SK72000A3 - Novel composition comprising an ssri and a beta-blocker - Google Patents
Novel composition comprising an ssri and a beta-blocker Download PDFInfo
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Abstract
Description
Farmaceutický prostriedok a jeho použitiePharmaceutical composition and its use
Oblasť technikyTechnical field
Vynález sa týka nových farmaceutických kompozícií selektívnych inhibítorov serotonínovéj re-absorpcie (selective serotonine re-uptake inhibitors, SSRI). Vynález sa bližšie týka formulácií, ktoré sú vhodné na zvýšenie terapeutickej účinnosti SSRI a najmä na zlepšenie začiatku terapeutického vplyvu.The invention relates to novel pharmaceutical compositions of selective serotonin re-uptake inhibitors (SSRIs). More particularly, the invention relates to formulations which are suitable for increasing the therapeutic efficacy of SSRIs, and in particular for improving the onset of therapeutic effect.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Artigas et al. (Árch. Gen. Psychiatry, 51, 248 až 251 (1994)) uvádzajú, že podávanie pindololu (2,5 mg trikrát denne) počas liečby s SSRI paroxetínom (20 mg raz za deň) zmierňuje depresiu pacientov, u ktorých nebola predchádzajúca liečba s paroxetínom úspešná.Artigas et al. (Ar. Gen. Psychiatry, 1994, 51, 248-251) report that administration of pindolol (2.5 mg three times a day) during treatment with SSRI paroxetine (20 mg once a day) alleviates depression in patients who have not received prior treatment with paroxetine successful.
Potom sa v EP-A-0 714 663 uviedlo, že možno zvýšiť účinok SSRI citaloprolamu, fluvoxamínu a paroxetínu súčasným podávaním v istých kombináciách s inter alia pindololom, penbutololom, propranolom a tertatolom a s ďalšími zlúčeninami, známymi ako serotonínové IA antagonisty, ale s vylúčením kombinácie paroxetín - pindolol.It was then reported in EP-A-0 714 663 that the effect of SSRIs of citaloprolam, fluvoxamine and paroxetine can be increased by concomitant administration in certain combinations with inter alia pindolol, penbutolol, propranol and tertatol and other compounds known as serotonin IA antagonists, but paroxetine-pindolol combinations.
V režime súčasného podávania je problémom zabezpečiť pacientovi pohodu, najmä v režime navrhovanom Artigasom, v ktorom sa liečiva denne podávajú na tri razy (za predpokladu, že dávka paroxetínu a prvá pindololová dávka sa podajú súčasne).In the co-administration regimen, the problem is to ensure the patient's well-being, especially in the regimen proposed by Artigas, in which the drugs are administered three times daily (assuming the paroxetine dose and the first pindolol dose are co-administered).
Tento vynález si kladie za cieľ prekonať problém, spojený so súčasným podávaním SSRI a látok, zvyšujúcich účinok SSRI.The present invention aims to overcome the problem associated with the simultaneous administration of SSRIs and SSRI enhancers.
Podstata vynálezuSUMMARY OF THE INVENTION
Podstatou vynálezu je farmaceutický prostriedok, ktorý obsahuje SSRI vo forme s rýchlym uvoľňovaním účinnej zložky a β-bloker vo forme s predĺženým uvoľňovaním. Farmaceutický prostriedok je zvyčajne v liekovej forme tabliet alebo kapsúl.The present invention provides a pharmaceutical composition comprising an SSRI in a rapid release form of the active ingredient and a β-blocker in a sustained release form. The pharmaceutical composition is usually in the form of tablets or capsules.
Typické SSRI, použité v tomto vynáleze sú paroxetín, fluvoxamín, citalopram a setralín. Výhodným SSRI je paroxetín. Súčasne podávaným výhodným βblokerom je pindolol.Typical SSRIs used in this invention are paroxetine, fluvoxamine, citalopram and setralin. A preferred SSRI is paroxetine. The co-administered preferred β-blocker is pindolol.
Výhodná kombinácia SSRI a β-blokera je paroxetín a pindolol. Tableta alebo kapsula výhodne obsahuje 20 mg paroxetínu v okamžite uvorniternej forme a 7,5 mg pindololu vo forme s predĺženým uvoľňovaním liečiva.A preferred combination of SSRI and β-blocker is paroxetine and pindolol. The tablet or capsule preferably contains 20 mg paroxetine in an immediate release form and 7.5 mg pindolol in a sustained release form.
Forma β-blokera s predĺženým uvoľňovaním typicky poskytuje plynulé ekvivalent liečiva trojnásobnej dennej dávky počas 12 až 16 hodín. Voliteľne sa uvedená dávka môže uvoľňovať v troch časovo rozlíšených etapách.The sustained release β-blocker form typically provides a continuous drug equivalent of a triple daily dose for 12 to 16 hours. Optionally, said dose may be released in three differentiated stages.
Ak sa SSRI kombinuje s β-blokerom, ktorý je v plynulé uvoľňujúcej formulácii, potom výhodná kompozícia podľa tohto vynálezu má formu dvojvrstvovej tablety; jedna vrstva obsahuje SSRI v bežnej rýchlo uvoľniteľnej formulácii druhá vrstva obsahuje β-bloker, formulovaný na postupné uvoľňovanie liečiva.When the SSRI is combined with a β-blocker that is in a sustained release formulation, then a preferred composition of the invention is in the form of a bilayer tablet; one layer contains an SSRI in a conventional quick release formulation the other layer contains a β-blocker formulated for sustained release of the drug.
Predĺžené uvoľňovanie sa môže dosiahnuť formuláciou β-blokera s akoukoľvek pomaly uvoľňujúcou zložkou alebo zmesou zložiek alebo pomocných látok, ktoré nevstupujú do interakcie s β-blokerom alebo s SSRI.Prolonged release can be achieved by formulating a β-blocker with any slow release component or mixture of components or excipients that do not interact with the β-blocker or SSRI.
Vhodné je, ak sa schopnosť pomaly uvoľňovať liečivo dosahuje zabudovaním β-blokera do zložky alebo pomocnej látky, ktorá v žalúdočnej šťave napúčava, vytvára typicky gél, ktorá sa rozpúšťa a/alebo obrusuje pri prechode tablety črevami pacienta a pritom sa uvoľňuje aktívna zložka. Rýchlosť uvoľňovania sa môže ovládať bežným spôsobom zmenami molekulovej hmotnosti pomocnej látky a/alebo ko-formuláciou primárnej pomocnej látky s materiálmi, ktoré sa rozpúšťajú alebo spôsobujú rozpadanie uvedenej pomocnej látky inou rýchlosťou ako sa rozpúšťa alebo rozpadá samotná primárna pomocná látka za vzniku mikropórov v napúčanej alebo gélovitej primárnej pomocnej látke.Suitably, the ability to slowly release the drug is achieved by incorporating the β-blocker into a component or excipient which swells in the gastric juice, typically forming a gel that dissolves and / or abrades as the tablet passes through the patient's intestines, releasing the active ingredient. The rate of release can be controlled in a conventional manner by varying the molecular weight of the excipient and / or co-formulating the primary excipient with materials that dissolve or cause disintegration of said excipient at a rate other than dissolving or disintegrating the primary excipient itself to form micropores in swollen or a gel-like primary excipient.
Vhodné primárne pomocné látky sa môžu vybrať z napúčavých spojivových látok ako je metylcelulóza, napríklad metylcelulóza dodávaná s obchodným názvom Methocel K4M a E5, etylcelulóza, polyakrylová kyselina, ako je napríklad dodávaná pod obchodnou značkou Carbopol 974P, polyakrylové estery, dodávané napríklad pod označením Eudragit L30D a RS30D, xantánová guma a škrob.Suitable primary excipients may be selected from swellable binders such as methylcellulose, for example methylcellulose supplied under the tradename Methocel K4M and E5, ethylcellulose, polyacrylic acid such as sold under the trademark Carbopol 974P, polyacrylic esters such as sold under the name Eudragit L30D and RS30D, xanthan gum and starch.
Uvoľňovací profil primárnej pomocnej látky sa môže upravovať zabudovaním plnív a látok napomáhajúcich rozpadu, ako je napríklad laktóza, bližšie monohydrát laktózy, mikrokryštalická celulóza, dodávaná napríklad s obchodným označením Avicel pH12, síran vápenatý, hydrogenfosforečnan divápenatý, dodávaný napríklad s obchodným názvom Encompress, polyvinylpyrolidón, dodávaný napríklad s obchodným názvom Povidone 30, hydrogenované rastlinné oleje, dodávané napríklad s obchodným názvom Lubritab.The release profile of the primary excipient can be adjusted by incorporating fillers and disintegrants such as lactose, closer lactose monohydrate, microcrystalline cellulose, supplied for example under the trade name Avicel pH12, calcium sulfate, dibasic calcium phosphate, sold for example under the trade name Encompress, polyvinyl supplied, for example, under the tradename Povidone 30, hydrogenated vegetable oils, sold for example under the tradename Lubritab.
Vo farmaceutických prostriedkoch podľa tohto vynálezu môžu byť zahrnuté tiež bežné tabletovacie prísady na výrobu tabliet, ako sú napríklad mastivá a iné, napríklad stearan horečnatý, behenát glycerolu, dodávaný napríklad s obchodným názvom Compritol 888.Also included in the pharmaceutical compositions of the present invention are conventional tabletting excipients for the manufacture of tablets, such as lubricants and others, for example magnesium stearate, glycerol behenate, marketed, for example, with the trade name Compritol 888.
Farmaceutický prostriedok môže byť voliteľne vo forme kapsúl, obsahujúcich poťahované pilulky β-blokera, ktoré sú zmesou poťahovaných piluliek s rôznymi dobami rozpúšťania, rozptýlenými v práškovej formulácii SSRI; tento systém je celý v rozpustnej kapsule.The pharmaceutical composition may optionally be in the form of capsules containing coated β-blocker pills which are a mixture of coated pills with different dissolution times dispersed in an SSRI powder formulation; this system is all in a soluble capsule.
Povlak piluliek β-blokera je výhodne taký materiál, ktorý je odolný voči žalúdočnej šťave, ale rozpúšťa sa napríklad v črevách. Doba rozpúšťania môže byť rôzna podľa hrúbky poťahu. Potiahnuté pilulky s rôznou hrúbkou povlaku sú výhodne zmiešané tak, že umožňujú v podstate plynulé uvoľňovanie pindololu; ak sa ale vyžaduje, môže to byť napríklad zmes piluliek s troma rôzne hrubými povlakmi; potom sa pindolol uvoľňuje v troch rôznych časových etapách počas vyžadovanej doby od podania, napríklad počas 12 až 14 hodín. Prášková formulácia SSRI sa môže pripraviť zmiešaním SSRI s bežnými pomocnými látkami. Rozpustné kapsuly, ktoré majú obsahovať kombináciu aktívnych látok môžu byť bežné želatínové kapsuly.The β-blocker pill coating is preferably a material that is resistant to gastric juice but dissolves, for example, in the intestines. The dissolution time may vary depending on the thickness of the coating. The coated pills of different coating thicknesses are preferably mixed so as to allow a substantially continuous release of pindolol; however, if desired, it may be, for example, a mixture of pills with three differently thick coatings; then, the pindolol is released at three different time stages over the required time from administration, for example 12 to 14 hours. An SSRI powder formulation can be prepared by mixing the SSRI with conventional excipients. Soluble capsules to be combined with the active ingredients may be conventional gelatin capsules.
V tomto vynáleze možno použiť typické formulácie s predĺženým uvoľňovaním hore uvedeného typu s hydrofiInou matricou a formulácie s uvoľňovaním účinnej látky v črevách, ktoré sú opísané v základných učebniciach z tohto odboru.Typical sustained release formulations of the aforementioned hydrophilic matrix type and intestinal release formulations described in the basic textbooks of the art may be used in the present invention.
-4Autori vynálezu zistili, že vhodný uvoľňovací profil na klinické použitie možno dosiahnuť vtedy, ak formulácia β-blokera s predĺženým uvoľňovaním pri meraní profilu uvoľňovania in vitro v prostredí kyseliny/tlmivého roztoku má doby rozpúšťania Tso% 1.73 hodiny, Tgo%8,45 hodín a Tioo% 14 hodín.The inventors have found that a suitable release profile for clinical use can be achieved if the extended release β-blocker formulation when measuring the in vitro release profile in an acid / buffer environment has a dissolution time of T 50% 1.73 hours, T 90% 8.45 hours and Tioo% 14 hours.
Výhodné uskutočnenie tohto vynálezu má podľa uvedeného formuláciu SSRI a β-blokera, v ktorej je β-bloker vo forme s predĺženým uvoľňovaním a má profil uvoľňovania in vitro: T50% = 1,73 hodiny ± 20 %, Tg0% = 8,45 hodín ± 20 % a T1Oo% = 14 hodín + 20 %.A preferred embodiment of the present invention has an SSRI and a β-blocker formulation in which the β-blocker is in sustained release form and has an in vitro release profile: T 50 % = 1.73 hours ± 20%, Tg 0 % = 8, 45 hours ± 20% and T 10 % = 14 hours + 20%.
Výhodným SSRI je hydrochlorid paroxetínu, najvýhodnejšie v dávke 20 mg, a β-bloker je pindolol, najvýhodnejšie v dávke 7,5 mg.The preferred SSRI is paroxetine hydrochloride, most preferably at a dose of 20 mg, and the β-blocker is pindolol, most preferably at a dose of 7.5 mg.
Pindolol sa typicky použije vo forme komerčne dostupného racemátu. Možno ale použiť aktívny izomér pindololu v dávke, nastavenej na rovnakú bioekvivalenciu so stanovenou dávkou racemátu.Pindolol is typically used in the form of a commercially available racemate. However, it is possible to use the active isomer of pindolol at a dose adjusted to the same bioequivalence with the determined dose of the racemate.
Terapeutické použitie kompozícií podľa tohto vynálezu, najmä kompozícií hydrochloridu paroxetínu a pindololu, zahŕňa liečbu alkoholizmu, stresu, depresie, obsesívnych kompulzných porúch (OCD), stavov paniky, chronickej bolesti, obezity, senilnej demencie, migrény, bulímie, anorexie, sociálnej fóbie, premenštruálneho syndrómu (PMS), depresie dospievajúcich, trichotilománie, dystýmie a látkovej závislosti; v ďalšom sa označujú ako poruchy.The therapeutic use of the compositions of the present invention, particularly paroxetine hydrochloride and pindolol hydrochloride compositions, includes the treatment of alcoholism, stress, depression, obsessive compulsive disorder (OCD), panic, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual. syndrome (PMS), adolescent depression, trichothilomania, dysthymia and substance dependence; hereinafter referred to as malfunctions.
Vynález zahŕňa tiež použitie SSRI a β-blokera, ktorý je vo forme s predĺženým uvoľňovaním na výrobu tabliet alebo kapsúl na liečbu alebo profylaxiu uvedených porúch u človeka a zvierat a spôsob liečby alebo profýlaxie uvedených porúch, ktorý zahŕňa podávanie tablety alebo kapsuly, obsahujúcej SSRI a β-bloker, ktorý je vo forme s predĺženým uvoľňovaním, osobe alebo zvieraťu, ktorá to potrebuje.The invention also encompasses the use of an SSRI and a β-blocker which is in sustained release form for the manufacture of tablets or capsules for the treatment or prophylaxis of said disorders in humans and animals, and a method of treating or prophylaxis of said disorders. A β-blocker in sustained release form to a person or animal in need thereof.
V použití a v spôsobe podľa tohto vynálezu bude výhodná tableta alebo kapsula, ktorá je formulovaná podľa tohto vynálezu s výhodnými hodnotami, uvedenými hore.In use and in the method of the present invention, a tablet or capsule that is formulated according to the present invention with the preferred values outlined above will be preferred.
Vynález sa ďalej objasňuje pomocou príkladov.The invention is further illustrated by examples.
-5Príkladv uskutočnenia vynálezu-5Examples of embodiments of the invention
Príklad 1Example 1
Pripravili sa dvojvrstvové tablety paroxetínu a pindololu, ktorý mal formu s predĺženým uvoľňovaním.Bilayer tablets of paroxetine and pindolol were prepared in sustained release form.
Pindololová zložkaPindolol component
Forma pindololu s predĺženým uvoľňovaním, založená na hydrofilnej matrici s rozpustným/rozpadavým plnivom na zvýšenie pórovitosti matrice pri hydratácii sa pripravila vysokúčinnou granuláciou za vlhka zmesi:The sustained release form of pindolol, based on a hydrophilic matrix with a soluble / disintegrating filler to increase the porosity of the matrix during hydration, was prepared by high performance wet granulation of a mixture of:
pindololová báza 7,5 hmotnostných dielov metylcelulóza (Methocel K4M) 35 hmotnostných dielov monohydrát laktózy 25 hmotnostných dielov mikrokryštalická celulóza (Avicel pH 12) 32 hmotnostných dielov.pindolol base 7.5 parts by weight methylcellulose (Methocel K4M) 35 parts by weight lactose monohydrate 25 parts by weight microcrystalline cellulose (Avicel pH 12) 32 parts by weight.
Po sušení a preosiati sa za miešania v bubnovej miešačke pridalo 0,5 hmotnostného dielu glycerolbehenátu (Compritol 888) ako mastiva.After drying and sieving, 0.5 part by weight of glycerol behenate (Compritol 888) was added as a lubricant with stirring in a tumbler.
Paroxetínová zložkaParoxetine component
Formulácia paroxetínu s okamžitým uvoľňovaním aktívnej zložky sa pripravila zmiešaním 20 hmotnostných dielov hydrochloridu paroxetínu s 80 hmotnostnými dielmi bežných pomocných látok a prísad.An immediate release formulation of paroxetine active ingredient was prepared by mixing 20 parts by weight of paroxetine hydrochloride with 80 parts by weight of conventional excipients and additives.
Tabletovanietabletting
100 mg množstvá pindololovej formulácie s predĺženým uvoľňovaním sa plnili do tabletovacích foriem v prvej plniacej polohe otáčavej tabletovacej dosky. Po prvotnom miernom stlačení práškovej formulácie v tabletovacej forme sa v druhej plniacej polohe nasypalo na formuláciu s predĺženým uvoľňovaním 152 mg paroxetínovej formulácie. Dvojvrstvová zmes sa potom v tabletovacej forme vystavila plnému lisovaciemu tlaku; pripravila sa 252 miligramová tableta, obsahujúca 20 mg hydrochloridu paroxetínu a 7,5 mg pindololu, ktorý je v matrici s100 mg amounts of the sustained release pindolol formulation were filled into tablet forms at the first fill position of the rotary tabletting plate. After the initial gentle compression of the powder formulation in tablet form, 152 mg of paroxetine formulation was poured onto the sustained release formulation in the second filling position. The bilayer mixture was then subjected to full compression pressure in tablet form; a 252 mg tablet was prepared containing 20 mg paroxetine hydrochloride and 7.5 mg pindolol, which is in a matrix with
-6predĺženým uvoľňovaním, pričom každá aktívna zložka je v samostatnej vrstve dvojvrstvovej tablety.- sustained release, wherein each active ingredient is in a separate layer of a bilayer tablet.
Claims (12)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9714675.7A GB9714675D0 (en) | 1997-07-11 | 1997-07-11 | Novel composition |
| PCT/EP1998/004971 WO1999002142A2 (en) | 1997-07-11 | 1998-07-07 | Novel composition comprising an ssri and a beta-blocker |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK72000A3 true SK72000A3 (en) | 2000-12-11 |
Family
ID=10815744
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK7-2000A SK72000A3 (en) | 1997-07-11 | 1998-07-07 | Novel composition comprising an ssri and a beta-blocker |
Country Status (26)
| Country | Link |
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| EP (1) | EP0996466A2 (en) |
| JP (1) | JP2002508003A (en) |
| KR (1) | KR20010021644A (en) |
| CN (1) | CN1262627A (en) |
| AP (1) | AP2000001728A0 (en) |
| AR (1) | AR016128A1 (en) |
| AU (1) | AU9340198A (en) |
| BG (1) | BG104119A (en) |
| BR (1) | BR9810996A (en) |
| CA (1) | CA2295822A1 (en) |
| CO (1) | CO4950552A1 (en) |
| DZ (1) | DZ2556A1 (en) |
| EA (1) | EA200000112A1 (en) |
| GB (1) | GB9714675D0 (en) |
| HU (1) | HUP0003074A3 (en) |
| ID (1) | ID24191A (en) |
| IL (1) | IL133869A0 (en) |
| MA (1) | MA24604A1 (en) |
| NO (1) | NO20000107D0 (en) |
| OA (1) | OA11276A (en) |
| PE (1) | PE99699A1 (en) |
| PL (1) | PL338017A1 (en) |
| SK (1) | SK72000A3 (en) |
| TR (1) | TR200000074T2 (en) |
| WO (1) | WO1999002142A2 (en) |
| ZA (1) | ZA986138B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE457169T1 (en) | 1998-10-15 | 2010-02-15 | Imp Innovations Ltd | COMPOUNDS FOR THE TREATMENT OF WEIGHT LOSS |
| PT1126826E (en) | 1998-11-02 | 2008-11-25 | Elan Pharma Int Ltd | Multiparticulate modified release composition of methylphenidate |
| KR101476574B1 (en) | 1999-10-29 | 2014-12-24 | 유로-셀티크 소시에떼 아노뉨 | Controlled release hydrocodone formulations |
| US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
| GB0004003D0 (en) * | 2000-02-22 | 2000-04-12 | Knoll Ag | Therapeutic agents |
| MXPA03003895A (en) | 2000-10-30 | 2003-07-28 | Euro Celtique Sa | Controlled release hydrocodone formulations. |
| WO2006030306A2 (en) * | 2004-09-17 | 2006-03-23 | Neurocure Ltd | Pindolol for treating premenstrual syndrome and premenstrual dysphoric disorder |
| CN100469356C (en) * | 2006-09-08 | 2009-03-18 | 山东益康药业有限公司 | Slowly released tablet of compound atenolol, and preparation method |
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|---|---|---|---|---|
| DE2732335C2 (en) * | 1976-07-27 | 1983-01-20 | Sandoz-Patent-GmbH, 7850 Lörrach | Tablet for the enteral administration of indolyloxyalkanolamine derivatives |
| CA2134038C (en) * | 1994-06-16 | 1997-06-03 | David Taiwai Wong | Potentiation of drug response |
| EP0714663A3 (en) * | 1994-11-28 | 1997-01-15 | Lilly Co Eli | Potentiation of drug response by a serotonin 1A receptor antagonist |
| DE69607904T2 (en) * | 1995-08-16 | 2000-10-05 | Lilly Co Eli | Potentiation of serotonin drug response |
| EP0792649A1 (en) * | 1996-02-29 | 1997-09-03 | Eli Lilly And Company | Treatment of sleep disorders |
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1997
- 1997-07-11 GB GBGB9714675.7A patent/GB9714675D0/en active Pending
-
1998
- 1998-07-07 SK SK7-2000A patent/SK72000A3/en unknown
- 1998-07-07 CN CN98806975A patent/CN1262627A/en active Pending
- 1998-07-07 PL PL98338017A patent/PL338017A1/en unknown
- 1998-07-07 ID IDW20000035A patent/ID24191A/en unknown
- 1998-07-07 CA CA002295822A patent/CA2295822A1/en not_active Abandoned
- 1998-07-07 IL IL13386998A patent/IL133869A0/en unknown
- 1998-07-07 TR TR2000/00074T patent/TR200000074T2/en unknown
- 1998-07-07 KR KR1020007000202A patent/KR20010021644A/en not_active Application Discontinuation
- 1998-07-07 AP APAP/P/1999/001728A patent/AP2000001728A0/en unknown
- 1998-07-07 EP EP98946294A patent/EP0996466A2/en not_active Withdrawn
- 1998-07-07 EA EA200000112A patent/EA200000112A1/en unknown
- 1998-07-07 HU HU0003074A patent/HUP0003074A3/en unknown
- 1998-07-07 JP JP50818599A patent/JP2002508003A/en active Pending
- 1998-07-07 BR BR9810996-0A patent/BR9810996A/en not_active Application Discontinuation
- 1998-07-07 AU AU93401/98A patent/AU9340198A/en not_active Abandoned
- 1998-07-07 WO PCT/EP1998/004971 patent/WO1999002142A2/en not_active Application Discontinuation
- 1998-07-08 DZ DZ980166A patent/DZ2556A1/en active
- 1998-07-10 AR ARP980103371A patent/AR016128A1/en unknown
- 1998-07-10 CO CO98039260A patent/CO4950552A1/en unknown
- 1998-07-10 ZA ZA9806138A patent/ZA986138B/en unknown
- 1998-07-10 MA MA25165A patent/MA24604A1/en unknown
- 1998-07-10 PE PE1998000612A patent/PE99699A1/en not_active Application Discontinuation
-
2000
- 2000-01-10 NO NO20000107A patent/NO20000107D0/en not_active Application Discontinuation
- 2000-01-11 OA OA1200000006A patent/OA11276A/en unknown
- 2000-02-01 BG BG104119A patent/BG104119A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BR9810996A (en) | 2000-08-08 |
| PL338017A1 (en) | 2000-09-25 |
| IL133869A0 (en) | 2001-04-30 |
| CA2295822A1 (en) | 1999-01-21 |
| OA11276A (en) | 2003-07-31 |
| CO4950552A1 (en) | 2000-09-01 |
| HUP0003074A2 (en) | 2001-01-29 |
| HUP0003074A3 (en) | 2001-12-28 |
| PE99699A1 (en) | 1999-12-21 |
| AU9340198A (en) | 1999-02-08 |
| ID24191A (en) | 2000-07-13 |
| AR016128A1 (en) | 2001-06-20 |
| ZA986138B (en) | 2000-01-10 |
| JP2002508003A (en) | 2002-03-12 |
| DZ2556A1 (en) | 2003-02-15 |
| WO1999002142A2 (en) | 1999-01-21 |
| MA24604A1 (en) | 1999-04-01 |
| CN1262627A (en) | 2000-08-09 |
| GB9714675D0 (en) | 1997-09-17 |
| NO20000107L (en) | 2000-01-10 |
| NO20000107D0 (en) | 2000-01-10 |
| KR20010021644A (en) | 2001-03-15 |
| AP2000001728A0 (en) | 2000-03-31 |
| EP0996466A2 (en) | 2000-05-03 |
| TR200000074T2 (en) | 2000-05-22 |
| WO1999002142A3 (en) | 1999-04-15 |
| EA200000112A1 (en) | 2000-10-30 |
| BG104119A (en) | 2000-12-29 |
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