SI8710339A8 - Process for obtaining pharmaceutical composition of metoprolol with controlled release - Google Patents
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POSTUPAK ZA DOBIVANiJE^PREPA^RftTA^STnCONTROLTSANIM OSLOBADJANJEMPROCEDURE FOR THE PREPARATION OF ^ PREP ^ RftTA ^ STnCONTROLTED RELEASE
Pronalazak spada u oblast dobivanja novh farmaceutskih proizvoda, a posebno se odnosi na postupak za dobivanje preparata sa kontrolisanim oslobadjanjem metoprolola. Preparat- koji se proizvodi prema pronalasku se koristi za lečen;|er kardiovaskularnih obolenja.The invention relates to the preparation of new pharmaceutical products, and in particular relates to a process for the preparation of metoprolol controlled release preparations. The preparation- manufactured according to the invention is used for the treatment of cardiovascular diseases.
Pronalaskom se rešava problem ostvarivanja preparata koji pruža jednaku koncentraciju leka u krvi zahvaljujuči kontrolisanom oslobadjanju, i daje se samo jednom dnevno.The invention solves the problem of obtaining a preparation that provides an equal concentration of drug in the blood thanks to controlled release, and is given only once a day.
Stanje_tehnikeState of the art
Metoprolol, koji ima strukturnu formuluMetoprolol, which has a structural formula
je poznat iz npr. DE-2 106 209. Lek, koji je beta-adrenoceptorski antagonist se poželjno koristi kao so, npr. tartarat.is known from e.g. DE-2 106 209. A drug that is a beta-adrenoceptor antagonist is preferably used as a salt, e.g. tartrate.
Metoprolol blokira adrenergičnu stimulaciju srca i tako smanjuje zahtev kardijarnog tkiva za kiseonikom. Očigledno, to objašnjava njegove podesne efekte kod angine pektoris i kardioprotektivnog delovanja kod miokardijalnih infrakcija. Pored toga metoprolol norm. lizuje krvni pritisak kod velikog broja pacijenata sa arterijskom hipertenzijom što je verovatno rezultat dodatnog dejstva na kontrol’ periferne rezistencije prema pretoku krvi.Metoprolol blocks adrenergic stimulation of the heart and thus reduces the requirement of cardiac tissue for oxygen. Obviously, this explains its beneficial effects in angina and cardioprotective action in myocardial infections. In addition, metoprolol norm. lyses blood pressure in a large number of patients with arterial hypertension, which is probably the result of an additional effect on the control of peripheral resistance to blood flow.
Za pacijente koji pate od kardiovaskularnih obo.renja''požel jno je da ima ju konstantnu koncentraciju leka koji se daje f Stokaj je poželjno kontrolisano oslobadjanje. leka tokom idGž^g'A^brib'dai<gi;.^nenaFor patients suffering from cardiovascular disorders, it is preferable to have a constant concentration of the drug administered f Controlled release is therefore desirable. of medicine during idGž ^ g'A ^ brib'dai <gi;. ^ nena
Prema najčešcem načinu lečehja, pcijentu se daje^pov.jed-najKtah.lgfee .According to the most common method of treatment, the patient is given ^ pov.jed-najKtah.lgfee.
Ti’t; 331-970. 34S-;S3 ko-ia se brzo rastvara dva puta anevno. To daje Dramenljiv.eruγη iYou wanted; 331-970. 34S-; S3 ko-ia dissolves rapidly twice anew. It gives Dramatic.eruγη i
koncentracije sa visokim vrednostima pika i dolje talasa kod koriščenja leka tokom dana.concentrations with high peak and down wave values when using the drug during the day.
Za doziranje jedanput dnevno metoprolol je unet u tablete sa kontrolisanim oslobadjanjem tipa sa nerastvornom matricom, npr.Durules1*. Medjutim oslobadjanje leka iz tableta sa matricom nije zadovoljavajuče jer se oko 50% doze oslobodi tokom nekoliko časova nakon davanja. Stoga je postavljen zahtev da se pronadje način da se dobije preparat leka koji imaju konstantnije kontrolisano oslobadjanje aktivne komponente tokom oko 20-24 h, pri čemu bi se ravnomernije koncentracije u ' krvi i efekti dobili za ceo interval doziranja.For once-daily dosing, metoprolol was administered in controlled release type tablets with insoluble matrix, eg Durules 1 *. However, the release of the drug from the matrix tablets is not satisfactory as about 50% of the dose is released within hours after administration. Therefore, a request was made to find a way to obtain a drug preparation having a more constant controlled release of the active component over about 20-24 h, whereby more uniform blood concentrations and effects would be obtained for the entire dosing interval.
Sistem oslobadjanja leka zvani Oros^može se upotrebiti za dobivanje kontrolisanog oslobadjanja npr. metoprolola za jednu dnevnu dozu. Sistem je opisan u U.S.Patentu 4 036 227 i u prilogu British Journal of Clinical Pharmacology ·(1985), 19, 69S-76S od Theeuwes F. et al. Oro^^ je sistem jedne jedinice i sastoji se od osmotski aktivnog jezgra koje se koji se uglavnom sastoji od supstance leka obmotane sepermeabilnom membranom kroz koju je probušen samo jedan mali otvor. Oslobadjanje leka iz sistema je konstantno sve dok se na membrani održava stalan osmotski pritisak. 50-60% od ukupnog sadržaja leka se oslobadja konstantnom brzinom.A drug release system called Oros ^ can be used to obtain controlled release e.g. metoprolol for one daily dose. The system is described in U.S. Patent 4 036 227 and attached to the British Journal of Clinical Pharmacology · (1985), 19, 69S-76S by Theeuwes F. et al. Oro ^^ is a system of one unit and consists of an osmotically active nucleus, consisting mainly of a drug substance wrapped in a sempermeable membrane through which only a small opening is drilled. The release of the drug from the system is constant as long as a constant osmotic pressure is maintained on the membrane. 50-60% of the total drug content is released at a constant rate.
U SE-A-8400085 je predloženo da se napravi jedan unutrašnji obloženi proizvod, koji sadrži npr. metoprolol, i sa sporim oslobadjanjem aktivnog jedinjenja u bližini debelog čreva. Ovakav preparat ne pruža konstantno i sporo otpuštanje metoprolola nezavisno od pH, što preparat prema ovom pronalasku pruža.It is proposed in SE-A-8400085 to make one inner coated product, containing e.g. metoprolol, and with the slow release of the active compound near the colon. Such a preparation does not provide a constant and slow release of metoprolol independently of pH, which the preparation of the present invention provides.
Depo-preparati koji se sastoje od velikog broja malih jedinica su takodje poznati iz EP 13263. Ovaj patent opisuje farmaceutski indiferentna jezgra prekrivena aktivnim jedinjenjem. Jezgra su način jena od raš|:vornog materijala, npr. laktoze. .Depot preparations consisting of a large number of small units are also known from EP 13263. This patent describes a pharmaceutically indifferent core coated with an active compound. The nuclei are a way of dissolving material, e.g. lactose. .
Depo-preparati''koji sadrže veliki broj malih jedinica, od ko j ih svaka oslobadja lek pri kontrolisanoj brzini su u prednosti u odnosu na depo-preparate koji se sastoje od jedne male jidice, npr. matricetablete ili tablete obavijene omotačem, koji kontroliše oslobadjanje. Moguče je na primer dobiti reproduktivno pražnjenje jedinica iz stomaka kada su upotrebljeni deliči manji od 1-2 mm. Cf.BogentoftDepot preparations containing a large number of small units, each of which releases the drug at a controlled rate, are preferred over depot preparations consisting of one small unit, e.g. matrix tablets or wrapped tablets controlling release. For example, it is possible to obtain reproductive emptying of units from the abdomen when fragments smaller than 1-2 mm are used. Cf.Bogentoft
- ret al.: Uticaj hrane na absorpciju acetijsalieilne kiseline iz unutrašnjih-obloženih oblika doziranja. Europ J Ciin Pharmacol 1978, 14, 351-355. Disperzija po velikoj površini gastrointestinalnog kanala daje veče ukupno reprodukvno vreme prolaženja što je povoljno na absorpciju. Cf.Edgar B, Bogentoft C and Lagerstrom PO: Uporedjivanje dva unutrašnje-prevučena preparata acetilsalicilne kiseline pračenjem nivoa stabilnih stanja salicilne kiseline i njenih metabolita u plazmi i urinu. Biopharmaceutics & Drug Disposition 1984 , 5, 251-260. Osim toga, preparati.dsa višestrukom jediničnom dozom su podesniji od leka u obliku preste jedinične doze s obzirom da se doza rastura u crevima. Rizik od lokalne iritacije i akomulacije nekoliko doza zbog kontrikcije u alimentarnom kanalu je takodje znatno niši.- ret al .: Effect of food on the absorption of acetylsalieic acid from internally-coated dosage forms. Europ J Ciin Pharmacol 1978, 14, 351-355. Dispersion over a large area of the gastrointestinal canal gives the evening total reproductive passage time which is favorable for absorption. Cf.Edgar B, Bogentoft C and Lagerstrom PO: Comparison of two acetylsalicylic acid internally-coated preparations by monitoring steady-state levels of salicylic acid and its metabolites in plasma and urine. Biopharmaceutics & Drug Disposition 1984, 5, 251-260. In addition, multiple unit dose preparations are more appropriate than a single unit dose formulation since the dose is dispersed in the intestine. The risk of local irritation and the accumulation of several doses due to contraction in the alimentary canal is also significantly lower.
Dalja pogodnost. sa višestrukim jediničnim preparatom je ta što se on može podeliti na manje porcije pri čemu sve one imaju iste osobine absorpcije. Time se omogučava veča fleksibilnost i selektivnost veličine doze.A further convenience. with a multiple unit preparation it is that it can be divided into smaller portions, all of which have the same absorption properties. This allows for greater flexibility and selectivity for dose size.
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Pronalazak se odnosi na postupak za dobivanje preparata koji sadrži metoprolol kao aktivan sastojak i koji ima kontrolisanu brzinu oslobadjanja leka tokom bar 15 h. Pravljenjem preparat koji sadrži veliki broj malih kompaktnih deliča od kojih svaki sadrži so metoprolola kao glavnu rastvornu komponentu i koji je prevučen sa polimernom membranom koja sadrži derivate celuloze bez protolizabilnih grupa, omogučeno je pripremanje podesnih oblika doziranja koji imaju. kontrolisanu brzinu oslobadjanja metoprolola, sasvim nezavisnih od pH, tokom oko 16 do 24 sata.The invention relates to a process for the preparation of a composition comprising metoprolol as an active ingredient and having a controlled rate of drug release for at least 15 h. By making a preparation containing a large number of small compact particles, each containing metoprolol salt as the main solubilizing component and coated with a polymeric membrane containing cellulose derivatives without protolyzable groups, it is possible to prepare suitable dosage forms which have. controlled release rate of metoprolol, completely pH independent, for about 16 to 24 hours.
Mali deliči, slojevi. koji sadrže metoprolol imaju veličinu od 0.25-2 mm, poželjno 0.35-1.0 mm.Little bits, layers. containing metoprolol have a size of 0.25-2 mm, preferably 0.35-1.0 mm.
Slojevi mogu sadržavati metoprolol sam ili se mogu 'sastojati od nerastvornog jezgra obavijenog metoprololom. Slojevi imaju vrlo visok sadržaj metoprolola, poželjno 95-100 m/m% od rastvornog dela slojeva. Nerastvorno jezgro ima veličinu od |ΰ. 1-1 .0' mm, poželjno 0.15-0.3 mm. Primeri nerastvornih jezgarla p^-emš- 'pronalasku, su silicijum dioksid i male cestice stakla. -jr. u.;···-·*.The layers may contain metoprolol alone or may consist of an insoluble core coated with metoprolol. The layers have a very high metoprolol content, preferably 95-100 w / w% of the soluble part of the layers. The insoluble nucleus has a size of | ΰ. 1-1 .0 'mm, preferably 0.15-0.3 mm. Examples of insoluble cores of the invention are silicon dioxide and small particles of glass. -jr. in.; ··· - · *.
Slojevi koji se koriste u pos-feupku preme' pronalasku su kompaktni, što znači da je njihova poroznost manja od 15 procenata.The layers used in the post-feupe preme 'invention are compact, meaning that their porosity is less than 15 percent.
Kao što se može videti sa sl.1, novi preparat dobiven postupkom prema pronalasku se odlikuje time što se bar 75% metoprolola oslobadja tokom 20 h a bar 50% doze metoprolola se oslobadja brzinom od 3-7 m/m%/h.As can be seen from FIG. 1, the new preparation obtained by the process of the invention is characterized in that at least 75% of metoprolol is released within 20 h and at least 50% of the metoprolol dose is released at a rate of 3-7 m / m% / h.
Metoprolol koji se koristi u preparatu može biti u obliku racemata, ili jednog od enantiomera, odnosno S-izomera. (Poželjno, koncentracija S-izomera treba da bude najmanje 95% u odnosu na R-oblik).The metoprolol used in the preparation may be in the form of a racemate, or one of the enantiomers or S-isomers. (Preferably, the S-isomer concentration should be at least 95% relative to the R-form).
Podesne rastvorne soli metoprolola imaju rastvor1jivost manju od 600 mg/ml u vodi na 25°C, poželjno 30-600 mg/ml u vodi na 25°C. Primeri podesnih soli su soli obrazovane od organskih karboksilnih kiselina, poželjno niže molekulske težine. Naročito poželjne soli su sukcinat, fumarat ili benzoat racemskog metoprolola i benzoat ili sorbat S-enantiomera metoprolola.Suitable metoprolol soluble salts have a solubility of less than 600 mg / ml in water at 25 ° C, preferably 30-600 mg / ml in water at 25 ° C. Examples of suitable salts are salts formed from organic carboxylic acids, preferably of lower molecular weight. Particularly preferred salts are succinate, fumarate or benzoate of racemic metoprolol and benzoate or sorbate of the S-enantiomer of metoprolol.
Vrlo rastvorne soli, npr. tartarat, hlorhidrat su manje podesne prema ovom pronalasku.Highly soluble salts, e.g. tartrate, hydrochloride are less suitable according to the present invention.
Primeri podesnih polimernih materijala su etil celuloza ili smeša etil celuloze sa hidroksipropilmetil celulozom, hidroksipropil celulozom, Eudragit RL ili Eudragit RS.Examples of suitable polymeric materials are ethyl cellulose or a mixture of ethyl cellulose with hydroxypropylmethyl cellulose, hydroxypropyl cellulose, Eudragit RL or Eudragit RS.
Etil celuloza je upotrebiva u varijantama različitih stepena viskoziteta. Prema pronalasku je pogodno da se upotrebi etil celuloza sa viskozitetom od 10-50 cps, ali se takodje mogu upotrebiti i drugi tipovi etil celuloze.Ethyl cellulose is usable in variants of varying degrees of viscosity. According to the invention, it is advantageous to use ethyl cellulose with a viscosity of 10-50 cps, but other types of ethyl cellulose may also be used.
Eudragit-' je trgovačko ime za vedi broj supstanci koje oblažu filmom na bazi akrilnih smola, koje proizvodi Rohm Pharma.Eudragit- 'is the trade name for many acrylic resin film-coated substances manufactured by Rohm Pharma.
Eudragit RL |L RS su kopolimeri sintetizovani iz estara akrilne i metakrilne’ kiseline sa niškim sadržajem kvaterernih amonijum ·' grupa. Molarni odnos ovih amonijum grupa prema preostalnim neutralnim estrima (met)akrilne kiseline je 1:20 za Eudragit RL i 1:40 za Eudragit RS, što rezultuje u različitim karakteristikama permeabilnosti.Eudragit RL | L RS are copolymers synthesized from acrylic and methacrylic 'acid esters with a low content of quaternary ammonium ·' groups. The molar ratio of these ammonium groups to the remaining neutral (meth) acrylic acid esters is 1:20 for Eudragit RL and 1:40 for Eudragit RS, resulting in different permeability characteristics.
Plastifikatori i/ili pigmenti se mogu dodati, polimsrnom sloju da bi se poboljšale tehničke osobine sloja iliPlasticizers and / or pigments may be added to the polymerscoat to improve the technical properties of the layer or
prevlake. Primeri poznatih plastifikatora su citratni estri, acetilovani monogliceridi i glicerintiriacetat, naročito je poželjan acetiltributilcitrat.coatings. Examples of known plasticizers are citrate esters, acetylated monoglycerides, and glycerylthiriacetate, especially acetyltributyl citrate.
Polimerna membrana je načinjena od jednog ili više polimera koji daju membranu sa karakteristikama permeabilnosti potpuno nezavisnim od pH u pH opsegu od 1.0-8.0.A polymeric membrane is made of one or more polymers which give a membrane with permeability characteristics completely independent of pH in the pH range of 1.0-8.0.
Svaki prevučeni sloj metoprolola prema ovom pron|alasku obrazuje jedinicu čije se odpuštanje individualno kontroliše, pri čemu se lek odpušta predhodno odredjenom brzinom. Stoga, obloženi slojevi prema ovom pronalasku omogučuju da se obrazuje i daje preparat u različitim oblicima doziranja. Oni kiogu da se pune u npr. čvrste želatinozne kapsule ili čaure ili komprimovane tablete i da još uvek daju željeni profil koncentracije i trajanje efekta u krvi.Each coated layer of metoprolol according to this invention forms a unit whose release is individually controlled, with the drug being released at a predetermined rate. Therefore, the coated layers according to the present invention allow for the formation and delivery of the preparation in various dosage forms. They charge the kioga in e.g. solid gelatin capsules or casings or compressed tablets and still give the desired concentration profile and duration of effect in the blood.
Kada se mali prevučeni deliči metoprolola tabletiraju, oni se mešaju sa aditivima npr. mikrokristalnom celulozom kao što jeWhen small coated metoprolol particles are tableted, they are mixed with additives e.g. microcrystalline cellulose such as
Avicel·^, koji poboljšava osobine tabletiranja i olakšava desintetraciju tablete, pri čemu se oslobadjaju individualni slojevi.Avicel · ^, which improves tableting properties and facilitates tablet desintetration, thereby releasing individual layers.
Pronalazak omogučava da se formulišu oblici farmaceutskog doziranja koji mogu da se daju jedanput dnevno i da još uvek proizvode skoro konstantne koncentracije leka u krvi tokom celokupnog intervala doziranja dok se ne da sledeča doza.The invention allows the formulation of pharmaceutical dosage forms that can be administered once a day and still produce near-constant concentrations of the drug in the blood over the entire dosing interval until the next dose.
DobivanjeGetting it
Postupak za proizvodnju preparata sa kontrolisanim odpuštanjem če u daljem tekstu biti bliže opisan. Pošto se prvo obrazuju slojevi koji sadrže metoprolol, dobiveni slojevi se oblažu sa polimernim slojem opisanim u primerima. Polimerna smeša se rastvara u organskom rastvaraču kao sto je etanol, izopropil alkohol i/ili metilen hlorid. Prskanje se može vršiti u tornju za oblaganje, ali se poželjno vrši u fluidizovanom sloju. Takodje se može iz vodene disperzije (lateks) nanositi i etil celuloza.The process for the manufacture of controlled release preparations will be described in more detail below. As the metoprolol-containing layers are first formed, the resulting layers are coated with the polymer layer described in the examples. The polymer mixture is dissolved in an organic solvent such as ethanol, isopropyl alcohol and / or methylene chloride. Spraying can be done in a coating tower, but preferably in a fluidized bed. Ethyl cellulose can also be applied from aqueous dispersion (latex).
Preparat dobiven postupkom prema pronalasku jfe naročito podesan za lečenje kardiovaskularnih poremečaj^V:-The preparation obtained by the method according to the invention is particularly suitable for the treatment of cardiovascular disorders ^ V: -
Pronalazak je detaljno opisan u sledečim primerima :The invention is described in detail in the following examples:
PRIMERIEXAMPLES
Primer 1Example 1
Metoprolol fumaratMetoprolol fumarate
Metilen hloridMethylene chloride
Etanol 95%Ethanol 95%
Si02 (0.15-0.25 mm)Si02 (0.15-0.25 mm)
Polimerni slojPolymer layer
Etil celuloza 10 cps Hidroksipropilmetil celuloza Acetiltributilcitrat Metilen hloridEthyl cellulose 10 cps Hydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride
Izopropil alkoholIsopropyl alcohol
1440 g 9618 g 3888 g1440 g 9618 g 3888 g
375 g375 g
265.6 g 58.4 g 36.0 g 6141 g 1544 g265.6 g 58.4 g 36.0 g 6141 g 1544 g
U fluidizovanom sloju granulatora metoprolol fumarat se prska preko jezgra silicijum dioksida iz rastvora 96% etanola. 400 g tako obrazovanih slojeva (granula) (frakcije 0.4-0.63 mm) je prevučeno sa polimernim slojem koji sadrži etil celulozu 10 cps, hidroksipropilmetil celulozu i acetiltributilcitrat prskanjem rastvora pomenutih supstanci u metilen hloridu i izopropilalkoholu. Prevučeni slojevi su potom punjeni u čvrste želatinozne kapsule.In the fluidized bed of the granulator, metoprolol fumarate is sprayed over a silica core from a solution of 96% ethanol. 400 g of the so-formed layers (granules) (0.4-0.63 mm fractions) were coated with a polymeric layer containing 10 cps ethyl cellulose, hydroxypropylmethyl cellulose and acetyltributylcitrate by spraying a solution of said substances in methylene chloride and isopropyl alcohol. The coated layers were then filled into hard gelatin capsules.
Primer 2Example 2
Metoprolol sukcinatMetoprolol succinate
Metilen hloridMethylene chloride
Etanol 95%Ethanol 95%
SiO-(0.15-0.25 mm) .ISiO- (0.15-0.25 mm) .I
Polimerni sldjPolymeric sldj
Etilceluloza 50 cpsEthylcellulose 50 cps
Hidroksipropilmetil celuloza Acetiltributilcitrat Metilen hlorid Izopropil alkoholHydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride Isopropyl alcohol
1440 g 9618 g 3888 g1440 g 9618 g 3888 g
375 g375 g
168.1 g 36.9 g 22.8 g 4167 g168.1 g 36.9 g 22.8 g 4167 g
815 g815 g
Aditivi za tableteTablet additives
Mikrokristalna celuloza 1 470.3 g Kukuruzni škrob 117.6 g Krompirov škrob 10.6 g Prečiščena voda 342.2 g Magnezijum stearat 1.2 gMicrocrystalline cellulose 1 470.3 g Corn starch 117.6 g Potato starch 10.6 g Purified water 342.2 g Magnesium stearate 1.2 g
Metoprolol sukcinat je prskan preko jezgra silicfjnm dioksidaMetoprolol succinate was sprayed over silica gel core
i.. Th” prema postupku opisanom u primeru 1. 400 g tako jobrazovanih granula je prevučeno sa polimernim filmom koji sadrži etil celulozu 50 cps., hidroksipropilmetil celulozu i acetiltributilcitrat. Dodatna masa za tabletiranje je načinjena vlažnim granulisanjem suve smeše mikrokristalne celuloze i kukuruznog škroba sa’ rastvorom krompirovog škroba i vode u planetarnom mikseru. Jednake količine (600 g) aktivnih i dodatnih granula su na kraju pomešane sa Mg-stearatom 0.1% i komprimovane u tablete.and .. Th ”according to the procedure described in Example 1. 400 g of the thus-formed granules were coated with a polymer film containing ethyl cellulose 50 cps., hydroxypropylmethyl cellulose and acetyltributyl citrate. The additional tabletting mass was made by wet granulating a dry mixture of microcrystalline cellulose and corn starch with a 'solution of potato starch and water in a planetary mixer. Equal amounts (600 g) of active and additional granules were finally mixed with Mg-stearate 0.1% and compressed into tablets.
Primer 3Example 3
Metoprolol sukcinat 100% u obliku kompaktnih sferičnih granula i sa prosečnom veličinom deliča od 0.42 mmMetoprolol succinate 100% in the form of compact spherical granules and with an average particle size of 0.42 mm
400 g metoprolol sulkcinata u granulama sa deličima manjim od 0.63 mm je prevučeno sa400 g of metoprolol sulccinate in granules with particles smaller than 0.63 mm were coated with
Etilceluloza 10 cpsEthylcellulose 10 cps
Hidroksipropilmetil celuloza Acetiltributilcitrat Metilen hlorid Izopropil alkoholHydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride Isopropyl alcohol
Dobiveni slojevi su formulisani u je gore opisano.The resulting layers were formulated in as described above.
177.1 g 38.9 g 24.0 g177.1 g 38.9 g 24.0 g
4094 g 1029 g farmaceutske preparate kao što4094 g 1029 g pharmaceutical preparations such as
Primer 4Example 4
Metoprolol sukcinat Metilen hlorid Etanol 95%Metoprolol succinate Methylene chloride Ethanol 95%
SiO2 (0.15-0.25 mm)SiO2 (0.15-0.25 mm)
1440 g 9618 g 3888 g1440 g 9618 g 3888 g
375 g375 g
Polimerni slojPolymer layer
Etilceluloza N-10 166.2 g Hidroksipropilmetil celuloza 39.0 g Acetiltributilcitrat 22.0 g Metilen hlorid 3889 g Izopropil alkohol 978 g Aditivi za tableteEthylcellulose N-10 166.2 g Hydroxypropylmethyl cellulose 39.0 g Acetyltributyl citrate 22.0 g Methylene chloride 3889 g Isopropyl alcohol 978 g Tablet additives
Mikrokristalna celuloza 429.3 g Kukuruzni škrob 67.1 g Laktoza u prahu 40.3 g Polividon 55.5 g Prečiščena voda 314.7 g Magnezijum stearat 1.2 gMicrocrystalline cellulose 429.3 g Cornstarch 67.1 g Lactose powder 40.3 g Polividone 55.5 g Purified water 314.7 g Magnesium stearate 1.2 g
Prevlaka za tablete (12.500 tableta)Tablet Coating (12,500 Tablets)
Hidroksipropilmetil celuloza 159.6 g Polietilen glikol 6000 39.9 g Boja titan dioksida 39.9 g Prečiščena voda 1356 g Specijalni parafin 1.6 gHydroxypropylmethyl cellulose 159.6 g Polyethylene glycol 6000 39.9 g Titanium dioxide color 39.9 g Purified water 1356 g Special paraffin 1.6 g
Metoprolol sukcinat je isprskan preko jezgara silicijum dioksida prema postupku opisanom u primerima 1 i 2. 400 g tako dcbivenih slojeva (frakcije 0.4-0.63 mm) je prevučeno sa polimernom smešom koja je takodje opisana gore. Prevučeni slojevi metoprolol sukcinata koji su takodje. dobiveni pomešani su sa aditivima u jednakim količinama i posle dodavanja 0.1% Mg-stearata, suva smeša je komprimovana u tablete. Konačno, tablete su obložene u tornju za oblaganje sa prevlakom za tablete koja je gore opisana.Metoprolol succinate was sprayed over silica cores according to the procedure described in Examples 1 and 2. 400 g of the layers thus formed (0.4-0.63 mm fractions) were coated with the polymer mixture also described above. Coated layers of metoprolol succinate which are also. they were mixed with the additives in equal amounts and after the addition of 0.1% Mg stearate, the dry mixture was compressed into tablets. Finally, the tablets are coated in the tablet coating tower described above.
Primer 5 j : *Example 5 j: *
S-enantiomerni metoprolol sorbat u obliku kompaktnih sferičnih granula u frakcijama 0.4-0.63 mm g metoprolol sorbata u granulama sa deličima manjim od 0.63 mm zajedno sa 360 g non-pareil granula sa deličima izmedju 0.75-1.Omm prevučeno je saS-enantiomeric metoprolol sorbate in the form of compact spherical granules in fractions 0.4-0.63 mm g of metoprolol sorbate in granules with particles smaller than 0.63 mm together with 360 g of non-pareil granules with particles between 0.75-1.Omm was coated with
Etilceluloza 10 cpsEthylcellulose 10 cps
Hidroksipropilmetil celuloza Acetiltributilcitrat Metilen hlorid Izopropil alkoholHydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride Isopropyl alcohol
51.7 g 11.3 g51.7 g 11.3 g
7.0 g7.0 g
1194 g 300 g1194 g 300 g
Dobiveni slojevi su formulisani u farmaceutske preparate kao što je gore opisano. .<4The resulting layers were formulated into pharmaceutical preparations as described above. . <4
Biofarmaceutska študijaBiopharmaceutical study
Koncentracije metoprolola u krvi posle jedne doze preparata sa kontrolisanim oslobadjanjem koji sadrži 190 mg metoprolol sukcinata prema primeru 4 ovog opisa i koncentracije u krvi nakon jedne doze Durulei^-a koji sadrži 200 mg metoprolol tartarata prikazane su na priloženom crtežu 2. 190 mg sukcinatne soli je ekvivalentno sa 200 mg metoprolol tartarata. Uporedjivanje je vršeno na 10 subjekata. Svaka tačka predstavlja srednju vrednost 10 subjekata. Kao što se može videti, preparat prema pronalasku daje skoro konstantna koncentraciju metoprolola tokom više od 20 sati, dok nerastvorni preparat na bazi matrice daje neželjeno visoku koncentraciju u krvi tokom prvih sati nakon davanja.Concentrations of metoprolol in blood after one dose of controlled release preparation containing 190 mg of metoprolol succinate according to example 4 of this description and blood concentrations after one dose of Durulei containing 200 mg of metoprolol tartrate are shown in the accompanying drawing 2. 190 mg of succinate salt is equivalent to 200 mg metoprolol tartrate. Comparisons were made on 10 subjects. Each point represents the mean of 10 subjects. As can be seen, the composition of the invention provides a nearly constant concentration of metoprolol for more than 20 hours, while the insoluble matrix-based preparation gives an undesirably high blood concentration during the first hours after administration.
Snižavanje brzine rada srca subjekata je primalo jednom dnevno tabletu koja je sadržavala 100 mg metoprolol tartarata i snižavanje brzine rada srca 5. dana lečenja je mereno i uporedjeno sa snižavanjem brzine rada srca 5. dana kod subjekata koji su primali preparat sa kontrolisanim oslobadjanjem prema primeru 4 pronalaska, koji sadrži 95 ml metoprolol sukcinata (ekvivalentno 100 mg metoprolol tartarata). Snižavanje brzine rada srca je ilustrovano na crtežuReduction of heart rate of subjects received once daily tablet containing 100 mg of metoprolol tartrate and decrease of heart rate on day 5 of treatment was measured and compared with decrease of heart rate on day 5 of subjects receiving the controlled release preparation according to example 4 of the invention, containing 95 ml of metoprolol succinate (equivalent to 100 mg of metoprolol tartrate). The decrease in heart rate is illustrated in the drawing
3. Kao što se može videti preparat prema pronalasku daje farmakodinamički efekat tokom 24 sata.3. As can be seen, the composition of the invention has a pharmacodynamic effect over 24 hours.
Najbolji način izvodjenja pronalaska je kako se smatra prestavljen primerom 4.The best way of performing the invention is to be considered as exemplified by Example 4.
Tablica I ilustruje in vitro oslobadjanje metoprolola iz preparata prema primerima 1-4. Kao što se može videti iz tablice, bar 50% doze metoprolola se oslobadja brzinom koja varira izmedju 3-7 m/m%/hTable I illustrates the in vitro release of metoprolol from the preparation of Examples 1-4. As can be seen from the table, at least 50% of the metoprolol dose is released at a rate that varies between 3-7 m / m% / h
- 10 o- 10 o
CM — cO oo ooCM - cO oo oo
O ΌO Ό
Ca) 00 oo coCa) 00 oo co
COCO., LTD
CM r*. oo «r cmCM r *. oo «r cm
P** coP ** co
Tablica 1. Kumulativno in vitro rastvaranje metoprolola u fosfatnom puferu pH Metod : USP aparat No.II, rotacija na 100 o.p.m.Table 1. Cumulative in vitro dissolution of metoprolol in phosphate buffer pH Method: USP apparatus No.II, rotation at 100 o.p.m.
CO eJOCO eJO
CM (0CM (0
CC
OJOJ
•n• n
C (0 •oC (0 • o
Ό (0 «Ό (0 «
O +J cO + J c
OJ uOJ u
o uo u
&&
oo co cooo co co
CM *3 \o p>% r*. co co ρά σ> oo oCM * 3 \ o p>% r *. co co ρά σ> oo o
CO CO COCO CO CO., LTD
CM cn CM co to mCM cn CM co to m
CM O «3m m «3cn oCM O «3m m« 3cn o
CO »a- CO tO O p>.CO »a- CO tO O p>.
CM CM CM enCM CM CM en
ΓάΓά
CO CO CMCO CO CM
CM r— Pa oCM r— Well
co σ> i co i— ρά co «oco σ> i co i— ρά co «o
CM I coCM I co
CO PaCO. Well
Ό· sr co i coSr · sr co and co
CO <—CO <-
CM CM ooCM CM oo
Pa CO I co pa «3-Pa CO I co pa «3-
-r ,L '-r, L '
Dos.2037Dos.2037
K δϋ'ί-1 YUK δϋ'ί-1 YU
20.0220.02
P-339/87P-339/87
NAVOD PRIJAVIOCA O NAJBOLJEM NJEMU PG3NATOM NAČINU ZA PRIVREDNU UPOTREBU PRIJAVLJENOG PRONALASKATHE APPLICANT'S STATEMENT ON THE BEST OF ITS PG3NOTH WAY FOR THE ECONOMIC USE OF THE APPLICATION FOUND
Metoprolol sukcinatMetoprolol succinate
Metilen hloridMethylene chloride
Etanol 95%Ethanol 95%
SiO2 (0.15-0.25 nun)SiO 2 (0.15-0.25 nun)
Polimerni slojPolymer layer
Etilceluloza N-10Ethylcellulose N-10
Hidroksipropilmetil celuloza Acetiltributilcitrat Metilen hlorid Izopropil alkohol Aditivi za tablete ♦Hydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride Isopropyl alcohol Tablet additives ♦
Mikrokristalna celulozaMicrocrystalline cellulose
Kukuruzni škrobCorn starch
Laktoza u prahuLactose powder
PolividonPolividon
Prečiščena vodaPurified water
Magnezijum stearatMagnesium stearate
Prevlaka za tablete (12.500 tableta)Tablet Coating (12,500 Tablets)
14401440
96189618
38883888
375 g375 g
g gg g
166.2 g166.2 g
39.0 g39.0 g
22.0 g 3889 g 978 γ g22.0 g 3889 g 978 γ g
429429
314 g314 g
g 3 g 5 g 7 g gg 3 g 5 g 7 g g
Hidroksipropilmetil celuloza 159.6 gHydroxypropylmethyl cellulose 159.6 g
Polietilen glikol 6000 39.9 gPolyethylene glycol 6000 39.9 g
Boja titan dioksida 39.9 gTitanium dioxide color 39.9 g
Prečiščena voda 1356 gPurified water 1356 g
Specijalni parafin 1.6 gSpecial paraffin 1.6 g
Metoprolol sukcinat je isprskan preko jezgara silicijum dioksida prema postupku opisanom u primerima 1 i 2. 400 g tako dobivenih slojeva (frakcije 0.4-0.63 mm) je prevučeno sa polimernom smešom ! koja je takodje opisana gore. Prevučeni slojevi metoprolol sukcinata koji su takodje dobiveni pomešani su sa aditivima u jednakim količinama i posle dodavanja 0.1% Mg-stearata, suva smeša je komprimovana u tablete. Konačno, tablete su obložene u tom ju za oblaganje sa prevlakom za tablete koja jefgore“opisana.Metoprolol succinate was sprayed over silica cores according to the procedure described in Examples 1 and 2. 400 g of the layers thus obtained (0.4-0.63 mm fractions) were coated with the polymer mixture! which is also described above. The coated layers of metoprolol succinate also obtained were mixed with the additives in equal amounts and after the addition of 0.1% Mg stearate, the dry mixture was compressed into tablets. Finally, the tablets are coated in a coated tablet for the tablets which are described herein.
Claims (13)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
YU33987A YU46418B (en) | 1987-03-04 | 1987-03-04 | PROCEDURE FOR PREPARATION OF THE PHARMACEUTICAL PREPARATION METOPROLOL WITH CONTROLLED RELEASE |
Publications (1)
Publication Number | Publication Date |
---|---|
SI8710339A8 true SI8710339A8 (en) | 1996-08-31 |
Family
ID=25549458
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SI8710339A SI8710339A8 (en) | 1987-03-04 | 1987-03-04 | Process for obtaining pharmaceutical composition of metoprolol with controlled release |
Country Status (2)
Country | Link |
---|---|
SI (1) | SI8710339A8 (en) |
YU (1) | YU46418B (en) |
-
1987
- 1987-03-04 YU YU33987A patent/YU46418B/en unknown
- 1987-03-04 SI SI8710339A patent/SI8710339A8/en unknown
Also Published As
Publication number | Publication date |
---|---|
YU46418B (en) | 1993-10-20 |
YU33987A (en) | 1988-12-31 |
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