Synthetic sugars as enablers for viscosity reduction of highly concentrated biological molecules

Abstract

The present invention provides synthetic sugars and methods for reducing the viscosity of biological molecule solutions or suspensions by using said synthetic sugars. The invention also provides pharmaceutical compositions comprising these synthetic sugars and a biological molecule, suitable for intravenous or subcutaneous injection, and methods for purifying biological molecules using these synthetic sugars to enhance the efficiency of downstream processes.

Description

Docket: 92482-A-PCT-US / GJG / YXSYNTHETIC SUGARS AS ENABLERS FOR VISCOSITY REDUCTION OF CONCENTRATED BIOLOGICAL MOLECULES

[0001] Throughout this application, various publications are referenced, including referenced in parenthesis. The disclosures of all publications mentioned in this application in their entireties are hereby incorporated by reference into this application in order to provide additional description of the art to which this invention pertains and of the features in the art which can be employed with this invention.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U. S. Provisional Application No. 63 / 749,383 filed January 24, 2025, the contents of which is hereby incorporated by reference.BACKGROUND OF THE INVENTION

[0003] Administration of biopharmaceutical products such as monoclonal antibodies (mAbs) and recombinant proteins has been proven to be a successful therapeutic approach.

[0004] Subcutaneous delivery of biopharmaceutical products brings many advantages, such as: 1) convenience and easy compliance of the patient, 2) reduced healthcare costs, 3) improved patient’s quality of life, 4) lower risk of infection and 5) facilitation of long-term repeated treatments (often the case for mAbs). However, the low volumes required for subcutaneous administration of these biopharmaceutical products also bring challenges to the formulation of these products. Usually for subcutaneous administration, there is an initial need of low volumes (typically between 1 and 2 mL) and a subsequent need for a high concentration of biopharmaceutical products in a solution. These biopharmaceutical products can be proteins and concentrated proteins tend to increase the solution’s viscosity, which in return increase propensity to aggregate, phase separation, gel formation and subvisible protein particle formation. The resulting high viscous solutions of these biopharmaceutical products carry additional issues, such as a high injection force and extra pain experienced by the patient.

[0005] Contrary to salts and amino acids that have been extensively used as viscosity reducers, hexose derivatives, such as sugars that are commonly used to stabilize proteins are known to significantly increase viscosity of high concentration protein solutions (Woods et al., 2011). For example, Walters described that formulation constituents, such as sugars, may further exacerbate the self-association tendency of the antibody and high concentrations of stabilizing excipients can lead to high viscosities. (Walters, 2017).

[0006] Although the exact mechanism of how the sugars increase viscosity of high concentration protein solutions remains unclear, preferential interaction theory affirms that sugar’s stabilizing effect operates through a preferential interaction / exclusion mechanism towards the protein (Sudrik et al., 2019).Sugars are excluded from the protein surroundings, leading to preferential hydration of the protein shell, which, in turn, shifts the equilibrium towards the more compact, natively folded state. This minimizes the exposure of hydrophobic regions at the protein surface, preventing protein aggregation. At higher protein concentrations, protein-protein interactions (PPIs) lead to more complex behaviors and the preferential exclusion behavior of sugars is enhanced. For example, when sugars are present in protein solutions (typically trehalose and glucose), the preferential exclusion effect drives sugar molecules away from proteins, increasing their effective volume and leaving less volume and water molecules in which to dissolve sugars (Xu et al., 2019). As a result, an increase in the effective sugar concentration is observed leading to an increase in viscosity.

[0007] To date it is unclear whether sugars and proteins form network interactions that could lead to increased viscosity. In 2019, Cloutier et al. used molecular dynamic simulations to examine the interactions of three sugars (sucrose, trehalose and sorbitol) with different IgGl antibodies and understand their impact in aggregation and viscosity (Cloutier et al., 2019). Cloutier et al. found that there are often stronger interactions between the excipients and the aromatic residues on the antibody surface, which may help prevent hydrophobic-hydrophobic interactions. However, not all the excipients reduced the viscosity of the two antibodies at 100 mg / mL, and the results appeared to be dependent on the antibody itself. Cloutier et al. also investigated the differences in the preferential exclusion behavior of sorbitol, sucrose, and trehalose, and found that the magnitude of exclusion was not solely determined by the excipient or the protein-water interfacial area, but also by specific protein attributes (Sudrik et al., 2019).BRIEF SUMMARY OF THE INVENTION

[0008] The hexose derivatives disclosed herein below are shown as successful protein stabilizers under stress conditions, such as pH, temperature and shaking. Further disclosed hereinbelow are hexose derivatives that also decrease viscosity of biopharmaceutical formulations, such as peptides, mAbs and fusion proteins, thereby enabling a smooth delivery of such molecules in intravenous administration or subcutaneous administration. A reduction of viscosity of concentrated biopharmaceutical formulations below 30 cP can be achieved.

[0009] The present invention provides a composition comprising a biological molecule and at least one compound or a salt thereof, wherein the compound has the following structure:whereinX isOH, orX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide; and[A]wherein when X isR2is -OH, -N3, or -N(H)C(=O)CH3; orR1and R2together with the carbon atoms to which they are attached formwherein R3is -H, -CH3, -CH2C(=O)OH, or -CH2OH; or[B]wherein when X is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide;, j> AthenR is;wherein for both [A] and [B], R4and R5are each independently H, halogen, -CH2OH, -CH2C(=O)OH, -OH, -O-alkyl, -CONH2, or optionally substituted alkyl;Y and Z are each independently H, OH, O-alkyl or optionally substituted alkyl;A is H, -OH, -CONH2, -O-NH2, -CO2NH2,- NH2, -OR6, or -NR7R8;wherein R6is H, -NH2, or optionally substituted alkyl; and R7and R8are each independently H, OH, O-alkyl or optionally substituted alkyl;n is 0-10; andm is 0-10;wherein the biological molecule is not lysozyme, adalimumab, ubiquitin or Factor IX.

[0010] The present invention provides a method of modifying the viscosity of a biological molecule solution or suspension, comprising adding at least one compound, or a salt thereof of the following structure to the biological molecule solution:XwhereinX is, ora hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide; and[A]wherein when X isR2is -OH, -N3, or -N(H)C(=O)CH3; orR1and R2together with the carbon atoms to which they are attached formwherein R3is -H, -CH3, -CH2C(=O)OH, or -CH2OH; or[B]wherein when X is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide;wherein for both [A] and [B], R4and R5are each independently H, halogen, -CH2OH, -CH2C(=O)OH, -OH, -O-alkyl, -CONH2, or optionally substituted alkyl;Y and Z are each independently H, OH, O-alkyl or optionally substituted alkyl;A is H, -OH, -CONH2, -O-NH2, -CO2NH2,- NH2, -OR6, or -NR7R8;wherein R6is H, -NH2, or optionally substituted alkyl; and R7and R8are each independently H, OH, O-alkyl or optionally substituted alkyl;n is 0-10; andm is 0-10.

[0011] The present invention provides a process of purifying a biological molecule; comprising a step of diafiltration, so as to purify the biological molecule, wherein the process comprises combining the biological molecule with at least one compound, or a salt thereof, having the following structure:whereinX isX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide; and[A]wherein when X isR2is -OH, -N3, or -N(H)C(=O)CH3; orR1and R2together with the carbon atoms to which they are attached formO R3, wherein R3is -H, -CH3, -CH2C(=O)OH, or -CH2OH; or [B]wherein when X is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide;then R1iswherein for both [A] and [B], R4and R5are each independently H, halogen, -CH2OH, -CH2C(=O)OH, -OH, -O-alkyl, -CONH2, or optionally substituted alkyl;Y and Z are each independently H, OH, O-alkyl or optionally substituted alkyl;A is H, -OH, -CONH2, -O-NH2, -CO2NH2,- NH2, -OR6, or -NR7R8;wherein R6is H, -NH2, or optionally substituted alkyl; and R7and R8are each independently H, OH, O-alkyl or optionally substituted alkyl;n is 0-10; andm is 0-10.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1. Viscosity Reducing effect of the excipients at 100 mM: true viscosity of (A) omalizumab (146 mg / mL), (B) infliximab (156 mg / mL), (C) evolocumab (152 mg / mL), (D) etanercept (143 mg / mL), (E) bevacizumab (200 mg / mL) and (F) Rituximab (208 mg / ML) measured at a shear rate of 3000 s'1and 25°C.

[0013] Figure 2. Viscosity Reducing effect of the excipients at 50, 100 and 150 mM: true viscosity of (A) omalizumab (154 mg / mL), (B) infliximab (165 mg / mL), (C) evolocumab (161 mg / mL) and (D) etanercept (158 mg / mL) measured at a shear rate of 3000 s'1and 25.

[0014] Figure 3. Diafiltration and concentration time of (A) omalizumab (154 mg / mL), (B) infliximab (165 mg / mL), (C) evolocumab (161 mg / mL), (D) etanercept (158 mg / mL), and (E) cetuximab (134 mg / mL) with and without the excipients at a range between 50 and 150 mM.

[0015] Figure 4. Stability study of high concentrated protein solutions in the presence of various excipients at 100 mM over 1 month at 4°C and 25 °C: (A) omalizumab, (B) infliximab, (C) evolocumab and (D) etanercept.DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention provides a composition comprising a biological molecule and at least one compound or a salt thereof, wherein the compound has the following structure:RR‘Formula Iwherein. R5one of R4and R5is H, the other is H, -CH3, -CH2OH, or CH2C(=O)OH;Y is H;Z is H;m is 0 or 1;n is 0 or 1;A is OH;R2is -OH, -N3, or -N(H)C(=O)CH3; orR1and R2together with the carbon atoms to which they are attached formwherein R3is -H, -CH3, -CH2C(=O)OH, or -CH2OH; andwherein the biological molecule is Insulin; Humulin; Novolin; Insulin human inhalation; Exubera; Insulin aspart; Novolog (aspart); Insulin glulisine; Apidra (glulisine); Insulin lispro; Humalog (lispro); Isophane insulin; NPH; Insulin detemir; Levemir (detemir); Insulin glargine; Lantus (glargine); Insulin zinc extended; Lente; Ultralente; Pramlintide acetate; Symlin; Growth hormone(GH); somatotropin; genotropin; humatrope; norditropin; NorIVitropin; Nutropin; Omnitrope; Protropin; Saizen; Serostim; Valtropin; Mecasermin; Increlex; Mecasermin rinfabate; IPlex; Factor VIII; Bioclate; Helixate; Kogenate; Recominate; ReFacto; Factor IX; Benefix; Antithromin III (AT-III); Thrombate III; Protein C concentrate; Ceprotin; P-Glucocerebrosidase; Cerezyme; P-Glucocerebrosidase; Ceredase (purified from pooled human placenta); Alglucosidase-a; Myozyme; Laronidase (a-l-iduronidase); Aldurazyme; Idursulphase (Iduronate-2-sulphatase); Elaprase; Galsulphase; Naglazyme; Agalsidase-P (human a-galactosidase A); Fabrazyme; a-1-Proteinase inhibitor; Aralast; Prolastin; Lactase; Lactaid; Pancreatic enzymes (lipase, amylase, protease); Arco-Lase, Cotazym, Creon, Donnazyme, Pancrease, Viokase, Zymase, Adenosine deaminase (pegademase bovine, PEG- AD A); Adagen; Pooled immunoglobulins; Octagam; Human albumin; Albumarc; Albumin; Albuminar; AlbuRx; Albutein; Flexbumin; Buminate; Plasbumin; Erythropoietin; Epoetin-a; Epogen; Procrit; Darbepoetin-a; Aranesp; Filgrastim (granulocyte colony stimulating factor; G-CS F); Neupogen; Pegfilgrastim (Peg-G-CSF); Neulasta; Sargramostim (granulocytemacrophage colony stimulating factor; GM-CS F); Leukine; Oprelvekin (interleukinll; IL11); Neumega; Human follicle-stimulating hormone (FSH); Gonal-F; Follistim; Human chorionic gonadotropin (HCG); Ovidrel; Luveris; Type I alpha-interferon; interferon alfacon 1; consensus interferon; Infergen; Interferon-a2a (IFNa2a); Roferon-A; Peglnterferon-a2a; Pegasys; Interferon-a2b (IFNa2b); Intron A; Peglnterferon-a2b; Peg-Intron; Interferon-an3 (IFNan3); Alferon N; Interferon-β1a (rIFN-β); Avonex; Rebif; Interferon-β1b (rIFN-β); Betaseron; Interferon-γ1b (IFNγ); Actimmune; Aldesleukin (interleukin 2 (IL2); epidermal thymocyte activating factor; ETAF); Proleukin; Alteplase (tissue plasminogen activator; tPA); Activase; Reteplase (deletion mutein of tPA); Retavase; Tenecteplase; TNKase; Urokinase; Abbokinase; Factor Vila; NovoSeven; Drotrecogin-α (activated protein C); Xigris; Salmon calcitonin; Fortical; Miacalcin; Teriparatide (human parathyroid hormone residues 1-34); Forteo; Exenatide; Byetta; Octreotide; Sandostatin; Dibotermin-α (recombinant human bone morphogenic protein 2; rhBMP2); Infuse; Recombinant human bone morphogenic protein 7 (rhBMP7); Osteogenic protein 1; Histrelin acetate (gonadotropin releasing hormone; GnRH); Supprelin LA; Vantas; Palifermin (keratinocyte growth factor KGF); kepivance; Becaplermin (platelet-derived growth factor; PDGF); Regranex; Trypsin; Granulex; Nesiritide; Natrecor; Botulinum toxin type A; Botox; Botulinum toxin type B; Myoblock; Collagenase; Santyl; Human deoxy-ribonuclease I; dornase-α; pulmozyme; Hyaluronidase (bovine, ovine); Amphadase (bovine); hydase (bovine); Vitrase (ovine); Hyaluronidase (recombinant human); hylenex; Papain; accuzyme; panafil; L-asparaginase; ELSPAR; Peg-asparaginase; Oncaspar; Rasburicase; Elitek; Lepirudin; Refludan; Bivalirudin; Angiomax; Streptokinase; Streptase; Anistreplase (anisoylated plasminogenstreptokinase activator complex; APSAC); Eminase; Bevacizumab; Avastin; Cetuximab; Erbitux; Panitumumab; Vectibix; Alemtuzumab; Campath; Rituximab; Rituxan; Trastuzumab; Herceptin; Abatacept; Orencia; Anakinra; Antril; Kineret; Abalimumab; Humira; Etanercept; Enbrel; Infliximab; Remicade; Alefacept; Amevive; Natalizumab; Tysabri; Eculizumab; Soliris; Antithymocyte globulin (rabbit); Thymoglobulin; Basiliximab; Simulect; Daclizumab; Zenapax; Muromonab-CD3; Orthoclone; OKT3; Omalizumab; Xolair; Palivizumab; Synagis; Enfuvirtide; Fuzeon; Abciximab; ReoPro; Pegvisomant; Somavert; Crotalidae polyvalent immune Fab (ovine); Crofab; Digoxin immune serum Fab (ovine); Digifab; Ranibizumab; Lucentis; Denileukin; Diftitox; Ontak; Ibritumomab; Tiuxetan; Zevalin; Gemtuzumab; Ozogamicin; Mylotarg; Tositumomab and I-tositumomab; Bexxar; Bexxar 1-131; Hepatitis B surface antigen (HBsAg); Engerix; Recombivax HB; HPV vaccine; Gardasil; OspA; LYMErix; Anti-Rhesus (Rh) immunoglobulin G; Rhophylac; Recombinant purified protein derivative (DPPD); Glucagon; GlucaGen; Growth hormone releasing hormone (GHRH); Geref; Secretin; ChiRhoStim (human peptide), SecreFlo (porcine peptide); Thyroid stimulating hormone (TSH); thyrotropin; Capromab pendetide; ProstaScint; Indium-lll-octreotide; OctreoScan; Satumomab pendetide; OncoScint; Arcitumomab; CEA-scan; Nofetumomab; Verluma; Apcitide; Acutect; Imciromab pentetate; Myoscint; Technetium fanolesomab; NeutroSpec; HIV antigens; Enzyme immunoassay; OraQuick; Uni-Gold; Hepatitis C antigens; Evolocumab, certolizumab pegol, Golimumab, Mepolizumab, Benralizumab, Reslizumab, Tezepelumab-ekko, Adalimumab, Dupilumab, Pembrolizumab, Zymfentra, or Recombinant immunoblot assay (RIBA); preferably, the biological molecule is Bevacizumab, Rituximab, Cetuximab, Etanercept, Infliximab, Omalizumab, or Evolocumab.

[0017] In some embodiments, the compound is in a salt form and in particular in the compound, R4 and R are each independently, -[CH2C(=O)O-][Na+], -[CH2C(=O)O-][K+], -[CH2C(=O)O-]2[Ca2+], -[CH2C(=O)O-]2[Cu2+], -[CH2C(=O)O-]2[Fe2+], -[CH2C(=O)O-]3[Fe3+], -[CH2C(=O)O-]2[Mg2+], or -[CH2C(=O)O-]2[Zn2+].

[0018] In some embodiments, the compound is in a salt form and in particular in the compound, A is [O’][Na+], -[O’][K+], -[O-]2[Ca2+], -[O-]2[Cu2+], -[O-]2[Fe2+], -[O-]3[Fe3+], -[O-]2[Mg2+], or -[ O’ ]2[Zn2+],

[0019] In some embodiments, the compound has the following structure:

[0020] In some embodiments, wherein in the compound,(a) one of R4and R5is H, or -CH3;(b) m is 0-5; more preferably, m is 0 or 1; and / or(c) n is 0-5; more preferably, n is 0 or 1.

[0021] In some embodiments, wherein in the compound, R1isor COOHcoon ■ preferably, R1is

[0022] In some embodiments, wherein in the compound, R1is

[0023] In some embodiments, wherein in the compound, R1is

[0024] In some embodiments, wherein in the compound, R2is -OH or -N(H)C(=O)CH3; preferably, R2is -OH.

[0025] In some embodiments, the compound has the structure:R2is -OH, -N3, or -N(H)C(=O)CH3

[0026] In some embodiments, the compound has the structure:R2is -OH, -N3, or -N(H)C(=O)CH3

[0027] In some embodiments, the compound has the structure:wherein R1isCOOHR2is -OH, -N3, or -N(H)C(=O)CH3

[0028] In some embodiments, the compound has the structure:whereinR1is -OC(H)(R4)(CH2)nC(=O)OH;R2is -OH, -N3, or -N(H)C(=O)CH3;R4is -H, -CH3, -CH2OH, or CH2C(=O)OH; andn is 0 or 1.

[0029] In some embodiments, the compound has the structure:whereinR1is -OC(H)(R4)(CH2)nC(=O)OH;R2is -OH, -N3, or -N(H)C(=O)CH3;R4is -H, -CH3, -CH2OH, or CH2C(=O)OH; andn is 0 or 1.

[0030] In some embodiments, when the compound isR1, and R2is OH, R4is CH3, R5is H, and n is 0, then the compound is

[0031] In some embodiments, when the compound is

[0032] In some embodiments, when the compound isR1, and R2is OH, R4is CH2OH, R5is H, and n is 0, then the compound is

[0033] In some embodiments, the compound has the structure:

[0034] In some embodiments, the compound has the structure:

[0035] In some embodiments, the compound has the structure:

[0036] In some embodiments, the compound has the following structure:whereinR2is -N(H)C(=O)CH3;one of R4and R5is H, the other is H, -CH3, -CH2OH, or CH2C(=O)OH;Y is H;Z is H;m is 0-5;n is 0-5;A is -OH or -ONH2.

[0037] In some embodiments, the compound is in a salt form and in particular in the compound, A is [O’][Na+], -[O’][K+], -[O-]2[Ca2+], -[O-]2[Cu2+], -[O-]2[Fe2+], -[O-]3[Fe3+], -[O’]2[Mg2+], or -[ O’ ]2[Zn2+],

[0038] In some embodiments, the compound isCO2Na’

[0039] In some embodiments, the compound isorCH3, or a salt thereof.

[0040] In some embodiments, the compound is

[0041] In some embodiments, the compound is

[0043] In some embodiments, the salt of the compound isOH

[0044] In some embodiments, the salt of the compound is

[0045] In some embodiments, the compound has the structure:OH

[0049] In some embodiments, the salt of the compound is

[0051] In some embodiments, the compound is

[0052] In some embodiments, the compound is

[0054] In some embodiments, the salt of the compound isCO2K+

[0055] In some embodiments, the salt of the compound is

[0056] The present invention provides a composition comprising a biological molecule and at least one compound or a salt thereof, wherein the compound has the following structure:„coRK / RX^^(CYZ^ / XAwhereinX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide; each of R4and R5is independently H, halogen, OH, O-alkyl, CONH2, CO2H, CO2-alkyl. or optionally substituted alkyl;each of Y and Z is independently H, OH, O-alkyl or optionally substituted alkyl;m is 0, 1 or 2;A =-OR6or -NR7R8,wherein R6is H,-NH2, or optionally substituted alkyl; and each of R7and R8is independently H, OH, O-alkyl or optionally substituted alky; andwherein the biological molecule is Bevacizumab, Rituximab, Cetuximab, Etanercept, Infliximab, Omalizumab, or Evolocumab.

[0057] In some embodiments, the compound is in a salt form and in particular in the compound, R4and R5are each independently, -[CH2C(=O)O-][Na+], -[CH2C(=O)O-][K+], -[CH2C(=O)O-]2[Ca2+], -[CH2C(=O)O-]2[Cu2+], -[CH2C(=O)O-]2[Fe2+], -[CH2C(=O)O-]3[Fe3+], -[CH2C(=O)O-]2[Mg2+], or -[CH2C(=O)O-]2[Zn2+].

[0058] In some embodiments, the compound is in a salt form and in particular in the compound, A is [O’][Na+], -[O'][K+], -[O-]2[Ca2+], -[O-]2[Cu2+], -[O-]2[Fe2+], -[O-]3[Fe3+], -[O-]2[Mg2+], or -[ O’ ]2[Zn2+],

[0059] In some embodiments, wherein in the compound,when X is glucosyl, then R4is optionally substituted alkyl,when each of R4and R5is H and m is 0, then X is other than glucuronic acid, and wherein when X is glucosyl or mannosyl, m=0, one of R4or R5is -alkyl-OH and the other is -H, and A is -NH2, then the compound is a beta-anomer.

[0060] In some embodiments, the compound has the structure:„coR\ / RX^^^^(CYZ)^^NR7R8whereinX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl,each of R4and R5is independently H, halogen, OH, O-alkyl, CONH2, or optionally substituted alkyl,each of R7and R8is independently H, OH, O-alkyl or optionally substituted alkyl, each of Y and Z is independently H, OH, O-alkyl or optionally substituted alkyl, m is 0, 1 or 2, andwhen X is glucosyl, then R4is optionally substituted alkyl.

[0061] In some embodiments, the compound has the structure:„coR\ / RX^^^^(CYZ)^^N R7R8whereineach of R4and R5is independently H, OH, O-alkyl or optionally substituted alkyl, each of R7and R8is independently H, OH, O-alkyl or optionally substituted alkyl.

[0062] In some embodiments, wherein in the compound, X is glucosyl, mannosyl or galactosyl; preferably, X is glucosyl or galactosyl.

[0063] In some embodiments, wherein in the compound, each of Y and Z is H.

[0064] In some embodiments, wherein in the compound, each of R4and R5is H, or R4is CH3 and R5is H, or R4is CONH2 and R5is H or R1is CO2CH3 and R2is H.

[0065] In some embodiments, wherein in the compound, each of R7and R8is H.

[0066] In some embodiments, the compound has the structure:OHwherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0067] In some embodiments, the compound has the structure:wherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0068] In some embodiments, the compound has the structure:OHwherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0069] In some embodiments, the hexosyl group is an alpha-anomer.

[0070] In some embodiments, the hexosyl group is a beta-anomer.

[0071] In some embodiments, the compound has the structure:wherein R4is H, CONH2 or optionally substituted alkyl.

[0072] In some embodiments, the compound has the structure:

[0073] In some embodiments, the compound has the structure:

[0074] In some embodiments, the compound has the structure:

[0075] In some embodiments, the compound has the structure:

[0076] In some embodiments, the compound has the structure:OH

[0077] In some embodiments, the compound has the structure:whereinX is an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, a galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, each of R4and R5is independently H, halogen, OH, O-alkyl, CONH2, CO2H, CO2-alkyl. or optionally substituted alkyl;each of Y and Z is independently H, OH, O-alkyl or optionally substituted alkyl,R6is independently H, NH2, or optionally substituted alkyl,m is 0, 1 or 2, and when each of R4and R5is H and m is 0, then X is other than glucuronic acid.

[0078] In some embodiments, wherein in the compound, X is glucuronic acid, mannuronic acid or galacturonic acid.

[0079] In some embodiments, wherein in the compound, each of Y and Z is H.

[0080] In some embodiments, the compound has the structure:whereinR4is H, optionally substituted alkyl or CO2H;R6is H; andm is 0, 1 or 2.

[0081] In some embodiments, the compound has the structure:OHwhereinR4is H, optionally substituted alkyl or CO2H;R6is H; andm is 0, 1 or 2.

[0082] In some embodiments, the compound has the structure:whereinR4is H, optionally substituted alkyl or CO2H;R6is H; andm is 0, 1 or 2.

[0083] In some embodiments, wherein in the compound, the uronic acid group is an alpha-anomer.

[0084] In some embodiments, wherein in the compound, the uronic acid group is a beta-anomer.

[0085] In some embodiments, the compound has the structure:

[0086] In some embodiments, the compound has the structure:

[0087] In some embodiments, the compound has the structure:OH H

[0088] In some embodiments, the compound has the structure:

[0089] In some embodiments, the salt of the compound has the structure:

[0090] In some embodiments, the salt of the compound has the structure:

[0091] In some embodiments, the compound is a sodium salt, iron salt, cooper salt, aluminum salt, potassium salt, calcium salt or magnesium salt.

[0092] In some embodiments, the compound is a sodium salt, potassium salt, calcium salt or magnesium salt; preferably a sodium salt or potassium salt.

[0093] In some embodiments, the compound has the structure:whereinX is a uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide;each of R4and R5is independently H, halogen, OH, O-alkyl, CONH2, CO2H, CO2-alkyl. or optionally substituted alkyl;each of Y and Z is independently H, OH, O-alkyl or optionally substituted alkyl;m is 0, 1 or 2; andA = NR7R8,wherein each of R7and R8is independently H, OH, O-alkyl or optionally substituted alkyl.

[0094] In some embodiments, the compound has the structure:wherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0095] In some embodiments, the compound has the structure:OHwherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0096] In some embodiments, the compound has the structure:wherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0097] In some embodiments, wherein in the compound, the uronic acid amide group is an alphaanomer.

[0098] In some embodiments, wherein in the compound, the uronic acid amide group is a beta-anomer.

[0099] In some embodiments, the compound has the structure:wherein R4is H, optionally substituted alkyl or CONH2.

[0100] In some embodiments, the compound has the structure:

[0101] In some embodiments, the compound has the structure:

[0102] In some embodiments, the composition further comprises a buffer.

[0103] In some embodiments, the composition is acidic.

[0104] In some embodiments, the composition has a pH less than 6.8.

[0105] In some embodiments, the composition has a pH less than 4.

[0106] In some embodiments, the composition has a pH around 3.

[0107] In some embodiments, the composition has a pH between 5 and 7.

[0108] In some embodiments, the composition is basic.

[0109] In some embodiments, the composition has a pH more than 7.2.

[0110] In some embodiments, the composition has a pH more than 10.

[0111] In some embodiments, the composition has a pH around 12.

[0112] In some embodiments, the composition has a pH between 7 and 8.

[0113] In some embodiments, the composition has a pH less than 12.

[0114] In some embodiments, the composition has a pH greater than 3.

[0115] In some embodiments, the composition has a pH greater than 3 and less than 12.

[0116] In some embodiments, the composition is acidic, preferably, the composition has a pH less than 6.8; more preferably, a pH between 5 and 7, more preferably, a pH less than 4, more preferably, a pH around 3.

[0117] In some embodiments, the composition is basic, preferably, the composition has a pH more than 7.2; more preferably, a pH between 7 and 8, more preferably, a pH more than 10, more preferably, a pH around 12.

[0118] In some embodiments, the biological molecule is present at a concentration from 0.1 mg / mL to about 2000 mg / mL; preferably from 10 mg / mL to 2000 mg / mL; more preferably, from 20 mg / mL to 2000 mg / mL; more preferably, from 30 mg / mL to 2000 mg / mL; more preferably, from 40 mg / mL to 2000 mg / mL; more preferably, from 50 mg / mL to 2000 mg / mL; more preferably, from 50 mg / mL to 1500 mg / mL; more preferably, from 50 mg / mL to 1000 mg / mL; more preferably, from 50 mg / mL to 800 mg / mL; more preferably, from 50 mg / mL to 600 mg / mL; more preferably, from 50 mg / mL to 300 mg / mL; more preferably, from 50 mg / mL to 200 mg / mL; more preferably, from 50 mg / mL to 180 mg / mL; more preferably, from 60 mg / mL to 160 mg / mL; more preferably, from 80 mg / mL to 160 mg / mL; more preferably, from 100 mg / mL to 160 mg / mL; more preferably, from 120 mg / mL to 160 mg / mL; from 140 mg / mL to 160 mg / mL.

[0119] In some embodiments, the compound is present at a concentration from 0.1 mM to about 2000mM; preferably from 10mM to 2000mM; more preferably, from 20mM to 2000mM; more preferably, from 30mM to 2000mM; more preferably, from 40mM to 2000mM; more preferably, from 50mM to 2000mM; more preferably, from 50mM to 1500mM; more preferably, from 50mM to 1000mM; more preferably, from 50mM to 800mM; more preferably, from 50mM to 600mM; more preferably, from 50mM to 300mM; more preferably, from 50mM to 200mM; more preferably, from 50mM to 180mM; more preferably, from 60mM to 160mM; more preferably, from 80 mM to 140mM; more preferably, from 80 mM to 130mM; more preferably, from 80 mM to 120mM; more preferably from 90 mM to 110mM; more preferably, 100mM.

[0120] In some embodiments, the composition is freeze dried, lyophilized, a solution, a liquid, a solid or a suspension.

[0121] In some embodiments, the compound is present at a concentration between about 0.1 mM to about 5 M.

[0122] In some embodiments, the compound is present at a concentration between about 0.01 M to about IM.

[0123] In some embodiments, the compound is present at a concentration between about 0.1 mM to about 5 M.

[0124] In some embodiments, the compound is present at a concentration from about 100 mM to about 200mM.

[0125] In some embodiments, the compound is present at a concentration between about 100 mM or about 200mM.

[0126] In some embodiments, the biological molecule is present at a concentration from about 100 mg / mL to about 200 mg / mL.

[0127] In some embodiments, the biological molecule is present at a concentration from about 150 mg / mL to about 180 mg / mL.

[0128] The present invention also provides a pharmaceutical composition comprising the compound disclosed herein.

[0129] The present invention provides a method of reducing the viscosity of a biological molecule solution or suspension, comprising adding at least one compound of the following structure to the biological molecule solution:. RR‘OHFormula Iwherein, R5one of R4and R5is H, the other is H, -CH3, -CH2OH, or CH2C(=O)OH;Y is H;Z is H;m is 0 or 1;A is OH, -CONH2, -O-NH2, -CO2NH2,- NH2, -OR6, or -NR7R8;wherein R6is H, -NH2, or optionally substituted alkyl; and R7and R8are each independently H, OH, O-alkyl or optionally substituted alkyl;R2is -OH, -N3, or -N(H)C(=O)CH3; orR1and R2together with the carbon atoms to which they are attached formHN OR3wherein R3is -H, -CH3, -CH2C(=O)OH, or -CH2OH.

[0130] In some embodiments, the compound is in a salt form and in particular in the compound, R4and R5are each independently, -[CH2C(=O)O-][Na+], -[CH2C(=O)O-][K+], -[CH2C(=O)O-]2[Ca2+], -[CH2C(=O)O-]2[Cu2+], -[CH2C(=O)O-]2[Fe2+], -[CH2C(=O)O-]3[Fe3+], -[CH2C(=O)O-]2[Mg2+], or -[CH2C(=O)O-]2[Zn2+].

[0131] In some embodiments, the compound is in a salt form and in particular in the compound, A is [O’][Na+], -[O’][K+], -[O-]2[Ca2+], -[O-]2[Cu2+], -[O-]2[Fe2+], -[O-]3[Fe3+], -[O-]2[Mg2+], or -[ O’ ]2[Zn2+],

[0132] In some embodiments, the compound has the following structure:

[0133] In some embodiments, wherein in the compound,(a) one of R4and R5is H, or -CH3;(b) m is 0-5; more preferably, m is 0 or 1; and / or(c) n is 0-5; more preferably, n is 0 or 1.

[0134] In some embodiments, wherein in the compound, R1is

[0135] In some embodiments, wherein in the compound, R1is

[0136] In some embodiments, wherein in the compound, R1is

[0137] In some embodiments, wherein in the compound, R2is -OH or -N(H)C(=O)CH3; preferably, R2is -OH.

[0138] In some embodiments, the compound has the structure:R2is -OH, -N3, or -N(H)C(=O)CH3

[0139] In some embodiments, the compound has the structure:wherein R1isCOOH'COOHR2is -OH, -N3, or -N(H)C(=O)CH3

[0140] In some embodiments, the compound has the structure:R2is -OH, -N3, or -N(H)C(=O)CH3

[0141] In some embodiments, the compound has the structure:whereinR1is -OC(H)(R4)(CH2)nC(=O)OH;R2is -OH, -N3, or -N(H)C(=O)CH3;R4is -H, -CH3, -CH2OH, or CH2C(=O)OH; andn is 0 or 1.

[0142] In some embodiments, the compound has the structure:whereinR1is -OC(H)(R4)(CH2)nC(=O)OH;R2is -OH, -N3, or -N(H)C(=O)CH3;R4is -H, -CH3, -CH2OH, or CH2C(=O)OH; andn is 0 or 1.

[0143] In some embodiments, when the compound isR1, and R2is OH, R4is CH3, R5is H, and n is 0, then the compound is

[0144] In some embodiments, when the compound is

[0145] In some embodiments, when the compound isR1, and R2is OH, R4is CH2OH, R5is H, and n is 0, then the compound is

[0146] In some embodiments, the compound has the structure:

[0147] In some embodiments, the compound has the structure:OH

[0148]

[0149]

[0150] In some embodiments, the salt of the compound isOH

[0151] In some embodiments, the compound has the structure:

[0152] In some embodiments, the compound is

[0153] In some embodiments, the compound isOH

[0154] In some embodiments, the salt of the compound is

[0155] In some embodiments, the salt of the compound isOH

[0156] In some embodiments, the compound is

[0157] In some embodiments, the compound is

[0160] In some embodiments, the salt of the compound isOHHer \ I \HO -O CO2 Na

[0161] The present invention provides a method of reducing the viscosity of a biological molecule solution or suspension, comprising adding at least one compound, or a salt thereof, of the following structure to the biological molecule solution:„coR\ / RwhereinX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide; each of R4and R5is independently H, halogen, OH, O-alkyl, CONH2, CO2H, CO2-alkyl. or optionally substituted alkyl;each of Y and Z is independently H, OH, O-alkyl or optionally substituted alkyl;m is 0, 1 or 2;A =-0R6or -NR7R8,wherein R6is H, -NH2, or optionally substituted alkyl; and each of R7and R8is independently H, OH, O-alkyl or optionally substituted alkyl.

[0162] In some embodiments, the compound is in a salt form and in particular in the compound, R4and R5are each independently, -[CH2C(=O)O-][Na+], -[CH2C(=O)O-][K+], -[CH2C(=O)O-]2[Ca2+], -[CH2C(=O)O-]2[Cu2+], -[CH2C(=O)O-]2[Fe2+], -[CH2C(=O)O-]3[Fe3+], -[CH2C(=O)O-]2[Mg2+], or -[CH2C(=O)O-]2[Zn2+].

[0163] In some embodiments, the compound is in a salt form and in particular in the compound, A is [O’][Na+], -[O-][K+], -[O-]2[Ca2+], -[O-]2[Cu2+], -[O’]2[Fe2+], -[O-]3[Fe3+], -[O’]2[Mg2+], or -[ O’ ]2[Zn2+],

[0164] In some embodiments, wherein in the compound,when X is glucosyl, then R4is optionally substituted alkyl,when each of R4and R5is H and m is 0, then X is other than glucuronic acid, and wherein when X is glucosyl or mannosyl, m=0, one of R4or R5is -alkyl-OH and the other is -H, and A is -NH2, then the compound is a beta-anomer.

[0165] In some embodiments, the compound has the structure:„coRK / RX^^^^(CYZ)Yr^N R7R8whereinX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl,each of R4and R5is independently H, halogen, OH, O-alkyl, CONH2, or optionally substituted alkyl,each of R7and R8is independently H, OH, O-alkyl or optionally substituted alkyl, each of Y and Z is independently H, OH, O-alkyl or optionally substituted alkyl, m is 0, 1 or 2, andwhen X is glucosyl, then R4is optionally substituted alkyl.

[0166] In some embodiments, the compound has the structure:A0R\ zRR7R8whereineach of R4and R5is independently H, OH, O-alkyl or optionally substituted alkyl, each of R7and R8is independently H, OH, O-alkyl or optionally substituted alkyl.

[0167] In some embodiments, wherein in the compound, X is glucosyl, mannosyl or galactosyl; preferably, X is glucosyl or galactosyl.

[0168] In some embodiments, wherein in the compound, each of Y and Z is H.

[0169] In some embodiments, wherein in the compound, each of R4and R5is H, or R4is CH3 and R5is H, or R4is CONH2 and R5is H or R1is CO2CH3 and R2is H.

[0170] In some embodiments, wherein in the compound, each of R7and R8is H.

[0171] In some embodiments, the compound has the structure:wherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0172] In some embodiments, the compound has the structure:wherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0173] In some embodiments, the compound has the structure:OHwherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0174] In some embodiments, the hexosyl group is an alpha-anomer.

[0175] In some embodiments, the hexosyl group is a beta-anomer.

[0176] In some embodiments, the compound has the structure:wherein R4is H, CONH2 or optionally substituted alkyl.

[0177] In some embodiments, the compound has the structure:

[0178] In some embodiments, the compound has the structure:

[0179] In some embodiments, the compound has the structure:

[0180] In some embodiments, the compound has the structure:

[0181] In some embodiments, the compound has the structure:whereinX is an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, a galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, each of R4and R5is independently H, halogen, OH, O-alkyl, CONH2, CO2H, CO2-alkyl. or optionally substituted alkyl;each of Y and Z is independently H, OH, O-alkyl or optionally substituted alkyl,R6is independently H, -NH2, or optionally substituted alkyl,m is 0, 1 or 2, and when each of R4and R5is H and m is 0, then X is other than glucuronic acid.

[0182] In some embodiments, wherein in the compound, X is glucuronic acid, mannuronic acid or galacturonic acid.

[0183] In some embodiments, wherein in the compound, each of Y and Z is H.

[0184] In some embodiments, the compound has the structure:whereinR4is H, optionally substituted alkyl or CO2H;R6is H; andm is 0, 1 or 2.

[0185] In some embodiments, the compound has the structure:OHwhereinR4is H, optionally substituted alkyl or CO2H;R6is H; andm is 0, 1 or 2.

[0186] In some embodiments, the compound has the structure:whereinR4is H, optionally substituted alkyl or CO2H;R6is H; andm is 0, 1 or 2.

[0187] In some embodiments, wherein in the compound, the uronic acid group is an alpha-anomer.

[0188] In some embodiments, wherein in the compound, the uronic acid group is a beta-anomer.

[0189] In some embodiments, the compound has the structure:CO2H, or

[0190] In some embodiments, the compound has the structure:In some embodiments, the compound has the structure:

[0191] OH

[0192] In some embodiments, the compound has the structure:

[0193] In some embodiments, the salt of the compound has the structure:

[0194] In some embodiments, the compound is a sodium salt, iron salt, cooper salt, aluminum salt, potassium salt, calcium salt or magnesium salt.

[0195] In some embodiments, the compound is a sodium salt, potassium salt, calcium salt or magnesium salt.

[0196] In some embodiments, the compound has the structure:whereinX is a uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide;each of R4and R5is independently H, halogen, OH, O-alkyl, CONH2, CO2H, CO2-alkyl. or optionally substituted alkyl;each of Y and Z is independently H, OH, O-alkyl or optionally substituted alkyl;m is 0, 1 or 2; andA = NR7R8,wherein each of R7and R8is independently H, OH, O-alkyl or optionally substituted alkyl.

[0197] In some embodiments, the compound has the structure:wherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0198] In some embodiments, the compound has the structure:OHwherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0199] In some embodiments, the compound has the structure:wherein R4is H, optionally substituted alkyl, or CONH2 and m is 0, 1 or 2.

[0200] In some embodiments, wherein in the compound, the uronic acid amide group is an alphaanomer.

[0201] In some embodiments, wherein in the compound, the uronic acid amide group is a beta-anomer.

[0202] In some embodiments, the compound has the structure:wherein R4is H, optionally substituted alkyl or CONH2.

[0203] In some embodiments, the compound has the structure:

[0204] In some embodiments, the compound has the structure:

[0205] In some embodiments, the biological molecule is a biopharmaceutical, protein, peptide, nucleotide, nucleic acids, polypeptide, virus, vaccines, gene therapy, antibody, antibody drug conjugate or bispecific antibody.

[0206] In some embodiments, the biological molecule is a biopharmaceutical.

[0207] In some embodiments, the biological molecule is a nucleotide.

[0208] In some embodiments, the biological molecule is a peptide.

[0209] In some embodiments, the biological molecule is a polypeptide.

[0210] In some embodiments, the biological molecule is a virus.

[0211] In some embodiments, the biological molecule is gene therapy.

[0212] In some embodiments, the biological molecule is an antibody.

[0213] In some embodiments, the biological molecule is an antibody drug conjugate.

[0214] In some embodiments, the biological molecule is an antibody.

[0215] In some embodiments, the biological molecule is a bispecific antibody.

[0216] In some embodiments, the biological molecule is a mixture of any one of biopharmaceutical, protein, nucleotide, peptide, polypeptide, virus, vaccines, gene therapy, antibody, antibody drug conjugate, and bispecific antibody.

[0217] In some embodiments, the biological molecule is Insulin; Humulin; Novolin; Insulin human inhalation; Exubera; Insulin aspart; Novolog (aspart); Insulin glulisine; Apidra (glulisine); Insulin lispro; Humalog (lispro); Isophane insulin; NPH; Insulin detemir; Levemir (detemir); Insulin glargine; Lantus (glargine); Insulin zinc extended; Lente; Ultralente; Pramlintide acetate; Symlin; Growth hormone (GH);somatotropin; genotropin; humatrope; norditropin; NorIVitropin; Nutropin; Omnitrope; Protropin; Saizen; Serostim; Valtropin; Mecasermin; Increlex; Mecasermin rinfabate; IPlex; Factor VIII; Bioclate; Helixate; Kogenate; Recominate; ReFacto; Factor IX; Benefix; Antithromin III (AT-III); Thrombate III; Protein C concentrate; Ceprotin; P-Glucocerebrosidase; Cerezyme; -Glucocerebrosidase; Ceredase (purified from pooled human placenta); Alglucosidase-a; Myozyme; Laronidase (a-l-iduronidase); Aldurazyme; Idursulphase (Iduronate-2-sulphatase); Elaprase; Galsulphase; Naglazyme; Agalsidase-P (human a-galactosidase A); Fabrazyme; a- 1 -Proteinase inhibitor; Aralast; Prolastin; Lactase; Lactaid; Pancreatic enzymes (lipase, amylase, protease); Arco-Lase, Cotazym, Creon, Donnazyme, Pancrease, Viokase, Zymase, Adenosine deaminase (pegademase bovine, PEG-ADA); Adagen; Pooled immunoglobulins; Octagam; Human albumin; Albumarc; Albumin; Albuminar; AlbuRx; Albutein; Flexbumin; Buminate; Plasbumin; Erythropoietin; Epoetin-a; Epogen; Procrit; Darbepoetin-a; Aranesp; Filgrastim (granulocyte colony stimulating factor; G-CS F); Neupogen; Pegfilgrastim (Peg-G-CSF); Neulasta; Sargramostim (granulocytemacrophage colony stimulating factor; GM-CS F); Leukine; Oprelvekin (interleukin 11; IL11); Neumega; Human follicle-stimulating hormone (FSH); Gonal-F; Follistim; Human chorionic gonadotropin (HCG); Ovidrel; Luveris; Type I alpha-interferon; interferon alfacon 1; consensus interferon; Infergen; Interferon-a2a (IFNa2a); Roferon-A; Peglnterferon-a2a; Pegasys; Interferon-a2b (IFNa2b); Intron A; Peglnterferon-a2b; Peg-Intron; Interferon-an3 (IFNan3); Alferon N; Interferon-β1a (rIFN-β); Avonex; Rebif; Interferon-β1b (rIFN-β); Betaseron; Interferon-γ1b (IFNγ); Actimmune; Aldesleukin (interleukin 2 (IL2); epidermal thymocyte activating factor; ETAF); Proleukin; Alteplase (tissue plasminogen activator; tPA); Activase; Reteplase (deletion mutein of tPA); Retavase; Tenecteplase; TNKase; Urokinase; Abbokinase; Factor Vila; NovoSeven; Drotrecogin-α (activated protein C); Xigris; Salmon calcitonin; Fortical; Miacalcin; Teriparatide (human parathyroid hormone residues 1-34); Forteo; Exenatide; Byetta; Octreotide; Sandostatin; Dibotermin-α (recombinant human bone morphogenic protein 2; rhBMP2); Infuse; Recombinant human bone morphogenic protein 7 (rhBMP7); Osteogenic protein 1; Histrelin acetate (gonadotropin releasing hormone; GnRH); Supprelin LA; Vantas; Palifermin (keratinocyte growth factor KGF); kepivance; Becaplermin (platelet-derived growth factor; PDGF); Regranex; Trypsin; Granulex; Nesiritide; Natrecor; Botulinum toxin type A; Botox; Botulinum toxin type B; Myoblock; Collagenase; Santyl; Human deoxy-ribonuclease I; dornase-α; pulmozyme; Hyaluronidase (bovine, ovine); Amphadase (bovine); hydase (bovine); Vitrase (ovine); Hyaluronidase (recombinant human); hylenex; Papain; accuzyme; panafil; L-asparaginase; ELSPAR; Peg-asparaginase; Oncaspar; Rasburicase; Elitek; Lepirudin; Refludan; Bivalirudin; Angiomax; Streptokinase; Streptase; Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC); Eminase; Bevacizumab; Avastin; Cetuximab; Erbitux; Panitumumab; Vectibix; Alemtuzumab; Campath; Rituximab; Rituxan; Trastuzumab; Herceptin; Abatacept; Orencia; Anakinra; Antril; Kineret; Abalimumab; Humira; Etanercept; Enbrel; Infliximab;Remicade; Alefacept; Amevive; Natalizumab; Tysabri; Eculizumab; Soliris; Antithymocyte globulin (rabbit); Thymoglobulin; Basiliximab; Simulect; Daclizumab; Zenapax; Muromonab-CD3; Orthoclone; OKT3; Omalizumab; Xolair; Palivizumab; Synagis; Enfuvirtide; Fuzeon; Abciximab; ReoPro; Pegvisomant; Somavert; Crotalidae polyvalent immune Fab (ovine); Crofab; Digoxin immune serum Fab (ovine); Digifab; Ranibizumab; Lucentis; Denileukin; Diftitox; Ontak; Ibritumomab; Tiuxetan; Zevalin; Gemtuzumab; Ozogamicin; Mylotarg; Tositumomab and I-tositumomab; Bexxar; Bexxar 1-131; Hepatitis B surface antigen (HBsAg); Engerix; Recombivax HB; HPV vaccine; Gardasil; OspA; LYMErix; AntiRhesus (Rh) immunoglobulin G; Rhophylac; Recombinant purified protein derivative (DPPD); Glucagon; GlucaGen; Growth hormone releasing hormone (GHRH); Geref; Secretin; ChiRhoStim (human peptide), SecreFlo (porcine peptide); Thyroid stimulating hormone (TSH); thyrotropin; Capromab pendetide; ProstaScint; Indium-lll-octreotide; OctreoScan; Satumomab pendetide; OncoScint; Arcitumomab; CEA-scan; Nofetumomab; Verluma; Apcitide; Acutect; Imciromab pentetate; Myoscint; Technetium fanolesomab; NeutroSpec; HIV antigens; Enzyme immunoassay; OraQuick; Uni-Gold; Hepatitis C antigens; Evolocumab, certolizumab pegol, Golimumab, Mepolizumab, Benralizumab, Reslizumab, Tezepelumab-ekko, Adalimumab, Dupilumab, Pembrolizumab, Zymfentra, or Recombinant immunoblot assay (RIBA).

[0218] In some embodiments, the biological molecule is in an emulsion.

[0219] In some embodiments, the biological molecule is Bevacizumab, Rituximab, Cetuximab, Etanercept, Infliximab, Omalizumab, or Evolocumab.

[0220] In some embodiments, the biological molecule is a biologic TNF inhibitor; preferably, the biological molecule is Etanercept, certolizumab pegol, or Golimumab.

[0221] In some embodiments, the biological molecule is Etanercept.

[0222] In some embodiments, the biological molecule is a monoclonal antibody.

[0223] In some embodiments, the monoclonal antibody is humanized IgGl monoclonal antibody.

[0224] In some embodiments, the humanized IgGl monoclonal antibody is Omalizumab, Mepolizumab, Benralizumab, Reslizumab, or Tezepelumab-ekko.

[0225] In some embodiments, the humanized IgGl monoclonal antibody is Omalizumab.

[0226] In some embodiments, the biological molecule is a chimeric monoclonal antibody.

[0227] In some embodiments, the biological molecule is Infliximab, Adalimumab, or Zymfentra.

[0228] In some embodiments, the biological molecule is Infliximab.

[0229] In some embodiments, the biological molecule is a biologic TNF inhibitor.

[0230] In some embodiments, the biologic TNF inhibitor is Etanercept, certolizumab pegol, or Golimumab.

[0231] In some embodiments, the biologic TNF inhibitor is Etanercept.

[0232] In some embodiments, the biological molecule is a monoclonal antibody.

[0233] In some embodiments, the monoclonal antibody is humanized IgGl monoclonal antibody.

[0234] In some embodiments, the humanized IgGl monoclonal antibody is Evolocumab, Omalizumab, Mepolizumab, Bevacizumab, Reslizumab, or Tezepelumab-ekko.

[0235] In some embodiments, the humanized IgGl monoclonal antibody is Evolocumab or Omalizumab.

[0236] In some embodiments, the biological molecule is a chimeric monoclonal antibody.

[0237] In some embodiments, the chimeric monoclonal antibody is Infliximab, Adalimumab, or Zymfentra.

[0238] In some embodiments, the chimeric monoclonal antibody is Infliximab.

[0239] In some embodiments, the biological molecule is a monoclonal antibody.

[0240] In some embodiments, the monoclonal antibody is humanized IgGl monoclonal antibody.

[0241] In some embodiments, the humanized IgGl monoclonal antibody is Evolocumab, Mepolizumab, Benralizumab, Reslizumab, or Tezepelumab-ekko.

[0242] In some embodiments, the humanized IgGl monoclonal antibody is Evolocumab.

[0243] In some embodiments, the composition further comprises a buffer solution; preferably, the buffer is L-histidine monohydrochloride monohydrate, sodium phosphate monobasic monohydrate, sodium acetate anhydrous, sucrose, L-histidine, sodium phosphate dibasic heptahydrate, acetic acid glacial or phosphoric acid.

[0244] In some embodiments, when the biological molecule is a humanized IgGl monoclonal antibody, or biologic TNF inhibitor, the pH of the biological molecule solution or suspension is acidic, preferably, the pH of the biological molecule solution or suspension has a pH less than 6.8; more preferably, a pH between 4 and 7, more preferably, a pH between 5 and 6.

[0245] In some embodiments, when the biological molecule is a chimeric monoclonal antibody, the pH of the biological molecule solution or suspension is basic, preferably, the pH of the biological molecule solution or suspension has a pH more than 7; more preferably, a pH between 7 and 8.

[0246] In some embodiments, the biological molecule is present at a concentration from 0.1 mg / mL to about 2000 mg / mL; preferably from 10 mg / mL to 2000 mg / mL; more preferably, from 20 mg / mL to 2000 mg / mL; more preferably, from 30 mg / mL to 2000 mg / mL; more preferably, from 40 mg / mL to 2000 mg / mL; more preferably, from 50 mg / mL to 2000 mg / mL; more preferably, from 50 mg / mL to 1500 mg / mL; more preferably, from 50 mg / mL to 1000 mg / mL; more preferably, from 50 mg / mL to 800 mg / mL; more preferably, from 50 mg / mL to 600 mg / mL; more preferably, from 50 mg / mL to 300 mg / mL; more preferably, from 50 mg / mL to 200 mg / mL; more preferably, from 50 mg / mL to 180 mg / mL; more preferably, from 60 mg / mL to 160 mg / mL; more preferably, from 80 mg / mL to 160 mg / mL; more preferably, from 100 mg / mL to 160 mg / mL; more preferably, from 120 mg / mL to 160 mg / mL; from 140 mg / mL to 160 mg / mL.

[0247] In some embodiments, the compound is present at a concentration from 0.1 mM to about 2000mM; preferably from 10mM to 2000mM; more preferably, from 20mM to 2000mM; more preferably, from 30mM to 2000mM; more preferably, from 40mM to 2000mM; more preferably, from 50mM to 2000mM; more preferably, from 50mM to 1500mM; more preferably, from 50mM to 1000mM; more preferably, from 50mM to 800mM; more preferably, from 50mM to 600mM; more preferably, from 50mM to 300mM; more preferably, from 50mM to 200mM; more preferably, from 50mM to 180mM; more preferably, from 60mM to 160mM; more preferably, from 80 mM to 140mM; more preferably, from 80 mM to 130mM; more preferably, from 80 mM to 120mM; more preferably from 90 mM to 110mM; more preferably, 100mM.

[0248] In some embodiments, the molar ratio between the compound and the biological molecule is about 200:1, 100:1; 50:1; 25:1; 10:1; 5:1;2:1, 1:1, 1:2, 1:5; 1:10; 1:20; 1:25; 1:50; 1:100 or 1: 200.

[0249] In some embodiments, the composition is pharmaceutical composition.

[0250] In some embodiments, the composition remains stable for a period at a temperature from 4 °C to 30 °C.

[0251] In some embodiments, the composition remains stable for a period at a room temperature.

[0252] In some embodiments, the composition remains stable for 3 months at a temperature from 4 °C to 30 °C; preferably, 4-25 °C; more preferably 4 °C.

[0253] In some embodiments, the composition remains stable for 2 months at a temperature from 4 °C to 30 °C; preferably, 4-25 °C; more preferably 4 °C.

[0254] In some embodiments, the composition remains stable for 1 month at a temperature from 4 °C to 30 °C; preferably, 4-25 °C; more preferably 4 °C.

[0255] In some embodiments, the composition remains stable for 1 month at a temperature from 4 °C to 30 °C; preferably, 4-25 °C; more preferably 25 °C.

[0256] In some embodiments, the composition remains stable for 2 months at a temperature from 4 °C to 30 °C; preferably, 4-25 °C; more preferably 25 °C.

[0257] In some embodiments, the composition remains stable for 3 months at a temperature from 4 °C to 30 °C; preferably, 4-25 °C; more preferably 25 °C.

[0258] In some embodiments, the pharmaceutical composition is used for intravenous or subcutaneous injection or administration.

[0259] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%.

[0260] In some embodiments, any of the compositions or liquid formulation disclosed herein can be an intravenous or subcutaneous injection into a subject, wherein the compositions or liquid formulation has a viscosity lower than 80 cP, 70 cP, 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP.

[0261] In some embodiments, any of the compositions or liquid formulation disclosed herein can be administered into a subject, wherein the compositions or liquid formulation has a viscosity lower than 80 cP, 70 cP, 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP.

[0262] In some embodiments, the present invention provides an intravenous or subcutaneous formulation for injection into a subject, wherein the intravenous or subcutaneous formulation has a viscosity lower than 80 cP, 70 cP, 60 cP, 50 cP, 40 cP, 30 cP; 20 cP or 10 cP, wherein the formulation comprises a biological molecule and at least one compound disclosed herein.

[0263] In some embodiments, the subject is a mammal, preferably, the subject is a human.

[0264] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced to below 80 cP, 70 cP, 60 cP, 50 cP, 40 cP, 30 cP, 20 cP or 10 cP.

[0265] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced to below 70 cP, 60 cP, 50 cP, 40 cP, or 30 cP.

[0266] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced to below 60 cP, 50 cP, 40 cP, or 30 cP.

[0267] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced to below 50 cP, 40 cP, or 30 cP.

[0268] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced to below 40 cP, or 30 cP.

[0269] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced to below 30 cP.

[0270] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced to below 20 cP.

[0271] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced to below 10 cP.

[0272] In some embodiments, the viscosity of the biological molecule solution or suspension is reduced to from 6 cP to 9 cP and the biological molecule is evolocumab.

[0273] In some embodiments, the composition comprises at least two compounds.

[0274] In some embodiments, the composition comprises at least three compounds.

[0275] In some embodiments, the composition comprises at least four compounds.

[0276] In some embodiments, each of the two, three, or four compounds are independently present at a concentration from 0.1 mM to about 2000mM; preferably from 10mM to 2000mM; more preferably, from 20mM to 2000mM; more preferably, from 30mM to 2000mM; more preferably, from 40mM to 2000mM; more preferably, from 50mM to 2000mM; more preferably, from 50mM to 1500mM; more preferably, from 50mM to 1000mM; more preferably, from 50mM to 800mM; more preferably, from 50mM to 600mM; more preferably, from 50mM to 300mM; more preferably, from 50mM to 200mM; more preferably, from 50mM to 180mM; more preferably, from 60mM to 160mM; more preferably, from 80 mM to 140mM; more preferably, from 80 mM to 130mM; more preferably, from 80 mM to 120mM; more preferably from 90 mM to 110mM; more preferably, 100mM.

[0277] In some embodiments, each of the two, three, or four compounds have the same concentration.

[0278] In some embodiments, each of the two, three, or four compounds have different concentrations.

[0279] In some embodiments, the composition comprises at least two compounds; wherein the ratio between two compounds is about 200:1, 100:1; 50:1; 25:1; 10:1; 5:1;2:1, 1:1 1:2, 1:5; 1:10; 1:20; 1:25; 1:50; 1:100 or 1: 200.

[0280] In some embodiments, the composition comprises at least two compounds, wherein the two compounds are GaGly and GL.

[0281] In some embodiments, the composition comprises at least two compounds, wherein the two compounds are GaGly and GaGlyA.

[0282] In some embodiments, one of the compounds decreases the viscosity of the biological molecule solution or suspension, which in turn reduces the shear stress at a given shear rate.

[0283] In some embodiments, the composition or the formulation disclosed herein further comprises a pharmaceutically acceptable acid, base or buffer.

[0284] In some embodiments, the composition or the formulation disclosed herein further comprises a pharmaceutically acceptable carrier or pharmaceutically active agent.

[0285] In some embodiments the composition or formulation disclosed herein further comprises a pharmaceutically acceptable excipient

[0286] In some embodiments the excipient is a tonicity / osmotic agent, a sugar or alcohol such as, Sodium chloride, Potassium chloride, Sucrose, Trehalose, Mannitol, Sorbitol, Lactose or Glucose.

[0287] In some embodiments the excipient is an Amino Acid such us Arginine, Glycine, Histidine, Alanine, Proline or Methionine.

[0288] In some embodiments the excipient is a Surfactant such as Polysorbate 20 (Tween 20), Polysorbate 80 (Tween 80) or Poloxamer 188.

[0289] In some embodiments the excipient is a Preservative such as Phenol, m-CresolBenzyl alcohol or Phenoxyethanol.

[0290] In some embodiments the excipient is a Solubility Enhancer / Aggregation Suppressor such as Arginine hydrochloride or a Cyclodextrin.

[0291] In some embodiments, the present invention provides a liquid formulation comprising omalizumab in an amount of at least about 120 mg / ml, at least one compound disclosed herein, and a pharmaceutically acceptable acid, base or buffer in an amount of at least about 10 mM, so as to have a pH of about 6.0 and have a viscosity of less than 80 cP.

[0292] In some embodiments, the present invention provides a liquid formulation comprising infliximab in an amount of at least about 150 mg / ml, at least one compound disclosed herein, and a pharmaceutically acceptable acid, base or buffer in an amount of at least about 4 mM, so as to have a pH of about 7,2 and have a viscosity of less than 40 cP.

[0293] In some embodiments, the present invention provides a liquid formulation comprising evolocumab in an amount of at least about 150 mg / ml, at least one compound disclosed herein, and a pharmaceutically acceptable acid, base or buffer in an amount of at least about 5 mM, so as to have a pH of about 5.0 and have a viscosity of less than 36 cP.

[0294] In some embodiments, the present invention provides a liquid formulation comprising etanercept in an amount of at least about 140 mg / ml, at least one compound herein, and a pharmaceutically acceptable acid, base or buffer in an amount of at least about 15 mM, so as to have a pH of about 6.3 and have a viscosity of less than 48 cP.

[0295] In some embodiments the liquid formulation is stored at room temperature.

[0296] In some embodiments, the present invention provides a method for reducing the viscosity of a biological molecule solution, wherein the method comprises adding at least one compound disclosed herein to the biological molecule solution or suspension at a concentration between about 80 mM and about 200 mM, wherein the viscosity of the biological molecule solution or suspension with the compound is reduced compared to the viscosity of the biological molecule solution or suspension without the compound.

[0297] In some embodiments, the present invention provides a method for reducing the viscosity of a biological molecule solution, wherein the method comprises adding one compound disclosed herein to the biological molecule solution or suspension at a concentration between about 80 mM and about 200 mM, wherein the viscosity of the biological molecule solution or suspension with the compound is reduced compared to the viscosity of the biological molecule solution or suspension without the compound.

[0298] In some embodiments, the present invention provides a method for reducing the viscosity of a biological molecule solution, wherein the method comprises adding at least two compounds disclosed herein to the biological molecule solution or suspension at a concentration between about 80 mM and about 200 mM, wherein the viscosity of the biological molecule solution or suspension with the compound is reduced compared to the viscosity of the biological molecule solution or suspension without the compound

[0299] In some embodiments, the present invention provides a method for reducing the viscosity of a biological molecule solution, wherein the method comprises adding at least three compounds disclosed herein to the biological molecule solution or suspension at a concentration between about 80 mM and about200 mM, wherein the viscosity of the biological molecule with the compound is reduced compared to the viscosity of the biological molecule without the compound.

[0300] In some embodiments the biological molecule is at room temperature.

[0301] In some embodiments, the present invention provides a method for reducing the viscosity of omalizumab solution or suspension, the method comprises adding at least one compound disclosed herein to the omalizumab solution or suspension at a concentration between about 80 mM and about 200 mM, wherein the viscosity of the omalizumab solution or suspension with the compound is reduced compared to the viscosity of omalizumab solution without the compound.

[0302] In some embodiments, the present invention provides a method for reducing the viscosity of infliximab solution or suspension, the method comprises adding at least one compound disclosed herein to the infliximab solution or suspension at a concentration between about 80 mM and about 200 mM, wherein the viscosity of the infliximab solution or suspension with the compound is reduced compared to the viscosity of infliximab solution or suspension without the compound.

[0303] In some embodiments, the present invention provides a method for reducing the viscosity of etanercept solution, the method comprises adding at least one compound disclosed herein to the etanercept solution or suspension at a concentration between about 80 mM and about 200 mM, wherein the viscosity of the etanercept solution or suspension with the compound is reduced compared to the viscosity of etanercept solution or suspension without the compound.

[0304] In some embodiments, the present invention provides a method for reducing the viscosity of evolocumab solution or suspension, the method comprises adding at least one compound disclosed herein to the evolocumab solution or suspension at concentration of between about 80 mM and about 200 mM, wherein the viscosity of the evolocumab solution with the compound is reduced compared to the viscosity of evolocumab solution or suspension without the compound.

[0305] In some embodiments, the present invention provides a method for reducing the viscosity of cetuximab solution or suspension, the method comprises adding at least one compound disclosed herein to the cetuximab solution or suspension at concentration of between about 80 mM and about 200 mM, wherein the viscosity of the cetuximab solution with the compound is reduced compared to the viscosity of cetuximab solution or suspension without the compound.

[0306] In some embodiments, the present invention provides a method for reducing the viscosity of bevacizumab solution or suspension, the method comprises adding at least one compound disclosed herein to the bevacizumab solution or suspension at concentration of between about 80 mM and about 200 mM,wherein the viscosity of the bevacizumab solution with the compound is reduced compared to the viscosity of bevacizumab solution or suspension without the compound.

[0307] In some embodiments, the present invention provides a method for reducing the viscosity of rituximab solution or suspension, the method comprises adding at least one compound disclosed herein to the rituximab solution or suspension at concentration of between about 80 mM and about 200 mM, wherein the viscosity of the rituximab solution with the compound is reduced compared to the viscosity of rituximab solution or suspension without the compound.

[0308] The present invention provides a process of purifying a biological molecule, comprising a step of diafiltration, so as to purify the biological molecule, wherein the process comprises combining the biological molecule with at least one compound, or a salt thereof disclosed herein.

[0309] The present invention provides a process of purifying a biological molecule, comprising a step of diafiltration, so as to purify the biological molecule, wherein the process comprises combining the biological molecule with at least two compounds, or a salt thereof disclosed herein.

[0310] In some embodiments, the process of purifying a biological molecule disclosed herein is faster than the process of purifying a biological molecule without adding the compound disclosed herein.

[0311] In some embodiments, one of the compounds decreases the viscosity of the biological molecule solution or suspension, which in turn reduces the shear stress at a given shear rate.

[0312] In some embodiments, the present invention provides a downstream process to purify a biological molecule solution, wherein the process comprises a step of ultrafiltration / diafiltration, so as to purify the biological molecule solution, wherein the process comprises combining the biological molecule with at least one compound, or a salt thereof having the following structure:X - R1.whereinX isX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide; and[A]wherein when X isR2is -OH, -N3, or -N(H)C(=O)CH3; orR1and R2together with the carbon atoms to which they are attached formK HN^O R3, wherein R3is -H, -CH3, -CH2C(=O)OH, or -CH2OH; or [B]wherein when X is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide;then R1isR4and R5are each independently -H, -halogen, -CH2OH, -OH, -O-alkyl, -CONH2, or optionally substituted alkyl;Y and Z are each independently -H, -OH, -O-alkyl or optionally substituted alkyl;A is H, -OH, -CONH2, -OR6, or -NR7R8;wherein R6is -H or optionally substituted alkyl; and R7and R8are each independently -H, -OH, -O-alkyl or optionally substituted alkyl;n is 0-10; andm is 0-10.

[0313] In some embodiments, the present invention provides a downstream process to purify a biological molecule solution, which comprises a step of ultrafiltration / diafiltration, so as to purify the biological molecule solution, wherein the process comprises combining the biological molecule with at least one compound, or a salt thereof disclosed herein.

[0314] In some embodiments, wherein(a) at least one of the compounds decreases the viscosity of the biological molecule solution or suspension, which in turn reduces the shear stress at a given shear rate, thereby reducing the concentration time and / or increasing permeate flux;(b) the viscosity of the biological molecule solution or suspension is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%; and / or wherein the process comprises combining the biological molecule with at least two, three, four, or five compounds; preferably, with at least two compounds;(c) the viscosity of the biological molecule solution or suspension is reduced to below 80 cP, 70 cP, 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; preferably the viscosity of the biological molecule solution or suspension is reduced to below 70 cP, 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 40 cP, 30 cP, 20 cP, or 10 cP; more preferablythe viscosity of the biological molecule solution or suspension is reduced to below 30 cP, 20 cP, or 10 cP;(d) wherein the biological molecule is Dupilumab, Cetuximab, Rituximab, Bevacizumab, Pembrolizumab, Trastuzumab, Etanercept, Infliximab, Omalizumab, or Evolocumab; preferably, the biological molecule is Etanercept, or Omalizumab.

[0315] In some embodiments, the compound is

[0316] In some embodiments, the compound is

[0317] In some embodiments, the compound is

[0318] In some embodiments, the compound isDefinitionsCompound name abbreviations

[0319] Abbreviations for the compounds of the present invention are as follows:

[0320] MglyA - mannosyl-glycolamide

[0321] MLA - mannosyl -lactamide

[0322] GBA - 3-glucosyl-butanamide

[0323] GaBA - 3-galactosyl-butanamide

[0324] GGlyA - glucosyl-glycolamide

[0325] GaGlyA - galactosyl-glycolamide

[0326] GLA - glucosyl-lactamide

[0327] GaLA - galactosyl-lactamide

[0328] b-GGlyA - beta-glucosyl-glycolamide

[0329] b-GLA - beta-glucosyl-lactamide

[0330] b-GaGlyA - beta-galactosyl-glycolamide

[0331] b-GBA - beta-3 -glucosyl -butanamide

[0332] a-MglyA - alpha-mannosyl-glycolamide

[0333] a-MLA - alpha-mannosyl-lactamide

[0334] b-GGly - beta-glucosyl-glycolate

[0335] b-GL - beta-glucosyl-lactate

[0336] b-GB - beta-3 -glucosyl -butyrate

[0337] b-GaGly - beta-galactosyl-glicolate

[0338] b-GaL - beta-galactosyl-lactate

[0339] Ac Acetate

[0340] BnBr Benzyl bromide

[0341] DIP di-myo-inositol phosphate

[0342] DGP di-Glycerol phosphate

[0343] DMAP 4-Dimethylaminopyridine

[0344] DMF Dimethylformamide

[0345] DSF Differential Scanning Fluorimetry

[0346] Et Ethyl

[0347] Et2O Diethyl ether

[0348] EtOAc Ethyl acetate

[0349] GG Glucosyl R-Glycerate

[0350] GGG α-D-glucopyranosyl-(1→6)-α-D-glucopyranosyl-(1→2)-D-glycerate

[0351] GL a-D-Glucosyl-S-lactate

[0352] Hex Hexane

[0353] MDH Malate dehydrogenase

[0354] Me Methyl

[0355] MeOH Methanol

[0356] MG Mannosyl (S)-Glycerate

[0357] MGA a-D-Mannosyl-D-glyceramide

[0358] MGG a-D-Mannopyranosyl-(1^2)-a-D-glucopyranosyl-(1^2)-D-glycerate

[0359] MGly a-D-Mannosyl-glycolate

[0360] MGGly (2R)-2-(l-O-a-D-mannopyranosyl)-3-(l-O-a-D-glucopyranosyl)-glycerate

[0361] ML a-D-Mannosyl-S-lactate

[0362] NaOMe Sodium methoxide

[0363] NIS N-Iodosuccinimide

[0364] NMR Nuclear magnetic resonance

[0365] Ph Phenyl

[0366] TLC Thin layer chromatography

[0367] SNase Staphylococcal nuclease

[0368] TBAF Tetra-n-butylammonium fluoride

[0369] TBDPSCl tert-Butylchlorodiphenylsilane

[0370] TBDMS tert-Butyldimethylsilane

[0371] TfOH Trifluoromethanesulfonic acid

[0372] THF Tetrahydrofuran

[0373] The term “biological molecule” describes, but not limited to biopharmaceutical, protein, nucleotide, nucleic acids, polypeptide, virus, vaccines, bacterium, gene therapy or antibody. It includeslarge macromolecules such as proteins, carbohydrates, lipids, and nucleic acids, as well as small molecules such as vitamins and hormones.

[0374] The term “protein”, as used herein refers to a polymer of amino acids linked to each other by peptide bonds to form a polypeptide that folds in a tridimensional form.

[0375] The term “fusion protein”, as used herein refers to proteins created by joining 2 or more domains encoded by different genes. The aim of a fusion protein is to combine the different attributes of genes to improve the ability of the protein to treat disease and improve the properties that are lacking in individual, natural proteins. When combining protein domains, one part acts as the receptor for binding, and the second part adds functionalities such as improving stability or novel targeting routes.

[0376] The term “recombinant proteins”, as used herein refers to proteins that are artificially produced using genetic engineering techniques. They have played a significant role in biomedical biotechnology, being used in research and as drugs in the treatment of various diseases. These proteins have undergone advancements over time, with improvements in their structures, properties, and administration routes, resulting in higher efficiency and increased safety.

[0377] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al., Nature, 256: 495 (1975), or may be made by recombinant DNA methods (see, e.g., U. S. Pat. No.4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352: 624-628 (1991) and Marks et al., Mol. Biol., 222:581-597 (1991), for example.

[0378] The term “viscosity reducing excipient”, as used herein, refers to any compound at a suitable concentration which is known to reduce the viscosity of a biological molecule solution, such as protein,nucleic acids, virus, vaccines, gene therapy solution or suspension by at least 5% compared to an identical composition not comprising the viscosity reducing excipient.

[0379] The term “stable”, as used herein, refers to biological molecule stability, such as protein, as the consortium of forces which maintain an equilibrium to allow the protein molecule to exist in a native or a folded state.

[0380] As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also pharmaceutically acceptable carriers as are slow-release vehicles.

[0381] As used herein, the term “pharmaceutically active agent” means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject. Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U. S. Department Of Health And Human Services, 30thedition, 2010), which are hereby incorporated by reference. Pharmaceutically active agents which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect.

[0382] The compounds of the present invention may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reactinga purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) " Pharmaceutical Salts", J. Pharm. Set. 66:1-19).

[0383] The compounds of the present invention may also form salts with basic amino acids such as lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance.

[0384] As used herein, “administering” an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art. The administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, fransbuccally, intranasally, liposomally, via inhalation, vaginally, infraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, infraventicularly, intratumorally, into cerebral parenchyma or infraparenchchymally.

[0385] The biological molecule used in the present invention may be administered in various forms, including those detailed herein. The treatment with the biological molecule may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.

[0386] The dosage of the biological molecule administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.

[0387] A dosage unit of the biological molecule used in the method of the present invention may comprise a single biological molecule or mixtures thereof with additional antitumor agents. The biological molecule can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The biological molecule may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduceddirectly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

[0388] The biological molecule used in the present invention can be administered in a mixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The biological molecule can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be coadministered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

[0389] Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modem Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugsand the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

[0390] The compounds of the present invention include neutral glycosylated amides (neutral amide-type) and dianionic glucuronidated acids (dionic uronic acid-type). Preferably, the neutral amide-type stabilizers contain only non-ionizable functional groups, e.g., amide and hydroxyl functional groups whereas the dianionic uronic acid-type stabilizers contain two ionizable carboxylic acid functional groups, one which is at C-6 of the hexose moiety and one which is linked to the hexose via the glycosidic bond. The dianionic uronic acid-type stabilizers of the present invention includes stabilizers, containing two ionizable acid groups, which are in their neutral form as well as the salts derived from their monoanionic and dianionic forms, e.g., as monosodium salt, disodium salt, monopotassium salt, dipotassium salt, calcium salt, magnesium salt, etc. In specific embodiments, the compound is a dipotassium salt.

[0391] The compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469-1474, (1997) IUPAC.

[0392] Except where otherwise specified, if the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in " Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.

[0393] The compounds of the subject invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

[0394] In the compound structures depicted herein, hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.

[0395] It is understood that where a numerical range is recited herein, the present invention contemplates each integer between, and including, the upper and lower limits, unless otherwise stated.

[0396] This invention also provides isotopic variants of the compounds disclosed herein. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It will be noted that any notation of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as12C,13C, or14C. Furthermore, any compounds containing13C or14C may specifically have the structure of any of the compounds disclosed herein. It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as1H,2H, or3H. Furthermore, any compounds containing2H or3H may specifically have the structure of any of the compounds disclosed herein. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed. It is to be understood that the invention encompasses all such isotopic forms.

[0397] It is understood that substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0398] As used herein, the term “halogen” refers to F, Cl, Br, and I.

[0399] As used herein, "alkyl" is intended to include both branched, straight-chain and cycloalkyl saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, alkyl specifically includes methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on. An embodiment can be C1-C12 alkyl, C1-C3 alkyl, C2-C12 alkyl, C3-C12 alkyl, C4-C12 alkyl and so on. Neighboring alkyl substituents may be linked to form a saturated carbocyclic ring. As herein, "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). Alkyl may be optionally substituted. For example, alkyl may be optionally substituted by oxygen, nitrogen, or sulfur atoms. As another example, alkyl may be optionally substituted by a phenyl, an alcohol, a halogen(i.e., F, Cl, Br, and I), an alkoxy group such as methoxy, ethoxy, n-propoxy and isopropoxy, an alkylthio group such as methylthio and ethylthio, a carboxylate or an acetate group.

[0400] A “O-alkyl” group means an (oxygen)-R radical where R is alkyl as defined above. For example, O-alkyl may be an oxygen atom bonded to a Cl to C6 straight chain or branched chain alkyl.

[0401] A “hexosyl” group is a hexose radical. Hexosyl groups may be, but are not limited to, glucosyl, mannosyl and galactosyl. Other Hexosyl groups include allosyl, altrosyl, gulosyl, idosyl and talosyl. Hexosyl includes unoxidized hexosyl groups but also may include oxidized hexosyl groups such as uronic acid groups. Uronic acid groups are a uronic acid radical which may be, but are not limited to, glucuronsyl, mannuronsyl and galacturonsyl. The hexose or oxidized hexose groups may be a D or L stereoisomer. The hexosyl group may be an alpha- or beta-anomer. The hexosyl group is linked to the parent substrate via an oxygen to C-l, C-2, C-3, C-4 or C-6. The hexosyl group may be an alpha- or beta-anomer.

[0402] A “glucosyl” group is a radical of a glucose molecule. The glucose molecule may be D or L mannose. A glucosyl group is linked to the parent substrate via an oxygen to C-l, C-2, C-3, C-4 or C-6. The glucosyl group may be an alpha- or beta-anomer. Unless otherwise specified, a glucosyl group is linked at the oxygen of the anomeric C-l. For example, glucosyl may be defined as:

[0403] A “galactosyl” group is a radical of a galactose molecule. The galactose molecule may be D or L mannose. A galactosyl group is linked to the parent substrate via an oxygen to C-l, C-2, C-3, C-4 or C-6. The galactosyl group may be an alpha- or beta-anomer. Unless otherwise specified, a galactosyl group is linked to the oxygen of the anomeric C-l. For example, galactosyl may be defined as:

[0404] A “mannosyl” group is a radical of a mannose molecule. The mannose molecule may be D or L mannose. A mannosyl group is linked to the parent substrate via an oxygen to C-l, C-2, C-3, C-4 or C-6. The mannosyl group may be an alpha- or beta-anomer. Unless otherwise specified, a mannosyl group is linked at the oxygen of the anomeric C-l. For example, mannosyl may be defined as:

[0405] A “glucuronosyl” or “glucuronic acid group” is a radical of a glucuronic acid molecule. The glucuronic acid group may be D or L glucuronic acid. A glucuronic acid group is linked to the parent substrate via an oxygen to C-l, C-2, C-3, C-4 or C-6. The glucuronic acid group may be an alpha- or beta-anomer. Unless otherwise specified, a glucuronic acid group is linked at the oxygen off of the anomeric C- 1. For example, glucuronic acid group may be defined as:

[0406] A “galacturonosyl” or “galacturonic acid group” is a radical of a galacturonic acid molecule. The galacturonic acid group may be D or L galacturonic acid. A galacturonic acid group is linked to the parent substrate via an oxygen to C-l, C-2, C-3, C-4 or C-6. The galacturonic acid group may be an alpha-or beta-anomer. Unless otherwise specified, a galacturonic acid group is linked at the oxygen of the anomeric C-l. For example, galacturonic acid group may be defined as:

[0407] A “mannuronosyl” or “mannuronic acid group” is a radical of a mannuronic acid molecule. The mannuronic acid group may be D or L mannuronic acid. A mannuronic acid group is linked to the parent substrate via an oxygen to C-l, C-2, C-3, C-4 or C-6. The mannuronic acid group may be an alpha-or beta-anomer. Unless otherwise specified, a mannuronic acid group is linked at the oxygen of the anomeric C-l. For example, mannuronic acid group may be defined as:

[0408] An “optionally substituted” group refers to a functional group in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or pluraly. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0409] The compounds disclosed herein also include any of the compounds disclosed herein modified by common protecting groups. For example, the compounds of the present invention include glycosylated amides as described herein but modified where the amide is protected by an amide protecting group, e.g., BOC, and the hydroxyl groups are protected by a hydroxyl protecting group, e.g., benzyl. As another example, the compounds of the present invention include glucuronidated acids where the carboxylic acid moiety is protected as an ester. Common protecting groups are known to a person of ordinary skill in the art as set forth in Greene's Protective Groups in Organic Synthesis (Wuts (2006)).

[0410] In choosing the compounds of the present invention, one of the ordinary skill in the art will recognize that the various substituents are to be chosen in conformity with well-known principles of chemical structure connectivity.

[0411] The compounds disclosed herein may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to stabilize a therapeutic biological molecule, the salt may be a pharmaceuticallyacceptable salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. The salts can be made using an organic or inorganic acid. Such salts include, but are not limited to, alkali metals and alkaline earth metal salts such as lithium sodium, potassium, beryllium, magnesium and calcium salts. Salts also include alkyl ammonium salts, ammonium salts and salts derived from amino acids. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively nontoxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. (See, e.g., Berge et al. (1977) " Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0412] The compounds of the present invention may be used in a pharmaceutical composition comprising a therapeutic biological molecule in admixture with suitable pharmaceutical diluents, extenders, excipients or carriers.

[0413] A “biological molecule” is a protein, nucleotide, polypeptide, antibody including monoclonal antibody, enzyme, or a fragment or mixture of any of the preceding. A biological molecule may also be a fragment of a cell, virus, liposome or tissue. In alternative embodiments, the biological molecule has therapeutic activity or it has no therapeutic activity.

[0414] In an embodiment, the biological molecule is a nucleic acid, a polypeptide, a whole cell, a virus, a virus like particle, a cell membrane, a cell component, a liposome, a tissue, or a mixture of any of the foregoing. In an embodiment, the biological molecule comprises one, two, three, or more species of biological molecule.

[0415] In an embodiment, the biological molecule is one or more species of nucleic acids. In an embodiment, the nucleic acid is RNA, DNA, or a mixture of RNA and DNA. In an embodiment, the RNA is single stranded RNA. In an embodiment, the RNA is double stranded. In an embodiment, the RNA is mRNA. In an embodiment, the RNA is an antisense oligonucleotide. In an embodiment, the DNA is double stranded. In an embodiment, the DNA is single stranded.

[0416] In an embodiment, the biological molecule is one or more species of whole cells.

[0417] In an embodiment, the biological molecule is a polypeptide.

[0418] In an embodiment, the polypeptide is an enzyme, an antibody, a plasma protein, or a hormone.

[0419] In an embodiment, the polypeptide is insulin, malate dehydrogenase, staphylococcal nuclease or lysozyme. In an embodiment, the polypeptide is insulin.

[0420] In an embodiment, the polypeptide is a recombinant polypeptide. In an embodiment, the polypeptide is isolated from a yeast or mammalian cell culture.

[0421] In an embodiment, polypeptide is not a recombinant polypeptide. In an embodiment, the polypeptide is isolated from a plant, an animal, a fungus, or a bacteria. In an embodiment, the polypeptide is an animal or human serum polypeptide.

[0422] In an embodiment, the composition further comprises a buffer.

[0423] In embodiments of the subject invention, the therapeutic biological molecule may be one of: Insulin; Humulin; Novolin; Insulin human inhalation; Exubera; Insulin aspart; Novolog (aspart); Insulin glulisine; Apidra (glulisine); Insulin lispro; Humalog (lispro); Isophane insulin; NPH; Insulin detemir; Levemir (detemir); Insulin glargine; Lantus (glargine); Insulin zinc extended; Lente; Ultralente; Pramlintide acetate; Symlin; Growth hormone (GH); somatotropin; genotropin; humatrope; norditropin; NorIVitropin; Nutropin; Omnitrope; Protropin; Saizen; Serostim; Valtropin; Mecasermin; Increlex; Mecasermin rinfabate; IPlex; Factor VIII; Bioclate; Helixate; Kogenate; Recominate; ReFacto; Factor IX; Benefix; Antithromin III (AT-III); Thrombate III; Protein C concentrate; Ceprotin; [3-Glucocerebrosidase; Cerezyme; [3-Glucocerebrosidase; Ceredase (purified from pooled human placenta); Alglucosidase-a; Myozyme; Laronidase (a-l-iduronidase); Aldurazyme; Idursulphase (Iduronate-2-sulphatase); Elaprase; Galsulphase; Naglazyme; Agalsidase-[3 (human a-galactosidase A); Fabrazyme; a- 1 -Proteinase inhibitor; Aralast; Prolastin; Lactase; Lactaid; Pancreatic enzymes (lipase, amylase, protease); Arco-Lase, Cotazym, Creon, Donnazyme, Pancrease, Viokase, Zymase, Adenosine deaminase (pegademase bovine, PEG-ADA); Adagen; Pooled immunoglobulins; Octagam; Human albumin; Albumarc; Albumin; Albuminar; AlbuRx; Albutein; Flexbumin; Buminate; Plasbumin; Erythropoietin; Epoetin-a; Epogen; Procrit; Darbepoetin-a; Aranesp; Filgrastim (granulocyte colony stimulating factor; G-CS F); Neupogen; Pegfilgrastim (Peg-G-CSF); Neulasta; Sargramostim (granulocytemacrophage colony stimulating factor; GM-CS F); Leukine; Oprelvekin (interleukinll; IL11); Neumega; Human follicle-stimulating hormone (FSH); Gonal-F; Follistim; Human chorionic gonadotropin (HCG); Ovidrel; Luveris; Type I alpha-interferon; interferon alfacon 1; consensus interferon; Infergen; Interferon-a2a (IFNa2a); Roferon-A; Peglnterferon-a2a; Pegasys; Interferon-a2b (IFNa2b); Intron A; Peglnterferon-a2b; Peg-Intron; Interferon-an3 (IFNan3); Alferon N; Interferon-fHa (rIFN-P); Avonex; Rebif; lntcrfcron-f> lb (rIFN- ); Betaseron; Interferon-ylb (IFNy); Actimmune; Aldesleukin (interleukin 2 (IL2); epidermal thymocyte activating factor; ETAF); Proleukin; Alteplase (tissue plasminogen activator; tPA); Activase; Reteplase (deletion mutein of tPA); Retavase; Tenecteplase; TNKase; Urokinase; Abbokinase; Factor Vila; NovoSeven; Drotrecogin-a(activated protein C); Xigris; Salmon calcitonin; Fortical; Miacalcin; Teriparatide (human parathyroid hormone residues 1-34); Forteo; Exenatide; Byetta; Octreotide; Sandostatin; Dibotermin-α (recombinant human bone morphogenic protein 2; rhBMP2); Infuse; Recombinant human bone morphogenic protein 7 (rhBMP7); Osteogenic protein 1; Histrelin acetate (gonadotropin releasing hormone; GnRH); Supprelin LA; Vantas; Palifermin (keratinocyte growth factor KGF); kepivance; Becaplermin (platelet-derived growth factor; PDGF); Regranex; Trypsin; Granulex; Nesiritide; Natrecor; Botulinum toxin type A; Botox; Botulinum toxin type B; Myoblock; Collagenase; Santyl; Human deoxy-ribonuclease I; dornase-α; pulmozyme; Hyaluronidase (bovine, ovine); Amphadase (bovine); hydase (bovine); Vitrase (ovine); Hyaluronidase (recombinant human); hylenex; Papain; accuzyme; panafil; L-asparaginase; ELSPAR; Pegasparaginase; Oncaspar; Rasburicase; Elitek; Lepirudin; Refludan; Bivalirudin; Angiomax; Streptokinase; Streptase; Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC); Eminase; Bevacizumab; Avastin; Cetuximab; Erbitux; Panitumumab; Vectibix; Alemtuzumab; Campath; Rituximab; Rituxan; Trastuzumab; Herceptin; Abatacept; Orencia; Anakinra; Antril; Kineret; Abalimumab; Humira; Etanercept; Enbrel; Infliximab; Remicade; Alefacept; Amevive; Natalizumab; Tysabri; Eculizumab; Soliris; Antithymocyte globulin (rabbit); Thymoglobulin; Basiliximab; Simulect; Daclizumab; Zenapax; Muromonab-CD3; Orthoclone; OKT3; Omalizumab; Xolair; Palivizumab; Synagis; Enfuvirtide; Fuzeon; Abciximab; ReoPro; Pegvisomant; Somavert; Crotalidae polyvalent immune Fab (ovine); Crofab; Digoxin immune serum Fab (ovine); Digifab; Ranibizumab; Lucentis; Denileukin; Diftitox; Ontak; Ibritumomab; Tiuxetan; Zevalin; Gemtuzumab; Ozogamicin; Mylotarg; Tositumomab and I-tositumomab; Bexxar; Bexxar 1-131; Hepatitis B surface antigen (HBsAg); Engerix; Recombivax HB; HPV vaccine; Gardasil; OspA; LYMErix; Anti-Rhesus (Rh) immunoglobulin G; Rhophylac; Recombinant purified protein derivative (DPPD); Glucagon; GlucaGen; Growth hormone releasing hormone (GHRH); Geref; Secretin; ChiRhoStim (human peptide), SecreFlo (porcine peptide); Thyroid stimulating hormone (TSH); thyrotropin; Capromab pendetide; ProstaScint; Indium- Ill-octreotide; OctreoScan; Satumomab pendetide; OncoScint; Arcitumomab; CEA-scan; Nofetumomab; Verluma; Apcitide; Acutect; Imciromab pentetate; Myoscint; Technetium fanolesomab; NeutroSpec; HIV antigens; Enzyme immunoassay; OraQuick; Uni-Gold; Hepatitis C antigens; oRecombinant immunoblot assay (RIBA).

[0424] In some embodiments, the biological molecule is Dupilumab, Cetuximab, Rituximab, Bevacizumab, Pembrolizumab, Trastuzumab, Etanercept, Infliximab, Omalizumab, or Evolocumab.

[0425] In some embodiments, the biological molecule is Etanercept, Infliximab, Omalizumab, or Evolocumab.

[0426] As used herein, “degradation” of a biological molecule includes, but not limited to, aggregation, denaturation, misfolding, proteolysis and precipitation of the biological molecule. Thedegradation may be induced by physical stress or it may be induced by chemical stress. Physical stress includes high temperature, low temperature, heating above the thermal unfolding temperature, freezing, agitation, shaking, surfaces and pressure. Chemical stress includes low pH, high pH, pH divergent from the ideal pH environment of the natively -folded protein (e.g., divergent by a pH of 1, 2, 3, 4 or 5), dehydration, organic solvents, oxidative stress, high concentration of salts, low concentration of salts and the presence of impurities such as detergents or chaeotropic agents.

[0427] A stabilized biological molecule retains its native structure and activity for longer period of time or across a broader range of conditions than an unstabilized biological molecule. Additionally, or alternatively, a stabilized biological molecule does not degrade under conditions which degrade an unstabilized form of the same biological molecule. A stabilized biological molecule has a higher melting temperature than an unstabilized biological molecule.

[0428] Techniques and compositions for making such compositions are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

[0429] The present invention also includes embodiments where a glucosyl, mannosyl, or galactosyl group is replaced with allosyl, altrosyl, gulosyl, idosyl or talosyl, or any of the corresponding uronic acids.

[0430] Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.

[0431] This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

[0432] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0433] In the discussion unless otherwise stated, adjectives such as “substantially” and “about” modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention, are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value. Unless otherwise indicated, the word “or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of and any combination of items it conjoins.

[0434] It should be understood that the terms “a” and “an” as used above and elsewhere herein refer to “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a,” “an” and “at least one” are used interchangeably in this application.

[0435] For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0436] In the description and claims of the present application, each of the verbs, “comprise,” “include” and “have” and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb. Other terms as used herein are meant to be defined by their well-known meanings in the art.General

[0437] For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments.

[0438] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of the invention.

[0439] Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0440] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0441] Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only.SYNTHESIS OF THE COMPOUNDS

[0442] A chemical library based on sugar derivatives was prepared in order to identify new organic compounds with increased protein stabilization properties. The diversify of the analogue structures was introduced by using different hexoses, such as glucose, galactose, mannose and glucosamine, and by using different glycosyl acceptors during the glycosylation reaction.

[0443] Galactose and glucosamine analogues were synthesized in addition to mannosides and glucosides in order to assess the contribution of the sugar structure for the stabilization effect. To our knowledge, only one galactose containing compatible solute has been isolated from hyperthermophiles, the P-galactopyranosyl-5 -hydroxylysine (GalHI) from Thermococcus litoralis'.

[0444] Several amino acids, like glutamate, proline, and glutamine, can function as compatible solutes in many mesophilic organisms and both a- and [3-amino acids are used for osmoadaptation (Costa 1998). In order to determine if an amino group or the extra charge would enhance the stabilisation effect glucosamine derivatives were synthesized. To our knowledge, only one glucosamine containing compatible solute has been isolated from hyperthermophiles, di-N-acetyl-glucosamine phosphate (DAGAP) from Rubrobacter xylanophilus'.OH(Empadinhas 2007).

[0445] DAGAP is structurally similar to the phosphodiester compatible solutes found in hyperthermophiles, like DIP or DGP, however, the role as a compatible solute has been refuted due to the concentrations that are too low to contribute to the cell’s osmotic balance.

[0446] All of the glycosyl acceptors chosen are charged and structurally related to glycerate with point modifications, such as more or less carbon atoms, loss of a hydroxyl group, an additional carboxylic group and the configuration at the asymmetric center, when present:CH OH HO' ''" QOHMo7 4 133 134Methyl glycolate Methyl (S)-lactate Ethyl 3-hydroxybutyrate Dimethyl (S)-malateOHT8DPSO TBDPSG9Methyl (2R)-3-O-tert-butyldiphenylsilyl-22,3-hidrooxypropanoate

[0447] For the synthesis of the glucose and galactose derivatives, thioglycoside donors 1 and 19 were synthesized. The results obtained for the glycosylation reaction of donors 1 and 19 with the glycosyl acceptors above using NIS / TfOH system (Lourenco 2009) in dichloromethane are described in Table 1. All acceptors were commercially available with exception of the methyl glycerate derivatives 9 and 135, which were synthesized according to the experimental procedures reported for D-serine (Lourenco 2009; Lok 1976).ROH, TfOH / NIS, CH₂Cl₂, 4A1: Glucose19: Galactose

[0448] Glycosylation reaction using thioglycoside donors 1 and 19.

[0449] Reactions gave a mixture of anomers for most of the glycosyl acceptors. This provided the opportunity to test a and anomers separately to determine the importance of the stereochemistry of the anomeric position for the stabilization effect. This was the case for the D / L- glycerate and malate galactosyl derivatives.

[0450] Synthesis of Methyl 2-O-(a-D-mannopyranosyl)acetate (5)

[0451] Synthesis of compound 5 was carried out according to the procedure described in literature: Carbohydrate Research 343 (2008), 3025-3033.

[0452] Synthesis of Methyl (2S)-2-O-(α-D-mannopyranosyl)-3-propanoate (11)

[0453] Synthesis of compound 11 was carried out according to the procedure described in literature: Carbohydrate Research 343 (2008), 3025-3033.

[0454] Scheme 1.5 MGIyAGaLAMLA

[0455] a) NH3, MeOH, -78°C / rt, >99%

[0456] Each starting material was treated with ammonium in methanol at -78°C and warmed to room temperature and produced the desired product via ester amidolysis at quantitative or near-quantitiatve yield (>99%).

[0457] The starting materials (1, 3, 5, 7, 9 and 11) and other related compounds may be synthesized using techniques and materials known to those of skill in the art. Additionally, starting materials in Scheme 1 have been reported in the literature and thus may be accessed as previously described. Compound 1 was reported in Carbohydrate Res. 2009, 344, 1646 (beta-anomer); J. Org Chem. 2003, 68, 6672; Tetrahedron Lett. 2000, 41, 8273. (alpha-anomer). The beta-anomer of Compound 3 was reported in WO 2008 / 007153 A2 and WO 2015 / 137838 Al. The alpha-anomer of Compound 5 was reported in Carbohydrate Res. 2008, 343, 3025, WO 2015 / 137838 Al and WO 2012 / 109283 Al. The starting materials (7, 9 and 11) in Scheme 2 have been prepared in the literature and are thus available at least by the same methods previously described. Compound 7 was reported in WO 2015 / 137838 Al (both configurations). The beta-anomer of Compound 9 was reported in WO 2008 / 007153 A2. The alpha-anomer of Compound 11 was reported in Carbohydrate Res. 2008, 343, 3025. The beta-anomer of amide 2 (b-GGlyA) was disclosed in Carbohydrate Res. 2013, 374, 29 and its structure was studied but, importantly, no particular function or effect of the compound was disclosed.

[0458] Scheme 2.OH13R=Et, MeR=Et, Me 16GaBAa) NH3, MeOH, -78°C / rt, >99%

[0459] Each starting material, as either ethyl or methyl ester, is treated with ammonium in methanol at -78°C and warmed to room temperature to produce the desired amide product via ester amidolysis at quantitative or near-quantitative yield. Compound 14 was produced in 99% yield from starting material 13.

[0460] The starting materials (13, 15 and 17) and other related compounds may be synthesized using techniques and materials known to those of skill in the art. Additionally, starting materials in Scheme 2 have been reported in the literature and thus may be accessed as previously described. Compound 13 (as ethyl ester) was reported in Phytochemistry 1997, 45 and Biotechnol. Lett., 1995, 17, 1169. Compound 15 (as ethyl and methyl esters) was reported in Biotechnol. Lett. 1997, 19, 583. The alpha-anomer of Compound 17 (as ethyl ester) was reported in WO 2015 / 137838 AL

[0461] Preparation of Dianioic Glucuronidated Acids

[0462] Gluco-, galacto- and mannuronic acids (Compounds 37-42) are prepared as described in Scheme 3. Due to the presence of the two carboxylic acid moieties, the resulting stabilizers are ionizable in two positions in contrast to trehalose and saccharose which are devoid of charge.

[0463] Scheme 3.19: R=H, glue 25: R=H, glue 20: R=Me, glue 26: R=Me, glue 21: R=H, gal 27: R=H, gal 22: R=Me, gal 28: R=Me, gal 23: R=H, man 29: R=H, man 24: R=Me, man 30: R=Me, manRCO2Na+31: R=H, glue 37: R=H, glue, 70% from 1932: R=Me, glue 38: R=Me, glue33: R=H, gal 39: R=H, gal34: R=Me, gal 40: R=Me, gal35: R=H, man 41: R=H, man36: R=Me, man 42: R=Me, man

[0464] a) BAIB / TEMPO, CH2Cl2 / H2O b) H2, Pd / C, 50 Psi, AcOEt, c) NaOH, H2O

[0465] The C-6 primary hydroxyl group is efficiently oxidized to the corresponding carboxylic acid with a BAIB / Tempo reagent combination. The benzyl ether protecting groups are next removed with Pd / C and H2 at 50 psi. Hydrolysis of the methyl ester with NaOH in water affords the sodium salts of the final products in quantitative yields. The final compounds under basic conditions presented two charges, derived from the two carboxylic acid functional groups. The disodium salt 37 was prepared at 70% overall yield from starting material 19. The disodium salt 38 was prepared at 66% overall yield from starting material 20.

[0466] The starting materials (19-24) and other related compounds may be synthesized using techniques and materials known to those of skill in the art. Additionally, starting materials in Scheme 2 have been reported in the literature and thus may be accessed as previously described. Compounds 19-22 were reported in WO 2015 / 137838 Al. The disodium salt 37 was previously disclosed in Carbohydrate Res. 1967, 5, 453 but no particular function or effect of the compound was disclosed.

[0467] Gluco-, galacto- and mannuronic acids (Compounds 37-42) are prepared as described in Scheme 3. Due to the presence of the two carboxylic acid moieties, the resulting stabilizers are ionizable in two positions in contrast to trehaolse and saccharose which are devoid of charge.

[0468] Preparation of diamido gluco-, manno- and galactosides

[0469] Diamides from gluco-, manno- and galactosides 46-48 were prepared in by reaction of 43-45 with ammonia in methanol.

[0470] Scheme 4.OH OHOCO2Me 43: GIU 46: GIU44: Gal 47: Gal45: Man 48: Mana) NH3, MeOH, -78°C-r.t.

[0471] Preparation of Additional Dianionic Glucuronidated Acids

[0472] Gluco-, galacto- and mannuronic acids (Compounds 55-60) are prepared as described in Scheme 5.

[0473] Scheme 5.R= CH3, glu. R= CH3, glu.R= CO2Me, glu. R= CO2Me, glu.R= CH3, gal. R= CH3, gal.R= CO2Me, gal. R= CO2Me, gal.R= CH3, man. R= CH3, man.R= CO2Me, man. R= CO2Me, man.49: R= CH3, glu. 55: R= CH3, glu.50: R= CO2Me, glu. 56: R= CO2Na, glu.51: R= CH3, gal. 57: R= CH3, gal.52: R= CO2Me, gal. 58: R= CO2Na, gal.53: R= CH3, man. 59: R= CH3, man.54: R= CO2Me, man. 60: R= CO2Na, man.a) BAIB / TEMPO, CH2Cl2 / H2O. b) H2, Pd / C, Psi, AcOEt. c) NaOH, H2O.

[0474] Preparation of Uronic Acid Amides

[0475] Gluco-, galacto- and mannuronic acid amides (Compounds 61-66 and 67-72) were prepared as described in Schemes 6 and 7. Uronic acid amides 61-66 were prepared in by reaction of 31-36 with ammonia in methanol. Uronic acid amides 67-72 were prepared in by reaction of 49-54 with ammonia in methanol.

[0476] Scheme31: R= H, glu. 61: R= H, glu.32: R= Me, glu. 62: R= Me, glu.33: R= H, gal. 63: R= H, gal.34: R= Me, gal. 64: R= Me, gal.35: R= H, man. 65: R= H, man.36: R= Me, man. 66: R= Me, man.a) NH3, MeOH, -78 °C.

[0477] Scheme 7.49 R= CH3, glu. 67 R: Me, glu.50 R= CO2Me, glu. 68 R: CONH2, glu.51 R= CH3, gal. 69 R: Me, gal.52 R= CO2Me, gal. 70 R: CONH2, gal.53 R= CH3, man. 71 R: Me, man.54 R= CO2Me, man. 72 R: CONH2, man.a) NH3, MeOH, -78 °C.

[0478] The compounds of the present invention may be prepared by methods described in International Publication Nos. WO 2019 / 092504 and WO 2015 / 137838, the entire contents of which are herein incorporated by reference.

[0479] In general, compounds of the present invention may be prepared using a number of methods known in the chemical arts, particularly in light of the description contained herein, in combination with the knowledge of the skilled artisan. Various starting materials, intermediates, and reagents may be purchased from commercial sources or made according to literature methods or adaptations thereof. Although other reagents, compounds or methods can be used in practice or testing, generalized methods for the preparation of the compounds of the present invention are illustrated by the following descriptions and reaction Schemes. The methods disclosed herein, including those outlined in the Schemes, descriptions, and Examples are for intended for illustrative purposes and are not to be construed in any manner as limitations thereon. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0480] Although specific embodiments of various aspects of the invention will be described with reference to the Schemes, Preparations and / or Examples, it should be understood that such embodiments are by way of example only and are merely illustrative of a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. The starting materials used for the synthesis of compounds described herein can be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo.), or the starting materials can be synthesized. The compounds described herein, and other related compounds havingdifferent substituents can be synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (Smith (2013)), Design and Strategy in Organic Synthesis (Hanessian (2013)) Greene's Protective Groups in Organic Synthesis (Wuts (2006)) and Fiesers' Reagents for Organic Synthesis (Volumes 1- 27) (Ho (2013)), each of which are incorporated by reference in their entirety.

[0481] General methods for the preparation of the compounds as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. (Trombotto et al. 2000; Matsumura et al. 1997; Krajewski et al. 1997; Faria et al. 2008; Xue et al. 2009; Moynihan et al. 2013; WO 2008 / 007153 A2; WO 2012 / 109263 Al; and WO 2015 / 137838)

[0482] The intermediate products described can be recovered by extraction, evaporation, or other techniques known in the art. The crude materials may then be optionally purified by chromatography, HPLC, recrystallization, trituration, distillation, or other techniques known in the art.

[0483] As would be appreciated by those skilled in the art, some of the methods useful for the preparation of such compounds, as discussed above, may require protection of a particular functionality, e.g., to prevent interference by such functionality in reactions at other sites within the molecule or to preserve the integrity of such functionality. The need for, and type of, such protection is readily determined by one skilled in the art, and will vary depending on, for example, the nature of the functionality and the conditions of the selected preparation method. Methods of introducing and removing protecting groups are well known to those of ordinary skill in the art and are described in Greene's Protective Groups in Organic Synthesis (Wuts (2006)). Alternate reagents, starting materials, as well as methods for optimizing or adapting the procedures described herein would also be readily determined by one skilled in the art.EXPERIMENTAL DETAILSMaterials and Methods

[0484] Proteins solution:• Etanercept (Enbrel®, Pfizer);• Omalizumab (Xolair®, Norvartis);• Evolocumab (Repatha®, Amgen);• Infliximab (Remsima®, Celltrion);• Bevacizumab (Avastin®, Roche);• Rituximab (Mabthera®, Roche );• Cetuximab (Erbitux®, Merck).

[0485] Hexose derivatives:• alpha-Mannosyl lactate (ML);• beta-Glucosyl lactate (GL);• beta-Galactosyl glycolate (GaGly);• alpha-Glucosyl lactamide (GLA);• alpha-Galactosyl glycolamide (GaGly A);• Beta-Galactosyl lactamide (GaLA)• Glucosyl R-Glycerate (GG)• Mannosyl (S)-Glycerate (MG)• Glucuronic Glycolate (GlcAGly)

[0486] Chemical structures of hexose derivatives are shown below in Table 1: Name Chemical Sturcturealpha-Mannosyl lactate (ML) H\ 0> QHO^ \HO- _ J0^^^^C02- Na+beta-Glucosyl lactate (GL)H1HO^ \ 0 C02Na HO - JOHbeta-Galactosyl glycolate (GaGly))HC)HA. / XQ CO2 Na+HO- OHalpha-Glucosyl lactamide (GLA) OHHO^ \HO-^_OH 1'CONH2alpha-Galactosyl glycolamide (GaGly A)( )HC)HHO- OH IO' ‘CONH2beta-Galactosyl lactamide (GaLA) OHOHCONH2HOH HBeta-Glucosyl R -Glycerate (GG) OHOH y-CO2K+HO-"7alpha-Mannosyl S-Glycerate (MG) 9HOHHO^V^I'°yHOX-*-4*^0HCO2K+Beta-Glucuronic Glycolate (GlcAGly) Q- Na+HO-X--*^VoOH T O Q- Na+

[0487] Buffers: L-histidine monohydrochloride monohydrate (Sigma-Aldrich), sodium phosphate monobasic monohydrate (Sigma-Aldrich), sodium acetate anhydrous (Sigma-Aldrich), sucrose (Sue) (Sigma-Aldrich), L-histidine (AppliChem), sodium phosphate dibasic heptahydrate (Honeywell), acetic acid glacial(Sigma-Aldrich) and phosphoric acid (85 wt. % in water, Sigma-Aldrich), sodium citrate dihydrate (Sigma- Aldrich).

[0488] Viscosity Measurement

[0489] Viscosity measurements were conducted on m-VROC™ Technology (RheoSense, California, USA) equipped with a C05 chip. Measurements were performed at room temperature using a 500 pL glass syringe (Hamilton, USA) and a shear rate of 3000 s'1. The required volume was 200 uL and samples tested in triplicates.

[0490] Protein Concentration Measurement

[0491] The concentration of the protein in the experimental solutions was determined by measuring the absorbance of the protein solution at a wavelength of 280 nm in a NanoPhotomer (Implen, Germany). Instrument was calibrated to zero absorbance with buffer. The final concentration of the protein in the solution was calculated using the extinction coefficient values in Table 2. The reported concentrations are the average of three measurements.

[0492] Table 2. Extinction coefficients at 280 nm.Sample Extinction coefficient (mL·mg-1·cm-1) Etanercept 1.180 [7]Infliximab 1.450 [8]Evolocumab 1.500 [9]Omalizumab 1.569

[0010] Rituximab 1.4Cetuximab 1.35Bevacizumab 1.75

[0493] Size-Exclusion Chromatography (SEC UPLC)

[0494] Size exclusion Chromatography was performed using a UPLC equipped with ACQUITY UPLC Protein BEH SEC Column (200 Å pore size, 1.7 μm particle size, 4.6 mm x 300 mm, Waters®). Samples were diluted to 1 mg / mL and the injection volume was 1 μL. The separation was performed at 0.4 mL / min flow rate and at 40°C. The running buffer was composed of 50 mM sodium phosphate and 400 mM sodium perchlorate at pH 6.5. UV detection was performed at 220 nm. The results were reported as % w / w compared with the control.

[0495] Accelerated Stability Studies

[0496] High concentration formulated samples were stored in Eppendorf® Protein LoBind tubes at room temperature (rt), (25°C) and 2-8°C for 4 weeks, and analyzed at specific timepoints by size exclusion chromatography.Example 1Omalizumab solution

[0497] Viscosity reducing effect of Glucosyl lactate (GL), Galactosyl glycolate (GaGly), Mannosyl lactate (ML), Galactosyl glycolamide (GaGly A), Glucosyl lactamide (GLA), Galactosyl lactamide (GaLA),Beta-Glucuronic Glycolate (GlcAGly) and two excipients combinations (Galactosyl glycolate (GaGly) with Glucosyl lactate(GL), and Galactosyl glycolate (GaGly) with Galactosyl glycolamide (GaGlyA)) in concentrated Omalizumab solution (146 and 154 mg / mL) formulated in 20 mM Histidine hydrochloride buffer at pH 6.0 was shown in Figures 1 and 2. Control solution was Omalizumab formulated in 20 mM Histidine hydrochloride buffer at pH of 6.0.

[0498] Sample Preparation

[0499] Formulation samples were prepared using viscosity reduction sugars at a range between 50 and 150 mM in 20 mM Histidine hydrochloride buffer at pH of 6.0. Sugar combinations were tested in using 50 mM solution of each sugar. mAb solutions containing the relevant excipients were concentrated by diafiltration using ultracentrifugal filters (Amicon® Ultra-4, 30 kDa MWCO) by exchanging the buffer with the excipient solution using four volumes and concentrating the mAb by reducing the solution volume until target concentration - 146 and 154 mg / mL. The concentration time was recorded for each sample and shown in Figure 3.Example 2Infliximab solution

[0500] Viscosity reducing effect of Glucosyl lactate (GL), Galactosyl glycolate (GaGly), Mannosyl lactate (ML), Galactosyl glycolamide (GaGkyA), Glucosyl lactamide (GaLa) and Galactosyl lactamide (GLA) in concentrated Infliximab solution (156 and 165 mg / mL) formulated in 5 mM Sodium phosphate buffer at pH 7.2 and 200-mM sucrose was shown in Figures 1 and 2. Control solution was Infliximab formulated in 5 mM Sodium phosphate buffer at pH 7.2 and 200-mM sucrose.

[0501] S ample Preparation

[0502] Formulation samples were prepared using viscosity reduction sugars at a range of 50 to 150 mM in 5 mM Sodium phosphate buffer at pH 7.2 and 200 mM sucrose, mAb solutions containing the relevant excipients were concentrated by diafiltration with ultracentrifugal filters (Amicon® Ultra-4, 30 kDa MWCO) by exchanging the buffer with the excipient solution above using four volumes and concentrating the mAb by reducing the solution volume until target concentration - 156 and 165 mg / mL. The concentration time was recorded for each sample and is shown in Figure 3.Example 3Evolocumab solution

[0503] Viscosity reducing effect of Mannosyl lactate (ML), Glucosyl lactamide (GLA) and Galactosyl lactamide (GLA) and glucuronic glycolate (GlcAGly) in concentrated Evolocumab solution (152 and 161 mg / mL) formulated in 10 mM Sodium acetate buffer at pH 5.0 was shown in Figures 1 and 2. Controlsolution was Evolocumab formulated in 10 mM Sodium acetate buffer at pH 5.0 shown in Figures 1 and 2.

[0504] Sample Preparation

[0505] Formulation samples were prepared using viscosity reduction sugars at a range of 50 to 150 mM in 10 mM Sodium acetate buffer at pH 5.0. mAb solutions containing the relevant excipients were concentrated by diafiltration with ultracentrifugal filters (Amicon® Ultra-4, 30 kDa MWCO) by exchanging the buffer with the excipient solution above using four volumes and concentrating the mAb by reducing the solution volume until target concentration - 152 and 161 mg / mL. The concentration time was recorded for each sample and is shown in Figure 3.Example 4Etanercept solution

[0506] Viscosity reducing effect of Glucosyl lactate (GL), Galactosyl glycolate (GaGly), Mannosyl lactate (ML), Galactosyl glycolamide (GaGlyA), Glucosyl lactamide (GLA) and Galactosyl lactamide (GaLA) in concentrated Etanercept solution (143 and 158 mg / mL) formulated in 20 mM Sodium phosphate buffer pH 6.3 was shown in Figures 1 and 2. Control solution was Etanercept formulated in 20 mM Sodium phosphate buffer at pH 6.3.

[0507] Sample Preparation

[0508] Formulation samples were prepared using viscosity reducing sugars at a range of 50 to 150 mM in 20 mM Sodium phosphate buffer at pH 6.3. mAb solutions containing the relevant excipients were concentrated by diafiltration with ultracentrifugal filters (Amicon® Ultra-4, 30 kDa MWCO) by exchanging the buffer with the excipient solution above using four volumes and concentrating the protein by reducing the solution volume until target concentration - 143 and 158 mg / mL. The concentration time was recorded for each sample and is shown in Figure 3.Example 5Bevacizumab solution

[0509] Viscosity reducing effect of Glucosyl lactate (GL), Mannosyl lactate (ML), Galactosyl glycolamide (GaGlyA), Glucosyl lactamide (GLA), • Mannosyl (S)-Glycerate (MG), Glucosyl R-Glycerate (GG) and Galactosyl lactamide (GaLA) in concentrated Bevacizumab solution (200 mg / mL) formulated in 20 mM Sodium phosphate buffer pH 6.2 was shown in Figures 1. E). Control solution was Bevacizumab formulated in 20 mM Sodium phosphate buffer at pH 6.2.

[0510] S ample PreparationFormulation samples were prepared using viscosity reducing sugars at a range of 100 mM in 20 mM Sodium phosphate buffer at pH 6.2. mAb solutions containing the relevant excipients were concentrated by diafiltration with ultracentrifugal filters (Amicon® Ultra-4, 30 kDa MWCO) by exchanging the buffer with the excipient solution above using four volumes and concentrating the protein by reducing the solution volume until target concentration - 200 mg / mL.Example 6Rituximab solution

[0511] Viscosity reducing effect of Glucosyl lactate (GL), Mannosyl lactate (ML), Galactosyl glycolamide (GaGlyA), Mannosyl (S)-Glycerate (MG), Galactosyl Glycolate (GaGly) and Glucuronic Glycolate (GlcAGly) in concentrated Rituximab solution (208 mg / mL) formulated in 20 mM Sodium citrate buffer pH 6.5 was shown in Figures 1. F). Control solution was Rituximab formulated in 20 mM Sodium citrate buffer at pH 6.3.

[0512] S ample Preparation

[0513] Formulation samples were prepared using viscosity reducing sugars at a range of 100 mM in 20 mM Sodium citrate buffer at pH 6.5. mAb solutions containing the relevant excipients were concentrated by diafiltration with ultracentrifugal filters (Amicon® Ultra-4, 30 kDa MWCO) by exchanging the buffer with the excipient solution above using four volumes and concentrating the protein by reducing the solution volume until target concentration - 208 mg / mL.

[0514] Cetuximab solution

[0515] Viscosity reducing effect of Glucosyl lactate (GL), Mannosyl lactate (ML), Galactosyl glycolamide (GaGlyA), Mannosyl (S)-Glycerate (MG), Glucosyl R-Glycerate (GG), Galactosyl Glycolate (GaGly), Galactosyl lactamide (GaLA) and Glucuronic Glycolate (GlcAGly) in concentrated Centuximab solution (134 mg / mL) formulated in 20 mM Sodium citrate buffer pH 5.6 was shown in Figures 1 E).Control solution was Cetuximab formulated in 20 mM Sodium citrate buffer at pH 5.6.

[0516] S ample Preparation

[0517] Formulation samples were prepared using viscosity reducing sugars at a range of 100 mM in 20 mM Sodium citrate buffer at pH 5.6. mAb solutions containing the relevant excipients were concentrated by diafiltration with ultracentrifugal filters (Amicon® Ultra-4, 30 kDa MWCO) by exchanging the buffer with the excipient solution above using four volumes and concentrating the protein by reducing the solution volume until target concentration - 134 mg / mL. The concentration time was recorded for each sample and is shown in Figure 3. E).DISCUSSIONResults

[0518] Omalizumab solution

[0519] A reduction of viscosity for Omalizumab was shown in Figure 1 (A), when concentrated at 146 mg / mL, for sugars Glucosyl lactate, Galactosyl glycolate, Mannosyl lactate, Galactosyl glycolamide Glucosyl lactamide, Galactosyl lactamide and a combination of Galactosyl glycolamide and Galactosyl glycolate. This represents a reduction of between 68% for Galactosyl glycolate and 22% for Galactosyl lactamide (GaLA).

[0520] Figure 2 (A) shows that for Omalizumab the solution viscosity is dependent on the excipient concentration, and that there is an optimal concentration for viscosity reduction (100 mM).

[0521] Regarding diafiltration and concentration time, it was found that some sugars also decrease this time compared to the control sample. For example, GaLA did not particularly decrease viscosity as much as the other sugars, but it contributed to the lowering of diafiltration and concentration time. It was shown that having a combination of a sugar that decreases viscosity plus a sugar that decreases diafiltration time can be used together without one affecting the other’s effect while providing both benefits. This was the case for GaGly / GaGlyA mixture and GaGly / GL mixture where a decrease in viscosity and in diafiltration time was found.

[0522] Regarding stability, under 1 month at 2-8 °C the Omalizumab monomer was maintained above 96%, and at 25 °C was above or equal to 93% for Glucosyl lactate, Galactosyl glycolate and Mannosyl lactate, but at 76% for the Galactosyl glycolamide sugar (Figure 4).

[0523] Infliximab solution

[0524] A reduction of viscosity for Infliximab was shown when concentrated at 156 mg / mL, for sugar Galactosyl glycolate, which represents a reduction of viscosity of 23%.

[0525] Figure 2 (B) shows that, at least for the range of concentrations tested, the excipient concentration appears to have no impact on the viscosity of Infliximab solutions.

[0526] The concentration time of this protein was not improved when adding the excipients, as shown in Figure 3 (B).

[0527] Regarding stability, under 1 month at 2-8 °C the Infliximab monomer was equal or above 98%, and at 25 °C was as well equal or above to 96% for Glucosyl lactate and Galactosyl glycolate (Figure 4).

[0528] Evolocumab solution

[0529] A reduction of viscosity for Evolocumab was shown when concentrated at 152 mg / mL, for sugar Mannosyl lactate and Glucosyl lactamide, which represents a reduction of viscosity of 84% and 49%, respectively.

[0530] Figure 2 (C) shows that for Evolocumab the solution viscosity is dependent on the excipient concentration, and that there is an optimal concentration for viscosity reduction (100 mM). The concentration time of this protein was not improved when adding the excipients, as shown in Figure 3 (D).

[0531] Regarding stability, under 1 month at 2-8 °C the Evolocumab monomer was equal or above 96%, and at 25 °C was equal to 95% for Mannosyl lactate, and 90% for Glucosyl lactamide (Figure 4).

[0532] Etanercept solution

[0533] A reduction of viscosity for etanercept was shown when concentrated at 143 mg / mL, for sugar Glucosyl lactate, which represents a reduction of viscosity of 39%.

[0534] Figure 2 (D) shows that for Etanercept the solution viscosity is dependent on the excipient concentration, and that there is an optimal concentration for viscosity reduction (100 mM).

[0535] Regarding diafiltration and concentration time, it was found that GaLa (at 100 mM), GL (150 mM) and ML (at 150 mM) were able to reduce the process time. Particularly it was found that GaLa although not contributing to viscosity decrease, contributes for the diafiltration and concentration time decrease (Figure 3 (C)).

[0536] Regarding stability, under 1 month at 2-8 °C the Etanercept monomer control decreased to 66%. In the presence of Mannosyl lactate, Glucosyl lactate, Glucosyl lactamide, etamecept native state was equal or above 99%. In the presence of Galactosyl glycolamide, the Etanercept native state was equal to 89%. Under one month at 25°C, Galactosyl glycolate and Mannosyl lactate were equal to 96% and 91% respectively, and the Galactosyl glycolamide, Glucosyl lactamide, and Glucosyl lactate were equal or below to 63% (Figure 4).

[0537] Bevacizumab solution

[0538] A reduction of viscosity for Bevacizumab was shown when concentrated at 200 mg / mL, for sugar Galactosyl glycolamide (GaGlyA), which represents a reduction of viscosity of 47% (Figure 1. E).

[0539] Rituximab solution

[0540] A reduction in viscosity for Rituximab was observed when concentrated at 208 mg / mL for all sugars tested, with a reduction ranging from 32% to 46% (Figure 1. F).

[0541] Cetuximab solution

[0542] During the dialfiltration and concentration of Cetuximab, it was found that all sugars were able to reduce the process time by 53% to 61%. In particular, ML was identified as the best performer (Figure 3E).

[0543] The experimental results show that sugar molecules GLA, GaGlyA, ML, GL and GaGly reduce the viscosity of concentrated protein solutions, such as humanized IgGl monoclonal antibody Omalizumab. Studies have shown that viscosity and self-association of IgGs can be attributed to only a few specific attractive interaction sites. While the precise mechanism of how the disclosed sugars reduce the viscosity of concentrated protein solutions is not fully elucidated, it may be that the amine group of GLA, GAGlyA and the charged salt forming sites of ML, GL and GaGly play an important role in binding to specific sites of a protein causing a disruption of the protein-protein interaction in the concentrated protein solutions. Therefore, compounds that have structural similarity with GLA, GaGlyA, ML, GL and GaGly are expected to possess the ability to reduce the viscosity of concentrated protein solutions. In particular, sugars that have the amine group of GLA, GAGlyA, and sugars that have the charged salt forming sites of ML, GL and GaGly are expected to possess the ability to reduce the viscosity of concentrated protein solutions.REFERENCES1. He, F., Woods, C. E., Litowski, J. R.e / al. Effect of Sugar Molecules on the Viscosity of High Concentration Monoclonal Antibody Solutions. Pharm. Res. 28, 1552-1560 (2011). https: / / doi.org / 10.1007 / s11095-011-0388-72. C. M. Sudrik, T. Cloutier, N. Mody, H. A. Sathish, and B. L. Trout, “Understanding the Role of Preferential Exclusion of Sugars and Polyols from Native State IgGl Monoclonal Antibodies and its Effect on Aggregation and Reversible Self-Association,” Pharm Res, vol. 36, no. 8, Aug. 2019, doi: 10.1007 / S11095-019-2642-33. A. Y. Xu, M. M. Castellanos, K. Mattison, S. Krueger, and J. E. Curtis, “Studying Excipient Modulated Physical Stability and Viscosity of Monoclonal Antibody Formulations Using Small-Angle Scattering,” Mol Pharm, vol. 16, no. 10. pp. 4319-4338. Oct. 2019, doi: 10.1021 / acs.molpharmaceut.9b00687.4. T. Cloutier, C. Sudrik, N. Mody, H. A. Sathish, and B. L. Trout, “Molecular Computations of Preferential Interaction Coefficients of IgGl Monoclonal Antibodies with Sorbitol, Sucrose, and Trehalose and the Impact of These Excipients on Aggregation and Viscosity,” Mol Pharm, vol. 16, no. 8, pp. 3657-3664, Aug. 2019, doi: 10.1021 / ACS.MOLPHARMACEUT.9B005455. Maycock et al. International Publication No. WO 2015 / 137838.6. Lourenco et al. International Publication No. WO 2019 / 0925047. M. Kiyoshi, K. I. Tatematsu, M. Tada, H. Sezutsu, H. Shibata, and A. Ishii-Watabe. “Structural insight and stability of TNFR-Fc fusion protein (Etanercept) produced by using transgenic silkworms”, The Journal of Biochemistry, vol. 169, no. 1, pp. 25-33, Feb. 2021, doi: 10.1093 / JB / MVAA092.8. Y. Zeng et al. “Caffeine as a Viscosity Reducer for Highly Concentrated Monoclonal Antibody Solutions,” J. Pharm. Sci., vol. 110, no. 11, pp. 3594-3604, Nov. 2021, doi: 10.1016 / j.xphs.2021.06.030.9. C. J. Sloey, S. Kanapuram, H. Cui, C. M. Chan, and E. Binabaji. “Low-viscosity, high-concentration evolocumab formulations and methods of making the same,” WO 2018 / 156741 Al, Aug. 30, 2018.10. P. K. Lai, G. Ghag, Y. Yu, V. Juan, L. Fayadat-Dilman, and B. L. Trout. “Differences in human IgGl and IgG4 S228P monoclonal antibodies viscosity and self-interactions: Experimental assessment and computational predictions of domain interactions,” MAbs, vol. 13, no. 1, 2021, doi: 10.1080 / 19420862.2021.1991256.11. Walters, International Publication No. WO 2017 / 055966.

Claims

CLAIMSWhat is claimed is:

1. A composition comprising a biological molecule and at least one compound or a salt thereof, wherein the compound has the following structure:X - R1.whereinX isX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide; and[A]wherein when X isR2is -OH, -N3, or -N(H)C(=O)CH3; orR1and R2together with the carbon atoms to which they are attached formO R3, wherein R3is -H, -CH3, -CH2C(=O)OH, or -CH2OH; or[B]wherein when X is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide;wherein for both [A] and [B], R4and R5are each independently -H, halogen, -CH2OH, - CH2C(=O)OH, -OH, -O-alkyl, -CONH2, or optionally substituted alkyl;Y and Z are each independently -H, -OH, -O-alkyl or optionally substituted alkyl;A is -H, -OH, -CONH2, -O-NH2, -CO2NH2,- NH2, -OR6, or -NR7R8;wherein R6is -H, -NH2, or optionally substituted alkyl; and R7and R8are each independently H, OH, O-alkyl or optionally substituted alkyl;n is 0-10;m is 0-10; andwherein the biological molecule is not lysozyme, adalimumab, ubiquitin or Factor IX.

2. The composition of claim 1[A], where the biological molecule is Insulin; Humulin; Novolin;Insulin human inhalation; Exubera; Insulin aspart; Novolog (aspart); Insulin glulisine; Apidra (glulisine); Insulin lispro; Humalog (lispro); Isophane insulin; NPH; Insulin detemir; Levemir (detemir); Insulin glargine; Lantus (glargine); Insulin zinc extended; Lente; Ultralente; Pramlintide acetate; Symlin; Growth hormone (GH); somatotropin; genotropin; humatrope; norditropin;NorIVitropin; Nutropin; Omnitrope; Protropin; Saizen; Serostim; Valtropin; Mecasermin; Increlex; Mecasermin rinfabate; IPlex; Factor VIII; Bioclate; Helixate; Kogenate; Recominate; ReFacto; Factor IX; Benefix; Antithromin III (AT-III); Thrombate III; Protein C concentrate; Ceprotin; P-Glucocerebrosidase; Cerezyme; P-Glucocerebrosidase; Ceredase (purified from pooled human placenta); Alglucosidase-a; Myozyme; Laronidase (a-l-iduronidase); Aldurazyme; Idursulphase (Iduronate-2-sulphatase); Elaprase; Galsulphase; Naglazyme; Agalsidase- (human a-galactosidase A); Fabrazyme; a- 1 -Proteinase inhibitor; Aralast; Prolastin; Lactase; Lactaid; Pancreatic enzymes (lipase, amylase, protease); Arco-Lase, Cotazym, Creon, Donnazyme, Pancrease, Viokase, Zymase, Adenosine deaminase (pegademase bovine, PEG-ADA); Adagen; Pooled immunoglobulins; Octagam; Human albumin; Albumarc; Albumin; Albuminar; AlbuRx; Albutein; Flexbumin; Buminate; Plasbumin; Erythropoietin; Epoetin-a; Epogen; Procrit; Darbepoetin-a; Aranesp; Filgrastim (granulocyte colony stimulating factor; G-CS F); Neupogen; Pegfilgrastim (Peg-G-CSF); Neulasta; Sargramostim (granulocytemacrophage colony stimulating factor; GM-CS F); Leukine; Oprelvekin (interleukinll; IL 11); Neumega; Human follicle-stimulating hormone (FSH); Gonal-F; Follistim; Human chorionic gonadotropin (HCG); Ovidrel; Luveris; Type I alpha-interferon; interferon alfacon 1; consensus interferon; Infergen; Interferon-a2a (IFNa2a); Roferon-A; Peglnterferon-a2a; Pegasys; Interferon-a2b (IFNa2b); Intron A; Peglnterferon-a2b; Peg-Intron; Interferon-an3 (IFNan3); Alferon N; Interferon-β1a (rIFN-β); Avonex; Rebif; Interferon-β1b (rIFN-β); Betaseron; Interferon-γ1b (IFNγ); Actimmune; Aldesleukin (interleukin 2 (IL2); epidermal thymocyte activating factor; ETAF); Proleukin; Alteplase (tissue plasminogen activator; tPA); Activase; Reteplase (deletion mutein of tPA); Retavase; Tenecteplase; TNKase; Urokinase; Abbokinase; Factor Vila; NovoSeven; Drotrecogin-α (activated protein C); Xigris; Salmon calcitonin; Fortical; Miacalcin; Teriparatide (human parathyroid hormone residues 1-34); Forteo; Exenatide; Byetta; Octreotide; Sandostatin; Dibotermin-α (recombinant human bone morphogenic protein 2; rhBMP2); Infuse; Recombinant human bone morphogenic protein 7 (rhBMP7); Osteogenic protein 1; Histrelin acetate (gonadotropin releasing hormone; GnRH); Supprelin LA; Vantas; Palifermin (keratinocyte growth factor KGF); kepivance; Becaplermin (platelet-derived growth factor; PDGF); Regranex; Trypsin; Granulex; Nesiritide; Natrecor; Botulinum toxin type A; Botox; Botulinum toxin type B; Myoblock; Collagenase; Santyl; Human deoxy-ribonuclease I; dornase-α; pulmozyme; Hyaluronidase (bovine, ovine); Amphadase (bovine); hydase (bovine); Vitrase (ovine); Hyaluronidase (recombinant human); hylenex; Papain; accuzyme; panafil; L-asparaginase; ELSPAR; Peg-asparaginase; Oncaspar; Rasburicase; Elitek; Lepirudin; Refludan; Bivalirudin; Angiomax; Streptokinase; Streptase; Anistreplase (anisoylated plasminogen streptokinase activatorcomplex; APSAC); Eminase; Bevacizumab; Avastin; Cetuximab; Erbitux; Panitumumab; Vectibix; Alemtuzumab; Campath; Rituximab; Rituxan; Trastuzumab; Herceptin; Abatacept; Orencia; Anakinra; Antril; Kineret; Abalimumab; Humira; Etanercept; Enbrel; Infliximab; Remicade; Alefacept; Amevive; Natalizumab; Tysabri; Eculizumab; Soliris; Antithymocyte globulin (rabbit); Thymoglobulin; Basiliximab; Simulect; Daclizumab; Zenapax; Muromonab- CD3; Orthoclone; OKT3; Omalizumab; Xolair; Palivizumab; Synagis; Enfuvirtide; Fuzeon; Abciximab; ReoPro; Pegvisomant; Somavert; Crotalidae polyvalent immune Fab (ovine); Crofab; Digoxin immune serum Fab (ovine); Digifab; Ranibizumab; Lucentis; Denileukin; Diftitox; Ontak; Ibritumomab; Tiuxetan; Zevalin; Gemtuzumab; Ozogamicin; Mylotarg; Tositumomab and I- tositumomab; Bexxar; Bexxar 1-131; Hepatitis B surface antigen (HBsAg); Engerix; Recombivax HB; HPV vaccine; Gardasil; OspA; LYMErix; Anti-Rhesus (Rh) immunoglobulin G; Rhophylac; Recombinant purified protein derivative (DPPD); Glucagon; GlucaGen; Growth hormone releasing hormone (GHRH); Geref; Secretin; ChiRhoStim (human peptide), SecreFlo (porcine peptide); Thyroid stimulating hormone (TSH); thyrotropin; Capromab pendetide; ProstaScint; Indium- Ill- octreotide; OctreoScan; Satumomab pendetide; OncoScint; Arcitumomab; CEA-scan; Nofetumomab; Verluma; Apcitide; Acutect; Imciromab pentetate; Myoscint; Technetium fanolesomab; NeutroSpec; HIV antigens; Enzyme immunoassay; OraQuick; Uni-Gold; Hepatitis C antigens; Evolocumab, certolizumab pegol, Golimumab, Mepolizumab, Benralizumab, Reslizumab, Tezepelumab-ekko, Dupilumab, Pembrolizumab, Adalimumab, Zymfentra, or Recombinant immunoblot assay (RIBA);preferably, the biological molecule is Cetuximab, Dupilumab, Pembrolizumab, Etanercept, Infliximab, Omalizumab, Bevacizumab, Rituximab, or Evolocumab.

3. The composition of claim 1 [B], wherein the biological molecule is Evolocumab.

4. The composition of claim 1, wherein the compound has the following structure:whereinoR4R5R1is (CYZ)mone of R4and R5is H, the other is -H, -CH3, -CH2OH, or CH2C(=O)OH;Z is -H;m is 0 or 1;A is -OH or -O-NH2; andR2is -OH, -N3, or -N(H)C(=O)CH3; orR1and R2together with the carbon atoms to which they are attached formR3wherein R3is -H, -CH3, -CH2C(=O)OH, or -CH2OH;preferably,(a) one of R4and R5is -H, or -CH3;(b) m is 0-5; more preferably, m is 0 or 1; and / or(c) n is 0-5; more preferably, n is 0 or 1.

5. The composition of claim 4, wherein the compound has the following structure:

6. The composition of any one of claims 4-5, wherein in the compound, R1isOH •COOH CH3’COOH 'O' COOH COOH 'CH3or COOHCOOH; preferably, R1is o COOH or ^o' COOH; orR1is7. The composition of any one of claims 4-6, wherein in the compound, R2is -OH or -N (H)C(=O)CH3;preferably, R2is -OH.

8. The compound of any one of claims 4-7, wherein the compound has the structure:

9. The composition of claim 4, wherein the compound has the structure:R1is -OC(H)(R4)(CH2)nC(=O)OH;R2is -OH, -N3, or -N(H)C(=O)CH3;R4is -H, -CH3, -CH2OH, or -CH2C(=O)OH; andn is 0 or 1.

10. The composition of claim 4, wherein the compound has the structure:whereinR1is -OC(H)(R4)(CH2)nC(=O)OH;R2is -OH, -N3, or -N(H)C(=O)CH3;R4is -H, -CH3, -CH2OH, or -CH2C(=O)OH; andn is 0 or 1;preferably, wherein when the compound isR1, and R2is -OH, R4is -CH3, R5is -H, and n is 0, then the compound ispreferably when the compound ispreferably when the compound isR1, and R2is -OH, R4is -CH2OH, R5is -H, and n is 0, then the compound is11. The composition of claim 4, wherein the compound is12. The composition of claim 11, wherein the salt of the compound ispreferably, the salt of the compound is13. The composition of claim 9, wherein the compound has the structure:or the compound isOH15. The composition of claim 10, wherein the compound isor the compound is16. The composition of claim 15, wherein the salt of the compound isOH17. The composition of claim 1 [B], wherein the compound has the following structure:whereinX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronicacid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide; each of R4and R5is independently -H, halogen, -OH, -O-alkyl, -CONH2, -CO2H, -CO2- alkyl, or optionally substituted alkyl;each of Y and Z is independently -H, -OH, -O-alkyl or optionally substituted alkyl; m is 0, 1 or 2;A =-OR6or -NR7R8,wherein R6is -H or optionally substituted alkyl; and each of R7and R8is independently -H, -OH, -O-alkyl or optionally substituted alkyl;preferably, in the compound,when X is glucosyl, then R4is optionally substituted alkyl,when each of R4and R5is -H and m is 0, then X is other than glucuronic acid, andwherein when X is glucosyl or mannosyl, m=0, one of R4or R5is -alkyl-OH and the other is -H, and A is -NH2, then the compound is a beta-anomer.

18. The composition of claim 17, wherein the compound has the structure:whereinX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl,each of R4and R5is independently -H, halogen, -OH, -O-alkyl, -CONH2, or optionally substituted alkyl,each of R7and R8is independently -H, -OH, -O-alkyl or optionally substituted alkyl, each of Y and Z is independently -H, -OH, -O-alkyl or optionally substituted alkyl, m is 0, 1 or 2, andwhen X is glucosyl, then R4is optionally substituted alkyl;preferably,each of R4and R5is independently -H, -OH, -O-alkyl or optionally substituted alkyl, oreach of R7and R8is independently -H, -OH, -O-alkyl or optionally substituted alkyl.

19. The composition of any one of claims 17-18, wherein in the compound,(a) X is glucosyl, mannosyl or galactosyl; preferably, X is glucosyl or galactosyl; (b) each of Y and Z is -H;(c) each of R4and R5is -H, or R4is -CH3 and R5is -H, or R4is -CONH2 and R5is -H or R1is -CO2CH3 and R2is -H; and / or(d) each of R7and R8is -H.

20. The composition of claim 18, wherein the compound has the structure:OHwherein R4is -H, optionally substituted alkyl, or -CONH2 and m is 0, 1 or 2;or wherein the compound has the structure:wherein R4is -H, optionally substituted alkyl, or -CONH2 and m is 0, 1 or 2;or wherein the compound has the structure:OHwherein R4is -H, optionally substituted alkyl, or -CONH2 and m is 0, 1 or 2.

21. The composition of any one of claims 17-20, wherein the hexosyl group is an alpha-anomer or a beta-anomer.L. The composition of claim 18, wherein the compound has the structure:preferably, the compound has the structure:

23. The composition of claims 18, wherein the compound has the structure:

24. The composition of claim 17, wherein the compound has the structure:whereinX is an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, a galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, each of R4and R5is independently H, halogen, OH, O-alkyl, CONH2, CO2H, CO2-alkyl. or optionally substituted alkyl;each of Y and Z is independently -H, -OH, -O-alkyl or optionally substituted alkyl,R6is independently -H or optionally substituted alkyl,m is 0, 1 or 2, and when each of R4and R5is H and m is 0, then X is other than glucuronic acid.

25. The composition of claim 24, wherein in the compound, X is glucuronic acid, mannuronic acid or galacturonic acid; or wherein in the compound, each of Y and Z is -H.

26. The composition of claim 25, wherein the compound has the structure:whereinR4is -H, optionally substituted alkyl or -CO2H;R6is -H; andm is 0, 1 or 2;or wherein the compound has the structure:OHwhereinR4is -H, optionally substituted alkyl or -CO2H;R6is -H; andm is 0, 1 or 2;or the compound has the structure:whereinR4is -H, optionally substituted alkyl or -CO2H;R6is -H; andm is 0, 1 or 2.

27. The composition of any one of claims 24-26, wherein in the compound, the uronic acid group is an alpha-anomer or a beta-anomer.

28. The composition of claim 24, wherein the compound has the structure:CO2H, orpreferably, the compound has the structure:or the compound has the structure:OH H OH29. The composition of claim 28, wherein the salt of the compound has the structure:preferably, the salt of the compound has the structure:

30. The composition of claim 24, wherein the compound is in the form of a sodium salt, potassium salt, calcium salt or magnesium salt.

31. The composition of claim 17, wherein the compound has the structure:whereinX is a uronic acid amide group selected from the group consisting of glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide;each of R4and R5is independently -H, halogen, -OH, -O-alkyl, -CONH2, -CO2H, -CO2-alkyl. or optionally substituted alkyl;each of Y and Z is independently -H, -OH, -O-alkyl or optionally substituted alkyl;m is 0, 1 or 2; andA = -NR7R8,wherein each of R7and R8is independently -H, -OH, -O-alkyl or optionally substituted alkyl.

32. The composition of claim 31, wherein the compound has the structure:wherein R4is -H, optionally substituted alkyl, or -CONH2 and m is 0, 1 or 2;or the compound has the structure:wherein R4is -H, optionally substituted alkyl, or -CONH2 and m is 0, 1 or 2;or the compound has the structure:wherein R4is -H, optionally substituted alkyl, or -CONH2 and m is 0, 1 or 2.

33. The composition of any one of claims 31-32, wherein in the compound, the uronic acid amide group is an alpha-anomer or a beta-anomer.

34. The composition of claim 31, wherein the compound has the structure:wherein R4is H, optionally substituted alkyl or CONH2;preferably, the compound has the structure:more preferably, the compound has the structure:

5. The composition of any one of claims 1-34, wherein(a) the composition is acidic, preferably, the composition has a pH less than 6.8; more preferably, a pH between 5 and 7, more preferably, a pH less than 4, more preferably, a pH around 3; (b) the composition is basic, preferably, the composition has a pH more than 7.2; more preferably, a pH between 7 and 8, more preferably, a pH more than 10, more preferably, a pH around 12; (c) the biological molecule is present at a concentration from 0.1 mg / mL to about 2000 mg / mL;preferably from 10 mg / mL to 2000 mg / mL; more preferably, from 20 mg / mL to 2000 mg / mL; more preferably, from 30 mg / mL to 2000 mg / mL; more preferably, from 40 mg / mL to 2000 mg / mL; more preferably, from 50 mg / mL to 2000 mg / mL; more preferably, from 50 mg / mLto 1500 mg / mL; more preferably, from 50 mg / mL to 1000 mg / mL; more preferably, from 50 mg / mL to 800 mg / mL; more preferably, from 50 mg / mL to 600 mg / mL; more preferably, from 50 mg / mL to 300 mg / mL; more preferably, from 50 mg / mL to 200 mg / mL; more preferably, from 50 mg / mL to 180 mg / mL; more preferably, from 60 mg / mL to 160 mg / mL; more preferably, from 80 mg / mL to 160 mg / mL; more preferably, from 100 mg / mL to 160 mg / mL; more preferably, from 120 mg / mL to 160 mg / mL; from 140 mg / mL to 160 mg / mL;(d) the composition comprises 2, 3, 4 or 5 compounds;(e) the compound(s) is present at a concentration from 0.1 mM to about 2000mM; preferably from 10mM to 2000mM; more preferably, from 20mM to 2000mM; more preferably, from 30mM to 2000mM; more preferably, from 40mM to 2000mM; more preferably, from 50mM to 2000mM; more preferably, from 50mM to 1500mM; more preferably, from 50mM to 1000mM; more preferably, from 50mM to 800mM; more preferably, from 50mM to 600mM; more preferably, from 50mM to 300mM; more preferably, from 50mM to 200mM; more preferably, from 50mM to 180mM; more preferably, from 60mM to 160mM; more preferably, from 80 mM to 140mM; more preferably, from 80 mM to 130mM; more preferably, from 80 mM to 120mM; more preferably from 90 mM to 110mM; more preferably, 100mM; or (f) the composition further comprises a pharmaceutical acceptable carrier, pharmaceutical active agent, and / or a buffer solution; preferably, the buffer is L-histidine monohydrochloride monohydrate, sodium phosphate monobasic monohydrate, sodium acetate anhydrous, sucrose, L-histidine, sodium phosphate dibasic heptahydrate, acetic acid glacial and phosphoric acid.

36. The composition of any one of claims 1-35, wherein(a) the composition is pharmaceutical composition; preferably, the pharmaceutical composition is used for intravenous or subcutaneous injection;(b) the composition remains stable for a period at a temperature of 4-30 °C;(c) the composition is in the liquid form;(d) the composition further comprises one or more of excipients; salts, surfactants, polyols, or sugars, amino acids, polymers; and / or(e) the composition comprises at least two compounds.

37. A method of modifying the viscosity of a biological molecule solution or suspension, comprising adding at least one compound or a salt thereof of any one of claims 1-36 to the biological molecule solution or suspension.

38. The method of claim 37, wherein the biological molecule is a biopharmaceutical, protein, nucleotide, polypeptide or antibody;preferably, the biological molecule is a biopharmaceutical, protein, nucleotide, nucleic acids, polypeptide, virus, vaccines, bacteria gene therapy or antibody,more preferably, a protein, wherein the protein is Insulin; Humulin; Novolin; Insulin human inhalation; Exubera; Insulin aspart; Novolog (aspart); Insulin glulisine; Apidra (glulisine); Insulin lispro; Humalog (lispro); Isophane insulin; NPH; Insulin detemir; Levemir (detemir); Insulin glargine; Lantus (glargine); Insulin zinc extended; Lente; Ultralente; Pramlintide acetate; Symlin; Growth hormone (GH); somatotropin; genotropin; humatrope; norditropin; NorIVitropin; Nutropin; Omnitrope; Protropin; Saizen; Serostim; Valtropin; Mecasermin; Increlex; Mecasermin rinfabate; IPlex; Factor VIII; Bioclate; Helixate; Kogenate; Recominate; ReFacto; Factor IX; Benefix; Antithromin III (AT-III); Thrombate III; Protein C concentrate; Ceprotin; P-Glucocerebrosidase; Cerezyme; P- Glucocerebrosidase; Ceredase (purified from pooled human placenta); Alglucosidase-a; Myozyme; Laronidase (a-l-iduronidase); Aldurazyme; Idursulphase (Iduronate-2- sulphatase); Elaprase; Galsulphase; Naglazyme; Agalsidase-P (human a-galactosidase A); Fabrazyme; a- 1 -Proteinase inhibitor; Aralast; Prolastin; Lactase; Lactaid; Pancreatic enzymes (lipase, amylase, protease); Arco-Lase, Cotazym, Creon, Donnazyme, Pancrease, Viokase, Zymase, Adenosine deaminase (pegademase bovine, PEG-ADA); Adagen; Pooled immunoglobulins; Octagam; Human albumin; Albumarc; Albumin; Albuminar; AlbuRx; Albutein; Flexbumin; Buminate; Plasbumin; Erythropoietin; Epoetin-a; Epogen; Procrit; Darbepoetin-a; Aranesp; Filgrastim (granulocyte colony stimulating factor; G-CS F); Neupogen; Pegfilgrastim (Peg-G-CSF); Neulasta; Sargramostim (granulocytemacrophage colony stimulating factor; GM-CS F); Leukine; Oprelvekin (interleukinl 1; IL11); Neumega; Human follicle-stimulating hormone (FSH); Gonal-F; Follistim; Human chorionic gonadotropin (HCG); Ovidrel; Luveris; Type I alphainterferon; interferon alfacon 1; consensus interferon; Infergen; Interferon-a2a (IFNa2a); Roferon-A; Peglnterferon-a2a; Pegasys; Interferon-a2b (IFNa2b); Intron A; Peglnterferon-a2b; Peg-Intron; Interferon-an3 (IFNan3); AlferonN; Interferon-pia(rIFN- P); Avonex; Rebif; Interferon-P lb (rIFN-P); Betaseron; Interferon-ylb (IFNy); Actimmune; Aldesleukin (interleukin 2 (IL2); epidermal thymocyte activating factor; ETAF); Proleukin; Alteplase (tissue plasminogen activator; tPA); Activase; Reteplase (deletion mutein of tPA); Retavase; Tenecteplase; TNKase; Urokinase; Abbokinase;Factor Vila; NovoSeven; Drotrecogin-α (activated protein C); Xigris; Salmon calcitonin; Fortical; Miacalcin; Teriparatide (human parathyroid hormone residues 1-34); Forteo; Exenatide; Byetta; Octreotide; Sandostatin; Dibotermin-α (recombinant human bone morphogenic protein 2; rhBMP2); Infuse; Recombinant human bone morphogenic protein 7 (rhBMP7); Osteogenic protein 1; Histrelin acetate (gonadotropin releasing hormone; GnRH); Supprelin LA; Vantas; Palifermin (keratinocyte growth factor KGF); kepivance; Becaplermin (platelet-derived growth factor; PDGF); Regranex; Trypsin; Granulex; Nesiritide; Natrecor; Botulinum toxin type A; Botox; Botulinum toxin type B; Myoblock; Collagenase; Santyl; Human deoxy-ribonuclease I; dornase-α; pulmozyme; Hyaluronidase (bovine, ovine); Amphadase (bovine); hydase (bovine); Vitrase (ovine); Hyaluronidase (recombinant human); hylenex; Papain; accuzyme; panafil; L-asparaginase; ELSPAR; Peg-asparaginase; Oncaspar; Rasburicase; Elitek; Lepirudin; Refludan; Bivalirudin; Angiomax; Streptokinase; Streptase; Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC); Eminase; Bevacizumab; Avastin; Cetuximab; Erbitux; Panitumumab; Vectibix; Alemtuzumab; Campath; Rituximab; Rituxan; Trastuzumab; Herceptin; Abatacept; Orencia; Anakinra; Antril; Kineret; Abalimumab; Humira; Etanercept; Enbrel; Infliximab; Remicade; Alefacept; Amevive; Natalizumab; Tysabri; Eculizumab; Soliris; Antithymocyte globulin (rabbit); Thymoglobulin; Basiliximab; Simulect; Daclizumab; Zenapax; Muromonab-CD3; Orthoclone; OKT3; Omalizumab; Xolair; Palivizumab; Synagis; Enfuvirtide; Fuzeon; Abciximab; ReoPro; Pegvisomant; Somavert; Crotalidae polyvalent immune Fab (ovine); Crofab; Digoxin immune serum Fab (ovine); Digifab; Ranibizumab; Lucentis; Denileukin; Diftitox; Ontak; Ibritumomab; Tiuxetan; Zevalin; Gemtuzumab; Ozogamicin; Mylotarg; Tositumomab and I-tositumomab; Bexxar; Bexxar 1-131; Hepatitis B surface antigen (HBsAg); Engerix; Recombivax HB; HPV vaccine; Gardasil; OspA; LYMErix; Anti-Rhesus (Rh) immunoglobulin G; Rhophylac; Recombinant purified protein derivative (DPPD); Glucagon; GlucaGen; Growth hormone releasing hormone (GHRH); Geref; Secretin; ChiRhoStim (human peptide), SecreFlo (porcine peptide); Thyroid stimulating hormone (TSH); thyrotropin; Capromab pendetide; ProstaScint; Indium-lll-octreotide; OctreoScan; Satumomab pendetide; OncoScint; Arcitumomab; CEA-scan; Nofetumomab; Verluma; Apcitide; Acutect; Imciromab pentetate; Myoscint; Technetium fanolesomab; NeutroSpec; HIV antigens; Enzyme immunoassay; OraQuick; Uni-Gold; Hepatitis C antigens; Evolocumab, certolizumab pegol, Golimumab, Mepolizumab, Benralizumab,Reslizumab, Tezepelumab-ekko, Adalimumab, Zymfentra, or Recombinant immunoblot assay (RIBA); Dupilumab, or Pembrolizumab,more preferably, the protein is Cetuximab, Dupilumab, Pembrolizumab, Etanercept, Infliximab, Omalizumab, Bevacizumab, Rituximab, or Evolocumab.

39. The method of any one of claims 37-38, wherein the biological molecule is a biologic TNF inhibitor; preferably, the biological molecule is Etanercept, certolizumab pegol, or Golimumab; more preferably, the biological molecule is Etanercept.

40. The method of any one of claims 37-38, wherein(a) the biological molecule is a monoclonal antibody; preferably, the monoclonal antibody is humanized IgGl monoclonal antibody; more preferably, the humanized IgGl monoclonal antibody is Omalizumab, Mepolizumab, Benralizumab, Reslizumab, or Tezepelumab-ekko; more preferably, the humanized IgGl monoclonal antibody is Omalizumab,(b) the biological molecule is a chimeric monoclonal antibody; preferably, the chimeric monoclonal antibody is Infliximab, Adalimumab, or Zymfentra; preferably, the chimeric monoclonal antibody is Infliximab;(c) the biological molecule is a biologic TNF inhibitor; preferably, the biologic TNF inhibitor is Etanercept, certolizumab pegol, or Golimumab; preferably, the biologic TNF inhibitor is Etanercept;(d) the biological molecule is a monoclonal antibody; preferably, the monoclonal antibody is humanized IgGl monoclonal antibody; more preferably, the humanized IgGl monoclonal antibody is Evolocumab, Omalizumab, Mepolizumab, Benralizumab, Reslizumab, or Tezepelumab-ekko; more preferably, the humanized IgGl monoclonal antibody is Evolocumab or Omalizumab; or(e) the biological molecule is a chimeric monoclonal antibody; preferably, the chimeric monoclonal antibody is Infliximab, Adalimumab, or Zymfentra; preferably, the chimeric monoclonal antibody is Infliximab;(f) the biological molecule is a monoclonal antibody; preferably, the monoclonal antibody is humanized IgGl monoclonal antibody; more preferably, the humanized IgGl monoclonal antibody is Evolocumab, Mepolizumab, Benralizumab, Reslizumab, or Tezepelumab-ekko; more preferably, the humanized IgGl monoclonal antibody is Evolocumab; or(g) the compound is in its salt form.

41. The method of any one of claims 37-40, wherein the method further comprises adding a buffer solution; preferably, the buffer solution is L-histidine monohydrochloride monohydrate, sodiumphosphate monobasic monohydrate, sodium acetate anhydrous, sucrose, L-histidine, sodium phosphate dibasic heptahydrate, acetic acid glacial and phosphoric acid.

42. The method of claims 37-41, wherein(a) when the biological molecule is a humanized IgGl monoclonal antibody, or biologic TNF inhibitor, the pH of the biological molecule solution or suspension is acidic, preferably, the pH of the biological molecule solution or suspension has a pH less than 6.8; more preferably, a pH between 4 and 7, more preferably, a pH less than 5-6;(b) when the biological molecule is a chimeric monoclonal antibody, the pH of the biological molecule solution or suspension is basic, preferably, the pH of the biological molecule solution or suspension has a pH more than 7; more preferably, a pH between 7 and 8; (c) the pl of the biological molecule is from 5.5 to 9.5;(d) the compound is present at a concentration from 0.1 mM to about 2000mM; preferably, from lOmM to 2000mM; more preferably, from 20mM to 2000mM; more preferably, from 30mM to 2000mM; more preferably, from 40mM to 2000mM; more preferably, from 50mM to 2000mM; more preferably, from 50mM to 1500mM; more preferably, from 50mM to 1000mM; more preferably, from 50mM to 800mM; more preferably, from 50mM to 600mM; more preferably, from 50mM to 300mM; more preferably, from 50mM to 200mM; more preferably, from 50mM to 180mM; more preferably, from 60mM to 160mM; more preferably, from 80 to 140mM; more preferably, from 80 to 130mM; more preferably, from 80 to 120mM; from 90 to 1 lOmM; more preferably, lOOmM;(e) the molar ratio between the compound and the biological molecule is about 200: 1, 100: 1;50:1; 25:1; 10:1; 5:1;2:1, 1:1, 1:2, 1:5; 1:10; 1:20; 1:25; 1:50; 1:100 or 1: 200; or (f) the solution or suspension further comprises a buffer solution; preferably, the buffer is L- histidine monohydrochloride monohydrate, sodium phosphate monobasic monohydrate, sodium acetate anhydrous, sucrose, L-histidine, sodium phosphate dibasic heptahydrate, acetic acid glacial, Tris(hydroxymethyl)aminomethane, (4-(2-hydroxyethyl)piperazine-l- ethane-sulfonic acid) (HEPES), 3-(N-Morpholino)propanesulfonic acid, 4- Morpholinepropanesulfonic acid (MOPS), or phosphoric acid.

43. The method of any one of claims 37-42, wherein(a) the viscosity of the biological molecule solution or suspension is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%;(b) the viscosity of the biological molecule solution or suspension is reduced to below 80 cP, 70 cP, 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; preferably the viscosity of the biologicalmolecule solution or suspension is reduced to below 70 cP, 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 50 cP, 40 cP, 30 cP, 20 cP or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 30 cP, 20 cP, or 10 cP; more preferably, the viscosity of the biological molecule solution or suspension is reduced to below lOcP;(c) the method comprises adding at least two compounds;preferably, one of the compounds decreases the viscosity of the biological molecule solution or suspension, which in turn reduces the shear stress at a given shear rate.

44. An intravenous or subcutaneous formulation for injection into a subject, wherein the intravenous or subcutaneous formulation has a viscosity lower than 80 cP, 70 cP, 60 cP, 50 cP, 40 cP, 30 cP; 20 cP or 10 cP, wherein the formulation comprises a biological molecule and at least one compound or a salt thereof of any one of claims 1-36.

45. The intravenous or subcutaneous formulation of claim 44, wherein the biological molecule is a protein, wherein the protein is Insulin; Humulin; Novolin; Insulin human inhalation; Exubera; Insulin aspart; Novolog (aspart); Insulin glulisine; Apidra (glulisine); Insulin lispro; Humalog (lispro); Isophane insulin; NPH; Insulin detemir; Levemir (detemir); Insulin glargine; Lantus (glargine); Insulin zinc extended; Lente; Ultralente; Pramlintide acetate; Symlin; Growth hormone (GH); somatotropin; genotropin; humatrope; norditropin; NorIVitropin; Nutropin; Omnitrope; Protropin; Saizen; Serostim; Valtropin; Mecasermin; Increlex; Mecasermin rinfabate; IPlex; Factor VIII; Bioclate; Helixate; Kogenate; Recominate; ReFacto; Factor IX; Benefix; Antithromin III (AT-III); Thrombate III; Protein C concentrate; Ceprotin; P-Glucocerebrosidase; Cerezyme; P- Glucocerebrosidase; Ceredase (purified from pooled human placenta); Alglucosidase-a; Myozyme; Laronidase (a-l-iduronidase); Aldurazyme; Idursulphase (Iduronate-2-sulphatase); Elaprase; Galsulphase; Naglazyme; Agalsidase-P (human a-galactosidase A); Fabrazyme; a-1- Proteinase inhibitor; Aralast; Prolastin; Lactase; Lactaid; Pancreatic enzymes (lipase, amylase, protease); Arco-Lase, Cotazym, Creon, Donnazyme, Pancrease, Viokase, Zymase, Adenosine deaminase (pegademase bovine, PEG- AD A); Adagen; Pooled immunoglobulins; Octagam; Human albumin; Albumarc; Albumin; Albuminar; AlbuRx; Albutein; Flexbumin; Buminate; Plasbumin; Erythropoietin; Epoetin-a; Epogen; Procrit; Darbepoetin-a; Aranesp; Filgrastim (granulocytecolony stimulating factor; G-CS F); Neupogen; Pegfilgrastim (Peg-G-CSF); Neulasta; Sargramostim (granulocytemacrophage colony stimulating factor; GM-CS F); Leukine; Oprelvekin (interleukinll; IL11); Neumega; Human follicle-stimulating hormone (FSH); Gonal-F; Follistim; Human chorionic gonadotropin (HCG); Ovidrel; Luveris; Type I alpha-interferon; interferon alfacon 1; consensus interferon; Infergen; Interferon-a2a (IFNa2a); Roferon-A; Peglnterferon-a2a; Pegasys; Interferon-a2b (IFNa2b); Intron A; Peglnterferon-a2b; Peg-Intron; Interferon-an3 (IFNan3); Alferon N; Interferon-β1a (rIFN-β); Avonex; Rebif; Interferon-β1b (rIFN-β); Betaseron; Interferon-γ1b (IFNγ); Actimmune; Aldesleukin (interleukin 2 (IL2); epidermal thymocyte activating factor; ETAF); Proleukin; Alteplase (tissue plasminogen activator; tPA); Activase; Reteplase (deletion mutein of tPA); Retavase; Tenecteplase; TNKase; Urokinase; Abbokinase; Factor Vila; NovoSeven; Drotrecogin-α (activated protein C); Xigris; Salmon calcitonin; Fortical; Miacalcin; Teriparatide (human parathyroid hormone residues 1-34); Forteo; Exenatide; Byetta; Octreotide; Sandostatin; Dibotermin-α (recombinant human bone morphogenic protein 2; rhBMP2); Infuse; Recombinant human bone morphogenic protein 7 (rhBMP7); Osteogenic protein 1; Histrelin acetate (gonadotropin releasing hormone; GnRH); Supprelin LA; Vantas; Palifermin (keratinocyte growth factor KGF); kepivance; Becaplermin (platelet-derived growth factor; PDGF); Regranex; Trypsin; Granulex; Nesiritide; Natrecor; Botulinum toxin type A; Botox; Botulinum toxin type B; Myoblock; Collagenase; Santyl; Human deoxy-ribonuclease I; dornase-α; pulmozyme; Hyaluronidase (bovine, ovine); Amphadase (bovine); hydase (bovine); Vitrase (ovine); Hyaluronidase (recombinant human); hylenex; Papain; accuzyme; panafil; L-asparaginase; ELSPAR; Peg-asparaginase; Oncaspar; Rasburicase; Elitek; Lepirudin; Refludan; Bivalirudin; Angiomax; Streptokinase; Streptase; Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC); Eminase; Bevacizumab; Avastin; Cetuximab; Erbitux; Panitumumab; Vectibix; Alemtuzumab; Campath; Rituximab; Rituxan; Trastuzumab; Herceptin; Abatacept; Orencia; Anakinra; Antril; Kineret; Abalimumab; Humira; Etanercept; Enbrel; Infliximab; Remicade; Alefacept; Amevive; Natalizumab; Tysabri; Eculizumab; Soliris; Antithymocyte globulin (rabbit); Thymoglobulin; Basiliximab; Simulect; Daclizumab; Zenapax; Muromonab-CD3; Orthoclone; OKT3; Omalizumab; Xolair; Palivizumab; Synagis; Enfuvirtide; Fuzeon; Abciximab; ReoPro; Pegvisomant; Somavert; Crotalidae polyvalent immune Fab (ovine); Crofab; Digoxin immune serum Fab (ovine); Digifab; Ranibizumab; Lucentis; Denileukin; Diftitox; Ontak; Ibritumomab; Tiuxetan; Zevalin; Gemtuzumab; Ozogamicin; Mylotarg; Tositumomab and I-tositumomab; Bexxar; Bexxar 1-131; Hepatitis B surface antigen (HBsAg); Engerix; Recombivax HB; HPV vaccine; Gardasil; OspA; LYMErix; Anti-Rhesus (Rh) immunoglobulin G; Rhophylac; Recombinant purified protein derivative (DPPD); Glucagon;GlucaGen; Growth hormone releasing hormone (GHRH); Geref; Secretin; ChiRhoStim (human peptide), SecreFlo (porcine peptide); Thyroid stimulating hormone (TSH); thyrotropin; Capromab pendetide; ProstaScint; Indium-lll-octreotide; OctreoScan; Satumomab pendetide; OncoScint; Arcitumomab; CEA-scan; Nofetumomab; Verluma; Apcitide; Acutect; Imciromab pentetate; Myoscint; Technetium fanolesomab; NeutroSpec; HIV antigens; Enzyme immunoassay; OraQuick; Uni-Gold; Hepatitis C antigens; Evolocumab, certolizumab pegol, Golimumab, Mepolizumab, Benralizumab, Reslizumab, Tezepelumab-ekko, Adalimumab, Zymfentra, or Recombinant immunoblot assay (RIBA); Dupilumab, or Pembrolizumab,preferably, the protein is Cetuximab, Dupilumab, Pembrolizumab, Etanercept, Infliximab, Omalizumab, Bevacizumab, Rituximab, or Evolocumab.

46. The intravenous or subcutaneous formulation of any one of claims 44-45, wherein the intravenous or subcutaneous formulation has a viscosity lower than 10 cP; preferably, a viscosity from 6 cP to 9 cP.

47. The intravenous or subcutaneous formulation of claims 46, wherein the intravenous orsubcutaneous formulation comprisesevolocumab.

48. The intravenous or subcutaneous formulation of claim 44 having at least two, three, four, or five compounds; preferably, having at least two compounds.

49. The intravenous or subcutaneous formulation of claim 48, wherein the compound has the following structure:

50. The intravenous or subcutaneous formulation of any one of claims 44-49, wherein(a) the concentration of the compound is from 5-300mM, preferably, from 10-200 mM; more preferably, from 50-150 mM’ more preferably 100 mM; and / or(b) the concentration of the biological molecule is from 100-500 mg / mL, preferably, from 130- 250 mg / mL; more preferably, from 140-200 mg / mL; more preferably, from 140-180 mg / mL.

51. The intravenous or subcutaneous formulation of any one of claims 44-50, wherein the biological molecule is Benvacizumab, Rituximab, Etanercept, Infliximab, Omalizumab, or Evolocumab.

52. The intravenous or subcutaneous formulation of any one of claims 44-51, further comprises a pharmaceutically acceptable carrier, and / or a pharmaceutically active agent.

53. An article of manufacture comprising a syringe containing the intravenous or subcutaneous formulation of any one of claims 44-52, and a pharmaceutically acceptable acid, base, or buffer, wherein the formulation has a viscosity of about 6cp to 40 cp.

54. The article of manufacture of claim 53, wherein(a) the acid, base, or buffer is comprised of arginine or histidine;(b) the compound in the intravenous or subcutaneous formulation has an amount of about 5- 200 mM;(c) the biological molecule in the intravenous or subcutaneous formulation has an amount of about 100-200 mg / ML; and / or(d) the pharmaceutically acceptable acid, base, or buffer has a amount of 5-200 mM.

55. A downstream process to purify a biological molecule solution, comprises a step of ultrafiltration / diafiltration, so as to purify the biological molecule solution, wherein the process comprises combining the biological molecule with at least one compound, or a salt thereof having the following structure:X - R1.whereinX isX is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide; and[A]wherein when X isR4 / R5then R1is0 n(CYZ)mA;R2is -OH, -N3, or -N(H)C(=O)CH3; orR1and R2together with the carbon atoms to which they are attached formKO R3, wherein R3is -H, -CH3, -CH2C(=O)OH, or -CH2OH; or [B]wherein when X is a hexosyl group selected from the group consisting of glucosyl, mannosyl, galactosyl, allosyl, altrosyl, gulosyl, idosyl and talosyl, or an uronic acid group selected from the group consisting of glucuronic acid, mannuronic acid, galacturonic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid and taluronic acid, or an uronic acid amide group selected from the group consisting of Glucuronamide, mannuronamide, galacturonamide, alluronamide, altruronamide, guluronamide, iduronamide and taluronamide;R4and R5are each independently -H, -halogen, -CH2OH, -OH, -O-alkyl, -CONH2, or optionally substituted alkyl;Y and Z are each independently -H, -OH, -O-alkyl or optionally substituted alkyl;A is H, -OH, -CONH2, -OR6, or -NR7R8;wherein R6is -H or optionally substituted alkyl; and R7and R8are each independently -H, -OH, -O-alkyl or optionally substituted alkyl;n is 0-10; andm is 0-10.

56. The process of claim 55, wherein(a) at least one of the compounds reduces the viscosity of the biological molecule solution;and / or wherein at least one of the compounds reduces the shear stress of the biological molecule solution, thereby reducing the concentration time and / or increasing permeate flux;(b) the viscosity of the biological molecule solution or suspension is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%; and / or wherein the process comprises combining the biological molecule with at least two, three, four, or five compounds; preferably, with at least two compounds;(c) the viscosity of the biological molecule solution or suspension is reduced to below 80 cP, 70 cP, 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; preferably the viscosity of the biological molecule solution or suspension is reduced to below 70 cP, 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 60 cP, 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 50 cP, 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 40 cP, 30 cP, 20 cP, or 10 cP; more preferably the viscosity of the biological molecule solution or suspension is reduced to below 30 cP, 20 cP, or 10 cP;wherein the biological molecule is Dupilumab, Cetuximab, Rituximab, Bevacizumab, Pembrolizumab, Trastuzumab, Etanercept, Infliximab, Omalizumab, or Evolocumab; preferably, the biological molecule is Etanercept, or Omalizumab.

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