Cyclodextrins as procoagulants
Inventors
MEIJERS, Josephus Cornelis Maria • Bakhtiari, Kamran • Peters, Stephan Leonard Maria • ZOLLINGER, Daniel Philipp
Assignees
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Publication Number
US-10813944-B2
Publication Date
2020-10-27
Expiration Date
Abstract
The invention relates to substituted cyclodextrins and pharmaceutically acceptable salts thereof, pharmaceutical compositions, kits of parts and their use as procoagulants. The invention further relates to methods of reversing an anticoagulant effect of an anticoagulant in a subject, methods for reducing or preventing bleeding in a subject and methods for the treatment or prevention of a blood coagulation disorder.
Core Innovation
The invention relates to substituted cyclodextrins of formula (I) bearing a sulfur tethered alkyl/R substituent, wherein n is an integer from 3 to 7, p+q is 6, 7 or 8 with specified p and q values, and R is selected from —COOH, —OH and —COO(1-4C)alkyl, and pharmaceutically acceptable salts or esters. The substituted cyclodextrins are used as procoagulants, including for reversing an anticoagulant effect.
The invention addresses treating a blood coagulation disorder, inducing or stimulating blood coagulation, reducing or preventing bleeding, and reversing an anticoagulant effect of an anticoagulant in a subject in need thereof. The claimed approach centers on administering a therapeutically effective amount of the defined substituted cyclodextrin.
The invention further encompasses substituted cyclodextrins of formula (II) with enumerated structural parameter combinations (p, q, m and R) and the use of these cyclodextrins in pharmaceutical compositions for topical administration, as well as kits comprising the substituted cyclodextrin together with a recombinant or isolated coagulation factor, including factor VIII or factor IX.
Claims Coverage
The independent claims comprise four core claim categories: a method for treating blood coagulation disorders and reversing anticoagulant effects using a defined substituted cyclodextrin; a topical pharmaceutical composition including the defined substituted cyclodextrin; defined substituted cyclodextrin structures of formula (II) with specific parameter sets; and a kit combining the defined substituted cyclodextrin with a recombinant or isolated coagulation factor. Across these independent claims, the document specifies multiple inventive features that constrain both the cyclodextrin structure and the intended coagulation-related function.
Method using substituted cyclodextrin of formula (I) to treat coagulation disorder and reverse anticoagulant effect
Administering to a subject a therapeutically effective amount of a substituted cyclodextrin of formula (I), wherein n is an integer from 3 to 7, R is selected from —COOH, —OH and —COO(1-4C)alkyl, and wherein p+q is 6, 7 or 8 with specified p and q combinations, optionally as a pharmaceutically acceptable salt or ester, for treating a blood coagulation disorder, inducing or stimulating blood coagulation, reducing or preventing bleeding, and reversing an anticoagulant effect of an anticoagulant.
Topical pharmaceutical composition of substituted cyclodextrin of formula (I)
Providing a pharmaceutical composition comprising at least one substituted cyclodextrin of formula (I), wherein n is an integer from 3 to 7, R is selected from —COOH, —OH and —COO(1-4C)alkyl, and wherein p+q is 6, 7 or 8 with specified p and q combinations, optionally as a pharmaceutically acceptable salt or ester, together with at least one pharmaceutically acceptable auxiliary, wherein the composition is formulated for topical administration as a gel, cream, ointment, dressing, compress, plaster, band-aid or patch.
Substituted cyclodextrin of formula (II) with enumerated parameter sets
A substituted cyclodextrin of formula (II) wherein p, q, m and R are defined by one of the enumerated combinations (including R as COOH or OH), and the cyclodextrin may be a pharmaceutically acceptable salt or ester of any of these cyclodextrins, or a substituted cyclodextrin of formula (II) wherein p is 0, q is 8, m is 5 and R is COOH.
Kit comprising substituted cyclodextrin of formula (I) and a recombinant or isolated coagulation factor
A kit comprising a substituted cyclodextrin of formula (I), wherein n is an integer from 3 to 7 and R is selected from —COOH, —OH and —COO(1-4C)alkyl, and wherein p+q is 6, 7 or 8 with specified p and q combinations (optionally as a pharmaceutically acceptable salt), and a recombinant or isolated coagulation factor.
Overall, the independent claims focus on administering or formulating specifically defined substituted cyclodextrins (formula (I) and formula (II)) and optionally combining them with a recombinant or isolated coagulation factor in a kit, with the core functional outcome being inducing or stimulating blood coagulation, reducing or preventing bleeding, and reversing an anticoagulant effect.
Stated Advantages
Treating a blood coagulation disorder.
Inducing or stimulating blood coagulation.
Reducing or preventing bleeding.
Reversing an anticoagulant effect of an anticoagulant.
Improving thrombin generation metrics, including reduced lag time and increased peak thrombin, with faster time-to-peak/ETP as described in the provided document content.
Documented Applications
Treating blood coagulation disorders and/or inducing or stimulating blood coagulation, reducing/preventing bleeding, and reversing anticoagulant effects in a subject as recited in the method claim.
Topical administration pharmaceutical compositions in gel, cream, ointment, dressing, compress, plaster, band-aid or patch formats as recited in the composition claim.
Kits combining the substituted cyclodextrin of formula (I) with a recombinant or isolated coagulation factor (including factor VIII or factor IX) as recited in the kit claim.
Reversing anticoagulant effects and improving bleeding/hemostasis outcomes described for in vivo mouse bleeding/hemostasis models under rivaroxaban anticoagulation and in hemophilia A settings, as stated in the provided document content.
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