqueous solution. While some embodiments have preferred compositions that are pleasant-tasting, other preferred compositions need not be pleasant-tasting because it is a significant advantage of the present invention that it is stable at room temperature and provided in a liquid form.
  • the polyols and PVP while stabilizing the composition, are not necessarily sufficient to mask the bitter taste of a steroidal drug such as PSP. This fact remains even when further sweeteners such as sodium saccharin USP present at 0.05-2 % w/v or aspartame present at about 0.1 to about 2 % w/v and further flavorants are admixed with the composition. A further debittering agent is still required to be present in order to create a pleasant tasting formulation.
  • That further debittering agent is found to be glycyrrhetic acid, derivatives of glycyrrhetic acid such as esters, amides, or thioesters, or salts of either the glycyrrhetic acid or glycyrrhizinate derivatives that can be present at about 0.01% to about 5.0% w/v, or, more preferably, for example, about 0.01% to about 0.5% w/v, or about 1.0% to about 5.0% w/v. Other preferred ranges include about 0.01% to about 0.05% w/v, or about 0.1% to about 0.5.0% w/v AG.
  • glycyrrhetic acid and derivatives thereof are a 10% solids solution, such as for example, ammonium glycyrrhizinate is a 10% solids solution in glycerol or propylene glycol under the name MAGNASWEET® MM 110 or MM 115 which is added in the amount of about 0.5 to about 5.0 % w/v.
  • Ammonium glycyrrhizinate (AG) is a preferred salt for use as a debittering agent.
  • the glycyrrhetic acid, deriviative or salt is preferably present at a weight ratio as compared to the PSP or other drug of about 1 : 100 to about 1:5, more preferably about 1 :50 to about 1 :10, and most preferably at weight ratio of about 1 :20 the glycyrrhizinate to drug. Also contemplated are weight ratios of glycerrhizinate to the PSP of 1:100, 1 :95, 1:90, 1:85, 1 :80, 1:75, 1:70, 1:65, 1 :60, 1:55, 1 :50, 1:45, 1 :40. 1 :35, 1:30, 1:25, 1:20, 1:15, 1 :10, and 1:5.
  • a composition that includes a pharmaceutically effective amount of a drug dissolved or dispersed in an aqueous medium that is preferably low in ethanol (e.g. less than 10%) or optionally free of ethanol, said aqueous medium comprising water, about 3% to about 10% w/v polyvinylpyrrolidone (PVP) as an optional component, about 55% to about 75% w/v Of C 3 -C 6 polyol, in which more than 55% w/v of the total composition is a non-reducing disaccharide, trisaccharide, or tetrasaccharide, about 0.01% to about 5.0% w/v glycyrrhetic acid, derivative or salt thereof, and one or more flavorants, that is stable at room temperature and may have a pleasant taste.
  • PVP polyvinylpyrrolidone
  • ammonium glycyrrhizinate used herein is a 10% ammonium glycyrrhizinate solids solution in glycerol or propylene glycol.
  • Such solutions e.g., MAGNASWEET MM 110 or MM 115 are discussed further below.
  • Ammonium glycyrrhizinate is available as a 10% weight percent-solution in glycerin or propylene glycol from MacAndrews & Forbes Company of Camden, NJ under the name MAGNASWEET ® MM 110 or MM 115, and also as a white, amorphous powder as MM 150.
  • the compositions of the invention comprise between about 0.1 to about 5 % w/v MAGNASWEET MM 110 or MM 115.
  • Ammonium glycyrrhizinate is the mon ⁇ ammonium salt of a triterpenoid saponin that consists of an aglycone of glycyrrhetic acid and a sugar moiety of two glucuronic acid units linked to each other. This is said by its manufacturer to be about 50 to about 100 times sweeter than sucrose, and is known to be useful in masking bitterness.
  • agents and processes have been used to provide a taste-masking or sweetening effect similar to ammonium glycyrrhizinate and include various flavors, sweeteners, acidic amino acids, lipids and surfactants including but not limited to dimethylaminoethyl methacrylate and neutral methacrylic acid esters, (WO 2004/022037 Al), processing approaches such as microencapsulation with resins and proteins, gelatinized starch, gums, cyclodextrins, chitosan, liposomes, removal of bitter contaminants by ion exchange resins, chemical modification and specific salt preparation.
  • ammonium glycyrrhizinate is a known bitterness-masking agent, as is PVP, neither material alone or with the before-discussed sweeteners and flavorants is sufficient to mask the bitter taste of a contemplated bitter-tasting drug. Rather, PVP and ammonium glycyrrhizinate appear to potentiate each other to provide the desired bitterness- masking effect. The mechanism by which the bitterness-masking is achieved is unknown. In
  • U.S. Patent Nos. 5,763,449 and No. 5,962,461 propose that polyvinylpyrrolidone, ammonium glycyrrhizinate and PSP may form a presently undefined complex in the aqueous medium, that complex acts to shield taste buds from the bitterness inherently present in the bitter- tasting drug.
  • the determination of a bitter taste is carried out by standard, well-known practices, and is a characteristic often listed along with a description of the drug in texts such as The Merck Index, 1 lth ed., S. Budavari et al. eds., Merck & Co., Inc., Rahway, NJ (1989) and Remington's Pharmaceutical Sciences, 18 th ed, A.
  • the final pH value of the compositions of the invention is about 6 to about 8, and preferably about 6.5 to about 7.5, and more preferably about 6.7 to about 7.4, and most preferably about 6.8 to about 7.2.
  • a system of sodium hydroxide (1 N) and hydrochloric acid (10 N) or one of citric acid and sodium citrate is typically used for pH value adjustments and maintenance.
  • Mono- and dibasic sodium or potassium phosphate salts and other salts can also be used as a buffer system to maintain the pH value of a contemplated composition.
  • a minimal .amount e.g., less than about 5% w/v, and more preferably less than about 2% w/v, of acid and base as buffering salts such as the above mono- and dibasic phosphate salts, because too much salt present in the composition can result in an unpleasant taste being imparted to the composition.
  • buffering salts such as the above mono- and dibasic phosphate salts
  • a composition of the invention may also contain additional sweeteners, and fiavorants, as well as colorants and thickeners. Flavorants such as bubble gum and chocolate flavors can provide opacity or translucency to a contemplated composition, while the composition other than the flavorant is transparent.
  • Exemplary thickeners include sodium alginate, gelatin or a polyalkylene oxide such as the polyoxyethylene-polyoxypropylene-polyethylene terpolymer available under the name PLURONIC ® F68 having an average of 75 polymerized ethylene oxide units on either side of 30 polymerized propylene oxide units, F-87 having 62 polymerized ethylene oxide units on either side of 39 polymerized propylene oxide units, or F-88 having an average of about 97 polymerized ethylene oxide groups on either side of about 39 polymerized propylene oxide groups that are available from BASF, Mount Olive, NJ.
  • a contemplated aqueous liquid pharmaceutical composition has a viscosity at 25 0 C between that of water and about that of corn syrup at 25°C.
  • preservatives such as sodium benzoate NF, methylparaben NF and propylparaben NF as discussed in U.S. Patent No. 5,763,449 and No. 5,962,461 also may be provided in the compositions of the present invention. Inclusion of such preservatives and removal of PVP from a test composition showed that protection from microbial attack was present, indicating that PVP may be binding to, and thereby partially removing, one or more of those preservatives from effective use in a contemplated composition.
  • composition A a solution or dispersion of about 30% w/v PVP is prepared in water (composition A).
  • composition A About one part PSP is slurried with about 5 parts by weight C 3 polyol (glycerin or propylene glycol or both) (slurry being composition B).
  • the two compositions, composition A and composition B are admixed and heated to a temperature of about 45°C with continued agitation. Agitation is continued at that temperature until a clear, non-settling solution or dispersion is formed, which generally takes about 30 minutes.
  • the PSP is admixed directly with the aqueous PVP.
  • the aqueous composition formed in the above process is cooled at a temperature below about 30 0 C and the ammonium glycyrrhizinate, other C 3 -C 6 polyols, flavorants, colorant if used and remaining ingredients are admixed until a homogenous composition is obtained.
  • These additions are typically carried out serially, with admixture to homogeneity between each admixture.
  • the preservatives are added and the pH value is thereafter adjusted as required.
  • Example 1 Comparative Example: U.S. Patent No. 5,962,461 Ethanol-Containing Prednisolone Sodium Phosphate Oral Liquid
  • An aqueous, room temperature storage stable and pleasant tasting PSP composition containing the following amounts of ingredients were prepared and subjected to 25°C and 60% RH storage for a period of nine months with a good product stability profile.
  • the composition was also placed under accelerated storage conditions at a temperature of 40°C and 75% RH for a period of three months, a recognized storage condition which simulates a two years of shelf life at room temperature.
  • a 6,000 liter contemplated aqueous composition of PSP was prepared by the admixture of three substantially homogeneous sub-compositions.
  • the first sub-composition was prepared by admixing the propylene glycol (4), methylparaben (9), propylparaben (10) and grape flavor (7) until substantially homogeneous.
  • the second subcomposition was prepared from a first portion of purified water (17), about 37 percent of the total compostion's weight, was heated to about 65° C ⁇ about 5° C and then admixed with the sucrose (2), soribitol (5), and MAGNASWEET® 110 (6) until substantially homogeneous.
  • the povidone (3) is then added to the batch tank and then mixed until completely wetted and dispersed.
  • the resulting admixture was cooled to a temperature of about 40°C or below.
  • the third sub- composition was prepared by admixture and agitation to substantial homogeneity of a second portion of purified water that constituted about 15 percent of the total composition comprising prednisolone sodium phosphate (1), to which was added sequentially the mono- and dibasic sodium phosphates (16 and 15), EDTA (12), sodium benzoate (8), and potassium sorbate (11).
  • the second and third sub-compositions were admixed to substantial homogeneity, followed by admixture of the first sub-composition and further mixing to substantial homogeneity.
  • the pH value was adjusted to the desired value of about 7.0 (6.9 - 7.3), and remainder of the purified water (15), about 4 percent, was then admixed to complete the preparation of the desired composition in a final volume of 6,000 liters. It is to be understood that such a desired composition can also be prepared in other manners.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique liquide qui contient une quantité efficace pharmaceutiquement d'un médicament dissous ou dispersé dans un milieu aqueux. Ce milieu aqueux renferme essentiellement de l'eau, entre environ 3 % et environ 10 % en poids de polyvinylpyrrolidone, entre environ 60 % et environ 75 % en poids de C3-C6 polyol qui contient plus de 55 % en poids d'un disaccharide, trisaccharide ou tétrasaccharide non réducteur, tel que le sucrose, facultativement entre environ 0,01 % et environ 0,5 % en poids d'un acide glycyrrhétique, d'un dérivé de glycyrrhizinate ou d'un sel associé, et au moins une essence et, de préférence, au moins un agent de conservation. Ladite composition liquide est stable à température ambiante et elle peut présenter un goût plaisant.
PCT/US2005/006576 2005-02-25 2005-02-25 Composition pharmaceutique liquide aqueuse stable a temperature ambiante WO2006093493A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP2007557006A JP2008531556A (ja) 2005-02-25 2005-02-25 室温で安定な水性の液状薬学的組成物
MX2007010163A MX2007010163A (es) 2005-02-25 2005-02-25 Composicion farmaceutica liquida acuosa estable a temperatura ambiente.
EP05724171A EP1850854A1 (fr) 2005-02-25 2005-02-25 Composition pharmaceutique liquide aqueuse stable a temperature ambiante
AU2005328349A AU2005328349A1 (en) 2005-02-25 2005-02-25 Room temperature stable aqueous liquid pharmaceutical composition
PCT/US2005/006576 WO2006093493A1 (fr) 2005-02-25 2005-02-25 Composition pharmaceutique liquide aqueuse stable a temperature ambiante
CA002597155A CA2597155A1 (fr) 2005-02-25 2005-02-25 Composition pharmaceutique liquide aqueuse stable a temperature ambiante

Applications Claiming Priority (1)

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PCT/US2005/006576 WO2006093493A1 (fr) 2005-02-25 2005-02-25 Composition pharmaceutique liquide aqueuse stable a temperature ambiante

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103344710A (zh) * 2013-06-05 2013-10-09 公安部物证鉴定中心 用于刑侦目的的使用液相色谱-串联质谱检测生物样品中地芬诺酯的方法
RU2660358C2 (ru) * 2012-09-26 2018-07-05 Бристол-Майерс Сквибб Холдингс Айеленд Жидкие лекарственные композиции апиксабана
EP3777829A1 (fr) * 2019-06-07 2021-02-17 Lamda Laboratories S.A. Solutions pharmaceutiques orales comprenant du chlorhydrate de nortriptyline

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2246044A1 (fr) * 2009-04-21 2010-11-03 Pierre Fabre Dermo-Cosmétique Solutions pédiatriques de bêta-bloquants

Citations (2)

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Publication number Priority date Publication date Assignee Title
US5763449A (en) * 1996-08-07 1998-06-09 Ascent Pediatrics, Inc. Pleasant-tasting aqueous liquid composition of a bitter-tasting drug
US20030118654A1 (en) * 2001-12-07 2003-06-26 B. Santos Joyce Bedelia Taste masked aqueous liquid pharmaceutical composition

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Publication number Priority date Publication date Assignee Title
JPH0714872B2 (ja) * 1990-02-06 1995-02-22 昭和薬品化工株式会社 シロップ剤組成物
JP4073121B2 (ja) * 1998-08-28 2008-04-09 エーザイ・アール・アンド・ディー・マネジメント株式会社 薬物の苦味等を軽減した組成物
JP4889948B2 (ja) * 2005-01-21 2012-03-07 興和株式会社 服用感に優れた内服液剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5763449A (en) * 1996-08-07 1998-06-09 Ascent Pediatrics, Inc. Pleasant-tasting aqueous liquid composition of a bitter-tasting drug
US20030118654A1 (en) * 2001-12-07 2003-06-26 B. Santos Joyce Bedelia Taste masked aqueous liquid pharmaceutical composition

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2660358C2 (ru) * 2012-09-26 2018-07-05 Бристол-Майерс Сквибб Холдингс Айеленд Жидкие лекарственные композиции апиксабана
US10016362B2 (en) 2012-09-26 2018-07-10 Bristol-Myers Squibb Company Apixaban liquid formulations
CN103344710A (zh) * 2013-06-05 2013-10-09 公安部物证鉴定中心 用于刑侦目的的使用液相色谱-串联质谱检测生物样品中地芬诺酯的方法
EP3777829A1 (fr) * 2019-06-07 2021-02-17 Lamda Laboratories S.A. Solutions pharmaceutiques orales comprenant du chlorhydrate de nortriptyline

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AU2005328349A2 (en) 2006-09-08
AU2005328349A1 (en) 2006-09-08
JP2008531556A (ja) 2008-08-14
EP1850854A1 (fr) 2007-11-07
MX2007010163A (es) 2008-02-22
CA2597155A1 (fr) 2006-09-08

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