HRP940557A2

HRP940557A2 - Process for the preparation of ceruroxime axetil as pharmaceutical preparation

Info

Publication number: HRP940557A2
Application number: HRP-927/88A
Authority: HR
Inventors: Michael Bernard James; Leonard Godfrey Elliott
Original assignee: Glaxo Group Ltd
Priority date: 1987-05-14
Filing date: 1994-09-16
Publication date: 1997-08-31
Also published as: HRP940557B1; SI8810927A; SI8810927B

Description

Ovaj izum se odnosi na farmaceutske preparate koji sadrže 1-acetoksietil ester cefuroksima, čiji je priznati naziv cefuroksim aksetil. This invention relates to pharmaceutical preparations containing 1-acetoxyethyl ester of cefuroxime, whose recognized name is cefuroxime axetil.

Cefuroksim, kao što je opisano u Britanskoj patentnoj prijavi Br. 1453049, je vrijedan antibiotik širokog spektra koji se karakterizira visokom aktivnošću protiv širokog opsega grampozitivnih i gramnegativnih mikroorganizama, pri čemu je ova osobina povećana vrlo visokom stabilnošću jedinja prema betalaktamazama koje proizvodi veći broj grata negativnih mikroorganizama. Cefuroksim i njegove soli su prvenstveno važni kao injeksioni antibiotici jer se slabo absorbiraju iz gastrointestinalnog trakta. Cefuroxime, as described in British Patent Application No. 1453049, is a valuable broad-spectrum antibiotic characterized by high activity against a wide range of gram-positive and gram-negative microorganisms, whereby this feature is enhanced by the very high stability of the compound against beta-lactamases produced by a large number of gram-negative microorganisms. Cefuroxime and its salts are primarily important as injectable antibiotics because they are poorly absorbed from the gastrointestinal tract.

Mi smo otkrili da esterifikacija karboksilne grupe cefuroksima kao 1acetoksietil estera da bi se dobio cefuroksim aksetil poboljšava efikasnost kod oralnog uzimanja kao što je opisano u Britanskoj patentnoj prijavi Br. 1571683. Prisustvo 1acetoksietil esterificirajuće grupe rezultira u znacajnoj absorpciji spojeva iz gastrointestinalnog trakta, poslije čega se esterificirana grupa hidrolizira putem enzima prisutnih u, na primjer, krvi i tkivu organizma da bi se dobila antibiotski aktivna kiselina. Naročito je podesno da se upotrijebi cefuroksim aksetil u amorfnom obliku kao što je opisano u Britanskoj patentnoj prijavi Br. 2127401. We have found that esterification of the carboxyl group of cefuroxime as 1-acetoxyethyl ester to give cefuroxime axetil improves oral efficacy as described in British Patent Application No. 1571683. The presence of 1-acetoxyethyl esterifying group results in significant absorption of compounds from the gastrointestinal tract, after which the esterified group is hydrolyzed by enzymes present in, for example, blood and tissue of the organism to obtain an antibiotically active acid. It is particularly convenient to use cefuroxime axetil in amorphous form as described in British Patent Application No. 2127401.

Cefuroksim aksetil je stoga proširio potencijalnu terapeutsku vrijednost cefuroksima omogućavajući upotrebu oblika antibiotika koji se može davati oralno a ne samo u obliku injekcija. Cefuroxime axetil has therefore expanded the potential therapeutic value of cefuroxime by allowing the use of a form of the antibiotic that can be administered orally rather than just by injection.

Prikladan način predstavljanja antibiotika za oralno davanje je u obliku granula koje se mogu davati kao otopina ili kao suspenzija ili se uzimaju regenerirani sa vodom. Otopine ili suspenzije granula kao, na primjer, sirup, su praktično prikladni za oralno davanje antibiotika djeci. Međutim, cefuroksim aksetil ima nevjerojatno gorak ukus koji se dugo osjeća i koji se ne može adekvatno maskirati dodavanjem zasladivača ili mirisa konvencionalnim oblicima granula. A convenient way of presenting antibiotics for oral administration is in the form of granules that can be given as a solution or as a suspension or taken regenerated with water. Solutions or suspensions of granules such as, for example, syrup, are practically suitable for oral administration of antibiotics to children. However, cefuroxime axetil has an incredibly bitter taste that lingers for a long time and cannot be adequately masked by adding sweeteners or fragrances to conventional granule forms.

Drugi problem nastaje zbog tendencije cefuroksim aksetila, kako u kristalnom obliku tako i u gore spomenutom amorfnom obliku, da gradi želatinoznu masu kada stupi u kontakt sa vodenom sredinom. Ovaj efekat želiranja zavisi od temperature, ali se ne javlja na tetaperaturama od oko 37°C, tj. na fiziološkim temperaturama na kojima bi došlo do dezintegracije granula koje se uzimaju oralno. Kada se cefuroksim aksetil relativno sporo dispergira u vodenoj sredini koja ga okružuje nakon ingestije ne postoji rizik da će se cefuroksim aksetil prisutan u preparatu gelirati. Another problem arises from the tendency of cefuroxime axetil, both in its crystalline form and in its aforementioned amorphous form, to form a gelatinous mass when it comes into contact with an aqueous medium. This gelling effect depends on the temperature, but it does not occur at temperatures of about 37°C, i.e. at physiological temperatures at which disintegration of granules taken orally would occur. When cefuroxime axetil disperses relatively slowly in the aqueous environment that surrounds it after ingestion, there is no risk that the cefuroxime axetil present in the preparation will gel.

Ovako obrazovanje gela bi dovelo do slabog otapanja cefuroksim aksetila i tako do slabe absorpcije iz gastrointestinalnog trakta, tj. slabe bioiskoristljivosti. U slučaju obrazovanja granula upotreba djelića malih promjera i velikog površinskog područja je poželjno da bi se izbjeglo ovako geliranje. This formation of a gel would lead to poor dissolution of cefuroxime axetil and thus poor absorption from the gastrointestinal tract, i.e. poor bioavailability. In the case of granule formation, the use of particles with small diameters and a large surface area is preferable in order to avoid this gelation.

U spravljanju cefuroksim aksetila u obliku granula važno je izbjeći oslobađanje lijeka u bilo kakvoj tečnoj suspenziji koja se koristi, ili naravno, u ustima. Ovakvi problemi se mogu svesti na minimum oblikovanja cefuroksim aksetila u vidu djelića prevučenih lipidima, čija prevlaka ima ograničenu propustljivost za vodu. Ma kakve rupe u prevlaci bi značile da gorak ukus nije efikasno maskiran i zbog toga je važno da prevlaka bude integralna. In preparing cefuroxime axetil in granule form, it is important to avoid release of the drug in any liquid suspension used, or of course, in the mouth. Such problems can be minimized by forming cefuroxime axetil in the form of particles coated with lipids, the coating of which has limited water permeability. Any holes in the coating would mean that the bitter taste is not effectively masked, and therefore it is important that the coating is integral.

Mi smo tako otkrili da se izuzetno gorak ukus cefuroksim aksetila može prevladati nanošenjem na djaliće cefuroksim aksetila integralnih lipidnih prevlaka koje su netopljive u vodi ali koje se lako disperziraju ili otapaju u gastrointestinalnoj tekućini. Ovako obrazovani djelići sa prevlakom, koji ne odaju gorak cefuroksim aksetil u vlažnoj okolini usta, raspadaju se u kontaktu sa gastrointestinalnom tekućinom, tako da omogućavaju brzu disperziju i otapanje u gastrointestinalnom traktu. We thus discovered that the extremely bitter taste of cefuroxime axetil can be overcome by applying integral lipid coatings to cefuroxime axetil tablets that are insoluble in water but which are easily dispersed or dissolved in the gastrointestinal fluid. The particles with a coating formed in this way, which do not give off bitter cefuroxime axetil in the moist environment of the mouth, disintegrate in contact with the gastrointestinal fluid, so that they enable rapid dispersion and dissolution in the gastrointestinal tract.

Britanska patentna prijava Br. 2081092 opisuje upotrebu voska (tj. lipida) kao prevlake da bi se maskirao gorak ukus medicinske tvari. Međutim, na str. 1, red 4, do str. 2,red 5, objašnjeno je da upotreba vdskastih prevlaka kao rezultat daje slabo otapanje medicinske tvari u probavnom kanalu kao što je dato na primjerima preparata opisanom u Britanskoj patentnoj prijavi Br. 1323161 koji sadrži penamecilin prevučen lipidima koji sadrže hidrogenizirano ulje dabrovine; u Britanskom patentnom spisu Br. 2081092 je predloženo da se ovaj problem prevlada miješanjem upotrebljenih voskova sa materijalima koji u vodi bubre. British Patent Application No. 2081092 describes the use of a wax (ie lipid) as a coating to mask the bitter taste of a medicinal substance. However, on p. 1, line 4, to p. 2, line 5, it is explained that the use of water-based coatings results in poor dissolution of the medicinal substance in the alimentary canal as given in the examples of preparations described in British Patent Application No. 1323161 containing penamecillin coated with lipids containing hydrogenated beech oil; in the British patent file No. 2081092 it was proposed to overcome this problem by mixing used waxes with water-swelling materials.

Ovo očigledno ne bi bilo odgovarajuće za granule cefuroksim aksetila koje kada obrazuju vodenu suspenziju moraju zadržati osobine maskiranog ukusa pri skladištenju do 14 dana. Ukoliko se koristi prevlaka koja sadrži materijale koji bubre u vodi, tada će se neizbježno izgubiti efekt maskiranja ukusa koji ima prevlaka ukoliko se preparat čuva u vodenoj sredini tokom ovog vremenskog perioda. This would obviously not be appropriate for cefuroxime axetil granules which, when forming an aqueous suspension, must retain the properties of masked taste when stored for up to 14 days. If a coating containing materials that swell in water is used, then the taste masking effect of the coating will inevitably be lost if the preparation is kept in an aqueous environment during this time period.

Lipidne prevlake su do sada takoder korištene da bi dale praškove sa slobodnim oticanjem (vidi na primjer US Patent br. 3247065) i u preparatima lijekova sa usporenim oslobađanjem koji se mogu formulirati kao tablete ili kapsule (vidi na primjer US Patent Br. 3146167). Ovi proizvodi su međutim mnogo većih dimenzija djelića nego što bi bilo prihvatljivo za unošenje u vodenu suspenziju za oralno davanje. Lipid coatings have also been used heretofore to provide free-swelling powders (see, for example, US Patent No. 3,247,065) and in sustained-release drug preparations that can be formulated as tablets or capsules (see, for example, US Patent No. 3,146,167). These products, however, have much larger particle sizes than would be acceptable for incorporation into an aqueous suspension for oral administration.

Osim toga a s obzirom na: In addition and with regard to:

(i) ranije upotrebe lipidnih prevlaka kod lijekova sa usporenim oslobađanjem, (i) previous use of lipid coatings with slow-release drugs,

(ii) problem niske bioiskoristljivosti lijekovite tvari kada se koriste voskovite prevlake kao što je opisano u Britanskoj patentnoj prijavi Br. 2081092, i (ii) the problem of low bioavailability of the drug substance when wax coatings are used as described in British Patent Application No. 2081092, i

(iii) poznate tendencije cefuroksim aksetila da se gelira uz kasniju slabu absorpciju iz gastrointestinalnog trakta, naročito je iznenađujuće da djelići cefuroksim aksetila sa integralnim lipidnim prevlakama omogućuju brzo dispergiranje i otapanje u gastrointestinalnom traktu i tako omogućavaju postizanje prihvatljivih nivoa bioiskoristljivosti. (iii) the known tendency of cefuroxime axetil to gel with subsequent poor absorption from the gastrointestinal tract, it is particularly surprising that particles of cefuroxime axetil with integral lipid coatings enable rapid dispersion and dissolution in the gastrointestinal tract and thus enable the achievement of acceptable levels of bioavailability.

Prema jednom aspektu izuma tako osiguravamo preparat koji obuhvaća cefuroksim aksetil u obliku djelića, pri čemu su djelici prevučeni inegralnom prevlakom lipida ili smjese lipida koji su netopljivi u vodi i koji služe kao maska gorkom ukusu cefuroksim aksetila kod oralnog davanja, ali koji se dispergiraju ili otapaju u kontaktu sa gastrointestinalnim fluidom. According to one aspect of the invention, we thus provide a preparation comprising cefuroxime axetil in the form of particles, wherein the particles are coated with an integral coating of lipids or lipid mixtures which are insoluble in water and which serve to mask the bitter taste of cefuroxime axetil when administered orally, but which disperse or dissolve in contact with gastrointestinal fluid.

Da bi se osigurali djelići cefuroksim aksetila maskiranog ukusa prihvatljivi za oralno uzimanje, točka topljenja upotrijebljenog lipida bi trebala biti dovoljno visoka da spriječi topljenje prevučenih djelića u ustima, pri čemu dolazi do oslobađanja gorkog ukusa aktivnog sastojka, ali ne tako visoka da dođe do topljenja samog cefuroksim aksetilnog aktivnog sastojka i/ili njegove kemijske degradacije tokom postupka prevlačenja. Tako ce lipid ili smjesa lipida za upotrebu u ovom izumu podesno imati točku topljenja od 30 do 80°C, a podesno od 40 do 70°C. To provide taste-masked cefuroxime axetil particles acceptable for oral administration, the melting point of the lipid used should be high enough to prevent melting of the coated particles in the mouth, releasing the bitter taste of the active ingredient, but not so high that it melts itself. active ingredient cefuroxime axetil and/or its chemical degradation during the coating process. Thus, the lipid or mixture of lipids for use in this invention will suitably have a melting point of 30 to 80°C, and suitably of 40 to 70°C.

Kada preparat prema izumu sadrži amorfni cefuroksiio aksetil, tocka topljenja lipida ili smjese lipida je još bolje od 45 do 60°C. When the preparation according to the invention contains amorphous cefuroxylio axetil, the melting point of the lipid or lipid mixture is even better from 45 to 60°C.

Podesni lipidi uključuju masne kiseline ili njihove monohidroksidne alkohole, fiksirana ulja, rnasti, voskove, sterole, fosfolipide i glikolipide. Lipidi mogu, na primjer, biti velike molekulske mase (C10-30) ravnog niza, zasićene ili nezasićene alifatične kiseline, kao stearinska kiselina ili palmitinska kiselina; trigliceridi, na primjer gliceril ester alifatične kiseline visoke molekulske mase (C10-30) što je trilaurat ili gliceril trimiristat; parcijalno hidrogenizirano biljno ulje kao što je ulje iz sjemena pamuka ili sojino ulje; vosak, na primjer pčelinji vosak ili karnaubavosak; alifatični alkoholi velike molekulske mase (C10-30) ravnog niza, kao što je stearil alkohol ili ketil alkohol; ili njihove smjese. Suitable lipids include fatty acids or monohydric alcohols thereof, fixed oils, fats, waxes, sterols, phospholipids and glycolipids. Lipids can, for example, be high molecular weight (C10-30) straight chain, saturated or unsaturated aliphatic acids, such as stearic acid or palmitic acid; triglycerides, for example a high molecular weight (C10-30) aliphatic acid glyceryl ester which is trilaurate or glyceryl trimyristate; a partially hydrogenated vegetable oil such as cottonseed oil or soybean oil; wax, for example beeswax or carnauba wax; high molecular weight (C10-30) straight chain aliphatic alcohols, such as stearyl alcohol or ketyl alcohol; or mixtures thereof.

Smjese masnih kiselina velike molekulske mase kao što su smjese stearinske kiseline i palmitinske kiseline, smjese alifatičnih alkohola ravnog niza visoke molekulske mase, kao što su ketostearil alkohol, smjese parcijalno hidrogeniziranog ulja iz sjemena parnuka i sojinog ulja i smjese alifaticnih kiselina visoke molekulske mase i gliceril estera kao što je smjesa stearinske kiseline i gliceril trilaurata, se na primjer mogu upotrijebiti. Posebno poželjan lipid koji osigurava dobru bioiskoristljivost i ima fizičke osobine posebne korapatibilne sa cefuroksim aksetilom, je stearinska kiselina u smjesi sa palmitinskom kiselinom u odnosu od 3:7 do 7:3 mas., bolje od oko 1:1 mas. Mixtures of high molecular weight fatty acids such as mixtures of stearic acid and palmitic acid, mixtures of high molecular weight straight chain aliphatic alcohols such as ketostearyl alcohol, mixtures of partially hydrogenated rapeseed oil and soybean oil, and mixtures of high molecular weight aliphatic acids and glyceryl esters such as a mixture of stearic acid and glyceryl trilaurate, for example, can be used. A particularly desirable lipid that ensures good bioavailability and has physical properties particularly compatible with cefuroxime axetil is stearic acid in a mixture with palmitic acid in a ratio of 3:7 to 7:3 by weight, better than about 1:1 by weight.

Preparat prema izumu može sadržavati cefuroksim aksetil u kristalnom obliku ili poželjnije u amorfnom obliku, na primjer kao što je opisano u Britanskoj patentnoj prijavi Br. 2127401. The preparation according to the invention may contain cefuroxime axetil in crystalline form or more preferably in amorphous form, for example as described in British Patent Application No. 2127401.

Ukoliko se želi, cefuroksim aksetil se može prvo prevući podprevlakom sa supstancom kojom se može prevlačiti. Ovo podprevlačenje može poslužiti da zaštiti cefuroksim aksetil u slučajevima kada postoji kemijska osjetljivost na lipid sa kojim je prevučen. If desired, cefuroxime axetil can first be coated with an undercoat with a coating substance. This undercoating may serve to protect cefuroxime axetil in cases where there is chemical sensitivity to the lipid with which it is coated.

Supstanca sa osobinama prevlake koja se koristi za podprevlačenje je poželjno u vodi topljiva i poželjno je to sredstvo koje gradi film. Sredstva za obrazovanje filma koja su korisna uključuju polisaharide kao što je maltodekstrin, alkilceluloze kao što su metil ili etil celuloza, hidfoksialkilceluloze (npr. hidroksipropilceluloza ili hidroksi propil metilceluloze), polivinilpirolidon i polimeri na bazi metakrilne kiseline. Ovi se mogu nanositi iz vodenih ili nevodenih sistema, prema potrebi. Maltodekstrin je naročito poželjan. Djelići prevučeni podprevlakom u kojima je cefuroksim aksetil prisutan u koncetraciji od 10 do 30% mas., na primjer oko 20% mas., mogu se podesno upotrijebiti za prevlačenje sa lipidom. The substance with coating properties used for undercoating is preferably water-soluble and is preferably a film-building agent. Useful film formers include polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose, hydroxyalkyl celluloses (eg, hydroxypropyl cellulose or hydroxy propyl methyl cellulose), polyvinylpyrrolidone, and methacrylic acid based polymers. These can be applied from aqueous or non-aqueous systems, as required. Maltodextrin is particularly preferred. Undercoating particles in which cefuroxime axetil is present in a concentration of 10 to 30% by weight, for example about 20% by weight, can conveniently be used for lipid coating.

Djelići prevučeni lipidom prema izumu će poželjno sadržavati od 5 do 90%, poželjno od 5 do 50% a još bolje od 5 ili 10 do 30% mas. cefuroksim aksetila. Kada se cefuroksim aksetil prvo prevlači podprevlakom, djelići prevučeni lipidom najpodesnije sadrže od 5 do 15% mas. cefuroksim aksetila; kada nema podprevlake, djelići prevučeni lipidom najpodesnije sadrže od 10 do 30% mas. cefuroksim aksetila. Particles coated with lipid according to the invention will preferably contain from 5 to 90%, preferably from 5 to 50% and even better from 5 or 10 to 30% by weight. cefuroxime axetil. When cefuroxime axetil is first coated with an undercoat, the lipid-coated fractions preferably contain from 5 to 15% by weight. cefuroxime axetil; when there is no sub-coating, lipid-coated particles most suitable contain from 10 to 30% by weight. cefuroxime axetil.

U općem slucaju, djelići sa integralnom lipidnom prevlakom za maskiranje gorkog ukusa cefuroksim aksetila mogu imati promjer manji od 250 mikrometara. In general, particles with an integral lipid coating to mask the bitter taste of cefuroxime axetil may have a diameter of less than 250 micrometers.

Prevučeni djelići sa promjerima u opsegu od 1 do 250 mikrometara su stoga najpodesniji. Veličina prevučenih djelića je važan faktor u pogledu bioiskoristljivosti cefuroksim aksetila i prihvatljivosti takvih proizvoda za oralno uzimanje, pri čemu prosječne veličine djelića od preko oko 250 mikrometara prosječnog promjera zapreminski imaju neželjeni pjeskovit okus. Farmaceutski proizvodi prema izumu će se stoga obično uzimati u obliku prevučenih djelića koji imaju prosječan promjer zapreminski od manje od 100 mikrona, npr. u opsegu od 20 do 100 mikrometara ili bolje od 30 do 60 mikrometara. Podesno je da se inegralna lipidna prevlaka nanosi na djeliće koji su prije prevlačenja imali srednji promjer zapreminski od manje 80 mikrometara, npr. u opsegu od 5 do 50 mikrometara. Coated particles with diameters in the range of 1 to 250 micrometers are therefore most suitable. Coated particle size is an important factor in the bioavailability of cefuroxime axetil and the acceptability of such products for oral administration, with average particle sizes greater than about 250 micrometers in volume average diameter having an undesirable gritty taste. The pharmaceutical products of the invention will therefore typically be taken in the form of coated particles having a volume average diameter of less than 100 microns, eg in the range of 20 to 100 micrometers or preferably 30 to 60 micrometers. Suitably, the integral lipid coating is applied to particles that prior to coating had a mean volume diameter of less than 80 micrometers, eg in the range of 5 to 50 micrometers.

Na primjer, amorfni cefuroksim eaksetil se može pripremiti u obliku šupljikavih mikrosfera sa srednjim zapreminskim promjerom od 5 do 50 rnikrometara metodom nanošenja prskanjem kao što je opisano u Britanskoj patentnoj prijavi br. 2127401. For example, amorphous cefuroxime eaxetil can be prepared in the form of hollow microspheres with a volume mean diameter of 5 to 50 micrometers by the spray application method as described in British Patent Application No. 2127401.

Prevučeni djelići prema izumu se mogu podesno pripremiti atomizacijom disperzije isitnjenog cefuroksim aksetila u istopljenom lipidu i hlađenjem prevučenih djelića koji se tako dobijaju i ovakav postupak čini dalji predmet izuma. Disperzija se može pripremiti dodavanjem isitnjenog cefuroksim aksetila u istopljeni lipid ili smjesu lipida ili alternativno miješanjem sastojaka disperzije zajedno u istopljenom stanju a potora topljenjem lipida ili smjese lipida. Isitnjeni cefuroksim aksetil se može dispergirati u istopljenom lipidu upotrebom konvencionalnih tehnika, na primjer, upotrebom miksera sjekača. U općem slučaju, temperatura istopljenog lipida će biti od 10 do 20°C iznad njegove točke topljenja. Coated particles according to the invention can conveniently be prepared by atomizing a dispersion of diluted cefuroxime axetil in molten lipid and cooling the coated particles thus obtained, and this procedure forms a further subject of the invention. The dispersion can be prepared by adding cooled cefuroxime axetil to a molten lipid or lipid mixture or alternatively by mixing the dispersion ingredients together in a molten state and then melting the lipid or lipid mixture. Powdered cefuroxime axetil can be dispersed in the molten lipid using conventional techniques, for example, using a chopper mixer. In general, the temperature of the molten lipid will be 10 to 20°C above its melting point.

Naročito poželjna disperzija za dobivanje lipidom prevučenih djelića cefuroksim aksetila je disperzija cefuroksim aksetila u smjesi sa stearinskom kiselinom i palmitiskom kiselinom u odnosu od 3:7 do 7:3 mas., poželjno u odnosu od oko 1:1 mas. Količina cefuroksim aksetila u disperzijama za dobijanje djelića prevučenih lipidom prema izumu je obračunata tako da se osigura željena količina cefuroksim aksetila u prevučenim djelićima kao što je gore objašnjeno. Istopljena disperzija se atomizira da bi se hlađenjem dobili djelići cefuroksim aksetila prevučeni lipidom. Tehnike koje se mogu upotrijebiti ukIjučuju upotrebu konvencionalnih atomizera kao što su rotacioni atomizer, mlaznice pod pritiskom, pneumatske mlaznice, i sonične mlaznice. A particularly preferred dispersion for obtaining lipid-coated particles of cefuroxime axetil is a dispersion of cefuroxime axetil in a mixture with stearic acid and palmitic acid in a ratio of 3:7 to 7:3 by weight, preferably in a ratio of about 1:1 by weight. The amount of cefuroxime axetil in the dispersions for obtaining the lipid-coated particles according to the invention is calculated to provide the desired amount of cefuroxime axetil in the coated particles as explained above. The molten dispersion is atomized to obtain lipid-coated cefuroxime axetil particles on cooling. Techniques that can be used include the use of conventional atomizers such as rotary atomizers, pressurized nozzles, pneumatic nozzles, and sonic nozzles.

Upotreba pneumatskih mlaznica a posebno atomizera sa pneumatskim mlaznicama gdje se miješaju dva fluida, unutra ili van, u standardnom aparatu gdje se vrši sušenje prsjanjem/hladenjem, je posebno podesna. Podesne mlaznice sa unutrašnjim miješanjem dva fluida opisane su npr. u Britanskoj patentnoj prijavi Br. 1412133. The use of pneumatic nozzles and especially atomizers with pneumatic nozzles where two fluids are mixed, inside or outside, in a standard apparatus where spray drying/cooling is carried out, is particularly suitable. Adjustable nozzles with internal mixing of two fluids are described, for example, in British Patent Application No. 1412133.

U procesu atomizacije koji koristi atomizer sa mlaznicom i unutrašnjim miješanjem dva fluida, koji čini poželjno izvođenje izuma, disperzija istopljenog lipida i cefuroksim aksetila se obično dovodi u gornji dio atomizera na temperaturi u opsegu od 60 do 80°C, poželjno 65 do 75°C, pri čemu precizna temperatura zavisi od posebnosti upotrebljenog lipidnog materijala. Plin za atomizaciju koji se dovodi u mlaznice može biti zrak ili inertan plin kao što je suhi dušik. In the atomization process using a nozzle atomizer and internal mixing of two fluids, which makes the preferred embodiment of the invention, the dispersion of molten lipid and cefuroxime axetil is usually fed into the upper part of the atomizer at a temperature in the range of 60 to 80°C, preferably 65 to 75°C , where the precise temperature depends on the particularity of the lipid material used. The atomizing gas supplied to the nozzles may be air or an inert gas such as dry nitrogen.

Temperatura plina će obično biti u opsegu od 60 do 90°C, poželjno 70 do 85°C pri čemu će precizna temperatura zavisiti od posebnosti upotrijebljenog lipidnog materijala. Mi smo utvrdili da je temperatura pri kojoj se održava stopljena disperzija poželjna u opsegu od 10 do 20°C iznad točke topljenja uzetog lipida ili smjese lipida da bi se osigurala željena viskoznost za atomizaciju. Pritisak atomizacije se poželjno kontrolira da bi se proizveli prevučeni djelići gore navedenih poželjnih dimenzija. The temperature of the gas will usually be in the range of 60 to 90°C, preferably 70 to 85°C, whereby the precise temperature will depend on the particularity of the lipid material used. We have determined that the temperature at which the molten dispersion is maintained is preferably in the range of 10 to 20°C above the melting point of the lipid or mixture of lipids taken to ensure the desired viscosity for atomization. The atomization pressure is preferably controlled to produce coated particles of the above preferred dimensions.

Prevučeni djelići se mogu očvrsnuti i sakupiti konvencionalnim tehnikama. Prevučeni djelići mogu podesno očvrsnuti dovođenjem struje hladnog zraka ili poželjno suhog dušika u komoru za prskanje na temperaturi od na primjer 0 do 30°C, poželjno 520°C tako da je hlađenje i očvršćavanje djelića kompletno. Proizvod se može na primjer sakupiti primjenom ciklonskog separatora, prahfiltera, ili gravitacijom. The coated particles can be solidified and collected using conventional techniques. The coated particles can be conveniently hardened by introducing a stream of cold air or preferably dry nitrogen into the spray chamber at a temperature of, for example, 0 to 30°C, preferably 520°C, so that the cooling and hardening of the particles is complete. The product can be collected, for example, by using a cyclone separator, a dust filter, or by gravity.

Kada se cefuroksim aksetil za dispergiranje u lipidnom materijalu oblaže podprevlakom, supstanca podprevlake se može nanositi na cefuroksim aksetil primjenom konvencionalnih metoda prevlačenja, na primjer, prevlačenjein prskanjem primjenom granulatora sa fluidiziranim slojem, centrifugalnog uređaja za oblaganje sa fluidiziranim slojem ili aparata za sušenje prskanjem ili se može prevlačiti pomoću rotacionog granulatora. U pripremanju djelića prevučenih lipidom gore opisanim postupkom, koncentracija cefuroksim aksetila prevučenog podprevlakom u istopljenog disperziji je podesno u opsegu od 20 do 80% mas., bolje od 35 do 65% mas. Prevlačenje lipidom tako poželjno osigurava 20 do 80%, bolje 3565%, mas., prevučenih djelića prema izumu koji su pripremljeni polazeći od cefuroksim aksetila prevučenog podprevlakom. When cefuroxime axetil for dispersing in a lipid material is coated with an undercoat, the undercoating substance can be applied to the cefuroxime axetil using conventional coating methods, for example, spray coating using a fluidized bed granulator, a centrifugal fluidized bed coater, or a spray dryer, or can be coated using a rotary granulator. In the preparation of lipid-coated particles by the process described above, the concentration of sub-coated cefuroxime axetil in the molten dispersion is suitably in the range of 20 to 80% by weight, preferably 35 to 65% by weight. The lipid coating thus preferably provides 20 to 80%, preferably 35-65%, by weight, of the coated particles according to the invention which are prepared starting from cefuroxime axetil coated with an undercoat.

Proizvodi u djelićima prema izumu se mogu upotrijebiti u farmaceutskim preparatima za oralno uzimanje i mogu biti u obliku suspenzije za davanje, kao suhi proizvodi za konstituiranje sa vodom ili drugim podesnim nosačima prije upotrebe za uzimanje u obliku suspenzije, ili za direktno uzimanje a zatim vode ili podesne tekućine. Products in particles according to the invention can be used in pharmaceutical preparations for oral administration and can be in the form of a suspension for administration, as dry products for constitution with water or other suitable carriers before use for administration in the form of a suspension, or for direct administration followed by water or suitable liquids.

Ovakvi preparati se mogu pripremiti na konvencionalan način sa farmaceutski prihvatljivim aditivima kao što su sredstva za suspendiranje i/ili vezivanje, npr. alkilceluloza kao što je metil celuloza, hidroksialkilceluloza, kao što je hidroksi propilceluloza i hidroksipropilmetilceluloza, natrij karboksimetilceluloza ili njihove smjese, preželatinizirani kukuruzni skrob ili polivinilpirolidon; punioci, npr. sukroza, skrob, laktoza i mikrokristalna celuloza; adsorbenti i sredstva za poboljšanje glatkoće kao što su talk, sluminij oksid i silicij dioksid; emulgirajuća i sredstva za zgušnjavanje npr. lecitin ili aluminij stearati; površinski aktivna sredstva, npr. natrij lauril sulfat ili nejonski polioksi etilen polioksi propilen kopolimeri; prezervativi npr. metil ili propil hidroksibenzoati ili sorbinska kiselina; sredstva za bojenje, npr. titan dioksidni pigmenti, slicne boje i željezo oksidni pigmenti; sredstva za miris npr. "mint" ukusi kao što je pepermint; i zasladivači npr. sorbitol i surkoza ili umjetni zasladivači npr. saharin i natrij ciklamat. Such preparations can be prepared in a conventional manner with pharmaceutically acceptable additives such as suspending and/or binding agents, e.g. alkylcellulose such as methyl cellulose, hydroxyalkylcellulose such as hydroxypropylcellulose and hydroxypropylmethylcellulose, sodium carboxymethylcellulose or mixtures thereof, pregelatinized corn starch or polyvinylpyrrolidone; fillers, eg sucrose, starch, lactose and microcrystalline cellulose; adsorbents and smoothing agents such as talc, aluminum oxide and silicon dioxide; emulsifying and thickening agents, eg lecithin or aluminum stearates; surfactants, eg sodium lauryl sulfate or nonionic polyoxyethylene polyoxypropylene copolymers; preservatives eg methyl or propyl hydroxybenzoates or sorbic acid; coloring agents, eg titanium dioxide pigments, similar colors and iron oxide pigments; fragrances eg "mint" flavors such as peppermint; and sweeteners eg sorbitol and surcose or artificial sweeteners eg saccharin and sodium cyclamate.

Kada su aditivi u čvrstom obliku, djelići prema izumu se mogu pomiješati sa aditivima u obliku suhe smjese aditiva ili se aditivi mogu sami formulirati u ekscipijentne granule za miješanje sa aktivnim djelićima prema izumu, ili još bolje, djelići prema izumu se mogu granulirati zajedno sa aditivima primjenom konvencionalnih tehnika. When the additives are in solid form, the particles according to the invention can be mixed with the additives in the form of a dry mixture of additives, or the additives can themselves be formulated into excipient granules for mixing with the active particles according to the invention, or even better, the particles according to the invention can be granulated together with the additives using conventional techniques.

Ovakve tehnike granuliranja uključuju upotrebu konvencionalnih granulatora npr. granulatora sa prskanjem, rotacionih granulatora, centrifugalnih granulatora sa fluidiziranim slojem, granulatora sa mikserom velikih brzina i tehnikama ekstruzije i sitnjenja. Sušenje se može vršiti konvencionalnim tehnikama, na primjer u granulatoru ili u sušnici ili sušnici sa vrućim zrakom. Poželjno je, naravno, da granule treba pripremiti metodom koja je podesna za osiguravanje granula željene veličine; ovo se obično može postići uobičajenim podešavanjem uvjeta granuliranja i, ako je potrebno, prosijavanjem granula koje su tako dobijene. Such granulation techniques include the use of conventional granulators such as spray granulators, rotary granulators, centrifugal fluidized bed granulators, high speed mixer granulators, and extrusion and comminution techniques. Drying can be done by conventional techniques, for example in a granulator or in a dryer or hot air dryer. Preferably, of course, the granules should be prepared by a method suitable for providing granules of the desired size; this can usually be achieved by the usual adjustment of the granulation conditions and, if necessary, by sieving the granules thus obtained.

Kada je farmaceutski preparat za oralno uzimanje u obliku suspenzije, ova može biti u vodenom ili nevodenom nosaču pod uvjetom da je isti kompatibilan sa lipidnim materijalorn prevlake. Podesni nevodeni nosači za suspendiranje uključuju, na primjer, badernovo ulje, frakcionisano kokosovo ulje ili uljne estere. When the pharmaceutical preparation for oral administration is in the form of a suspension, it can be in an aqueous or non-aqueous carrier, provided that it is compatible with the lipid coating material. Suitable non-aqueous suspending vehicles include, for example, safflower oil, fractionated coconut oil or oil esters.

U daljnjem aspektu, prema tome, izum osigurava farmaceutski preparat za oralno uzimanje koji obuhvaća preparat prema izumu zajedno sa jednim ili više farmaceutskih nosača ili ekscipijenata. In a further aspect, the invention therefore provides a pharmaceutical preparation for oral administration comprising a preparation according to the invention together with one or more pharmaceutical carriers or excipients.

Posebno su osigurane granule za oralno davanje koje obuhvaćaju prevučene djeliće cefuroksim aksetila prema izumu zajedno sa jednim ili više farmaceutski prihvatljivih ekscipijenata. Materijal ekscipijenta poželjno obuhvaća zasladivače, na primjer sukrozu. Drugi farmaceutski prihvatljivi ekscipijenti koji mogu biti prisutni uključuju one koji su opisani ranije. Granule se mogu pripremiti prijemom gore opisanih konvencionalnih metoda. Granuliranje se može postići, na primjer, miješanjem sastojaka, i granuliranjem sa vodom. Dobivene granule se mogu propustiti kroz sito da bi se uklonili djelići suviše velikih dimenzija. Granule promjera ispod 1000 mikrometara, a posebno ispod 800 mikrometara su najpoželjnije. Specially provided are granules for oral administration comprising coated particles of cefuroxime axetil according to the invention together with one or more pharmaceutically acceptable excipients. The excipient material preferably comprises sweeteners, for example sucrose. Other pharmaceutically acceptable excipients that may be present include those described earlier. Granules can be prepared by adopting the conventional methods described above. Granulation can be achieved, for example, by mixing the ingredients, and granulating with water. The resulting granules can be passed through a sieve to remove particles that are too large. Granules with a diameter below 1000 micrometers, and especially below 800 micrometers, are most preferred.

Kada se djelići prema izumu formuliraju u vodenoj sredini, ona poželjno sadrži visoke koncentracije oralno prihvatljive otopine koja pomaže u održavanju osobina maskiranja ukusa lipidne prevlake. Tako, na primjer, vodena sredina može da sadrži šečer, na primjer sukrozu, poželjno u koncentraciji od 50 do 35% mas., poželjno 60 do 80% mas. Ovakva otopina može podesno da se unese u granule koje sadrže isitnjeni proizvod prema izumu. U slučaju sukroze ona takoder služi kao zasladivač i kao prezervativ. When the particles according to the invention are formulated in an aqueous medium, it preferably contains high concentrations of an orally acceptable solution that helps maintain the taste-masking properties of the lipid coating. Thus, for example, the aqueous medium can contain sugar, for example sucrose, preferably in a concentration of 50 to 35% by weight, preferably 60 to 80% by weight. Such a solution can conveniently be introduced into granules containing the refined product according to the invention. In the case of sucrose, it also serves as a sweetener and as a preservative.

Farmaceutski preparat prema izumu, formuliran za oralno davanje kao suspenzija, može se konstituirati sa podesnom količinom vode, za upotrebu u oralnom uzimanju cefuroksim aksetila. Djelići će obično biti u takvom obliku da daju multidoznu suspenziju koja sadrži ekvivalent od 500 mg do 10 g cefuroksima ili jednost.ruku dozu suspenzije koja sadrži ekvivalenat od 100-1000 mg cefuroksima. The pharmaceutical preparation according to the invention, formulated for oral administration as a suspension, can be constituted with a suitable amount of water, for use in oral administration of cefuroxime axetil. The particles will usually be in such a form as to provide a multidose suspension containing the equivalent of 500 mg to 10 g of cefuroxime or a single dose suspension containing the equivalent of 100-1000 mg of cefuroxime.

Upotrijebljene doze za tretiranje ljudi će obično biti u opsegu od 100-3000 mg cefuroksima na dan, npr. 250 do 2000 mg cefuroksima na dan za odrasle i 125 do 1000 rng cefuroksima na dan za djecu, mada će precizna doza između ostalog zavisiti i od frekfencije uzimanja. Dosages used to treat humans will usually be in the range of 100-3000 mg cefuroxime per day, eg 250 to 2000 mg cefuroxime per day for adults and 125 to 1000 rng cefuroxime per day for children, although the precise dose will depend on, among other things, frequency of intake.

Izum je ilustriran slijedećim primjerima. The invention is illustrated by the following examples.

Cefuroksim aksetil upotrijebljen u primjerima je sprejanjem osušen amorfni materijal visoke čistoće kao što je opisan u Britanskoj patentnoj prijavi br. 2127401 sa srednjim promjerom djelića, zapreminski, u opsegu od 550 mikrometara (um). The cefuroxime axetil used in the examples is a high purity spray dried amorphous material as described in British Patent Application No. 2127401 with a mean particle diameter, by volume, in the range of 550 micrometers (um).

Revel A je stearinska kiselina koja se koristi u prehrani, Hyfac je komercijalna stearinska kiselina, Dynasan 112 je gliceril trilaurat i Dynasan 114 je gliceril trimiristat. Revel A, Hyfac, Dynasan 112 i Dynasan 114 su trgovački nazivi. Stearinska kiselina BPC je opisana kao smjesa masnih kiselina, uglavnom stearinske i palmitinske kiseline, u Britanskom farrnaceutskom kodeksu (1973). Revel A is food grade stearic acid, Hyfac is commercial grade stearic acid, Dynasan 112 is glyceryl trilaurate and Dynasan 114 is glyceryl trimyristate. Revel A, Hyfac, Dynasan 112 and Dynasan 114 are trade names. Stearic acid BPC is described as a mixture of fatty acids, mainly stearic and palmitic acids, in the British Pharmaceutical Codex (1973).

U "National Formulary XV, 1980" Sjedinjenih Država, stearinska kiselina USNF je opisana kao kiselina koja sadrži ne manje od 40% stearinske kiseline, ne manje od 40% palmitinske kiseline i ne manje od 90% stearinske i palmitinske kiseline. In "National Formulary XV, 1980" of the United States, stearic acid USNF is described as an acid containing not less than 40% stearic acid, not less than 40% palmitic acid, and not less than 90% stearic and palmitic acid.

Posebna rnjerenja veličina djelića u primjerima 1 do 3 izvedena su optičkim mikroskopom, Coulter Counterom i Special measurements of particle sizes in examples 1 to 3 were performed with an optical microscope, a Coulter Counter and

pomoću lasera primjenom slijedećih metoda: using a laser using the following methods:

1. Optički mikroskop 1. Optical microscope

Mali uzorak materijala prevučenog lipidom suspendiran je na mikroskopskoj pločici u silikonskoj tekućini i djelići su promatrani i brojani pri povećanju od x 100 primjenom Imanco FMS mikroskopa. A small sample of the lipid-coated material was suspended on a microscope slide in liquid silicone and particles were observed and counted at x100 magnification using an Imanco FMS microscope.

Za svaku grupu pripremljene su po dvije pločice i brojano je devet polja po pločici. Veličina djelića je određivana u odnosu na Britanski standard (8S 3406y 1961) i rangirana od 60 um do 7.5 um. Pročitana vrijednost za svaku veličinu je zabilježena i upotrijebljena za obračunavanje srednjeg zapreminskog promjera (VMD) primjenom slijedeće formule: Two plates were prepared for each group and nine fields per plate were counted. Particle size was determined in relation to the British Standard (8S 3406y 1961) and ranked from 60 um to 7.5 um. The read value for each size was recorded and used to calculate the volumetric mean diameter (VMD) using the following formula:

[image] [image]

M (χi) = broj u datoj velicini M (χi) = number in the given quantity

χi = srednja točka veličine (trake) χi = midpoint of size (bars)

2. ‘Coulter Counter’ 2. 'Coulter Counter'

Mali uzorak materijala prevučenog iipidom suspendiran je u Coulterovors disperzantu na mikroskopskoj pločici. Izvjesna količina ovog disperziranog uzorka je dodata u posudu za mjerenje Coulter Countera, koji je sadržavao 1% otopinu natrij klorida u destiliranoj vodi procjeden kroz 0.45 ,um filter sa miliporama, dok indeks koncentracije na Coulter Counteru (model TAII) nije bio izmedu 5 i 20%. Sadržaj posude je potom soniciran tokom 30 sec., premješten u Coulter Counter i miješan tokom jedne minute prije nego što je započeto sa čitanjem. Čitani su brojevi koji su označavali veličine traka u opsegu od 8.0 um do 128.0 um. Brojanje je ponovljeno poslije ukupno četiri minute miješanja. A small sample of lipid-coated material was suspended in Coulterovors dispersant on a microscope slide. A certain amount of this dispersed sample was added to the measuring vessel of the Coulter Counter, which contained a 1% solution of sodium chloride in distilled water filtered through a 0.45 µm filter with millipores, until the concentration index on the Coulter Counter (model TAII) was between 5 and 20 %. The contents of the dish were then sonicated for 30 sec., transferred to the Coulter Counter and mixed for one minute before the reading was started. Numbers indicating band sizes ranging from 8.0 µm to 128.0 µm were read. Counting was repeated after a total of four minutes of mixing.

Prosjek od jednog i četiri minute brojanja je uzet za svaku veličinu trake i upotrijebljen za izračunavanje VMD (ista formula kao kod metode 1). An average of one and four minute counts was taken for each band size and used to calculate the VMD (same formula as method 1).

Mjerenje je ponovljeno od početka pripremanja uzorka za minimum pet odvojenih uzoraka. Pet VMD vrijednosti su uzete za izračunavanje prosjeka jedne srednje vrijednosti preparata. The measurement was repeated from the beginning of sample preparation for a minimum of five separate samples. Five VMD values were taken to calculate the average of one mean value of the preparation.

Izuzev kada nije drugačije navedeno, sve ovdje date reference koje se odnose na promjere po zapremini, izmjerene su metodom pomoću Coulter Cpuntera. Unless otherwise stated, all references given herein to diameters by volume have been measured using the Coulter Cpunter method.

3 Rasipanje laserske svjetlosti 3 Scattering of laser light

Uzorak od 5 mg materijala prevučenog lipidom je dodato u 5 ml 0.25% Tweena 80 u destiliranoj vodi i sonificirano tokom 60 sekundi. Posudica sa uzorkom je dva puta okretana da bi se sadržaji izmješali, i uzorak je onda ukapan u stanicu za mjerenje mjerača djelića Malvern 3600 Etipa sve dok nije postignuta zamračenost snopa od 0.2. Očitavanja su izvedena nakon jedne i nakon četiri minute miješanja u stanici sa uzorkom. A 5 mg sample of the lipid-coated material was added to 5 ml of 0.25% Tween 80 in distilled water and sonicated for 60 seconds. The sample container was swirled twice to mix the contents, and the sample was then instilled into the measuring station of a Malvern 3600 Etipa particle counter until a beam obscuration of 0.2 was achieved. Readings were taken after one and four minutes of mixing in the cell with the sample.

VMD vrijednost za svaki uzorak je obračunata. Mjerenja na minimalno pet uzoraka su izvedena za svaku grupu i dobivena je srednja vrijednost preparata. The VMD value for each sample was calculated. Measurements on a minimum of five samples were performed for each group and the mean value of the preparation was obtained.

Primjer 1 Example 1

Disperzija amorfnog cefuroksiro aksetila (150 g) u prašku stearinske kiseline BPC (850 g) je pripremljena topljenjem lipida, podizanjem temperature istopljenog lipida na temperaturu od oko 15°C iznad njegove točke topljenja i dodavanjem cefuroksim aksetila uz miješanje. A dispersion of amorphous cefuroxime axetil (150 g) in BPC stearic acid powder (850 g) was prepared by melting the lipid, raising the temperature of the melted lipid to a temperature of about 15°C above its melting point and adding cefuroxime axetil with stirring.

Stopljena disperzija lipid/cefuroksim aksetil je unijeta u aparat za sušenje prskanjem/hlađenjem primjenom peristaltičke pumpe i atomizirana je primjenom mlaznice sa dva fluida i miješanja izvana /dimenzija mlaznice na izlazu 2.54 mm (izlaz tekućine) i 3.81 do 4.57 mm (kružni izlaz za atomizirani fluid) / sa zrakom na temperaturi od 65-70°C i pritiskom atomizacije od oko 345 kPa (50 psi). Proizvod je ohlađen primjenom struje zraka dovedenog u komoru za prskanje na temperaturi okoline i očvrsnut proizvod je sakupljen u ciklonskom separatoru. The molten lipid/cefuroxime axetil dispersion was fed into a spray/cooling dryer using a peristaltic pump and atomized using a two-fluid nozzle and external mixing/nozzle outlet dimensions 2.54 mm (fluid outlet) and 3.81 to 4.57 mm (circular outlet for atomized fluid) / with air at a temperature of 65-70°C and an atomization pressure of about 345 kPa (50 psi). The product was cooled by applying a stream of air supplied to the spray chamber at ambient temperature and the solidified product was collected in a cyclone separator.

Primjer 2 Example 2

Disperzija amorfnog cefuroksim aksetila (150 g) u prašku stearinske kiseline BPC (850 g) je pripremljena od suhe smjese sastojaka topljenjem lipida, i održavanjem temperature na oko 15°C iznad točke topljenja lipida. A dispersion of amorphous cefuroxime axetil (150 g) in BPC stearic acid powder (850 g) was prepared from a dry mixture of ingredients by melting the lipids, and maintaining the temperature at about 15°C above the melting point of the lipids.

Istopljena disperzija lipid/cefuroksim aksetil je upumpana u aparat sušenja prskanjem/hlađenjem brzinom od 300-500 ml/ minuti i atornizirana upotrebom mlaznice sa unutrašnjim miješanjem dva fluida (nabavlja se kod Delavan Limited, Midnes, Cheshire catalogue no. 321631 i kao što je opisano u Britanskoj patentnoj prijavi No. 1412133) sa zrakom na temperaturi od 65-70°C i pri pritisku atomizacije od 276345 kPa (4050 psi). Proizvod je ohlađen primjenom struje zraka dovedenog u komoru za prskanje na temperaturi okoline i očvrsli proizvod je sakupljenom primjenom gravitacije. The molten lipid/cefuroxime axetil dispersion was pumped into a spray/cooling dryer at a rate of 300-500 ml/minute and atomized using an internal mixing nozzle (available from Delavan Limited, Midnes, Cheshire catalog no. 321631 and as described in British Patent Application No. 1412133) with air at a temperature of 65-70°C and at an atomizing pressure of 276345 kPa (4050 psi). The product is cooled by applying a stream of air supplied to the spray chamber at ambient temperature and the solidified product is collected by the application of gravity.

Primjer 3 Example 3

Disperzija amorfnog cefuroksim aksetila u prašku stearinske kiseline BPC je pripremljena kao u primjeru 2. Istopljena disperzija lipid/cefuroksim aksetil je pumpana primjenom pumpe sa prijenosom u aparat za sušenje prskanjem/ hlađenjem i atomizirana primjenom mlaznice sa vanjskim miješanjem dva fluida (2.0 mm prečnik) sa zrakom na temperaturi od 75°C i pri pritisku atomiziranja od 310 kPa (45 psi). Proizvod je ohlađen primjenom struje zraka dovedenog u komoru za prskanje pri temperaturi okoline i očvrsli proizvod je sakupljen u ciklonskom separatoru. A dispersion of amorphous cefuroxime axetil in BPC stearic acid powder was prepared as in Example 2. The molten lipid/cefuroxime axetil dispersion was pumped using a pump with transfer to a spray/cooling dryer and atomized using a nozzle with external mixing of the two fluids (2.0 mm diameter) with air at a temperature of 75°C and an atomizing pressure of 310 kPa (45 psi). The product was cooled by applying a stream of air supplied to the spray chamber at ambient temperature and the solidified product was collected in a cyclone separator.

Slijedeće veličine djelića su zabilježene za grupe materijala pripremljenog prema postupcima opisanim u primjerima 13: The following particle sizes were recorded for groups of material prepared according to the procedures described in Examples 13:

[image] [image]

Sve veličine djelića su izražene u VMD n = broj izmjerenih uzoraka. All particle sizes are expressed in VMD n = number of measured samples.

Primjer 4 Example 4

Suha smjesa cefuroksim aksetila (124 g) i praška stearinske kiseline BPC (676 g) grijana je na 68°C uz miješanje da bi se lipid istopio i obrazovala suspenzija. Istopljena disperzija lipid/cefuroksim aksetil je prebačena u komoru za hlađenje prskanjem brzinom od oko 400 ml/minuti prirnjenom pritiska na posudu sa istopljenom masom. Ova je potom atomizirana primjenom mlaznice sa dva fluida sa unutrašnjim miješanjem (kao što je opisano u primjeru 2), sa zrakom na temperaturi od 78°C i pri pritisku od 380 kPa (55 psi). Proizvod je ohlađen u struji zraka dovedenog u komoru za prskanje i stvrdnuti materijal je sakupljen gravitacijom. A dry mixture of cefuroxime axetil (124 g) and BPC stearic acid powder (676 g) was heated to 68°C with stirring to melt the lipid and form a suspension. The molten lipid/cefuroxime axetil dispersion was transferred to the cooling chamber by spraying at a rate of about 400 ml/minute by applying pressure to the container with the molten mass. This was then atomized using a dual fluid nozzle with internal mixing (as described in Example 2), with air at a temperature of 78°C and a pressure of 380 kPa (55 psi). The product is cooled in a stream of air supplied to the spray chamber and the solidified material is collected by gravity.

Prosječni zapreminski promjer djelića (Coulter Counter) 51.um. Sadržaj cefuroksim aksetila 15.4%. Average volume diameter of particles (Coulter Counter) 51.um. Cefuroxime axetil content 15.4%.

Primjer 5 Example 5

Disperzija za prevlačenje lipidom je pripremljena topljenjem lipida, povišavanjem temperature istopljenog lipida do temperature od 15°C iznad njegove točke topljenja i dodavanjem odgovarajuće količine cefuroksim aksetila uz miješanje primjenom jakog miksera. The lipid coating dispersion was prepared by melting the lipid, raising the temperature of the molten lipid to a temperature of 15°C above its melting point, and adding an appropriate amount of cefuroxime axetil while stirring using a high-powered mixer.

Istopljena disperzija lipid/cefuroksim aksetil je pumpana u konvencionalni aparat za sušenje prskanjem/zamrzavanjem pri čemu je visina komore za prskanje 1.82 m a brzina približno 300 ml/minuti, i atomizirana primjenom mlaznice sa dva fluida sa vanjskim miješanjem (kao što je opisano u primjeru 1), pri pritisku atomizacije u opsegu od 275 do 414 kPa (40 do 60 psi). Proizvod je ohlađen primjenom struje zraka dovedenog u komoru za prskanje na 7-11°C. Čvrsti proizvod je sakupljen u ciklonskom separatoru. The molten lipid/cefuroxime axetil dispersion was pumped into a conventional spray/freeze dryer with a spray chamber height of 1.82 m and a velocity of approximately 300 ml/minute, and atomized using an externally stirred two-fluid nozzle (as described in Example 1 ), at atomization pressures in the range of 275 to 414 kPa (40 to 60 psi). The product is cooled using a stream of air supplied to the spray chamber to 7-11°C. The solid product was collected in a cyclone separator.

Slijedeće smjese cefuroksim aksetila i različitih lipida su ohlađene prskanjem da bi se dobili djelići cefuroksim aksetila prevučeni lipidom, maskiranog ukusa. Dobijeni promjeri djelića su određeni pomoću optickog mikroskopa primjenom "Ouantimet 970" analizatora slike. The following mixtures of cefuroxime axetil and various lipids were spray-cooled to obtain lipid-coated, taste-masked cefuroxime axetil particles. The obtained particle diameters were determined using an optical microscope using an "Ouantimet 970" image analyzer.

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Primjer 6 Example 6

Djelići cefuroksim aksetila prevučeni maltodekstrinofn su pripremljeni dispergiranjem maltodekstrina (400 g), tutifruti ukusa (1 g) i škroba 1500 (25 g) u destiliranoj vodi (do 11) u snažnom mikseru. Cefuroksim aksetil (100 g) je dispergiran u ovoj suspenziji primjenom snažnog miksera i suspenzija je potom osušena prskanjem primjenom konvencionalne tehnike sušenja prskanjem. Proizvod je sakupljen u ciklonskom separatoru. Cefuroksim aksetil prevučen maltodekstrihom je potom prevucen Stearinskom kiselinom BPC kao što je opisano u primjeru 5. Cefuroxime axetil particles coated with maltodextrin were prepared by dispersing maltodextrin (400 g), tutifruti flavor (1 g) and starch 1500 (25 g) in distilled water (up to 11) in a high-powered mixer. Cefuroxime axetil (100 g) was dispersed in this suspension using a high powered mixer and the suspension was then spray dried using a conventional spray drying technique. The product is collected in a cyclone separator. Cefuroxime axetil coated with maltodextrich was then coated with Stearic acid BPC as described in Example 5.

%m/m Masa (g) %m/m Mass (g)

Stearinska kiselina u prašku BPC 60 600 Stearic acid in powder BPC 60 600

Cefuroksim aksetil prevucen maltodekstrinom 40 400 Cefuroxime axetil coated with maltodextrin 40 400

Srednji numerički promjer djelića 7.51/um Mean numerical diameter of particles 7.51/um

(95% od ukupnih dobijenih djelića je imao promjer ispod 23.um). (95% of the total particles obtained had a diameter below 23 µm).

Prosječan zapreminski promjer djelića 46.0,um. The average volume diameter of the particles is 46.0 µm.

Primjer 7 Example 7

Primjenom postupaka opisanih u primjerima 5 i 6 slijedeće smjese cefuroksim aksetila i razlicitih lipida su ohlađene prskanjem dajući djeliće cefuroksim aksetila prevučene lipidom i maskiranog ukusa: Applying the procedures described in Examples 5 and 6, the following mixtures of cefuroxime axetil and various lipids were spray-cooled to yield lipid-coated, taste-masked cefuroxime axetil particles:

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Farmaceutski primjer Pharmaceutical example

Cefuroksim aksetil prevučen stearinskom kiselinom BPC je kombiniran sa sukrozom i odgovarajućim sredstvom za ukus u niže prikazanom odnosu. Ovi materijali su pomiješani, zatim granulirani na konvencionalan način primjenom vode kao granulacionog fluida. Poslije sušenja, granule se mogu prosijati da bi se uklonili aglomerati, a potom se pune u bočice. Cefuroxime axetil coated with stearic acid BPC is combined with sucrose and the appropriate flavoring agent in the ratio shown below. These materials are mixed, then granulated in a conventional manner using water as the granulation fluid. After drying, the granules can be sieved to remove agglomerates, and then filled into bottles.

Suspenzija za oralno uzimanje se proizvodi konstituiranjem sa vodom da bi se dobilo 125 mg cefuroksima na 5 ml suspenzije. The suspension for oral administration is produced by reconstitution with water to obtain 125 mg of cefuroxime per 5 ml of suspension.

Sastojci % m/m Ingredients % m/m

Stearinskom kiselinom BPC prevučen BPC coated with stearic acid

Cefuroksim aksetil 24.92 Cefuroxime axetil 24.92

Sukroza 74.75 Sucrose 74.75

Ukus (šumsko voće) 0.33 Taste (forest fruit) 0.33

Claims

1. Process for obtaining a preparation comprising cefuroxime axetil in a powdered form, wherein the particles have integral lipid coatings or lipid mixtures that are insoluble in water and which serve to mask the bitter taste of cefuroxime axetil after oral intake, but which are dispersed or dissolved in contact with the gastrointestinal fluid, characterized in that the powdered cefuroxime axetil is dispersed in a molten lipid or lipid mixture, the dispersion is atomized to obtain particles with an integral coating of the lipid or lipid mixture, and the thus obtained coated particles are cooled and collected.

2. The method according to claim 1, characterized in that the lipid or mixture of lipids has a melting point in the range of 30 to 80°C.

3. The method according to claim 2, characterized in that the lipid or mixture of lipids has a melting point in the range of 40 to 70°C.

4. The method according to claim 1, characterized in that the lipid or mixture of lipids comprises one or more straight-chain aliphatic carboxylic acids with 10 to 30 carbon atoms.

5. The method according to claim 4, characterized in that the mixture of lipids includes a mixture of stearic and palmitic acids in a ratio of 3:7 to 7:3 by weight.

6. The method according to claim 5, indicated by the fact that the mixture of stearic and palmitic acids in a ratio of about 1:1 by weight.

7. The method according to any of the preceding claims, indicated by the fact that the quantities of crushed cefuroxime axetil and lipid or lipid mixture are such as to ensure the production of coated particles of cefuroxime axetil containing 5 to 90% by weight. cefuroxime axetil.

8. The method according to claim 7, indicated by the fact that the amounts of crushed cefuroxime axetil and lipids or lipid mixtures are such as to ensure the production of coated particles containing 10 to 30% by weight. cefuroxime axetil.

9. The method according to any of the preceding claims, characterized in that the cefuroxime axetil is amorphous cefuroxime axetil.

10. The method according to claim 9, characterized in that cefuroxime axetil is spray-dried cefuroxime axetil in the form of hollow microspheres.

11. A method according to any of the preceding claims, characterized in that the dispersion is atomized to provide coated fractions with a diameter in the range of 1 to 250 micrometers.

12. A process according to any of the preceding claims, characterized in that the dispersion is atomized to provide coated particles having a volume mean diameter of less than 100 micrometers.

13. The method according to any of the preceding claims, characterized in that the dispersion is atomized by means of an atomization device with a pneumatic nozzle.

14. The method according to claim 13, characterized in that the atomization device is an atomizer that has a nozzle with internal mixing of two fluids.

15. The method according to claim 13 or claim 14, characterized in that the melted dispersion is atomized at a temperature in the range of 10 to 20°C above the melting point of the lipid or mixture of lipids used.

16. The method according to any one of claims 13 to 15, characterized in that the pulverized cefuroxime axetil before coating has a volume mean particle diameter in the range of 5 to 50 micrometers.

17. The method according to any one of claims 13 to 16, characterized in that the quantities of pulverized cefuroxime axetil and lipids or lipid mixtures used are such as to provide coated particles containing 5 to 50 wt.% cefuroxime axetil.

18. The method according to claim 17, characterized in that the amounts of used crushed cefuroxime axetil and lipid or lipid mixture are such as to provide coated particles containing from 5 to 30 wt.% of cefuroxime axetil.

19. A process according to any one of claims 13 to 18, characterized in that the dispersion is atomized to provide coated particles having diameters in the range of 1 to 250 micrometers.

20. A process according to any one of claims 13 to 19, characterized in that the dispersion is atomized to provide coated particles having a volume mean diameter below 100 micrometers.

21. A process according to claim 20, characterized in that the dispersion is atomized to provide coated particles having a volume mean diameter of 20 to 100 micrometers.

22. A process according to claim 21, characterized in that the dispersion is atomized to provide coated particles having a volume mean diameter of 30 to 60 micrometers.

23. The method according to any of the preceding claims, characterized in that the coated particles are then formulated for oral administration by incorporation with one or more pharmaceutical carriers or excipients.

24. The method according to claim 23, characterized in that the coated particles are shaped into granules.

25. The method according to claim 23, characterized in that the coated particles are suspended in an aqueous medium.

26. The method of claim 23, wherein the coated particles are formulated together with an orally acceptable solution that serves to help maintain the taste masking properties of the lipid coating in suspension in a liquid medium.

27. The method according to claim 25, characterized in that the aqueous medium contains sugar in a concentration of 50 to 85 wt.%.