SI21601A - Therapeutic system - Google Patents
Therapeutic system Download PDFInfo
- Publication number
- SI21601A SI21601A SI200300245A SI200300245A SI21601A SI 21601 A SI21601 A SI 21601A SI 200300245 A SI200300245 A SI 200300245A SI 200300245 A SI200300245 A SI 200300245A SI 21601 A SI21601 A SI 21601A
- Authority
- SI
- Slovenia
- Prior art keywords
- amoxicillin
- therapeutic system
- capsule
- tablet
- floating
- Prior art date
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Izum spada v področje farmacevtske tehnologije in se nanaša na nov terapevtski sistem za odmerjanje amoksicilina in klavulanske kisline v enkratnem dnevnem odmerku. Del odmerka predstavlja vsaj ena farmacevtska oblika s takojšnjim sproščanjem amoksicilina in klavulanske kisline, del odmerka pa vsaj ena farmacevtska oblika, ki se zadržuje v želodcu in odloženo in zadržano sprošča amoksicilin.The invention relates to the field of pharmaceutical technology and relates to a new therapeutic system for dosing amoxicillin and clavulanic acid in a single daily dose. Part of the dose is at least one immediate-release pharmaceutical formulation of amoxicillin and clavulanic acid and part of the dose is at least one gastric-retained and delayed-release formulation of amoxicillin.
Prikaz problema:View problem:
Obstaja stalna potreba po novih, pacientu prijaznih zdravilih v farmacevtskih oblikah, ki vsebujejo amoksicilin in klavulansko kislino ter zagotavljajo enostaven in zanesljiv način odmerjanja ter učinkovitejše zdravljenje bakterijskih okužb.There is an ongoing need for new, patient-friendly medicines in pharmaceutical formulations containing amoxicillin and clavulanic acid, providing an easy and reliable dosage and more effective treatment of bacterial infections.
Stanje tehnike:State of the art:
Za zdravljenje bakterijskih okužb so na trgu različne farmacevtske oblike, ki vsebujejo amoksicilin in klavulansko kislino. Namenjene so za jemanje trikrat ali dvakrat na dan. V večini primerov se amoksicilin in klavulanska kislina začneta sproščati iz farmacevtske oblike takoj, ko le-ta pride v želodec. V teh oblikah sta amoksicilin in klavulanska kislina v razmerju 2:1,4:1, 7:1,8:1, 14:1 in 16:1.Various pharmaceutical forms containing amoxicillin and clavulanic acid are on the market for the treatment of bacterial infections. They are intended to be taken three or twice a day. In most cases, amoxicillin and clavulanic acid begin to be released from the pharmaceutical form as soon as it enters the stomach. In these forms, amoxicillin and clavulanic acid are in the ratio of 2: 1,4: 1, 7: 1,8: 1, 14: 1 and 16: 1.
Znano je, da je amoksicilin substanca, ki ima ozko absorpcijsko okno v zgornjem delu gastrointestinalnega trakta, to je v želodcu in zgornjem delu tankega črevesa.Amoxicillin is known to be a substance that has a narrow absorption window in the upper gastrointestinal tract, that is, in the stomach and upper intestine.
V EP 1044680 so opisane farmacevtske oblike s prirejenim sproščanjem, ki vsebujejo 1900 do 2600 mg amoksicilina in tako količino klavulanske kisline, da je razmerje med njima 12 : 1 do 20:1. Sestavljene so iz faze, ki omogoča takojšnje sproščanje klavulanske kisline in dela amoksicilina ter faze, ki omogoča počasno sproščanje amoksicilina. Prednostne so večplastne tablete. Enkratno dozo je mogoče zagotoviti s kombinacijo večih tablet ali kapsul. Opisane oblike so primerne za dajanje dvakrat na dan.EP 1044680 describes modified release pharmaceutical formulations containing 1900 to 2600 mg of amoxicillin and a quantity of clavulanic acid such that the ratio between them is 12: 1 to 20: 1. They consist of a phase that allows the immediate release of clavulanic acid and part of amoxicillin and a phase that allows the slow release of amoxicillin. Multilayer tablets are preferred. A single dose can be provided by a combination of several tablets or capsules. The forms described are suitable for administration twice daily.
V WO 02/30392 so opisane oblike za enkrat dnevno dajanje amoksicilina in klavulanske kisline. Primerne so samo za zdravljenje lažjih infekcij. Oblika naj bi zagotavljala koncentracijo amoksicilina nad MIK=2 pg/mL več kot osem ur v dozirnem intervalu. Enkratna dnevna doza je 1700 do 2500 mg amoksicilina in 100 do 150 mg kalijevega klavulanata. Dnevno dozo je mogoče zagotoviti z eno tableto, npr. disperzibilno ali žvečilno, možno pa je kombinirati več običajnih tablet ali kapsul, od katerih nekatere vsebujejo amoksicilin in klavulanat, ostale pa samo amoksicilin. Opisana je tudi tableta iz dveh vrst granulatov, granulat s takojšnjim sproščanjem vsebuje amoksicilin trihidrat, granulat s počasnim sproščanjem pa kristalni natrijev amoksicilin, citronsko kislino, ksantan gumo in druge pomožne snovi. Taka tableta v želodcu razpade na osnovne granule, pri čemer se granule s takojšnjim sproščanjem takoj raztopijo, amoksicilin se absorbira. Granule s počasnim sproščanjem pa se počasi raztapljajo, verjetno del granul zapusti želodec še preden se raztopijo. Če neraztopljene preidejo zgornji del tankega črevesa, kjer ima amoksicilin absorpcijsko okno, se ta del amoksicilina sploh ne absorbira. Za zdravljenje infekcij z bolj rezistentnimi sevi taka oblika ni primerna.WO 02/30392 discloses the once daily administration of amoxicillin and clavulanic acid. They are only suitable for the treatment of minor infections. The formulation is expected to provide an amoxicillin concentration above MIC = 2 pg / mL for more than eight hours in the dosing interval. The single daily dose is 1700 to 2500 mg of amoxicillin and 100 to 150 mg of potassium clavulanate. The daily dose can be provided with one tablet, e.g. dispersible or chewable, but it is possible to combine several conventional tablets or capsules, some containing amoxicillin and clavulanate and others containing amoxicillin only. A tablet of two types of granules is also described, the immediate-release granule contains amoxicillin trihydrate, and the slow-release granulate contains crystalline sodium amoxicillin, citric acid, xanthan gum and other excipients. Such a tablet is broken down into basic granules in the stomach, with the immediate-release granules dissolved immediately and the amoxicillin absorbed. The slow-release granules, however, slowly dissolve, probably leaving part of the granules before dissolving. If the undissolved pass through the upper intestine, where the amoxicillin has an absorption window, this part of amoxicillin is not absorbed at all. Such a formulation is not suitable for the treatment of infections with more resistant strains.
Farmacevtske oblike s prirejenim sproščanjem amoksicilina in klavulanske kisline so poznane tudi iz patentnih prijav WO 95/20946, WO 95/28148, WO 96/04908, WO 94/27557 in WO 98/22091.Pharmaceutical forms with modified release of amoxicillin and clavulanic acid are also known from patent applications WO 95/20946, WO 95/28148, WO 96/04908, WO 94/27557 and WO 98/22091.
Opis izumaDescription of the invention
Izum se nanaša na terapevtski sistem za odmerjanje amoksicilina in klavulanske kisline v enkratnem dnevnem odmerku, ki obsega vsaj eno farmacevtsko obliko s takojšnjim sproščanjem amoksicilina in klavulanske kisline in vsaj eno farmacevtsko obliko, ki se zadržuje v želodcu ter odloženo in zadržano sprošča amoksicilin v želodcu.The invention relates to a therapeutic dosage system of amoxicillin and clavulanic acid in a single daily dose comprising at least one immediate-release pharmaceutical formulation of amoxicillin and clavulanic acid and at least one gastric and delayed and delayed release of amoxicillin.
Bistvo izuma je v uporabi farmacevtske oblike, ki se zadržuje v želodcu in omogoči odloženo in počasno sproščanje amoksicilina v želodcu. Raztopljen amoksicilin se sproti absorbira iz želodca ali pa v raztopljeni obliki prehaja v zgornji del tankega črevesa, kjer se sproti in hitro absorbira. S tem dosežemo optimalno absorpcijo amoksicilina saj se praktično ves amoksicilin absorbira preden preide absorpcijsko okno. Zato je mogoče v primerjavi s farmacevtskimi oblikami, ki ne zagotavljajo zadrževanja farmacevtske oblike v želodcu, že z nižjimi odmerki doseči večjo biološko uporabnost in doseči ustrezne plazemske koncentracije amoksicilina za doziranje enkrat na dan. V primerjavi s poznanimi oblikami dosežemo z nižjim dnevnim odmerkom amoksicilina ustrezne terapevtske plazemske koncentracije amoksicilina v dnevnem dozirnem intervalu.The invention is in the form of a pharmaceutical formulation which is retained in the stomach and allows the delayed and slow release of amoxicillin in the stomach. Dissolved amoxicillin is either absorbed from the stomach or into the upper intestine in dissolved form, where it is absorbed and rapidly absorbed. This achieves optimal absorption of amoxicillin since virtually all amoxicillin is absorbed before it passes the absorption window. Therefore, it is possible to achieve higher bioavailability and lower amoxicillin plasma concentrations for once-daily dosing compared to non-retention dosage forms of the stomach. Compared to the known forms, a lower therapeutic dose of amoxicillin is achieved with a corresponding therapeutic plasma concentration of amoxicillin at a daily dosing interval.
V plazmi se na ta način vzdržujejo koncentracije amoksicilina, ki se v povprečju ne razlikujejo veliko od od cmax (najvišja koncentracija amoksicilina v krvi), ki bi se pojavile po aplikaciji samo odmerka s takojšnjim sproščanjem, ki je del tega terapevtskega sistema. Tako so koncentracije amoksicilina v gastrointestinalnem traktu v območju, v katerem ne pride do pojava nasičenosti absorpcije. S tem se ne izgublja učinkovina zaradi absorpcijskega okna, z manj neabsorbirane učinkovine pa posledično lahko pričakujemo manj stranskih učinkov s strani gastrointestinalnega trakta, glede na višje odmerke, ki preidejo območje absorpcijskega okna.In this way, plasma concentrations of amoxicillin are maintained that are not on average significantly different from those of cma x (the highest blood amoxicillin concentration) that would occur after administration of an immediate-release dose that is part of this therapeutic system. Thus, the concentrations of amoxicillin in the gastrointestinal tract are in the range where absorption saturation does not occur. This does not lose the active substance due to the absorption window, and as a result the less unabsorbed active ingredient can consequently expect less side effects from the gastrointestinal tract, given higher doses that cross the absorption window area.
Nov terapevtski sistem je za bolnika prijaznejši in predstavlja prednost pred poznanimi farmacevtskimi oblikami, namenjenimi za dvakrat ali trikrat dnevno peroralno jemanje amoksicilina in klavulanske kisline. Omogoča bolj enostavno in zanesljivo odmerjanje in jemanje zdravila po navodilih zdravnika in proizvajalca. Na ta način je zagotovljeno učinkovitejše zdravljenje.The new therapeutic system is more patient-friendly and represents an advantage over the known pharmaceutical formulations intended for oral administration of amoxicillin and clavulanic acid twice or three times daily. It allows for easier and more reliable dosing and administration of the medicine as instructed by your doctor and manufacturer. This ensures more effective treatment.
Terapevtski sistem, ki je predmet izuma, je namenjen empiričnemu zdravljenju lažjih do srednje težkih bakterijskih okužb, ki jih povzročajo bakterijski sevi, ki so občutljivi na kombinacijo amoksicilina in klavulanske kisline. Med te bakterijske seve na primer med drugim sodijo po Gramu pozitivne aerobne bakterije kot so npr. St. pneumoniae, St. pyogenes, St. viridans, St. bovis, Staph. aureus, Staph. Epidermidis, Listeria spp., Enterococcus spp., po Gramu negativne aerobne bakterije kot so npr. H. influenzae, M. cattharalis, E. coli Proteus spp., Klebsiella spp., N. gonorrhoeae, N. meningitidis, Pasteurella multocida ter anaerobne bakterije kot so npr. Peptococcus spp., Peptostreptococcus spp., Clostridium spp., Actinomyces israellii. Omenjene bakterije povzročajo okužbe zgornjega in spodnjega dela dihal, okužbe sečil, okužbe rodil, gonorejo, okužbe kože in mehkih tkiv, okužbe kosti in vezivnega tkiva, holecistitis, okužbe obzobnih tkiv, okužbe v zvezi z ugrizi živali ali človeka in mešane okužbe, ki so jih povzročili po Gramu negativni in pozitivni mikroorganizmi ter anaerobi: kronični sinusitis in otitis, peritonzilarni absces, absces v dojki, aspiracijska pljučnica, peritonitis, holangitis, zapleti po operacijah v trebušni votlini, abdominalne okužbe.The therapeutic system of the invention is intended to empirically treat mild to moderate bacterial infections caused by bacterial strains sensitive to the combination of amoxicillin and clavulanic acid. These bacterial strains include, for example, Gram positive aerobic bacteria such as St. pneumoniae, St. pyogenes, St. viridans, St. bovis, Staph. aureus, Staph. Epidermidis, Listeria spp., Enterococcus spp., Gram negative aerobic bacteria such as e.g. H. influenzae, M. cattharalis, E. coli Proteus spp., Klebsiella spp., N. gonorrhoeae, N. meningitidis, Pasteurella multocida, and anaerobic bacteria such as Peptococcus spp., Peptostreptococcus spp., Clostridium spp., Actinomyces israellii. These bacteria cause upper and lower respiratory tract infections, urinary tract infections, birth defects, gonorrhea, skin and soft tissue infections, bone and connective tissue infections, cholecystitis, periodontal tissue infections, animal or human bite infections, and mixed infections that are Gram negative and positive microorganisms and anaerobes: chronic sinusitis and otitis, peritonzilar abscess, breast abscess, aspiration pneumonia, peritonitis, cholangitis, complications after abdominal surgery, abdominal infections.
Po farmakokinetičnih lastnostih terapevtski sistem, ki je predmet izuma, zagotavlja v plazmi in posledično v tkivih takšne koncentracije amoksicilina in klavulanske kisline, ki so terapevtsko učinkovite in dosegajo ali presegajo minimalno inhibitorno koncentracijo (MIK) domnevnega povzročitelja za kombinacijo amoksicilin/klavulanska kislina. Minimalna inhibitorna koncentracija (MIK) je tista koncentracija amoksicilina in klavulanske kisline, ki še zavre razmnoževanje konkretnega bakterijskega seva. Pri večini izoliranih kliničnih sevov je minimalna inhibitorna koncentracija za kombinacijo amoksicilin/klavulanska kislina 1,0/0,5 gg/mL ali manj ob uporabi standardne metode za določanje MIK pri razmerju amoksicilin:klavulanska kislina 2:1. Terapevtski sistem, ki je predmet izuma, zagotavlja ob enkrat dnevnem odmerjanju koncentracije amoksicilina 4,0 μg/mL preko primerljivega dela dozirnega intervala, to je najmanj 7 ur. To je podobno kot pri odmerjanju že znanih farmacevtskih oblik z amoksicilinom in klavulansko kislino, ki se odmerjajo peroralno dvakrat ali trikrat dnevno.According to the pharmacokinetic properties, the therapeutic system of the invention provides in plasma and consequently in tissues such concentrations of amoxicillin and clavulanic acid that are therapeutically effective and reach or exceed the minimum inhibitory concentration (MIC) of the suspected agent for the amoxicillin / clavulanic acid combination. Minimum inhibitory concentration (MIC) is that of amoxicillin and clavulanic acid, which further inhibits the reproduction of a specific bacterial strain. In most isolated clinical strains, the minimum inhibitory concentration for the amoxicillin / clavulanic acid combination is 1.0 / 0.5 gg / mL or less using the standard method for determining the MIC at an amoxicillin: clavulanic acid ratio of 2: 1. The therapeutic system of the invention provides at a daily dose of amoxicillin concentration of 4.0 μg / mL over a comparable portion of the dosing interval, i.e., at least 7 hours. This is similar to the dosage of the known pharmaceutical forms with amoxicillin and clavulanic acid, which are orally administered twice or thrice daily.
Enkraten dnevni odmerek amoksicilina in klavulanske kisline zagotovimo s kombinacijo ene ali več farmacevtskih oblik, iz katerih se amoksicilin in klavulanska kislina sprostita hitro po zaužitju, ter ene ali več farmacevtskih oblik, ki se zadržujejo v želodcu in iz katerih se amoksicilin sprošča počasi tako, da je koncentracija amoksicilina 4,0 /zg/mL najmanj 7 ur in 1,0/zg/mL najmanj 12 ur.A single daily dose of amoxicillin and clavulanic acid is provided by a combination of one or more pharmaceutical forms, from which amoxicillin and clavulanic acid are released rapidly after ingestion, and one or more gastric-retained pharmaceutical forms, from which amoxicillin is released slowly such that the amoxicillin concentration is 4.0 / wg / mL for at least 7 hours and 1.0 / w / mL for at least 12 hours.
Enkraten dnevni odmerek amoksicilina je lahko od 800 do 4000 mg, odmerek klavulanske kisline pa od 50 do 250 mg. Razmerje amoksicilina in klavulanske kisline je od 3:1 do 35:1. Prednostne so oblike, v katerih je razmerje od 10:1 do 30:1, predvsem 12:1, 13:1,22:1.A single daily dose of amoxicillin can range from 800 to 4000 mg and a dose of clavulanic acid from 50 to 250 mg. The ratio of amoxicillin to clavulanic acid is from 3: 1 to 35: 1. Forms in which the ratio is from 10: 1 to 30: 1, especially 12: 1, 13: 1,22: 1, are preferred.
Amoksicilin je lahko v obliki amoksicilin trihidrata ali kristalnega natrijevega amoksicilina ali kot kombinacija obeh. Klavulanska kislina je v obliki soli, npr. kalijevega klavulanata.Amoxicillin can be in the form of amoxicillin trihydrate or crystalline sodium amoxicillin or a combination of both. Clavulanic acid is in the form of a salt, e.g. potassium clavulanate.
Prednostni enkratni dnevni odmerki so 1500/125, 1600/125, 2000/125, 2750/125 ter 2650/80.Preferred single daily doses are 1500/125, 1600/125, 2000/125, 2750/125 and 2650/80.
Ena ali več farmacevtskih oblik, ki zagotavljajo del odmerka za takojšnje sproščanje, lahko vsebuje od 300 do 2000 mg amoksicilina in od 50 do 250 mg klavulanske kisline.One or more dosage forms providing part of the immediate-release dose may contain from 300 to 2000 mg of amoxicillin and from 50 to 250 mg of clavulanic acid.
Del odmerka za takojšnje sproščanje lahko zagotovimo z eno ali več farmacevtskimi oblikami, ki so izbrane iz skupine, ki jo sestavljajo: tableta, lakirana tableta, hitro razpadljiva tableta, disperzibilna tableta, šumeča tableta, žvečljiva tableta, kapsula, granulat v vrečki, suspenzija ter pelete. Lahko kombiniramo več enakih ali različnih oblik, z enako ali različno dozo. Lahko npr. uporabimo eno ali več tablet 500/125, 875/125, 500/62,5 1000/80 mg, disperzibilno tableto 500/125, 875/125 1000/125, 1000/80 mg, ali njihove kombinacije. Nekatere tablete lahko vsebujejo amoksicilin in klavulansko kislino, druge samo amoksicilin. Prednostna je uporaba ene farmacevtske oblike s takojšnjim sproščanjem amoksicilina in klavulanske kisline.Part of the immediate-release dose can be provided by one or more pharmaceutical forms selected from the group consisting of: tablet, lacquer tablet, rapidly disintegrating tablet, dispersible tablet, effervescent tablet, chewable tablet, capsule, granulate in the bag, suspension and pellets. Multiple identical or different forms can be combined with the same or different dosage. We can e.g. use one or more tablets 500/125, 875/125, 500 / 62,5 1000/80 mg, dispersible tablet 500/125, 875/125 1000/125, 1000/80 mg, or combinations thereof. Some tablets may contain amoxicillin and clavulanic acid, others just amoxicillin. It is preferable to use one pharmaceutical formulation with immediate release of amoxicillin and clavulanic acid.
Farmacevtske oblike za takojšnje sproščanje amoksicilina in klavulanske kisline lahko vsebujejo tudi snovi, ki izboljšajo absorpcijo amoksicilina iz gastrointestinalnega trakta. Kot pospeševalci absorpcije amoksicilina so primerne površinsko aktivne snovi, maščobne kisline, gliceridi s srednje dolgimi verigami, steroidni detergenti (soli žolčnih kislin), acil karnitini in alkanoil holini (estri karnitina in holina in maščobnih kislin s srednje dolgimi in dolgimi verigami), N-acil derivati alfa-amino kislin in N-acil derivati ne-alfa-amino kislin, hitozani ter drugi mukoadhezivni polimeri. Posebej primerni pospeševalci absorpcije so npr. natrijev deoksiholat, natrijev tauroholat, polisorbat 80, natrijev lavrilsulfat, natrijev dodecilsulfat, oktanojska kislina, natrijev dokuzat, natrijev lavrat, gliceril monolavrat, stearinska kislina, palmitinska kislina, palmitoleinska kislina, glicerilmonooleat, natrijev tauroholat, etilendiamintetraocetna kislina, natrijev edetat, natrijev citrat, /?-ciklodekstrin in natrijev salicilat. Prednostni pospeševalci so natrijev deoksiholat, natrijev dokuzat in natrijev lavrilsulfat.The immediate release dosage forms of amoxicillin and clavulanic acid may also contain substances that enhance the absorption of amoxicillin from the gastrointestinal tract. Surfactants, fatty acids, medium-chain glycerides, steroidal detergents (bile acids), acyl carnitines and alkanoyl cholines (carnitine and choline esters and medium- and long-chain fatty acids), are suitable as promoters of amoxicillin absorption. alpha-amino acid acyl derivatives and non-alpha-amino acid N-acyl derivatives, chitosans and other mucoadhesive polymers. Particularly suitable absorption enhancers are e.g. sodium sodium, sodium taurocholate, polysorbate, sodium lauryl sulfate, sodium dodecylate, sodium docusate, glyceryl monolavrate, stearic acid, gatherel - Cyclodextrin and sodium salicylate. Preferred accelerators are sodium deoxycholate, sodium docusate and sodium lauryl sulfate.
Del odmerka za odloženo in zadržano sproščanje amoksicilina zagotavlja ena ali več farmacevtskih oblik, ki se zadržujejo v želodcu. Farmacevtske oblike, ki se zadržujejo v želodcu, so lahko npr. plavajoče farmacevtske oblike, težke farmacevtske oblike, bioadhezivne farmacevske oblike, farmacevtske oblike, ki v želodcu ekspandirajo, farmacevtske oblike, ki se zaradi specifične oblike zadržujejo v želodcu in ne morejo preiti skozi pilorus v duodenum in druge. Plavajoča farmacevtska oblika je lahko npr. plavajoča kapsula ali plavajoča tableta. Prednostna je plavajoča kapsula. Del odmerka, ki se sprošča odloženo in zadržano, je lahko porazdeljen med več plavajočih kapsul ali tablet. V tem delu je od 500 do 2000 mg amoksicilina. Farmacevtska oblika, ki se zadržuje v želodcu, lahko opcijsko vsebuje tudi klavulansko kislino.Part of the dose for delayed and delayed release of amoxicillin is provided by one or more gastric retention dosage forms. Pharmaceutical forms which are retained in the stomach may be e.g. floating pharmaceutical forms, heavy pharmaceutical forms, bioadhesive pharmaceutical forms, gastric expanding pharmaceutical forms, pharmaceutical forms which, due to their specific form, are retained in the stomach and cannot pass through the pylorus into the duodenum and others. The floating pharmaceutical form may be e.g. floating capsule or floating tablet. A floating capsule is preferred. The portion of the dose that is delayed and withheld can be distributed between several floating capsules or tablets. This section contains between 500 and 2000 mg of amoxicillin. The gastric retention formulation may optionally also contain clavulanic acid.
Enkraten odmerek 1500 mg amoksicilina in 125 mg klavulanske kisline lahko zagotovimo npr. z eno lakirano tableto 500/125 in dvema plavajočima kapsulama, ki vsebujeta po 500 mg amoksicilina. Enkraten odmerek 1600 mg amoksicilina in 125 mg klavulanske kisline lahko zagotovimo npr. z eno lakirano tableto 500/125 in dvema plavajočima kapsulama, ki vsebujeta po 550 mg amoksicilina, enkraten odmerek 2650 mg amoksicilina in 80 mg klavulanske kisline pa npr. z disperzibilno tableto 1000/80 in tremi plavajočimi kapsulami, ki vsebujejo po 550 mg amoksicilina. Enkraten odmerek 2525 mg amoksicilina in 125 mg klavulanske kisline lahko dosežemo npr. z eno lakirano tableto 875/125 in tremi plavajočimi kapsulami, ki vsebujejo po 550 mg amoksicilina. Enkraten odmerek 2000 mg amoksicilina in 125 mg klavulanske kisline lahko zagotovimo npr. z eno lakirano tableto 500/125 in tremi plavajočimi kapsulami, ki vsebujejo po 500 mg amoksicilina.A single dose of 1500 mg amoxicillin and 125 mg clavulanic acid can be provided e.g. with one 500/125 lacquered tablet and two floating capsules containing 500 mg amoxicillin each. A single dose of 1600 mg amoxicillin and 125 mg clavulanic acid can be provided e.g. with one 500/125 lacquered tablet and two floating capsules containing 550 mg amoxicillin each, a single dose of 2650 mg amoxicillin and 80 mg clavulanic acid, e.g. with a 1000/80 dispersible tablet and three floating capsules containing 550 mg amoxicillin each. A single dose of 2525 mg amoxicillin and 125 mg clavulanic acid can be achieved e.g. with one lacquered tablet 875/125 and three floating capsules containing 550 mg amoxicillin each. A single dose of 2000 mg amoxicillin and 125 mg clavulanic acid can be provided e.g. with one 500/125 lacquered tablet and three floating capsules containing 500 mg amoxicillin each.
Predmet izuma je tudi plavajoča kapsula z odloženim in zadržanim sproščanjem amoksicilina, ki se uporablja v terapevtskem sistemu, ki je predmet izuma, za zagotovitev enkratnega dnevnega odmerka v kombinaciji s farmacevtsko obliko, ki omogoča hitro sproščanje amoksicilina in klavulanske kisline. Sproščanje je odloženo za približno eno uro, kar je definirano z raztapljanjem kapice ali obloge kapsule.The subject of the invention is also a floating capsule of delayed and delayed release of amoxicillin used in the therapeutic system of the invention to provide a single daily dose in combination with a pharmaceutical form that allows for the rapid release of amoxicillin and clavulanic acid. The release is delayed by about one hour, which is defined by the dissolution of the cap or capsule lining.
Plavajočo kapsulo sestavlja obloženo telo kapsule, obložena ali neobložena kapica, granulat ter vsaj ena tableta, pri čemer granulat in tableta vsebujeta amoksicilin. Amoksicilin je lahko v obliki trihidrata, kot kristalni natrijev amoksicilin ali kot kombinacija obeh. Telo in kapica kapsule sta v osnovi iz polimernega materiala kot so npr. hidroksipropilmetilceluloza (HPMC), želatina in škrob. Prednostne so kapsule iz hidroksipropilmetilceluloze. Kapsule so lahko obložene v celoti, lahko pa je obloženo samo telo kapsule. Telo in kapica sta lahko obložena z enako ali različno oblogo. Če sta oblogi različni, se mora obloga na kapici raztopiti prej kot obloga na telesu kapsule.The floating capsule consists of a coated capsule body, a coated or uncoated cap, a granulate and at least one tablet, the granulate and the tablet containing amoxicillin. Amoxicillin may be in the form of trihydrate, as crystalline sodium amoxicillin, or as a combination of both. The body and cap of the capsule are essentially made of polymeric material such as e.g. hydroxypropyl methylcellulose (HPMC), gelatin and starch. Hydroxypropyl methylcellulose capsules are preferred. The capsules may be fully coated, but only the body of the capsule may be coated. The body and cap may be lined with the same or different lining. If the lining is different, the lining on the cap should dissolve sooner than the lining on the capsule body.
Primerne so dobro topne ali slabo topne obloge oziroma obloge, ki se počasi raztapljajo. Uporabljajo se topni ali netopni polimeri oziroma kombinacije netopnih polimerov s topnimi polimeri, kot so npr. kombinacije etilceluloze in hidroksipropilmetilceluloze, hidroksipropilceluloze, hidroksietilcluloze, metilceluloze ali polivinilpirolidona, kombinacija kopolimerov metakrilata/trimetilamonioetilmetakrilata (npr. Eudragit RL PO, Eudragit RL 100, Eudragit RL30D, Eudragit RS PO, Eudragit RS 100, Eudragit RS30D ali njihove kombinacije) in hidroksipropilmetilceluloze, hidroksipropilceluloze, hidroksietilceluloze ali metilceluloze, kombinacija nevtralnega polimera metakrilata (npr. Eudragit NE 30 D, Eudragit NE 40 D) in hidroksipropilmetilceluloze, hidroksipropilceluloze, hidroksietilceluloze, metilceluloze ali polivinilpirolidona. Obloge lahko vsebujejo tudi druge pomožne snovi, ki se običajno uporabljajo v oblogah, kot so polnila, npr. smukec, laktoza, polisaharidi in drugi, mehčala, npr. dibutilsebacat, trietilcitral, polietilenglikol, adipinska kislina, kokosovo olje, oleinska kislina, in drugi, barvila npr. titanov dioksid, laki, pigmenti in drugi, antioksidanti in druge pomožne snovi. Obloga lahko vsebuje tudi bioadhezivne polimere.Good soluble or poorly soluble coatings or slow-dissolving coatings are suitable. Soluble or insoluble polymers or combinations of insoluble polymers with soluble polymers such as e.g. a combination of ethylcellulose and hydroxypropylmethylcellulose, hydroxypropylcellulose, hidroksietilcluloze, methylcellulose or polyvinylpyrrolidone, a combination of copolymers of methacrylate / trimetilamonioetilmetakrilata (eg. Eudragit RL PO, Eudragit RL 100, Eudragit RL30D, Eudragit RS PO, Eudragit RS 100, Eudragit RS30D or their combinations) and hydroxypropylmethylcellulose, hydroxypropylcellulose , hydroxyethylcellulose or methylcellulose, a combination of a neutral methacrylate polymer (e.g. Eudragit NE 30 D, Eudragit NE 40 D) and hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose or polyvinylpyrrolidone. The liners may also contain other excipients commonly used in liners such as fillers, e.g. talc, lactose, polysaccharides and others, plasticizers, e.g. dibutylsebacate, triethylcitral, polyethylene glycol, adipic acid, coconut oil, oleic acid, and others, dyes e.g. titanium dioxide, varnishes, pigments and others, antioxidants and other excipients. The coating may also contain bioadhesive polymers.
Posebej primerna obloga je kombinacija etilceluloze in hidroksipropilceluloze ali kombinacija Surelease® in hidroksipropilmetilceluloze v razmerju 70:30, 60:40 ali 50:50. Surelease® je trgovsko ime za vodno disperzijo etilceluloze proizvajalca Colorcon.Particularly suitable coating is a combination of ethylcellulose and hydroxypropylcellulose or a combination of Surelease® and hydroxypropylmethylcellulose in a ratio of 70:30, 60:40 or 50:50. Surelease® is a trade name for the aqueous dispersion of ethylcellulose by Colorcon.
Pred nanosom funkcionalne obloge lahko kapsulo ali dele kapsule obložimo z disperzijo (raztopino ali suspenzijo) hidrofilnega polimera npr. hidroksipropilmetilceluloze, hidroksipropilceluloze, hidroksietilceluloze.Prior to application of the functional coating, the capsule or parts of the capsule may be coated with a dispersion (solution or suspension) of a hydrophilic polymer, e.g. hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose.
Kapsule ali njene dele lahko oblagamo prazne (pred polnjenjem) ali pa oblagamo že napolnjene kapsule z granulatom in tabletami. Nanos obloge je od 0,5 do 10 mg/cm2, če jih oblagamo pred polnjenjem, oziroma od 0,5 do 30 mg/cm2, če oblagamo že napolnjene kapsule z granulatom in tabletami. Debelina obloge je od 2 do 200 //m, prednostno 10 do 50 //m, če jih oblagamo pred polnjenjem, oziroma 2 do 600 //m, če oblagamo že napolnjene kapsule z granulatom in tabletami.The capsules or portions thereof may be lined empty (before filling) or the already filled capsules may be filled with granules and tablets. The coating is 0.5 to 10 mg / cm 2 when coated before filling, or 0.5 to 30 mg / cm 2 when coated with granules and tablets. The thickness of the coating is from 2 to 200 // m, preferably 10 to 50 // m, when coated before filling, or 2 to 600 // m, when coated with already filled capsules with granulate and tablets.
Odloženo sproščanje dosežemo z vrsto obloge ali kombinacijo obloženega telesa in neobložene kapice ali kombinacijo različnih oblog.Delayed release is achieved by type of lining or combination of lined body and unlined lids or combination of different lining.
Obloge nanesemo po postopkih, ki so v farmacevtski tehnologiji običajni za oblaganje kapsul. Disperzija za oblaganje je lahko raztopina ali suspenzija polimerov ter drugih pomožnih snovi. Topilo za pripravo disperzije za oblaganje je lahko naprimer voda, etanol, metanol, propan-2-ol, aceton, etilacetat, ocetna kislina, glikoli, diklorometan, dimetilformamid, dimetilsulfoksid, kloroform, toluen, metilen klorid, benzen, etoksietil acetat, etilen glikol monoacetat, etil laktat, monoetil acetat, metiletil keton ter njihove kombinacije.The coatings are applied according to procedures customary in pharmaceutical technology for capsule coating. The coating dispersion may be a solution or suspension of polymers and other excipients. The solvent for the preparation of the coating dispersion may be, for example, water, ethanol, methanol, propan-2-ol, acetone, ethyl acetate, acetic acid, glycols, dichloromethane, dimethylformamide, dimethylsulfoxide, chloroform, toluene, methylene chloride, benzene, ethoxyethyl acetate, ethylene monoacetate, ethyl lactate, monoethyl acetate, methylethyl ketone and combinations thereof.
Kapsule ali del kapsule, t.j. telo ali kapico kapsule, lahko poleg prve funkcionalne obloge obložimo še z drugo funkcionalno oblogo, ki je lahko po sestavi enaka ali različna kot prva obloga. V drugi oblogi lahko uporabimo topne ali netopne polimere ali kombinacijo netopnih in topnih polimerov. Druge pomožne snovi so lahko enake kot v prvi oblogi. Postopki za izdelavo druge funkcionalne obloge so enaki kot postopki za izdelavo prve funkcionalne obloge.A capsule or part of a capsule, i.e. body or capsule cap, in addition to the first functional lining, may be lined with a second functional lining that may be the same or different in composition as the first lining. In another coating, soluble or insoluble polymers or a combination of insoluble and soluble polymers may be used. Other excipients may be the same as in the first coating. The procedures for making the second functional lining are the same as the procedures for making the first functional lining.
Granulat vsebuje amoksicilin in vsaj eno hidrofilno ali lipofilno snov, ki nadzoruje sproščanje. Uporabljajo se polimerne ali nepolimerne snovi. Primerne polimerne snovi so hidroksipropilceluloza, hidroksipropilmetilceluloza, metilceluloza, etilceluloza, hidroksietilceluloza, natrijeva karboksimetilceluloza, celulozni acetat ftalat, polivinil acetat ftalat, hidroksimetilcelulozni ftalat, polivinilalkohol, polivinilpirolidon, metilhidroksietilceluloza, natrijeva karboksimetilceluloza, polimeri in kopolimeri akrilne in metakrilne kisline, kopolimeri etilakrilata in metilakrilata, maltodekstrin, guma ksantan, guar guma, guma akacije, alginska kislina in natrijev alginat. Nepolimerne snovi so lahko vosek karnauba, cetilni alkohol, hidrogenirano rastlinsko olje, hidrogenirano ricinovo olje, glicerol monostearat, glicerol palmitostearat, zmes mono-, di- in trgliceridov in drugi.The granulate contains amoxicillin and at least one hydrophilic or lipophilic substance that controls release. Polymeric or non-polymeric substances are used. Suitable polymeric materials are hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hidroksimetilcelulozni phthalate, polyvinyl alcohol, polyvinylpyrrolidone, methylhydroxyethylcellulose, sodium carboxymethylcellulose, polymers and copolymers of acrylic and methacrylic acid, copolymers of ethyl acrylate and methyl acrylate, maltodextrin, xanthan gum, guar gum, acacia gum, alginic acid and sodium alginate. Non-polymeric substances may be carnauba wax, cetyl alcohol, hydrogenated vegetable oil, hydrogenated castor oil, glycerol monostearate, glycerol palmitostearate, a mixture of mono-, di-, and triclycerides, and others.
Prednosto se uporabljajo hidroksipropilmetilceluloza, metilceluloza in etilceluloza.Hydroxypropyl methylcellulose, methylcellulose and ethylcellulose are preferred.
Granulat lahko vsebuje tudi druge pomožne snovi kot naprimer različna polnila, veziva, razgrajevala, drsila, maziva ter snovi, ki izboljšajo absorpcijo amoksicilina iz gastrointestinalnega trakta. Kot polnila se lahko uporabljajo mikrokristalna 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, silikonizirani 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 granulate may also contain other excipients such as various fillers, binders, decomposers, gliders, lubricants and substances that enhance the absorption of amoxicillin from the gastrointestinal tract. The fillers may be microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminum silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulfate, 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 include 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 laurate sodium sodium sulfate , talc, etc. Preferred lubricants are calcium or magnesium stearate and stearic acid.
Kot pospeševalci absorpcije amoksicilina so primerne površinsko aktivne snovi, maščobne kisline, gliceridi s srednje dolgimi verigami, steroidni detergenti (soli žolčnih kislin), acil karnitini in alkanoil holini (estri karnitina in holina in maščobnih kislin s srednje dolgimi in dolgimi verigami), N-acil derivati alfa-amino kislin in Nacil derivati ne-alfa-amino kislin, hitozani ter drugi mukoadhezivni polimeri. Posebej primerni pospeševalci absorpcije so npr. natrijev deoksiholat, natrijev tauroholat, polisorbat 80, natrijev lavrilsulfat, natrijev dodecilsulfat, oktanojska kislina, natrijev dokuzat, natrijev lavrat, gliceril monolavrat, stearinska kislina, palmitinska kislina, palmitoleinska kislina, glicerilmonooleat, natrijev tauroholat, etilendiamintetraocetna kislina, natrijev edetat, natrijev citrat, β-ciklodekstrin in natrijev salicilat. Prednostni pospeševalci so natrijev deoksiholat, natrijev dokuzat in natrijev lavrilsulfat.Surfactants, fatty acids, medium-chain glycerides, steroidal detergents (bile acids), acyl carnitines and alkanoyl cholines (carnitine and choline esters and medium- and long-chain fatty acids), are suitable as promoters of amoxicillin absorption. alpha-amino acid acyl derivatives; non-alpha-amino acid acyl derivatives, chitosans and other mucoadhesive polymers. Particularly suitable absorption enhancers are e.g. sodium sodium, sodium taurocholate, polysorbate, sodium lauryl sulfate, sodium dodecylate, sodium docusate, glyceryl monolavrate, stearic acid, gatherel β-cyclodextrin and sodium salicylate. Preferred accelerators are sodium deoxycholate, sodium docusate, and sodium lauryl sulfate.
Granulat pripravimo po postopkih, ki se v farmacevtiki običajno uporabljajo za pripravo granulatov, npr. enostavno mešanje prahov (direktna zmes) ter suho ali vlažno granuliranje. Pri suhem granuliranju uporabimo npr. postopek briketiranja ali kompaktiranja. Topilo pri vlažnem granuliranju je lahko naprimer voda, etanol, metanol, propan-2-ol, aceton, etilacetat, ocetna kislina, glikoli, diklorometan, dimetilformamid, dimetilsulfoksid, kloroform, toluen, metilen klorid, benzen, etoksietil acetat, etilen glikol monoacetat, etil laktat, monoetil acetat, metiletil keton ter njihove kombinacije.The granulate is prepared according to the methods commonly used in the pharmaceutical industry for the preparation of granules, e.g. easy mixing of powders (direct mixture) and dry or wet granulation. For dry granulation, e.g. briquetting or compacting process. The wet granulation solvent may be, for example, water, ethanol, methanol, propan-2-ol, acetone, ethyl acetate, acetic acid, glycols, dichloromethane, dimethylformamide, dimethylsulfoxide, chloroform, toluene, methylene chloride, benzene, ethoxyethyl acetate, ethylene glycol, ethylene glycol, ethyl lactate, monoethyl acetate, methylethyl ketone and combinations thereof.
Tableta vsebuje amoksicilin in pomožne snovi, ki so lahko enake kot v granulatu, lahko pa so različne. Sestava tablete je lahko kvalitativno in procentualno enaka ali različna kot granulat. Opcijsko je lahko tableta pripravljena samo iz pomožnih snovi, brez amoksicilina.The tablet contains amoxicillin and excipients, which may be the same as the granulate but may be different. The composition of the tablet may be qualitatively and percentally the same or different as the granulate. Optionally, the tablet can only be made of excipients without amoxicillin.
Plavajoča kapsula, ki je predmet izuma, lahko vsebuje eno ali več tablet. Te so lahko po sestavi enake ali različne. Lahko kombiniramo tablete z amoksicilinom s tabletami, ki amoksicilina ne vsebujejo, tablete s sestavo, ki je enaka ali različna od sestave granulata.The floating capsule of the invention may contain one or more tablets. These may be the same or different in composition. Amoxicillin tablets can be combined with tablets that do not contain amoxicillin, tablets with a composition that is the same or different from the composition of the granulate.
Tableta vsebuje vsaj eno hidrofilno ali lipofilno snov, ki nadzoruje sprožanje. Za ta namen lahko uporabimo polimerne ali nepolimerne snovi. Izmed polimernih snovi se lahko uporabljajo hidroksipropilceluloza, hidroksipropilmetilceluloza, metilceluloza, etilceluloza, hidroksietilceluloza, natrijeva karboksimetilceluloza, celulozni acetat ftalat, polivinil acetat ftalat, hidroksimetilcelulozni ftalat, polivinilalkohol, polivinilpirolidon, metilhidroksietilceluloza, natrijeva karboksimetilceluloza, polimeri in kopolimeri akrilne in metakrilne kisline, kopolimeri etilakrilata in metilakrilata, maltodekstrin, guma ksantan, guar guma, guma akacije, alginska kislina in natrijev alginat. Nepolimerne snovi so lahko vosek karnauba, cetilni alkohol, hidrogenirano rastlinsko olje, hidrogenirano ricinovo olje, glicerol monostearat, glicerol palmitostearat zmes mono-, di- in trgliceridov in drugi.The tablet contains at least one hydrophilic or lipophilic substance that controls triggering. Polymeric or non-polymeric substances may be used for this purpose. Among the polymeric materials may be used hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hidroksimetilcelulozni phthalate, polyvinyl alcohol, polyvinylpyrrolidone, methylhydroxyethylcellulose, sodium carboxymethylcellulose, polymers and copolymers of acrylic and methacrylic acid, copolymers of ethyl acrylate and methyl acrylate, maltodextrin, xanthan gum, guar gum, acacia gum, alginic acid and sodium alginate. Non-polymeric substances may be carnauba wax, cetyl alcohol, hydrogenated vegetable oil, hydrogenated castor oil, glycerol monostearate, glycerol palmitostearate a mixture of mono-, di- and triclycerides and others.
Prednosto se uporabljajo hidroksipropilmetilceluloza, hidroksipropilceluloza, metilceluloza in etilceluloza.Preferably, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and ethylcellulose are used.
Tableta vsebuje tudi pomožne snovi kot so npr. polnila, veziva, razgrajevala, površinsko aktivne snovi, drsila, maziva ter snovi, ki izboljšajo absorpcijo amoksicilina v gastrointestinalnem traktu. Kot polnila se lahko uporabljajo mikrokristalna 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 tablet also contains excipients such as. fillers, binders, decomposers, surfactants, gliders, lubricants and substances that enhance the absorption of amoxicillin in the gastrointestinal tract. The fillers may be microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminum silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulfate, 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 pospeševalci absorpcije amoksicilina so primerne površinsko aktivne snovi, maščobne kisline, gliceridi s srednje dolgimi verigami, steroidni detergenti (soli žolčnih kislin), acil karnitini in alkanoil holini (estri karnitina in holina in maščobnih kislin s srednje dolgimi in dolgimi verigami), N-acil derivati alfa-amino kislin in Nacil derivati ne-alfa-amino kislin, hitozani ter drugi mukoadhezivni polimeri. Posebej primerni pospeševalci absorpcije so npr. natrijev deoksiholat, natrijev tauroholat, polisorbat 80, natrijev lavrilsulfat, natrijev dodecilsulfat, oktanojska kislina, natrijev dokuzat, natrijev lavrat, gliceril monolavrat, stearinska kislina, palmitinska kislina, palmitoleinska kislina, glicerilmonooleat, natrijev tauroholat, etilendiamintetraocetna kislina, natrijev edetat, natrijev citrat, /?-ciklodekstrin in natrijev salicilat. Prednostni pospeševalci so natrijev deoksiholat, natrijev dokuzat in natrijev lavrilsulfat.Surfactants, fatty acids, medium-chain glycerides, steroidal detergents (bile acids), acyl carnitines and alkanoyl cholines (carnitine and choline esters and medium- and long-chain fatty acids), are suitable as promoters of amoxicillin absorption. alpha-amino acid acyl derivatives; non-alpha-amino acid acyl derivatives, chitosans and other mucoadhesive polymers. Particularly suitable absorption enhancers are e.g. sodium sodium, sodium taurocholate, polysorbate, sodium lauryl sulfate, sodium dodecylate, sodium docusate, glyceryl monolavrate, stearic acid, gatherel - Cyclodextrin and sodium salicylate. Preferred accelerators are sodium deoxycholate, sodium docusate and sodium lauryl sulfate.
Tablete pripravimo po postopkih, ki so poznani v farmacevtski tehnologiji, to je z direktnim tabletiranjem zmesi prahov ali tabletiranjem granulata, ki ga pripravimo z vlažnim ali suhim granuliranjem. Pri suhem granuliranju uporabimo npr. postopek briketiranja ali kompaktiranja. Pri vlažnem granuliranju je lahko kot topilo naprimer voda, etanol, metanol, propan-2-ol, aceton, etilacetat, ocetna kislina, glikoli, diklorometan, dimetilformamid, dimetilsulfoksid, kloroform, toluen, metilen klorid, benzen, etoksietil acetat, etilen glikol monoacetat, etil laktat, monoetil acetat, metiletil keton ter njihove kombinacije.The tablets are prepared by methods known in the pharmaceutical technology, i.e. by direct tableting of a powder mixture or tableting of a granulate prepared by wet or dry granulation. For dry granulation, e.g. briquetting or compacting process. For wet granulation, the solvent may be, for example, water, ethanol, methanol, propan-2-ol, acetone, ethyl acetate, acetic acid, glycols, dichloromethane, dimethylformamide, dimethylsulfoxide, chloroform, toluene, methylene chloride, benzene, ethoxyethyl acetate, monoacetyl glycol , ethyl lactate, monoethyl acetate, methylethyl ketone and combinations thereof.
Snovi, ki izboljšajo absorpcijo amoksicilina iz gastrointestinalnega trakta, so lahko v plavajoči farmacevtski obliki v granulatu in/ali v tableti. Lahko so samo v farmacevtski obliki za takojšnje sproščanje, lahko samo v plavajoči farmacevtski obliki, lahko pa v obeh.Substances that enhance the absorption of amoxicillin from the gastrointestinal tract may be in floating pharmaceutical form in granulate and / or tablet form. They can only be in immediate release pharmaceutical form, only in floating pharmaceutical form, or both.
Predmet izuma je tudi metoda za zdravljenje bakterijskih okužb, ki obsega odmerjanje amoksicilina in klavulanske kisline v enkratnem dnevnem odmerku, ki je zagotovljen s terapevtskim sistemom, ki obsega vsaj eno farmacevtsko obliko s takojšnjim sproščanjem amoksicilina in klavulanske kisline ter vsaj eno farmacevtsko obliko, ki se zadržuje v želodcu in odloženo ter zadržano sprošča amoksicilin. Tako odmerjanje zagotavlja plazemsko koncentracijo amoksicilina najmanj 7 ur nad 4 pg/mL in najmanj 12 ur nad 1 //g/mL, kar je več kot znaša MIK za večino sevov, ki so občutljivi na kombinacijo amoksicilina in klavulanske kisline.The invention also provides a method for the treatment of bacterial infections comprising the dosing of amoxicillin and clavulanic acid in a single daily dose provided by a therapeutic system comprising at least one immediate-release pharmaceutical formulation of amoxicillin and clavulanic acid and at least one retained in the stomach and delayed and restrained by the release of amoxicillin. Such dosage provides a plasma concentration of amoxicillin for at least 7 hours above 4 pg / mL and at least 12 hours above 1 // g / mL, which is higher than the MIC for most strains sensitive to the combination of amoxicillin and clavulanic acid.
Terapevtski sistem, ki je predmet izuma, t.j. vsaj ena farmacevtska oblika s takojšnjim sproščanjem amoksicilina in klavulanske kisline in vsaj ena farmacevtska oblika, ki se zadržuje v želodcu in omogoča odloženo in zadržano sproščanje amoksicilina in predstavlja enkraten dnevni odmerek, je embaliran v ločenem delu pretisnega omota. Posamezni dnevni odmerki so ločeni s perforacijo pretisnega omota in nedvoumno označeni z zaporednimi dnevi od začetka terapije.The therapeutic system of the invention, i.e. at least one immediate release dosage form of amoxicillin and clavulanic acid, and at least one gastric retention formulation allowing delayed and delayed release of amoxicillin and a single daily dose are packaged in a separate portion of the blister. The individual daily doses are separated by blister perforation and unambiguously labeled consecutive days from the start of therapy.
Izum obsega tudi terapevtski sistem, ki zagotavlja enkraten dnevni odmerek amoksicilina, brez klavulanske kisline, pri čemer del dnevnega odmerka predstavlja vsaj ena farmacevtska oblika s takojšnjim sproščanjem amoksicilina, odloženo in zadržano sproščanje amoksicilina pa zagotavlja vsaj ena farmacevtska oblika, ki se zadržuje v želodcu, prednostno plavajoča kapsula.The invention also includes a therapeutic system providing a single daily dose of amoxicillin, without clavulanic acid, with part of the daily dose being at least one immediate-release formulation of amoxicillin, and delayed and delayed release of amoxicillin provided by at least one gastric-retaining formulation, preferably a floating capsule.
Izum obsega tudi terapevtski sistem, ki ga dajemo dvakrat na dan in s katerim dosežemo plazemske koncentracije amoksicilina, ki so dlje časa nad MIK kot obstoječe farmacevtske oblike za dvakrat dnevno odmerjanje.The invention also includes a twice-a-day therapeutic system to achieve plasma concentrations of amoxicillin, which are longer than the MIC for longer than the existing twice-daily dosage forms.
Zlasti v primeru hujših infekcij lahko terapevtski sistem, ki je predmet izuma, dajemo dvakrat na dan. Primeren enkraten odmerek pri dvakrat dnevnem odmerjanju je naprimer 1600 mg amoksicilina in 125 mg klavulanske kisline. Tako odmerjanje je ugodno glede preprečevanja rezistence bakterij (najmanj 60% intervala odmerjanja nad MIK=4 gg/mL, najmanj 80% intervala odmerjanja nad MIK=2 gg/mL in najmanj 90% intervala odmerjanja nad MIK=1 gg/mL). S to obliko se približamo infuziji, ki je klinično primernejša oblika odmerjanja beta laktamskih antibiotikov kot odmerjanje v intervalih. Tak način odmerjanja nove oblike dvakrat dnevno bi bil primeren v začetku terapije, kar v medicinski terminologiji imenujejo tudi udarni odmerek, ki omogoča hitro doseganje učinkovite koncentracije protimikrobnega zdravila v krvi.Particularly in the case of serious infections, the therapeutic system of the invention may be administered twice daily. A suitable single dose of twice daily dosing is, for example, 1600 mg amoxicillin and 125 mg clavulanic acid. Such dosage is advantageous for the prevention of bacterial resistance (at least 60% of the dosing interval above MIC = 4 gg / mL, at least 80% of the dosing interval above MIK = 2 gg / mL and at least 90% of the dosing interval above MIK = 1 gg / mL). With this form we approach infusion, which is a more clinically appropriate form of beta-lactam antibiotic dosing than interval dosing. Such a twice-daily dosage regimen would be appropriate at the beginning of therapy, also referred to in medical terminology as a stroke dose that allows an effective antimicrobial blood concentration to be achieved rapidly.
Izum pojasnujejo, vendar nikakor ne omejujejo, naslednji izvedbeni primeri:The following embodiments are explained, but by no means limited, by the invention:
Primer 1:Example 1:
Terapevtski sistem z enkratnim dnevnim odmerkom 1600 mg amoksicilina in 125 mg klavulanske kisline (1600/125) zagotovimo z običajno lakirano tableto, ki vsebuje 500 mg amoksicilina v obliki trihidrata in 125 mg klavulanske kisline v obliki kalijevega klavulanata (Amoksiklav® 500/125) ter dvema plavajočima kapsulama s po 550 mg amoksicilina v obliki trihidrata.The single-dose therapeutic system of 1600 mg amoxicillin and 125 mg clavulanic acid (1600/125) is provided with a conventional lacquer tablet containing 500 mg amoxicillin as trihydrate and 125 mg clavulanic acid as potassium clavulanate (Amoxiclav® 500/125), and two floating capsules of 550 mg amoxicillin in the form of trihydrate.
Sestava plavajoče kapsule:Float capsule composition:
Postopek izdelave:Manufacturing process:
Amoksicilin trihidrat, Methocel, Avicel in magnezijev stearat smo homogeno zmešali, da smo pripravili granulat.Amoxicillin trihydrate, Methocel, Avicel and magnesium stearate were mixed homogeneously to prepare the granulate.
Amoksicilin trihidrat, Methocel, Avicel in magnezijev stearat smo homogeno zmešali in tako pripraviljen granulat smo tabletirali v tabletke z maso 180 mg. HPMC E6 smo raztapljali v vodi 45 minut in Surelease suspendirali v raztopini HPMC ob stalnem mešanju 10 minut, da smo dobili 10% suspenzijo. Suspenzijo smo razprševali na telesa HPMC kapsul v perforiranem bobnu za oblaganje pri temperaturi 40°C, da smo dobili ustrezen nanos obloge.Amoxicillin trihydrate, Methocel, Avicel and magnesium stearate were mixed homogeneously and the granulate thus prepared was tableted into 180 mg tablets. HPMC E6 was dissolved in water for 45 minutes and the Surelease suspended in HPMC solution with constant stirring for 10 minutes to give a 10% suspension. The suspension was sprayed onto the bodies of the HPMC capsules in a perforated coating drum at 40 ° C to obtain a suitable coating of the coating.
V obložena telesa kapsul smo napolnili 560 mg granulata in tabletko ter zaprli z neobloženo kapico kapsule.Filled 560 mg granules and a pill into the coated body of the capsule and closed with an uncoated capsule cap.
Primer 2:Example 2:
Terapevtski sistem z enkratnim dnevnim odmerkom 2000 mg amoksicilina in 125 mg klavulanske kisline (2000/125) zagotovimo z lakirano tableto Amoksiklav® 500/125 in tremi plavajočimi kapsulami s po 500 mg amoksicilinaThe single-dose therapeutic system of 2000 mg amoxicillin and 125 mg clavulanic acid (2000/125) is provided with an Amoxiclav® 500/125 lacquered tablet and three 500 mg amoxicillin floating capsules.
Sestava plavajoče kapsule:Float capsule composition:
Postopek izdelave:Manufacturing process:
Amoksicilin trihidrat, Methocel, Avicel in magnezijev stearat smo homogeno zmešali, da smo pripravili granulat.Amoxicillin trihydrate, Methocel, Avicel and magnesium stearate were mixed homogeneously to prepare the granulate.
Amoksicilin trihidrat, Methocel, Avicel in magnezijev stearat smo homogeno zmešali in tako pripravljen granulat smo tabletirali v tabletke z maso 180 mg.Amoxicillin trihydrate, Methocel, Avicel and magnesium stearate were mixed homogeneously and the granulate thus prepared was tableted into 180 mg tablets.
HPMC E6 smo raztapljali v vodi 45 minut in Surelease suspendirali v raztopini HPMC ob stalnem mešanju 10 minut, da smo dobili 10% suspenzijo. Suspenzijo smo razprševali na telesa HPMC kapsul v perforiranem bobnu za oblaganje pri temperaturi 40 °C, da smo dobili ustrezen nanos obloge.HPMC E6 was dissolved in water for 45 minutes and the Surelease suspended in HPMC solution with constant stirring for 10 minutes to give a 10% suspension. The suspension was sprayed onto the bodies of the HPMC capsules in a perforated coating drum at 40 ° C to obtain a suitable coating of the coating.
V obložena telesa kapsul smo napolnili 560 mg granulata in tabletko ter zaprli z neobloženo kapico kapsule.Filled 560 mg granules and a pill into the coated body of the capsule and closed with an uncoated capsule cap.
Primer 3:Example 3:
Opis farmakokinetične študije za terapevtski sistem 1600/125 mg:Description of the pharmacokinetic study for the 1600/125 mg therapeutic system:
Študija je bila izvedena na 12-tih zdravih prostovoljcih moškega spola, starosti 1845 let, s telesno težo v območju ±10% idealne telesne teže. Potekala je po navzkrižnem načrtu z enkratnim odmerkom zdravila v pogojih s hrano. Prostovoljci so prejeli v prvi periodi zdravilo Amoksiklav® tableto 500mg/125mg s hitrim sproščanjem in v drugi periodi terapevtski sistem za enkrat dnevno odmerjanje 1600mg/125mg (1 tableta Amoksiklav® 500mg/125mgin 2 plavajoči kapsuli s po 550 mg amoksicilina). Doba izpiranja med dvema periodama je bila 7 dni. Časi odvzemov krvnih vzorcev so bili: pred aplikacijo zdravila nato pa 0,25, 0,5, 0,75, 1, 1,25, 1,5, 1,75, 2, 2,5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 in 24 ur po aplikaciji zdravila, to je 22 vzorcev na prostovoljca na periodo.The study was conducted on 12 healthy male volunteers, aged 1845, with a body weight in the range of ± 10% of ideal body weight. It was a cross-sectional design of a single dose of the drug under food conditions. In the first period, volunteers received Amoxiclav® 500mg / 125mg rapid-release tablet in the first period and 1600mg / 125mg once-daily therapeutic system (1 Amoxiclav® 500mg / 125mg tablet 2 550 mg amoxicillin floating capsules) in the second period. The rinsing period between the two periods was 7 days. Blood sampling times were: before drug administration, then 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, respectively. 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours after drug administration, that is 22 samples per volunteer per period.
V plazmi smo določili koncentracijo amoksicilina in klavulanske kisline. S primerjavo plazemskih koncentracijskih profilov amoksicilina obeh zdravil smo lahko določili prispevek plavajočih kapsul v terapevtskem sistemu za enkrat dnevno odmerjanje. Opazili smo bimodalno plazemsko koncentracijsko krivuljo amoksicilina po aplikaciji terapevtskega sistema za enkrat dnevno odmerjanje 1600mg/125mg.Plasma concentrations of amoxicillin and clavulanic acid were determined. By comparing the plasma concentration profiles of amoxicillin of the two drugs, we were able to determine the contribution of floating capsules to the once daily single dose therapeutic system. A bimodal plasma concentration curve of amoxicillin was observed following the administration of a once daily dosing system of 1600mg / 125mg.
S študijo smo za amoksicilin določili čas nad MIK=1 pg/mL in čas nad MIK=4 pg/mL za terapevtski sistem za enkrat dnevno odmerjanje amoksicilina in klavulanske kisline 1600mg/125mg.The study determined for amoxicillin a time above MIK = 1 pg / mL and a time above MIK = 4 pg / mL for a once daily dosing system of amoxicillin and clavulanic acid 1600mg / 125mg.
Rezultati študije so:The results of the study are:
čas nad MIK=1 pg/mL: 12,5h, čas nad MIK=4 pg/mL: 7,88h, kar pomeni 52,1% (za MIK=1pg/mL) in 32,8% (za MIK=4 pg/mL ) 24- urnega intervala odmerjanja zdravila. Glede klavulanske kisline sta obe zdravili bioekvivalentni.time above MIK = 1 pg / mL: 12.5h, time above MIK = 4 pg / mL: 7.88h, representing 52.1% (for MIK = 1pg / mL) and 32.8% (for MIK = 4 pg / mL) for a 24-hour dosing interval. In terms of clavulanic acid, both drugs are bioequivalent.
Claims (44)
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI200300245A SI21601A (en) | 2003-09-24 | 2003-09-24 | Therapeutic system |
EP04713281A EP1596841B1 (en) | 2003-02-21 | 2004-02-20 | Therapeutic system comprising amoxicillin and clavulanic acid |
SI200430999T SI1596841T1 (en) | 2003-02-21 | 2004-02-20 | Therapeutic system comprising amoxicillin and clavulanic acid |
US10/545,111 US20060121106A1 (en) | 2003-02-21 | 2004-02-20 | Therapeutic system comprising amoxicillin and clavulanic acid |
DE602004016963T DE602004016963D1 (en) | 2003-02-21 | 2004-02-20 | Therapeutisches system mit amoxicillin und clavulansäure |
CA2516327A CA2516327C (en) | 2003-02-21 | 2004-02-20 | Therapeutic system comprising amoxicillin and clavulanic acid |
AT04713281T ATE410152T1 (en) | 2003-02-21 | 2004-02-20 | THERAPEUTIC SYSTEM WITH AMOXICILLIN AND CLAVULANIC ACID |
PL377683A PL213804B1 (en) | 2003-02-21 | 2004-02-20 | Therapeutic system comprising amoxicillin and clavulanic acid |
BR0407438-6A BRPI0407438A (en) | 2003-02-21 | 2004-02-20 | Therapeutic system comprising amoxicillin and clavulanic acid |
EA200501223A EA011215B1 (en) | 2003-02-21 | 2004-02-20 | Therapeutic system comprising amoxicillin and clavulanic acid |
PCT/SI2004/000010 WO2004073695A1 (en) | 2003-02-21 | 2004-02-20 | Therapeutic system comprising amoxicillin and clavulanic acid |
MXPA05008843A MXPA05008843A (en) | 2003-02-21 | 2004-02-20 | Therapeutic system comprising amoxicillin and clavulanic acid. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI200300245A SI21601A (en) | 2003-09-24 | 2003-09-24 | Therapeutic system |
Publications (1)
Publication Number | Publication Date |
---|---|
SI21601A true SI21601A (en) | 2005-04-30 |
Family
ID=34511417
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SI200300245A SI21601A (en) | 2003-02-21 | 2003-09-24 | Therapeutic system |
Country Status (1)
Country | Link |
---|---|
SI (1) | SI21601A (en) |
-
2003
- 2003-09-24 SI SI200300245A patent/SI21601A/en not_active IP Right Cessation
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2595033C (en) | Gastroresistant pharmaceutical formulations containing rifaximin | |
KR100270491B1 (en) | Improved pulsatile once-a-day delivery systems for minocycline | |
JP3140764B2 (en) | Pulsatile once-daily release system of minocycline | |
CA2717456A1 (en) | Modified release pharmaceutical compositions comprising mycophenolate and processes thereof | |
CA2740146A1 (en) | Immediate release dosage forms of sodium oxybate | |
KR20080059409A (en) | Pharmaceutical dosage forms having immediate release and/or controlled release properties | |
JP2006522162A (en) | Tetracycline once a day formulation | |
AU2017328245B2 (en) | Extended release pharmaceutical composition of Clozapine | |
KR100531065B1 (en) | Medicament Formulation with a Controlled Release of an Active Agent | |
US20040033262A1 (en) | Sustained release pharmaceutical composition of a cephalosporin antibiotic | |
GB2414668A (en) | Sustained release delivery system for tetracycline compounds | |
WO1994004135A1 (en) | Oral preparation for release in lower digestive tracts | |
MXPA04007894A (en) | Colonic release composition. | |
CA2516327C (en) | Therapeutic system comprising amoxicillin and clavulanic acid | |
EP1216032B1 (en) | Oral controlled release formulations | |
KR20090086128A (en) | Pharmaceutical composition of memantine | |
JP3122478B2 (en) | Lower gastrointestinal release oral formulation | |
SI21601A (en) | Therapeutic system | |
SI21401A (en) | Therapeutic system | |
US20040096496A1 (en) | Sustained release pharmaceutical composition of a cephalosporin antibiotic | |
WO2023089553A1 (en) | Controlled release formulations of flavoxate and process for preparation thereof | |
NO177553B (en) | Process for the preparation of a pharmaceutical dosing system | |
NO177554B (en) | Process for the preparation of a multi-coated composition comprising a pharmaceutical dosing system |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
OO00 | Grant of patent |
Effective date: 20041005 |
|
KO00 | Lapse of patent |
Effective date: 20130429 |