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Cellular uptake of bioactive agents

The use of carbohydrates in an aqueous vehicle enhances the cellular uptake of bioactive compounds like glutamine by 100-2000 times, overcoming solubility and absorption limitations, effectively treating various physiological disorders by delivering higher concentrations of amino acids and other small molecules.

Inactive Publication Date: 2008-01-24
EISAI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The method significantly increases the cellular uptake of bioactive agents like glutamine, glycylsarcosine, and acyclovir into epithelial cells, providing therapeutic benefits for various physiological disorders by delivering higher concentrations of amino acids and other small molecules effectively.

Problems solved by technology

Depletion of glutamine results in atrophy of epithelial tissue, with associated bacterial translocation.
The effectiveness of amino acid supplementation has been limited in some individuals due to aging or disease.
Effective supplementation with certain amino acids is further limited to varying degrees by the low aqueous solubility and limited cellular uptake of some amino acids.
Transport of small molecules into various cell types is controlled by alternate transport systems, making it more difficult to devise methods for increasing cellular uptake into particular cell types.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Evaluation of Cellular Uptake of Glutamine in Combination With Sucrose and Sorbitol

[0062] 1. Materials and Methods

[0063] Distilled, deionized water (107 ml) was added to 207 grams of a mixture of sucrose, sorbitol, and glutamine with excipients (Aesgen-14) as listed in Table 1.

TABLE 1Aesgen-14 (AES-14)L-glutamine240.0Kg57.94 w %* 50.00% w / v**Sucrose144.0Kg34.77 w % 30.00% w / v Crystalline Sorbitol13.44Kg3.24 w %2.80% w / vGlycerin14.0Kg2.92 w %2.52% w / vSodium Phosphate2.6Kg0.63 w %0.54% w / vMonobasic (Anhydrous)Avicel Cellulose874.0g0.18 w %0.17% w / vGel Type CL-611Citric Acid (Anhydrous)280.0g0.07 w %0.06% w / vXanthan Gum230.0g0.05 w %0.04% w / vCarrageenan230.0g0.05 w %0.04% w / vArtificial Flavor230.0g0.05 w %0.04% w / vMethylparaben207.0g0.04 w %0.04% w / vPotassium Sorbate Powder180.0g0.04 w %0.04% w / v30% Simethicone Emulsion115.0g0.02 w %0.02% w / v

*Weight percents are expressed as percent of total weight of dry ingredients for reconstitution with water in a 240 ml bottle.

**Weight / volume...

example 2

Effect of AES-14 on Drug Uptake and Permeability

[0072] The cellular uptake and permeability enhancing effect of a pharmaceutical vehicle on four model drugs (L-glutamine, L-asparagine, glycylsarcosine, acyclovir, along with half saturation L-glutamine) across Caco-2 cell monolayers were measured in this experiment. Uptake and permeability of each compound was measured in the apical-to-basolateral direction, with and without vehicle.

Methods

[0073] Materials. Two amino acids (L-glutamine, L-asparagine), a dipeptide (glycylsarcosine), and a therapeutic agent (and acyclovir) with low permeability were studied. Each compound was tritiated. 14C-mannitol was used as an evaluation of monolayer / cell integrity (i.e. as a low uptake / permeability marker).

[0074] Uptake and Permeability Assessments. Compound cellular uptake into and permeability across Caco-2 monolayers was measured. Caco-2 monolayers were grown using a recently developed, rapid culture system, that requires 4 days rather tha...

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Abstract

Provided is a composition and a method for increasing cellular uptake of bioactive agents, particularly those compounds termed “small molecules” into the cells of mammalian tissue, such as the epithelial cells of the mucosa.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 11 / 255,771, filed Oct. 21, 2005, which application is a continuation of U.S. patent application Ser. No. 10 / 796,261, filed Mar. 9, 2004, which is a divisional of U.S. patent application Ser. No. 09 / 993,465, filed Nov. 14, 2001, now U.S. Pat. No. 6,734,170, which is a continuation under 37 CFR § 1.53(b) of PCT Application Serial No. PCT / US00 / 13260, filed May 15, 2000 and published as WO 00 / 69470 on Nov. 23, 2000, which claimed priority from provisional U.S. Patent Application No. 60 / 134,442, filed May 17, 1999, which applications and publications are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Absorption of biomolecules, such as amino acids and proteins, is critical to cellular function. About 75 percent of the solids in the mammalian body are proteins, including enzymes, polypeptides such as cytokines, nucleoproteins, transport proteins, and structural proteins....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/197A61P29/00C12N5/07A23L1/305A61K9/00A61K9/08A61K31/198A61K31/525A61K31/711A61K47/10A61K47/26A61K47/36A61P1/04A61P3/02A61P17/02A61P31/12C12N5/071
CPCA23L1/3051A61K9/0014A61K47/26A61K31/197A61K31/198A61K9/0095A23L33/175A61P1/02A61P1/04A61P17/02A61P29/00A61P3/02A61P31/12Y02A50/30
Owner EISAI INC