Analysis of sulfated polysaccharides
AssigneeMomenta Pharmaceuticals, Inc.
InventorsGanesh Venkataraman, Zachary Shriver, Malikarjun Sundaram, Yi-Wei QI, Ram Sasisekharan
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Abstract
The invention relates to methods and products associated with analyzing and monitoring heterogeneous populations of sulfated polysaccharides. In particular therapeutic heparin products including low molecular weight heparin products and methods of analyzing and monitoring these products are described.
Claims330
A method of analyzing a sample comprising a composition which includes a polysaccharide, the method comprising providing a structural signature for the composition, thereby analyzing the composition.
A method for determining bioequivalence comprising the steps of:
- a. providing or determining the structural signature of a first composition;
- b. providing or determining the bioavailability of the first composition;
- c. providing or determining the structural signature of a second composition;
- d. providing or determining the bioavailability of the second composition;
- and
- e. comparing the structural compositions and bioavailability of the first and second compositions;
- thus determining the bioequivalence of the compositions.
The method of claim 23, wherein the subject is a human or veterinary subject or experimental animal.
A method of analyzing a polysaccharide drug, the method comprising:
- a. determining a first structural signature for a first batch of drug having a first level of preselected patient reaction;
- b. determining a second structural signature, for a second batch of drug having a second level of preselected patient reaction;
- and
- c. comparing the first and second structural signature determinations to determine the presence or absence of a correlation between a property of the drug with a preselected level of patient reaction.
A method of analyzing a composition which includes a mixed population of polysaccharides, the method comprising:
- a. providing the composition or a sample which includes the composition;
- and
- b. determining if one or more of:
- ΔU2SHNS,6S is present in a preselected range;
- ΔU2SHNS is present in a preselected range;
- ΔUHNS,6S is present in a preselected range;
- ΔU2SHNAc,6S is present in a preselected range;
- ΔUHNS is present in a preselected range;
- ΔU2SHNAc is present in a preselected range;
- ΔUHNAc,6S is present in a preselected range;
- or ΔUHNAc,6SGHNS,3S,6S, ΔUHNS,6SGHNS,3S,6S, ΔUHNAc,6SGHNS,3S, or ΔUHNS,6SGHNS,3S, or a mixture thereof is present in a preselected range in the composition, thereby analyzing the composition.
A method of analyzing a composition which includes a mixed population of polysaccharides, the method comprising the steps of:
- a. providing the composition or a sample which includes the composition;
- and
- b. determining if one or more of:
- ΔU2SHNS,6S is present in the range of 15-85 mole %;
- ΔU2SHNS is present in the range of 0.1-20 mole %;
- ΔUHNS,6S is present in the range of 0.1-20 mole %;
- ΔU2SHNAc,6S is present in the range of 0.1-10 mole %;
- ΔUHNS is present in the range of 0.1-10 mole %;
- ΔU2SHNAc is present in the range of 0.1-5 mole %;
- ΔUHNAC,6S is present in the range of 0.1-15 mole %;
- or ΔUHNAc,6SGHNS,3S,6S, ΔUHNS,6SGHNS,3S,6S, ΔUHNAc,6SGHNS,3S, or ΔUHNS,6SGHNS,3S or a mixture thereof is present in the range of 0.1-20 mole % in the composition;
- thereby analyzing the composition.
A method of analyzing a sample of a heparin having a selected biological activity, comprising the steps of:
- a. providing the sample;
- and
- b. determining if a component known to be correlated with the selected activity is present in the sample;
- thereby analyzing the sample.
A method of analyzing a sample of LMWH comprising the steps of:
- a. providing the sample;
- and
- b. determining if a non-natural sugar, e.g., a modified sugar, is present in the sample;
- thereby analyzing the sample.
A method of analyzing a sample or a subject the method comprising the steps of:
- a. providing a sample;
- b. determining if one or more components chosen from the group consisting of ΔUHNAc,6SGHNS,3S,6S;
- ΔUHNS,6SGHNS,3S,6S;
- ΔUHNAc,6SGHNS,3S;
- ΔUHNS,6SGHNS,3S or a fragment or fragments thereof is present in the sample;
- and
- c. optionally, measuring the level of the component or components;
- thereby monitoring the subject.
A method of analyzing a sample, the method comprising the steps of:
- a. providing a sample;
- and
- b. determining if one or more structural signature outputs known to be associated with anti-IIa activity is present in the sample;
- and
- c. optionally, determining the level of the component or components;
- thereby analyzing the sample or subject.
A method of analyzing a sample or a subject, the method comprising the steps of:
- a. providing a sample;
- and
- b. determining if one or more non-natural sugars, e.g., modified sugars, is present in the sample;
- and
- c. optionally, determining the level of the non-natural sugar;
- thereby monitoring the subject.
A LMWH composition comprising a tag.
A method of evaluating a sample for the presence of a LMWH comprising a tag comprising the steps of
- a. providing a sample;
- b. optionally purifying the sample;
- and
- c. determining the presence of the tag in the sample,
- thereby evaluating the presence of the LMWH in the sample.
A LMWH preparation having an increased or decreased ratio of anti-IIa activity and anti-Xa activity.
A method of producing a LMWH preparation having or not having a pre-selected biological activity, the method comprising the steps of:
- a. providing one or more aliquots of heparin;
- b. optionally fractionating the heparin;
- c. modifying the aliquots of heparin under conditions designed to produce the activity;
- and
- d. optionally purifying the digested aliquots.
A panel of two or more LMWH preparations having different ratios of anti-IIa activity and anti-Xa activity.
A method of treating a subject, comprising
- a. providing a panel of two or more LMWH preparations having different ratios of anti-IIa activity and anti-Xa activity;
- b. selecting a LMWH preparation having a desired ratio;
- and
- c. administering one or more doses of a therapeutically effective amount of the LMWH preparation to the subject.
A LMWH composition having both anti-Xa and anti-IIa activity comprising less than or equal to 20% <2000 Da species, greater than or equal to 68% 2000-8000 Da species, and less than or equal to 18% >8000 Da species, preferably with an average molecular weight of about 4500 Da, wherein the anti-Xa activity is >50% neutralizable by protamine and the anti-IIa activity is >70% neutralizable by protamine.
A LMWH that is substantially free of non-natural sugars and comprising less than or equal to 20% <2000 Da species, greater than or equal to 68% 2000-8000 Da species, and less than or equal to 18% >8000 Da species, preferably with an average molecular weight of about 4500 Da.
A LMWH which, as compared with enoxaparin, is enriched in non-natural sugars and comprising less than or equal to 20% <2000 Da species, greater than or equal to 68% 2000-8000 Da species, and less than or equal to 18% >8000 Da species, preferably with an average molecular weight of about 4500 Da.
A method of making one or more batches of a LMWH preparation which has a batch-to-batch variation of a preselected range from a preselected value for one or more component saccharide chosen from the group consisting of ΔU2SHNS,6S;
- ΔU2SHNS;
- ΔUHNS,6S;
- ΔU2SHNAc,6S;
- ΔUHNS;
- ΔU2SHNAc;
- ΔUHNAc,6S;
- and ΔUHNAc,6SGHNS,3S,6S the method comprising the steps of:
- a. selecting a desired value;
- b. providing an aliquot of UFH;
- c. optionally fractionating the aliquot;
- d. determining the level of the component in the aliquot;
- and
- e. selecting a batch or batches with less than the preselected range of variation from the desired value.
A method of making one or more batches of a LMWH preparation which has a batch-to-batch variation of less than a preselected range from a preselected value, e.g., less than 2.5%, more preferably less than 2% or less than 1%, for one or more component saccharide chosen from the group consisting of p1-p8, the method comprising the steps of:
- a. selecting a value;
- b. providing an aliquot of UFH or LMWH;
- c. precipitating the aliquot
- d. optionally subjecting the aliquot to an ion exchange process
- e. contacting the aliquot with an agent under conditions such that the desired value will result.
A composition comprising multiple batches of a LMWH preparation, wherein, for each of the batches, the mole % of one or more component chosen from the group consisting of p1-p8 varies less than a preselected variation,
A composition comprising multiple batches of a LMWH preparation, wherein the glycoprofile of each of the batches for one or more component chosen from the group consisting of p9-p10 varies less than a preselected variation.
A record having an element which identifies a polysaccharide an element which identifies one or more components of the polysaccharide, and an element which identifies a range of mole % of the components.
A method for determining the safety or suitability of a heparin for use in a particular indication, comprising the steps of:
- a. providing the structural signature of the heparin;
- b. providing a reference structural signature;
- c. determining if the heparin is acceptable.
Dependencies are inferred from the claim text.