A new drug carrier, N?-deoxycholyl-l-lysyl-methylester, for enhancing insulin absorption in the intestine

Lee, Sungbae; Lee, J.; Lee, D. Y.; Kim, S. K.; Lee, Y.; Byun, Youngro

doi:10.1007/s00125-004-1658-2

Cited by 43 publications

(35 citation statements)

References 30 publications

(27 reference statements)

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“…Oral delivery of the insulin:DCK complex improved oral insulin absorption in rats by 6-fold [346]. In dogs, absorption of the insulin-DCK complex (42 IU/kg) was comparable to the i.v.…”

Section: Peptide Hydrophobisationmentioning

confidence: 91%

Intestinal permeation enhancers for oral peptide delivery

Maher

Mrsny

Brayden

2016

Advanced Drug Delivery Reviews

282

201

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Publication informationAdvanced Drug Delivery Reviews, (Part B): 277-319 Publisher ElsevierItem record/more information http://hdl.handle.net/10197/7800Publisher's statement þÿ T h i s i s t h e a u t h o r s v e r s i o n o f a w o r k t h a t w a s a c c e p t e d f o r p u b l i c a t i o n i n A d v a n c e d D r u g Delivery Reviews. Changes resulting from the publishing process, such as peer review,

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“…Oral delivery of the insulin:DCK complex improved oral insulin absorption in rats by 6-fold [346]. In dogs, absorption of the insulin-DCK complex (42 IU/kg) was comparable to the i.v.…”

Section: Peptide Hydrophobisationmentioning

confidence: 91%

Intestinal permeation enhancers for oral peptide delivery

Maher

Mrsny

Brayden

2016

Advanced Drug Delivery Reviews

282

201

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“…In a previous study, we developed a new oral delivery carrier based on bile acids, which could improve the oral bioavailability of therapeutically active peptides without damaging the tissue structure of the mucous membrane (8,9). Based on the observation that associated bile acid could increase the absorption of a poorly absorbable drug in the intestine, we prepared a positively charged carrier by simple modification of bile acid, cholic acid, with ethylenediamine for the negatively charged small organic molecules, CRO.…”

mentioning

confidence: 99%

“…and a hydrophilic ␤-side (10, 13). The natural physicochemical and enterohepatic circulation properties of the bile acids could be utilized for the preparation of new drugs (4,7,8,16). Our concept was to design a delivery carrier based on bile acid molecules that could physically interact with oppositely charged hydrophilic, and thus poorly absorbable, drugs.…”

mentioning

confidence: 99%

“…Once CEA makes an ion-pairing interaction with CRO based on opposite electrostatic charges, it increases the lipophilicity and stability of the native drug by combining a hydrophobic steroid nucleus of bile acid with CRO. Increased lipophilicity improves the absorption of the drug by the mucosal membrane, and increased stability would prolong the therapeutic activity of the drug in the gastrointestinal region (8). Furthermore, these synthetic delivery carriers would maintain the biological activities of the therapeutic drug at a reduced enhancer concentration, because the enhancer directly interacts with drugs by electrostatic interaction, unlike other prodrug forms or conventional penetration enhancers.…”

mentioning

confidence: 99%

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Pharmacokinetics of a New, Orally Available Ceftriaxone Formulation in Physical Complexation with a Cationic Analogue of Bile Acid in Rats

Lee

Kim

Lee

et al. 2006

Antimicrob Agents Chemother

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Oral administration of ceftriaxone associated with a bile acid-based new oral carrier, cholylethylenediamine, in 50% propylene glycol to rats at doses of 25 and 50 mg/kg of body weight resulted in a significant increase in intestinal absorption, as evidenced by 55% improvement in the bioavailability, whereas ceftriaxone alone showed a bioavailability of less than 1%.The introduction of new oral cephalosporins, or formulation development of existing and highly promising parenteral cephalosporins, provides a possibility for follow-up oral treatment after initial parenteral treatment, thus reducing hospitalization time and costs (5,6,14). Ceftriaxone (CRO) is a widely used injectable broad-spectrum cephalosporin that exhibits potent activity against gram-positive and gram-negative bacteria (1, 2, 11, 12). However, the therapeutic utility of ceftriaxone is limited, as it requires parenteral infusion for its administration. In this respect, the development of an oral formulation of CRO would be helpful in rapid and proper step-down therapy that would lead to better patient compliance without compromising the therapeutic activity.In a previous study, we developed a new oral delivery carrier based on bile acids, which could improve the oral bioavailability of therapeutically active peptides without damaging the tissue structure of the mucous membrane (8, 9). Based on the observation that associated bile acid could increase the absorption of a poorly absorbable drug in the intestine, we prepared a positively charged carrier by simple modification of bile acid, cholic acid, with ethylenediamine for the negatively charged small organic molecules, CRO. This scheme was designed with the goal of preparing a carrier that could physically associate with the drug by ion pair interaction to improve its lipophilicity without altering the structure of the native drug. In the present study, we show that the positively charged bile acid analogue forms a complex with CRO and report the impact of this association on the oral bioavailability.Cholylethylendiamine (CEA) was synthesized by using cholic acid and ethylenediamine as precursors. A delivery agent was composed of the hydrophobic part of bile acid and the positive charge of ethylenediamine, thereby facilitating an ionpairing interaction with anionic drug, CRO. The complex formation in aqueous medium was reversible and dependent on the molar ratio between CRO and the delivery agent. Since CRO/CEA complexes showed significantly reduced solubility in water, the lyophilized drug complex was reformulated by the addition of one of the most common water-soluble solvents, propylene glycol (PG) (15), as a prototype formulation.The partition coefficients of CRO/CEA complexes were investigated in an n-octanol/water system. CRO concentrations were analyzed on a reversed-phase high-performance liquid chromatograph (RP-HPLC) (Shimadzu, Tokyo, Japan) as previously described (3). Briefly, a 50-l aliquot of supernatant was injected into an RP-HPLC fitted with an Eclipse XDB analytical column (25...

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“…General structural formula of bile acid-peptide conjugates studied by Swaan et al [100]. Recombinant human insulin has covalently been attached to deoxycholic acid derivatives with the aim of synthesizing orally active insulin analogs [123,124]. Conjugation to bile acid might, but increase the metabolic stability against peptidases as well as absorption from the intestine enabling oral administration of insulin instead of parenteral injections, prolong the biological activity of native insulin in the physiological conditions.…”

Section: Bile Acid-containing Prodrugsmentioning

confidence: 99%

Exploitation of Bile Acid Transport Systems in Prodrug Design

Sievänen

2007

Molecules

102

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Abstract:The enterohepatic circulation of bile acids is one of the most efficient recycling routes in the human body. It is a complex process involving numerous transport proteins, which serve to transport bile acids from the small intestine into portal circulation, from the portal circulation into the hepatocyte, from the hepatocyte into the bile, and from the gall bladder to the small intestine. The tremendous transport capacity and organ specificity of enterohepatic circulation combined with versatile derivatization possibilities, rigid steroidal backbone, enantiomeric purity, availability, and low cost have made bile acids attractive tools in designing pharmacological hybrid molecules and prodrugs with the view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, specifically targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically reasonable systemic concentrations of active agents. This article briefly describes bile acid transport proteins involved in enterohepatic circulation, summarizes the key factors affecting on the transport by these proteins, and reviews the use of bile acids and their derivatives in designing prodrugs capable of exploiting the bile acid transport system.

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A new drug carrier, N?-deoxycholyl-l-lysyl-methylester, for enhancing insulin absorption in the intestine

Abstract: The results of this study demonstrate that the insulin/DCK formulation can be absorbed in the intestine and that it is biologically efficacious. We therefore suggest that this oral formulation could be used as an alternative to injectable insulin with enhanced clinical effects.

Cited by 43 publications

References 30 publications

Intestinal permeation enhancers for oral peptide delivery

Intestinal permeation enhancers for oral peptide delivery

Pharmacokinetics of a New, Orally Available Ceftriaxone Formulation in Physical Complexation with a Cationic Analogue of Bile Acid in Rats

Exploitation of Bile Acid Transport Systems in Prodrug Design

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