SI20244A - Melt granulation - Google Patents
Melt granulation Download PDFInfo
- Publication number
- SI20244A SI20244A SI9900119A SI9900119A SI20244A SI 20244 A SI20244 A SI 20244A SI 9900119 A SI9900119 A SI 9900119A SI 9900119 A SI9900119 A SI 9900119A SI 20244 A SI20244 A SI 20244A
- Authority
- SI
- Slovenia
- Prior art keywords
- form according
- pharmaceutical
- pharmaceutical form
- clarithromycin
- granulate
- Prior art date
Links
- 238000007909 melt granulation Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000005469 granulation Methods 0.000 claims abstract description 7
- 230000003179 granulation Effects 0.000 claims abstract description 7
- 239000000155 melt Substances 0.000 claims abstract description 6
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- 229960002626 clarithromycin Drugs 0.000 claims description 29
- 238000000576 coating method Methods 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 14
- 239000008187 granular material Substances 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
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- 239000000654 additive Substances 0.000 claims description 5
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- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 3
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
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- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
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- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical class O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
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- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
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- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
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- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
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Abstract
Description
Ta izum spada v področje farmacevtske tehnologije ter obravnava granulacijo v talini.The present invention falls within the field of pharmaceutical technology and addresses melt granulation.
V ožjem smislu ta izum obravnava enostaven enostopenjski postopek oblaganja klaritromicina ali njegovih derivatov z granulacijo v talini za učinkovito prekritje grenkobe ter novo, bolniku prijazno peroralno farmacevtsko obliko, ki je primerna tudi za sladkorne bolnike, hkrati pa omogoča variacije hitrosti in mesta sproščanja aktivne učinkovine.In a narrower sense, the present invention provides a simple one-step process for coating clarithromycin or its derivatives with melt granulation to effectively cover bitterness and a novel, patient-friendly oral pharmaceutical formulation also suitable for diabetic patients, while allowing variations in the rate and site of release of the active ingredient.
Prikaz problemaView the problem
Klaritromicin je rahlo bazičen, v vodi praktično netopen in na kislino občutljiv makrolidni antibiotik izjemno grenkega okusa, ki ostane v ustih še nekaj ur po zaužitju terapevtskega odmerka. Ker nekatere skupine bolnikov ne morejo zaužiti trdnih zdravilnih pripravkov (tablete, kapsule), hkrati pa so ravno ti bolniki (otroci, starejši, bolniki z motnjami požiranja, ...) še posebej občutljivi za (ne)sprejemljivost okusa zdravilnega pripravka, obstaja potreba po učinkoviti tehnološki rešitvi za prekritje ali celo zakritje grenkobe klaritromicina ali njegovih derivatov, torej potreba po izdelavi bolniku prijazne in hkrati terapevtsko učinkovite suspenzije za peroralno uporabo.Clarithromycin is a slightly basic, water-insoluble and acid-sensitive macrolide antibiotic of extremely bitter taste, which remains in the mouth for several hours after administration of a therapeutic dose. Because some groups of patients cannot take solid medicines (tablets, capsules), and at the same time, these patients (children, the elderly, patients with swallowing disorders, ...) are particularly sensitive to the (in) acceptability of the taste of the medicinal product, there is a need an effective technological solution for covering or even masking the bitterness of clarithromycin or its derivatives, hence the need to make a patient-friendly and, at the same time, a therapeutically effective suspension for oral use.
Komercialno dosegljiva peroralna suspenzija s klaritromicinom vsebuje precej sladkorja (ki ne odpravi priokusa po zaužitju), a je kljub temu relativno neprijetnega okusa, tehnologija priprave pa je mnogostopenjska in zato draga.A commercially available clarithromycin oral suspension contains a lot of sugar (which does not eliminate the aftertaste) but is nonetheless a relatively unpleasant taste, and the preparation technology is multistage and therefore expensive.
Naš izum torej izhaja iz potrebe, da bi izdelali okusno, učinkovito in po enostopenjskem postopku pripravljeno peroralno suspenzijo s klaritromicinom ali njegovimi derivati.Our invention therefore arises from the need to produce a tasteful, effective and one-step prepared oral suspension with clarithromycin or derivatives thereof.
Stanje tehnikeThe state of the art
Klaritromicin je polsintetični antibiotik, nastal z metiliranjem eritromicina na laktonskem položaju C6. Sinteza je opisana v patentih US 4.331.803 in US 4.672.109. Učinkuje na po Gramu pozitivne bakterije in se zaradi širokega spektra antimikrobne aktivnosti uporablja klinično. Na tržišču je v obliki lakiranih tablet, suspenzije ter tablet s podaljšanim sproščanjem.Clarithromycin is a semi-synthetic antibiotic produced by methylation of erythromycin at the C6 lactone position. The synthesis is described in US Patents 4,331,803 and US 4,672,109. It has Gram-positive bacteria and is clinically used due to its wide range of antimicrobial activity. It is available on the market in the form of lacquer tablets, suspension and prolonged-release tablets.
Različne (per)oralne farmacevtske oblike s klaritromicinom so opisane tudi v naslednjih patentih:Various (per) oral pharmaceutical forms with clarithromycin are also described in the following patents:
JP-patent št. 85/163823 opisuje (per)oralno zdravilo s klaritromicinom in citronsko kislino, ki povečuje absorpcijo antibiotika v prebavnem traktu, dezintegranti, nosilci in lubrikanti.JP-patent no. 85/163823 describes a (per) oral drug with clarithromycin and citric acid, which increases the absorption of the antibiotic in the gastrointestinal tract, disintegrants, carriers and lubricants.
Umaknjena EP-prijava št. 277.042 opisuje (per)oralno farmacevtsko obliko (tudi z makrolidi) z izboljšanim okusom s prevleko iz posebnih polimerov (zlasti polivinil acetal dietilaminoacetata - AEA), topnih v želodčnem soku in s povprečnimi premeri delcev pod 60 μηη.Withdrawn EP application no. No. 277,042 describes a (per) oral pharmaceutical formulation (including macrolides) with a taste, coated with special polymers (especially polyvinyl acetal diethylaminoacetate - AEA) soluble in gastric juice and having an average particle diameter of less than 60 μηη.
US-patent št. 4.808.411 opisuje farmacevtsko obliko z eritromicinom ali derivati in karbomerom, lahko v obliki delcev ionskega kompleksa, prevlečenih s polimerom, pri čemer so delci lahko suspendirani v tekočem nosilcu.U.S. Pat. No. 4,808,411 describes a pharmaceutical formulation with erythromycin or derivatives and a carbomer, which may be in the form of polymer-coated ionic complex particles, the particles being suspended in a liquid carrier.
JP-patent št. 01-308.223 opisuje pripravo s filmom prevlečenih mikrogranul zdravila z zadržanim delovanjem, ki poleg klaritromicina vsebujejo AEA in vodo.JP-patent no. 01-308.223 describes the preparation of film-coated microgranules of sustained-release medicinal products containing AEA and water in addition to clarithromycin.
Umaknjena EP-prijava št. 302.370 ter WO-patentna prijava št. 90/08537 opisujeta izboljšane (per)oralne farmacevtske oblike (oljna raztopina, suspenzija, emulzija) eritromicina in derivatov za polnjenje v mehke želatinske kapsule z N-metil-pirolidonom.Withdrawn EP application no. 302.370 and WO-patent application no. No. 90/08537 describes improved (per) oral pharmaceutical forms (oily solution, suspension, emulsion) of erythromycin and derivatives for filling into soft gelatin capsules with N-methyl-pyrrolidone.
EP-B-420.992 opisuje postopek za proizvodnjo (per)oralne farmacevtske oblike (tudi z makrolidi) s prekritim okusom, ki obsega razpršitev suspenzije zdravila v mrzlo vodno raztopino AEA.EP-B-420.992 describes a process for the production of a (co) oral flavored pharmaceutical formulation (including macrolides) comprising the dispersion of a drug suspension into a cold AEA aqueous solution.
JP-patent št. 02-279.622 opisuje peroralna zdravila z AEA, pripravljena s fino granulacijo zdravila (klaritromicin), dispergiranega v raztaljeni oljni bazi (kakaova mast), suspendiranje finih delcev v vodni raztopini AEA in sušenje suspenzije z razprševanjem.JP-patent no. No. 02-279,622 describes oral medications with AEA prepared by fine granulation of a drug (clarithromycin) dispersed in a molten oil base (cocoa grease), suspension of fine particles in AEA aqueous solution, and spray drying.
US-patent št. 5.017.383 opisuje metodo za proizvodnjo fino prevlečene farmacevtske oblike, ki obsega mešanje zmrznjenih delcev tekočega medija z zdravilom (tudi z makrolidi) in prevleke v obliki finega praška, ki adherira na površino delcev.U.S. Pat. No. 5,017,383 describes a method for the production of a finely coated pharmaceutical formulation comprising mixing frozen particles of a liquid medium with a drug (including macrolides) and a coating in the form of a fine powder that adheres to the surface of the particles.
JP-patent št. 05-255.075 opisuje granulacijo makrolidov v talini, kjer prevleko sestavljajo v želodcu topni polimeri (zlasti Eudragit E), dispergirani v spojinah z nizkim tališčem, končna granulacija pa poteka z razprševanjem. Za dokončno pripravo suhega sirupa zmešajo granule s sladkorjem in hidroksipropil metil celulozo (HPMC).JP-patent no. 05-255.075 describes the granulation of macrolides in a melt, where the coating is composed of stomach-soluble polymers (especially Eudragit E) dispersed in low-melting compounds and the final granulation is by spraying. To finish the dry syrup, mix the granules with sugar and hydroxypropyl methyl cellulose (HPMC).
US-patenta št. 5.599.556 in 5.609.909 opisujeta prekritje okusa inkapsuliranih delcev klaritromicina s prolaminskimi prevlekami pred pripravo suspenzije.U.S. Pat. Nos. 5,599,556 and 5,609,909 describe the overlapping of taste of encapsulated clarithromycin particles with prolamin coatings prior to preparation of the suspension.
WO-patentna prijava št. 96/34628 opisuje (per)oralno farmacevtsko obliko (tudi z makrolidi) za prekritje okusa (zlasti suhi sirup), ki vsebuje zdravilo z neprijetnim okusom, v želodcu topni višji polimer (zlasti AEA ali Eudragit E) in monoglicerid z nizkim tališčem (zlasti gliceril monostearat) v stabilni kristalni obliki β (prehod iz metastabilne oblike a z dodatnim stresanjem pri zvišani temperaturi) ter metodo za prekritje okusa.WO-patent application no. 96/34628 describes a (per) oral pharmaceutical form (also with macrolides) for taste coating (especially dry syrup) containing an unpleasant drug, gastric soluble polymer (in particular AEA or Eudragit E) and low melting point monoglyceride (in particular glyceryl monostearate) in stable crystalline form β (transition from metastable form with additional shaking at elevated temperature) and method for covering the taste.
WO-patentna prijava št. 97/16174 opisuje postopek za vodno granulacijo makrolidnega antibiotika s karbomerom (akrilnim polimerom).WO-patent application no. 97/16174 describes a process for the aqueous granulation of a macrolide antibiotic with a carbomer (acrylic polymer).
US-patent št. 5.705.190 opisuje trdno (per)oralno farmacevtsko obliko (tudi klaritromicina) z nadzorovanim sproščanjem, ki vsebuje v vodi slabo topno zdravilo, vodotopno alginatno sol, kompleksno sol alginske kisline s kovinskim kationom ter organsko karboksilno kislino, ki olajša raztapljanje zdravila.U.S. Pat. No. 5,705,190 describes a solid (per) oral, controlled-release pharmaceutical formulation (including clarithromycin) containing a poorly soluble drug, a water-soluble alginate salt, an alginic acid complex with metal cation, and an organic carboxylic acid to facilitate drug dissolution.
US-patent št. 5.707.646 opisuje farmacevtsko obliko (tudi z makrolidi) za (per)oralno uporabo (zlasti suhi sirup), ki vsebuje zdravilo z neprijetnim okusom, funkcionalni polimer (zlasti AEA ali/in Eudragit E) v snovi s tališčem pri 40-120 °C, sladkorni alkohol (npr. sorbitol) in bazični oksid (zlasti MgO).U.S. Pat. No. 5,707,646 describes a pharmaceutical form (including macrolides) for (per) oral use (especially dry syrup) containing an unpleasant drug, functional polymer (in particular AEA or / and Eudragit E) in a substance with a melting point at 40-120 ° C, sugar alcohol (eg sorbitol) and basic oxide (especially MgO).
WO-patentna prijava št. 98/46239 opisuje farmacevtsko obliko s podaljšanim delovanjem, ki vsebuje derivat eritromicina in hidrofilni vodotopni polimer, ki ima pri (per)oralni uporabi izboljšan profil okusa in manj gastrointestinalnih stranskih učinkov v primerjavi z navadno obliko, tehnologija priprave pa med drugim vključuje postopke mokre granulacije, sušenja, sejanja in mletja.WO-patent application no. 98/46239 describes a sustained-release pharmaceutical formulation containing an erythromycin derivative and a hydrophilic water-soluble polymer having (per) oral use an improved taste profile and less gastrointestinal side effects than the conventional form, and preparation technology includes, among others, wet granulation processes , drying, sieving and milling.
V patentni in drugi literaturi s tega področja obstajajo torej številne objave, ki opisujejo sestavo in pripravo najrazličnejših farmacevtskih oblik s klaritromicinom; nismo pa našli nobenega literaturnega vira, ki bi opisoval tako enostaven postopek za pripravo suspenzije klaritromicina, pri čemer ima ta suspenzija tako enostavno sestavo, dober vonj in okus ter možnosti nadgradnje za diabetike, poleg tega pa kontrolo hitrosti in mesta sproščanja aktivne učinkovine.There are therefore numerous publications in the patent and other literature in the field describing the composition and preparation of a wide variety of clarithromycin pharmaceutical forms; however, we have not found any literature source describing such a simple process for the preparation of a clarithromycin suspension, with such a simple composition, good odor and taste, as well as upgrading options for diabetics, as well as speed and release control of the active substance.
Opis nove rešitve z izvedbenimi primeriDescription of the new solution with implementation examples
Predmet izuma je nova peroralna farmacevtska oblika s klaritromicinom ali njegovimi derivati. Grenak okus klaritromicina smo presenetljivo uspešno prekrili z oblaganjem klaritromicina, ki lahko nastopa samostojno ali v homogeni zmesi z običajnimi pomožnimi snovmi, z lipidno, filmotvorno snovjo z nizkim tališčem (pod 100 °C). Granulat smo izdelali v talini v mešalcu-granulatorju, torej v eni stopnji in v eni posodi ter brez uporabe vsakršnih topil. Iz granulata lahko pripravimo različne običajne končne farmacevtske oblike, kot so npr. suspenzija v koncentracijah 125 mg / 5 ml in 250 mg / 5 ml, tablete ali kapsule.The present invention is a novel oral pharmaceutical formulation with clarithromycin or derivatives thereof. The bitter taste of clarithromycin was surprisingly successfully covered by the coating of clarithromycin, which can act alone or in a homogeneous mixture with conventional excipients, with a low melting point lipid (below 100 ° C). The granulate was made in the melt in a mixer-granulator, ie in one stage and in one container, without using any solvents. Various conventional finished pharmaceutical forms, such as e.g. suspension in concentrations of 125 mg / 5 ml and 250 mg / 5 ml, tablets or capsules.
Osnova za oblaganje je lahko klaritromicin sam ali njegova zmes z ekscipienti, kot so npr. laktoza, kalcijev karbonat, natrijev hidrogen fosfat, NaCI, citronska kislina, PEG, ali pa v želodcu netopni polimeri, kot npr. Eudragit L ali S (1:1 ali 1:2 kopolimer metakrilne kisline in MMA), mikrokristalna celuloza, ipd. Masno razmerje med klaritromicinom in temi ekscipienti je 5:1 - 1:1,2.The coating base may be clarithromycin alone or a mixture thereof with excipients such as e.g. lactose, calcium carbonate, sodium hydrogen phosphate, NaCI, citric acid, PEG, or gastric insoluble polymers such as e.g. Eudragit L or S (1: 1 or 1: 2 copolymer of methacrylic acid and MMA), microcrystalline cellulose, etc. The weight ratio of clarithromycin to these excipients is 5: 1 - 1: 1,2.
Kot lipidno, v vodi skoraj netopno, filmotvorno snov lahko uporabimo višji maščobni alkohol, prednostno stearil, cetostearil ali cetil, ali ustrezno kislino, npr. stearinsko, ali fizikalno zmes ali ester več takih sestavin, npr. stearil stearat. Masno razmerje med klaritromicinom in temi ekscipienti je 2:1 - 1:2.As a lipidic, water-insoluble, film-forming substance, a higher fatty alcohol, preferably stearyl, cetostearyl or cetyl, or a suitable acid, e.g. a stearin, or physical mixture or ester of several such ingredients, e.g. stearyl stearate. The weight ratio of clarithromycin to these excipients is 2: 1 - 1: 2.
Granuliranje s talino izvedemo tako, da zmes klaritromicina (z eventualno dodanimi pomožnimi snovmi) in lipidne snovi za oblaganje med mešanjem v granulatorju segrejemo do tališča lipidne snovi, nato pa počasi ohladimo nastali granulat. Za končno pripravo granulata za suspenzijo dodamo še povečevala viskoznosti in stabilizatorje, kot so guma ksantan, guma guar, silikagel, magnezijev aluminijev silikat, ipd. Za boljši okus, vonj in izgled lahko dodamo sladkor ali sladila, npr. aspartam, natrijev saharinat ali eritritol, karamel, vanilijevo ali sadno aromo ter barvila. Vsi navedeni dodatki za pripravo suspenzij sami nikakor ne morejo prekriti grenkobe klaritromicina.Granulation with the melt is carried out by heating the mixture of clarithromycin (with any auxiliary substances added) and the lipid coating materials to the melting point of the lipid substance while stirring in the granulator and then slowly cooling the resulting granulate. Viscosity enhancers and stabilizers such as xanthan gum, guar gum, silica gel, magnesium aluminum silicate, and the like are added to the final preparation of the granulate for suspension. Sugar or sweeteners can be added for better taste, aroma and appearance, e.g. aspartame, saccharin sodium or erythritol, caramel, vanilla or fruit flavor and colorants. All of these suspension supplements alone cannot in any way cover the bitterness of clarithromycin.
Kot izboljšavo izumljene farmacevtske oblike lahko sladkor nadomestimo s polioli, s čimer postane farmacevtska oblika širše uporabna - tudi za sladkorne bolnike. Za ta namen sta zelo primerna npr. ksilitol in manitol ter njune kombinacije z maltitolom, maltolom in sorbitolom. Izumljena farmacevtska oblika je tako edina peroralna suspenzija s klaritromicinom, ki ni osnovana na sladkorju (saharozi).As an improvement to the invented pharmaceutical form, the sugar can be replaced by polyols, thereby making the pharmaceutical form more widely used - even for diabetics. They are very suitable for this purpose, e.g. xylitol and mannitol and combinations thereof with maltitol, maltol and sorbitol. The invented pharmaceutical form is thus the only non-sugar based (sucrose) oral clarithromycin oral suspension.
Maščobni alkoholi, kot je stearil alkohol, imajo sorazmerno s koncentracijo zadrževalni učinek za sproščanje aktivne učinkovine iz farmacevtske oblike. To lahko uporabimo za kontrolo hitrosti sproščanja klaritromicina in izdelamo peroralno suspenzijo s podaljšanim delovanjem.Fatty alcohols, such as stearyl alcohol, have, in proportion to their concentration, a retention effect for the release of the active ingredient from the pharmaceutical form. This can be used to control the rate of clarithromycin release and to produce a sustained-release oral suspension.
Dodatno ali opcijsko lahko z nanosom gastrorezistentnega sloja na granulatno osnovo iz taline vplivamo na mesto sproščanja klaritromicina v prebavnem traktu. V ta namen uporabimo polimere, ki tvorijo gastrorezistentno oblogo, kot so šelak, celulozni acetat ftalat, HPMC ftalat, etilcelulozni lateks, polimetakrilate, ...In addition or optionally, the application of the gastro-resistant layer to the melt granulate base may affect the site of clarithromycin release in the gastrointestinal tract. For this purpose, we use polymers that form a gastroresistant coating such as shellac, cellulose acetate phthalate, HPMC phthalate, ethylcellulose latex, polymethacrylates, ...
Izum pojasnjujejo, vendar z ničimer ne omejujejo, naslednji izvedbeni primeri:The following embodiments are explained, but not limited in any way, by the invention:
ss
Primer 1Example 1
V mešalcu granulatorju homogeno pomešamo 2 kg klaritromicina in 2 kg stearilnega alkohola. Med mešanjem segrejemo do tališča in vmes vključimo sekalec. Nato ohlajamo ob stalnem mešanju. Nastanejo okrogle granule / pelete. Dodamo suhe dodatke.In the mixer granulator, 2 kg of clarithromycin and 2 kg of stearyl alcohol are homogeneously mixed. While stirring, warm to the melting point and turn on the chopper. Then cool with constant stirring. Round granules / pellets are formed. Dry additives are added.
Suhi dodatki na stekleničko, oz. k 5,00 g klaritromicin-stearilnega granulata (pelet):Dry additives per bottle, respectively. to 5.00 g of clarithromycin-stearyl granulate (pellet):
- Na2HPO4------------------------------------1,000 g- At 2 HPO 4 ------------------------------------ 1,000 g
- NaCI------------------------------------------1,000 g- NaCI ------------------------------------------ 1,000 g
- aspartam------------------------------------0,100 g- aspartame ------------------------------------ 0,100 g
- aerosil----------------------------------------0,400 g- Aerosil ---------------------------------------- 0.400 g
- aroma vanilija-----------------------------0,070 g- Vanilla flavor ----------------------------- 0,070 g
- amonijev glicirizinat---------------------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
- titanov dioksid-----------------------------0,050 g- titanium dioxide ----------------------------- 0,050 g
- barvilo kinolin rumeno-----------------0,010 g skupaj suhe snovi na stekleničko—69,000 g dodamo vode---------------------------------55,000 g dobimo volumen suspenzije----------100,000 ml vsebnost suspenzije·- Quinoline yellow color ----------------- 0,010 g total solids per bottle - 69,000 g water added ----------------- ---------------- 55,000 g obtain a suspension volume ---------- 100,000 ml suspension content ·
125 mg klaritromicina / 5 ml125 mg clarithromycin / 5 ml
Primer 2Example 2
Postopek je enak kot v Primeru 1, le da homogeno pomešamo 1,25 kg klaritromicina, 1,25 kg stearinske kisline in 1,5 kg NaH2PO4.The procedure was the same as in Example 1, except that homogeneously mixed 1.25 kg of clarithromycin, 1.25 kg of stearic acid and 1.5 kg of NaH 2 PO 4 .
Suhi dodatki na stekleničko, oz. k 7,2 g klaritromicin-obloženega granulata (pelet);Dry additives per bottle, respectively. to 7.2 g of clarithromycin-coated granulate (pellet);
- NaCI-------------------------------------------1,000 g- NaCI ------------------------------------------- 1,000 g
- aspartam-------------------------------------0,100 g- aspartame ------------------------------------- 0,100 g
- aerosil-----------------------------------------0,400 g- Aerosil ----------------------------------------- 0,400 g
- aroma karamel----------------------------0,070 g- caramel flavor ---------------------------- 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
- titanov dioksid----------------------------0,050 g- titanium dioxide ---------------------------- 0,050 g
- barvilo kinolin rumeno----------------0,010 g- Quinoline yellow color ---------------- 0,010 g
- citronska kislina--------------------------0,010 g- citric acid -------------------------- 0,010 g
Primer 3Example 3
Priprava granulata je enaka kot v primerih 1 ali 2.The preparation of the granulate is the same as in cases 1 or 2.
Dodatno nanesemo gastrorezistentno oblogo; za 200 mg peletnih jeder pripravimo naslednjo disperzijo:Gastroresistant coating is additionally applied; prepare the following dispersion for 200 mg of pellet cores:
- HPMC ftalat 55------------------------48,612 mg- HPMC Phthalate 55 ------------------------ 48,612 mg
- dibutil sebacat---------------------------0,893 mg- dibutyl sebacate --------------------------- 0,893 mg
- smukec-------------------------------------0,495 mg- talc ------------------------------------- 0,495 mg
- etanol------------------------------------332,143 mg- ethanol ------------------------------------ 332,143 mg
- aceton-----------------------------------332,143 mg- acetone ----------------------------------- 332,143 mg
V primeru nanosa gastrorezistentne obloge zmanjšamo dodatek sladila za 50 mg, sicer je priprava končne suspenzije enaka kot v primeru 1.In the case of a gastro-resistant coating, the sweetener additive is reduced by 50 mg, otherwise the preparation of the final suspension is the same as in Example 1.
Primer 4Example 4
Priprava granulata je enaka kot v primerih 1 ali 2.The preparation of the granulate is the same as in cases 1 or 2.
Dodatno nanesemo gastrorezistentno oblogo; za 500 mg peletnih jeder pripravimo vodno disperzijo:Gastroresistant coating is additionally applied; Aqueous dispersion is prepared for 500 mg of pellet cores:
- 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
- smukec-------------------------------------0,495 mg- talc ------------------------------------- 0,495 mg
- voda--------------------------------------332,143 mg- water -------------------------------------- 332,143 mg
Priprava vodne disperzije: trietil citrat, smukec in antipenilo suspendiramo v vodi ter homogeniziramo, nato pa med mešanjem dodamo k disperziji Eudragita tik pred uporabo. Filtriramo.Preparation of aqueous dispersion: The triethyl citrate, talc and antifoam are suspended in water and homogenized and then added to the Eudragit dispersion shortly before use. We filter.
Lek, tovarna farmacevtskih in kemičnih izdelkov d.d.Lek, a pharmaceutical and chemical factory d.d.
Claims (14)
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9900119A SI20244A (en) | 1999-05-19 | 1999-05-19 | Melt granulation |
| RU2001134166/14A RU2001134166A (en) | 1999-05-19 | 2000-05-18 | MELT GRANULATION |
| AU49697/00A AU4969700A (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
| PCT/SI2000/000013 WO2000069415A2 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
| HU0201233A HUP0201233A3 (en) | 1999-05-19 | 2000-05-18 | Pharmaceutical composition in the form of granulate and its preparation by melt granulation |
| SK1664-2001A SK16642001A3 (en) | 1999-05-19 | 2000-05-18 | Pharmaceutical formulation in granular form |
| YU82001A YU82001A (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
| EEP200100607A EE200100607A (en) | 1999-05-19 | 2000-05-18 | Pharmaceutical composition in granular form and a process for its preparation |
| CZ20014133A CZ20014133A3 (en) | 1999-05-19 | 2000-05-18 | Pharmaceutical preparation and process for preparing thereof |
| PL00351654A PL351654A1 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
| EP00931886A EP1183013A2 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
| HR20010932A HRP20010932A2 (en) | 1999-05-19 | 2001-12-18 | Melt granulation |
| BG106236A BG106236A (en) | 1999-05-19 | 2001-12-19 | Melt granulation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9900119A SI20244A (en) | 1999-05-19 | 1999-05-19 | Melt granulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SI20244A true SI20244A (en) | 2000-12-31 |
Family
ID=20432471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI9900119A SI20244A (en) | 1999-05-19 | 1999-05-19 | 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. |
| MXPA03003146A (en) * | 2000-10-13 | 2004-12-06 | Advancis Pharmaceuticals | Extended release erythromycin derivatives. |
| EP1484056B1 (en) * | 2002-02-21 | 2013-08-14 | Otsuka Pharmaceutical Co., Ltd. | Sustained release preparations and process for producing the same |
| 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 |
|---|---|---|---|---|
| WO1991019486A1 (en) * | 1990-06-14 | 1991-12-26 | Kalmo Enterprises, Inc. | Stable aqueous drug suspensions |
| JP3265680B2 (en) * | 1992-03-12 | 2002-03-11 | 大正製薬株式会社 | Oral pharmaceutical composition |
| KR0168715B1 (en) * | 1992-11-30 | 1999-01-15 | 밋첼 아이. 커시너 | 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 YU YU82001A patent/YU82001A/en unknown
- 2000-05-18 AU AU49697/00A patent/AU4969700A/en not_active Abandoned
- 2000-05-18 CZ CZ20014133A patent/CZ20014133A3/en unknown
- 2000-05-18 SK SK1664-2001A patent/SK16642001A3/en unknown
- 2000-05-18 HU HU0201233A patent/HUP0201233A3/en unknown
- 2000-05-18 WO PCT/SI2000/000013 patent/WO2000069415A2/en not_active Application Discontinuation
- 2000-05-18 EP EP00931886A patent/EP1183013A2/en not_active Withdrawn
- 2000-05-18 PL PL00351654A patent/PL351654A1/en not_active Application Discontinuation
- 2000-05-18 EE EEP200100607A patent/EE200100607A/en unknown
- 2000-05-18 RU RU2001134166/14A patent/RU2001134166A/en not_active Application Discontinuation
-
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 |
|---|---|
| WO2000069415A3 (en) | 2001-04-26 |
| SK16642001A3 (en) | 2002-05-09 |
| AU4969700A (en) | 2000-12-05 |
| CZ20014133A3 (en) | 2002-03-13 |
| WO2000069415A2 (en) | 2000-11-23 |
| EP1183013A2 (en) | 2002-03-06 |
| HUP0201233A2 (en) | 2002-08-28 |
| HRP20010932A2 (en) | 2003-04-30 |
| PL351654A1 (en) | 2003-05-19 |
| EE200100607A (en) | 2003-02-17 |
| RU2001134166A (en) | 2003-08-27 |
| YU82001A (en) | 2004-07-15 |
| BG106236A (en) | 2002-08-30 |
| HUP0201233A3 (en) | 2003-10-28 |
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| Date | Code | Title | Description |
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| IF | Valid on the event date | ||
| KO00 | Lapse of patent |
Effective date: 20060330 |