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Gastrointestinal Absorption Enhancer Mediated By Proton-Coupled Transporter and Its Preparing Method

a proton-coupled transporter and enhancer technology, which is applied in the direction of antibacterial agents, peptide/protein ingredients, drug compositions, etc., can solve the problems of insufficient pharmacological effects, cell damage, and inability to obtain substrate specificity in absorption, so as to improve the cellular absorption of pharmaceutical compositions and excellent gastrointestinal absorption

Inactive Publication Date: 2008-05-22
OTSUKA PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a pharmaceutical preparation that improves the gastrointestinal absorption of a pharmaceutical composition by using a proton-coupled transporter and a pH-sensitive polymer. The pH-sensitive polymer is added in an amount sufficient to give the gastrointestinal tract a pH at which the proton-coupled transporter optimally functions for cellular uptake of the compound. The pharmaceutical preparation can be produced using the described method. The invention also provides a method for evaluating the pH at which the proton-coupled transporter optimally functions for cellular uptake of the compound. The pharmaceutical preparation can be used for oral administration or other methods of delivery. The invention also provides specific examples of pH-sensitive polymers that can be used in the pharmaceutical preparation.

Problems solved by technology

However, many candidate compounds for medicinal products exhibit low absorbability when administered orally since they have a low membrane permeability in the gastrointestinal tract or they are unstable therein, thereby facing a condition of being unable to maintain the blood concentration for sufficient pharmacological effects.
However, these methods pose the problem of cell damage by the absorption enhancers, which are primarily added to enhance absorption.
However, these methods cause problems such that no substrate specificity is obtained in absorption.
However, this reference does not suggest the use of transporters to improve gastrointestinal absorption, and has, as with the prior art methods described above, the problem of not imparting substrate specificity to gastrointestinal absorption.
In addition, there have been no prior art methods that enhance the absorption of organic compounds that are, despite being substrates for influx transporters, of poor absorbability.

Method used

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  • Gastrointestinal Absorption Enhancer Mediated By Proton-Coupled Transporter and Its Preparing Method
  • Gastrointestinal Absorption Enhancer Mediated By Proton-Coupled Transporter and Its Preparing Method
  • Gastrointestinal Absorption Enhancer Mediated By Proton-Coupled Transporter and Its Preparing Method

Examples

Experimental program
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Effect test

example 1

[0093]To investigate the effect of extracellular fluid on the cellular uptake of dipeptides and β-lactam antibiotics transported by PEPT1, the cellular uptake of dipeptides, i.e., [14C]glycylsarcosine ([14C]GlySar) and [3H]carnosine, and β-lactam antibiotics, i.e., cefadroxil (CDX), cefixime (CFIX), and FK089, was evaluated at pH 5.0 to 7.0 using gastrointestinal tract model cells (Caco-2 cells).

[0094]Cells cultured on 4-well plates were rinsed 3 times with 1 mL Hanks' balanced salt solution (HBSS: 0.952 mM CaCl2, 5.36 mM KCl, 0.441 mM KH2PO4, 0.812 mM MgSO4, 136.7 mM NaCl, 0.385 mM Na2HPO4, 25 mM D-glucose, 10 mM HEPES; pH 7.4; osmotic pressure 315 mOs / kg) heated to 37° C., and uptake was initiated by adding 250 μL HBSS containing medical fluid. Uptake was terminated at a predetermined period of time by washing the cells 3 times with 1 mL ice-cooled HBSS. After the completion of uptake, 0.25 mL 5 N NaOH was added, and the cells were agitated for 2 hours to solubilize, followed by n...

example 2

[0100]To investigate whether it is possible to control pH by adding pH-sensitive polymers, the effect of such a polymer on the pH of MES buffer was examined.

[0101]A methacrylic acid copolymer (Eudragit L100-55) was used as a pH-sensitive polymer, and an aminoalkyl / methacrylate copolymer (Eudragit RS PO) was used as a pH-insensitive polymer.

[0102]A polymer (methacrylic acid copolymer Eudragit L100-55 or, of a pH-insensitive polymer, aminoalkyl / methacrylate copolymer Eudragit RS PO) was added to MES buffer (pH 6.0). Subsequently, the pH of the buffer was measured by a pH meter.

[0103]The pH of the buffer decreased as Eudragit L100-55 was added (FIG. 2). In FIG. 2, plots () represent the pH of the MES buffer containing Eudragit RS PO, and plots (◯) represent the pH of the MES buffer containing Eudragit L100-55. Compared with the pH of the buffer having no polymer content, pH was decreased to about 3.0 when Eudragit L100-55 was added to a proportion of 20%. In contrast, the use of Eudra...

example 3

[0104]To investigate whether gastrointestinal absorption in rats of β-lactam antibiotics under physiological conditions can be improved by controlling the gastrointestinal pH, absorption of a zwitterionic compound (CDX) and an anionic compound (CFIX) in the presence and absence of a pH-sensitive polymer (Eudragit L100-55) was examined using the in situ closed loop method (FIG. 6 shows a diagram).

[0105]The oral composition of the invention was prepared by adding a β-lactam antibiotic (CDX or CFIX) to 10 mM MES buffer (pH 6.0) such that the buffer contained CDX in an amount of 1 mM or CFIX in an amount of 0.5 mM, and further adding Eudragit L100-55 to the buffer so that it contained in a proportion of 10 or 20 wt. % based on the amount of the entire oral composition. A β-lactam antibiotic solution containing no Eudragit L100-55 was prepared as a control.

[0106]These compositions were administered into the intestinal loops prepared at the caecum junction of SD male rats (junction betwee...

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Abstract

The present invention provides a pharmaceutical preparation that can improve absorption of a pharmaceutical compound in the gastrointestinal tract and that provides, through oral administration or like method, a blood concentration from which sufficient remedial effects can be expected, and a method for producing such a preparation. The invention is directed to a pharmaceutical preparation exhibiting excellent gastrointestinal absorbability comprising a compound recognized by a proton-coupled transporter and a pH-sensitive polymer in an amount sufficient for the gastrointestinal tract to acquire a pH at which the proton-coupled transporter optimally absorbs the compound into a cell.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Divisional of U.S. application Ser. No. 10 / 541,019, filed Jun. 28, 2005; which is a 371 of PCT / JP2004 / 000070, filed Jan. 8, 2004; the disclosure of which is incorporated herein by reference.TECHNICAL FIELD[0002]The present invention relates to a gastrointestinal absorption enhancer mediated by a proton-coupled transporter and a method for preparing it.BACKGROUND OF THE INVENTION[0003]For many chronically diseased areas, oral administration is generally considered as a desirable route of pharmaceutical administration in view of convenience and cost. However, many candidate compounds for medicinal products exhibit low absorbability when administered orally since they have a low membrane permeability in the gastrointestinal tract or they are unstable therein, thereby facing a condition of being unable to maintain the blood concentration for sufficient pharmacological effects.[0004]Moreover, it is known that there are so...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/30A61K45/08A61K47/32A61P31/04A61P31/12A61P35/00A61P43/00
CPCA61K47/32A61K9/0053A61K9/08A61K31/545A61K31/546A61P1/00A61P1/14A61P31/04A61P31/12A61P35/00A61P43/00A61K38/02A61K45/00
Inventor TSUJITAMAI, IKUMISAI, YOSHIMICHIODOMI, MASAAKITOYOBUKU, HIDEKAZU
Owner OTSUKA PHARM CO LTD
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