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Agent improving proton-driven transporter-mediated absorption in digestive tract and process for producing the same

Inactive Publication Date: 2006-06-08
TSUJI AKIRA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] An object of the invention is to provide a pharmaceutical preparation that can improve cellular absorption of a pharmaceutical composition and that can provide, through oral administration or like method, a blood concentration from which sufficient remedial effects can be expected, and to provide a method for producing such a preparation. Specifically, an object of the invention is to provide a pharmaceutical preparation having an excellent gastrointestinal absorbability comprising a compound recognized by a proton-coupled transporter and a pH-sensitive polymer in an amount sufficient to give a desirable pH at which the proton-coupled transporter optimally transports the compound into a cell in the gastrointestinal tract, and a production method thereof.
[0011] (2) By adding a specific amount of pH-sensitive polymers to the substrate, the driving force of peptide transporters is increased and the gastrointestinal absorption of substrates having a tendency to be poorly absorbed is improved.
[0038] Item 20. Use of a pH-sensitive polymer, to enhance gastrointestinal absorbability of a compound recognized by a proton-coupled transporter, in an amount sufficient to impart to the gastrointestinal tract a pH at which the proton-coupled transporter optimally transports the compound into a cell.
[0084] In particular, it is preferable to formulate an enteric, sustained-release pharmaceutical preparation or the like that can deliver the medicament and pH-sensitive polymer throughout the gastrointestinal tract. Furthermore, the pharmaceutical preparation can be formulated into a liquid form (such as solution, suspension, syrup, and the like) containing the medicament and pH-sensitive polymer, thereby, compared with conventional tablets, enabling more thorough delivery of the medicament and pH-sensitive polymer, due to its water content, throughout the gastrointestinal tract. The pharmaceutical preparation can be formulated into these forms according to known methods.
[0085] The pharmaceutical preparation of the invention enhances the absorbability of a compound recognized by a proton-coupled transporter in the gastrointestinal tract because the gastrointestinal tract is conditioned by the pH-sensitive polymer contained therein to the pH optimum for cellular uptake of the compound. In particular, since the pharmaceutical preparation of the invention contains a pH-sensitive polymer in an amount sufficient to maintain the pH optimum for cellular uptake, medicament (substrate) can be readily absorbed even in the lower gastrointestinal tract (ileum and so on) where the amount of protons is decreased, and thereby a decrease in transporting ability of proton-coupled transporters is inhibited. Hence, the pharmaceutical preparation of the invention, even when administered orally, can provide a sufficient blood concentration of a medicament and achieve high bioavailability. Incidentally, the pH-sensitive polymer temporarily controls the pH of the gastrointestinal tract and does not adversely affect the gastrointestinal tract. The phrase “the pH-sensitive polymer temporarily controls the pH” means that the pH of a site where a substrate is absorbed into cells is impermanently controlled for an amount of time necessary for the cellular absorption of the substrate to complete.

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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  • Agent improving proton-driven transporter-mediated absorption in digestive tract and process for producing the same
  • Agent improving proton-driven transporter-mediated absorption in digestive tract and process for producing the same
  • Agent improving proton-driven transporter-mediated absorption in digestive tract and process for producing the same

Examples

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Effect test

example 1

[0094] 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).

[0095] 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 b...

example 2

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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 o...

example 3

[0105] 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).

[0106] 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.

[0107] These compositions were administered into the intestinal loops prepared at the caecum junction of SD male rats (junction b...

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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

TECHNICAL FIELD [0001] 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 [0002] 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. [0003] Moreover, it is known that there are some organic compounds that show a tendency of being barely absorbed although they are reported to be recognized by influx transporters expressed in small-intestinal epithelial cells (for example, Sakamato et al., J. Antibiot. 38 (1985): 496-504, and K...

Claims

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Application Information

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IPC IPC(8): A61K31/401A61K31/198A61K9/20A61K31/716A61K45/08A61K47/32A61P31/04A61P31/12A61P35/00A61P43/00
CPCA61K47/32A61K9/0053A61K9/08A61K31/545A61K31/546A61P1/00A61P1/14A61P31/04A61P31/12A61P35/00A61P43/00A61K38/02A61K45/00
Inventor TSUJI, AKIRATAMAI, IKUMISAI, YOSHIMICHIODOMI, MASAAKITOYOBUKU, HIDEKAZU
Owner TSUJI AKIRA
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