HRP20010932A2 - Melt granulation - Google Patents
Melt granulation Download PDFInfo
- Publication number
- HRP20010932A2 HRP20010932A2 HR20010932A HRP20010932A HRP20010932A2 HR P20010932 A2 HRP20010932 A2 HR P20010932A2 HR 20010932 A HR20010932 A HR 20010932A HR P20010932 A HRP20010932 A HR P20010932A HR P20010932 A2 HRP20010932 A2 HR P20010932A2
- Authority
- HR
- Croatia
- Prior art keywords
- pharmaceutical formulation
- formulation according
- clarithromycin
- granulation
- pharmaceutically acceptable
- Prior art date
Links
- 238000007909 melt granulation Methods 0.000 title description 2
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 30
- 229960002626 clarithromycin Drugs 0.000 claims description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 239000000725 suspension Substances 0.000 claims description 15
- 239000008187 granular material Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 238000002844 melting Methods 0.000 claims description 11
- 238000005469 granulation Methods 0.000 claims description 10
- 230000003179 granulation Effects 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 238000000576 coating method Methods 0.000 claims description 9
- 230000008018 melting Effects 0.000 claims description 9
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- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- Communicable Diseases (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Liquid Deposition Of Substances Of Which Semiconductor Devices Are Composed (AREA)
- Glanulating (AREA)
Description
Tehničko područje Technical area
Internacionalna klasifikacija patenta: A 61 J 3/02, C 07 G 11/00 International patent classification: A 61 J 3/02, C 07 G 11/00
Prezentirana inovacija pripada području farmaceutske tehnologije i pokazuje granulaciju taljenjem. The presented innovation belongs to the field of pharmaceutical technology and shows granulation by melting.
Specifičnije, prezentirani izum pokazuje jednostavni jednofazni postupak oblaganja klaritromicina ili njegovih derivata granulacijom taljenjem zato da se učinkovitije prekrije njegova gorčina, isto tako novo je, bliskost pacijenata s oralnom formulacijom prikladnom i za dijabetičare, koji ponekad isto tako omogućuju različite količine i mjesta otpuštanja aktivne komponente. More specifically, the presented invention shows a simple one-phase coating process of clarithromycin or its derivatives by melt granulation in order to more effectively cover its bitterness, also new, the closeness of patients with an oral formulation suitable for diabetics, which sometimes also allow different amounts and places of release of the active component .
Tehnički problem Technical problem
Klaritromicin je slabo bazičan, praktično u vodi netopljiv, makrolidni antibiotik osjetljiv na kiseline, ostavlja u ustima veoma gorak okus nekoliko sati nakon uzimanja terapijske doze. Clarithromycin is weakly basic, practically insoluble in water, a macrolide antibiotic sensitive to acids, leaving a very bitter taste in the mouth several hours after taking a therapeutic dose.
Budući da neke grupe pacijenata (djeca, starije osobe, pacijenti sa smetnjama u gutanju) ne mogu uzimati krute medicinske preparate, (tablete, kapsule), a neke grupe su također jako osjetljive na (ne)prihvatljiv okus medicinskih preparata, postoji potreba za otkrićem učinkovitog tehnološkog rješenja za oblaganjem ili prekrivanjem gorkog okusa klaritromicina ili njegovih derivata, tj. potreba za pripremom suspenzije za oralnu aplikaciju, koja će pacijentima biti prihvatljiva i terapijski učinkovita. Since some groups of patients (children, the elderly, patients with swallowing disorders) cannot take solid medical preparations (tablets, capsules), and some groups are also very sensitive to the (un)acceptable taste of medical preparations, there is a need to discover an effective technological solution for coating or covering the bitter taste of clarithromycin or its derivatives, i.e. the need to prepare a suspension for oral application, which will be acceptable to patients and therapeutically effective.
Komercijalno dostupne oralne suspenzije s klaritromicinom sadržavaju znatnu količinu šećera (koja ne eliminira gorak okus nakon uzimanja lijeka), nego ostaje još uvijek relativno neugodan okus. Međutim, tehnologija njihovog pripremanja se sastoji od više faza i zbog toga je skupa. Commercially available oral suspensions with clarithromycin contain a considerable amount of sugar (which does not eliminate the bitter taste after taking the drug), but still remains a relatively unpleasant taste. However, the technology of their preparation consists of several stages and is therefore expensive.
Tako, prezentirani izum polazi od potrebe pripreme suspenzije za oralnu aplikaciju klaritromicina i njegovih derivata, koji će biti ukusni, učinkoviti i koji se može dobiti procesom koji ima jednu fazu. Thus, the presented invention is based on the need to prepare a suspension for oral application of clarithromycin and its derivatives, which will be palatable, effective and which can be obtained by a one-stage process.
Prior art Prior art
Klaritromicin je semisintetski antibiotik dobiven metilacijom eritromicina u laktonskoj poziciji C6. Sinteza je opisana u US 4,331,803 i US 4,672,109. Učinkovit je protiv gram pozitivnih bakterija i, klinički se upotrebljava zbog širokog spektra antimikrobnog djelovanja. Na tržištu je dostupan u obliku obloženih tableta, suspenzija i tableta s produženim otpuštanjem. Clarithromycin is a semi-synthetic antibiotic obtained by methylation of erythromycin in the lactone position C6. The synthesis is described in US 4,331,803 and US 4,672,109. It is effective against gram-positive bacteria and is used clinically due to its wide spectrum of antimicrobial activity. It is available on the market in the form of coated tablets, suspensions and extended-release tablets.
Različite oralne farmaceutske formulacije s klaritromicinom su također opisane u slijedećim patentima: Various oral pharmaceutical formulations with clarithromycin are also described in the following patents:
JP 85/163823 pokazuje oralni lijek s klaritromicinom, citronska kiselina povećava absorpciju antibiotika u probavnom traktu, sredstvima za dezintegraciju, ekscipiensima i lubrikantima. JP 85/163823 shows an oral drug with clarithromycin, citric acid increases the absorption of antibiotics in the digestive tract, disintegrants, excipients and lubricants.
EP 0277042 pokazuje oralnu farmaceutsku formulaciju (i s makrolidima) dobrog okusa i obloženu osobito polimerima (specijalno polivinil acetal dietilaminoacetatom-AEA), topljivim u probavnom traktu i ima srednju vrijednost promjera čestica ispod 60 µm. EP 0277042 shows an oral pharmaceutical formulation (also with macrolides) with a good taste and coated in particular with polymers (especially polyvinyl acetal diethylaminoacetate-AEA), soluble in the digestive tract and having a mean particle diameter below 60 µm.
US 4,808,411 prikazuje farmaceutsku formulaciju s eritromicinom ili njegovim derivatima i karbomerom, moguće u obliku ion-komleks čestica obloženih s polimerom, koje se može suspendirati u tekućem nosaču. US 4,808,411 discloses a pharmaceutical formulation with erythromycin or its derivatives and a carbomer, possibly in the form of ion-complex particles coated with a polymer, which can be suspended in a liquid carrier.
JP 01-308,223 pokazuje pripremanje film-obloženih mikrogranula, koje podupiru-otpuštanje medikamenta, koje sadržavaju AEA i vodu dodanu klaritromicinu. JP 01-308,223 shows the preparation of film-coated microgranules, which support the release of medication, containing AEA and water added to clarithromycin.
EP 0302370 i WO 90/08537 pokazuje poboljšanu oralnu farmaceutsku formulaciju (uljnu otopinu, suspenziju, emulziju) eritromicina i derivata koji su punjeni u mekane želatinozne kapsule s N-metil-pirolidonom. EP 0302370 and WO 90/08537 shows an improved oral pharmaceutical formulation (oil solution, suspension, emulsion) of erythromycin and derivatives which are filled in soft gelatin capsules with N-methyl-pyrrolidone.
EP-B-0420992 pokazuje proces za proizvodnju oralnih farmaceutskih formulacija (isto tako i s makrolidima) s maskiranim okusom, koje obuhvaćaju raspršivanje ljekovite suspenzije u ledenu vodenu otopinu AEA. EP-B-0420992 shows a process for the production of taste-masked oral pharmaceutical formulations (also with macrolides) comprising dispersing a medicinal suspension into an ice-cold aqueous solution of AEA.
JP 02-279,622 pokazuje oralne lijekove sa AEA, pripremljene finom granulacijom lijeka (klaritromicin) raspršenog u rastaljenu uljnu bazu (kakao maslac), čemu slijedi suspendiranje finih čestica u vodenu otopinu AEA i spray-drying suspenzije. JP 02-279,622 shows oral drugs with AEA, prepared by fine granulation of the drug (clarithromycin) dispersed in a melted oil base (cocoa butter), followed by suspending the fine particles in an aqueous solution of AEA and spray-drying the suspension.
US 5,017,383 pokazuje postupak proizvodnje fino obloženih farmaceutskih formulacija, koje obuhvaćaju izmiješane smrznute dijelove tekućeg medija s lijekom (isto tako i makrolide) i obložene u obliku finog praška koji prianja na površinu čestice. US 5,017,383 shows a process for the production of finely coated pharmaceutical formulations, which comprise mixed frozen portions of a liquid medium with a drug (also macrolides) and coated in the form of a fine powder that adheres to the particle surface.
JP 05-255,075 pokazuje granulaciju taljenjem makrolida, gdje obloženi sloj sadržava polimere topljive u želucu (osobito Eudragit E), koji je raspršen u supstanciji niskog tališta. Finalna granulacija se provodi sprejanjem. Finalna priprema suhog sirupa je kompletirana miješanjem granula sa šećerom i hidroksi metil celulozom (HPMC). JP 05-255,075 shows macrolide melting granulation, where the coated layer contains stomach-soluble polymers (especially Eudragit E), which is dispersed in a low-melting substance. Final granulation is carried out by spraying. The final preparation of the dry syrup is completed by mixing the granules with sugar and hydroxy methyl cellulose (HPMC).
US 5,599,556 i US 5,609,909 pokazuju maskiranje okusa enkapsuliranjem čestica klaritromicina oblaganjem prolaminom prior to preparacije suspenzije. US 5,599,556 and US 5,609,909 show taste masking by encapsulating clarithromycin particles by coating them with prolamine prior to suspension preparation.
WO 96/34628 pokazuje oralne farmaceutske formulacije (isto tako i s makrolidima) za maskiranje okusa (osobito suhih sirupa), koji sadržavaju lijek neugodnog okusa, visokim polimerom topivim u želucu (osobito AEA i Eudragit E) i monogliceridom niskog tališta (osobito gliceril monostearat) u stabilni kristalni (3 oblik (transformiran iz metastabilnog a oblika dodatnim miješanjem na povišenoj temperaturi), i postupkom maskiranja okusa. WO 96/34628 shows oral pharmaceutical formulations (also with macrolides) for taste masking (especially dry syrups), which contain an unpleasant-tasting drug, a highly gastric-soluble polymer (especially AEA and Eudragit E) and a low-melting monoglyceride (especially glyceryl monostearate). into a stable crystalline (3) form (transformed from the metastable a form by additional mixing at an elevated temperature), and by a taste masking process.
WO 97/16174 pokazuje se proces vodene granulacije makrolidnih antibiotika s karbomerom (aklilični polimer). WO 97/16174 shows a process for aqueous granulation of macrolide antibiotics with carbomer (acrylic polymer).
US 5,705,190 pokazuje kontrolirano otpuštanje farmaceutskih formulacija (isto tako i s klaritromicinom) koji sadržavaju medikament tjedno topiv u vodi, alginatnu sol topljivu u vodi, kompleksnu sol alginične kiseline s kationima metala i organsku karboksilnu kiselinu koja omogućuje dissolution lijeka. US 5,705,190 shows controlled release pharmaceutical formulations (also with clarithromycin) containing a weekly water-soluble drug, a water-soluble alginate salt, a complex salt of alginic acid with metal cations, and an organic carboxylic acid that enables dissolution of the drug.
US 5,707,646 pokazuje farmaceutsku formulaciju (isto tako i s makrolidima) za oralnu upotrebu (osobito suhi sirup) koja sadržava medikament neugodnog okusa, funkcionalni polimer (osobito AEA ili/i Eudragit E) u supstanciji s talištem 40-120°C, šećerni alkohol (npr. sorbitol) i bazni oksid (osobito MgO). US 5,707,646 shows a pharmaceutical formulation (also with macrolides) for oral use (especially dry syrup) containing an unpleasant-tasting drug, a functional polymer (especially AEA or/and Eudragit E) in a substance with a melting point of 40-120°C, a sugar alcohol (e.g. . sorbitol) and basic oxide (especially MgO).
WO 98/46239 pokazuje farmaceutsku formulaciju produženog otpuštanja koja sadržava derivat eritromicina i hidrofilni vodotopivi polimer, koji ako se oralno aplicira osigurava prolif okusa i mali broj gastrointestinalnih nuspojava u usporedbi s uobičajenim oblicima. Tehnološki postupak uključuje, inter alia, vlažnu granulaciju, sušenje, postupak sijanja i mljevenja. WO 98/46239 shows an extended release pharmaceutical formulation containing an erythromycin derivative and a hydrophilic water soluble polymer, which when administered orally provides a rich taste and a low number of gastrointestinal side effects compared to conventional forms. The technological process includes, inter alia, wet granulation, drying, screening and grinding.
Prema tome, postoje brojne publikacije u patentima i drugoj literaturi tog područja koje pokazuju sastav i postupak pripremanja različitih farmaceutskih formulacija s klatritromicinom. Međutim, u literaturi nismo našli podatak koji prikazuje tako jednostavan postupak pripremanja suspenzije klaritromicina koja ima tako jednostavnu kompoziciju, dobar miris i okus isto tako kao mogućnost izrade za dijabetičare. Dodatno, isto tako je moguće kontrolirati količinu i mjesto otpuštanja aktivne komponente. Accordingly, there are numerous publications in patents and other literature in the field showing the composition and process of preparing various pharmaceutical formulations with clatrithromycin. However, we did not find information in the literature showing such a simple procedure for preparing a clarithromycin suspension that has such a simple composition, good smell and taste as well as the possibility of making it for diabetics. Additionally, it is also possible to control the amount and location of the release of the active component.
Tehničko rješenje Technical solution
Cilj prezentiranog izuma je nova oralna formulacija s klaritromicinom i njegovim derivatima. Iznenađujuće, gorak okus klaritromicina biti će veoma zadovoljavajuće maskiran oblaganjem klaritromicina, koji može biti prisutan sam ili u homogenoj smjesi s uobičajenim adjuvantima, s lipidnim film-formirajućim supstancijama koje imaju nisko talište (ispod 100°C). Granulat se priprema s talinom u mikseru-granulatoru, na taj način u jednoj fazi i u jednoj posudi bez upotrebe ijednog otapala. Od granulata različitih uobičajenih finalnih farmaceutskih formulacija mogu se pripremiti suspenzije u koncentraciji 125 mg/5 ml i 250 mg/ 5 ml, tablete ili kapsule. The aim of the presented invention is a new oral formulation with clarithromycin and its derivatives. Surprisingly, the bitter taste of clarithromycin will be very satisfactorily masked by coating clarithromycin, which may be present alone or in a homogeneous mixture with the usual adjuvants, with lipid film-forming substances having a low melting point (below 100°C). The granulate is prepared with melt in a mixer-granulator, thus in one phase and in one container without the use of any solvent. Granules of various common final pharmaceutical formulations can be used to prepare suspensions in concentrations of 125 mg/5 ml and 250 mg/5 ml, tablets or capsules.
Baza za oblaganje može biti sam klaritromicin ili smjesa s ekscipiensima kao što su laktoza, kalcijev karbonat, natrijev hidrogen fosfat, NaCl, limunska kiselina, PEG ili polimeri netopivi u želucu kao što je Eudragit L ili S (1:1 ili 1:2 kopilimer metakrilične kiseline i MMA), mikrokristalna celuloza itd. Težinski omjer između klaritromicina i tih ekscipiensa iznosi 5:1 do 1:1.2. The coating base can be clarithromycin alone or a mixture with excipients such as lactose, calcium carbonate, sodium hydrogen phosphate, NaCl, citric acid, PEG or gastric insoluble polymers such as Eudragit L or S (1:1 or 1:2 copolymer methacrylic acid and MMA), microcrystalline cellulose, etc. The weight ratio between clarithromycin and these excipients is 5:1 to 1:1.2.
Kao lipidne film-formirajuće supstancije skoro netopive u vodi može se koristiti visoke masne alkohole, preferira se stearil, cetistearil ili cetilni alkohol ili odgovarajuće kiseline kao što je stearinska kiselina ili fizička smjesa ili ester pojedinih takvih komponenti npr. stearil stearat. Težinski omjer između klaritromicina i tih ekscipiensa iznosi 2:1 do 1:2. As lipid film-forming substances almost insoluble in water, high fatty alcohols can be used, preferably stearyl, cetistearyl or cetyl alcohol or corresponding acids such as stearic acid or a physical mixture or ester of individual such components, eg stearyl stearate. The weight ratio between clarithromycin and these excipients is 2:1 to 1:2.
Granulacija taljenjem izvodi se na takav način da smjesu klaritromicina (moguće s dodatkom adjuvansa) i lipida za oblaganje zagrije se u granulatoru uz miješanje do točke taljenja lipidne komponente i dobivene granule se polagano hlade. Za finalno pripremanje granula za suspenziju isto tako treba dodati izmjenjivač viskoziteta i stabilizator kao što su xanthan gum, guar gum, silika gel, magnezijev aluminijev silikat. Za bolji okus, miris i izgled, šećer ili tvari za zaslađivanje kao što su aspartam, natrijev saharinat ili eritriol, karamel, vanilija ili aroma voća i bojila također se mogu dodati. Međutim, svi navedeni aditivi za pripremanje suspenzija ne mogu prekriti gorki okus samog klaritromicina. Granulation by melting is performed in such a way that the mixture of clarithromycin (possibly with the addition of an adjuvant) and lipid for coating is heated in the granulator with stirring to the melting point of the lipid component and the resulting granules are slowly cooled. For the final preparation of granules for suspension, a viscosity changer and stabilizer such as xanthan gum, guar gum, silica gel, magnesium aluminum silicate should also be added. For better taste, smell and appearance, sugar or sweetening substances such as aspartame, sodium saccharinate or erytriol, caramel, vanilla or fruit flavoring and coloring may also be added. However, all the listed additives for preparing suspensions cannot cover the bitter taste of clarithromycin itself.
Farmaceutska formulacija prezentiranog izuma može se poboljšati upotrebom poliola umjesto šećera, što ju čini prihvatljivom za dijabetičare. U to svrhu mogu se koristiti npr. ksilitol i manitol i njihove kombinacije s maltitolom, maltolom i sorbitolom. Zato, prezentirana farmaceutska formulacija predstavlja samo oralnu suspenziju s klaritromicinom, koja nije bazirana na šećeru (saharozi). The pharmaceutical formulation of the present invention can be improved by the use of polyols instead of sugar, making it acceptable for diabetics. For this purpose, for example, xylitol and mannitol and their combinations with maltitol, maltol and sorbitol can be used. Therefore, the presented pharmaceutical formulation is only an oral suspension with clarithromycin, which is not based on sugar (sucrose).
Masni alkoholi kao što je stearilni alkohol posjeduje u proporcionalnim koncentracijama produženi učinak na otpuštanje aktivne komponente farmaceutske formulacije. To svojstvo može se koristiti za kontrolu otpuštanja klaritromicina i može se pripremiti oralna suspenzija s produženim djelovanjem. Fatty alcohols such as stearyl alcohol have, in proportional concentrations, a prolonged effect on the release of the active component of the pharmaceutical formulation. This property can be used to control the release of clarithromycin and a sustained-release oral suspension can be prepared.
Dopunski ili po izboru, primjenom gastrorezistentnog sloja na bazu granula taljenjem, mjesto otpuštanja klaritromicina u probavnom traktu može biti napadnuto. Ovdje se mogu koristiti polimeri koji formiraju gastrorezistentni sloj koji oblaže kao što je shellac, celuloza acetat ftalat, HPMC ftalat, etilceluloza lateks, polimetakrilati itd. Additionally or optionally, by applying a gastro-resistant layer to the base of the granules by melting, the release site of clarithromycin in the digestive tract can be attacked. Polymers that form a gastro-resistant coating such as shellac, cellulose acetate phthalate, HPMC phthalate, ethyl cellulose latex, polymethacrylates, etc. can be used here.
Prezentirani izum ilustriran je ali ne u svrhu da se ograniči slijedećim Primjerima: The presented invention is illustrated but not intended to be limited by the following Examples:
Primjer 1 Example 1
U granulatoru s miješalicom homogeno se izmiješa 2 kg klaritromicina i 2 kg stearil alkohola. Tijekom miješanja zagrijava se do točke taljenja i tada se sjekač isključi. Potom se ohladi uz stalno miješanje. Formiraju se sferične granule/pelete. Na to se dodaju suhi aditivi. 2 kg of clarithromycin and 2 kg of stearyl alcohol are homogeneously mixed in a granulator with a mixer. During mixing, it is heated to the melting point and then the cutter is switched off. It is then cooled with constant stirring. Spherical granules/pellets are formed. Dry additives are added to it.
Suhi aditivi po bočici ili na 5.00 g klaritromicin-stearil granulata (peleta): Dry additives per bottle or per 5.00 g of clarithromycin-stearyl granules (pellets):
Na2HPO4 1.000 g Na2HPO4 1,000 g
NaCl 1.000 g NaCl 1,000 g
aspartam 0.100 g aspartame 0.100 g
aerosil 0.400 g Aerosil 0.400 g
aroma vanilije 0.070 g vanilla aroma 0.070 g
amonijev glicirhizinat 0.140 g ammonium glycyrrhizinate 0.140 g
ksilitol 60.690 g xylitol 60,690 g
metil hidroksibenzoat 0.260 g methyl hydroxybenzoate 0.260 g
titan oksid 0.050 g titanium oxide 0.050 g
kvinolin žuto sredstvo za bojanje 0.010 g quinoline yellow coloring agent 0.010 g
ukupno suha tvar po bočici 69.000 g total dry matter per bottle 69,000 g
dodano vodo 55 000 g added water 55,000 g
dobiveni volumen suspenzije 100.000 g resulting volume of suspension 100,000 g
suspenzioni koncentrat 125 mg klaritromicina/5 ml suspension concentrate 125 mg clarithromycin/5 ml
Primjer 2 Example 2
Postupak je identičan onom u Primjeru 1, osim što se homogeno izmiješa 1.25 kg klaritromicina, 1.25 kg stearinske kiseline i 1.5 kg NaH2PO4. The procedure is identical to that in Example 1, except that 1.25 kg of clarithromycin, 1.25 kg of stearic acid and 1.5 kg of NaH2PO4 are homogeneously mixed.
Suhi aditivi po bočici ili na 7.2 g klaritromicin-obloženih granula (peleta): Dry additives per bottle or per 7.2 g of clarithromycin-coated granules (pellets):
NaCl 1.000 g NaCl 1,000 g
aspartam 0.100 g aspartame 0.100 g
aerosil 0.400 g Aerosil 0.400 g
aroma karamela 0.070 g caramel aroma 0.070 g
eritritol 0.140 g erythritol 0.140 g
maltitol 60.690 g maltitol 60,690 g
metil hidroksibenzoat 0.260 g methyl hydroxybenzoate 0.260 g
titan oksid 0.050 g titanium oxide 0.050 g
kvinolin žuto sredstvo za bojanje 0.010 g quinoline yellow coloring agent 0.010 g
citronska kiselina 0.010 g citric acid 0.010 g
Primjer 3 Example 3
Postupak pripremanja granula identičan je onom u Primjeru 1 ili 2. The procedure for preparing the granules is identical to that in Example 1 or 2.
Dodatno, stavi se gastrorezistentni sloj; za 200 mg jezgre peleta pripremi se slijedeća disperzija: Additionally, a gastro-resistant layer is placed; for 200 mg of pellet core, prepare the following dispersion:
HPMC ftalat 55 48.612 mg HPMC phthalate 55 48,612 mg
dibutil sebacat 0.893 mg dibutyl sebacate 0.893 mg
talk 0.495 mg talc 0.495 mg
etanol 332.143 mg ethanol 332,143 mg
aceton 332.143 mg acetone 332,143 mg
Ako se stavlja gastrorezistentni sloj, količina zaslađivača se smanji za 50 mg, inače priprema finalne suspenzije identična je onoj u Primjeru 1. If a gastro-resistant layer is applied, the amount of sweetener is reduced by 50 mg, otherwise the preparation of the final suspension is identical to that in Example 1.
Primjer 4 Example 4
Postupak pripremanja granula identičan je onom u Primjeru 1 ili 2. The procedure for preparing the granules is identical to that in Example 1 or 2.
Dodatno, stavi se gastrorezistentni sloj; za 500 mg jezgre pelete pripremi se slijedeća disperzija: Additionally, a gastro-resistant layer is placed; for 500 mg of pellet core, prepare the following dispersion:
Eudragit L 30 D-55 48.612 mg Eudragit L 30 D-55 48,612 mg
trietil citrat 0.893 mg triethyl citrate 0.893 mg
talk 0.495 mg talc 0.495 mg
voda 332.143 mg water 332,143 mg
Pripremanje vodene disperzije: trietil citrat, talk i sredstvo protiv pjenjenja dispergira se u vodi i homogenizira. Neposredno prije upotrebe, disperziju se doda uz miješanje u Eudragit i filtrira. Preparation of aqueous dispersion: triethyl citrate, talc and anti-foaming agent are dispersed in water and homogenized. Immediately before use, the dispersion is added with stirring to Eudragit and filtered.
Claims (14)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9900119A SI20244A (en) | 1999-05-19 | 1999-05-19 | Melt granulation |
| PCT/SI2000/000013 WO2000069415A2 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20010932A2 true HRP20010932A2 (en) | 2003-04-30 |
Family
ID=20432471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20010932A HRP20010932A2 (en) | 1999-05-19 | 2001-12-18 | Melt granulation |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1183013A2 (en) |
| AU (1) | AU4969700A (en) |
| BG (1) | BG106236A (en) |
| CZ (1) | CZ20014133A3 (en) |
| EE (1) | EE200100607A (en) |
| HR (1) | HRP20010932A2 (en) |
| HU (1) | HUP0201233A3 (en) |
| PL (1) | PL351654A1 (en) |
| RU (1) | RU2001134166A (en) |
| SI (1) | SI20244A (en) |
| SK (1) | SK16642001A3 (en) |
| WO (1) | WO2000069415A2 (en) |
| YU (1) | YU82001A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA02009587A (en) * | 2000-03-28 | 2003-05-14 | Biochemie Gmbh | Granulated particles with masked taste. |
| EP1333807A4 (en) * | 2000-10-13 | 2005-06-29 | Advancis Pharmaceuticals | Extended release erythromycin derivatives |
| DK1484056T3 (en) * | 2002-02-21 | 2013-09-08 | Otsuka Pharma Co Ltd | Slow release compositions and processes for their preparation |
| US7943585B2 (en) | 2003-12-22 | 2011-05-17 | Sandoz, Inc. | Extended release antibiotic composition |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2085342A1 (en) * | 1990-06-14 | 1991-12-15 | Milton R. Kaplan | Stable aqueous drug suspensions |
| JP3265680B2 (en) * | 1992-03-12 | 2002-03-11 | 大正製薬株式会社 | Oral pharmaceutical composition |
| WO1994012157A1 (en) * | 1992-11-30 | 1994-06-09 | Kv Pharmaceutical Company | Tastemasked pharmaceutical materials |
| IT1312058B1 (en) * | 1999-04-09 | 2002-04-04 | Pharmaplus S R L | METHOD FOR MICRO-ENCAPSULATION OF MEDICATIONS. |
-
1999
- 1999-05-19 SI SI9900119A patent/SI20244A/en not_active IP Right Cessation
-
2000
- 2000-05-18 EE EEP200100607A patent/EE200100607A/en unknown
- 2000-05-18 AU AU49697/00A patent/AU4969700A/en not_active Abandoned
- 2000-05-18 PL PL00351654A patent/PL351654A1/en not_active Application Discontinuation
- 2000-05-18 HU HU0201233A patent/HUP0201233A3/en unknown
- 2000-05-18 EP EP00931886A patent/EP1183013A2/en not_active Withdrawn
- 2000-05-18 RU RU2001134166/14A patent/RU2001134166A/en not_active Application Discontinuation
- 2000-05-18 WO PCT/SI2000/000013 patent/WO2000069415A2/en not_active Application Discontinuation
- 2000-05-18 YU YU82001A patent/YU82001A/en unknown
- 2000-05-18 CZ CZ20014133A patent/CZ20014133A3/en unknown
- 2000-05-18 SK SK1664-2001A patent/SK16642001A3/en unknown
-
2001
- 2001-12-18 HR HR20010932A patent/HRP20010932A2/en not_active Application Discontinuation
- 2001-12-19 BG BG106236A patent/BG106236A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SK16642001A3 (en) | 2002-05-09 |
| EP1183013A2 (en) | 2002-03-06 |
| PL351654A1 (en) | 2003-05-19 |
| WO2000069415A3 (en) | 2001-04-26 |
| SI20244A (en) | 2000-12-31 |
| WO2000069415A2 (en) | 2000-11-23 |
| EE200100607A (en) | 2003-02-17 |
| BG106236A (en) | 2002-08-30 |
| CZ20014133A3 (en) | 2002-03-13 |
| YU82001A (en) | 2004-07-15 |
| HUP0201233A2 (en) | 2002-08-28 |
| RU2001134166A (en) | 2003-08-27 |
| HUP0201233A3 (en) | 2003-10-28 |
| AU4969700A (en) | 2000-12-05 |
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