EP1830819A1 - Stable pharmaceutical composition comprising amoxicillin and clavulanic acid - Google Patents

Stable pharmaceutical composition comprising amoxicillin and clavulanic acid

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Publication number
EP1830819A1
EP1830819A1 EP05822286A EP05822286A EP1830819A1 EP 1830819 A1 EP1830819 A1 EP 1830819A1 EP 05822286 A EP05822286 A EP 05822286A EP 05822286 A EP05822286 A EP 05822286A EP 1830819 A1 EP1830819 A1 EP 1830819A1
Authority
EP
European Patent Office
Prior art keywords
amoxicillin
excipients
clavulanic acid
pharmaceutical formulation
formulation according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05822286A
Other languages
German (de)
French (fr)
Inventor
Janez Kerc
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lek Pharmaceuticals dd
Original Assignee
Lek Pharmaceuticals dd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lek Pharmaceuticals dd filed Critical Lek Pharmaceuticals dd
Publication of EP1830819A1 publication Critical patent/EP1830819A1/en
Withdrawn legal-status Critical Current

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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
    • A61K9/20—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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • Stable pharmaceutical composition comprising amoxicillin and clavulanic acid
  • the present invention belongs to the field of pharmaceutical technology and relates to novel improved pharmaceutical formulations comprising amoxicillin and clavulanic acid.
  • Amoxicillin is a broad-spectrum /Mactam antibiotic
  • clavulanic acid is a ⁇ - lactamase inhibitor. Combinations of both are the medicaments of choice for many infectious diseases.
  • Stability of clavulanic acid is a key problem of the stability of pharmaceutical formulations comprising amoxicillin and clavulanic acid.
  • Amoxicillin is generally used in the form of trihydrate and clavulanic acid in the form of potassium clavulanate, which is extremely moisture sensitive and may degrade quickly in the presence of water. The problem is particularly evident in case of pharmaceutical formulations with a higher ratio of amoxicillin and clavulanic acid and in pharmaceutical formulations comprising a small portion of excipients.
  • Medicaments comprising amoxicillin and clavulanic acid are available on the market in different formulations, for instance as conventional immediate-release tablets, powder to be reconstituted into water suspension, sachets, chewable tablets, multilayer tablets, modified release tablets.
  • the formulations comprising amoxicillin and clavulanic acid in ratios 2:1 , 4:1 , 7:1, 8:1 , 14:1 or 16:1 are available.
  • Tablets comprising amoxicillin and clavulanic acid are conventionally prepared so that both active substances and intra-granular excipients are first dry granulated (slugging, compacting). The granulate thus obtained is then mixed with extra- granular excipients and the mixture is compressed into tablets.
  • the process for the preparation of such tablets is described for instance in WO 92/19227.
  • Tablets comprising amoxicillin and clavulanic acid can be manufactured by preparing a first granulate comprising amoxicillin and clavulanic acid and a second granulate comprising amoxicillin only, and then both granulates are mixed in appropriate ratios and then further processed to obtain tablets with a desired ratio of amoxicillin and clavulanic acid.
  • the process for the preparation of such tablets is described in WO 98/35672.
  • Agglomerates of amoxicillin free of other excipients may be mixed with clavulanic acid and excipients and directly compressed into tablets. The process for the preparation of such tablets is described for instance in WO 97/33564.
  • a further object of the invention is a process for the preparation of these pharmaceutical formulations.
  • the formulations comprise granulate consisting of amoxicillin and a part of excipients and further comprise clavulanic acid which is added outside the granulate together with the remaining excipients.
  • the pharmaceutical formulation of the invention may be immediate-release or modified and controlled-release. It may be a tablet or coated tablet, capsule or coated capsule, powder or granulate to be reconstituted into suspension, sachets, chewable tablets, dispersible tablets, orodispersible tablets, multilayer tablets, compression coated tablets. Preferable formulations are immediate release film coated tablets.
  • Amoxicillin in the pharmaceutical formulations of the present invention is usually in the form of amoxicillin trihydrate, but it may be also in the form of sodium crystalline amoxicillin.
  • Clavulanic acid is usually in the form of the salt such as, for example, clavulanate potassium. Amoxicillin and clavulanic acid may be in the ratio from 1 : 1 to 30 : 1, preferably 2: 1, 4 : 1, 7 : 1 , 8: 1, 12 : 1, 14 : 1 , 16 : 1 and 20 : 1.
  • the suitable doses of amoxicillin may be between 300 and 3000 mg, and the doses of clavulanic acid between 50 and 300 mg, preferably from 800 to 1100 mg of amoxicillin and from 60 to 125 mg of clavulanic acid. Particularly preferable are 875/125, 1000/125, 1050/125 tablets.
  • the formulations of the present invention are manufactured by the method of dry granulation in such a manner that amoxicillin and clavulanic acid are not granulated together.
  • Amoxicillin alone is dry granulated with a part of excipients (intra-granular excipients).
  • the compacting or slugging technological procedure may be used, slugs or compacts are milled or sieved, and clavulanic acid and selected excipients (extra-granular excipients) are added to the sieved mixture. Clavulanic acid is added extra granularly.
  • the mixture thus prepared may be filled into capsules, sachets, glass or plastic bottles, or the mixture is compressed into immediate-release tablets, or modified and controlled- release tablets, respectively, chewable tablets, dispersible tablets, orodispersible tablets, multilayer tablets, compression coated tablets.
  • Tablets of the present invention are hard and have suitable physical and technological properties for handling or further processing. Tablets may be coated or uncoated.
  • the pharmaceutical formulations of the present invention may in the granulate comprise intra-granular excipients such as, for example, fillers, binders, disintegrants, dissolution and absorption enhancers of the active substances from the gastrointestinal tract, release-control substances, glidants and lubricants.
  • intra-granular excipients such as, for example, fillers, binders, disintegrants, dissolution and absorption enhancers of the active substances from the gastrointestinal tract, release-control substances, glidants and lubricants.
  • Suitable intra-granular fillers may be selected from microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, lactose, starch, pregelatinized starch, saccharose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulphate, dextrates, dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc, and others, preferably microcrystalline cellulose, silicified microcrystalline cellulose and lactose.
  • Suitable intra-granular binders may be selected from starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ethylcellulose, guar gum, hydrogenate vegetable oil, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminium silicate, maltodextrin, polymethacrylates, zein, preferably microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.
  • Suitable intra-granular disintegrants may be selected from starch, pregelatinized starch, sodium starch glycollate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose, polacrilin potassium, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, colloidal silicon dioxide, guar gum, magnesium aluminium silicate, and others, preferably cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone.
  • Suitable intra-granular dissolution and absorption enhancers of the active substances from the gastrointestinal tract may be surfactants, fatty acids, middle- chain glycerides, bile acids, their salts and derivatives, acyl carnitine and alkanoyl choline (carnitine and choline esters and middle- and long-chain fatty acids), N- acyl derivatives of ⁇ -amino acids, N-acyl derivatives of non- ⁇ -amino acids, chitosans and other mucoadhesive polymers.
  • Especially suitable dissolution and absorption enhancers of the active substances from the gastrointestinal tract are sodium deoxycholate, sodium taurocholate, polysorbate 80, sodium lauryl sulphate, sodium dodecylsulphate, octanoic acid, sodium docusate, sodium laurate, glyceryl monolaurate, stearic acid, palmitic acid, palmitoleic acid, glyceryl monooleate, sodium taurocholate, ethylenediaminotetraacetic acid, sodium edetate, ⁇ -cyclodextrines and sodium salicylate.
  • Preferred dissolution and absorption enhancers are sodium deoxycholate, sodium docusate and sodium lauryl sulphate.
  • Suitable intra-granular glidants may be selected from magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, polyethylene glycols of different molecular weights, magnesium trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch, and others.
  • Preferred glidant is colloidal silicon dioxide.
  • Suitable intra-granular lubricants may be selected from stearic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, talc, and others.
  • Preferred lubricants are magnesium and calcium stearate, and stearic acid.
  • the pharmaceutical formulations of the present invention may also comprise intra- granular release-control excipients.
  • polymers such as, for example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethyl- cellulose, hydroxypropylmethyl cellulose phthalate, polyethylene glycols of different molecular weights, different derivatives of acrylic and methacrylic acid, xanthan gum, alginic acid, sodium alginate, polyvinylpyrrolidone, polyethylene oxides, or nonpolymer substances such as, for example, hydrogenated vegetable oil, hydrogenated castor oil, glycerol monostearate, glycerol palmitostearate, and others.
  • the granulate comprising amoxicillin is homogeneously mixed with clavulanic acid and extra-granular excipients such as, for example, fillers, binders, disintegrants, dissolution and absorption enhancers of the active substances from the gastrointestinal tract, release-control substances, glidants and lubricants.
  • extra-granular excipients such as, for example, fillers, binders, disintegrants, dissolution and absorption enhancers of the active substances from the gastrointestinal tract, release-control substances, glidants and lubricants.
  • Extra-granular fillers may be selected from microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, lactose, starch, pregelatinized starch, saccharose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulphate, dextrates, dextrin, maitodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc, and others, preferably microcrystalline cellulose, silicified microcrystalline cellulose and lactose.
  • Suitable extra-granular binders may be starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ethylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminium silicate, maltodextrin, polymethacrylates, zein, preferably microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolydone.
  • Suitable extra-granular disintegrants may be starch, pregelatinized starch, sodium starch glycollate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium, carboxymethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose, polacrilin potassium, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, colloidal silicon dioxide, guar gum, magnesium aluminium silicate, and others, preferably cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone.
  • the extra-granular dissolution and absorption enhancers of the active substances from the gastrointestinal tract may be selected from surfactants, fatty acids, middle-chain glycerides, bile acids, their salts and derivatives, acyl carnitine and alkanoyl choline (carnitine and choline esters and middle- and long-chain fatty acids), N-acyl derivatives of ⁇ -amino acids and N-acyl derivatives of non- ⁇ -amino acids, chitosans and other mucoadhesive polymers.
  • surfactants fatty acids, middle-chain glycerides, bile acids, their salts and derivatives, acyl carnitine and alkanoyl choline (carnitine and choline esters and middle- and long-chain fatty acids), N-acyl derivatives of ⁇ -amino acids and N-acyl derivatives of non- ⁇ -amino acids, chitosans and other mucoadhesive polymers
  • Especially suitable dissolution and absorption enhancers of the active substances from the gastrointestinal tract are sodium deoxycholate, sodium taurocholate, polysorbate 80, sodium lauryl sulphate, sodium dodecylsulphate, octanoic acid, sodium docusate, sodium laurate, glyceryl monolaurate, stearic acid, palmitic acid, palmitoleic acid, glyceryl monooleate, ethylenediaminotetraacetic acid, sodium edetate, sodium citrate, ⁇ - cyclodextrines and sodium salicylate.
  • Preferred dissolution and absorption enhancers are sodium deoxycholate, sodium docusate and sodium lauryl sulphate.
  • Extra-granular glidants may be selected from magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, polyethylene glycols of different molecular weights, magnesium trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch, and others, preferable is colloidal silicon dioxide.
  • Suitable extra-granular lubricants may be selected from stearic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, talc, and others.
  • Preferred lubricants are magnesium and calcium stearate, and stearic acid.
  • the pharmaceutical formulations of the present invention may also comprise extra-granular release-control excipients.
  • Suitable may be different polymers such as, for instance, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethyl- cellulose, hydroxypropylmetyl cellulose phthalate, polyethylene glycol of different molecular weights, different derivatives of acrylic and methacrylic acid, xanthan gum, alginic acid, sodium alginate, polyvinylpyrrolidone, polyethylene oxides, or nonpolymer substances such as, for example, hydrogenated vegetable oil, hydrogenated castor oil, glycerol monostearate, glycerol palmitostearate, and others.
  • compositions may be coated with a suitable coat which controls release of the active substances from the pharmaceutical formulation or it is only a protective coat.
  • a coat may be applied from the aqueous or nonaqueous medium.
  • the coat may be prepared from polymer or nonpolymer substances. Suitable polymers may be selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methyicellulose, ethylcellulose, hydroxyethyl - cellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxymethyl cellulose phthalate, polyvinyl alcohol, methylhydroxyethylcellulose, sodium carboxymethylcellulose, polymers of acrylic and methacrylic acid, maltodextrin, and others.
  • Nonpolymer substances may be selected from camauba wax, cetyl alcohol, saccharose, glucose, shellac, and others.
  • the coat may also comprise other excipients which are conventionally used for coating such as fillers, for example, talc, lactose, polysaccharides and others, plasticizers, for example, dibutyl sebacate, triethyl citrate, polyethylene glycol, adipic acid, coconut oil, oleic acid and others, colouring agents, for example, titanium dioxide, lakes, pigments and others, antioxidants and others.
  • Coats are applied by the techniques which are conventional for pharmaceutical formulation coating in the pharmaceutical technology.
  • a coating dispersion may be a solution or suspension of polymers and other excipients.
  • Solvents used for the preparation of a coating dispersion may be, for example, water, ethanol, methanol, propan-2-ole, acetone, ethyl acetate, acetic acid, glycols, dichloromethane, dimethylformamide, dimethyisulphoxide, chloroform, toluene, methylene chloride, benzene, ethoxyethyl acetate, ethylene glycol monoacetate, ethyl lactate, monoethyl acetate, methyl ethyl ketone and their combinations.
  • the proportion of excipients in the pharmaceutical formulations of the invention is from 5% by weight to 50% by weight, preferably from 10 to 30%.
  • the pharmaceutical formulations of the present invention are stable at room temperature and under elevated temperature and humidity conditions.
  • the results indicate essentially better stability of the tablets of the present invention compared to tablets comprising granulate in which amoxicillin and clavulanic acid are granulated together.
  • the object of the present invention is also a process for the preparation of the pharmaceutical formulations of the invention. They are prepared by the method of dry granulation of amoxicillin and intra-granular excipients. To the thus obtained granulate clavulanic acid and the extra-granular excipients are added. The obtained mixture is compressed into tablets or filled into capsules or sachets.
  • the process for the preparation of the formulations of the present invention comprises the following key steps:
  • Potassium clavulanate is highly water sensitive substance. Therefore, certain excipients containing water are dried previously or already pre-dried excipients are used. Manufacturing is carried out under dry conditions of less than 30% relative air humidity.
  • Tablets - amoxicillin and clavulanic acid are granulated together:
  • the milled granulate, Ac-di-sol-dried, Polyplasdon XL-dried and Aerosil were mixed in the Muller drum on the Soneco mixer for 15 minutes.
  • Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute.
  • the mixed granulate was compressed into oval biconvex tablets with the average weight of 1610 mg and the hardness 18-35 kp on the rotary tablet press Killian T300.
  • the tablet cores were coated with a film coat (30 mg), the average total weight of the coated tablet is 1640 mg.
  • the tablet cores were coated with the film coat of the following composition:
  • talc and titanium dioxide were dispersed in 7.1 kg of ethanol while mixing at 7200 rpm (a colouring concentrate).
  • hydroxypropylcellulose, ethylcellulose, polysorbate and triethyl citrate were dissolved in 23.233 kg of ethanol while mixing at 1000 rpm and a colouring concentrate was added.
  • the suspension thus prepared was sprayed over the tablets in the perforated coating pan Manesty XL labO2 at 30-35 0 C to obtain an average amount of the coat of 30 mg.
  • the coated tablets were dried and polished with talc.
  • the coated tablets were packed into Alu/Alu blister packs and stored under the conditions of 40°C/75% relative air humidity in a controlled area chamber. After one month a decrease of 7.4% of in the assay of clavulanic acid was determined with respect to the initial assay of clavulanic acid.
  • Amoxicillin trihydrate, Prosolv-dried, Ac-di-sol-dried, Polyplasdon XL-dried, Texapon and Aerosil were mixed in the Muller drum on the Soneco mixer for 10 min, and sieved through a 2 mm screen on the oscillating granulator Frewitt MG- 636.
  • Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute.
  • the mixture was slugged on the slugging machine Fette P 2000 into slugs with the average weight of 1600 mg and hardness 15-30 kp.
  • the slugs were ground on the Frewitt MGH-6 mill using knives through the net with 1.25 mm openings. To the milled granulate it was added:
  • the milled granulate, Potassium clavulanate, Ac-di-sol-dried, Polyplasdon XL- dried and Aerosil were mixed in the Muller drum on the Soneco mixer for 15 minutes.
  • Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute.
  • the mixed granulate was compressed into oval biconvex tablets with the average weight of 1610 mg and the hardness 18-35 kp on the rotary tablet press Killian T300.
  • the tablet cores were coated with a film coat (30 mg), the average total weight of the coated tablet is 1640 mg.
  • the tablet cores were coated with the film coat of the following composition:
  • talc and titanium dioxide were dispersed in 7.1 kg of ethanol while mixing at 7200 rpm (a colouring concentrate).
  • hydroxypropylcellulose, ethylcellulose, polysorbate and triethyl citrate were dissolved in 23.233 kg of ethanol while mixing at 1000 rpm and a colouring concentrate was added.
  • the suspension thus prepared was sprayed over the tablets in the perforated coating pan Manesty XL lab02 at 30-35 0 C to obtain an average amount of the coat of 30 mg.
  • the coated tablets were dried and polished with talc.
  • Example 3 The coated tablets were packed into Alu/Alu blister packs and stored under the conditions of 40°C/75% relative air humidity in a controlled area chamber. After one month a decrease of 3.7% of in the assay of clavulanic acid was determined with respect to the initial assay of clavulanic acid.
  • Example 3
  • Amoxicillin trihydrate, Prosolv-dried, Ac-di-sol-dried, Polyplasdon XL-dried and Aerosil were mixed in the Muller drum on the Soneco mixer for 10 min, and sieved through a 2 mm screen on the oscillating granulator Frewitt MG-636.
  • Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute.
  • the mixture was slugged on the slugging machine Fette P 2000 into slugs with the average weight of 1600 mg and hardness 15-30 kp.
  • the slugs were ground on the Frewitt MGH-6 mill using knives through the net with 1.25 mm openings. To the milled granulate it was added:
  • the milled granulate, potassium clavulanate, Ac-di-sol-dried, Polyplasdon XL-dried and Aerosil were mixed in the Muller drum on the Soneco mixer for 15 minutes.
  • Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute.
  • the mixed granulate was compressed into oval biconvex tablets with the average weight of 1610 mg and the hardness 18-35 kp on the rotary tablet press Killian T300
  • the tablet cores were coated with a film coat (30 mg), the average total weight of the coated tablet is 1640 mg.
  • the tablet cores were coated with the film coat of the following composition:
  • talc and titanium dioxide were dispersed in 7.1 kg of ethanol while mixing at 7200 rpm (a colouring concentrate).
  • hydroxypropylcellulose, ethylcellulose, polysorbate and triethyl citrate were dissolved in 23.233 kg of ethanol while mixing at 1000 rpm and a colouring concentrate was added.
  • the suspension thus prepared was sprayed over tablets in the perforated coating pan Manesty XL labO2 at 30-35 0 C to obtain an average amount of the coat of 30 mg.
  • the coated tablets were dried and polished with talc.

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Abstract

The present invention relates to improved pharmaceutical formulations comprising amoxicillin and clavulanic acid. They comprise granulate prepared from amoxicillin and a part of excipients, the granulates being mixed with clavulanic acid and the remaining part of excipients and optionally compressed into tablets. The invention further relates to a process for preparing these formulations.

Description

Stable pharmaceutical composition comprising amoxicillin and clavulanic acid
The present invention belongs to the field of pharmaceutical technology and relates to novel improved pharmaceutical formulations comprising amoxicillin and clavulanic acid.
Amoxicillin is a broad-spectrum /Mactam antibiotic, and clavulanic acid is a β- lactamase inhibitor. Combinations of both are the medicaments of choice for many infectious diseases. Stability of clavulanic acid is a key problem of the stability of pharmaceutical formulations comprising amoxicillin and clavulanic acid. Amoxicillin is generally used in the form of trihydrate and clavulanic acid in the form of potassium clavulanate, which is extremely moisture sensitive and may degrade quickly in the presence of water. The problem is particularly evident in case of pharmaceutical formulations with a higher ratio of amoxicillin and clavulanic acid and in pharmaceutical formulations comprising a small portion of excipients. Thus, there is a constant need for improved pharmaceutical formulations which provide good stability of clavulanic acid in a combination with amoxicillin and excipients.
Medicaments comprising amoxicillin and clavulanic acid are available on the market in different formulations, for instance as conventional immediate-release tablets, powder to be reconstituted into water suspension, sachets, chewable tablets, multilayer tablets, modified release tablets. The formulations comprising amoxicillin and clavulanic acid in ratios 2:1 , 4:1 , 7:1, 8:1 , 14:1 or 16:1 are available.
Tablets comprising amoxicillin and clavulanic acid are conventionally prepared so that both active substances and intra-granular excipients are first dry granulated (slugging, compacting). The granulate thus obtained is then mixed with extra- granular excipients and the mixture is compressed into tablets. The process for the preparation of such tablets is described for instance in WO 92/19227.
Tablets comprising amoxicillin and clavulanic acid can be manufactured by preparing a first granulate comprising amoxicillin and clavulanic acid and a second granulate comprising amoxicillin only, and then both granulates are mixed in appropriate ratios and then further processed to obtain tablets with a desired ratio of amoxicillin and clavulanic acid. The process for the preparation of such tablets is described in WO 98/35672.
Agglomerates of amoxicillin free of other excipients may be mixed with clavulanic acid and excipients and directly compressed into tablets. The process for the preparation of such tablets is described for instance in WO 97/33564.
It has now been found that very stable formulations comprising amoxycillin and clavulanic acid can be obtained by a process comprising granulating amoxycillin with a part of excipients, blending the obtained granulate with clavulanic acid and the remaining excipients and optionally compressing the mixture into the tablets.
It is an object of the present invention to provide pharmaceutical formulations comprising amoxicillin and clavulanic acid with improved stability. A further object of the invention is a process for the preparation of these pharmaceutical formulations.
Description of the invention
It is an object of the present invention to provide stable pharmaceutical formulations which comprise granulate comprising amoxicillin and a part of excipients, the granulate being mixed with clavulanic acid and the remaining part of excipients and optionally compressed into tablets and optionally having a coat. The formulations comprise granulate consisting of amoxicillin and a part of excipients and further comprise clavulanic acid which is added outside the granulate together with the remaining excipients.
The pharmaceutical formulation of the invention may be immediate-release or modified and controlled-release. It may be a tablet or coated tablet, capsule or coated capsule, powder or granulate to be reconstituted into suspension, sachets, chewable tablets, dispersible tablets, orodispersible tablets, multilayer tablets, compression coated tablets. Preferable formulations are immediate release film coated tablets.
Amoxicillin in the pharmaceutical formulations of the present invention is usually in the form of amoxicillin trihydrate, but it may be also in the form of sodium crystalline amoxicillin. Clavulanic acid is usually in the form of the salt such as, for example, clavulanate potassium. Amoxicillin and clavulanic acid may be in the ratio from 1 : 1 to 30 : 1, preferably 2: 1, 4 : 1, 7 : 1 , 8: 1, 12 : 1, 14 : 1 , 16 : 1 and 20 : 1.
The suitable doses of amoxicillin may be between 300 and 3000 mg, and the doses of clavulanic acid between 50 and 300 mg, preferably from 800 to 1100 mg of amoxicillin and from 60 to 125 mg of clavulanic acid. Particularly preferable are 875/125, 1000/125, 1050/125 tablets.
The formulations of the present invention are manufactured by the method of dry granulation in such a manner that amoxicillin and clavulanic acid are not granulated together. Amoxicillin alone is dry granulated with a part of excipients (intra-granular excipients). For granulation the compacting or slugging technological procedure may be used, slugs or compacts are milled or sieved, and clavulanic acid and selected excipients (extra-granular excipients) are added to the sieved mixture. Clavulanic acid is added extra granularly. The mixture thus prepared may be filled into capsules, sachets, glass or plastic bottles, or the mixture is compressed into immediate-release tablets, or modified and controlled- release tablets, respectively, chewable tablets, dispersible tablets, orodispersible tablets, multilayer tablets, compression coated tablets. Tablets of the present invention are hard and have suitable physical and technological properties for handling or further processing. Tablets may be coated or uncoated.
The pharmaceutical formulations of the present invention may in the granulate comprise intra-granular excipients such as, for example, fillers, binders, disintegrants, dissolution and absorption enhancers of the active substances from the gastrointestinal tract, release-control substances, glidants and lubricants.
Suitable intra-granular fillers may be selected from microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, lactose, starch, pregelatinized starch, saccharose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulphate, dextrates, dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc, and others, preferably microcrystalline cellulose, silicified microcrystalline cellulose and lactose. Suitable intra-granular binders may be selected from starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ethylcellulose, guar gum, hydrogenate vegetable oil, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminium silicate, maltodextrin, polymethacrylates, zein, preferably microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.
Suitable intra-granular disintegrants may be selected from starch, pregelatinized starch, sodium starch glycollate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose, polacrilin potassium, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, colloidal silicon dioxide, guar gum, magnesium aluminium silicate, and others, preferably cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone. Suitable intra-granular dissolution and absorption enhancers of the active substances from the gastrointestinal tract may be surfactants, fatty acids, middle- chain glycerides, bile acids, their salts and derivatives, acyl carnitine and alkanoyl choline (carnitine and choline esters and middle- and long-chain fatty acids), N- acyl derivatives of α-amino acids, N-acyl derivatives of non-α-amino acids, chitosans and other mucoadhesive polymers. Especially suitable dissolution and absorption enhancers of the active substances from the gastrointestinal tract are sodium deoxycholate, sodium taurocholate, polysorbate 80, sodium lauryl sulphate, sodium dodecylsulphate, octanoic acid, sodium docusate, sodium laurate, glyceryl monolaurate, stearic acid, palmitic acid, palmitoleic acid, glyceryl monooleate, sodium taurocholate, ethylenediaminotetraacetic acid, sodium edetate, β-cyclodextrines and sodium salicylate. Preferred dissolution and absorption enhancers are sodium deoxycholate, sodium docusate and sodium lauryl sulphate.
Suitable intra-granular glidants may be selected from magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, polyethylene glycols of different molecular weights, magnesium trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch, and others. Preferred glidant is colloidal silicon dioxide.
Suitable intra-granular lubricants may be selected from stearic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, talc, and others. Preferred lubricants are magnesium and calcium stearate, and stearic acid. The pharmaceutical formulations of the present invention may also comprise intra- granular release-control excipients. They may be different polymers such as, for example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethyl- cellulose, hydroxypropylmethyl cellulose phthalate, polyethylene glycols of different molecular weights, different derivatives of acrylic and methacrylic acid, xanthan gum, alginic acid, sodium alginate, polyvinylpyrrolidone, polyethylene oxides, or nonpolymer substances such as, for example, hydrogenated vegetable oil, hydrogenated castor oil, glycerol monostearate, glycerol palmitostearate, and others.
In the next step of the technological procedure, the granulate comprising amoxicillin is homogeneously mixed with clavulanic acid and extra-granular excipients such as, for example, fillers, binders, disintegrants, dissolution and absorption enhancers of the active substances from the gastrointestinal tract, release-control substances, glidants and lubricants.
Extra-granular fillers may be selected from microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, lactose, starch, pregelatinized starch, saccharose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulphate, dextrates, dextrin, maitodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc, and others, preferably microcrystalline cellulose, silicified microcrystalline cellulose and lactose.
Suitable extra-granular binders may be starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ethylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminium silicate, maltodextrin, polymethacrylates, zein, preferably microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolydone.
Suitable extra-granular disintegrants may be starch, pregelatinized starch, sodium starch glycollate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium, carboxymethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose, polacrilin potassium, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, colloidal silicon dioxide, guar gum, magnesium aluminium silicate, and others, preferably cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone. The extra-granular dissolution and absorption enhancers of the active substances from the gastrointestinal tract may be selected from surfactants, fatty acids, middle-chain glycerides, bile acids, their salts and derivatives, acyl carnitine and alkanoyl choline (carnitine and choline esters and middle- and long-chain fatty acids), N-acyl derivatives of α-amino acids and N-acyl derivatives of non-α-amino acids, chitosans and other mucoadhesive polymers. Especially suitable dissolution and absorption enhancers of the active substances from the gastrointestinal tract are sodium deoxycholate, sodium taurocholate, polysorbate 80, sodium lauryl sulphate, sodium dodecylsulphate, octanoic acid, sodium docusate, sodium laurate, glyceryl monolaurate, stearic acid, palmitic acid, palmitoleic acid, glyceryl monooleate, ethylenediaminotetraacetic acid, sodium edetate, sodium citrate, β- cyclodextrines and sodium salicylate. Preferred dissolution and absorption enhancers are sodium deoxycholate, sodium docusate and sodium lauryl sulphate.
Extra-granular glidants may be selected from magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, polyethylene glycols of different molecular weights, magnesium trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch, and others, preferable is colloidal silicon dioxide. Suitable extra-granular lubricants may be selected from stearic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, talc, and others. Preferred lubricants are magnesium and calcium stearate, and stearic acid.
The pharmaceutical formulations of the present invention may also comprise extra-granular release-control excipients. Suitable may be different polymers such as, for instance, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethyl- cellulose, hydroxypropylmetyl cellulose phthalate, polyethylene glycol of different molecular weights, different derivatives of acrylic and methacrylic acid, xanthan gum, alginic acid, sodium alginate, polyvinylpyrrolidone, polyethylene oxides, or nonpolymer substances such as, for example, hydrogenated vegetable oil, hydrogenated castor oil, glycerol monostearate, glycerol palmitostearate, and others.
Pharmaceutical formulations may be coated with a suitable coat which controls release of the active substances from the pharmaceutical formulation or it is only a protective coat. A coat may be applied from the aqueous or nonaqueous medium. The coat may be prepared from polymer or nonpolymer substances. Suitable polymers may be selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methyicellulose, ethylcellulose, hydroxyethyl - cellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxymethyl cellulose phthalate, polyvinyl alcohol, methylhydroxyethylcellulose, sodium carboxymethylcellulose, polymers of acrylic and methacrylic acid, maltodextrin, and others.
Nonpolymer substances may be selected from camauba wax, cetyl alcohol, saccharose, glucose, shellac, and others. The coat may also comprise other excipients which are conventionally used for coating such as fillers, for example, talc, lactose, polysaccharides and others, plasticizers, for example, dibutyl sebacate, triethyl citrate, polyethylene glycol, adipic acid, coconut oil, oleic acid and others, colouring agents, for example, titanium dioxide, lakes, pigments and others, antioxidants and others. Coats are applied by the techniques which are conventional for pharmaceutical formulation coating in the pharmaceutical technology. A coating dispersion may be a solution or suspension of polymers and other excipients. Solvents used for the preparation of a coating dispersion may be, for example, water, ethanol, methanol, propan-2-ole, acetone, ethyl acetate, acetic acid, glycols, dichloromethane, dimethylformamide, dimethyisulphoxide, chloroform, toluene, methylene chloride, benzene, ethoxyethyl acetate, ethylene glycol monoacetate, ethyl lactate, monoethyl acetate, methyl ethyl ketone and their combinations.
The proportion of excipients in the pharmaceutical formulations of the invention is from 5% by weight to 50% by weight, preferably from 10 to 30%.
The pharmaceutical formulations of the present invention are stable at room temperature and under elevated temperature and humidity conditions. The results indicate essentially better stability of the tablets of the present invention compared to tablets comprising granulate in which amoxicillin and clavulanic acid are granulated together.
The object of the present invention is also a process for the preparation of the pharmaceutical formulations of the invention. They are prepared by the method of dry granulation of amoxicillin and intra-granular excipients. To the thus obtained granulate clavulanic acid and the extra-granular excipients are added. The obtained mixture is compressed into tablets or filled into capsules or sachets. The process for the preparation of the formulations of the present invention comprises the following key steps:
- Preparation of the mixture of amoxicillin and intra-granular excipients,
- Dry granulation - slugging or compacting of the mixture of amoxicillin and intra- granular excipients,
- Grinding and sieving of obtained granulate ( the slugs or compacts),
- Mixing of the sieved granulate with clavulanic acid and extra-granular excipients,
- Optionally tablet compressing or encapsulating,
- Optionally application of the coat.
Potassium clavulanate is highly water sensitive substance. Therefore, certain excipients containing water are dried previously or already pre-dried excipients are used. Manufacturing is carried out under dry conditions of less than 30% relative air humidity.
The present invention is illustrated but in no way limited by the following examples:
Example 1 :
Tablets - amoxicillin and clavulanic acid are granulated together:
Amoxicillin trihydrate, Potassium clavulanate, Prosolv-dried, Ac-di-sol-dried, Polyplasdon XL-dried and Aerosil were mixed in the Muller drum on the Soneco mixer for 10 min, and sieved through a 2 mm screen on the oscillating granulator Frewitt MG-636. Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute. The mixture was slugged on the slugging machine Fette P 2000 into slugs with the average weight of 1600 mg and hardness 15-30 kp. The slugs were ground on the Frewitt MGH-6 mill using knives through the net with 1.25 mm openings. To the milled granulate it was added:
The milled granulate, Ac-di-sol-dried, Polyplasdon XL-dried and Aerosil were mixed in the Muller drum on the Soneco mixer for 15 minutes. Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute. The mixed granulate was compressed into oval biconvex tablets with the average weight of 1610 mg and the hardness 18-35 kp on the rotary tablet press Killian T300.
The tablet cores were coated with a film coat (30 mg), the average total weight of the coated tablet is 1640 mg.
The tablet cores were coated with the film coat of the following composition:
In the mixing vessel talc and titanium dioxide were dispersed in 7.1 kg of ethanol while mixing at 7200 rpm (a colouring concentrate).
In the mixing vessel hydroxypropylcellulose, ethylcellulose, polysorbate and triethyl citrate were dissolved in 23.233 kg of ethanol while mixing at 1000 rpm and a colouring concentrate was added. The suspension thus prepared was sprayed over the tablets in the perforated coating pan Manesty XL labO2 at 30-350C to obtain an average amount of the coat of 30 mg. The coated tablets were dried and polished with talc.
The coated tablets were packed into Alu/Alu blister packs and stored under the conditions of 40°C/75% relative air humidity in a controlled area chamber. After one month a decrease of 7.4% of in the assay of clavulanic acid was determined with respect to the initial assay of clavulanic acid.
Example 2:
Tablets - amoxicillin granulated with excipients
Amoxicillin trihydrate, Prosolv-dried, Ac-di-sol-dried, Polyplasdon XL-dried, Texapon and Aerosil were mixed in the Muller drum on the Soneco mixer for 10 min, and sieved through a 2 mm screen on the oscillating granulator Frewitt MG- 636. Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute. The mixture was slugged on the slugging machine Fette P 2000 into slugs with the average weight of 1600 mg and hardness 15-30 kp. The slugs were ground on the Frewitt MGH-6 mill using knives through the net with 1.25 mm openings. To the milled granulate it was added:
The milled granulate, Potassium clavulanate, Ac-di-sol-dried, Polyplasdon XL- dried and Aerosil were mixed in the Muller drum on the Soneco mixer for 15 minutes. Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute. The mixed granulate was compressed into oval biconvex tablets with the average weight of 1610 mg and the hardness 18-35 kp on the rotary tablet press Killian T300.
The tablet cores were coated with a film coat (30 mg), the average total weight of the coated tablet is 1640 mg.
The tablet cores were coated with the film coat of the following composition:
In the mixing vessel talc and titanium dioxide were dispersed in 7.1 kg of ethanol while mixing at 7200 rpm (a colouring concentrate).
In the mixing vessel hydroxypropylcellulose, ethylcellulose, polysorbate and triethyl citrate were dissolved in 23.233 kg of ethanol while mixing at 1000 rpm and a colouring concentrate was added. The suspension thus prepared was sprayed over the tablets in the perforated coating pan Manesty XL lab02 at 30-350C to obtain an average amount of the coat of 30 mg. The coated tablets were dried and polished with talc.
The coated tablets were packed into Alu/Alu blister packs and stored under the conditions of 40°C/75% relative air humidity in a controlled area chamber. After one month a decrease of 3.7% of in the assay of clavulanic acid was determined with respect to the initial assay of clavulanic acid. Example 3:
Tablets - amoxicillin granulated with excipients
Amoxicillin trihydrate, Prosolv-dried, Ac-di-sol-dried, Polyplasdon XL-dried and Aerosil were mixed in the Muller drum on the Soneco mixer for 10 min, and sieved through a 2 mm screen on the oscillating granulator Frewitt MG-636. Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute. The mixture was slugged on the slugging machine Fette P 2000 into slugs with the average weight of 1600 mg and hardness 15-30 kp. The slugs were ground on the Frewitt MGH-6 mill using knives through the net with 1.25 mm openings. To the milled granulate it was added:
The milled granulate, potassium clavulanate, Ac-di-sol-dried, Polyplasdon XL-dried and Aerosil were mixed in the Muller drum on the Soneco mixer for 15 minutes. Sieved Mg stearate using a manual 0.8 mm screen was added to the sieved mixture and mixed in the Muller drum on the Soneco mixer for 1 minute. The mixed granulate was compressed into oval biconvex tablets with the average weight of 1610 mg and the hardness 18-35 kp on the rotary tablet press Killian T300
The tablet cores were coated with a film coat (30 mg), the average total weight of the coated tablet is 1640 mg.
The tablet cores were coated with the film coat of the following composition:
In the mixing vessel talc and titanium dioxide were dispersed in 7.1 kg of ethanol while mixing at 7200 rpm (a colouring concentrate).
In the mixing vessel hydroxypropylcellulose, ethylcellulose, polysorbate and triethyl citrate were dissolved in 23.233 kg of ethanol while mixing at 1000 rpm and a colouring concentrate was added. The suspension thus prepared was sprayed over tablets in the perforated coating pan Manesty XL labO2 at 30-350C to obtain an average amount of the coat of 30 mg. The coated tablets were dried and polished with talc.

Claims

Claims
1. A pharmaceutical formulation comprising
- a granulate comprising amoxicillin and excipients
- clavulanic acid
- optionally a coat.
2. The pharmaceutical formulation according to claim 1 wherein amoxicillin is in the form of amoxicillin trihydrate and clavulanic acid in the form of potassium clavulanate.
3. The pharmaceutical formulation according to claim 1 wherein the ratio of amoxicillin and clavulanic acid is from 1 :1 to 30:1.
4. The pharmaceutical formulation according to claims 1 and 3 wherein the ratio of amoxicillin and clavulanic acid is 4:1, 7:1 , 8:1 , 12:1 , 16:1, 20:1.
5. The pharmaceutical formulation according to claim 1 wherein the excipients are selected from the group comprising fillers, binders, disintegrants, dissolution and absorption enhancers, glindants and lubricants.
6. The pharmaceutical formulation according to claim 1 wherein granulate comprising amoxicillin and excipients is prepared by dry granulation.
7. The pharmaceutical formulation according to claim 1 wherein granulate is obtained by slugging or compacting of the mixture of amoxicillin and excipients.
8. The pharmaceutical formulation according to claim 1 wherein clavulanic acid is added extragranularly.
9. The pharmaceutical formulation according to claim 1 further comprising extra- granular excipients.
10. The pharmaceutical formulation according to claim 1 which is a tablet.
11. The pharmaceutical formulation according to claims 1 and 10 which comprises 1050 mg of amoxicillin and 125 mg of clavulanic acid.
12. The pharmaceutical formulation according to claim 1 which is a capsule.
13. The pharmaceutical formulation according to claim 1 which is a sachet.
14. A process for preparing a pharmaceutical formulation according to claim 1 comprising the following steps:
- preparation of the mixture of amoxicillin and excipients,
- dry granulation of the mixture of amoxicillin and excipients,
- grinding and sieving of granulate,
- mixing of the sieved granulate with clavulanic acid and other excipients,
- optionally tablet compressing or capsulating,
- optionally application of a coat.
EP05822286A 2004-12-24 2005-12-22 Stable pharmaceutical composition comprising amoxicillin and clavulanic acid Withdrawn EP1830819A1 (en)

Applications Claiming Priority (2)

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SI200400350A SI21912A (en) 2004-12-24 2004-12-24 Stable pharmaceutical forms containing amoxicillin and clavulanic acid
PCT/EP2005/013898 WO2006066930A1 (en) 2004-12-24 2005-12-22 Stable pharmaceutical composition comprising amoxicillin and clavulanic acid

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