Classifications

• • 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
  • 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
• • A—HUMAN NECESSITIES
  • 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
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

• This invention relates to the masking of the taste of bitter tasting pharmaceuticals.
• the invention relates to the taste masking of dispersible compositions containing bitter tasting basic active ingredients, especially macrolide antibiotics such as erythromycin, roxithromycin, azithromycin, clarithromycin, and others.
• Dispersible pharmaceutical compositions have the advantage of being easier to swallow than capsules or tablets. This advantage is of particular benefit to paediatric 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, microencapsulation of the active ingredient, and complex formation of the active ingredient.
• 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 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.
• sweetening agents such as aspartame, saccharine, and ammonium glycerrhizinate have distinctive and 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.
• US patent no. 5,609,909 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 method has limited application for immediate releasing macrolide suspensions. Organic coating materials are required for this method as well as equipment such as a Glatt-Wurster fluid bed coater.
• US patent no. 6,153,220 discloses the spray-drying of an active drug with a cationic copolymer, synthesized from dimethyl amino ethyl 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.
• 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.
• US patent no. 5,633,006 utilizes alkaline earth oxides, alkaline earth hydroxides and alkaline hydroxides for taste masking bitter pharmaceutical compositions containing the macrolide antibiotic azithromycin.
• Azithromycin tends to adsorb to the alkaline earth oxide resulting in reduced bitterness of the compositions.
• the dosage forms suggested for this method are limited to chewable tablets and oral suspensions.
• US patent no. 5,792,373 (Yajima) utilizes a polymer that is soluble in the stomach together with a monoglyceride in the ⁇ -crystal form to mask the taste of pharmaceutical compositions for oral administration.
• 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.
• a taste-masked granule comprising a complex between clarithromycin and carbomer is described in US patent no. 4,808,41 1 (Lu).
• the aqueous granulation of the clarithromycin carbomer complex is described in US patent no. 5,919,489 (Gerhardt).
• the number of pharmaceutical 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 such as a fatty acid ester.
• a lipid such as a fatty acid ester.
• the proportion of lipid in known taste masking formulations is comparatively high and is typically greater than 20 % by weight of the active ingredient.
• US patent no. 5,635,200 (Douglas) describes a taste masking 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 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 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.
• 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 % 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 release of the active ingredient from the composition when used by a patient.
• 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.
• 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 agent.
• a dispersible pharmaceutical composition including:
• 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 masked.
• the bitter tasting active ingredient is a macrolide antibiotic, 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 Wegn Patent Application No. P20020231 A.
• 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.
• 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.
• the alkaline agent is in the amount 2 to 12 % by weight of the active ingredient.
• 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 hydroxide.
• 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, docusate sodium, polysorbates, and sorbitan fatty acid esters.
• 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, mannitol, sorbitol, starch, calcium carbonate, dibasic calcium phosphate, silica, and pre-gelatinized starch.
• 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 , 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 .
• 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, and Polacrillin potassium.
• the disintegrating agent is cationic polymer aminoalkyl methacrylate copolymer E.
• 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.
• 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.
• 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 lauryl sulphate.
• 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 S C.
• 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.
• 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.
• 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.
• any bitter tasting basic drug, or combination of bitter tasting drugs is contemplated in this invention.
• 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 azithromycin employed is preferably in form of isostructural pseudopolymorphs which exhibits superior dissolution properties as disclosed in Wegn Patent Application No. P20020231A.
• compositions of the invention include any dispersible composition, particularly granules, powders and tablets. Although tablets and capsules are simple to administer and convenient, children and elderly pat ents can have difficulty in swallowing them. For high dose drugs, size s a limitation, Dispersible pharmaceutical compositions are therefore conven ent and easier to administer. Dispersible pharmaceutical compositions are also able to be titrated as required by patients. 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 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'.
• 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 used for the same purpose.
• the drying temperature of the powder bed can be kept between 65 S C to 70 S C 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, 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 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 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 °C), but desirably melts readily with the application of mild temperatures (i.e. about 55- 95 °C). Mixtures, whose components may individually fall outside this melting temperature range, but whose average melting point is within this range, are also included.
• 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.
• 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 agents generally help with dispersion of tablets and with dissolution.
• 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 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 carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide.
• excipients used alone or in combination can be added to improve the flow properties of the dispersible compositions.
• diluting agents include cellulose, microcrystalline cellulose, mannitol, sorbitol, starch, pre-gelatinized starch, gelatinized starch, directly compressible microcrystalline cellulose, lactose, calcium carbonate, silica, and dibasic calcium phosphate.
• compositions of the invention utilize diluting granules that consist of a blend of microcrystalline cellulose and maize starch in various ratios from 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 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.
• 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.
• the cationic polymer amino alkyl methacrylate copolymer E (EudragitTM 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.
• a sweetening agent such as aspartame, ammonium glycerrhizinate (e.g. magnasweetTM), saccharin sodium and other saccharides, acesulfame potassium, or mannitol, is preferably incorporated as a secondary sweetener.
• sweetening agents in high' dose is undesirable because of unpleaseant aftertastes and generally to avoid ' giving patients unnecessary . amounts of additives., _
• a low level (2 to 5%)" of sweetening agent is preferably a'dded to provide a sweet taste.
• Aspartame is
• flavouring agenf for a* alkaline bitter drug is difficult.
• Citrus flavours are hot useful as they impart a bitter taste
• some other flavours such as "mint and vanilla, synergistically reduce the bitterness of preparations.
• Flavouring agents evaluated are vanilla, banana, cherry, pineapple, caramel, chocolate, mint and related flavouring compounds. Formulations with acceptable tastes were obtained with mild flavours and also when no flavouring agent was added.
• a lubricating agent such as magnesium stearate or calcium stearate, or related pharmaceutically acceptable lubricating compounds
• 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.
• Example 1 Granular matrix with reduced bitterness
• 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 (SEM). 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.
• SEM scanning electron microscopy
• Example 2 Granular matrix with reduced bitterness
• 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 compression.
• Example 3 Granular matrix with reduced bitterness
• 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 S C. Dried granules were sized to give fast disintegrating and flowing granules.
• Example 5 EudragitTM EPO as a disintegrating/dispersing agent in dispersible tablets
• Example 2 The granular matrix of Example 2 and the diluting granules of Example 4 were 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, and talc.
• the mixture was then lubricated with magnesium stearate.
• the following disintegrating/dispersing agents were used: aminoalkyl methacrylate copolymer E (EudragitTM EPO), carmellose sodium, sodium starch glycollate, and polacrillin potassium. 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.
• EudragitTM 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.
• Example 6 Dispersible pharmaceutical composition such as tablets
• Example 1 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 other excipients: aspartame, aminoalkyl methacrylate copolymer E
• Tablets were compressed using granules of dispersible compositions and evaluated for taste, uniformity of dispersion and other pharmacopoeia! 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.
• 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 reduced bitterness was varied as shown in the table below.
• the level of tribasic sodium phosphate and aspartame was also varied as shown in the table below. Compositions were assessed in 5 volunteers.
• compositions were separately dispersed in 60 ml water and were evaluated for taste, immediately after dispersion.
• composition VII and VIII which contained fatty acid ester glycerol 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 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 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.
• composition XII is the same as VII without azithromycin.
• the taste of the dispersion was compared with composition VII without the drug azithromycin.
• the composition was ' marked as XII.
• compositions VII, IX, X and XI by 20 volunteers.

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  • 2003-04-02 CN CNA038260204A patent/CN1744881A/zh active Pending
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