SI21350A - Pharmaceutical forms containing amoxicillin and clavulanic acid - Google Patents

Abstract

The invention refers to formed particles which contain amoxicillin and clavulanic acid and are recovered according to the wet granulation procedure. The invention refers also to the manufacturing procedure of these particles and to pharmaceutical forms which they contain.

Description

Lek farmacevtska družba d. d.Lek pharmaceutical company d. d.

Farmacevtske oblike, ki vsebujejo amoksicilin in klavulansko kislinoPharmaceutical forms containing amoxicillin and clavulanic acid

Področje tehnike, na katerega se nanaša izumFIELD OF THE INVENTION

Izum spada v področje farmacevtske tehnologije in se nanaša na farmacevtske oblike, ki vsebujejo amoksicilin in klavulansko kislino.The invention is within the field of pharmaceutical technology and relates to pharmaceutical forms containing amoxicillin and clavulanic acid.

Predmet izuma so formirani delci, ki vsebujejo amoksicilin in klavulansko kislino in so pridobljeni s postopkom vlažnega granuliranja. Predmet izuma je tudi postopek za pripravo teh delcev ter farmacevtske oblike, ki jih vsebujejo.The object of the invention is formed particles containing amoxicillin and clavulanic acid and obtained by the wet granulation process. The subject of the invention is also a process for the preparation of these particles and the pharmaceutical forms containing them.

Stanje tehnikeThe state of the art

Zdravila, ki vsebujejo amoksicilin in klavulansko kislino, so na trgu v različnih oblikah: kot običajne tablete s takojšnjim sproščanjem, prašek za rekonstitucijo v vodno suspenzijo, vrečke, žvečilne tablete, večslojne tablete. Poznane so oblike, v katerih je razmerje amoksicilina in klavulanske kisline 2:1, 4:1, 7:1, 8:1, 14:1 ali 16:1.Medicines containing amoxicillin and clavulanic acid are marketed in various forms: as normal immediate-release tablets, reconstituted powder for aqueous suspension, sachets, chewable tablets, multilayer tablets. Formulations in which the ratio of amoxicillin to clavulanic acid are known are 2: 1, 4: 1, 7: 1, 8: 1, 14: 1 or 16: 1.

Tablete, ki vsebujejo amoksicilin in klavulansko kislino, običajno pripravijo tako, da učinkovini in del pomožnih snovi najprej suho granulirajo (briketiranje, kompaktiranje). Tako pridobljen granulat zmešajo s preostalim delom pomožnih snovi in zmes tabletirajo. Postopki za pripravo takih tablet so opisani npr. v patentnih prijavah WO 92/19227, WO 95/28927 in WO 98/35672.Tablets containing amoxicillin and clavulanic acid are usually prepared by first granulating the active ingredients and a portion of the excipients to dry granulation (briquetting, compacting). The granulate thus obtained is mixed with the remainder of the excipients and tableted. Methods for preparing such tablets are described e.g. in WO 92/19227, WO 95/28927 and WO 98/35672.

V patentni prijavi WO 01/62231 so opisane farmacevtske oblike, ki vsebujejo zmes vsaj štirih različnih vrst pelet. Nekatere od njih vsebujejo amoksicilin, druge klavulansko kislino. Zaradi različne hitrosti sproščanja učinkovin iz pelet je možno pripraviti oblike z različnim profilom sproščanja,Patent Application WO 01/62231 describes pharmaceutical formulations containing a mixture of at least four different types of pellets. Some of them contain amoxicillin, others clavulanic acid. Due to the different rate of release of the active ingredients from the pellets, it is possible to prepare forms with different release profiles,

V WO 95/25516 so opisane granule, ki poleg amoksicilina in/ali klavulanske kisline vsebujejo tudi eno ali več površinsko aktivnih snovi, npr. natrijev lauril sulfat.WO 95/25516 describes granules which, in addition to amoxicillin and / or clavulanic acid, also contain one or more surfactants, e.g. sodium lauryl sulfate.

Opis izumaDescription of the invention

Predmet izuma so formirani delci, ki vsebujejo amoksicilin in klavulansko kislino. Delci so lahko sferični ali pa nepravilnih oblik. Pridobimo jih z metodo vlažnega granuliranja. Za granuliranje lahko uporabimo farmacevtsko sprejemljiva organska topila ali njihove zmesi, lahko pa tudi disperzijo veziva v organskem topilu.The object of the invention is formed particles containing amoxicillin and clavulanic acid. The particles may be spherical or irregular in shape. They are obtained by the wet granulation method. Pharmaceutically acceptable organic solvents or mixtures thereof, as well as dispersing the binder in an organic solvent, may be used for granulation.

Amoksicilin je v delcih, ki so predmet izuma, običajno v obliki amoksicilin trihidrata, lahko pa tudi v obliki natrijevega kristalnega amoksicilina. Klavulanska kislina je običajno v obliki soli kot je npr. kalijev klavulanat. Amoksicilin in klavulanska kislina sta lahko v razmerju od 1 :1 do 30 : 1, prednostno 2:1,4:1,7:1,8:1,12:1, 14 : 1, 16 : 1 in 20 : 1.Amoxicillin is usually in the form of amoxicillin trihydrate in the particles of the invention, but may also be in the form of sodium crystalline amoxicillin. Clavulanic acid is usually in the form of salts such as e.g. potassium clavulanate. Amoxicillin and clavulanic acid may be in the ratio of 1: 1 to 30: 1, preferably 2: 1,4: 1,7: 1,8: 1,12: 1, 14: 1, 16: 1 and 20: 1.

Delci, ki so predmet izuma, vsebujejo poleg učinkovin še pomožne snovi kot so npr. polnila, veziva, razgrajevala, drsila in maziva. Kot polnila se lahko uporabljajo mikrokristalna celuloza, uprašena celuloza, laktoza, škrob, preželatiniran škrob, šaha roza, glukoza, manitol, sorbitol, kalcijev fosfat, kalcijev hidrogen fosfat, aluminijev silikat, natrijev klorid, kalijev klorid, kalcijev karbonat, kalcijev sulfat, dekstrati, dekstrin, maltodekstrin, glicerol palmitostearat, hidrogenirano rastlinsko olje, kaolin, magnezijev karbonat, magnezijev oksid, polimetakrilati, smukec, idr. , prednostno mikrokristalna celuloza in laktoza. Primerna veziva so lahko škrob, aluminijev silikat, hidroksipropilceluloza, preželatiniran škrob, želatina, natrijeva karboksimetilceluloza, poliviniipirolidon, alginska kislina, natrijev alginat, akacia, karbomer, dekstrin, etilceluloza, guar guma, hidrogenirano rastlinsko olje, metilceluloza, hidroksietilceluloza, hidroksipropilceluloza, hidroksipropilmetilceluloza, glukozni sirup, magnezijev maltodekstrin, polimetakrilati, zein, prednostno hidroksipropilmetilceluloza in polivinilpirolidon. Kot razgrajevala se lahko uporabljajo škrob, preželatiniran škrob, natrijev škrob glikolat, natrijeva karboksimetilceluloza, premerežena natrijeva karboksimetilceluloza, kalcijeva karboksimetilceluloza, metilceluloza, mikrokristalna celuloza, uprašena celuloza, kalijev polakriiin, premereženi polivinilpirolidon, alginska kislina, natrijev alginat, koloidni silicijev dioksid, guar guma, magnezijev aluminijev silikat, idr., prednostno natrijev škrob glikolat, premrežena natrijeva karboksimetilceluloza in premreženi polivinilpirolidon. Kot drsita se lahko uporabljajo magnezijev stearat, kalcijev stearat, aluminijev stearat, stearinska kislina, palmitinska kislina, cetanol, stearol, polietilenglikoli različnih molskih mas, magnezijev trisilikat, kalcijev fosfat, koloidni silicijev dioksid, smukec, uprašena celuloza, škrob, idr., prednostno koloidni silicijev dioksid. Kot maziva so primerni stearinska kislina, kalcijev, magnezijev, cinkov ali aluminijev stearat, silikonizirani smukec, glicerol monostearat, glicerol palmitostearat, hidrogenirano ricinovo olje, hidrogenirano rastlinsko olje, mineralno olje, lahko mineralno olje, polietilenglikol, natrijev benzoat, natrijev iaurilsulfat, natrijev stearilfumarat, smukec, idr. Prednostna maziva so magnezijev in kalcijev stearat ter stearinska kislina.The particles of the invention contain, in addition to the active ingredients, excipients such as e.g. fillers, binders, decomposers, sliders and lubricants. Microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, chess pink, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminum silicate, sodium chloride, potassium chloride, calcium carbonate, may be used as fillers. , dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc, etc. , preferably microcrystalline cellulose and lactose. Suitable binders may be starch, aluminum silicate, hydroxypropylcellulose, pregelatinized starch, gelatin, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium alginate, acacia, carbomer, dextrin, ethyl cellulose, guar cell, ethyl cellulose, guar cell, hydrocellulose. glucose syrup, magnesium maltodextrin, polymethacrylates, zein, preferably hydroxypropylmethylcellulose and polyvinylpyrrolidone. As for the like as for the like as for the corners like as for the rest of the room, the carbohydrates, the meticulosides, the meticulosides, the intestines, ascending , magnesium aluminum silicate, etc., preferably sodium starch glycolate, cropped sodium carboxymethylcellulose and cropped polyvinylpyrrolidone. Magnesium stearate, calcium stearate, aluminum stearate, stearic acid, palmitic acid, cetanol, sterol, polyethylene glycols of different molar masses, magnesium trisilicate, calcium phosphate, colloidal silica, talc, powdered, cellulose, powdered, cellulose, powdered, cellulose, can be used as glides. colloidal silica. Suitable lubricants are stearic acid, calcium, magnesium, zinc or aluminum stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium sulfate benzoate sodium sodium sulfate , talc, etc. Preferred lubricants are magnesium and calcium stearate and stearic acid.

Delci, ki so predmet izuma, lahko vsebujejo tudi pomožne snovi, ki uravnavajo sproščanje. To so lahko različni polimeri, kot so npr. metilceluloza, etilceluloza, hidroksietilceluloza, hidroksipropilmetilceluloza, hidroksipropilceluloza, natrijeva karboksimetilceluloza, hidroksipropilmetil celulozni ftalat, polietilen glikoli različnih molskih mas, različni derivati akrilne in metakrilne kisline, ksantanska guma, alginska kislina, natrijev alginat, polivinilpirolidon, polietilenoksidi, ali nepolimerne snovi, kot so npr. hidrogenirano rastlinsko olje, hidrogenirano ricinovo olje, glicerol monostearat, glicerol palmitostearat, idr.The particles of the invention may also contain excipients that regulate release. These may be different polymers such as e.g. Methylcellulose, Methylcellulose, Hydroxypropylmethylcellulose, Methylcellulose, Methylcellulose, Methylcellulose, Methylcellulose, Methylcellulose, Methylcellulose, Methylcellulose, Methylcellulose, Methylcellulose . hydrogenated vegetable oil, hydrogenated castor oil, glycerol monostearate, glycerol palmitostearate, etc.

Formirani delci, ki so predmet izuma, imajo dobre pretočne in stisljive lastnosti. Delež pomožnih snovi v delcih je od 10 ut.% do 40 ut.%. Velikost delcev je od 50 pm do 3000 pm.The molded particles of the invention have good flow and compressible properties. The proportion of excipients in the particles is from 10% to 40% by weight. The particle size is from 50 pm to 3000 pm.

Formirane delce lahko obložimo s primerno oblogo, ki uravnava sproščanje ali je samo zaščitna obloga. Obiogo lahko izdelamo iz polimernih ali nepolimernih snovi. Primerni polimeri, ki jih lahko uporabimo so hidroksipropilceluloza, hidroksipropilmetilceluloza, metilceluloza, etilceluloza, hidroksietilceluloza, natrijeva karboksimetilceluloza, celulozni acetat ftalat, polivinil acetat ftalat, hidroksimetilcelulozni ftalat, polivinilalkohol, metilhidroksietilceiuloza, natrijeva karboksimetilceluloza, polimeri akrilne in metakrilne kisline, maitodekstrin, in drugi. Nepolimerne snovi so lahko vosek karnauba, cetilni alkohol, saharoza, glukoza, šelak, idr.The formed particles can be coated with a suitable release-regulating coating or just a protective coating. Obiogo can be made from polymeric or non-polymeric substances. Suitable polymers, which can be used are hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hidroksimetilcelulozni phthalate, polyvinyl alcohol, metilhidroksietilceiuloza, sodium carboxymethylcellulose, polymers of acrylic and methacrylic acid, maitodekstrin, and others. Non-polymeric substances may be carnauba wax, cetyl alcohol, sucrose, glucose, shellac, etc.

Obloga lahko vsebujeje tudi druge sestavine, ki se običajno uporabljajo v oblogah, kot so polnila npr. smukec, laktoza, polisahardi in drugi, mehčala npr. dibutilsebacat, trietilcitrat, polietilenglikol, adipinska kislina, kokosovo olje, oleinska kislina idr. , barvila npr. titanov dioksid, laki, pigmenti in drugi, antioksidanti in drugi.The coating may also contain other ingredients commonly used in coatings such as fillers e.g. talc, lactose, polysaccharides and others, softeners e.g. dibutylsebacate, triethyl citrate, polyethylene glycol, adipic acid, coconut oil, oleic acid and the like. , dyes e.g. titanium dioxide, varnishes, pigments and others, antioxidants and others.

Predmet izuma so tudi farmacevtske oblike, ki vsebujejo zgoraj opisane formirane delce. Lahko uporabimo obložene in/ali neobložene delce. Lahko jih polnimo v vrečke ali kapsule, lahko jih stisnemo skupaj s potrebnimi pomožnimi snovmi v tablete. Tablete so lahko eno ali večplastne, disperzibilne, oralnodisperzibilne, šumeče, žvečljive, pastile. Tako pripravljene tablete so trdne in imajo ustrezne fizikalno tehnološke lastnosti. Z dodatkom ustreznih pomožnih snovi lahko kontroliramo sproščanje učinkovine iz tablete. Kot pomožne snovi, ki jih dodamo formiranim delcem za pripravo tablet, lahko uporabimo različna polnila, veziva, razgrajevala, drsila in maziva. Kot polnila se lahko uporabljajo mikro kristalna celuloza, uprašena celuloza, laktoza, škrob, preželatiniran škrob, saharoza, glukoza, manitol, sorbitol, kalcijev fosfat, kalcijev hidrogen fosfat, aluminijev silikat, natrijev klorid, kalijev klorid, kalcijev karbonat, kalcijev sulfat, dekstrati, dekstrin, maltodekstrin, glicerol palmitostearat, hidrogenirano rastlinsko olje, kaolin, magnezijev karbonat, magnezijev oksid, polimetakrilati, smukec, idr. , prednostno mikrokristalna celuloza in laktoza. Primerna veziva so lahko škrob, preželatiniran škrob, želatina, natrijeva karboksimetilceluloza, polivinilpirolidon, alginska kislina, natrijev alginat, akacia, karbomer, dekstrin, etilceluloza, guar guma, hidrogenirano rastlinsko olje, metilceluloza, hidroksietilceluloza, hidroksipropilceluloza, hidroksipropilmetilceluloza, glukozni sirup, magnezijev aluminijev silikat, maltodekstrin, polimetakrilati, zein, prednostno hidroksipropilceluloza, hidroksipropilmetilceluloza in polivinilpirolidon. Kot razgrajevala se lahko uporabljajo škrob, preželatiniran škrob, natrijev škrob glikolat, natrijeva karboksimetilceluloza, premerežena natrijeva karboksimetilceluloza, kalcijeva karboksimetilceluloza, metilceluloza, mikrokristalna celuloza, uprašena celuloza, kalijev polakrilin, premereženi polivinilpirolidon, alginska kislina, natrijev alginat, koloidni silicijev dioksid, guar guma, magnezijev aluminijev silikat, idr., prednostno natrijev škrob glikolat, premrežena natrijeva karboksimetilceluloza in premreženi polivinilpirolidon. Kot drsila se lahko uporabljajo magnezijev stearat, kalcijev stearat, aluminijev stearat, stearinska kislina, palmitinska kislina, cetanol, stearol, polietilenglikoli različnih molskih mas, magnezijev trisilikat, kalcijev fosfat, koloidni silicijev dioksid, smukec, uprašena celuloza, škrob, idr, prednostno koloidni silicijev dioksid. Kot maziva so primerni stearinska kislina, kalcijev, magnezijev, cinkov ali aluminijev stearat, siiikonizirani smukec, glicerol monostearat, glicerol palmitostearat, hidrogenirano ricinovo olje, hidrogenirano rastlinsko olje, mineralno olje, lahko mineralno olje, polietilenglikol, natrijev benzoat, natrijev laurilsulfat, natrijev stearilfumarat, smukec, idr. Prednostna maziva so kalcijev ali magnezijev stearat ter stearinska kislina.The invention also provides pharmaceutical formulations containing the above-described formed particles. Coated and / or uncoated particles may be used. They can be filled into bags or capsules, and can be compressed with the necessary excipients into tablets. The tablets may be single or multilayered, dispersible, orally dispersible, effervescent, chewable, lozenges. The tablets thus prepared are solid and have adequate physico-technological properties. The release of the active ingredient from the tablet can be controlled by the addition of suitable excipients. Various fillers, binders, disintegrators, sliders and lubricants can be used as auxiliaries to be added to the formed particles for tablet preparation. Micro crystalline cellulose, powdered cellulose, lactose, starch, pregelatinised starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminum silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulphate, calcium carbonate, may be used as fillers. , dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc, etc. , preferably microcrystalline cellulose and lactose. Suitable binders may be starch, pregelatinized starch, gelatin, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ethylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, glucose syrup, magnesium aluminum silicate, maltodextrin, polymethacrylates, zein, preferably hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. As for the like as for the rest of the things like as for the rest of the things, like, as for the rest of the things, as a whole , magnesium aluminum silicate, etc., preferably sodium starch glycolate, cropped sodium carboxymethylcellulose and cropped polyvinylpyrrolidone. Magnesium stearate, calcium stearate, aluminum stearate, stearic acid, palmitic acid, cetanol, sterol, polyethylene glycols of different molar masses, magnesium trisilicate, calcium phosphate, colloidal silica, talc, powdered colloid, powdered colloid, powdered colloid, can be used silica. Suitable lubricants are stearic acid, calcium, magnesium, zinc or aluminum stearate, Si-ionized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium sulfate, sodium sulfate , talc, etc. Preferred lubricants are calcium or magnesium stearate and stearic acid.

Kot snovi za kontrolirano sproščanje učinkovine lahko uporabimo polimerne ali nepolimerne snovi. Primerni polimeri, ki jih lahko uporabimo so hidroksipropilceluloza, hidroksipropilmetilceluloza, metilceluloza, etilceluloza, hidroksietilceluloza, natrijeva karboksimetilceluloza, celulozni acetat ftalat, polivinil acetat ftalat, hidroksimetilcelulozni ftalat, polivinilalkohol, metilhidroksietilceluloza, natrijeva karboksimetilceluloza, polimeri akrilne in metakrilne kisline, maltodekstrin, in drugi. Nepolimerne snovi so lahko vosek karnauba, cetilni alkohol, hidrogenirano rastlinsko olje, hidrogenirano ricinovo olje, glicerol monostearat, glicerol palmitostearat in drugi.Polymeric or non-polymeric substances can be used as controlled release agents. Suitable polymers, which can be used are hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hidroksimetilcelulozni phthalate, polyvinyl alcohol, methylhydroxyethylcellulose, sodium carboxymethylcellulose, polymers of acrylic and methacrylic acid, maltodextrin, and others. Non-polymeric substances may include carnauba wax, cetyl alcohol, hydrogenated vegetable oil, hydrogenated castor oil, glycerol monostearate, glycerol palmitostearate and others.

Kapsule in tablete so lahko prekrite z oblogo, ki jo lahko nanesemo iz vodnega ali nevodnega medija. Obloga lahko uravnava sproščanje ali je samo zaščitna obloga. Oblogo lahko izdelamo iz polimernih ali nepolimernih snovi. Primerni polimeri, ki jih lahko uporabimo, so hidroksipropilceluloza, hidroksipropilmetilceluloza, metilceluloza, etilceluloza, hidroksietilceluloza, natrijeva karboksimetilceluloza, celulozni acetat ftalat, polivinil acetat ftalat, hidroksimetilcelulozni ftalat, polivinilalkohol, metilhidroksietilceluloza, natrijeva karboksimetilceluloza, polimeri akrilne in metakrilne kisline, maltodekstrin, in drugi. Nepolimerne snovi so lahko vosek karnauba, cetilni alkohol, saharoza, glukoza, šelak in drugi.The capsules and tablets may be coated with a coating that can be applied from aqueous or non-aqueous media. The lining can regulate the release or is only a protective lining. The coating may be made of polymeric or non-polymeric substances. Suitable polymers that can be used are hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hidroksimetilcelulozni phthalate, polyvinyl alcohol, methylhydroxyethylcellulose, sodium carboxymethylcellulose, polymers of acrylic and methacrylic acid, maltodextrin, and other . Non-polymeric substances may include carnauba wax, cetyl alcohol, sucrose, glucose, shellac and others.

Obloga lahko vsebujeje tudi druge sestavine, ki se običajno uporabljajo v oblogah, kot so polnila npr. smukec, laktoza, polisahardi in drugi, mehčala npr. dibutilsebacat, trietilcitrat, polietilenglikol in drugi, barvila npr. titanov dioksid, laki, pigmenti in drugi, antioksidanti in drugi.The coating may also contain other ingredients commonly used in coatings such as fillers e.g. talc, lactose, polysaccharides and others, softeners e.g. dibutylsebacate, triethyl citrate, polyethylene glycol and others, dyes e.g. titanium dioxide, varnishes, pigments and others, antioxidants and others.

Formirani delci so primerni za izdelavo večenotnih oblik kot so npr. kapsule ali tablete z osnovnimi formiranimi delci, .pri čemer večenotna oblika razpade na posamezne osnovne formirane delce, iz katerih se sprošča učinkovina. Formirani delci so primerni tudi za izdelavo večenotnih oblik kot so vrečke in dozatorji za večenotne sisteme in drugo. Uporabimo lahko neobložene in/ali obložene delce.The formed particles are suitable for producing multi-unit shapes such as e.g. capsules or tablets with basic formed particles, wherein the multi-unit form is broken down into individual basic formed particles from which the active substance is released. The formed particles are also suitable for the production of multi-unit forms such as bags and dispensers for multi-unit systems and more. Uncoated and / or coated particles may be used.

Formirane delce, ki so predmet izuma in vsebujejo amoksicilin in klavulansko kislino, lahko kombiniramo s podobnimi delci, ki vsebujejo samo amoksicilin.The formed particles of the invention containing amoxicillin and clavulanic acid can be combined with similar particles containing amoxicillin only.

izum se nanaša tudi na postopek za pripravo formiranih delcev pravilnih in nepravilnih oblik. Pripravimo jih z vlažno granulacijo z organskim topilom. Za granulacijo lahko uporabimo samo topilo ali pa disperzijo veziva v organskem topilu.The invention also relates to a process for preparing formed particles of regular and irregular shapes. They are prepared by wet granulation with an organic solvent. Only the solvent or the dispersion of the binder in the organic solvent can be used for granulation.

Formirane delce nepravilnih oblik pripravimo po postopku, ki obsega naslednje ključne faze:Formed irregularly shaped particles are prepared by a process comprising the following key stages:

- pripravo zmesi amoksicilin trihidrata in kalijevega klavulanata ter pomožnih snovi (z vezivom ali brez)- preparation of a mixture of amoxicillin trihydrate and potassium clavulanate and excipients (with or without binder)

-vlažno granuliranje z organskim topilom ali vlažno granuliranje z disperzijo veziva v organskem topilu.- wet granulation with an organic solvent or wet granulation with dispersion of a binder in an organic solvent.

- sušenje delcev- drying of particles

- mletje ali sejanje posušenih delcev- grinding or sieving of dried particles

- opcijsko nanos obloge- Optional coating

Formirane delce sferične oblike (sferonizati, pelete) pripravimo po postopku, ki obsega naslednje ključne faze:Formed spherical shaped particles (spheronites, pellets) are prepared by a process comprising the following key phases:

- pripravo zmesi amoksicilin trihidrata in kalijevega klavulanata ter pomožnih snovi (z vezivom ali brez)- preparation of a mixture of amoxicillin trihydrate and potassium clavulanate and excipients (with or without binder)

- vlažno granuliranje z organskim topilom ali vlažno granuliranje z disperzijo veziva v organskem topilu.- wet granulation with an organic solvent or wet granulation with dispersion of a binder in an organic solvent.

- iztiskanje vlažne zmesi skozo mrežico- extruding the wet mixture through the mesh

- krogličenje- ball rolling

- sušenje delcev- drying of particles

- opcijsko nanos obloge δ- optional coating of δ

Najprimernejša topila, ki jih lahko uporabimo za granuliranje so farmacevtsko sprejemljiva organska topila, pri čemer nista vključena izopropanol, in metilendiklorid. Najprimernejša topila so aceton, etanol in acetonitril.The most suitable solvents that can be used for granulation are pharmaceutically acceptable organic solvents, excluding isopropanol, and methylenedichloride. Acetone, ethanol, and acetonitrile are the preferred solvents.

V organskem topilu lahko dispergiramo vezivo, da dobimo raztopino ali suspenzijo in to disperzijo uporabimo za granuliranje.A binder can be dispersed in an organic solvent to obtain a solution or suspension and this dispersion is used for granulation.

Kalijev klavulanat je substanca, ki je zelo občutljiva na vodo. Zato vse pomožne snovi pred uporabo predhodno sušimo ali uporabimo že predhodno posušene pomožne snovi ali pa izdelane formirane delce na koncu ustrezno posušimo. Proizvodnja poteka v suhih pogojih pri največ 30% relativni zračni vlagi.Potassium clavulanate is a substance that is very sensitive to water. Therefore, all excipients are pre-dried, or pre-dried excipients are used before use, or the resulting formed particles are eventually properly dried. Production takes place in dry conditions at a maximum of 30% relative humidity.

Izum pojasnjujejo in nikakor ne omejujejo naslednji izvedbeni primeri:The following embodiments are explained and in no way limited by the invention:

Primer 1:Example 1:

Tablete 875/125 mgTablets 875/125 mg

Ingredienti Ingredients masa mass Amoksicilin Amoxicillin 875,00 mg 875,00 mg kot tri hidrat like three hydrates 1008,00 mg 1008,00 mg Klavulanska kislina Clavulanic acid 125,00 mg 125,00 mg kot kalijev klavulanat as potassium clavulanate 149,88 mg 149.88 mg Laktoza brezvodna Lactose anhydrous 154,12 mg 154.12 mg Hidroksipropil celuloza Hydroxypropyl cellulose 20,00 mg 20,00 mg Mikrokristalna celuloza Microcrystalline cellulose 14,00 mg 14,00 mg Premrežena natrijeva karboksimetil celuloza Cross-linked sodium carboxymethyl cellulose 10,00 mg 10.00 mg Magnezijev stearat Magnesium stearate 5,00 mg 5.00 mg Skupaj Together 1361,00 mg 1361,00 mg Aceton Acetone 630,00 mg 630,00 mg

Postopek izdelave: amoksicilin trihidrat, kalijev klavulanat, laktozo, mikrokristalno celulozo, hidroksipropilcelulozo in premreženo karboksimetil celulozo smo homogeno zmešali in granulirali z acetonom, da so dobili formirane delce. Vlažne formirane delce smo posušili v vakuumu pri 40°C (približno 3 ure, do izgube pri sušenju 6% (80°C, 20 min). K posušenim formiranim delcem smo dodali magnezijev stearat in zmes homogeno zmešali. Na običajni tabletirki smo tabletirali tablete z ustrezno maso in ustreznimi fizikalno tehnološkimi lastnostmi.Method of manufacture: Amoxicillin trihydrate, potassium clavulanate, lactose, microcrystalline cellulose, hydroxypropyl cellulose and cross-linked carboxymethyl cellulose were homogeneously mixed and granulated with acetone to form particles. The wet molded particles were dried in vacuo at 40 ° C (about 3 hours, to a drying loss of 6% (80 ° C, 20 min). Magnesium stearate was added to the dried molded particles and the mixture was stirred homogeneously. with appropriate mass and appropriate physico-technological properties.

Testiranje stabilnosti je pokazalo, da so tablete stabilne.Stability testing showed that the tablets were stable.

Primer 2:Example 2:

Tablete 875/125 mgTablets 875/125 mg

Ingredienti Ingredients masa mass Amoksicilin Amoxicillin 875,00 mg 875,00 mg kot trihidrat as a trihydrate 1008,00 mg 1008,00 mg Klavulanska kislina Clavulanic acid 125,00 mg 125,00 mg kot kalijev klavulanat as potassium clavulanate 149,88 mg 149.88 mg Laktoza brezvodna Lactose anhydrous 154,12 mg 154.12 mg Polivinilpirolidon Polyvinylpyrrolidone 20,00 mg 20,00 mg Mikrokristalna celuloza Microcrystalline cellulose 14,00 mg 14,00 mg Premrežena natrijeva karboksimetil celuloza Cross-linked sodium carboxymethyl cellulose 10,00 mg 10.00 mg Magnezije stearat Magnesium stearate 5,00 mg 5.00 mg Skupaj Together 1361,00 mg 1361,00 mg Aceton Acetone 630,00 mg 630,00 mg

Postopek izdelave: amoksicilin trihidrat, kalijev klavulanat, laktozo, mikrokristalno celulozo, polivinilpirolidon in premreženo karboksimetil celulozo smo homogenoManufacturing process: amoxicillin trihydrate, potassium clavulanate, lactose, microcrystalline cellulose, polyvinylpyrrolidone and cross-linked carboxymethyl cellulose were homogeneous

-1010 zmešali in granulirali z acetonom, da smo dobili formirane delce. Vlažne formirane delce smo posušili v vakuumu pri 40°C (približno 3 ure, do izgube pri sušenju 6% (80°C, 20 min). K posušenim formiranim delcem smo dodali magnezijev stearat tn zmes homogeno zmešali. Na običajni tabletirki smo tabletirali tablete z ustrezno maso in ustreznimi fizikalno tehnološkimi lastnostmi.-1010 was mixed and granulated with acetone to give the formed particles. The wet molded particles were dried in vacuo at 40 ° C (about 3 hours, to a drying loss of 6% (80 ° C, 20 min). Magnesium stearate tn was added to the dried molded particles and the mixture was homogeneously mixed. with appropriate mass and appropriate physico-technological properties.

Testiranje stabilnosti je pokazalo, da so tablete stabilne.Stability testing showed that the tablets were stable.

Primer 3:Example 3:

Tablete 875/125 mgTablets 875/125 mg

Ingredienti Ingredients masa mass Amoksicilin Amoxicillin 875,00 mg 875,00 mg kot trihidrat as a trihydrate 1008,00 mg 1008,00 mg Klavulanska kislina Clavulanic acid 125,00 mg 125,00 mg kot kalijev klavulanat as potassium clavulanate 149,88 mg 149.88 mg Laktoza brezvodna Lactose anhydrous 14,00 mg 14,00 mg Polivinilpirolidon Polyvinylpyrrolidone 20,00 mg 20,00 mg Mikrokristalna celuloza Microcrystalline cellulose 154,12 mg 154.12 mg Premrežena natrijeva karboksimetil celuloza Cross-linked sodium carboxymethyl cellulose 10,00 mg 10.00 mg Magnezijev stearat Magnesium stearate 5,00 mg 5.00 mg Skupaj Together 1361,00 mg 1361,00 mg Aceton Acetone 630,00 mg 630,00 mg

Postopek izdelave: amoksicilin trihidrat, kalijev klavulanat, laktozo, mikrokristalno celulozo, polivinilpirolidon in premreženo karboksimetil celulozo smo homogeno zmešali in granulirali z acetonom, da smo dobili formirane delce. Vlažne formirane delce smo posušili v vakuumu pri 40°C (približno 3 ure, do izgube pri sušenju 6% (80°C, 20 min). K posušenim formiranim delcem smo dodali magnezijev stearat inMethod of manufacture: Amoxicillin trihydrate, potassium clavulanate, lactose, microcrystalline cellulose, polyvinylpyrrolidone and cross-linked carboxymethyl cellulose were homogeneously mixed and granulated with acetone to form particles. The wet formed particles were dried in vacuo at 40 ° C (about 3 hours, to a drying loss of 6% (80 ° C, 20 min). Magnesium stearate was added to the dried formed particles and

-1111 zmes homogeno zmešali. Na običajni tabletirki smo tabletirali tablete z ustrezno maso in ustreznimi fizikalno tehnološkimi lastnostmi.-1111 mix homogeneously. On a conventional tablet, tablets of appropriate mass and with corresponding physico-technological properties were tableted.

Testiranje stabilnosti je pokazalo, da so tablete stabilne.Stability testing showed that the tablets were stable.

Primer 4:Example 4:

Pelete 875/125 mgPellets 875/125 mg

Ingredienti Ingredients masa mass Amoksicilin Amoxicillin 875,00 mg 875,00 mg kot trihidrat as a trihydrate 1011,56 mg 1011,56 mg Klavulanska kislina Clavulanic acid 125,00 mg 125,00 mg kot kalijev klavulanat as potassium clavulanate 151,33 mg 151.33 mg Laktoza brezvodna Lactose anhydrous 149,11 mg 149.11 mg Hidroksipropil celuloza Hydroxypropyl cellulose 20,00 mg 20,00 mg Mikrokristalna celuloza Microcrystalline cellulose 14,00 mg 14,00 mg Premrežena natrijeva karboksimetil celuloza Cross-linked sodium carboxymethyl cellulose 10,00 mg 10.00 mg Skupaj Together 1356,00 mg 1356,00 mg Aceton Acetone 730,00 mg 730,00 mg

Postopek izdelave: amoksicilin trihidrat, kalijev klavulanat, laktozo, mikrokristalno celulozo, hidroksipropilcelulozo in premreženo karboksimetil celulozo smo homogeno zmešali in granulirali z acetonom. Vlažno maso smo ekstrudirali skozi mrežo z 0,8 mm velikimi odprtinami, da so nastali ekstrudati. Vlažne ekstrudate smo nato krogličili v aparaturi za krogličenje (sferonizator), da so nastali formirani delci sferične oblike. Formirane delce sferične oblike smo posušili v vakuumu pri 40°C (približno 3 ure, do izgube pri sušenju 6% (80°C, 20 min).Method of manufacture: amoxicillin trihydrate, potassium clavulanate, lactose, microcrystalline cellulose, hydroxypropyl cellulose and cross-linked carboxymethyl cellulose were homogeneously mixed and granulated with acetone. The wet mass was extruded through a mesh with 0.8 mm large openings to form extrudates. The wet extrudates were then spherical in a spherical apparatus to form spherical shaped particles. The formed spherical particles were dried in vacuo at 40 ° C (about 3 hours, to a drying loss of 6% (80 ° C, 20 min).

-1212-1212

Primer 5:Example 5:

Pelete 875/125 mgPellets 875/125 mg

Ingredienti Ingredients masa mass Amoksicilin Amoxicillin 875,00 mg 875,00 mg kot trihidrat DC as DC trihydrate 1019,80 mg 1019.80 mg Klavulanska kislina Clavulanic acid 125,00 mg 125,00 mg kot kalijev klavulanat as potassium clavulanate 150,00 mg 150,00 mg Laktoza brezvodna Lactose anhydrous 142,20 mg 142.20 mg Hidroksipropii celuloza Hydroxypropyl cellulose 20,00 mg 20,00 mg Polivinilipirolidon Polyvinylpyrrolidone 20,00 mg 20,00 mg Mikrokristalna celuloza Microcrystalline cellulose 14,00 mg 14,00 mg Premrežena natrijeva karboksimetil celuloza Cross-linked sodium carboxymethyl cellulose 10,00 mg 10.00 mg Skupaj Together 1376,00 mg 1376,00 mg Aceton Acetone 630,00 mg 630,00 mg

Postopek izdelave: amoksicilin trihidrat, kalijev klavulanat, laktozo, mikrokristalno celulozo, hidroksipropilcelulozo, polivinilpirolidon in premreženo karboksimetil celulozo smo homogeno zmešali in granulirali z acetonom. Vlažno maso smo ekstrudirali skozi mrežo z 1,5 mm velikimi odprtinami, da so nastali ekstrudati. Vlažne ekstrudate smo krogličili v aparaturi za krogličenje (sferonizator), da so nastali formirani delci pravilne sferične oblike. Formirane delce sferične oblike smo posušili v vakuumu pri 40°C (približno 3 ure, do izgube pri sušenju 6% (80°C, 20 min).Manufacturing process: amoxicillin trihydrate, potassium clavulanate, lactose, microcrystalline cellulose, hydroxypropylcellulose, polyvinylpyrrolidone and cross-linked carboxymethyl cellulose were homogeneously mixed and granulated with acetone. The wet mass was extruded through a mesh with 1.5 mm openings to form extruders. Wet extrudates were spherical in a spherical apparatus to form formed particles of regular spherical shape. The formed spherical particles were dried in vacuo at 40 ° C (about 3 hours, to a drying loss of 6% (80 ° C, 20 min).

Testiranje stabilnosti je pokazalo, da so'delci stabilni.Stability testing showed that the co-components were stable.

-1313-1313

Primer 6:Example 6:

Pelete 875/125 mgPellets 875/125 mg

Ingredienti Ingredients masa mass Amoksicilin Amoxicillin 875,00 mg 875,00 mg kot trihidrat DC as DC trihydrate 1019,80 mg 1019.80 mg Klavulanska kislina Clavulanic acid 125,00 mg 125,00 mg kot kalijev klavulanat as potassium clavulanate 150,00 mg 150,00 mg Laktoza brezvodna Lactose anhydrous 142,20 mg 142.20 mg hidroksipropilceluloza hydroxypropylcellulose 20,00 mg 20,00 mg Polivinilpirolidon Polyvinylpyrrolidone 20,00 mg 20,00 mg Mikrokristalna celuloza Microcrystalline cellulose 14,00 mg 14,00 mg Premrežena natrijeva karboksimetil celuloza Cross-linked sodium carboxymethyl cellulose 10,00 mg 10.00 mg Skupaj Together 1376,00 mg 1376,00 mg Etanol Ethanol 730,00 mg 730,00 mg

Postopek:Process:

Postopek izdelave: amoksicilin trihidrat, kalijev klavulanat, laktozo, mikrokristalno celulozo, hidroksipropilcelulozo, polivinilpirolidon in premreženo karboksimetil celulozo smo homogeno zmešali in granulirali z etanolom. Vlažno maso smo ekstrudirali skozi mrežo z 1,5 mm velikimi odprtinami, da so nastali ekstrudati. Vlažne ekstrudate smo krogi ičili v aparaturi za krog lice nje (sferonizator), da so nastali formirani sferični delci pravile oblike. Formirane delce sferične oblike smo posušili v vakuumu pri 40°C (približno 3 ure, do izgube pri sušenju 6% (80°C, 20 min).Manufacturing process: amoxicillin trihydrate, potassium clavulanate, lactose, microcrystalline cellulose, hydroxypropylcellulose, polyvinylpyrrolidone and cross-linked carboxymethyl cellulose were homogeneously mixed and granulated with ethanol. The wet mass was extruded through a mesh with 1.5 mm openings to form extrudates. We moistened the extrudates with circles in an apparatus for a face circle (spheronizer) to form formed spherical particles of regular shape. The formed spherical particles were dried in vacuo at 40 ° C (about 3 hours, to a drying loss of 6% (80 ° C, 20 min).

Claims (24)

Patentni zahtevkiPatent claims 1. Formirani delci, ki vsebujejo amoksicilin in klavulansko kislino, označeni s tem, da so pridobljeni s postopkom vlažnega granuliranja.Formed particles containing amoxicillin and clavulanic acid, characterized in that they are obtained by the wet granulation process. 2. Formirani delci po zahtevku 1, označeni s tem, da vsebujejo amoksicilin v obliki amoksicilin trihidrata in klavulansko kislino v obliki kalijevega klavulanata.Formed particles according to claim 1, characterized in that they contain amoxicillin in the form of amoxicillin trihydrate and clavulanic acid in the form of potassium clavulanate. 3. Formirani delci po zahtevku 1, označeni s tem, da je razmerje amoksicilina in klavulanske kisline od 1:1 do 30:1.Formed particles according to claim 1, characterized in that the ratio of amoxicillin to clavulanic acid is from 1: 1 to 30: 1. 4. Formirani delci po zahtevkih 1 in 3, označeni s tem, da je razmerje amoksicilina in klavulanske kisline 4:1, 7:1,8:1, 12:1, 16:1,20:1.Formed particles according to claims 1 and 3, characterized in that the ratio of amoxicillin to clavulanic acid is 4: 1, 7: 1,8: 1, 12: 1, 16: 1,20: 1. 5. Formirani delci po zahtevku 1, označeni s tem, da dodatno vsebujejo polnila, veziva, razgrajevala, drsita, maziva.Molded particles according to claim 1, characterized in that they further comprise fillers, binders, decomposers, slides, lubricants. 6. Formirani delci po zahtevku 1, označeni s tem, da se kot topilo pri vlažnem granuliranju uporablja organsko topilo.Formed particles according to claim 1, characterized in that an organic solvent is used as the wet granulation solvent. 7. Formirani delci po zahtevku 6, označeni s tem, da organsko topilo ni izopropanol ali metilendiklorid.Formed particles according to claim 6, characterized in that the organic solvent is not isopropanol or methylenedichloride. 8. Formirani delci po zahtevku 1 in 6, označeni s tem, da se kot topilo pri granuliranju uporablja aceton.Molded particles according to claims 1 and 6, characterized in that acetone is used as the solvent in the granulation. -1515-1515 9. Formirani delci po zahtevku 1, označeni s tem, da se pri vlažnem granuliranju uporablja disperzija veziva v organskem topilu.Molded particles according to claim 1, characterized in that the wet granulation uses a dispersion of the binder in an organic solvent. 10. Formirani delci po zahtevku 9, označeni s tem, da je vezivo hidroksipropilceluloza in / ali polivinilpirolidon.Formed particles according to claim 9, characterized in that the binder is hydroxypropylcellulose and / or polyvinylpyrrolidone. 11. Formirani delci po zahtevku 1, označeni s tem, da so nepravilnih oblik.Molded particles according to claim 1, characterized in that they are irregular in shape. 12. Formirani delci po zahtevku 1, označeni s tem, da so sferične oblike.Molded particles according to claim 1, characterized in that they are spherical in shape. 13. Formirani delci po zahtevku 1, označeni s tem, da imajo oblogo.Molded particles according to claim 1, characterized in that they have a coating. 14. Farmacevtska oblika, ki vsebuje formirane delce po zahtevku 1.A pharmaceutical formulation comprising formed particles according to claim 1. 15. Farmacevtska oblika po zahtevku 14, označena s tem, da vsebujejo formirane delce nepravilnih oblik.15. Pharmaceutical form according to claim 14, characterized in that they contain formed particles of irregular shape. 16. Farmacevtska oblika po zahtevku 14, označena s tem, da vsebujejo formirane delce sferične oblike.16. A pharmaceutical form according to claim 14, characterized in that they comprise spherical shaped particles. 17. Farmacevtska oblika po zahtevku 14, označene s tem, daje večenotna oblika.17. A pharmaceutical formulation according to claim 14, characterized in that it is a multi-unit form. 18. Farmacevtska oblika po zahtevku 14, označene s tem, da je kapsula.18. The pharmaceutical form according to claim 14, characterized in that it is a capsule. 19. Farmacevtska oblika po zahtevku 14, označene s tem, da je tableta.A pharmaceutical formulation according to claim 14, characterized in that it is a tablet. 20. Farmacevtska oblika po zahtevku 14, označene s tem, da je vrečka.A pharmaceutical formulation according to claim 14, characterized in that it is a bag. 21 .Farmacevtska oblika po zahtevku 14, označena s tem, da ima oblogo.Pharmaceutical form according to claim 14, characterized in that it has a coating. -1616-1616 22. Postopek za pripravo formiranih delcev po zahtevku 1, označen s tem, da obsega naslednje stopnje:Process for the preparation of formed particles according to claim 1, characterized in that it comprises the following steps: - pripravo zmesi amoksicilin trihidrata in kalijevega klavulanata ter pomožnih snovi (z vezivom ali brez),- preparation of a mixture of amoxicillin trihydrate and potassium clavulanate and excipients (with or without binder), - vlažno granuliranje z organskim topilom ali vlažno granuliranje z disperzijo veziva v organskem topilu,- wet granulation with an organic solvent or wet granulation with dispersion of a binder in an organic solvent, - sušenje delcev,- drying of particles, - mletje ali sejanje posušenih delcev,- grinding or sieving of dried particles, - opcijsko nanos obloge.- optional coating. 23. Postopek za pripravo formiranih delcev po zahtevku 1, označen s tem, da obsega naslednje stopnje:23. A process for the preparation of molded particles according to claim 1, characterized in that it comprises the following steps: - pripravo zmesi amoksicilin trihidrata in kalijevega klavulanata ter pomožnih snovi (z vezivom ali brez)- preparation of a mixture of amoxicillin trihydrate and potassium clavulanate and excipients (with or without binder) - vlažno granuliranje z organskim topilom ali vlažno granuliranje z disperzijo veziva v organskem topilu.- wet granulation with an organic solvent or wet granulation with dispersion of a binder in an organic solvent. - iztiskanje vlažne zmesi skozo mrežico- extruding the wet mixture through the mesh - krogličenje- ball rolling - sušenje delcev- drying of particles - opcijsko nanos obloge.- optional coating. 24. Postopek za pripravo formiranih delcev po zahtevku 22 in 23, označen s tem, da se kot topilo uporablja aceton.Process for the preparation of formed particles according to claims 22 and 23, characterized in that acetone is used as the solvent.