Preparation and Characterization of Salmon Calcitonin–biotin Conjugates

Çetin, Meltem; Youn, Yu Seok; Çapan, Yılmaz; Lee, Kang Choon

doi:10.1208/s12249-008-9165-2

Cited by 14 publications

(3 citation statements)

References 34 publications

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“…Even though it is difficult to compare the results of different research groups due to differences in the calcitonin dose, the dosage form and/or the detection method, we aimed to assess the potential of our best formulation with respect to the outcomes of other studies [30,33,34] . Since the values for the AAC were not available, the assessment of our formulation was based on a comparison of the c min values given.…”

Section: Resultsmentioning

confidence: 99%

Liposomes coated with thiolated chitosan enhance oral peptide delivery to rats

Gradauer

Barthelmes

Vonach

et al. 2013

Journal of Controlled Release

116

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The aim of the present study was the in vivo evaluation of thiomer-coated liposomes for an oral application of peptides. For this purpose, salmon calcitonin was chosen as a model drug and encapsulated within liposomes. Subsequently, the drug loaded liposomes were coated with either chitosan–thioglycolic acid (CS–TGA) or an S-protected version of the same polymer (CS–TGA–MNA), leading to an increase in the particle size of about 500 nm and an increase in the zeta potential from approximately − 40 mV to a maximum value of about + 44 mV, depending on the polymer. Coated liposomes were demonstrated to effectively penetrate the intestinal mucus layer where they came in close contact with the underlying epithelium. To investigate the permeation enhancing properties of the coated liposomes ex vivo, we monitored the transport of fluoresceinisothiocyanate-labeled salmon calcitonin (FITC-sCT) through rat small intestine. Liposomes coated with CS–TGA–MNA showed the highest effect, leading to a 3.8-fold increase in the uptake of FITC-sCT versus the buffer control. In vivo evaluation of the different formulations was carried out by the oral application of 40 μg of sCT per rat, either encapsulated within uncoated liposomes, CS–TGA-coated liposomes or CS–TGA–MNA-coated liposomes, or given as a solution serving as negative control. The blood calcium level was monitored over a time period of 24 h. The highest reduction in the blood calcium level, to a minimum of 65% of the initial value after 6 h, was achieved for CS–TGA–MNA-coated liposomes. Comparing the areas above curves (AAC) of the blood calcium levels, CS–TGA–MNA-coated liposomes led to an 8.2-fold increase compared to the free sCT solution if applied orally in the same concentration. According to these results, liposomes coated with S-protected thiomers have demonstrated to be highly valuable carriers for enhancing the oral bioavailability of salmon calcitonin.

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Section: Resultsmentioning

confidence: 99%

Liposomes coated with thiolated chitosan enhance oral peptide delivery to rats

Gradauer

Barthelmes

Vonach

et al. 2013

Journal of Controlled Release

116

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“…Furthermore, direct site-specific PEGylation to the lysine-18 of salmon calcitonin (sCT) increased peptide stability and led to decreased serum calcium levels upon intra-duodenal instillation in rats [33]. Biotinylation of sCT has been shown to increase transmucosal flux across Caco-2 monolayers through targeting of apical membrane biotin receptors [34]. An alkylated PEGylated amphiphilic insulin conjugate (HIM-2, Biocon Corp., India) increased oral F of insulin in dogs [35] and has reached Phase II clinical studies [36].…”

Section: [11] Alternative Approaches To Delivery Of Poorly Permeablementioning

confidence: 99%

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

197

176

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A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable Class III drugs across the intestinal epithelium.To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository.Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be coreleased in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. The most advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C 10 ) , a compound already approved as a direct food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level and in vitro and in vivo efficacy and safety studies.In specific clinical examples, we review how C 10 -based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET® (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for anti-sense oligonucleotides (ISIS Pharmaceuticals, USA).Keywords: Oral drug delivery, Sodium caprate (C 10 ), absorption promoter, drug delivery platforms, clinical trials, oral formulation, drug delivery systems.3 TJs form a barrier to the uncontrolled absorption of noxious luminal antigens (gate function), and maintain epithelial polarity (fence function) [8,9]. In general, the TJ consists of a restrictive pathway (shunt) with a sharp molecular size cut off, and a second unrestrictive pathway (small pore) that permits paracellular permeation of molecules of radii <4.0 Å [10,11]. Depending on the intestinal region, TJ pore sizes range from 6-22Å, sufficient to permit mannitol (6.7 Å) and EDTA (10.8 Å) to permeate to an extent, whereas the passage of inulin (30-40 Å) and fluorescent-dextran 4kDa (FD-4, 26 Å) is essentially impeded [12][13][14][15][16].A number of approaches have been used to promote oral delivery of Class III drugs ( Alternatively, the use of nanoparticles comprising biocompatible polymers (e.g. chitosan,polylactide-co-glycolide, starch and glucans) can protect cargoes from GI proteases, increase GI retention and promote absorption across gut associated lymphoid tissue (GALT) and to a lesser extent, enterocytes [45][46][47]. Most data on nanoparticle absorption from rodent models suggest that M cells in the follicle-associated epithelium of Peyer's patches (PP) are the favored site of uptake for particles of diameter 500nm-1000nm [45].Given the paucity of M cells in the GI tract of adults, the relevance of PP uptake remains controversial ...

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“…It is used nasally as a spray once a day, alternating with an injection used once a day or once every other day (Mark and Ettinger, 2003). Because sCT has very low permeability across biological membranes and also is metabolized by intestinal serine proteases (Cetin et al, 2008), replacement of this conventional delivery by an oral delivery system has proven difficult. Shah and Khan (2004) investigated the maximum permeability region of sCT in GIT of rats, and also determined the transport mechanisms of sCT through Caco-2 cell monolayer.…”

Section: Discussionmentioning

confidence: 99%

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles:in vitroandin vivoevaluation

Çetin

Aktaş

Vural

et al. 2011

Journal of Microencapsulation

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The main objective of this study was to prepare salmon calcitonin (sCT)-loaded Eudragit®RSPO, Eudragit®L100 and Eudragit®-poly(lactic-co-glycolic acid) blend nanoparticles for in vitro and in vivo evaluation as an oral drug delivery system. The prepared nanoparticles ranged in size from 179.7 to 308.9 nm with a polydispersity index between 0.051 and 2.75, and had surface charges ~ -11 to +6 mV. Efficient sCT encapsulation and release was observed with all the nanoparticle formulations. The polymer type was an important factor that influenced the release characteristics and the in vivo hypocalcemic effect. Nanoparticle formulations were also prepared with sodium taurodeoxycholate (NaTDC) and characterized. No statistically significant difference was noted between the hypocalcemic effect of any of the nanoparticle formulations with and without NaTDC (p > 0.05). The use of Eudragit®RSPO nanoparticles appears to be a potential approach for the oral delivery of sCT.

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Preparation and Characterization of Salmon Calcitonin–biotin Conjugates

Cited by 14 publications

References 34 publications

Liposomes coated with thiolated chitosan enhance oral peptide delivery to rats

Liposomes coated with thiolated chitosan enhance oral peptide delivery to rats

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles:in vitroandin vivoevaluation

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