AU2003214486A1 - Pharmaceutical compositions having reduced bitter taste - Google Patents
Pharmaceutical compositions having reduced bitter taste Download PDFInfo
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- AU2003214486A1 AU2003214486A1 AU2003214486A AU2003214486A AU2003214486A1 AU 2003214486 A1 AU2003214486 A1 AU 2003214486A1 AU 2003214486 A AU2003214486 A AU 2003214486A AU 2003214486 A AU2003214486 A AU 2003214486A AU 2003214486 A1 AU2003214486 A1 AU 2003214486A1
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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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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Description
WO 2004/087096 PCT/HR2003/000013 I PHARMACEUTICAL COMPOSITIONS HAVING REDUCED BITTER TASTE FIELD OF INVENTION 5 This invention relates to the masking of the taste of bitter tasting pharmaceuticals. In particular, the invention relates to the taste masking of dispersible compositions containing bitter tasting basic active ingredients, especially macrolide antibiotics such as erythromycin, roxithromycin, 10 azithromycin, clarithromycin, and others. BACKGROUND Overcoming the bitterness of certain pharmaceutical active ingredients is a 15 continuous challenge for formulation scientists. The challenge is even greater for dispersible pharmaceutical compositions, in contrast to other types of formulations such as capsules and non-dispersible tablets. Dispersible pharmaceutical compositions have the advantage of being easier to swallow than capsules or tablets. This advantage is of particular benefit to paediatric 20 and geriatric patients who prefer easy-to-swallow preparations. A number of techniques are known for masking the bitter taste of active ingredients in pharmaceutical powders, granules and dispersible tablets intended for oral use. These include coating the powders or granules, 25 microencapsulation of the active ingredient, and complex formation of the active ingredient. However, these techniques can be limited by the number of excipients required, the amounts of each component needed, the level of complexity of manufacturing processes, and the use of volatile organic solvents. There are often also scale-up problems associated with such 30 complex techniques. French patent no. FR 2793690 (Dominique) describes the use of high concentrations (up to 20 %) of sweetening agents, other than sugars, in dispersible macrolide compositions. However, sweetening agents such as 35 aspartame, saccharine, and ammonium glycerrhizinate have distinctive and WO 2004/087096 PCT/HR2003/000013 2 undesirable after tastes themselves. They also each have other side effects when used in high concentrations. These traditional sweeteners are, in any case, not effective in masking the taste of powerfully bitter pharmaceutical actives such as azithromycin. 5 US patent no. 5,609,909 (Meyer) discloses the use of prolamine fractions of grain proteins applied as coatings over the drug core using a water-insoluble oil or wax as a plasticizing agent. This hnethod has limited application for immediate releasing macrolide suspensions. Organic coating materials are 10 required for this method as well as equipment such as a Glatt-Wurster fluid bed coater. US patent no. 6,153,220 (Cumming) discloses the spray-drying of an active drug with a cationic copolymer, synthesized from dimethyl amino ethyl 15 methacrylate and methacrylic acid esters, to mask taste. Organic solvents are used in this method. Additionally, there is a limit to the drug dose that can be used, e.g. a ratio of drug to polymer of up to 1:6. pH dependent polymers often used for enteric coatings or in delayed release 20 preparations have been used for taste masking. US patent no. 5,409,711 (Mapelli) discloses the use of a polymeric membrane which is soluble above pH 5 for the taste masking of granules. An acidic substance is added to the composition to prevent the dissolution of membrane in the mouth. Dispersible granules obtained by this process release the drug only above pH 5. 25 An important disadvantage of formulations prepared by encapsulation and spray drying is that volatile organic solvents such as methylene chloride, chloroform, cyclohexane, carbon tetrachloride, methylethyl ketone, acetone, ethyl alcohol, methyl alcohol or isopropyl alcohol may be needed to dissolve 30 the coating agent. Such solvents are regarded as environmentally unfriendly and it is necessary to eliminate them from products or reduce the amounts of them to acceptable levels. Alkaline substances used to reduce drug release from encapsulated 35 microcapsules have been evaluated in pharmaceutical mixtures. US patent WO 2004/087096 PCT/HR2003/000013 3 no. 4,656,027 (Sjoovist) discloses the use of an alkaline substance encapsulated with a drug and an hydrophobic polymer to mask the taste of bitter substance. Again, the use of organic solvents for encapsulation is undesirable for environmental reasons. In addition, there is a limit on drug 5 loading and there are difficulties with the production of large batches. US patent no. 5,633,006 (Catania) utilizes alkaline earth oxides, alkaline earth hydroxides and alkaline hydroxides for taste masking bitter pharmaceutical compositions containing the macrolide antibiotic azithromycin. Azithromycin 10 tends to adsorb to the alkaline earth oxide resulting in reduced bitterness of the compositions. However, in some cases such adsorption alters the drug release kinetics. The dosage forms suggested for this method are limited to chewable tablets and oral suspensions. 15 Formulation scientists working on macrolide antibiotics have used functional polymers with basic oxides to provide taste-masked products. US patent no. 5,707,646 (Yajima) discloses the use of a functional polymer in conjunction with a substance having a low melting point, a basic oxide, and a sugar alcohol for taste masking. However, the requirement of spray drying 20 technology, low drug loading and high amounts of fatty acid ester are limitations on this method. US patent no. 5,792,373 (Yajima) utilizes a polymer that is soluble in the stomach together with a monoglyceride in the 3-crystal form to mask the taste 25 of pharmaceutical compositions for oral administration. However, the high proportion of monoglyceride with respect to the active ingredient retards drug release. Limiting factors for this method include the use of functional polymers that are unstable at high temperatures, low drug loading, and the process of spray drying. 30 A taste-masked granule comprising a complex between clarithromycin and carbomer is described in US patent no. 4,808,411 (Lu). The aqueous granulation of the clarithromycin carbomer complex is described in US patent no. 5,919,489 (Gerhardt). However, the number of pharmaceutical WO 2004/087096 PCT/HR2003/000013 4 manufacturing processes and techniques needed, such as complexation, granulation, and drying, make this method undesirable. A feature of many taste masking formulations is the incorporation of a lipid 5 such as a fatty acid ester. However, the proportion of lipid in known taste masking formulations is comparatively high and is typically greater than 20 % by weight of the active ingredient. For example, US patent no. 5,635,200 (Douglas) describes a taste masking 10 composition of the drug ranitidine where a ranitidine core is coated with a lipid. The amount of lipid used is greater than 20 % by weight. It is well understood that the amount of lipid needed when dispersing a drug through the lipid is significantly greater than the amount of lipid needed when merely coating a drug core with the lipid. Therefore, if dispersing ranitidine through a 15 lipid, significantly greater than 20% by weight lipid in the composition would be needed. US patent no. 5,380,535 (Geyer) describes a chewable tablet where an unpalatable drug is dispersed or dissolved in a lipid. The amount of lipid used 20 is 5-50 % by weight of the composition. However, these proportions by weight of the composition equate to much greater proportions by weight of the active ingredient. Dispersible formulations, compared with chewable tablets, typically require an even greater amount of lipid. 25 The primary purpose of including a lipid in a taste-masking formulation is to limit release or dissolution of the active ingredient in the mouth (in the case of a chewable tablet) and to limit release or dissolution of the active when added to water or when in the mouth (in the case of a dispersible composition) where it will be tasted. Therefore, a minimum level of lipid in the composition of 20 30 % is typically required. However, the consequence of a high level of lipid is the retardation of drug release from the composition leading to a delay in absorption of the active ingredient into the blood stream. There is therefore a need for a dispersible composition which effectively masks the bitter tastes of certain active ingredients while not suffering from problems of retarded 35 release of the active ingredient from the composition when used by a patient.
WO 2004/087096 PCT/HR2003/000013 5 The applicant has now found a simple, reproducible, novel drug delivery system for dispersible pharmaceutical compositions with reduced bitterness for bitter alkaline drugs and which contains a surprisingly low level of lipid. 5 The invention relates to the use of lipids, such as fatty acid esters, an alkaline substance and a surface active agent to form a granular matrix that reduces the bitterness of an active ingredient. The dispersible composition includes granules of the active ingredient and granules of a fast disintegrating diluting 10 agent. It is an object of the invention to provide a dispersible pharmaceutical composition containing a low level of lipid which goes at least some way to masking the taste of bitter tasting active ingredients, or at least to provide a 15 useful alternative. STATEMENTS OF INVENTION In a first aspect of the invention there is provided a dispersible pharmaceutical 20 composition including: (i) a bitter tasting active ingredient; (ii) a lipid granulating agent in the amount of 1 to 16 % by weight of the active ingredient; and (iii) an alkaline agent in the amount of 1 to 20 % by weight 25 of the active ingredient; where the bitter taste of the active ingredient is partially or completely masked. It is preferred that the bitter tasting active ingredient is a macrolide antibiotic, 30 more preferably the macrolide antibiotic is selected from erythromycin, clarithromycin, roxithromycin, and azithromycin, including any solvate or hydrate thereof. The azithromycin employed is preferably in form of isostructural pseudopolymorphs which exhibits superior dissolution properties as disclosed in Croatian Patent Application No. P20020231A. 35 WO 2004/087096 PCT/HR2003/000013 6 The lipid granulating agent is preferably in the amount 2 to 8 % by weight of the active ingredient. The lipid granulating agent may be any fatty acid ester, oil, fat, or wax. 5 However, the lipid granulating agent is preferably selected from glycerol mono-, di-, and tri-stearate, glycerol mono-, di-, and tri-palmitostearate, glycerol mono-, di-, and tri-behenate, glycerol mono-, di-, and tri-oleate, hydrogenated castor oil, a cetomacrogol emulsifying wax, carnuba wax, cetyl alcohol, and a cetyl ester. 10 It is preferred that the alkaline agent is in the amount 2 to 12 % by weight of the active ingredient. A variety of alkaline agents may be used, but preferably the alkaline agent is selected from sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium 15 hydroxide. It is preferred that the composition further includes a surface active agent in the amount of not more than 2 % by weight of the active ingredient. The surface active agent is preferably selected from sodium lauryl sulphate, 20 docusate sodium, polysorbates, and sorbitan fatty acid esters. It is also preferred that the composition further includes a diluting agent in the amount of 5 to 60% by weight of the total composition. The diluting agent is preferably selected from cellulose, microcrystalline cellulose, lactose, 25 mannitol, sorbitol, starch, calcium carbonate, dibasic calcium phosphate, silica, and pre-gelatinized starch. Preferably the diluting agent is prepared in the form of granules using a combination of microcrystalline cellulose and starch in a ratio from 1:3 to 3:1, 30 and a water insoluble cellulose. The water insoluble cellulose is preferably ethyl cellulose in the amount of 2 to 10 % by weight of the granules. The microcrystalline cellulose and starch are preferably in a ratio from 1.25:1 to 2:1.
WO 2004/087096 PCT/HR2003/000013 7 It is further preferred that the composition includes a disintegrating agent in the amount of 1 to 12 % by weight of the total composition. The disintegrating agent is preferably selected from carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, aminoalkyl methacrylate copolymer E, 5 and Polacrillin potassium. In a preferred embodiment of the invention the disintegrating agent is cationic polymer aminoalkyl methacrylate copolymer E. 10 It is also preferred that the composition further includes a sweetening agent in the amount of 1 to 10% by weight of the total composition. The sweetening agent is preferably selected from aspartame, coated aspartame, ammonium glycerrhizinate, saccharin sodium, acesulfame potassium, and sugars. 15 Preferably the composition further includes one or more flavouring agents in the amount of 1 to 6% by weight of the total composition. The one or more flavouring agents are preferably selected from agents having a vanilla, banana, cherry, pineapple, chocolate, caramel, or mint flavour. 20 Preferably the composition also includes a lubricating system made up of a lubricating agent, a glidant and a flow agent. The lubricating agent is preferably selected from magnesium stearate, calcium stearate, stearic acid, and polyoxyethylene stearates. The preferred glidant is talc and the preferred flow agent is selected from silicone dioxide, fatty acid esters, and sodium 25 lauryl sulphate. In a second aspect of the invention there is provided a process for the preparation of a composition according to claim 1 including the steps: (i) mixing the bitter tasting active ingredient with the 30 lipid granulating agent and with the alkaline agent to give a granular matrix; (ii) optionally further blending the granular matrix with one or more of a disintegrating agent, a sweetening agent, a flavouring agent, and a flow agent. 35 WO 2004/087096 PCT/HR2003/000013 8 Preferably the granular matrix is prepared by hot melt spiral granulation. The hot melt spiral granulation may be carried out at any suitable temperature butis preferably carried out at a temperature below 80 2C. 5 In one embodiment of the process the composition is compressed to provide water-dispersible tablets. In an alternative embodiment, the composition is not compressed to provide water-dispersible granules or powder. DETAILED DESCRIPTION 10 The invention relates to dispersible compositions containing bitter alkaline drug substances including macrolide antibiotics, either alone or in combination with other active substances, and a process for the preparation of such compositions. 15 As used herein, the term "dispersible composition" means any solid dosage form, including tablets, granules, pellets, and powders, which disperses in water (including cold water) to form a suspension for drinking. 20 Any bitter tasting basic drug, or combination of bitter tasting drugs, is contemplated in this invention. However, the invention relates particularly to macrolide antibiotics, especially erythromycin, roxithromycin, azithromycin, and clarithromycin. The drug will typically be in the form of a stable hydrate, solvate, or salt, and may be in any crystalline or amorphous form. The 25 azithromycin employed is preferably in form of isostructural pseudopolymorphs which exhibits superior dissolution properties as disclosed in Croatian Patent Application No. P20020231A. The compositions of the invention include any dispersible composition, 30 particularly granules, powders and tablets. Although tablets and capsules are simple to administer and convenient, children and elderly patients can have difficulty in swallowing them. For high dose drugs, size is a limitation. Dispersible pharmaceutical compositions are therefore convenient and easier to administer. Dispersible pharmaceutical compositions are also able to be 35 titrated as required by patients.
WO 2004/087096 PCT/HR2003/000013 9 The bitterness of the oral suspension formed when dispersible compositions of bitter drugs are dispersed in water is very difficult to mask. Dispersible pharmaceutical compositions made in accordance with the present invention 5 reduce bitterness and do not hamper the dissolution characteristics of the drug substance, even when compressed. The compositions meet the requirements of the British Pharmacopoeia for dispersible pharmaceutical compositions including 'dispersible tablets'. 10 The granular matrix of a dispersible pharmaceutical composition can be prepared by a number of methods. One preferred method is the process of hot melt spiral granulation. The use of a traditional fluid bed dryer is known for developing 'granules with reduced bitterness'. Other equipment, such as intensive mixers and blending equipment with hot air provisions, may also be 15 used for the same purpose. The drying temperature of the powder bed can be kept between 65 2C to 70 2C when a fatty acid ester such as glycerol dibehenate or glycerol distearate is used to illustrate the invention. Hot melt spiral granulation has advantages over spray drying, 20 microencapsulation and even particle coating or encapsulation technologies which require specialized equipment. The technique is environmentally friendly, reproducible and scalable. The granulation agent used to form the granular matices by hot melt 25 granulation is a lipid. The lipid may be a wax, oil, fatty acid, fatty alcohol, monoglyceride, diglyceride, or triglyceride. Carbon chain lengths are typically C12-C30 and they may be saturated or unsaturated. Examples include glycerol monostearate, glycerol distearate, glycerol behenate, glycerol dibehenate, and glycerol palmitostearate. The lipid may also be 30 hydrogenated castor oil, a cetomacrogol emulsifying wax, carnuba wax, cetyl alcohol, or a cetyl ester. It is to be appreciated that any suitable combination of two or more lipids may be used. The preferred lipid is normally solid at room temperature (18-22 OC), but 35 desirably melts readily with the application of mild temperatures (i.e. about 55- WO 2004/087096 PCT/HR2003/000013 10 95 0C). Mixtures, whose components may individually fall outside this melting temperature range, but whose average melting point is within this range, are also included. 5 The applicant has surprisingly found that the preferred lipid amount is as low as 1 to 16 %, preferably 2 to 8%, by weight of the active pharmaceutical ingredient. The key advantage of keeping the amount of lipid as low as possible is that the affect on drug dissolution/release is minimised while still reducing the bitter taste of the drug. 10 A wetting agent, such as sodium lauryl sulphate, is preferably incorporated (not more then 2% for granules with reduced bitterness). Other wetting agents include docusate sodium, polysorbates, and sorbitan fatty acid esters. A wetting agent is dispersion aid. When used in small quantities, wetting 15 agents generally help with dispersion of tablets and with dissolution. To stabilize the pH of the composition, an alkaline substance such as sodium carbonate or tri-basic sodium phosphate is added in the amount of 1 to 20 %, preferably 2 to 14 %, in the anhydrous form, by weight of the active 20 pharmaceutical ingredient. Intra-granular and extra-granular addition of alkaline substances have been evaluated and both reduce the bitterness of the dispersible compositions. Alkaline substances that dissolve rapidly when the dispersible composition is added to water aid in the formation of a uniform dispersion. Typical alkaline agents include sodium carbonate, potassium 25 carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide. Other excipients used alone or in combination can be added to improve the flow properties of the dispersible compositions. These diluting agents include 30 cellulose, microcrystalline cellulose, mannitol, sorbitol, starch, pre-gelatinized starch, gelatinized starch, directly compressible microcrystalline cellulose, lactose, calcium carbonate, silica, and dibasic calcium phosphate. Preferred compositions of the invention utilize diluting granules that consist of 35 a blend of microcrystalline cellulose and maize starch in various ratios from WO 2004/087096 PCT/HR2003/000013 11 1:3 to 3:1 with the preferred range of 1.25:1.0 to 1.75:1.0. Ethyl cellulose (2 to 10 %) in the form of an aqueous dispersion with a plactisizer (e.g. SureleaseTM) may be used as a granulating agent for the diluting granules. The excipient combination has been evaluated for compressibility of the blend 5 formed when mixed with the granular matrix with reduced bitterness. The disintegration and flow properties of the dispersible pharmaceutical compositions of the invention are improved when these diluting granules are used. 10 The granular matrix of the bitter tasting active ingredient may be further processed into dispersible dosage forms using diluting granules and other diluting substances. The granules of diluting agent have good flow properties, compressibility and disintegration characteristics. Surprisingly, investigations found that the cationic polymer amino alkyl methacrylate copolymer E 15 (Eudragit TM E, EPO) is a suitable disintegrating agent in the dispersible dosage composition. Amino alkyl methacrylate copolymer E is poly (butyl methacrylate, (2-dimethyl amino ethyl) methacrylate, methyl methacrylate 1:2:1. Other disintegrating agents include carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, and Polacrillin potassium. 20 A sweetening agent, such as aspartame, ammonium glycerrhizinate (e.g. magnasweetM), saccharin sodium and other saccharides, acesulfame potassium, or mannitol, is preferably incorporated as a secondary sweetener. The use sweetening agents in high' dose is undesirable because of 25 unpleaseant aftertastes and generally to avoid diving patients unnecessary. amounts of qdditives.,. In the present invention a low level (2 to 5%) of sweetening agent is preferably added to provide a sweet taste. Aspartame is preferred as the sweetening agent for dispersible compositions such as tablets. "' 30 ' :" Selecting .a flavouring aghnf for aA alkaline bilter drug is difficult. Citrus flavours 'are hot useful 'as they impart a bitter taste Whereas some other flavqurs, such as'"mint and vanilla, synergistically reduce the bitterness of preparations. Flavourin'g agents evaluated are vanilla, banana, cherry, 35 pineapple, caramel, chocolate, mint and related. flavouring compounds.
WO 2004/087096 PCT/HR2003/000013 12 Formulations with acceptable tastes were obtained with mild flavours and also when no flavouring agent was added. The incorporation of a lubricating agent, such as magnesium stearate or 5 calcium stearate, or related pharmaceutically acceptable lubricating compounds, is preferable. Magnesium stearate is preferred as the most commonly used agent in pharmaceutical compositions. A flow agent, such as silicone dioxide, and an anti-adhesive agent (glidant), such as purified talc, are also preferred in the dispersible compositions of the invention. 10 The invention will be better understood by referring to the following examples of dispersible compositions. However, the examples are for illustrative purposes and it should be understood that the invention is not limited to these examples. 15 EXAMPLES Example 1: Granular matrix with reduced bitterness Ingredient Quantity (mg) Composition (% w/w) Azithromycin (as 528.26 89.63 isostructural pseudopolymorph) for 500 mg Azithromycin Sodium lauryl sulfate 3.00 0.51 Tri-basic sodium 36.98 6.27 phosphate (anhydrous) Glycerol dibehenate 21.13 3.59 Total Weight 589.37 100.00 20 The granular matrix was prepared with azithromycin, glycerol dibehenate and sodium lauryl sulphate. Tri-basic sodium phosphate was added either intra granularly in the granular matrix or externally in the dispersible composition. The granular matrix was examined using scanning electron microscopy 25 (SEM).
WO 2004/087096 PCT/HR2003/000013 13 Components were mixed and then granulated using a fluid bed processor with an attachment for spiral granulation. These granules were then used to prepare dispersible compositions. 5 Example 2: Granular matrix with reduced bitterness Ingredient Quantity (mg) Composition (% w/w) Azithromycin (as 528.26 86.53 isostructural pseudopolymorph) for 500 mg Azithromycin Sodium lauryl sulfate 3.00 0.49 Tri-basic sodium 36.98 6.06 phosphate, anhydrous Glycerol dibehenate 42.22 6.92 Total Weight 610.46 100.00 10 The granular matrix was prepared by intra-granular additional of glycerol dibehenate to give a matrix containing 8 % by weight of glycerol dibehenate. These granules with a higher amount of fatty acid esters showed good taste masking. The granules were used for dispersible compositions without 15 compression. Example 3: Granular matrix with reduced bitterness Ingredient Quantity (mg) Composition (% w/w) Azithromycin (as 528.26 89.63 isostructural pseudopolymorph) for 500 mg Azithromycin Sodium lauryl sulfate 3.00 0.51 WO 2004/087096 PCT/HR2003/000013 14 Tri-basic sodium phosphate 36.98 6.27 (anhydrous) Glycerol distearate 21.13 3.59 Total Weight 589.37 100.00 These granules were prepared with intra-granular or extra-granular use of tri basic sodium phosphate. Glycerol distearate was used as the granulating agent. These granules can be used to form a variety of dispersible 5 compositions. Example 4: Diluting granules Ingredient Quantity (g) Composition (% w/w) Microcrystalline cellulose 240.00 57.69 (Avicel PH 101) Starch (Maize Starch) 160.00 38.46 Ethylcellulose (As Surelease) 16.00 3.85 Total weight 416.00 100.00 10 Diluting granules were prepared using microcrystalline cellulose (AvicelTM PH 101) and maize starch. The granulating agent used was an aqueous dispersion of ethylcellulose (SureleaseTM). Granules were dried at 60 -C. Dried granules were sized to give fast disintegrating and flowing granules. 15 Example 5: EudragitTM EPO as a disintegrating/dispersing agent in dispersible tablets The granular matrix of Example 2 and the diluting granules of Example 4 were 20 mixed. The granules were passed through a sieve (40#) and blended with other excipients: aspartame, a disintegrating/dispersing agent, tribasic sodium phosphate, anhydrous colloidal silica, arid talc. The mixture was then lubricated with magnesium stearate. The following disintegrating/dispersing agents were used: aminoalkyl methacrylate copolymer E (EudragitTM EPO), 25 carmellose sodium, sodium starch glycollate, and polacrillin potassium.
WO 2004/087096 PCT/HR2003/000013 15 Tablets were compressed using granules of dispersible compositions and evaluated for ease of dispersion by putting tablets in 60 ml water at 25 'C in a 150 ml glass beaker. 5 The results with carmellose cellulose, sodium starch glycollate and polacrillin potassium were not satisfactory. Some agglomerated tablet mass was observed at the end of 3 minutes in the beaker. 10 Eudragit T M EPO was used at 100 mg per tablet, good tablet dispersion was observed (see table below). These tablets complied with disintegration tests for tablets under dispersible tablets and uniformity of dispersion. Evaluation of EudragitTM EPO as disintegrating/dispersing agent 15 Amount (mg) of EudragitTM EPO in Observations formulation as per Example 6 0 Tablet dispersion was incomplete within 3 minutes. 50 Tablet dispersion was improved but incomplete within 3 minutes. 100 Tablet dispersion was complete within 1 to 3 minutes. 150 Tablet dispersion was complete within 1 to 3 minutes. Example 6: Dispersible pharmaceutical composition such as tablets Ingredient Quantity/tablet (mg) Composition (% w/w) Granular matrix with 552.41 43.33 reduced bitterness (for WO 2004/087096 PCT/HR2003/000013 16 500mg Azithromycin) Diluting granules 523.59 41.07 Aspartame 30.00 2.35 Aminoalkyl methacrylate 100.00 7.84 copolymer E (EudragitTM EPO) Tri-basic sodium 40.00 3.14 phosphate (anhydrous) Anhydrous, colloidal silica 5.00 0.39 Talc 12.00 0.94 Magnesium stearate 12.00 0.94 Tablet weight 1275.00 100.00 The granular matrix of Example 1 and the diluting granules of Example 4 were mixed. The granules were passed through a sieve (40#) and blended with 5 other excipients: aspartame, aminoalkyl methacrylate copolymer E (EudragitTM EPO), tribasic sodium phosphate, anhydrous colloidal silica, and talc. The mixture was then lubricated with magnesium stearate. Tablets were compressed using granules of dispersible compositions and 10 evaluated for taste, uniformity of dispersion and other pharmacopoeial tests. Reconstituted tablets were found to be acceptable for taste as well as other tablet characteristics such as dissolution, assay, hardness, friability and ease of reconstitution. 15 Example 7: Evidence for masking of bitterness Compositions for taste evaluation included granules containing azithromycin 500 mg, diluting granules (granules of starch and microcrystalline cellulose), aminoalkyl methacrylate copolymer E (Eudragit T M EPO), talc, colloidal silica 20 and magnesium stearate. The level of fatty acid ester in the granules with reduced bitterness was varied as shown in the table below. The level of WO 2004/087096 PCT/HR2003/000013 17 tribasic sodium phosphate and aspartame was also varied as shown in the table below. Compositions were assessed in 5 volunteers. Ingredients Composition trials for taste evaluation I II Ill IV V VI VII VIII Glycerol dibehenate 4% 4% 4% 4% 4% Tribasic sodium 7% 7% 7% 7% 7% phosphate anhydrous Aspartame (mg) 30 100 30 100 30 100 Preferred rating of F F F E F E B C Taste Evaluation Percentage values are relative to the weight of azithromycin (as dehydrate) 5 The compositions were separately dispersed in 60 ml water and were evaluated for taste, immediately after dispersion. Taste evaluation: 10 A: palatable, acceptable preparation B: palatable, acceptable preparation with very low bitterness and very low aftertaste C: palatable, acceptable preparation with low bitter taste and low aftertaste. D: palatable, acceptable preparation with low bitter taste and unacceptable 15 after taste. E: Not palatable preparation due to bitter aftertaste and bitter taste. F: Not palatable preparation due to very bitter taste. The composition VII and VIIIl which contained fatty acid ester glycerol 20 dibehenate, alkaline buffer salt sodium phosphate and sweetening agent aspartame were significantly better than I to VI. The composition VIII was too sweet and also exhibited a bitter after taste. Example 8: Evidence for masking of bitterness 25 WO 2004/087096 PCT/HR2003/000013 18 Compositions for taste evaluation included granules containing azithromycin 500 mg, diluting granules (granules of starch and microcrystalline cellulose), aminoalkyl methacrylate copolymer E (EudragitTM EPO), talc, colloidal silica and magnesium stearate. The level of fatty acid ester in the granules with 5 reduced bitterness and aspartame was fixed as shown in the table below. The level of tribasic sodium phosphate was fixed but used extra-granularly except in XI where it was used intra-granularly. Compositions were assessed in 5 volunteers. 10 Ingredients Composition trials for taste evaluation VII IX X XI Glycerol dibehenate 4% 4% 4% 4% Sodium Phosphate tri- 7% 7% 7% 7% (intra basic, anhydrous granular) Aspartame (mg) 30 30 30 30 Vanilla (mg) - 25 - Banana (mg) - - 25 Preferred rating B C C B Percentage values are relative to the weight of azithromycin (as dehydrate) In the following table, composition XII is the same as VII without azithromycin. The taste of the dispersion was compared with composition VII without the 15 drug azithromycin. The composition was'marked as XII. Preferred ratings of compositions VII, IX, X and XI by 20 volunteers. Volunteer No Compositions for taste evaluation VII IX X XI XII 1 B C D B A 2 B C C B A 3 B C D A A 4 B D C B A 5 C D D B A WO 2004/087096 PCT/HR2003/000013 19 6 B C C B A 7 B D D B A 8 B C C B A 9 B D D B B 10 B C C A A 11 B C C B A 12 B D D B A 13 B C C B A 14 B D D B A 15 A C D B A 16 B C C B A 17 B C C B A 18 B C C B A 19 B C C A A 20 B D D B A Preferred rating B C C B A Taste evaluation: A: palatable, acceptable preparation B: palatable, acceptable preparation with very low bitterness and very low 5 aftertaste C: palatable, acceptable preparation with low bitter taste and low aftertaste. D: palatable, acceptable preparation with low bitter taste and unacceptable aftertaste. E: Not palatable preparation due to bitter aftertaste and bitter taste. 10 F: Not palatable preparation due to very bitter taste. Observations: Volunteers showed acceptance level for these formulations of azithromycin. Acceptability for compositions without flavouring components was more than 15 that for the compositions with flavouring components such as vanilla and banana indicating flavouring was non-obligatory for these types of formulations. Sodium phosphate tri-basic, anhydrous when used intra granularly with fatty acid esters exhibited marginally better acceptance.
WO 2004/087096 PCT/HR2003/000013 20 Although the invention has been described by way of example, it should be appreciated that variations or modifications may be made without departing from the scope of the claims. Furthermore, where known equivalents exist to 5 specific features, such equivalents are incorporated as if specifically referred to in this specification. 10 15 20 25 30 35
Claims (31)
1. A dispersible pharmaceutical composition including: (i) a bitter tasting active ingredient; 5 (ii) a lipid granulating agent in the amount of 1 to 16 % by weight of the active ingredient; and (iii) an alkaline agent in the amount of 1 to 20 % by weight of the active ingredient; where the bitter taste of the active ingredient is partially or completely 10 masked.
2. A composition according to claim 1 where the bitter tasting active ingredient is a macrolide antibiotic. 15
3. A composition according to claim 2 where the macrolide antibiotic is selected from erythromycin, clarithromycin, roxithromycin, and azithromycin, including and preferebly azithromycin in the form of isostructural pseudopolymorph which exhibits superior dissolution properties (as one disclosed in Croatian Patent Application No. 20 P20020231A.)
4. A composition according to any of claims 1 to 3 where the lipid granulating agent is in the amount 2 to 8 % by weight of the active ingredient. 25
5. A composition according to any one of claims 1 to 4 where the lipid granulating agent is a wax, fatty acid, fatty alcohol or is a mono-, di-, or tri-glyceride of one or more fatty acids. 30
6. A composition according to claim 5 where the lipid granulating agent is selected from glycerol mono-, di-, and tri-stearate, glycerol mono-, di-, and tri-palmitostearate, glycerol mono-, di-, and tri-behenate, glycerol mono-, di-, and tri-oleate, hydrogenated castor oil, a cetomacrogol emulsifying wax, carnuba wax, cetyl alcohol, and a cetyl ester. 35 WO 2004/087096 PCT/HR2003/000013 22
7. A composition according to any one of claims 1 to 6 where the alkaline agent is in the amount 2 to 12 % by weight of the active ingredient. 5
8. A composition according to any one of claims 1 to 7 where the alkaline agent is selected from sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide. 10
9. A composition according to any one of claims 1 to 8 further including a surface active agent in the amount of not more than 2 % by weight of the active ingredient.
10. A composition according to claim 9 where the surface active agent is 15 selected from sodium lauryl sulphate, docusate sodium, polysorbates, and sorbitan fatty acid esters.
11. A cqmposition according to any one of claims 1 to 10 further including a diluting agent in the amount of 5 to 60% by weight of the total 20 composition.
12. A composition according to claim 11 where the diluting agent is selected from cellulose, microcrystalline cellulose, lactose, mannitol, sorbitol, starch, calcium carbonate, dibasic calcium phosphate, silica, 25 and pre-gelatinized starch.
13. A composition according to claim 11 where granules of diluting agent are prepared using a combination of microcrystalline cellulose and starch in a ratio from 1:3 to 3:1, and a water insoluble cellulose. 30
14. A composition according to claim 13 where the water insoluble cellulose is ethyl cellulose in the amount of 2 to 10 % by weight of the granules. WO 2004/087096 PCT/HR2003/000013 23
15. A composition according to claim 13 where the microcrystalline cellulose and starch are in a ratio from 1.25:1 to 2:1.
16. A composition according to any one of claims 1 to 15 further including 5 a disintegrating agent in the amount of 1 to 12 % by weight of the total composition.
17. A composition according to claim 16 where the disintegrating agent is selected from carmellose sodium, croscarmellose sodium, sodium 10 starch glycolate, crospovidone, aminoalkyl methacrylate copolymer E, and Polacrillin potassium.
18. A composition according to claim 17 where the disintegrating agent is cationic polymer aminoalkyl methacrylate copolymer E. 15
19. A composition according to any one of claims 1 to 18 further including a sweetening agent in the amount of 1 to 10% by weight of the total composition.
20 20. A composition according to claim 19 where the sweetening agent is selected from aspartame, coated aspartame, ammonium glycerrhizinate, saccharin sodium, acesulfame potassium, and sugars.
21. A composition according to any one of claims 1 to 20 further including 25 one or more flavouring agents in the amount of 1 to 6% by weight of the total composition.
22. A composition according to claim 21 where the one or more flavouring agents are selected from agents having a vanilla, banana, cherry, 30 pineapple, chocolate, caramel, or mint flavour.
23. A composition according to any one of claims 1 to 22 further including a lubricating system made up of a lubricating agent, a glidant and a flow agent. 35 WO 2004/087096 PCT/HR2003/000013 24
24. A composition according to claim 23 where the lubricating agent is selected from magnesium stearate, calcium stearate, stearic acid, and polyoxyethylene stearates. 5
25. A composition according to claim 23 where the glidant is talc.
26. A composition according to claim 23 where the flow agent is selected from silicone dioxide, fatty acid esters, and sodium lauryl sulphate. 10
27. A process for the preparation of a composition according to claim 1 including the steps: (i) mixing the bitter tasting active ingredient with the lipid granulating agent and with the alkaline agent to give a granular matrix; and 15 (ii) optionally incorporating wetting agent and further blending the granular matrix with one or more of a disintegrating agent, a sweetening agent, a flavouring agent, and a flow agent. 20
28. A process according to claim 27 where the granular matrix is prepared by hot melt spiral granulation.
29. A process according to claim 28 where the hot melt spiral granulation is carried out at a temperature below 80 LC. 25
30. A process according to any one of claims 27 to 29 where the composition is compressed to provide water-dispersible tablets.
31. A process according to any one of claims 27 to 29 where the 30 composition is not compressed to provide water-dispersible granules or powder.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/HR2003/000013 WO2004087096A1 (en) | 2003-04-02 | 2003-04-02 | Pharmaceutical compositions having reduced bitter taste |
Publications (1)
Publication Number | Publication Date |
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AU2003214486A1 true AU2003214486A1 (en) | 2004-10-25 |
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ID=33104888
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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AU2003214486A Abandoned AU2003214486A1 (en) | 2003-04-02 | 2003-04-02 | Pharmaceutical compositions having reduced bitter taste |
Country Status (8)
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EP (1) | EP1608333A1 (en) |
JP (1) | JP2006514968A (en) |
CN (1) | CN1744881A (en) |
AU (1) | AU2003214486A1 (en) |
CA (1) | CA2521253A1 (en) |
EA (1) | EA200501552A1 (en) |
HR (1) | HRP20050867A2 (en) |
WO (1) | WO2004087096A1 (en) |
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EP1691787B1 (en) | 2003-12-04 | 2008-07-02 | Pfizer Products Inc. | Method for making pharmaceutical multiparticulates |
US9101160B2 (en) | 2005-11-23 | 2015-08-11 | The Coca-Cola Company | Condiments with high-potency sweetener |
JP4963846B2 (en) * | 2006-03-03 | 2012-06-27 | エルメッド エーザイ株式会社 | Orally disintegrating tablet and method for producing the same |
US8017168B2 (en) | 2006-11-02 | 2011-09-13 | The Coca-Cola Company | High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith |
MX346673B (en) | 2010-04-15 | 2017-03-29 | Chromocell Corp | Compounds, compositions, and methods for reducing or eliminating bitter taste. |
TWI564008B (en) * | 2010-09-30 | 2017-01-01 | 鹽野義製藥股份有限公司 | Formulation for solubility enhancement of poorly soluble drugs |
JP6038128B2 (en) | 2011-06-03 | 2016-12-07 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | A biomarker for predicting and evaluating the reactivity of thyroid and renal cancer subjects to lenvatinib compounds |
EP2768492B1 (en) | 2011-10-20 | 2018-09-12 | Chromocell Corporation | Compounds, compositions, and methods for reducing or eliminating bitter taste |
CN102824311A (en) * | 2012-09-11 | 2012-12-19 | 广西禾力药业有限公司 | Azithromycin granules capable of covering up bitter |
EP2801349A1 (en) | 2013-05-06 | 2014-11-12 | Siegfried AG | Oral Pharmaceutical Formulation |
KR102329681B1 (en) | 2014-08-28 | 2021-11-23 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | High-purity quinoline derivative and method for manufacturing same |
BR112017017428A2 (en) * | 2015-02-25 | 2018-04-03 | Eisai R&D Management Co., Ltd. | " method for suppressing the bitterness of quinoline derivative " |
CA2978226A1 (en) | 2015-03-04 | 2016-09-09 | Merck Sharpe & Dohme Corp. | Combination of a pd-1 antagonist and a vegfr/fgfr/ret tyrosine kinase inhibitor for treating cancer |
BR112017027227B1 (en) | 2015-06-16 | 2023-12-12 | Eisai R&D Management Co., Ltd | ANTI-CANCER AGENT |
JP6315741B2 (en) * | 2015-08-18 | 2018-04-25 | 合同会社Pharma Seeds Create | Composition for oral cavity containing NSAIDs or heparins |
CN105534940B (en) * | 2016-02-19 | 2018-12-07 | 国药集团致君(深圳)坪山制药有限公司 | A kind of diclofenac sodium extended action tablet composition and preparation method thereof |
CN114796222B (en) * | 2019-09-04 | 2024-03-29 | 普济生物科技(台州)有限公司 | Coated granules, solid dispersions and formulations containing vortioxetine hydrobromide for taste masking in the oral cavity |
CN112076168A (en) * | 2020-09-24 | 2020-12-15 | 丽珠集团丽珠制药厂 | Roxithromycin dispersible tablet and preparation method thereof |
CN112641718B (en) * | 2020-12-25 | 2022-07-29 | 山东大学 | Taste-masking compound based on porous carrier and preparation method and application thereof |
CN113181133A (en) * | 2021-04-25 | 2021-07-30 | 海南通用三洋药业有限公司 | Preparation method of roxithromycin capsules |
CN116420874A (en) * | 2023-04-26 | 2023-07-14 | 仙乐健康科技股份有限公司 | A composition without bitter taste and product comprising the same |
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US5380535A (en) * | 1991-05-28 | 1995-01-10 | Geyer; Robert P. | Chewable drug-delivery compositions and methods for preparing the same |
TW271400B (en) * | 1992-07-30 | 1996-03-01 | Pfizer | |
PL197989B1 (en) * | 1997-12-19 | 2008-05-30 | Smithkline Beecham Corp | Method of making tablets undergoing dispersion after being crushed in patient's teeth |
KR100768034B1 (en) * | 1999-03-17 | 2007-10-17 | 다이이찌 세이야꾸 가부시기가이샤 | Pharmaceutical composition |
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2003
- 2003-04-02 CN CNA038260204A patent/CN1744881A/en active Pending
- 2003-04-02 AU AU2003214486A patent/AU2003214486A1/en not_active Abandoned
- 2003-04-02 JP JP2004570049A patent/JP2006514968A/en active Pending
- 2003-04-02 CA CA002521253A patent/CA2521253A1/en not_active Abandoned
- 2003-04-02 WO PCT/HR2003/000013 patent/WO2004087096A1/en not_active Application Discontinuation
- 2003-04-02 EP EP03710062A patent/EP1608333A1/en not_active Withdrawn
- 2003-04-02 EA EA200501552A patent/EA200501552A1/en unknown
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2005
- 2005-09-30 HR HR20050867A patent/HRP20050867A2/en not_active Application Discontinuation
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JP2006514968A (en) | 2006-05-18 |
EA200501552A1 (en) | 2006-04-28 |
CA2521253A1 (en) | 2004-10-14 |
CN1744881A (en) | 2006-03-08 |
WO2004087096A1 (en) | 2004-10-14 |
EP1608333A1 (en) | 2005-12-28 |
HRP20050867A2 (en) | 2005-12-31 |
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