Acid Salt Forms of Polymer-Drug Conjugates and Alkoxylation Methods

a polymer-drug conjugate and acid salt technology, applied in the field of acid salt compositions, can solve the problems of poor aqueous solubility of pharmaceutical agents, low bioavailability, instability,

Inactive Publication Date: 2013-06-06
NEKTAR THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]In one or more embodiments of the invention, a composition is provided, the composition comprising mixed salts of water soluble polymer-active agent conjugates, wherein the active agent in the conjugate has at least one amine or other basic nitrogen-containing group, and further wherein the amine or

Problems solved by technology

Challenges associated with the formulation and delivery of pharmaceutical agents can include poor aqueous solubility of the pharmaceutical agent, toxicity, low bioavailability, instability, and rapid in-vivo degradation, to name just a few.
Although many approaches have been devised for improving the delivery of pharmaceutical agents, no single approach is without its potential drawbacks.
Another challenge associated with preparing active agent conjugates of water-soluble polymers waters is the ability to prepare relatively pure water-soluble polymers in a consistent and reproducible method.
The preparation of the polymeric reagent suitable to the regulatory requirements for dr

Method used

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  • Acid Salt Forms of Polymer-Drug Conjugates and Alkoxylation Methods
  • Acid Salt Forms of Polymer-Drug Conjugates and Alkoxylation Methods
  • Acid Salt Forms of Polymer-Drug Conjugates and Alkoxylation Methods

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation 1

Preparation of Pentaerythritolyl-4-Arm-(Peg-1-Methylene-2 Oxo-Vinylamino Acetate Linked-Irinotecan)-20K′4-Arm-Peg-Gly-Irino-20K Mixed Acid Salt

[0316]

[0317]All solvents used in synthesis were anhydrous.

Step 1. Conjugation of t-boc-glycine to Irinotecan-HCl salt (>95% yield)

[0318]Irinotecan-HCl-trihydrate (1 mole or 677 g) and DMF (10 L) were charged into a distiller at 60T. Upon dissolution of the irinotecan-HCl-trihydrate in DMF, full vacuum was slowly applied in order to remove water from the irinotecan-HCl-trihydrate by azeotropic distillation at 60° C. Upon solids formation from the residual DMF, heptane (up to 60 L) was charged into the distiller to remove residual DMF at 40-50° C. Upon removal of heptane by visual inspection, the azeotropic distillation was stopped and the solid (irinotecan-HCl) was allowed to cool to 17±2° C. For the coupling reaction, t-hoc-glycine (1.2 mole), 4-DMAP (0.1 mole) dissolved in DCM (1 L), and DCM (19 L) were charged into the distille...

example 2

Characterization of “4-Arm-Peg-Gly-Irino-20K” Product as a Mixed Salt

[0328]The product from Example 1 was analyzed by ion chromatography (IC analysis). See Table 1 below for IC analytical results for various product lots of 4-arm-PEG-Gly-Irino-20K.

TABLE 1Mole Percent of Irinotecan bound to PEGLOT NO.TFA SALTHCl SALTFREE BASE0105936  5 (low)02064 (high)30 603027 (low)244 9 (high)040532621050542620060572815070533314080532720090441936100334126Average of last 7502922lots

[0329]Based upon the IC results provided in Table 1, it can be seen that the product formed in Example 1,4-arm-PEG-Gly-Irino-20K, is a partial mixed salt of approximately 50 mole percent TFA salt, 30 mole percent HCl salt, and 20 mole percent free base, based upon conjugated irinotecan molecules in the product. The mixture of salts was observed even after repeated (1-3) recrystallizations of the product. In the various product lots analyzed above, it can be seen that about 35-65 mole percent of the irinotecan molecules i...

example 3

Stress Stability Studies of 4-Arm-Peg-Gly-Imo-20K

[0331]Stability studies were conducted in an attempt to evaluate the 4-arm-PEG-Gly-Irino-20K product composition. Compositions containing varying amounts of protonated irinotecan, as well as differing in the amount of TFA versus HCl salt were examined.

[0332]Stress Stability Studies

[0333]The product formed in Example 1,4-arm-PEG-Gly-Irino-20K, compound 5. (approximately 1-2 g) was weighed into PEG PE ‘whirl top’ bags and placed into another ‘whirl top’ bag in order to simulate the API packaging conditions. In one study (results shown in FIG. 1), samples were placed in an environmental chamber at 25° C. / 60% RH for 4 weeks. In another study, samples were placed in an environmental chamber at 40° C. / 75% RH for up to several months (results shown in FIG. 2 and FIG. 3). Samples were taken and analyzed on a periodic basis over the course of the studies.

Results

[0334]The results of the studies are shown in FIG. 1, FIG. 2 and FIG. 3. In FIG. 1,...

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Abstract

Among other aspects, provided herein is a mixed-acid salt of a water-soluble polymer-drug conjugate, along with related methods of making and using the same. The mixed-salt acid salt is stably formed, and appears to be more resistant to hydrolytic degradation than the corresponding predominantly pure acid salt or free base forms of the polymer-drug conjugate. The mixed acid salt is reproducibly prepared and recovered, and provides surprising advantages over non-mixed acid salt forms of the water-soluble polymer drug conjugate.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority under 35 U.S.C. §119(e) to each of U.S. Provisional Patent Application Ser. No. 61 / 262,463, filed 18 Nov. 2009, and U.S. Provisional Patent Application Ser. No. 61 / 290,072, filed 24 Dec. 2009, both of which are incorporated herein by reference in their entireties.FIELD[0002]This disclosure relates generally to mixed acid salt compositions of water-soluble polymer-drug conjugates, pharmaceutical compositions thereof, and methods for preparing, formulating, administering and using such mixed acid salt compositions. This disclosure also relates generally to alkoxylation methods for preparing alkoxylated polymeric materials from a previously isolated alkoxylated oligomer, as well as to compositions comprising the alkoxylated polymeric material, methods for using the alkoxylated polymeric material, and the like.BACKGROUND[0003]Over the years, numerous methods have been proposed for improving the ...

Claims

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Application Information

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IPC IPC(8): C08G65/48A61K47/48C07C51/41C07C53/18
CPCA61K47/48215C08G65/329C08G65/33396C07D491/22C07C51/412C07C53/18C08G65/48C08L2203/02A61K47/60C08G65/331A61K31/4745A61P1/04A61P11/00A61P15/00A61P35/00
Inventor CHONG, ANTHONY O.LEE, SEOJUJOSHI, BHALCHANDRA V.BRAY, BRIANNIE, SHAOYONGSPENCE, PATRICK L.KOZLOWSKI, ANTONIMCMANUS, SAMUEL P.TIPNIS, SACHINLAVATY, GREGSWALLOW, DAVIDHANDLEY, JOHN R.SCHAEFER, ANTHONY G.
Owner NEKTAR THERAPEUTICS INC
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