DK2279007T3 - Pegylerede rekombinante forbindelser af humant væksthormon - Google Patents

Pegylerede rekombinante forbindelser af humant væksthormon Download PDF

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DK2279007T3
DK2279007T3 DK09738181.8T DK09738181T DK2279007T3 DK 2279007 T3 DK2279007 T3 DK 2279007T3 DK 09738181 T DK09738181 T DK 09738181T DK 2279007 T3 DK2279007 T3 DK 2279007T3
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hgh
peg
linker
conjugate
pharmaceutical composition
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DK09738181.8T
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Thomas Wegge
Ulrich Hersel
Harald Rau
Susanne Kindermann
Torben Lessmann
Grethe Nørskov Rasmussen
Kennett Sprogøe
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Ascendis Pharma Growth Disorders Div As
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Priority claimed from EP08155408A external-priority patent/EP2113256A1/en
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    • A61K38/27—Growth hormone [GH], i.e. somatotropin
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    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/61—Growth hormone [GH], i.e. somatotropin

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Claims (16)

1. Farmaceutisk sammensætning omfattende egnede farmaceutiske excipi-enser og også omfattende en in vivo hos mennesker klinisk virksom mængde af et rekombinant humant væksthormon (rhGH)-PEGyleret prodrug-konjugat, hvor PEG er forbundet med rhGH via en selvhydrolyserbar (selvspaltning) transitorisk linker; hvilket prodrug-konjugat er kendetegnet ved, at: (1) : konjugatet har en GH-aktivitet, som er mindre end 5% af det native væksthormon uden PEG; og (2) : linker-autohydrolyseraten er således, at in v/Vo-halveringstiden er fra 10 timer til 600 timer, hvilket måles ved intravenøs injektion af konjugatet i rotter, efterfulgt af blodprøvetagning med tidsintervaller, forberedelse af plasma og analyse af hGH under anvendelse af ELISA; og hvor det PEGvIerede prodrua-koniuqat har den kemiske struktur (A):
(A), hvor HN-rhGH betegner rhGH-resten knyttet til den forbigående transitoriske linker; R1, R2, R3, R4 og R5 er uafhængigt udvalgt blandt hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiært butyl; PEG betegner pegyleringsresten knyttet til den transitoriske linker; n = 1 eller 2; og X er udvalgt blandt C1 til C8 alkyl eller C1 til C12 heteroalkyl; og hvor PEG'en er forgrenet og indeholder mindst 3 kæder.
2. Farmaceutisk sammensætning ifølge krav 1, hvor autohydrolyseraten er således, at in v/Vo-halveringstiden er op til 5 gange kortere end det tilsvarende hGH-PEGylerede prodrug-konjugats in v/Yro-halveringstid.
3. Farmaceutisk sammensætning ifølge krav 2, hvor in v/Vo-halveringstiden er op til 3 gange kortere end det tilsvarende hGH-PEGylerede prodrug-konjugats in v/Yro-halveringstid.
4. Farmaceutisk sammensætning ifølge krav 2 eller 3, hvor in vivo-halveringstiden er op til 2 gange kortere end det tilsvarende hGH-PEGylerede prodrug-konjugats in v/Yro-halveringstid.
5. Farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 4, hvor sammensætningen er en sammensætning til subkutan indgivelse, intramuskulær indgivelse eller intravenøs injektion.
6. Farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 5, hvor det PEGylerede prodrug har en samlet PEG-belastning pr. væksthormonmolekyle på mindst 25 kDa.
7. Farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 6, hvor delstrukturen af formel (I) i struktur (A) ifølge krav 1, som er
(i). er udvalgt fra gruppen bestående af:
8. Farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 7, hvor delstrukturen af formel (II) i struktur (A) ifølge krav 1, som er
(li), er udvalgt fra gruppen bestående af:
9. Farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 8, hvor PEG-X i formel (A) ifølge krav 1 er PEG-W i formel III: PEG—(|j|) hvor PEG-W er udvalgt fra gruppen bestående af:
10. Farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 6, hvor prodrug-konjugat-strukturen er:
11. Farmaceutisk sammensætning ifølge et hvilket som helst af de foregående krav, hvor linker-selvspaltningsraten in vivo er således, at in vivo-halveringstiden er fra 20 til 300 timer.
12. Farmaceutisk sammensætning ifølge et hvilket som helst af de foregående krav, hvor linker-selvspaltningsraten in vivo er således, at in vivo- halveringstiden er fra 20 til 150 timer.
13. Farmaceutisk sammensætning ifølge et hvilket som helst af de foregående krav, hvor linker-selvspaltningsraten in vivo er således, at in vivo-halveringstiden er fra 30 til 100 timer.
14. Farmaceutisk sammensætning ifølge et hvilket som helst af de foregående krav, hvor linker-selvspaltningsraten in vivo er således, at in vivo-halveringstiden er fra 30 til 75 timer.
15. Klinisk virksom mængde af den farmaceutiske sammensætning ifølge et hvilket som helst af kravene 1 til 14 til anvendelse i en fremgangsmåde til behandling af en GFI-relateret sygdom hos et menneskeligt individ, hvor sygdommen er udvalgt blandt væksthormonmangel, væksthormonmangel indtrådt i voksenalderen; Turners syndrom; Prader-Willi syndrom; korttarmssyndrom; kronisk nyreinsufficiens; SGA (small for gestational age); AIDS wasting; anti-aldring; reumatoid artritis; idiopatisk lille højde; væksthæmning-homeobox-gen; somatopause; Noonans syndrom; knogledysplasier; Downs syndrom; væksthæmning forbundet med langvarig brug af steroider; Aars-kogs syndrom; kronisk nyresygdom; juvenil reumatoid artritis; cystisk fibrose; hiv-infektion hos børn i HAART-behandling; væksthæmning hos børn født med en meget lav fødselsvægt, undtagen SGA; knogledysplasier; hypochon-droplasi; achondroplasi; idiopatisk væksthæmning; GHD hos voksne; fraktur i eller af lange knogler; frakturer i eller af spongiøse knogler; patienter efter sene- eller ledbåndskirurgi; distraktionsosteogenese; sygdomme, der skyldes hofte- eller discus-alloplastik, menisk-opheling, spondylodeser eller prote-sefiksation; sygdomme, der skyldes fiksation af osteosyntesemateriale; manglende heling eller dårlig heling af frakturer; sygdomme, der skyldes osteotomi; sygdomme, der skyldes implantation af transplantat; degeneration af ledbrusk i knæ forårsaget af traume eller artritis; osteoporose hos patienter med Turners syndrom; osteoporose hos mænd; voksne patienter i kronisk dialyse (APCD); kardiovaskulær sygdom forbundet med underernæring hos APCD; ophævelse af kakeksi hos APCD; cancer hos APCD; kronisk obstruk-tiv lungesygdom hos APCD; hiv hos APCD; ældre med APCD; kronisk leversygdom hos APCD; træthedssyndrom hos APCD; Crohns sygdom; nedsat leverfunktion; mænd med hiv-infektion; korttarmsyndrom; central fedme; hiv associeret lipodystrofisyndrom; mandlig infertilitet; patienter efter større elek-tiv kirurgi, alkohol- eller lægemiddelafgiftning, neurologisk traume; aldring; skrøbelige ældre; osteoarthritis; traumatisk beskadiget brusk; erektil dysfunktion; fibromyalgi; hukommelsesforstyrrelser; depression; traumatisk hjerneskade; subaraknoidalblødning; meget lav fødselsvægt; metabolisk syndrom; glucocorticoidmyopati; og væksthæmning på grund af glucocorticoidbehand-ling hos børn.
16. Prodrug udvalgt fra gruppen bestående af
hvor m er et heltal fra 200 til 250, og n er et heltal fra 100 til 125;
hvor n er et heltal fra 400 til 500;
hvor n er et heltal fra 400 til 500; og
hvor n er et heltal fra 400 til 500.
DK09738181.8T 2008-04-29 2009-04-29 Pegylerede rekombinante forbindelser af humant væksthormon DK2279007T3 (da)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP08155408A EP2113256A1 (en) 2008-04-29 2008-04-29 PEGylated rhGH compounds
EP08162865 2008-08-22
EP08167289 2008-10-22
PCT/EP2009/055194 WO2009133137A2 (en) 2008-04-29 2009-04-29 Pegylated recombinant human growth hormone compounds

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DK16156852.2T DK3050576T3 (da) 2008-04-29 2009-04-29 Pegylerede rekombinante forbindelser af humant væksthormon

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CY (2) CY1117882T1 (da)
DK (2) DK2279007T3 (da)
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