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Polymer-drug conjugates

Inactive Publication Date: 2007-05-03
SMARTCELLS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025]“Small molecule”: As used herein, the term “small molecule” refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis), that have a relatively low molecular weight. Typically, small molecules are monomeric and have a molecular weight of less than about 1500 g/mol. Preferred small molecules are biologically active in that they produce a local or systemic effect in animals, preferably mammals, more preferably humans. In certain preferred embodim

Problems solved by technology

In other embodiments, the spacer is susceptible to digestion by the enzyme.

Method used

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  • Polymer-drug conjugates
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Examples

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example 1

Insulin and Glycogen

Insulin

[0087] Human recombinant insulin (HRI) is a well established and well characterized biologic protein made from E. coli. HRI is readily available in large, pharmaceutical-grade quantities from a number of manufacturers, including Eli Lilly, Novo Nordisk, and Diosynth. Insulin activity can be determined using an in vitro insulin receptor binding assay (e.g., see Example 13) and in vivo pharmacokinetic and pharmacodynamic studies using SD rat models (e.g., see later Examples).

Glycogen

[0088] Glycogen can be produced from Golden Bantam sweet corn (Curry Seed Company, Elk Point, S.Dak.) according to a modified procedure (Morris and Morris, J. Biol. Chem. 130:535-544, 1939). Briefly, 10 g of moist sweet corn kernels are ground and extracted with 3×100 ml of deionized water. The combined extracts are strained to remove coarse particles, and filtered through a fritted funnel to remove insoluble starches. The extract is then concentrated to one third the volu...

example 2

Generalized CNBr Conjugation Method

[0089] This example describes a generalized method for making insulin-glycogen conjugates using cyanogen bromide (CNBr) as a coupling agent. Briefly, a known mass of glycogen is dissolved in deionized water at a concentration of 10 mg / ml. Solid CNBr is added to the resulting solution at a CNBr to glycogen mass ratio between 0.05 and 1.5 and the pH maintained constant at 10.7+ / −0.2 using 3N sodium hydroxide (NaOH) solution. After stirring for 15 minutes, another equal mass of solid CNBr equal is added and the pH maintained constant at 10.7+ / −0.2 while stirring for 45 minutes. Insulin is then added to the solution at an insulin to glycogen mass ratio between 0.05 and 0.60 and the pH adjusted to 9.15 using solid sodium bicarbonate. The solution is stirred overnight, ultrafiltered exhaustively against deionized water using a 50 kDa MWCO polyethersulfone disc membrane filter (Millipore, Bedford, Mass.), and lyophilized. The resulting powder is then pu...

example 3

Generalized CDAP Conjugation Method

[0090] This example describes a generalized method for making insulin-glycogen conjugates using cyanodimethylamino-pyridinium tetrafluoroborate (CDAP) as a coupling agent. This synthesis was used to prepare various insulin-glycogen conjugates that are described in later Examples. The inventors have found that this method produces increased insulin loading as compared to the CNBr method of Example 2. Briefly, 8.0 g of glycogen is dissolved in 160 ml of 25 mM HEPES, 0.15 M NaCl, pH 9.0. 2.4-12.0 mL of a 1.0M CDAP solution in DMSO is added dropwise to the glycogen solution at 0° C. After stirring for 1 minute, a volume equal to that of the CDAP solution consisting of 0.2M triethylamine (TEA) is added dropwise over one minute. At this time, the pH of the reaction solution is adjusted to 9.0 using 1.2N HCl. Then, 80-2000 ml of a 10 mg / ml insulin solution in a 20 mM HEPES (pH 9.0) solution is added over the next three minutes and the pH adjusted again ...

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Abstract

A conjugate that includes a drug covalently linked to a polymer. Upon administration, the conjugate is digested by an enzyme that is present at the site of administration thereby releasing a therapeutic agent. The conjugate may demonstrate substantially the same pharmacokinetic and pharmacodynamic behavior as the drug itself. A material for controllably releasing a conjugate in response to the local concentration of a molecular indicator. The material includes a plurality of conjugates and a plurality of multivalent cross-linking agents. The polymers of the conjugates include an analog of the indicator within their covalent structure. The multivalent cross-linking agents include cross-link receptors that interact with the indicator analog and thereby cross-link the conjugates. These non-covalent interactions are competitively disrupted when an amount of the molecular indicator is present thereby causing the material to release the conjugate in a manner that is dependent on the local concentration of indicator.

Description

PRIORITY INFORMATION [0001] This application claims priority to U.S. Ser. No. 60 / 728,652 filed Oct. 19, 2005. The entire contents of this application are hereby incorporated by reference. BACKGROUND OF THE INVENTION [0002] The majority of “controlled-release” drug delivery systems known in the prior art (e.g., U.S. Pat. No. 4,145,410 to Sears which describes drug release from capsules which are enzymatically labile) are incapable of releasing drugs at intervals and concentrations which are in direct proportion to the amount of a molecular indicator (e.g., a metabolite) present in the human body. The delivery or release of drug in these prior art systems is thus not literally “controlled,” but simply a slow release which is independent of external or internal factors. [0003] The treatment of diabetes mellitus with injectable insulin is a well-known and studied example where uncontrolled, slow release of insulin is undesirable. In fact, it is apparent that the simple replacement of th...

Claims

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Application Information

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IPC IPC(8): A61K38/28C07K14/605C07K14/61C07K14/62
CPCA61K38/25A61K38/26A61K38/28A61K47/48215A61K47/4823A61K47/48784C08B30/18C08B37/00C08B37/003C08B37/0069C08B37/0072C08B37/0084Y10S436/827A61K47/60A61K47/61A61K47/6903A61P3/10
Inventor LANCASTER, THOMAS M.NALEWANSKI, MATTHEWZION, TODD C.
Owner SMARTCELLS
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