SK102199A3 - Peptides comprising a t-cell epitope specific to collagen ii, their use and pharmaceutical compositions containing such peptides - Google Patents
Peptides comprising a t-cell epitope specific to collagen ii, their use and pharmaceutical compositions containing such peptides Download PDFInfo
- Publication number
- SK102199A3 SK102199A3 SK1021-99A SK102199A SK102199A3 SK 102199 A3 SK102199 A3 SK 102199A3 SK 102199 A SK102199 A SK 102199A SK 102199 A3 SK102199 A3 SK 102199A3
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- Slovakia
- Prior art keywords
- apg
- amino acid
- ppg
- peptide
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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Abstract
Description
Oblasť technikyTechnical field
Predkladaný vynález poskytuje nové peptidy odvodené z kolagénu CII, spôsoby ich prípravy a ich použitie v terapii, osobitne na liečenie reumatoidnej artritídy a príbuzných autoimúnnych ochorení.The present invention provides novel peptides derived from collagen CII, methods for their preparation and their use in therapy, particularly for the treatment of rheumatoid arthritis and related autoimmune diseases.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Molekuly kolagénu patria k hlavným štruktúrnym proteínom spojivového tkaniva. Skladajú sa z troch polypeptidových reťazcov, ktoré vytvárajú rozsiahlu trojzávitnicovú štruktúru s jedinečnou opakujúcou sa aminokyselinou sekvenciou X-Y-Gly. Extracelulárny matrix chrupavky je jedinečný tým že obsahuje hlavne kolagén typu II, ale obsahuje aj typy IX a XI. CII sa nedávno klonoval z myši a stanovila sa celá jeho aminokyselinová sekvencia s dĺžkou 1419 aminokyselín (Metsarantam a kol., 1991, J.Biol.Chem. 266: 16862-9).Collagen molecules are among the major structural proteins of connective tissue. They consist of three polypeptide chains that form an extensive triple helical structure with a unique repeating amino acid sequence of X-Y-Gly. The extracellular cartilage matrix is unique in that it mainly contains type II collagen but also contains types IX and XI. CII was recently cloned from a mouse and its entire 1419 amino acid sequence was determined (Metsarantam et al., 1991, J. Biol. Chem. 266: 16862-9).
Predpokladá sa, že kolagén typu II je skrytý pred bunkami imunitného systému, pretože sa vyskytuje iba v avaskulárnych (neprekrvených) tkanivách, ako je chrupavka a hmota sklovca oka. Imunitný systém nie je preto úplne tolerantný k svojmu vlastnému kolagénu typu II. Izolovaný proteín CII má schopnosť po inj ikovaní s Freundovým kompletným adjuvans vyvolať tkanivovo špecifické autoimúnne ochorenie. Táto indukovaná choroba sa nazýva kolagénom indukovaná artritída (CIA). CIA sa normálne indukuje injekciou cudzieho CII, ktorý vyvolá produkciu T-buniek a protilátok schopných rozpoznať zodpovedajúci vlastný proteín.Type II collagen is believed to be hidden from cells of the immune system since it occurs only in avascular (non-bloodied) tissues such as cartilage and vitreous humor of the eye. The immune system is therefore not completely tolerant of its own type II collagen. Isolated CII protein has the ability to induce tissue-specific autoimmune disease upon injection with Freund's complete adjuvant. This induced disease is called collagen-induced arthritis (CIA). CIA is normally induced by injection of foreign CII, which induces the production of T cells and antibodies capable of recognizing the corresponding self-protein.
Citlivosť k CIA u myší je obmedzená na myši s MHC I-Aq a I-AE. Väzbové motívy týchto molekúl sú podobné motívom ľudskýchCIA susceptibility in mice is limited to mice with MHC IA q and IA E. The binding motifs of these molecules are similar to human motifs
DR4 a DRI.' Preto sa predpokladá, že CII je autoantigén v prípade reumatoidnej artritídy (RA) .DR4 and DRI. ' Therefore, CII is believed to be an autoantigen in rheumatoid arthritis (RA).
Na liečenie RA nie je v súčasnosti k dispozícii žiadna kauzálna terapia. Doterajšie spôsoby liečenia, ako je napr. použitie kortikosteroidov, sú nešpecifické, pretože celkovo potláčajú imunitnú odpoveď. Súčasný výskum naznačil, že dôležitú úlohu v patogenéze RA hrajú autoreaktívne T-bunky, čo viedlo k predstave, že tolerizácia týchto patogénnych T-buniek nazálnym/perorálnym podávaním imunogénnych peptidov by mohla mať liečebný potenciál.No causal therapy is currently available for the treatment of RA. Existing methods of treatment, such as e.g. The use of corticosteroids is non-specific since they generally suppress the immune response. Recent research has suggested that autoreactive T cells play an important role in the pathogenesis of RA, leading to the idea that tolerance to these pathogenic T cells by nasal / oral administration of immunogenic peptides could have therapeutic potential.
Miyahara, H. a kol. (Immunology, 1995, 86: 110-115) opísali použitie fragmentu kolagénu typu II na potlačenie artritídy u myší. Avšak použitý fragment (CII 607-621) neobsahoval väzbový motív pre žiadnu z HLA-DR molekúl súvisiacich s RA u človeka a nemôže sa preto použiť ako toleragén na liečenie RA u človeka.Miyahara, H. et al. (Immunology, 1995, 86: 110-115) described the use of a type II collagen fragment to suppress arthritis in mice. However, the fragment used (CII 607-621) did not contain a binding motif for any of the HLA-DR molecules related to RA in humans and cannot therefore be used as a tolerance for treating RA in humans.
Dokument WO 96/20950 opisuje peptidy kolagénu typu II schopné viazať sa na HLA DRB1 ľudského proteínu MHC, ktoré by mohli byť podlá uvedeného návrhu užitočné pri liečení RA. Avšak tieto peptidy, ktoré sú prítomné v úseku 273 až 404 proteínu kolagénu CII, majú iba slabú účinnosť v relevantných testoch pre predpokladané toleragény pre RA. Peptidy podlá predkladaného vynálezu majú významne vyššiu terapeutickú účinnosť.WO 96/20950 discloses type II collagen peptides capable of binding to HLA DRB1 of a human MHC protein, which could be useful in the treatment of RA. However, these peptides, which are present in the stretch 273 to 404 of collagen CII protein, have only poor potency in the relevant assays for putative RA toleragens. The peptides of the present invention have significantly higher therapeutic efficacy.
Podstata vynálezuSUMMARY OF THE INVENTION
Predkladaný vynález poskytuje peptidy, o ktorých sa zistilo, že boli mimoriadne účinné pri indukcii imunitnej tolerancie k epitopom T-buniek odvodených z kolagénu CII. Tieto peptidy sa môžu využiť na liečenie autoimúnnych ochorení ako je reumatoidná artritída.The present invention provides peptides that have been found to be extremely effective in inducing immune tolerance to T cell epitopes derived from collagen CII. These peptides can be used to treat autoimmune diseases such as rheumatoid arthritis.
Predkladaný vynález preto poskytuje izolovaný peptid, ktorý má alebo obsahuje aminokyselinovú sekvenciu vzorca (I):The present invention therefore provides an isolated peptide having or comprising the amino acid sequence of Formula (I):
A1Xaa-Gly-A4-A5-Gly-A7-Xaa-Gly (I) kdeA 1 Xaa-Gly-A 4 -A 5 -Gly-A 7 -Xaa-Gly (I) where
A1 je aminokyselinový zvyšok s aromatickým alebo alifatickým bočným reťazcomA 1 is an amino acid residue with an aromatic or aliphatic side chain
A4 je asparagínový alebo arginínový zvyšok alebo aminokyselinový zvyšok s aromatickým alebo alifatickým bočným reťazcomA 4 is an asparagine or arginine residue or an amino acid residue with an aromatic or aliphatic side chain
A5 je akákoľvek prirodzene sa vyskytujúca aminokyselinaA 5 is any naturally occurring amino acid
A7 je aminokyselina s negatívne nabitým zvyškom,A 7 is an amino acid with a negatively charged residue,
Xaa je akýkoľvek aminokyselinový zvyšok aXaa is any amino acid residue a
Gly je glycínový zvyšok.Gly is a glycine residue.
Peptidy podľa predkladaného vynálezu sú výhodne peptidy, ktoré obsahujú 9, 10, 11, 12, 13, 14 alebo 15 aminokyselín, výhodnejšie sú to peptidy s 9 aminokyselinami.The peptides of the present invention are preferably peptides containing 9, 10, 11, 12, 13, 14 or 15 amino acids, more preferably 9 peptides.
Pre peptidy podľa predkladaného vynálezu platia nasledujúce navzájom nezávislé výhodné znaky.The peptides of the present invention are subject to the following independent advantageous features.
A1 je F, I, L, A alebo P a najvýhodnejšie F,A 1 is F, I, L, A or P and most preferably F,
A4 je F, I, L, A, N alebo P a najvýhodnejšie F,A 4 is F, I, L, A, N or P and most preferably F,
A5 je K alebo R,A 5 is K or R,
A7 je E, D, Q, P alebo N a najvýhodnejšie Q.A 7 is E, D, Q, P or N, and most preferably Q.
K výhodným peptidom podľa predkladaného vynálezu patria peptidy buď obsahujúce, alebo sami majúce jednu z nasledujúcich aminokyselinových sekvencii:Preferred peptides of the present invention include peptides either containing or having one of the following amino acid sequences:
(sekvencia SEQ ID NO.: 10).(SEQ ID NO .: 10).
K príkladom výhodných peptidov podlá predkladaného vynálezu patria tiež peptidy, ktoré buď obsahujú alebo sami majú jednu z nasledovných aminokyselinových sekvencii:Examples of preferred peptides of the present invention also include peptides that either contain or have themselves one of the following amino acid sequences:
výhodnejšie AAG RVG PPG ANG NPG (sekvencia SEQ ID NO.: 33) a najvýhodnejšie PPG ANG NPG PAG PPG (sekvencia SEQ ID NO.: 35).more preferably AAG RVG PPG ANG NPG (SEQ ID NO .: 33) and most preferably PPG ANG NPG PAG PPG (SEQ ID NO .: 35).
Výhodne peptidy podľa predkladaného vynálezu obsahujú sekvenciu 9 až 15 aminokyselín prítomnú v neprerušenom rade v úseku 701 až 721 kolagénu II.Preferably, the peptides of the present invention comprise a sequence of 9 to 15 amino acids present in an uninterrupted sequence in the region 701 to 721 of collagen II.
Predkladaný vynález sa tiež týka peptidu, ktorý obsahuje epitop T-bunky špecifický pre kolagén II, a tento peptid obsahuje aspoň 9 aminokyselín v neprerušenej súvislej sekvencii zhodnej so sekvenciou vybratou z úsekov 110 až 239, 338 až 379 aThe present invention also relates to a peptide comprising a T-cell epitope specific for collagen II, which peptide comprises at least 9 amino acids in an uninterrupted contiguous sequence identical to a sequence selected from regions 110-239, 338-379, and
587 až 895 sekvencie kolagénu II, kde každá aminokyselina je voliteľne nahradená funkčne ekvivalentnou aminokyselinou, pričom peptid má vzorec (I) definovaný vyššie.587 to 895 of the collagen II sequence, wherein each amino acid is optionally replaced with a functionally equivalent amino acid, wherein the peptide has formula (I) as defined above.
Vynález ďalej poskytuje farmaceutický prípravok obsahujúci peptid podľa predkladaného vynálezu v spojení s farmaceutický prijateľným nosičom alebo riedidlom. Prípravok sa vhodne použije na to, že poskytne toleranciu k autoimunitnej chorobe, ako je napríklad reumatioidná artritída alebo relapsujúca polychondritída.The invention further provides a pharmaceutical composition comprising the peptide of the present invention in association with a pharmaceutically acceptable carrier or diluent. The formulation is suitably used to provide tolerance to an autoimmune disease such as rheumatoid arthritis or relapsing polychondritis.
Vynález ďalej poskytuje použitie peptidu podľa predkladaného vynálezu alebo prípravku podlá predkladaného vynálezu na výrobu lieku na použitie pri liečení autoimúnnych ochorení.The invention further provides the use of a peptide of the present invention or a composition of the present invention for the manufacture of a medicament for use in the treatment of autoimmune diseases.
Vynález sa ďalej týka spôsobu liečenia človeka alebo zvieraťa postihnutého autoimúnnou chorobou, ako je napr. reumatoidná artritída alebo relapsujúca polychondritída, pričom tento spôsob obsahuje podávanie terapeuticky účinného množstva peptidu alebo prípravku človeku alebo zvieraťu podlá vynálezu.The invention further relates to a method of treating a human or animal suffering from an autoimmune disease, such as e.g. rheumatoid arthritis or relapsing polychondritis, the method comprising administering a therapeutically effective amount of a peptide or preparation to a human or animal of the invention.
Peptidy podlá predkladaného vynálezu sa môžu pripraviť spôsobmi, ktoré sú odborníkovi známe. Napr. to môže byť pomocou štandardnej techniky peptidovej väzby) na syntetizátora peptidov Synthesis of Peptides,The peptides of the present invention may be prepared by methods known to those skilled in the art. E.g. this may be by using a standard peptide bonding technique) on the Synthesis of Peptides peptide synthesizer,
University Press, 1991, (vytváranie automatického The Chemical postupnej kondenzácie pevnej fáze pomocou (pozri napr. Jones, J.University Press, 1991, (Creating Automatic The Chemical Gradual Solid Phase Condensation Using (see, e.g., Jones, J.
pp. 132-156, First edition, Oxford a R. Epton (ed) Innovation andpp. 132-156, First edition, Oxford, and R. Epton (ed) Innovation and
Perspectives in Solid Phase Peptide Synthesis, SPCC (UK), Ltd., 1990) . Príprava začína od C-koncovej aminokyseliny, ktorá sa môže získať už štepená na metylbenzhydrylamín, benzhydrylamín alebo chlormetylovanú živicu, alebo na iný vhodný pevný nosič. Ďalšie aminokyseliny sa pridávajú postupne krom za krokom potom, ako sa ochránili ich bočné reťazce. Pri tejto kondenzačnej metóde sú alfa-aminoskupiny aminokyselín chránené pomocou F-moc alebo t-Boc. Ochranné skupiny bočných reťazcov aminokyselín sú v odbore dobre známe. Celý chránený peptid sa uvolní z chlórmetylovanej živice amoniolýzou, čím sa získa chránený amid alebo z metylbenzhydrylamínovej alebo benzhydrylamínovej živice acidolýzou.Perspectives in Solid Phase Peptide Synthesis, SPCC (UK) Ltd. 1990). The preparation starts from the C-terminal amino acid, which can be obtained already cleaved to methylbenzhydrylamine, benzhydrylamine or chloromethylated resin, or to another suitable solid support. Additional amino acids are added step-by-step after their side chains have been protected. In this condensation method, alpha-amino groups of amino acids are protected by F-moc or t-Boc. Amino acid side chain protecting groups are well known in the art. The entire protected peptide is released from the chloromethylated resin by ammonolysis to give the protected amide or from methylbenzhydrylamine or benzhydrylamine resin by acidolysis.
Peptidy podľa predkladaného vynálezu sa môžu tiež pripraviť metódou v roztoku, buď postupnou kondenzáciou alebo kondenzáciou fragmentov (pozri napr.: Jones, 1. The Chemical Synthesis of Peptides, pp. 115-131, First edition, Oxford University Press, 1991). Aminokyselina s vhodne chránenou alfa-aminoskupinou sa naviaže na aminokyselinu s vhodne chránenou alfa-karboxylovou skupinou (v závislosti na vybranej metóde syntézy táto ochrana nemusí byť nutná) pomocou diimidov, symetrických alebo nesymetrických anhydridov alebo pomocou iných kondenzačných činidiel alebo spôsobov odborníkovi známych.. Tieto spôsoby môžu byť buď chemické alebo enzýmové. Skupiny chrániace alfaaminoskupinu a/alebo alfa-karboxylovú skupinu sa odstránia a ďalšia vhodne chránená aminokyselina alebo blok aminokyselín sa pripojí, čím sa predĺži rastúci peptid. V každej syntéze sa môže použiť rôzna kombinácia ochranných skupín a chemických/enzýmových spôsobov a stratégia kondenzácie/syntézy peptidu.The peptides of the present invention can also be prepared by a solution method, either by sequential condensation or by condensation of fragments (see, e.g., Jones, 1. The Chemical Synthesis of Peptides, pp. 115-131, First Edition, Oxford University Press, 1991). The amino acid with a suitably protected alpha-amino group is linked to the amino acid with a suitably protected alpha-carboxyl group (depending on the synthetic method chosen, this protection may not be necessary) using diimides, symmetrical or unsymmetrical anhydrides or other condensing agents or methods known to those skilled in the art. the methods may be either chemical or enzymatic. The alpha amino protecting group and / or the alpha-carboxyl group are removed and another suitably protected amino acid or amino acid block is attached to extend the growing peptide. A different combination of protecting groups and chemical / enzyme methods and peptide coupling / synthesis strategies may be used in each synthesis.
Peptidy podľa predkladaného vynálezu sú definované ako peptidy obsahujúce T-bunkový epitop. Inými slovami sú teda schopné aktivovať T-bunky. Existuje niekoľko známych spôsobov, ako stanoviť silu väzby. Výhodne je peptid podľa predkladaného vynálezu schopný aktivovať T-bunku s väzbovou silou najmenej 2 podľa uvoľňovacieho IFN-γ testu a/alebo s hodnotou stimulačného indexu najmenej 3. Test uvolňovania IFN-γ sa môže uskutočňovať spôsobmi v odbore známymi alebo spôsobom, ktorý je ďalej opísaný v príkladoch. Podobne stimulačný index sa môže stanoviť pomocou v odbore známych proliferačných testov, napr. testom opísaným v Analysis of type II collagen reactive T cells in mouse, Andersson a Holmdahl, Eur. J. Immunol. 20: 1016-1066, 1990. Výhodne sa test uskutočňuje spôsobom opísaným v príkladoch tejto prihlášky.The peptides of the present invention are defined as peptides comprising a T-cell epitope. In other words, they are able to activate T cells. There are several known ways to determine binding strength. Preferably, the peptide of the present invention is capable of activating a T-cell with a binding force of at least 2 according to an IFN-γ release assay and / or a stimulation index value of at least 3. The IFN-γ release assay can be performed by methods known in the art or described in the examples. Similarly, the stimulation index can be determined using art-known proliferation assays, e.g. the assay described in Analysis of type II collagen reactive T cells in mice, Andersson and Holmdahl, Eur. J. Immunol. 20: 1016-1066, 1990. Preferably, the assay is performed as described in the examples of this application.
Peptidy podlá vynálezu sú využiteľné pri liečení bez toho aby boli modifikované, ale alternatívne sa môžu peptidy tiež modifikovať, napr. sa môžu konjugovať, t.j. kovalentne naviazať na nosičový systém, napr. na mukózové väzbové štruktúry, ako je napr. cholerový β-toxín, čo pomáha absorpcii v čreve.The peptides of the invention are useful in the treatment without being modified, but alternatively the peptides may also be modified, e.g. may be conjugated, i. covalently attach to a carrier system, e.g. to mucose binding structures such as e.g. cholera β-toxin, which assists absorption in the intestine.
II
Peptidy podlá predkladaného vynálezu sa môžu použiť na liečenie, profylaxiu alebo stanovenie diagnózy autoimúnnych ochorení a termíny terapia alebo liečenie používané v tomto texte je potrebné chápať tak, že zahrňujú súčasne profylaxiu a diagnostiku.The peptides of the present invention may be used for the treatment, prophylaxis or diagnosis of autoimmune diseases, and the terms therapy or treatment used herein are intended to include prophylaxis and diagnosis simultaneously.
Peptid podlá predkladaného vynálezu je izolovaný peptid, to znamená, že k peptidom podľa predkladaného vynálezu nepatria peptidy prítomné v organizme. Peptidy podlá vynálezu môžu byť buď z prirodzených alebo rekombinantne pripravených peptidov alebo proteínov alebo sa môžu syntetizovať chemicky, ako sa opisuje v tejto prihláške.The peptide of the present invention is an isolated peptide, that is, the peptides of the present invention do not include peptides present in the body. The peptides of the invention may be either natural or recombinantly prepared peptides or proteins, or may be synthesized chemically as described in this application.
Zlúčeniny podľa vynálezu sa môžu podávať v dávkach od 10 μς do 10 mg na deň buď ako jediná dávka alebo rozdelené do 2 až 4 dávok na deň. Jednotková lieková forma obsahuje dávku 2,5 μς až 10 mg zlúčeniny podľa predkladaného vynálezu. Zlúčenina podľa vynálezu sa môže podávať intranazálnym spôsobom vo forme roztoku, suspenzie, HFA aerosólu alebo vo forme prípravku obsahujúceho suchý prášok, napr. pomocou aplikátora Turbuhaler®, alebo systémových spôsobom, napr. perorálne vo forme tabliet, piluliek, toboliek, sirupov, prášku, granulátu alebo tiež parenterálne vo forme sterilných parenterálnych roztokov alebo suspenzií, alebo tiež rektálne vo forme čapíkov.The compounds of the invention may be administered in doses ranging from 10 µg to 10 mg per day, either as a single dose or divided into 2-4 doses per day. The unit dosage form contains a dose of 2.5 µg to 10 mg of the compound of the present invention. The compound of the invention may be administered by the intranasal route in the form of a solution, suspension, HFA aerosol or in the form of a dry powder formulation, e.g. using a Turbuhaler® applicator, or in a systemic manner, e.g. orally in the form of tablets, pills, capsules, syrups, powders, granules or also parenterally in the form of sterile parenteral solutions or suspensions, or also rectally in the form of suppositories.
Zlúčeniny podlá predkladaného vynálezu sa môžu podávať samotné alebo vo forme farmaceutického prípravku, ktorý obsahuje zlúčeninu podlá vynálezu v kombinácii s farmaceutický prijateľným riedidlom, adjuvans alebo nosičom. Osobitne výhodné sú také zlúčeniny, ktoré neobsahujú látky schopné vyvolať nepriaznivú, napr. alergickú reakciu.The compounds of the present invention may be administered alone or in the form of a pharmaceutical composition comprising a compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are those compounds which do not contain substances capable of eliciting adverse effects, e.g. allergic reaction.
Práškové prípravky a pod tlakom balené HFA aerosóly zlúčenín podlá vynálezu sa môžu podávať nazálnou inhaláciou. Na inhaláciu je zlúčenina podlá vynálezu jemne rozdrvená. Rozdrvená zlúčenina má výhodne častice so štatistickým stredným priemerom (podľa hmotnosti) 10 pm a je suspendovaná v zmesi propelentov s pomocou disperzačného činidla, ako je napr. mastná kyselina obsahujúca 8 až 20 atómov uhlíka (napr. kyselina olejová) alebo jej soľ, žlčová kyselina, fosfolipid, alkylsacharid, perfluorovaný alebo polyetoxylovaný surfaktant alebo iné farmaceutický prijateľné disperzačné činidlo.Powder formulations and pressurized packaged HFA aerosols of the compounds of the invention may be administered by nasal inhalation. For inhalation, the compound of the invention is finely divided. The comminuted compound preferably has particles with a statistical mean diameter (by weight) of 10 µm and is suspended in a mixture of propellants with the aid of a dispersant such as e.g. a C8-C20 fatty acid (e.g., oleic acid) or a salt thereof, a bile acid, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or another pharmaceutically acceptable dispersing agent.
Zlúčeniny podlá predkladaného vynálezu sa tiež môžu podávať prostredníctvom inhalátora na suchý prášok. Takýto inhalátor môže byť buď jednodávkový alebo viacdávkový inhalátor a môže to byť vdychovo ovládaný inhalátor suchého prášku.The compounds of the present invention may also be administered via a dry powder inhaler. Such an inhaler may be either a single dose or multi dose inhaler and may be an breath actuated dry powder inhaler.
Jednou možnosťou prípravy je zmiešať jemne rozdrvenú zlúčeninu podľa vynálezu s nosičovou látkou, napr. mono-, dialebo polysacharidom, cukrovým alkoholom alebo inými polyolmi. Vhodnými nosičmi sú cukry, napr. laktóza, glukóza, rafinóza, malezitóza, laktitol, maltitol, trehalóza, sacharóza, manitol a škrob. Alternatívne sa jemne rozdrvená zlúčenina môže obaliť (potiahnuť) inou látkou. Prášková zmes sa tiež môže plniť do tvrdých želatínových toboliek, z ktorých každá obsahuje požadovanú dávku účinnej látky.One method of preparation is to admix the finely divided compound of the invention with a carrier, e.g. mono-, dialbo, or polysaccharide, sugar alcohol or other polyols. Suitable carriers are sugars, e.g. lactose, glucose, raffinose, malesitose, lactitol, maltitol, trehalose, sucrose, mannitol and starch. Alternatively, the finely divided compound may be coated (coated) with another substance. The powder mixture can also be filled into hard gelatin capsules, each containing the desired dose of the active ingredient.
Farmaceutický prípravok obsahujúci zlúčeninu podľa predkladaného vynálezu je výhodne vo forme tabliet, piluliek, toboliek, sirupov, prášku alebo granulátu na perorálne podávanie alebo vo forme sterilných roztokov alebo suspenzií na parenterálne podávanie alebo vo forme čapíkov na rektálne podávanie.The pharmaceutical composition comprising the compound of the present invention is preferably in the form of tablets, pills, capsules, syrups, powder or granules for oral administration or in the form of sterile solutions or suspensions for parenteral administration or in the form of suppositories for rectal administration.
Na perorálne podávanie sa môže účinná látka zmiešať s adjuvans alebo nosičom, akým je napr. laktóza, sacharóza, sorbitol, manitol, alebo škroby, ako sú zemiakový, kukuričný škrob alebo amylopektín, deriváty celulózy, spájadlom ako je napr. želatína alebo polyvinylpyrolidon a lubrikantom, ako napr.For oral administration, the active ingredient may be admixed with an adjuvant or carrier, e.g. lactose, sucrose, sorbitol, mannitol, or starches such as potato, corn starch or amylopectin, cellulose derivatives, a binder such as e.g. gelatin or polyvinylpyrrolidone and a lubricant such as e.g.
stearan horečnatý, stearan vápenatý, polyetylénglykol, vosky, parafín a pod., a potom lisovať do tabliet.magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
Pokiaľ sú požadované obaľované tablety, jadro pripravené vyššie opísaným spôsobom sa môže obaliť koncentrovaným cukrovým roztokom, ktorý môže obsahovať arabskú gumu, želatínu, mastenec, oxid titaničitý, a pod. Alternatívne sa môže tableta obaliť vhodným polymérom rozpustenom v prchavom organickom rozpúšťadle.If coated tablets are desired, the core prepared as described above may be coated with a concentrated sugar solution which may contain gum arabic, gelatin, talc, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a volatile organic solvent.
Na prípravu mäkkých želatínových toboliek sa zlúčenina podľa predkladaného vynálezu môže zmiešať napr. s rastlinným olejom alebo polyetylénglykolom. Tvrdé želatínové tobolky môžu obsahovať granulát zlúčeniny buď s vyššie opísanými pomocnými látkami pre tablety, napr. laktózou, sacharózou, sorbitolom, manitolom, škrobmi, derivátmi celulózy alebo želatínou. Do tvrdých želatínových toboliek sa tiež môžu plniť kvapalné alebo polotuhé formy liečiva.For the preparation of soft gelatin capsules, the compound of the present invention may be admixed e.g. with vegetable oil or polyethylene glycol. Hard gelatine capsules may contain a granulate of the compound with either the above-described tablet excipients, e.g. lactose, sucrose, sorbitol, mannitol, starches, cellulose derivatives or gelatin. Liquid or semi-solid drug forms can also be filled into hard gelatine capsules.
Kvapalné prípravky na perorálne podávanie môžu byť vo forme sirupov alebo suspenzií, napr. vo forme roztokov obsahujúcich zlúčeninu podľa vynálezu a cukor, a ďalej zmesi etanolu, vody, glycerolu a propylénglykolu. Takéto kvapalné prípravky môžu prípadne obsahovať farbivá, chuťové a vonné korigencie, sacharín a karboxymetylcelulózu ako zahusťovadlo, prípadne ďalšie pomocné látky odborníkovi známe.Liquid preparations for oral administration may be in the form of syrups or suspensions, e.g. in the form of solutions containing a compound of the invention and a sugar, and a mixture of ethanol, water, glycerol and propylene glycol. Such liquid preparations may optionally contain coloring agents, flavoring and perfuming agents, saccharin and carboxymethylcellulose as a thickening agent, or other excipients known to those skilled in the art.
Predkladaný vynález je ďalej ilustrovaný pomocou príkladov, ktoré ho v žiadnom prípade nijako neobmedzujú.The present invention is further illustrated by the following non-limiting examples.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Reťazce peptidu CII, uvedené v tabuľke 1, z ktorých každý sa skladá z 15 aminokyselín, sa syntetizovali pomocou automatického syntetizátora SMPS 350 (Zinsser, Frankfurt/Main,The peptide CII sequences shown in Table 1, each consisting of 15 amino acids, were synthesized using an SMPS 350 automatic synthesizer (Zinsser, Frankfurt / Main,
Nemecko) chemickou cestou s Fmoc (Atherton, Sheppard, Solid Phase Peptide Synthesis - A Practical Approach. IRL Press, Oxford). Každý peptid sa acetyloval na N-konci a amidoval na Ckonci. Kvalita peptidu sa hodnotila pomocou HPLC a hmotnostnou spektroskopiou vzorky peptidu sa potvrdila očakávaná molekulová hmotnosť.Germany) chemically with Fmoc (Atherton, Sheppard, Solid Phase Peptide Synthesis - A Practical Approach, IRL Press, Oxford). Each peptide was acetylated at the N-terminus and amidated at the C-terminus. Peptide quality was assessed by HPLC and the expected molecular weight was confirmed by mass spectroscopy of the peptide sample.
Úseky aminokyselín, ktoré sú zobrazený hrubým písmom, sú tzv. „core sekvencie, t.j. úseky aminokyselín, ktoré sa viažu najsilnejšie, v porovnaní s väzbovou silou štruktúrne blízko príbuzných peptidov.The stretches of amino acids that are shown in bold are so-called. The core sequence, i. stretches of amino acids that bind most strongly compared to the binding force structurally close to related peptides.
Tabuľka 1Table 1
Príklad 2 ’Example 2 ’
Myší CII sa extrahoval z mečovitého výbežku hrudnej kosti známym spôsobom pepsínovým štiepením a potom sa ďalej purifikoval vysolením. Potkaní CII sa opäť známym spôsobom purifikoval zo Swarmovho chondrosarkómu. Kolagény sa rozpustili v O,1M kyseline octovej. Kolagén, ktorý sa použil na restimuláciu buniek primárnych lymfatických uzlín, sa denaturoval 30 minút inkubáciou pri 56 °C.Mouse CII was extracted from the sword lobe of the sternum in a known manner by pepsin digestion and then further purified by salting. Rat CII was again purified from Swarm's chondrosarcoma in a known manner. The collagens were dissolved in 0.1 M acetic acid. The collagen that was used to restimulate the primary lymph node cells was denatured for 30 minutes by incubation at 56 ° C.
Príklad 3Example 3
Aby sa mohla testovať proliferačná odpoveď a uvoľňovanie cytokínov odobratými bunkami lymfatických uzlín, myšacie samce (B10.Q X DBA/1)F1 sa vo veku 7 až 10 týždňov imunizovali do chodidla zadných končatín 50 pg myšacieho CII alebo syntetického peptidu emulgovaného v CFA (obsahujúcom H37Ra, Difco, Detroit, MI) . Artritída sa indukovala u rovnakých myší vo veku 7 až 10 týždňov tým, že sa myši imunizovali do koreňa chvosta dávkou 100 μς potkanieho CII emulgovaného CFA pripraveného podľa príkladu 2.To test for proliferative response and cytokine release by lymphoid node cells, male mice (B10.QX DBA / 1) F1 were immunized in the hindlimb foot with 50 µg of mouse CII or a synthetic peptide emulsified in CFA (containing H37Ra) at 7-10 weeks of age. , Difco, Detroit, MI). Arthritis was induced in the same 7 to 10-week-old mice by immunizing the mice at the root of the tail with a dose of 100 µl of rat CII emulsified CFA prepared according to Example 2.
Po 5 týždňoch sa imunitná reakcia myší zosilnila dávkou 50 μς CII emulgovaného v hmotnostnom pomere 1:1 IFA (Difco, Detroit, MI) . Zo silno artritických kĺbov sa odsatím odobrali bunky lymfatických uzlín, spojili a ďalej opísaným spôsobom testovali v proliferačnom teste na reaktivitu s panelom myšacích peptidov CII pripravených podľa príkladu 1.After 5 weeks, the immune response of the mice was boosted with a dose of 50 µg of CII emulsified in a 1: 1 weight ratio of IFA (Difco, Detroit, MI). Lymph node cells were aspirated from strongly arthritic joints, pooled, and tested in a proliferation assay for reactivity with a panel of mouse CII peptides prepared according to Example 1 as described below.
Uvoľňovanie cytokínov sa testovalo v 50 μΐ supernatantu z indukovaných kultúr buniek primárnych lymfatických uzlín, ktoré sa restimulovali in vitro panelom peptidov CII pripravených podľa príkladu 1 pomocou minisúprav IFN-γ a IL-4 (Endogen, Cambridge, MA). Výsledky sú uvedené v tabuľke 2.Cytokine release was tested in 50 μΐ of supernatant from induced primary lymph node cell cultures that were restimulated in vitro with a panel of CII peptides prepared according to Example 1 using IFN-γ and IL-4 mini kits (Endogen, Cambridge, MA). The results are shown in Table 2.
Tabuľka 2Table 2
Príklad 4Example 4
Z buniek lymfatických uzlín myší indukovaných myšacím CII sa odobrali buď T alebo B bunky pomocou magneticky aktivovaného triediča buniek (MACS) so superparamagnetickými mikroperličkami konjugovanými s potkaňou monoklonálnou protilátkou L3T4 (CD4) alebo potkaňou anti-myšou protilátkou B220 CD45R) (obidve protilátky od Miltenyi Biotec GmbH, Bergish Gladbach, Nemecko) v podstate podlá odporučenia výrobcu, okrem toho, že PBS/BSA pufor sa nahradil s PBS obsahujúcim 2% FCS, 5 mM EDTA, 50 μΜ 2-ME a mM HEPES. Frakcie sa analyzovali prietokovým cytometrom FACScan (Becton Dickinson) pomocou konjugátu (FITC-anti-myšaci CD3-8) na označenie (zafarbenie) T-buniek a konjugátu (FITC-antimyšaci ľahký reťazec k) na označenie B-buniek (Pharmigen, San Diego, CA) . Bunky sa po separácii trikrát prepláchli médiom DMEM bez séra a potom sa použili v proliferačnom teste podľa príkladu 3. Obohatené T-bunky CD4+ ako bunky reprezentujúce antigén sa zmiešali s bunkami sleziny zo syngénnych myší v • hmotnostnom pomere 1:2. Bunky AP sa použili vo forme suspenzie jednotlivých buniek zo slezín opracovaných s 0,84 % NH4C1 pri pH 7,4, aby prebehla lýza červených krviniek.Either T or B cells were harvested from the lymph node cells induced by mouse CII using a magnetically activated cell sorter (MACS) with superparamagnetic microspheres conjugated to rat monoclonal antibody L3T4 (CD4) or rat anti-mouse antibody B220 CD45R) (both antibodies from Milteny) GmbH, Bergish Gladbach, Germany) essentially as recommended by the manufacturer, except that PBS / BSA buffer was replaced with PBS containing 2% FCS, 5 mM EDTA, 50 μΜ 2-ME and mM HEPES. Fractions were analyzed with a FACScan flow cytometer (Becton Dickinson) using a conjugate (FITC-anti-mouse CD3-8) to label (stain) T cells and a conjugate (FITC-anti-mouse light chain k) to label B cells (Pharmigen, San Diego). , CA). The cells were washed three times with serum-free DMEM after separation and then used in the proliferation assay of Example 3. Enriched CD4 + T cells as antigen-presenting cells were mixed with spleen cells from syngeneic mice at a 1: 2 weight ratio. AP cells were used as a suspension of single spleen cells treated with 0.84% NH 4 Cl at pH 7.4 to lyse the red blood cells.
Tabuľka 3Table 3
JJ
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