HRP920377A2 - Process for the preparatin of a carrier base material for drug dosage forms with an extended release of active substance - Google Patents

Process for the preparatin of a carrier base material for drug dosage forms with an extended release of active substance Download PDF

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HRP920377A2
HRP920377A2 HR920377A HRP920377A HRP920377A2 HR P920377 A2 HRP920377 A2 HR P920377A2 HR 920377 A HR920377 A HR 920377A HR P920377 A HRP920377 A HR P920377A HR P920377 A2 HRP920377 A2 HR P920377A2
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hydroxypropylmethylcellulose
alkali metal
tablets
dosage forms
metal carboxylate
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HR920377A
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Croatian (hr)
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Norman G Gaydord
Ashok Nigalaye
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Forest Labaratories Inc
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Description

Područje tehnike The field of technology

Izum je iz područja farmaceutske industrije. Oznaka izuma prema Međunarodnoj klasifikaciji patenata je A61K 9/22; A61K 9/26. The invention is from the pharmaceutical industry. The designation of the invention according to the International Classification of Patents is A61K 9/22; A61K 9/26.

Tehnički problem Technical problem

Izumom je riješen tehnički problem osnovnog nosivog materijala koji se, u doznim oblicima lijekova s produženim izdvajanjem kombinira s aktivnom supstancijom. Poboljšane karakteristike izdvajanja u odnosu na materijale iz dosadašnje nauke rezultat su prisutnosti karboksilata alkalnih metala u nosivom materijalu. The invention solves the technical problem of the basic carrier material, which is combined with the active substance in dosage forms of drugs with extended release. Improved extraction characteristics compared to materials from prior art are the result of the presence of alkali metal carboxylates in the carrier material.

Stanje tehnike State of the art

Davanje lijekova koji, da bi bili efikasni, zahtijevaju visoku dozu, može se vršiti u obliku pojedinačne, potencijalno toksične doze ili u obliku više doza. Drugo rješenje je da se jednim davanjem postigne kontinuirano doziranje, i to kontroliranim i produženim izdvajanjem lijeka iz krute pojedinačne doze. Administering drugs that, in order to be effective, require a high dose can be done in the form of a single, potentially toxic dose or in the form of multiple doses. Another solution is to achieve continuous dosing with a single administration, by controlled and prolonged extraction of the drug from a solid single dose.

Da bi se, međutim, u pojedinačnu dozu smjestila dovoljna količina ljekovite supstancije čije efikasno djelovanje zahtijeva visoku dozu, a da se u isto vrijeme ne bi značajnije povećala veličina pojedinačne doze, potrebno je koristiti osnovni nosivi materijal koji u malim koncentracijama efikasno usporava izdvajanje lijeka. However, in order to place a sufficient amount of a medicinal substance in a single dose, the effective action of which requires a high dose, without at the same time significantly increasing the size of the individual dose, it is necessary to use a basic carrier material that effectively slows down the release of the drug in small concentrations.

Hidroksipropilmetilceluloze se široko koriste kao vezivni materijal, kao matrice ili kao osnovni nosači u krutim doznim oblicima za produženo izdvajanje aktivnih supstancija. Po potrebi im se dodaju i sredstva za podmazivanje i ekscipijenti. Komercijalno dostupna hidroksipropilmetilceluloza zapravo predstavlja niz kemijskih spojeva od kojih svaki ima različitu kemijsku strukturu i sastav pri čemu je metoksilni sadržaj u opsegu od 16.5 do 30 mas.%, a hidroksipropoksilni sadržaj u opsegu od 4 do 32 mas.%. Sve hidroksipropilmetilceluloze su također, dostupne u više viskozitetnih nivoa. Hydroxypropylmethylcelluloses are widely used as binding material, as matrices or as basic carriers in solid dosage forms for extended release of active substances. If necessary, lubricants and excipients are added to them. Commercially available hydroxypropylmethylcellulose actually represents a series of chemical compounds, each of which has a different chemical structure and composition, with the methoxyl content ranging from 16.5 to 30 wt.%, and the hydroxypropoxyl content ranging from 4 to 32 wt.%. All hydroxypropylmethylcelluloses are also available in multiple viscosity levels.

Komercijalne oznake različitih hidroksipropilmetilceluloza daju se na osnovi viskoziteta 2% vodene otopine na 20ºC. Viskoziteti se kreću u rasponu od 5 do 100.000 mPa.sec i odgovaraju prosječnim molekularnim težinama od ispod 10.000 do preko 150.000, izračunano na osnovu podataka danih u "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974). Commercial designations of various hydroxypropylmethylcelluloses are given based on the viscosity of a 2% aqueous solution at 20ºC. Viscosities range from 5 to 100,000 mPa.sec and correspond to average molecular weights from below 10,000 to over 150,000, calculated from data given in "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974).

Christenson i Dale (U.S. Patent 3,065,143) i Huber, Dale i Christenson (J.Pharm. Sci., 55, 974 (1966)) opisuju dobivanje tablete s produženim izdvajanjem za koju se kao vezivno sredstvo koristi hidroksipropilmetilceluloza visokog viskoziteta, tj. visoke molekularne težine i to u količini od barem jedne trećine ukupne mase tablete. Vezivna sredstva uključuju i hidroksipropilmetilcelulozu viskoziteta 4.000 mPa-sec, danas poznatu kao Methocel E4M, koja ima metoksilni sadržaj od 28-30 mas.% i hidroksipropoksilni sadržaj od 7.5-12 mas.% i prosječnu molekularnu težinu od 93.000. Također su opisane hidroksipropilmetilceluloze s viskozitetom 4.000 odnosno 15.000 mPa-sec, danas poznate kao Methocel K4M odnosno K15M koje imaju metoksilni sadržaj od 19-24 mas.%, hioroksipropoksilni sadržaj od 4-12 mas.% i prosječnu molekularnu težinu od 89.000 odnosno 124.000. Christenson and Dale (U.S. Patent 3,065,143) and Huber, Dale and Christenson (J.Pharm. Sci., 55, 974 (1966)) describe the preparation of an extended release tablet using high viscosity, i.e. high molecular weight, hydroxypropylmethylcellulose as a binder. weight and in the amount of at least one third of the total weight of the tablet. Binding agents include hydroxypropylmethylcellulose with a viscosity of 4,000 mPa-sec, known today as Methocel E4M, which has a methoxyl content of 28-30 wt.% and a hydroxypropoxyl content of 7.5-12 wt.% and an average molecular weight of 93,000. Also described are hydroxypropylmethylcelluloses with a viscosity of 4,000 or 15,000 mPa-sec, known today as Methocel K4M or K15M, which have a methoxyl content of 19-24 wt.%, a hydroxypropoxyl content of 4-12 wt.% and an average molecular weight of 89,000 or 124,000, respectively.

Christenson i njegovi suradnici su pretpostavili da se voda brzo apsorbira i stvara gel barijeru na površini tablete. Kontrola izdvajanja lijeka postiže se njegovom difuzijon kroz gel barijeru, kao i laganim raspadanjem ove barijere. Christenson and his colleagues hypothesized that water is rapidly absorbed and forms a gel barrier on the surface of the tablet. The control of drug release is achieved by its diffusion through the gel barrier, as well as by the slight disintegration of this barrier.

Christenson i Huber (U.S. patent 3,590,117) su izvjestili da ni hidroksipropilmetilceluloza niskog, niti hidroksipropilmetilceluloza visokog viskoziteta ne omogućavaju izradu dugotrajnih pastila. Christenson and Huber (U.S. Patent 3,590,117) reported that neither low-viscosity hydroxypropylmethylcellulose nor high-viscosity hydroxypropylmethylcellulose made long-lasting pastilles.

Lapidus (Disertacija, Rutgers State University, 1967) i Lapidus i Lordi (J. Pharm. Sci., 55, 840 (1966); 57, 1292 (1968)) izvještavaju o korištenju hidroksipropilmetilceluloza s viskozitetom od 25 i 15.000 mPa-sec, koje imaju metoksilni sadržaj od 19-24 mas.% i hidroksipropoksilni sadržaj od 4-12 mas.%, odnosno Methocel-a K25 i K15M, u komprimiranim farmaceutskim tabletama. Lapidus (Dissertation, Rutgers State University, 1967) and Lapidus and Lordi (J. Pharm. Sci., 55, 840 (1966); 57, 1292 (1968)) report the use of hydroxypropylmethylcelluloses with viscosities of 25 and 15,000 mPa-sec, respectively. which have a methoxyl content of 19-24 wt.% and a hydroxypropoxyl content of 4-12 wt.%, i.e. Methocel K25 and K15M, in compressed pharmaceutical tablets.

Salomon, Doelker i Buri (Pharm. Acta Helv., 54 (3), 82 (1979)) su opisali potrebu za prisustvom više od 30 mas.% hidroksipropilmetilceluloze viskoziteta od 15.000 mPa-sec, s metoksilnim sadržajem od 19-24 mas.% i hidroksipropoksilnim sadržajem od 4-12 mas.% (Methocel K15M) u tabletama koje sadržavaju kalijev klorid, kako bi se izdvajanje lijeka produžilo na više od nekoliko sati. Salomon, Doelker and Buri (Pharm. Acta Helv., 54 (3), 82 (1979)) described the need for the presence of more than 30 wt.% hydroxypropylmethylcellulose with a viscosity of 15,000 mPa-sec, with a methoxyl content of 19-24 wt. % and hydroxypropoxyl content of 4-12 wt.% (Methocel K15M) in tablets containing potassium chloride, in order to prolong the release of the drug for more than a few hours.

Sheth i Tossounian (U.S. patenti 4,126,672; 4,140,755; i 4,167,558) su opisali krute dozne oblike koji sadrže 20-75% hidroklorida, kao stoje hidroksipropilmetilceluloza s viskozitetom od 4000 mPa-sec, u kombinaciji s različitim aditivima uključujući spojeve koji stvaraju plinove, npr. kalcijev karbonat i inertne masne materije, što dovodi do hidrodinamički uravnoteženog proizvoda čija je gustoća, u dodiru sa želučanom tekućinom, manja od jedan tako da on pliva i izdvaja lijek iz svog sastava. Sheth and Tossounian (U.S. Patents 4,126,672; 4,140,755; and 4,167,558) have described solid dosage forms containing 20-75% hydrochloride, such as hydroxypropylmethylcellulose with a viscosity of 4000 mPa-sec, in combination with various additives including gas-forming compounds, e.g. calcium carbonate and inert fatty substances, which leads to a hydrodynamically balanced product whose density, in contact with gastric fluid, is less than one, so that it swims and separates the drug from its composition.

Schor, Nigalaye i Gaylord (U.S. patent 4,389,393) opisuju krute pojedinačne dozne oblike s produženim izdvajanjem u kojima osnovni nosivi materijal čini manje od jedne trećine mase doznog oblika i sastoji se od hidroksipropilmetilceluloze viskoziteta od najmanje 4.000 mPa-sec, prosječnom molekularnom težinom od najmanje 50.000, metoksilnim sadržajem od 16-24 mas.% i hidroksipropoksilnim sadržajem od 4-32 mas.%, odnosno od Methocel-a J i Methocel-a K. Schor, Nigalaye and Gaylord (U.S. Patent 4,389,393) describe solid extended-release single dosage forms in which the base carrier material constitutes less than one-third of the weight of the dosage form and consists of hydroxypropylmethylcellulose of a viscosity of at least 4,000 mPa-sec, an average molecular weight of at least 50,000 , with a methoxyl content of 16-24 wt.% and a hydroxypropoxyl content of 4-32 wt.%, i.e. from Methocel J and Methocel K.

Uporaba hidroksipropilmetilceluloza visokog viskoziteta - Methocel-a E, F i K - u krutim doznim oblicima lijekova s produženim izdvajanjem, opisano je i u tehničkom biltenu "Formulating Sustained Release Pharmaceutical Products vvith Methocel" (The Dow Chemical Co., 1982). The use of high-viscosity hydroxypropylmethylcelluloses - Methocel E, F and K - in solid dosage forms of drugs with extended release is also described in the technical bulletin "Formulating Sustained Release Pharmaceutical Products with Methocel" (The Dow Chemical Co., 1982).

Do sada navedeno stanje tehnike opisuje da su hidroksipropilmetilceluloze visokih viskoziteta i različitih kemijskih sastava korisne za dobivanje krutih doznih oblika lijekova s produženim izdvajanjem. Nasuprot tome, Schor, Nigalaye i Gaylord (U.S. patent 4,369,172) opisuju da se terapeutski preparati s produženin izdvajanjem mogu dobiti i kada se kao osnovni nosivi materijal upotrijebi hidroksipropilmetilceluloza niskog viskoziteta, s hidroksipropcksilnim sadržajem od 9-15 mas.% i prosječnom molekularnom težinom manjom od 50.000. The state of the art described so far describes that hydroxypropylmethylcelluloses of high viscosity and different chemical compositions are useful for obtaining solid dosage forms of drugs with extended release. In contrast, Schor, Nigalaye and Gaylord (U.S. Patent 4,369,172) describe that extended release therapeutic preparations can be obtained when low viscosity hydroxypropylmethylcellulose, with a hydroxypropyl content of 9-15% by weight and an average molecular weight of less than of 50,000.

Lowey i Stafford (U.S. patent 3,870,790) i Schor (U.S. patent 4,226,844) opisali su da se efikasne tablete s produženim izdvajanjem mogu dobiti kada se kao osnovni nosivi materijal koristi modificirana hidroksipropilmetilceluloza niskog viskoziteta s hidroksipropoksilnim sadržajem manjim od 9 mas.% i s prosječnom molekularnom težinom od 23000, na primjer Mathocel E50. Modifikacija je vršena izlaganjem 1-hidroksipropilmetilceluloze niskog viskoziteta u visokoj vlažnosti zraka i zatim njenim sušenjem na zraku. To je dovelo do povećanja karboksilnog sadržaja u polimeru. Lowey and Stafford (U.S. Patent 3,870,790) and Schor (U.S. Patent 4,226,844) described that effective extended-release tablets can be obtained when a low viscosity modified hydroxypropylmethylcellulose with a hydroxypropoxyl content of less than 9 wt.% and an average molecular weight is used as the basic carrier material. from 23000, for example Mathocel E50. The modification was performed by exposing low-viscosity 1-hydroxypropylmethylcellulose to high air humidity and then drying it in air. This led to an increase in the carboxyl content in the polymer.

Davis i Gaylord (L.S. patent 4,540,566) i Daly, Davis i Kennerley (International J. Pharmaceutics, 18, 201 (1984)) opisuju da prisutnost sulfata ili sulfonat alkalnog metala produžava oblik izdvajanja lijeka iz tableta koje kao osnovni nosivi materijal sadrže modificiranu hidroksipropilmetilcelulozu niskog viskoziteta. Davis and Gaylord (L.S. Patent 4,540,566) and Daly, Davis and Kennerley (International J. Pharmaceutics, 18, 201 (1984)) describe that the presence of an alkali metal sulfate or sulfonate prolongs the release form of tablets containing modified hydroxypropylmethylcellulose as the basic carrier material. viscosity.

Lowey (U.S. patent 4,259,314) opisuje uporabu smjese sušene hidroksipropilmetilceluloze viskoziteta u opsegu od 50 do 4.000 mPa-sec s hidroksipropilcelulozom u dobivanju farmaceutskih preparata s kontroliranim izdvajanjem ljekovite supstancije. Lowey (U.S. patent 4,259,314) describes the use of a mixture of dried hydroxypropylmethylcellulose with a viscosity in the range of 50 to 4,000 mPa-sec with hydroxypropylcellulose in the preparation of pharmaceutical preparations with controlled release of the medicinal substance.

Sadašnji izum se odnosi na daljnja poboljšanja u osnovnom nosivom materijalu koji sadržava hidroksipropilmetilcelulozu visoke molekularne težine, kao i na krute farmaceutske pojedinačne dozne oblike s produženim izdvajanjem koji sadrže takav poboljšani nosivi materijal. Poboljšanja su rezultat prisutnosti karboksilata alkalnog metala u osnovnom nosivom materijalu. The present invention relates to further improvements in the base carrier material containing high molecular weight hydroxypropylmethylcellulose, as well as to solid pharmaceutical extended release dosage forms containing such improved carrier material. The improvements are a result of the presence of alkali metal carboxylates in the base carrier material.

Opis rješenja tehničkog problema s primjerima izvođenja Description of the solution to the technical problem with implementation examples

Cilj sadašnjeg izuma je da osigura postupak za dobivanje osnovnog nosivog materijala koji sadržava hidroksipropilmetilcelulozu i karboksilate alkalnih metala i koji se može koristiti u proizvodnji terapeutski aktivnih krutih doznih oblika lijekova s produženim izdvajanjem, koji ga sadržavaju u kombinaciji s terapeutski aktivnim medikamentom. Takvi preparati mogu se dati oralno, bukalno, sublingvalno, itd., u obliku lozengi i tableta, kao i u obliku supozitorija i drugih krutih pojedinačnih doznih oblika. The aim of the present invention is to provide a process for obtaining a basic carrier material containing hydroxypropylmethylcellulose and alkali metal carboxylates and which can be used in the production of therapeutically active solid dosage forms of drugs with extended release, which contain it in combination with a therapeutically active medication. Such preparations can be administered orally, buccally, sublingually, etc., in the form of lozenges and tablets, as well as in the form of suppositories and other solid single dosage forms.

Još jedan cilj izuma je da se osigura poboljšani osnovni nosivi materijal za uporabu u krutim farmaceutskim pojedinačnim doznim oblicima koji sadrže visoku dozu aktivne supstancije. Another object of the invention is to provide an improved basic carrier material for use in solid pharmaceutical unit dosage forms containing a high dose of active substance.

Sadašnji izum se odnosi na postupak za dobivanje osnovnog nosivog materijala koji se može koristiti u proizvodnji terapeutski aktivnih krutih doznih oblika koji, nakon davanja, pokazuju kontrolirano i produženo izdvajanje lijeka koji sadrže smjesu medikamenta i navedenog materijala, pri čemu se osnovni nosivi materijal sastoji od (a) jednog ili više u vodi topivih neionskih celuloznih etera, pri čemu je barem jedan od ovih celuloznih etera hidroksipropilmetilceluloza s prosječnom molekularnom težinom od najmanje 50.000, i (b) od karboksilata alkalnog metala, pri čemu nosiva osnova čini manje od 30 mas.% ukupne mase doznog oblika. The present invention relates to a process for obtaining a basic carrier material that can be used in the production of therapeutically active solid dosage forms that, after administration, show a controlled and extended release of a drug containing a mixture of a medication and the specified material, wherein the basic carrier material consists of ( a) one or more water-soluble nonionic cellulose ethers, wherein at least one of these cellulose ethers is hydroxypropylmethylcellulose with an average molecular weight of at least 50,000, and (b) of an alkali metal carboxylate, wherein the carrier base constitutes less than 30 wt.% total mass of the dosage form.

Osnovni nosivi materijal dobiven postupkom iz izuma može se koristiti u proizvodnji terapijski aktivnih krutih doznih oblika koji ga sadrže u smjesi s medikamentom pri čemu smjesa od bitnih sastojaka sadrži (a) jedan ili više u vodi topivih neionskih celuloznih etera, pri čemu je bar jedan od celuloloznih etera hidroksipropilmetilceluloza s prosječnom molekularnom težinom od najmanje 50.000, i (b) karboksilat alkalnog metala. The basic carrier material obtained by the process of the invention can be used in the production of therapeutically active solid dosage forms that contain it in a mixture with a medication, wherein the mixture of essential ingredients contains (a) one or more water-soluble nonionic cellulose ethers, wherein at least one of cellulose ethers of hydroxypropylmethylcellulose having an average molecular weight of at least 50,000, and (b) an alkali metal carboxylate.

Poželjno je da odnos celuloznog etera prema karboksilatu alkalnog metala u nosivoj osnovi bude u opsegu od 1/0.05 do 1/3. Sadržaj hidroksipropilmetilceluloze u preparatu poželjno čini od 3 do 25 mas.% doznog oblika, a terapeutski će aktivan medikament poželjno činiti najmanje 70 mas.% doznog oblika. It is preferable that the ratio of cellulose ether to alkali metal carboxylate in the carrier base is in the range of 1/0.05 to 1/3. The content of hydroxypropylmethylcellulose in the preparation preferably makes up from 3 to 25 wt.% of the dosage form, and the therapeutically active medication will preferably make up at least 70 wt.% of the dosage form.

Hidroksipropilmetilcelulozne materijale koji su osobito poželjni za uporabu u nosivoj osnovi predstavljaju materijali koji (a) imaju metoksilni sadržaj od 28-30 mas.% i hidroksipropoksilni sadržaj od 7.5-12 mas.%, i (b) imaju metoksilni sadržaj od 19-24 mas.% i hidroksipropoksilni sadržaj od 4-12 mas.%. Hydroxypropylmethylcellulose materials that are particularly desirable for use in the carrier base are materials that (a) have a methoxyl content of 28-30 wt.% and a hydroxypropoxyl content of 7.5-12 wt.%, and (b) have a methoxyl content of 19-24 wt.% .% and hydroxypropoxyl content of 4-12 wt.%.

Karboksilat alkalnog metala koji se koristi u postupku poželjno će predstavljati sol karboksilne kiseline s 8-40 ugljikovih atoma. Najpoželjnije je da se koriste natrijev stearat ili natrijev laurat. The alkali metal carboxylate used in the process will preferably be a salt of a carboxylic acid having 8-40 carbon atoms. It is most preferable to use sodium stearate or sodium laurate.

Osnovni nosivi materijali i terapeutski aktivni medikamenti mogu se homogeno smiješati bilo kojom prikladnom tehnikom miješanja. Za dobivanje krutih pojedinačnih doznih oblika, prikladne količine sastojaka se miješaju, oblikuju i komprimiraju pod uvjetima koji su prikladni za dobivanje krutog pojedinačnog doznog oblika željene veličine i željenih karakteristika produženog izdvajanja. Base carrier materials and therapeutically active medicaments can be mixed homogeneously by any suitable mixing technique. To obtain solid unit dosage forms, suitable amounts of the ingredients are mixed, shaped and compressed under conditions suitable to obtain a solid unit dosage form of the desired size and the desired extended release characteristics.

U skladu sa sadašnjim izumom, sada je ustanovljeno da se, miješanjem hidroksipropilmetilceluloze s karboksilatom alkalnog metala, mogu ostvariti značajne prednosti i poboljšanja u odnosu na proizvode iz prijašnje nauke koji sadrže u vodi topive neionske celulozne etere, naročito hidroksipropilmetilcelulozu visoke molekularne težine, kao osnovne nosive materijale. In accordance with the present invention, it has now been found that, by mixing hydroxypropylmethylcellulose with an alkali metal carboxylate, significant advantages and improvements can be achieved over prior art products containing water-soluble nonionic cellulose ethers, especially high molecular weight hydroxypropylmethylcellulose, as basic carriers materials.

Hidroksipropilmetilceluloze koje su efikasne u sadašnjem izumu uključuju, ali bez ograničenja, komercijalno dostupne hidroksipropilmetilceluloze visokih viskoziteta, tj. visokih molekularnih težina. Uključeni su materijali različitih viskoziteta koji imaju prosječnu molekularnu težinu od najmanje 50.000, bez obzira na kemijsku strukturu. Tako će, ukoliko je viskozitet najmanje oko 500 mPa.sec, efikasne biti hidroksipropilmetilceluloze koje imaju sljedeće metoksilne i hidroksipropoksilne sadržaje: Hydroxypropylmethylcelluloses that are effective in the present invention include, but are not limited to, commercially available high viscosity, ie high molecular weight, hydroxypropylmethylcelluloses. Included are materials of various viscosities that have an average molecular weight of at least 50,000, regardless of chemical structure. Thus, if the viscosity is at least around 500 mPa.sec, hydroxypropylmethylcelluloses that have the following methoxyl and hydroxypropoxyl contents will be effective:

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Uporaba niskih koncentracija hidroksipropilmetilceluloze visokog viskoziteta kao osnovnog nosivog materijala u krutim pojedinačnim doznim oblicima opisano je u U.S. patentu 4,389,393. Sada je neočekivano otkriveno da prisustvo karboksilata alkalnog metala dovodi do još više odloženog i produženog vremena izdvajanja nego što je to moguće osigurati korištenjem hidroksipropilmetilceluloze u istim koncentracijama u doznom obliku, ali u odsutnosti karboksilata alkalnog metala. Ovo dopušta da se pripremaju pojedinačni dozni oblici s većom koncentracijom aktivnog medikamenta, a da se istodobno održe željene karakteristike odloženog i produženog izdvajanja. The use of low concentrations of high viscosity hydroxypropylmethylcellulose as the base carrier material in solid unit dosage forms is described in U.S. Pat. patent 4,389,393. It has now been unexpectedly discovered that the presence of an alkali metal carboxylate leads to an even more delayed and prolonged release time than can be provided by using hydroxypropylmethylcellulose at the same concentrations in the dosage form, but in the absence of the alkali metal carboxylate. This allows individual dosage forms to be prepared with a higher concentration of the active medication while simultaneously maintaining the desired delayed and extended release characteristics.

Karboksilati alkalnog metala koji su efikasni u sadašnjem izumu uključuju alkalmetalne soli karboksilnih kiselina s 8 do 40 ugljikovih atoma. Kiseline mogu imati pravu ili račvastu strukturu ugljikovodičnog niza, mogu sadržavati aliciklične i/ili aromatične skupine i mogu biti zasićene ili nezasićene. Primjeri karboksilata alkalnih metala uključuju natrijev kaprilat, natrijev pelargonat, kalijev palmitat, natrijev stearat, natrijev arhidat, natrijev behenat, kalijev lignocerat, natrijev oleat, kalijev oleat, natrijev ricinoleat, natrijev linoleat i slične. Alkali metal carboxylates which are effective in the present invention include alkali metal salts of carboxylic acids having 8 to 40 carbon atoms. Acids may have a straight or branched hydrocarbon chain structure, may contain alicyclic and/or aromatic groups, and may be saturated or unsaturated. Examples of alkali metal carboxylates include sodium caprylate, sodium pelargonate, potassium palmitate, sodium stearate, sodium archidate, sodium behenate, potassium lignocerate, sodium oleate, potassium oleate, sodium ricinoleate, sodium linoleate and the like.

Maseni odnos hidrkosipropilmetilceluloze prema karboksilatu alkalnog metala u krutim doznim oblicima je poželjno od 1/0.05 do 1/3, a njihova kombinirana masa poželjno ne čini više od 30 mas.% ukupne mase krutog doznog oblika. Kruti dozni oblici mogu poželjno sadržavati od 3 do 25 mas.% hidroksipropilmetilceluloze. Poželjno je da terapeutski aktivni madikament čini barem 70 mas. % ukupne mase doznog oblika. The mass ratio of hydroxypropylmethylcellulose to alkali metal carboxylate in solid dosage forms is preferably from 1/0.05 to 1/3, and their combined mass preferably does not make up more than 30 wt.% of the total mass of the solid dosage form. Solid dosage forms can preferably contain from 3 to 25 wt.% of hydroxypropylmethylcellulose. It is desirable that the therapeutically active drug constitutes at least 70 wt. % of the total weight of the dosage form.

Iako se točna priroda interakcije između karboksilata alkalnog metala i hidroksipropilmetilceluloze ne zna, niti bismo se željeli vezati za bilo koju teoriju, vjeruje se da miješanje ove dvije komponente dovodi do ionsko-dipolne interakcije. Kada se kruti pojedinačni dozni oblik postavi u vodenu sredinu, ugljovodikov dio u vezanom karboksilatu alkalnog metala potpomaže hidrofobno vezanje između hidroksipropilmetilceluloznih lanaca, čime se usporava izdvajanje medikamenta koji je inkorporiran među njih do još većeg stupnja nego što je slučaj kada je u pitanju sama nabubrila hidroksipropilmetilceluloza. Although the exact nature of the interaction between the alkali metal carboxylate and hydroxypropylmethylcellulose is not known, nor do we wish to be bound by any theory, it is believed that the mixing of these two components leads to an ion-dipole interaction. When the solid single dosage form is placed in an aqueous environment, the hydrocarbon moiety in the bound alkali metal carboxylate promotes hydrophobic bonding between the hydroxypropylmethylcellulose chains, thereby retarding the release of the drug incorporated between them to an even greater degree than is the case with the swollen hydroxypropylmethylcellulose alone. .

Hidroksipropilmetilceluloza iz sadašnjeg izuma može se koristiti sa ili bez prethodnog vlaženja ili sličnog tretmana. Njena smjesa s karboksilatom alkalnog metala i s aktivnim medikamentom ima odličnu sposobost komprimiranja. Tablete koje se pripreme od ovakve smjese su krute i imaju veliku gustoću, teško se lome i tijekom dužih perioda osiguravaju kontrolirano i produženo izdvajanje ljekovite supstancije. Kruti oblici lijeka iz sadašnjeg izuma su stabilni i njihova brzina izdvajanja se tijekom dugih perioda skladištenja ne mijenja ni u kakvoj značajnoj mjeri (ukoliko se uopće mijenja). The hydroxypropylmethylcellulose of the present invention may be used with or without prior wetting or similar treatment. Its mixture with alkali metal carboxylate and active medication has excellent compressibility. Tablets prepared from this mixture are rigid and have a high density, they are difficult to break and during long periods they ensure a controlled and extended extraction of the medicinal substance. The solid forms of the drug of the present invention are stable and their release rate does not change significantly (if at all) during long periods of storage.

Hidroksipropilmetilceluloza prosječne molekularne težine od najmanje 50.000 može se u osnovnom nosivom materijalu, zajedno s karboksilatom alkalnog metala, koristiti sama ili u smjesi s drugim neionskim celuloznim eterima. Poželjno je da hidroksipropilmetilcelulozu prosječne molekularne težine od najmanje 50.000 čini najmanje 3 mas. % ukupne mase krutog doznog oblika. Hydroxypropylmethylcellulose with an average molecular weight of at least 50,000 can be used in the basic carrier material, together with an alkali metal carboxylate, alone or in a mixture with other nonionic cellulose ethers. It is preferable that hydroxypropylmethylcellulose with an average molecular weight of at least 50,000 constitutes at least 3 wt. % of total mass of solid dosage form.

Aktivni sastojak može biti bilo koja vrsta lijeka koji djeluje lokalno u usnoj šupljini ili sustavno. Jedinični dozni oblik koji sadržava sustavni lijek može se davati oralno, kako bi se aktivni lijek prenio u gastrointestinalni trakt i iz njega u krv, tjelesne tekućine i tkiva, bez pojave pretjeranog maksimuma koncentracije. Alternativno, aktivni medikament može biti bilo koja vrsta lijeka koji djeluje kroz bukalna tkiva usne šupljine, kako bi se aktivni sastojak prenio direktno u krv, čime se izbjegava metaboliziranje kroz jetru i kontakt sa želučanom i intestinalnom tekućinom koja ima nepoželjno inaktivirajuće djelovanje, ili razara mnoge aktivne sastojke osim ukoliko su posebno zaštićeni protiv djelovanja ovih tekućina (npr. enterološkim oblaganjem ili slično). Aktivni medikament može također pripadati tipu lijekova koji se u krv mogu prenijeti kroz rektalna tkiva. Tako je izum primjenljiv na sublingvalne lozenge, bukalne tablete, supozitorije i komprimate. Ovi potonji su namijenjeni tome da budu progutani u obliku pojedinačne doze i daju, nakon unošenja u gastrointestinalni trakt u skladu s propisanim režimom, kontrolirano i sporo izdvajanje aktivnog medikamenta, a istodobno su zaštićeni protiv inaktivirajuće želučane tekućine. The active ingredient can be any type of medicine that acts locally in the oral cavity or systemically. A unit dosage form containing a systemic drug can be administered orally, in order to transport the active drug into the gastrointestinal tract and from it into the blood, body fluids and tissues, without excessive peak concentrations. Alternatively, the active medication can be any type of medication that acts through the buccal tissues of the oral cavity, in order to transfer the active ingredient directly into the blood, thus avoiding metabolization through the liver and contact with gastric and intestinal fluid that has an undesirable inactivating effect, or destroys many active ingredients unless they are specially protected against the action of these liquids (eg enterological coating or similar). The active drug may also belong to the type of drugs that can be transferred into the blood through the rectal tissues. Thus, the invention is applicable to sublingual lozenges, buccal tablets, suppositories and compresses. These latter are intended to be swallowed in the form of a single dose and provide, after introduction into the gastrointestinal tract in accordance with the prescribed regimen, a controlled and slow release of the active medication, while at the same time they are protected against inactivating gastric fluid.

Primjeri aktivnih medikamenata uključuju antacide, antiinflamatorne supstancije, koronarne vazodilatatore, cerebralne vazodilatatore, periferne vazodilatatore antiinfektivna sredstva, psihotropna sredstva, antipsihotike, stimulativna sredstva, antihistaminike, laksative, dekongestante, vitamine, gastrointestinalne sedative, sredstva protiv dijareje, antanginialne lijekove, antiaritmike, antihipertenzivne lijekove, vazokonstriktore i sredstva protiv migrene, antikoagulante i antitrombotska sredstva, analgetike, antipiretike, hipnotike, sedative, antiemetike, sredstva protiv morske bolesti, antikonvulzante, neuromuskularne lijekove, hiper i hipoglikemijska sredstva, tiroidne i antitiroidne preparate, diuretike, antispazmotike, relaksante maternice, minerale i dodatke za prehranu, sredstva protiv pretilosti, anabolike, eritropoitske lijekove, antiastmatike, ekspektorante, sredstva za suzbijanje kašlja, mukolitike, antiuricemske lijekove, kao i druge lijekove i supstancije koje djeluju lokalno u ustima, kao što su lokalni analgetici, lokalni anestitici itd. Examples of active drugs include antacids, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, anti-infectives, psychotropic agents, antipsychotics, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, antidiarrheal agents, antianginal drugs, antiarrhythmics, antihypertensive drugs , vasoconstrictors and anti-migraine agents, anticoagulants and antithrombotic agents, analgesics, antipyretics, hypnotics, sedatives, antiemetics, anti-seasickness agents, anticonvulsants, neuromuscular drugs, hyper and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, minerals and nutritional supplements, antiobesity agents, anabolics, erythropoietic drugs, antiasthmatics, expectorants, cough suppressants, mucolytics, antiuricemic drugs, as well as other drugs and substances that act lok orally, such as local analgesics, local anesthetics, etc.

Smjesa karboksilata alkalnog metala i hidroksipropilmetilceluloze s prosječnom molekularnom težinom od najmanje 50 000 tvori ono što bi se moglo nazvati sporootapajućim nosačem dugog djelovanja. Nosač po svojoj prirodi ima zaštitno, ublažavajuće i pufersko djelovanje u organizmu i omogućuje aktivnom medikamentu da pokaže svoje optimalno terapeutsko djelovanje i to kako trenutačno, tako i tijekom dužeg vremenskog perioda, čime se ostvaruje potpun terapijski efekt cijele ili gotovo cijele količine danog lijeka. Ovaj neočekivano visok stupanj efikasnosti predstavlja osobitu prednost ostvarenu izumom i smanjuje na minimum sporedno djelovanje lijeka. A mixture of alkali metal carboxylates and hydroxypropylmethylcellulose with an average molecular weight of at least 50,000 forms what may be termed a slow-dissolving, long-acting carrier. The carrier, by its very nature, has a protective, mitigating and buffering effect in the body and enables the active medication to show its optimal therapeutic effect, both immediately and over a longer period of time, which achieves the full therapeutic effect of the entire or almost entire amount of the given medication. This unexpectedly high degree of efficiency represents a special advantage achieved by the invention and reduces the side effects of the drug to a minimum.

U pripremi tableta koje sadrže aktivnu komponentu koja se može davati oralno i koja se kasnije može sistemski apsorbirati, kao što su medikamenti navedeni u prijašnjem tekstu, hidroksipropilmetilceluloza i karboksilat alkalnog metala se potpuno izmiješaju s medikamentom, koji može biti u obliku praha, granula ili u otopini, kao i s bilo kakvim dodatnim sastojcima koji su konvencionalni u proizvodnji tableta, kao što su magnezijev stearat, laktoza, škrob, dimljeni silicijev dioksid, hidrogenizirano biljno ulje i, uopće vezivna sredstva, punitelji, sredstva za dezintegraciju i slično. Hidroksipropilmetilceluloza i karboksilat alkalnog metala mogu se miješati u vodi, alkoholu ili drugoj sredini koja je poznata u nauci, zatim se mogu sušiti da bi se dobile granule, i da bi se tek onda pomiješale s medikamentom ili drugim sastojcima. Alternativno, medikament se može granulirati zajedno s hidroksipropilmetil-celulozom i karboksilatom alkalnog metala prije miješanja s drugim sastojcima. In the preparation of tablets that contain an active component that can be administered orally and that can later be systemically absorbed, such as the medications listed in the previous text, hydroxypropylmethylcellulose and alkali metal carboxylate are completely mixed with the medication, which can be in the form of powder, granules or in solution, as well as with any additional ingredients conventional in the manufacture of tablets, such as magnesium stearate, lactose, starch, fumed silica, hydrogenated vegetable oil and, in general, binders, fillers, disintegrants and the like. Hydroxypropylmethylcellulose and alkali metal carboxylate can be mixed in water, alcohol, or other medium known in the art, then dried to form granules, and then mixed with the medicament or other ingredients. Alternatively, the medicament may be granulated together with hydroxypropylmethylcellulose and an alkali metal carboxylate prior to mixing with the other ingredients.

Cijela smjesa se zatim, u količini dovoljnoj da bi se dobila uniformna partija tableta, npr. 50 000, od kojih će svaka sadržavati efikasnu količinu aktivnog sastojka, podvrgava tabletiranju u konvencionalnim aparatima za tabletiranje na pritisku komprimiranja od 135 × 105 do 1100 × 105 Pa. S obzirom na korištenje specifičnog nosivog materijala iz sadašnjeg izuma u proizvodnji tableta, dobiva se proizvod koji ima željenu tvrdoću, niski stupanj lomljivosti i unaprijed određeno kontrolirano i produženo djelovanje, kao i regularno odloženo izdvajanje ljekovite supstancije tijekom perioda od 0.25-36 sati ovisno o točnoj veličini tablete, tvrdoće i konkretnog sastava nosača. Na taj način je moguće dobiti tablete s kontroliranim i laganim kontinuiranim izdvajanjem i to na relativno jednostavan i ekonomičan način u industrijskim razmjerima, nasuprot ranije upotrebljavanim i predlaganim kompliciranijim i kompleksnijim materijalima i postupcima. The entire mixture is then, in an amount sufficient to obtain a uniform batch of tablets, e.g. 50,000, each of which will contain an effective amount of active ingredient, subjected to tableting in conventional tableting apparatus at a compression pressure of 135 x 105 to 1100 x 105 Pa . With regard to the use of a specific carrier material from the present invention in the production of tablets, a product is obtained that has the desired hardness, a low degree of friability and a predetermined controlled and prolonged action, as well as a regular delayed release of the medicinal substance during a period of 0.25-36 hours depending on the exact tablet size, hardness and specific carrier composition. In this way, it is possible to obtain tablets with a controlled and easy continuous release and in a relatively simple and economical way on an industrial scale, in contrast to the more complicated and complex materials and procedures used and proposed earlier.

Sadržaj vlage u nosaču koji se koristi u dobivanju tableta s kontroliranim izdvajanjem lijeka, može biti u opsegu od 0.1-10%, pri čemu je niži kraj ovog opsega poželjan kada se radi s medikamentima osjetljivim na vlagu. Ukoliko je sadržaj vlage izvan ovog opsega, moguće ga je podesiti korištenjem suhog ili vlažnog zraka sobne ili povišene temperature. Koristi se prikladna oprema, kao što su statične ili konveksne komore, komore s forsiranim upuhivanjem zraka, vakuumske komore i druga oprema koja je poznata stručnjacima u ovom području. Za vrijeme tabletiranja, sadržaj vlage u nosaču ima utjecaj na kompaktnost tableta dobivenih pod danim pritiskom komprimiranja. Međutim, sadržaj vlage ima manji utjecaj na karakteristike kontroliranog izdvajanja od sastava nosača i njegove koncentracije. The moisture content of the carrier used in the formulation of controlled release tablets may be in the range of 0.1-10%, with the lower end of this range being preferred when dealing with moisture sensitive medicaments. If the moisture content is outside this range, it can be adjusted using dry or moist air at room or elevated temperature. Suitable equipment is used, such as static or convex chambers, forced air chambers, vacuum chambers, and other equipment known to those skilled in the art. During tableting, the moisture content of the carrier has an influence on the compactness of tablets obtained under a given compression pressure. However, the moisture content has less influence on the characteristics of the controlled separation than the composition of the carrier and its concentration.

Oblik izdvajanja aktivnog medikamenta iz nosača prema sadašnjem izumu može se kontrolirati u skladu s konkretnim lijekom i njegovim planiranim terapetuskim učinkom. Za sublingvalne lozenge ili tablete, vrijeme izdvajanja može varirati od 0.25 do 4 sata. Za bukalne tablete, vrijeme izdvajanja može biti od 0.25 do 24 sata. Za oralno dane tablete, vrijeme izdvajanja može biti 2-4 sata, 4-8 sati, 8-10 sati, 15-18 sati, 20-24 sata, itd., već prema potrebi. Za vaginalne i rektalne supozitorije, vrijeme izdvajanja se kreće od 2 do 36 sati premda, ukoliko je indiciranono, može biti i kraće ili duže. Moguće je osigurati kontrolirano izdvajanje s neuobičajeno pouzdanim karakteristikama. Izum je veoma svestrane i prilagodljive prirode, što omogućuje širok spektar primjena i krajnjih potreba. The form of extracting the active medication from the carrier according to the present invention can be controlled in accordance with the specific drug and its planned therapeutic effect. For sublingual lozenges or tablets, the extraction time can vary from 0.25 to 4 hours. For buccal tablets, the withdrawal time can be from 0.25 to 24 hours. For orally administered tablets, the withdrawal time can be 2-4 hours, 4-8 hours, 8-10 hours, 15-18 hours, 20-24 hours, etc., depending on the need. For vaginal and rectal suppositories, the withdrawal time ranges from 2 to 36 hours, although, if indicated, it can be shorter or longer. It is possible to provide controlled extraction with unusually reliable characteristics. The invention is very versatile and adaptable in nature, which enables a wide range of applications and ultimate needs.

Ilustrativne primjere koji opisuju sadašnji izum u daljnjem tekstu ne treba shvatiti kao ograničavajuće. Stručnjacima u ovom području će varijacije u njegovoj primjeni biti sasvim jasne. Illustrative examples describing the present invention hereinafter should not be construed as limiting. Variations in its application will be readily apparent to those skilled in the art.

PRIMJERI 1-2 EXAMPLES 1-2

Teofilinske tablete s kontroliranim izdvajanjem pripremljene su od granuliranog, bezvodnog teofilina i od hidroksipropilmetilceluloze (HPMC) viskoziteta 4 000 mPa.sec s metoksilnim sadržajem od 19-24 mas %, hidroksipropoksilnim sadržajem od 4-12 mas.% i prosječnom molekularnom težinom od 89 000, koja se komercijalno dobiva pod nazivom Methocel K4M. Tablete su proizvedene sa ili bez natrijevog stearata. Controlled-release theophylline tablets are prepared from granular, anhydrous theophylline and from hydroxypropylmethylcellulose (HPMC) with a viscosity of 4,000 mPa.sec, a methoxyl content of 19-24 wt.%, a hydroxypropoxyl content of 4-12 wt.%, and an average molecular weight of 89,000. , which is commercially available under the name Methocel K4M. Tablets are manufactured with or without sodium stearate.

Teofilinske tablete od 306 mg su dobivene od sljedećih sastojaka: Theophylline tablets of 306 mg are obtained from the following ingredients:

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Sastojci 1 i 2 su izmiješani, smjesi je dodan sastojak 3 i zatim, nakon miješanja, sastojci 4 i 5. Smjesa je miješana 20 minuta i zatim je podvrgnuta komprimiranju u Parr-ovoj preši za tablete sa sitom od 9.525. Tvrdoća tableta je određivana na Penwalt Stokes-ovom uređaju za testiranje tvrdoće. Ingredients 1 and 2 were mixed, ingredient 3 was added to the mixture and then, after mixing, ingredients 4 and 5. The mixture was mixed for 20 minutes and then compressed in a Parr tablet press with a 9.525 screen. Tablet hardness was determined on a Penwalt Stokes hardness tester.

Brzine izdvajanja su određivane pri pH 7.0 uz uporabu uređaja za otapanje s rotacijskom košarom, opisanog u U.S. Pharmacopeia, poglavlje XX, str. 959. Lopatica je rotirala brzinom od 100 obrtaja u minuti, a temperatura vodene sredine je održavana na 37ºC. Rezultati su dani u sljedećoj tablici: Extraction rates were determined at pH 7.0 using a rotary basket solubilizer described in U.S. Pat. Pharmacopeia, Chapter XX, p. 959. The blade rotated at a speed of 100 revolutions per minute, and the temperature of the water medium was maintained at 37ºC. The results are given in the following table:

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Izdvojene količine su također određivane pri pH 7.0 uz uporabu uređaja za otapanje s rotacijskom lopaticom, opisanog u U.S. Pharmacopeia, vol. XX, str. 959. Lopatica je rotirala brzinom od 50 obrtaja u minuti, a temperatura vodene sredine je održavana na 37°C. Rezultati su dani u sljedećoj tablici: The amounts recovered were also determined at pH 7.0 using a rotary vane solubilizer described in U.S. Pat. Pharmacopeia, vol. XX, p. 959. The blade rotated at a speed of 50 revolutions per minute, and the temperature of the water medium was maintained at 37°C. The results are given in the following table:

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PRIMJERI 3-4 EXAMPLES 3-4

Teofilinske tablete s kontroliranim izdvajanjem pripremljene su od bezvodnog teofilina i hidroksipropilmetilcel ulože (HPMC) viskoziteta 4000 mPa.sec s metoksilnim sadržajem 28-30 mas. %, hidroksipropoksilnim sadržajem 7,5-12 mas. % i prosječnom molekularnom težinom od 93 000, koja se komercijalno dobiva pod nazivom Methocel E4M. Tablete su pripremljene sa i bez natrij laurata. Controlled-release theophylline tablets were prepared from anhydrous theophylline and hydroxypropylmethylcellulose (HPMC) with a viscosity of 4000 mPa.sec and a methoxyl content of 28-30 wt. %, with a hydroxypropoxyl content of 7.5-12 wt. % and with an average molecular weight of 93,000, which is commercially available under the name Methocel E4M. Tablets are prepared with and without sodium laurate.

Dobivene su teofilinske tablete od 306 mg od sljedećih sastojaka: Theophylline tablets of 306 mg were obtained from the following ingredients:

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Sastojci su izmiješani na isti način kao u Primjerima 1-2 i komprimirani su u preši za peletiranje uz korištenje sita od 9.525 mm. The ingredients were mixed in the same manner as in Examples 1-2 and compressed in a pellet press using a 9,525 mm screen.

Brzine izdvajanja su određivane pri pH na 37°C u korištenju metoda s rotacijskom košarom pri 100 okretaja u minuti. Teofilinske tablete od 306 mg imale su sljedeće osobine: Extraction rates were determined at pH 37°C using the rotary basket method at 100 rpm. Theophylline tablets of 306 mg had the following properties:

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Izdvojene količine su također određivane na pH 7.0 na 37ºC uz uporabu metoda s rotacijskom lopaticom pri 50 obrtaja u minuti. Dobiveni su sljedeći rezultati: Extracted amounts were also determined at pH 7.0 at 37ºC using the rotary vane method at 50 rpm. The following results were obtained:

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PRIMJER 5 EXAMPLE 5

Teofilinske tablete s kontroliranim izdvajanjem dobivene su od bezvodnog teofilina i hidroksipropilmetilceluloze (HPMC) viskoziteta 4 000 mPa.sec (Methocel E4M) korištene u Primjerima 3-4, u prisustvu natrijevog stearata. Controlled release theophylline tablets were prepared from anhydrous theophylline and hydroxypropylmethylcellulose (HPMC) of viscosity 4,000 mPa.sec (Methocel E4M) used in Examples 3-4, in the presence of sodium stearate.

Teofilinske tablete od 306 mg dobivene su iz sljedećih sastojaka: Theophylline tablets of 306 mg are obtained from the following ingredients:

[image] [image]

Sastojci su izmiješani kako je opisano u Primjeru 4, a tablete su dobivene uporabom sita od 9.525 mm. Tvrdoća i brzine izdvajanja teofilinskih tableta od 306 mg su određivane kako je opisano u prethodnim primjerima, da bi se dobili sljedeći rezultati: The ingredients were mixed as described in Example 4, and tablets were obtained using a 9,525 mm sieve. The hardness and release rates of the 306 mg theophylline tablets were determined as described in the previous examples to give the following results:

[image] PRIMJERI 6-7 [image] EXAMPLES 6-7

Teofilinske tablete s kontroliranim izdvajanjem dobivene su od bezvodnog teofilina i HPMC viskoziteta 15000 mPa.sec s metoksilnim sadržajem od 19-24 mas.%, hidroksipropoksilnim sadržajem od 4-12 mas.% i prosječnom molekularnom težinom od 124 000, dobivene pod komercijalnim nazivom Methocel K15M. Tablete su pripremane sa i bez natrij laurata. Controlled-release theophylline tablets are obtained from anhydrous theophylline and HPMC viscosity 15,000 mPa.sec with a methoxyl content of 19-24 wt.%, a hydroxypropoxyl content of 4-12 wt.% and an average molecular weight of 124,000, obtained under the commercial name Methocel K15M. The tablets were prepared with and without sodium laurate.

Teofilinske tablete od 306 mg dobivene su od sljedećih sastojaka: Theophylline tablets of 306 mg are obtained from the following ingredients:

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Sastojci su izmiješani kao stoje opisano u Primjerima 1-2 i komprimirani su u preši za palete uz korištenje sita od 9.525 mm. The ingredients were mixed as described in Examples 1-2 and compressed in a pallet press using a 9,525 mm screen.

Brzine izdvajanja su određivane pri pH 1.5, na 37°C, uz uporabu metoda s košarom koja rotira pri 100 obrtaja u minuti. Teofilinske tablete od 306 mg su imale sljedeće osobine: Extraction rates were determined at pH 1.5, at 37°C, using the basket method rotating at 100 revolutions per minute. Theophylline tablets of 306 mg had the following properties:

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PRIMJERI 8-9 EXAMPLES 8-9

Ibuprofenske tablete s kontroliranim izdvajanjem dobivene su od ibuprofena i HPMC viskoziteta 4000 mPa.sec (Methocel K4M) korištene u Primjerima 1-2. Tablete su pripremane sa i bez natrijum stearata. Controlled release ibuprofen tablets were obtained from ibuprofen and HPMC viscosity 4000 mPa.sec (Methocel K4M) used in Examples 1-2. The tablets were prepared with and without sodium stearate.

Ibuprofenske tablete od 700 mg su dobivene iz sljedećih sastojaka: Ibuprofen tablets of 700 mg are obtained from the following ingredients:

[image] [image]

Sastojci su izmiješani kao stoje opisano u Primjerima 1-2 i komprimirani u preši za pelete uz korištenje sita od 9.525 mm. The ingredients were mixed as described in Examples 1-2 and compressed in a pellet press using a 9,525 mm screen.

Brzine izdvajanja su određene na pH 7.2 na 37ºC uz korištenje metoda s košarom koja rotira pri 100 obrtaja u minuti. Ibuprofenske tablete od 700 mg su imale sljedeće osobine: Extraction rates were determined at pH 7.2 at 37ºC using the rotating basket method at 100 rpm. Ibuprofen tablets of 700 mg had the following properties:

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PRIMJERI 10-11 EXAMPLES 10-11

Aspirinske tablete s kontroliranim izdvajanjem pripremljene su od U.S.P. aspirina i HPMC viskoziteta 4 000 mPa.sec (Methocel K4M) korištene u Primjerima 1-2. Tablete su pripremljene sa i bez natrij stearata. Controlled-release aspirin tablets are prepared from the U.S.P. aspirin and HPMC viscosity 4,000 mPa.sec (Methocel K4M) used in Examples 1-2. Tablets are prepared with and without sodium stearate.

Tablete aspirina od 650 mg pripremljene su od sljedećih sastojaka: Aspirin tablets of 650 mg are prepared from the following ingredients:

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Sastojci su izmiješani kao što je opisano u Primjerima 1-2. Smjesa je podvrgnuta komprimiranju u stroju za tabletiranje s kalupom od 7.13×15.88 mm pod pritiskom komprimiranja od 27.45 mPa, kako bi se dobilo 1 000 tableta u obliku kapsule zarezanih preko pola s jedne strane. The ingredients were mixed as described in Examples 1-2. The mixture was compressed in a tableting machine with a 7.13×15.88 mm mold under a compression pressure of 27.45 mPa to obtain 1,000 capsule-shaped tablets scored over half on one side.

Brzine izdvajanja su određivane na pH na 37ºC uz korištenje metoda s lopaticom koja rotira pri 100 obrtaja u minuti, a rezultati su bili sljedeći: Extraction rates were determined at pH at 37ºC using the paddle method rotating at 100 rpm and the results were as follows:

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Claims (6)

1. Postupak za dobivanje osnovnog nosivog materijala za dozne oblike lijekova s produženim izdvajanjem aktivne supstancije, naznačen time, što se priprema smjesa koja, od bitnih komponenata, sadržava karboksilat alkalnog metala i jedan ili više u vodi topivih neionskih celuloznih etera od kojih je barem jedan hidroksipropilmetilceluloza prosječne molekularne težine od najmanje 50.000.1. Process for obtaining the basic carrier material for dosage forms of drugs with prolonged release of the active substance, indicated by the fact that a mixture is prepared which, as essential components, contains an alkali metal carboxylate and one or more water-soluble nonionic cellulose ethers, of which at least one is hydroxypropylmethylcellulose with an average molecular weight of at least 50,000. 2. Postupak prema zahtjevu 1, naznačen time, što smjesa sadržava hidroksipropilmetilcelulozu i karboksilat alkalnog metala u masenom odnosu od 1/0.05 do 1/3.2. The method according to claim 1, characterized in that the mixture contains hydroxypropylmethylcellulose and alkali metal carboxylate in a mass ratio of 1/0.05 to 1/3. 3. Postupak prema zahtjevu 1, naznačen time, što karboksilat alkalnog metala predstavlja sol karboksilne kiseline s 8 do 40 ugljikovih atoma.3. The method according to claim 1, characterized in that the alkali metal carboxylate is a salt of a carboxylic acid with 8 to 40 carbon atoms. 4. Postupak prema zahtjevu 1, naznačen time, stoje karboksilat alkalnog metala natrij stearat ili natrij laurat. 4. The method according to claim 1, characterized in that the alkali metal carboxylate is sodium stearate or sodium laurate. 5. Postupak prema zahtjevu 1, naznačen time, što hidroksipropilmetilceluloza ima metoksilni sadržaj od 28-30 mas.% i hidroksipropoksilni sadržaj od 7.5 - 12 mas. %.5. The method according to claim 1, characterized in that hydroxypropylmethylcellulose has a methoxyl content of 28-30 wt.% and a hydroxypropoxyl content of 7.5-12 wt.%. %. 6. Postupak prema zahtjevu 1, naznačen time, što hidroksipropilmetilceluloza, ima metoksilni sadržaj od 19-24 mas.% i hidroksipropoksilni sadržaj od 4 - 12.6. The method according to claim 1, characterized in that hydroxypropylmethylcellulose has a methoxyl content of 19-24 wt.% and a hydroxypropoxyl content of 4-12.
HR920377A 1987-12-21 1992-09-21 Process for the preparatin of a carrier base material for drug dosage forms with an extended release of active substance HRP920377A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US13566787A 1987-12-21 1987-12-21
US07/284,931 US4983398A (en) 1987-12-21 1988-12-15 Sustained release drug dosage forms containing hydroxypropylmethylcellulose and alkali metal carboxylates
YU230888A YU46701B (en) 1987-12-21 1988-12-20 PROCEDURE U FOR OBTAINING BASIC SUPPORTING MATERIAL FOR DOSAGE FORMS OF MEDICINAL PRODUCTS WITH EXTENDED RELEASE OF ACTIVE SUBSTANCE

Publications (1)

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HRP920377A2 true HRP920377A2 (en) 1995-08-31

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