US 2015O157721A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0157721 A1 W (43) Pub. Date: Jun. 11, 2015 (54) POLYMER-CARBOHYDRATE CONJUGATES (52) U.S. Cl. FOR DRUG DELVERY TECHNOLOGY CPC ................. A61K 47/26 (2013.01); A61K 47/28 (2013.01) (71) Applicant: Nian Wu, North Brunswick, NJ (US) (57) ABSTRACT (72) Inventor: Nian Wu, North Brunswick, NJ (US) The invention comprises compounds, methods of making, s s and methods of using. The compounds may have a linear or cylic backbone and three or four appended functional groups: (21) Appl. No.: 14/561,219 one or two lipohilic compounds including sterols or "fat soluble' vitamins, one or two hydrophilic polymer, and one or two carbohydrate. A group of polymer-carbohydrate con (22) Filed: Dec. 5, 2014 jugates having a central backbone and three appended func tional groups are disclosed wherein one lipophilic compound is void of both steroid acids. The conjugate may have fatty Related U.S. Application Data acids as the primary lipophilic carrier, one hydrophilic poly (60) Provisional application No. 61/912,228, filed on Dec. mer, and one carbohydrate. Specific functional groups may be 5, 2013 selected for specific applications in formulating pharmaceu s ticals, cosmetics, nutriceuticals, and the like. Typical cou pling reaction of the conjugates may involve one or more or combinations or in series of alkylation including N-alkylation Publication Classification or O-alkylation, etherification, esterification and amidation chemical processes. A variety of linkers between the back (51) Int. Cl. bone and functional groups may also be selected to modify A6 IK 47/26 (2006.01) the carriers or center backbones for the coupling reactions A6 IK 47/28 (2006.01) and optimize performance of the conjugates. P s\ X,\ x. Xs X-B Xis aX-B and/orf X. S X7-- - H Backbone1 Sugar"NBackbone1 H Sugar \ and/or \ PEG D PEG PEG H PEG Sugar belt- Sugar isitor H -heir | st and/or |-> PEG and/or | Sugar D D D Patent Application Publication Jun. 11, 2015 US 2015/O157721 A1 P s x," X X- b. *is SA x and/or X2 2H--- Ef H H 1.Backbone1 S ugars ackbone1 Sugar \ and/or / PEG D PEG PEG PEG Sugar net- Sugar her i-ester } s and/or } PEG and/or | Sugar D D D Figure : Commercial PEG-carbohydrate conjugates O 4 3. 13 18 3) 34 Time (hr) Figure 2 US 2015/O157721 A1 Jun. 11, 2015 POLYMER-CARBOHYDRATE CONUGATES tively high vehicle contents which may cause side effects FOR DRUG DELIVERY TECHNOLOGY Such as allergic reactions “Cremophor-based paclitaxel 0001. This application claims priority to the provisional chemo drug triggers fatal allergic reactions. The Medical patent application Ser. No. 61/912,228, entitled “Polymer News. 9 June 2009. Carbohydrate Conjugates for Drug Delivery Technology’ 0005. In the design of safe and biocompatible delivery filed in the U.S. Patent and Trademark Office on Dec. 5, 2013, systems, several important factors may be taken into account by Nian Wu. including high solubilization properties and retaining power of the carrier and appropriate Surface characteristics to permit FIELD OF THE INVENTION interactions with potential targeting tissue sites or cell mem 0002 The present invention relates to polymer-carbohy brane permeations. drate conjugates, detailed and specific disclosures are given for synthetic polyethyleneglycol (PEG)-carbohydrate conju 0006. The important role of sugars in many specific inter gates with sterols or so called “fat solable' vitamins ("lipo actions in living systems is well recognized. Large molecular vitamin') as the lipophilic carriers excluding both steroid weight carriers such as proteins or liposomes may be modi acids and fatty acids as the primary lipophilic component in fied with sugars for specific drug delivery (Monsigny M, the conjugates and preferably having Substantially monodis Roche AC, Midoux P and Mayer R. Adv. Drug Delivery Rev., perse PEG chains ifused for intravenous drug administration. 14 (1994): 1-24; Palomino E. Adv. Drug Delivery Rev., 13 More particularly, the present invention relates to novel poly (1994)311-323. Lipid-sugar particles have been used for mer-carbohydrate conjugates having sterols or steroid alco drug delivery to the brain for providing prolonged duration hols or lipophilic Vitamin component to increase lipophilic local anesthesia when injected at the Sciatic nerve in rats characters in the hydrophobic portion or polymer-carbohy Kohane DS, Lipp M. Kinney R. Lotan N. Langer R., Pharm. drate conjugates and their use for drug delivery, cosmetics Res. 17 (2000) 1243-1249. Since sugar-lipids are composed and other purposes. of materials that occur naturally in the human body Suggests potential advantages over Some other polymer-based con BACKGROUND OF INVENTION trolled-release terms of biocompatibility Kohane DS, Lipp 0003 Polyethyleneglycol (PEG) is widely used as a water M. Kinney R. Anthony D, Lotan N. Langer R. J. Biomed. soluble carrier for polymer-drug conjugates. PEG is undoubt Mat. Res. 59 (2002) 450-459; Menei P. Daniel V. Montero edly the most studied and applied synthetic polymer in the Menei C, Brouillard M. Pouplard-Barthelaix A, Benoit JP, biomedical field Duncan, R. Nature Rev. Drug Discov. 2003, Biomaterials, 14 (1993) 470-478. Lipid-sugars have a good 2, 347-360. As an uncharged, water-soluble, nontoxic, non biocompatibility as shown by the results of the in vitro and in immunogenic polymer, PEG is an ideal material for biomedi vivo studies Kohane DS, Lipp M. Kinney R. Anthony D, cal applications. Covalent attachment of PEG to biologically Lotan N, Langer R.J. Biomed. Mat. Res. 59 (2002) 450-459). active compounds is often useful as a technique for alteration and control of biodistribution and pharmacokinetics, mini 0007 Sterol is classified as a lipid in one of the eight lipid mizing toxicity of these compounds Duncan, R. and categories Fahy E. Subramaniam S. Brown H A, et al. Kopecek, J., Adv. Polym. Sci. 57 (1984), 53-101). PEG pos (2005). A comprehensive classification system for lipids”. J. sesses several beneficial properties: Very low toxicity Pang, Lipid Res. 46 (5): 839-61. The lipid classification scheme is S. N.J., J. Am. Coil. Toxicol, 12 (1993), 429–456, excellent chemically based and driven by the distinct hydrophobic and solubility in aqueous solutions Powell, G. M., Handbook of hydrophilic elements that compose the lipid. Sterols and Water Soluble Gums and Resins, R. L. Davidson (Ed.), Ch. 18 related compounds play essential roles in the physiology of (1980), MGraw-Hill, New York, and extremely low immu eukaryotic organisms are a Subgroup of the steroids. They nogenicity and antigenicity Dreborg, S. Crit. Rev. Ther: Drug occur naturally in plants, animals, and fungi, the most famil Carrier Syst., 6 (1990),315-365). The polymer is known to be iar type of animal sterol is cholesterol. Cholesterol is vital to non-biodegradable, yet it is readily excretable after adminis animal cell membrane structure and function and forms part tration into living organisms. In vitro study showed that its of the cellular membrane in animals, where it affects the cell presence in aqueous Solutions has shown no deleterious effect membrane's fluidity and serves as secondary messenger in on protein conformation or activities of enzymes. PEG also developmental signaling Alberts B. Johnson A. Lewis J. Raff exhibits excellent pharmacokinetic and biodistribution M. Roberts K, and Walter P (2002). Molecular biology of the behavior. Yamaoka, T., Tabata, Y. and Ikada, Y., J. Pharm. cell. 4"Edition, NewYork: Garland Science. p. 1874). For the Sci. 83 (1994), 601-606). distinction and clarity, sterols or steroid alcohols ultilized in 0004 Over last three decades, some of promising drug the present invention, as showed in General Formula 1, are carriers that have been investigated in Systemic delivery sys not water soluble and different chemical compounds from tems includes liposomes, polymeric nanoparticles, polymeric those of steroid acids such as cholic acid or other bile acids. micelles, ceramic nanoparticles and dendrimers (Cherian et al. Drug. Dev. Ind. Pharm, 26: (2000) 459-463; Lian and Ho. J. Pharm. Sci, 90 (2001) 66T-680; Adams et al. Pharm. Sci,92 (2003) 1343-1355; Na et al. Eur: J. Med Chem. 41 (2006) 670-674; Kaur et al. J. Control. Rel, 127(2008) 97-109). Systemic drug delivery may be achieved by intravenous or intraperipheral injection and therefore is noninvasive. The drugs may be administered repeatedly as needed. However, in HO order to achieve therapeutic concentrations at the target site, systemic administration requires large dosages with rela US 2015/O157721 A1 Jun. 11, 2015 General Formula 1: Basic Structure of Sterols in the reasons: the pi bond electrons are more polarizable, thus Invention contributing to instantaneous dipole moments, and the vinylic bond tends to be slightly polar, contributing to the permanent 0008. The present invention compromises one of the three dipole moment. In a symmetrical trans disubstituted double carrier groups consisting of a sterol or Sterol-like or "fat bonds, the sum of the dipole moments is Zero. In the analo soluble' vitamin component including but not limited to cho gous cis double bonds, the vector sum of the two dipoles is lesterol, Stigmasterol, ergosterol, hopanoids, phytosterol, directed perpendicular to the double bond. This results in a sitosterol, campesterol, brassicasterol, avenasterol adosterol, non-Zero molecular dipole. The permanent dipole results in and stanols (saturated Steroid alcohols or hydrogenated Ste an increased boiling temperature and lower melting points. rols). Sterols are biological importance as a highly compat Lipophilic vitamins have a general structure of conjugated ible vehicle for drug delivery, for instance cholesterol makes double bonds which increase non-polar interactions with up about 10-50 percent of the total lipid in natural cell mem hydrophobic molecules.