SI9300330A - Peroral preparation for gastric antibacterial treatement, process for the preparation thereof and use - Google Patents

Peroral preparation for gastric antibacterial treatement, process for the preparation thereof and use Download PDF

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SI9300330A
SI9300330A SI9300330A SI9300330A SI9300330A SI 9300330 A SI9300330 A SI 9300330A SI 9300330 A SI9300330 A SI 9300330A SI 9300330 A SI9300330 A SI 9300330A SI 9300330 A SI9300330 A SI 9300330A
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formulation
active
infections
gastrointestinal tract
stomach
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Karl-Erik Lennart Falk
John Albert Sjoegren
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Astra Ab
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Abstract

An oral formulation with extended release for treatment of infections in the upper gastrointestinal tract as well as processes for the preparation and the use thereof.

Description

PERORALNA FORMULACIJA ZA ŽELODČNO PROTIBAKTERIJSKO TERAPIJO, POSTOPEK IZDELAVE IN UPORABAOral formulation for gastric antibacterial therapy, manufacturing process and administration

Tehnično področjeTechnical area

Izum se nanaša na formulacijo za zdravljenje infekcij zgornjega predela gastrointestinalnega trakta, posebaj infekcij, ki jih povzroča Helicobacter pylori, in na postopek izdelave omenjenih formulacij, kot tudi njihovo uporabo.The invention relates to a formulation for the treatment of upper gastrointestinal tract infections, in particular infections caused by Helicobacter pylori, and to the method of making said formulations, as well as their use.

Omenjene formulacije imajo podaljšano sproščanje protimikrobne(ih) učinkovin(e) v zgornjem predelu gastrointestinalnega trakta.These formulations have a sustained release of the antimicrobial active ingredient (s) in the upper gastrointestinal tract.

Osnove iznmaThe basics of it

Helicobacter pylori (H. pylori) je pred nedavnim odkrita bakterija, ki so jo prvič vzgojili v kulturi v Avstraliji, leta 1982 (Warren JR Lancet 1983; 1: str. 1273), in je vzbudila veliko zanimanje, zaradi njene verjetne etiološke vloge v številnih motnjah v zgornjem predelu gastrointestinalnega trakta. Imajo ga za glavnega povzročitelja pri razvoju peptičnega ulkusa (Helicobacter pylori, Poročilo z delovnega srečanja. Svetovni kongres o gastroenterologiji, Sydney 1990). H. pylori naj bi bil etiološki povzročitelj v večini primerov kroničnega nespecifičnega gastritisa. Kronično aktivni gastritis je močno povezan z infekcijami H. pylorL Organizem so našli v povezavi s kroničnim aktivnim gastritisom v skoraj 100% primerov. Nadalje, na podlagi kontrolirane študije na 372 pacientih zaključujejo, da je infekcija s H. pylori povezana s povečanim tveganjem za želodčni adenokarcinom in je mogoče kofaktor v patogenzi teh malignih obolenj (Parsonnet J., Friedman G.D., Daniel M.S. et al. N. Engl. J. Med. 1991; 325: str. 112731).Helicobacter pylori (H. pylori) was a recently discovered bacterium that was first grown in culture in Australia in 1982 (Warren JR Lancet 1983; 1: p. 1273), and has attracted considerable interest due to its likely etiological role in many disorders of the upper gastrointestinal tract. They regard it as a major agent in the development of peptic ulcer (Helicobacter pylori, Work Meeting Report. World Congress on Gastroenterology, Sydney 1990). H. pylori is thought to be the etiologic agent in most cases of chronic nonspecific gastritis. Chronically active gastritis is strongly associated with H. pylorL infections The organism was found in association with chronic active gastritis in almost 100% of cases. Furthermore, a controlled study of 372 patients concluded that H. pylori infection was associated with an increased risk of gastric adenocarcinoma and may be a cofactor in the pathogenesis of these malignancies (Parsonnet J., Friedman G. D., Daniel M. S., et al. N. Engl. J. Med. 1991; 325: 112731).

Natančen patogenetski mehanizem H. pylori še ni poznan. Enako je neznana pot njegovega prenosa, smatrajo pa, da se prenaša po poti fecesusta in verjetno preko vode. H. pylori najdemo po vsem svetu, seveda je pogostejši v manj razvitih državah in v zahodnih državah, pri pacientih z nižjim ekonomskim standardom. Celotna razširjenost v zahodnih državah je približno 52% in se povečuje z leti.The exact pathogenetic mechanism of H. pylori is not yet known. Equally unknown is the route of its transmission, but it is thought to be transmitted by the faeces route and probably via water. H. pylori is found worldwide, of course, it is more common in less developed countries and western countries, with patients of lower economic standard. The overall prevalence in western countries is approximately 52% and has increased over the years.

H. pylori je Gram-negativna mikroaerofilna bakterija, ki meri v dolžino približno 3,5 pg in ima premer 1 pm. Zaradi prisotnosti 4-6 bičkov na koncu njegove tipično S-aste ali spiralne oblike se bakterija v mukusu (sluznici) lahko zelo hitro giblje. Živi tesno pritrjen na celice želodčnega epitela med plastjo sluznice in kolonizira v želodcu, pretežno v antrumu.H. pylori is a Gram-negative microaerophilic bacterium that measures approximately 3.5 pg in length and has a diameter of 1 pm. Due to the presence of 4-6 whiskers at the end of its typically S-aste or helical shape, the bacterium in the mucus (mucosa) can move very quickly. It lives tightly attached to the cells of the gastric epithelium between the mucosal layer and colonizes in the stomach, predominantly in the antrum.

In vitro študije kažajo na visoko občutljivost H. pylori na številne antibiotike (McNulty C.A., Dent J.C., Eur.J. Ciin. Microbiol. Infect. Dis. 1988; 7: str. 566-569), (Lambert T., Megraud F., Gerbaud G. et al. Antimicrob. Agents Chemother. 1986; 30: str. 510-511). Vendar so in vivo študije pokazale, da je povezava, med in vitro občutljivostjo H. pylori in rezultati zdravljenja in vivo, za protibakterijske učinkovine majhna. Režim uničevanja, s katerim danes dobimo boljše rezultate (odstranitev H. pylori pri 80-90% zdravljenih bolnikov) je trojna terpija (Axon A.T.R. Scand. J. GastroenteroL 1989; 24 (priloga 160): str. 35-38). Terapija je kombinacija bizmutovega pripravka, metronidazola in amoksicilina ali tetraciklina. Vendar režim doziranja zahteva več tablet, ki jih moramo aplicirati večkrat dnevno. To je za pacienta težavno in izkazalo se je, da je za dosego visoke stopnje odstranitve mikroba sodelovanje bolnika zelo pomembno. Pogosti so stranski učinki, pretežno, zaradi metronidazola ali bizmuta. Približno 30% bolnikov je poročalo o stranskih učinkih (Axon ATR, Scand. J. GastroenteroL 1989; 24: (priloga 160): 35-38).In vitro studies indicate a high sensitivity of H. pylori to many antibiotics (McNulty CA, Dent JC, Eur.J. Ciin. Microbiol. Infect. Dis. 1988; 7: pp. 566-569), (Lambert T., Megraud F. ., Gerbaud G. et al. Antimicrob. Agents Chemother. 1986; 30: pp. 510-511). However, in vivo studies have shown that there is little association between the in vitro susceptibility of H. pylori and the results of in vivo treatment for antibacterial agents. The destructive regimen for better results today (removal of H. pylori in 80-90% of treated patients) is triple therapy (Axon A.T.R. Scand. J. GastroenteroL 1989; 24 (annex 160): pp. 35-38). Therapy is a combination of bismuth preparation, metronidazole and amoxicillin or tetracycline. However, the dosage regimen requires several tablets, which must be administered several times a day. This is difficult for the patient and has proven to be very important to achieve a high level of microbial removal. Side effects, mostly due to metronidazole or bismuth, are common. Approximately 30% of patients reported side effects (Axon ATR, Scand. J. GastroenteroL 1989; 24: (supplement 160): 35-38).

Monoterapija z različnimi antibiotiki, za katere je poznano, da so in vitro zelo učinkoviti proti H. pylori, je premalo učinkovita in vivo. Amoksicilin, na primer, uniči H. pylori peroralno le pri približno 20% zdravljenih bolnikov. Kombinacija dveh učinkovin je v večji meri uniči bakterije, kot monoterapija. Bizmutovi preparati (bizmutov subsalicilat ali koloidni bizmutov subcitrat) v kombinaciji z amoksicilinom uničijo H. pylori pri 44% zdravljenih bolnikov, bizmut + metronidazol, amoksicilin + tinidazol in amoksicilin + metronidazol pri približno 55% bolnikih (Chiba N., Rademaker J.W, Rao B.V et al. Gut 1991; 32: str. A1220-1221, (izvleček)).Monotherapy with various antibiotics known to be highly effective against H. pylori in vitro is not effective enough in vivo. Amoxicillin, for example, destroys H. pylori orally in only about 20% of treated patients. The combination of the two active ingredients is more likely to destroy bacteria than monotherapy. Bismuth preparations (bismuth subsalicylate or colloidal bismuth subcitrate) in combination with amoxicillin destroy H. pylori in 44% of treated patients, bismuth + metronidazole, amoxicillin + tinidazole, and amoxicillin + metronidazole in approximately 55% of patients (Chiba N., Radaker W., Rad. W.W. et al. Gut 1991; 32: pp. A1220-1221, (abstract).

Protibakterijske učinkovine so kombinirali tudi z zaviralci izločanja kisline. Kombinacije s histami^-blokatorji ne kažejo izboljšanja. Zaviralci protonske črpalke, npr. omeprazol, ki ima sam zelo majhen učinek na H. pylori kaže sinergistični učinek v kombinaciji z antibiotiki. Poročajo, da 750 mg doza amoksicilina 2-krat dnevno skupaj s 40 mg omeprazola 1-krat dnevno, odstrani H. pylori pri 54% pacientov (Unge P., Eriksson K., Bergman B. et al. Gastroenterol. 1992; 102(4); str. A183 (izvleček)). Iz razpoložljivih informacij, ne razberemo razlage za sinergistični učinek.The antibacterial agents were also combined with acid secretion inhibitors. Combinations with histami ^ -blockers show no improvement. Proton pump inhibitors, e.g. omeprazole, which itself has a very small effect on H. pylori, shows a synergistic effect when combined with antibiotics. A 750 mg dose of amoxicillin twice daily, together with 40 mg omeprazole once daily, has been reported to remove H. pylori in 54% of patients (Unge P., Eriksson K., Bergman B. et al. Gastroenterol. 1992; 102 ( 4); pp. A183 (abstract)). From the information available, we do not understand the synergistic effect.

Veliko antibiotikov ima relativno kratkotrajno delovanje in jih apliciramo 34-krat dnevno. Poiskusi, da bi podaljšali delovanje z uporabo pripravkov s podaljšanim sproščanjem, so bili na splošno neuspešni, zaradi slabe absorpcije antibiotika iz gastrointestinahiega trakta, po aplikaciji pripravkov s počasnim sproščanjem (Delgado Charro M.B., Vila Jato J.L. Int. J. Pharm. 1992; 78; 35; str. 35-41). Namesto tega, antibiotike aplicirajo v zdravilnem pripravku s hitro absorpcijo, npr. tablete ali kapsule. Da bi dosegli dovolj dolgo delovanje, so doze višje.Many antibiotics have a relatively short duration of action and are administered 34 times a day. Attempts to prolong the use of sustained-release preparations have generally been unsuccessful due to poor absorption of the antibiotic from the gastrointestinal tract following administration of slow-release preparations (Delgado Charro MB, Vila Jato JL Int. J. Pharm. 1992; 78 ; 35; pp. 35-41). Instead, antibiotics are administered in a fast-absorbing drug preparation, e.g. tablets or capsules. In order to achieve long enough duration, doses are higher.

V vseh predhodnih študijah za uničenje H. pylori so bile uporabljene zdravilne oblike, iz katerih se se protibakterijse učinkovine hitro sprostile, poskušali so tudi povečati stopnjo učinkovitosti z uporabo zelo visokih doz protibakterijsldh učinkovin, kot tudi zaviralcev protonske črpalke. Na primer, pri 82% zdravljenih bolnikov so uničili bakterijo z 10 dnevno terapijo s 40 mg omeprazola 2-krat dnevno v kombinaciji z 1 g amoksicilina 2-krat dnevno, temu je sledila 6 tedenska monoterapija z 20 mg omeprazola 1krat dnevno. (Bayerdorffer E., Mannes G.A., Sommer A. et al. Gastroenterol. 1992; 102(4); A38 (izvleček)).In all previous studies to destroy H. pylori, medicinal forms were used to release the antibacterial agents rapidly, and to increase the efficacy by using very high doses of antibacterial agents as well as proton pump inhibitors. For example, in 82% of treated patients, the bacterium was destroyed by 10 days of 40 mg omeprazole twice daily in combination with 1 g amoxicillin twice daily followed by 6 weeks monotherapy with 20 mg omeprazole once daily. (Bayerdorffer E., Mannes G.A., Sommer A. et al. Gastroenterol. 1992; 102 (4); A38 (abstract)).

Opis izumaDescription of the invention

Ugotovili smo, da se učinkovitost zdravljenja lahko izboljša na popolnoma drugačen način, z aplikacijo protibakterijskih učinkovin v formulaciji s podaljšanim delovanjem in aplikacijo formulacije na tak način, da ostane v želodcu več ur. Ni še znano, ali so bakterije H. pylori dovzetne za zdravljenje s protibakterijskimi učinkovinami v želodcu ah se mora učinkovina absorbirati in doseči bakterije preko krvnega obtoka. Izboljšan učinek pripravka, označenegaa s tem, da se zanjo zahteva patentna zaščita, kaže na to, da je pomemben lokalen učinek v želodcu.We have found that the effectiveness of treatment can be improved in a completely different way, by administering antibacterial agents in a sustained-release formulation and applying the formulation in such a way that it remains in the stomach for several hours. It is not yet known whether H. pylori is susceptible to treatment with antibacterial agents in the stomach, ah the substance should be absorbed and reach the bacteria through the bloodstream. The improved effect of the preparation, characterized in that it requires patent protection, indicates that it is a significant local effect in the stomach.

Primeri formulacij, s podaljšanim čas zadrževanja v želodcu so bioadhezivni sistemi, ki delujejo preko interakcije s sluznico ali sluzjo. Drugi način za podaljšanje zaostajanja v želodcu so sistemi, ki nabrekajo in v stiku z želodčno tekočino povečajo svoj volumen na velikost, ki sistemu preprečuje prehod skozi pilorus. Nadaljni primeri so pripravki z visoko gostoto ali sistemi, ki lebdijo na želodčni vsebini. Opazili so, da velike tablete, ki se ne razgradijo, ali kapsule lahko ostanejo v želodcu več ur. Čas zadrževanja v želodcu je podaljšan še posebaj v primeru, ko se tableta ali kapsula aplicira skupaj s hrano, zaradi sejalne vloge pilorusa, ko je želodec v fazi prebave. (Davis S.S, Hardy J.G., Taylor M.J. et al. Int. J. Pharm. 1984; 21: str. 331-340). Hrana istočasno zadržuje izločanje tablet ali pelet, vendar je učinek manj izražen. V literaturi lahko zasledimo, da je kritična velikost 7 mm (Khosla R. Nottingham: University of Nottingham, >987 (Diss)).Examples of formulations with prolonged residence time in the stomach are bioadhesive systems that interact via mucosal or mucous membranes. Another way to prolong the lag in the stomach is by swelling and in contact with the gastric fluid to increase its volume to a size that prevents the system from passing through the pylorus. Further examples are high density preparations or systems floating on gastric contents. It has been observed that large tablets that do not break down or capsules can remain in the stomach for hours. The residence time in the stomach is especially extended when the tablet or capsule is given with food, due to the sowing role of the pylorus when the stomach is in the digestive phase. (Davis S.S., Hardy J.G., Taylor M.J. et al. Int. J. Pharm. 1984; 21: pp. 331-340). At the same time, food retains the secretion of tablets or pellets, but the effect is less pronounced. We can see in the literature that the critical size is 7 mm (Khosla R. Nottingham: University of Nottingham,> 987 (Diss)).

Učinkovina naj bi se sprostila v 1-24 urah, najbolj zaželeno v 1-6 urah. Da bi dosegli učinkovito zdravljenje infekcij s H. pylori, mora pripravek ostati v želodcu najmanj 2-4 ure, najbolje dlje kot 6 ur. Pretežni del učinkovine se mora sprostiti preden tablete zapustijo želodec. Učinkovine, primerne za pripravke, ki se nanašajo na izum, so npr. ampicllin, amoksicilin, benzilpenicilin, fenoksimetilpenicilin, bakampicilin, pivampicilin, karbenicilin, kloksacilin, ciklacilin, dikloksacilin, meticilin, oksacilin, piperacilin, tikarcilin, fluldoksacilin, cefuroksim, cefetamet, cefetram, cefiksim, cefoksitin, ceftazidim, ceftizoksim, latamoksef, cefoperazon, ceftriaksom, cefsulodin, cefotaksim, cefaleksin, cefaklor, cefadroksil, cefalotin, cefazolin, cefpodoksim, ceftibuten, aztreonam, tigemonam, eritromicin, diritromicin, roksitromicin, azitromicin, klaritromicin, klindamicin, paldimicin, linkomicin, vankomicin, spektinomicin, tobramicin, paromomicin, metronidazol, tinidazol, ornidazol, amifloksacin, cinoksacin, ciprofloksacin, difloksacin, enoksacin, fleroksacin, norfloksacin, ofloksacin, temafloksacin, doksiciklin, minociklin, tetraciklin, klortetraciklin, oksitetraciklin, metacildin, rolitetraciklin, nitrofurantoin, nalidiksinska kislina, gentamicin, rifampicin, amikacin, netilmicin, imipenem, cilastatin, kloramfenikol, furazolidon, nifuroksazid, sulfadiazin, sulfametoksazol, bizmutov subsalicilat, koloidni bizmutov subcitrat, gramicidin, mecilinam, kloksikinin, klorheksidin, diklorobenzilni alkohol, metil2-pentilfenol. Aktivne učinkovine so lahko v standardni obliki ali uporabljene kot soli, hidrati, estri itd. Bolj zaželena je kombinacija dveh ali več zgoraj navedenih učinkovin, na primer, da se zmanjša možnost nastanka rezistence. Protimikrobne učinkovine se lahko kombinirajo z drugimi učimkovinami, ki se uporabljajo za zdravljenje obolenj, ki jih povzroča kislina, na primer zaviralci želodčne črpalke ali 1¾ blokatorji, kot je, na primer, omeprazol.The active substance is expected to be released within 1-24 hours, most preferably within 1-6 hours. In order to achieve effective treatment for H. pylori infections, the preparation should remain in the stomach for at least 2-4 hours, preferably longer than 6 hours. Most of the active substance should be released before the tablets leave the stomach. The active ingredients suitable for the compositions of the invention are e.g. ampicllin, amoxicillin, benzylpenicillin, phenoxymethylpenicillin, bacampicillin, pivampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, methicillin, oxacillin, piperacillin, ticarcillin, fluldoksacilin, cefuroxime, cefetamet, CEFETRA, cefixime, cefoxitin, ceftazidime, ceftizoxime, latamoxef, cefoperazone, ceftriaksom, cefotaxime, cefotaxime, cefacelin, cefazolin, cefepolecin, cefibroxin, cefotoxin ornidazole, amifloxacin, cynoxacin, ciprofloxacin, difloxacin, enoxacin, fleroxacin, ofloxacin, temafloxacin, doxycycline, minocycline, tetracycline, oxytiricline, oxytiricline, metacildin , chloramphenicol, furazole idon, nifuroxazide, sulfadiazine, sulfamethoxazole, bismuth subsalicylate, colloidal bismuth subcitrate, gramicidin, mecillinam, cloxyquinine, chlorhexidine, dichlorobenzyl alcohol, methyl 2-pentylphenol. The active substances may be in the standard form or used as salts, hydrates, esters, etc. A combination of two or more of the abovementioned ingredients is desirable, for example, to reduce the possibility of resistance. Antimicrobial agents may be combined with other substances used to treat acid-induced diseases, such as gastric pump inhibitors or 1¾ blockers, such as omeprazole.

Formulacije, ki naj bi se uporabljale, so velike nerazgradljive tablete ali kapsule, npr. inertne matriks tablete (Hui H., Robinson J.R., Lee V.H.L. Oblikovanje in proizvodnja oralnih sistemov s kontroliranim sproščanjem, v Robinson J.R., Lee V.H.L. urednika Controlled Drug Delivery. Fundamentals and applications. New York: Marcel Dekker, Inc, 1987: 373432), ozmotske črpalke (Davis S.S., Fara J.W. Osmotske črpalke. V Hardy J.G., Davis S.S., Wilson C.G., uredniki Drug Delivery to the Gastrointestinal Tract. Chichster: Ellis Horwood Limited, 1989: str. 97-109) in z membrano obložene tablete. Naprej, sistemi, ki nabrekajo (Banker, US Patent + No. 261,242), lebdeči sistemi (Davis S,S, Stockwell AF, Taylor M.J et al. Pharm. Res., 1986; 3: str. 208-213), (Washington N., WilsonThe formulations to be used are large non-degradable tablets or capsules, e.g. inert matrix tablets (Hui H., Robinson JR, Lee VHL Design and production of controlled release oral systems, in Robinson JR, Lee VHL of Controlled Drug Delivery. Fundamentals and applications. New York: Marcel Dekker, Inc., 1987: 373432), osmotic pumps (Davis SS, Fara JW Osmotic pumps. In Hardy JG, Davis SS, Wilson CG, editors Drug Delivery to the Gastrointestinal Tract. Chichster: Ellis Horwood Limited, 1989: pp. 97-109) and membrane-coated tablets. Forward, swelling systems (Banker, US Patent + No. 261,242), hovering systems (Davis S, S, Stockwell AF, Taylor MJ et al. Pharm. Res., 1986; 3: pp. 208-213), ( Washington N., Wilson

C.G., Greaves J.L. et aLScand. J. GastroenteroL 1988; 23: str. 920-924). formulacije z visoko gostoto (Devereux J.E., Newton J.M., Short M.B., J. Pharm. Pharmacol., 1990; 42: str. 500-501) in mukoadhezivni sistemi (Junginger H.E, Pharm. Ind. 1991; 53: str. 1056-1065) pripravljeni iz, na primer, polikarbofila, poliakrilne kisline, metilceluloze, polietilenoksida, hitosana, tragakanta, natrijeve karboksimetilceluloze.C.G., Greaves J.L. et aLScand. J. GastroenteroL 1988; 23: p. 920-924). high-density formulations (Devereux JE, Newton JM, Short MB, J. Pharm. Pharmacol., 1990; 42: pp. 500-501) and mucoadhesive systems (Junginger HE, Pharm. Ind. 1991; 53: pp. 1056- 1065) prepared from, for example, polycarbophil, polyacrylic acid, methylcellulose, polyethylene oxide, chitosan, tragacanth, sodium carboxymethylcellulose.

Primer, iz zgoraj navedenih formulacij, je inertna porozna matriks tableta, ki jo dobimo z mešanjem učinkovine z voski ah v vodi netopnimi polimeri in s polnih in vezalci. Za zadrževanje difuzije se lahko uporabijo: parafin, polivinilklorid, etilceluloza, stearinska kislina, cetilni alkohol, karnauba vosek, polietilen, polivinil acetat, polimetil metakrilat. Drugi ekscipienti, uporabljeni za izdelavo takih tablet so, na primer, laktoza, manitol, kalcijev fosfat, magnezijev stearat, hidroksipropilmetilceluloza, metilceluloza, polivinilpirolidon, aluminijev silikat, natrijev karbonat, kalijev fosfat ali drugi ustrezni materiali.An example, from the above formulations, is an inert porous matrix tablet, which is obtained by mixing the active ingredient with waxes that are water-insoluble polymers and full and binders. The following may be used to retain diffusion: paraffin, polyvinyl chloride, ethylcellulose, stearic acid, cetyl alcohol, carnauba wax, polyethylene, polyvinyl acetate, polymethyl methacrylate. Other excipients used to make such tablets are, for example, lactose, mannitol, calcium phosphate, magnesium stearate, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, aluminum silicate, sodium carbonate, potassium phosphate or other suitable materials.

Primeri:Examples:

Namen predloženega izuma je zagotoviti pripravke s povečanim obsegom sproščanja, s podaljšanim časom zadrževanja v želodcu po peroralni aplikaciji, in vsebujejo eno ali več protimikrobnih učinkovin.The purpose of the present invention is to provide increased release formulations, prolonged gastric residence time after oral administration, and containing one or more antimicrobial agents.

Primer 1:Example 1:

Amoksicilin natrij Amoxicillin sodium 830 830 g Mr Rücker Parafin Paraffin 500 500 g Mr Rücker Etilceluloza Ethylcellulose 60 60 g Mr Rücker Magnezijev stearat Magnesium stearate 28.8 28.8 g Mr Rücker

Amoksicilin natrij smo mešali v planetarnem mešalcu 5 minut skupaj s parafinom. Dobljeno zmes smo nato 5 minut vlažili z raztopino etflceluloze in izopropanola in sušili. Granulat smo presejali skozi 1.0 nm sito in 2 minuti izboljševali drsljivost z magnezijevim stearatom.Amoxicillin sodium was stirred in a planetary mixer for 5 minutes with paraffin. The resulting mixture was then moistened with a solution of ethylcellulose and isopropanol for 5 minutes and dried. The granulate was sieved through a 1.0 nm sieve and the glide was improved with magnesium stearate for 2 minutes.

Granulat smo stisnili v tablete na tabletirki, katere pečati so imeli premer 13 mm. Vsaka tableta je vsebovala 415 mg amoksicilina v obliki natrijeve soli. Profil sproščanja je prikazan na sliki 1.The granulate was pressed into tablets on a tablet whose seals were 13 mm in diameter. Each tablet contained 415 mg of amoxicillin as sodium salt. The release profile is shown in Figure 1.

Primer 2:Example 2:

Amoksicilin trihidrat 215.6 gAmoxicillin trihydrate 215.6 g

Parafin 250 gParaffin 250 g

Natrijev karbonat 209 gSodium carbonate 209 g

Etilceluloza 30 gEthylcellulose 30 g

Magnezijev stearat 14.1 gMagnesium stearate 14.1 g

Sestavine, ki so navedene v Primeru 2 smo oblikovali v tableto z modificiranim sproščanjem, in vsebuje 375 mg amoksicilina na tableto. Tableto smo pripravili na sledeč način:The ingredients listed in Example 2 were formulated into a modified-release tablet containing 375 mg amoxicillin per tablet. The tablet was prepared as follows:

amoksicilin. trihidrat, parafin in natrijev karbonat smo mešali 5 minut v planetarnem mečalcu. Nadalje je postopek enak, kot v Primeru 1. Profil sproščanja učinkovine je prikazan na sliki 2.amoxicillin. the trihydrate, paraffin and sodium carbonate were stirred for 5 minutes in a planetary sword. Further, the procedure is the same as in Example 1. The release profile of the active substance is shown in Figure 2.

Primer 3:Example 3:

Amoksicilin trihidrat Amoxicillin trihydrate 215 215 Trinatrijev fosfat Trisodium phosphate 209 209 Polivinilpirolidon Polyvinylpyrrolidone 20 20 Magnezijev stearat Magnesium stearate 20 20

Po granultranju smo zmes stisnili v tablete in sušili, kot v Primeru 1. Tablete smo oblagali s porozno membransko prevleko, ki je vsebovala polivinilklorid v acetonu, tako kot (Kallstrand G., Ekman B., J. Pharm. Sci. 1983; 72(7): str. 772-775). Mikronizirano saharozo (velikost delcev je manjša od 10 pm) smo suspendirali v raztopino polimera. Oblagali smo z razprševanjem suspenzije na premikajočo se ploščo s tabletami z brezračnim razprševalcem. Oblaganje smo izvajali toliko časa, dokler masa obloge vsake tablete ni dosegla 50 mg.After granulation, the mixture was compressed into tablets and dried as in Example 1. The tablets were coated with a porous membrane coating containing polyvinyl chloride in acetone, as in (Kallstrand G., Ekman B., J. Pharm. Sci. 1983; 72 (7): pp. 772-775). Micronized sucrose (particle size less than 10 pm) was suspended in a polymer solution. We sprayed the suspension onto a moving tablet with a non-airless sprayer. Coating was performed until the weight of the coating of each tablet reached 50 mg.

Primer 4:Example 4:

Amoksicilin trihidrat Amoxicillin trihydrate 244 244 g Mr Rücker Etilcehiloza Ethyl cyclose 268 268 g Mr Rücker Hitosan* Chitosan * 366 366 g Mr Rücker Klorovodikova kislina Hydrochloric acid 0.13 0.13 g Mr Rücker Prečiščena voda** Purified Water ** q.s. q.s. Etanol Ethanol q.s. q.s.

* Hitosan je polimer, ki ga pridobimo z deacetiliranjem biopolimera hitina (sestavljajo ga N-glukozaminskie enote). Različne vrste hitosana se med seboj ločijo po molekulski masi in stopnji acetiliranosti.* Chitosan is a polymer obtained by deacetylation of the chitin biopolymer (consisting of N-glucosamine units). The different types of chitosan are separated by molecular weight and degree of acetylation.

** Uporabili smo jo pri izdelavi pelet in odstranili kasneje med izdelavo.** We used it in pellet making and removed later during production.

Bioadhezivne pelete so bile izdelane z uporabo običajne tehnologije oblaganja z razprševanjem (fluid-bed coating). Amoksicilin trihidrat smo uspešno obložili z raztopino, ki je vsebovala hitosan oziroma etilcelulozo.Bioadhesive pellets were manufactured using conventional fluid bed bed technology. Amoxicillin trihydrate was successfully coated with a solution containing chitosan or ethylcellulose.

Claims (17)

PATENTNI ZAHTEVKIPATENT APPLICATIONS 1. Peroralna formulacija, ki vsebuje aktivno substanco za zdravljenje infekcij v zgornjem predelu gastrointestinalnega trakta, označena s tem, da se zadržuje v želodcu daljši čas medtem, ko se aktivne učinkovine v omenjenem času neprestano sproščajo.An oral formulation comprising an active substance for the treatment of infections in the upper gastrointestinal tract, characterized in that it is retained in the stomach for a longer period while the active ingredients are continuously released during said period. 2. Formulacija, po zahtevku 1, označena s tem da je želeni čas zadrževanja najmanj 1 ura, med tem časom, pa se aktivne učinkovine neprestano sproščajo.A formulation according to claim 1, characterized in that the desired retention time is at least 1 hour, during which time the active ingredients are continuously released. 3. Formulacija, po zahtevku 1, označena s tem, da formulacija vsebuje eno ah več protibakterijskih učinkovin.The formulation according to claim 1, characterized in that the formulation contains one or more antibacterial agents. 4. Formulacija, po zahtevku 1, označena s tem, da je povzročitelj infekcije Helicobacter pylori.A formulation according to claim 1, characterized in that it is a Helicobacter pylori infection agent. 5. Formulacija, po zahtevku 1, označena s tem, da je aktivna učinkovina amoksicilin.5. The formulation of claim 1 wherein the active ingredient is amoxicillin. 6. Formulacija, po zahtevku 1, označena s tem, da vsebuje kombinacijo dveh ali več aktivnih učinkovin.6. The formulation of claim 1 comprising a combination of two or more active ingredients. 7. Formulacija, po zahtevku 1, označena s tem, da ima zdravilni pripravek bioadhezivne lastnosti.7. The formulation of claim 1, wherein the medicament has bioadhesive properties. 8. Formulacija, po zahtevku 1, označena s tem, da je formulacija s podaljšanim sproščanjem, ki se ne razgradi, vsebuje protibakterijske učinkovine.8. The formulation of claim 1 wherein the sustained-release, non-degradable formulation contains antibacterial agents. 9. Formulacija, po zahtevku 8, označena s tem, da velikost ni manjša kot 7 mm.A formulation according to claim 8, characterized in that the size is not less than 7 mm. 10. Formulacija, po zahtevku 9, označena s tem, da je sproščanje aktivne učinkovine nadzorovano z nerazgradljevo membrano.A formulation according to claim 9, characterized in that the release of the active substance is controlled by a non-degradable membrane. 11. Formulacija, po zahtevku 9, označena s tem, da je formulacija inertno porozno ogrodje-matriks.A formulation according to claim 9, characterized in that the formulation is an inert porous matrix framework. 12. Postopek izdelave pripravka, po zahtevku 11, označen s tem, da je aktivna učinkovina pomešana s polimeri ali materiali v količini, ki dosega 10% zmesi in je dobljena mešanica stisnjena v tableto.A method of manufacturing a composition according to claim 11, characterized in that the active ingredient is mixed with polymers or materials in an amount up to 10% of the mixture and the resulting mixture is compressed into a tablet. 13. Postopek, po zahtevku 12, označen s tem, da je tableta segreta nad temperaturo tališča voskastega materiala, da dobimo zadržano profil sproščanja in izboljšano mehansko trdnost tablete.Process according to claim 12, characterized in that the tablet is heated above the melting point of the waxy material to obtain a retained release profile and improved mechanical strength of the tablet. 14. Uporaba pripravka, po zahtevku 1, za pripravo aktivnega zdravilnega pripravka za zdravljenje infekcij v zgornjem predelu gastrointestinalnega trakta.Use of a composition according to claim 1 for the preparation of an active therapeutic composition for the treatment of infections in the upper gastrointestinal tract. 15. Uporaba formulacije, po zahtevku 1, ki vsebuje aktivno substanco za ' zdravljenje infekcij v zgornjem predelu gastrointestinahiega trakta, ki se zadržuje v želodcu daljši čas, medtem, ko se aktivne učinkovine v omenjenem času neprestano sproščajo, skupaj z zaviralci izločanja kisline.Use of a formulation according to claim 1 containing an active substance for the treatment of infections in the upper gastrointestinal tract, which persists in the stomach for a prolonged period while the active ingredients are continuously released during the said period, together with acid secretion inhibitors. 16. Uporaba formulacije, po zahtevku 1, ki vsebuje aktivno substanco za j zdravljenje infekcij v zgornjem predelu gastrointestinahiega trakta, ki se zadržuje v želodcu daljši čas, medtem, ko se aktivne učinkovine v omenjenem času neprestano sproščajo, skupaj z zaviralci protonske črpalke.Use of a formulation as claimed in claim 1, containing an active substance for the treatment of infections in the upper gastrointestinal tract, which is retained in the stomach for a prolonged period, while the active ingredients are continuously released during said time, together with proton pump inhibitors. 17. Uporaba, po zahtevku 16, formulacije, ki vsebuje aktivno substanco za j zdravljenje infekcij v zgornjem predelu gastrointestinahiega trakta, ki se zadržuje v želodcu daljši čas, medtem, ko se aktivne učinkovine v omenjenem času neprestano sproščajo, skupaj z zaviralci protonske črpalke, označena s tem, da je zaviralec protonske črpalke omeprazol.Use according to claim 16, of a formulation containing an active substance for the treatment of infections in the upper gastrointestinal tract, which is retained in the stomach for a prolonged period while the active ingredients are continuously released during said time, together with proton pump inhibitors, characterized in that the proton pump inhibitor is omeprazole.
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