PEGylation of Octreotide: I. Separation of Positional Isomers and Stability Against Acylation by Poly(D,L-lactide-co-glycolide)

Na, Dong Hee; DeLuca, Patrick P.

doi:10.1007/s11095-005-2589-4

Cited by 84 publications

(97 citation statements)

References 23 publications

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“…Therefore, the α-amino group of the N terminus would be more reactive than that of the Lys residue at low pH, whereas the ε-amino group of the Lys residue would be more susceptible to the MA-conjugation reaction at high pH. This phenomenon was demonstrated in the previous studies (9). As shown in Fig.…”

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confidence: 59%

“…Among several instability issues of peptides in PLGA matrix, the formation of acylated peptide impurities has emerged as significant instability mechanism in PLGA formulations (5,6). The acylated peptides are formed as a result of acylation of peptide's amines with ester backbone of PLGA followed by release of peptides conjugated with lactic or glycolic acid units by polymer hydrolysis (7)(8)(9). Nucleophilic groups of peptides, such as the primary amino groups present in the N terminus and Lys residue, have been reported to be the major targets for peptide acylation (8).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the efficacy of water-soluble divalent cationic salts was proposed for inhibition of acylation of octreotide in PLGA microspheres (18,19). We previously proposed the covalent conjugation of PEG to peptide for inhibiting peptide acylation and increasing the pharmacokinetic property (9,(20)(21)(22). This study proposes the reversible blocking of peptide's amino groups using maleic anhydride (MA), which is reversible amine-protective reagent (23).…”

Section: Introductionmentioning

confidence: 99%

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Reversible Blocking of Amino Groups of Octreotide for the Inhibition of Formation of Acylated Peptide Impurities in Poly(Lactide-co-Glycolide) Delivery Systems

et al. 2011

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Abstract. The purpose of this study was to develop a novel method to inhibit the formation of acylated peptide impurities in poly(D,L-lactide-co-glycolide) (PLGA) formulations by reversely blocking the amino groups of octreotide with maleic anhydride (MA). Two mono-MA conjugates with different modification sites (N terminus and Lys residue) and di-MA conjugate of octreotide were prepared and isolated by reversed-phase high-performance liquid chromatography (RP-HPLC). The polymer interaction of peptides and the formation of acylated peptides were monitored by RP-HPLC. The stability of MA-octreotide conjugates in PLGA films was studied in 0.1 M phosphate buffer (pH 7.4) at 37°C. The conjugation of MA to octreotide substantially inhibited the interaction of peptide with PLGA polymer and the subsequent formation of acylated peptide impurities. The MA-octreotides were successfully converted to intact octreotide as pH drops by PLGA hydrolysis. In PLGA films, MAoctreotide also showed complete inhibition of peptide acylation. In conclusion, MA conjugation provides a viable approach for stabilizing peptides in PLGA delivery systems.

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confidence: 59%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reversible Blocking of Amino Groups of Octreotide for the Inhibition of Formation of Acylated Peptide Impurities in Poly(Lactide-co-Glycolide) Delivery Systems

et al. 2011

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“…Measurement Condition 8,19) A CAPCELL PAK C 18 HPLC packed column type MG 5 µm (4.6 mm I.D.×150 mm); flow rate 1.5 mL/min; column oven set at 40°C; injection volume 200 µL; detection wavelength 215 nm. The mobile phase consisted of deionized water containing 1% trifluoroacetic acid (TFA) and acetonitrile (75 : 25).…”

Section: Methodsmentioning

confidence: 99%

Prediction of the Stability of Octreotide in a Mixed Infusion

Takasu

Yoshida

Shimizu

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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The purpose of this study was to predict the stability of octreotide in a mixed infusion containing sodium bisulfite (SBS). In aqueous solution the hydrolysis of octreotide was found to be accelerated by pH, and by increasing concentrations of SBS. Equations for the degradation rate constants (k obs ) of pH and SBS were derived. The fractional rate constants were estimated by the nonlinear least-squares method (quasiNewton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the pH characteristic (PHC) curve. From these results, an equation was derived giving the residual ratio (%) of octreotide at any time after mixing an infusion containing SBS at any temperature in the pH range 4.0-7.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).Key words stability prediction; octreotide; pH; sodium bisulfite (SBS); pH characteristic (PHC) curve; degradation rate constant, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin.1-3) The cyclic structure of octreotide ( Fig. 1) seems to play an important role in determining its unique pharmacological activity.Octreotide is increasingly used to treat symptoms of sickness and vomiting in terminal care patients suffering from gastrointestinal ileus. It is also used, in combination with standard therapies, in the symptom management of inoperable bowel obstructions in terminal cancer patients. [4][5][6] In Japan, octreotide is usually administered subcutaneously, but in the U.S. it is more often administered by deep subcutaneous (intrafat) or intravenous injection.3) The pharmacokinetics of octreotide are similar to those of many other agents administered continuously via intravenous or subcutaneous infusion, 7) and similar changes in pharmacokinetics would be expected if octreotide were to be administered by continuous intravenous administration instead of sustained subcutaneous administration, i.e., without the need for special equipment (e.g., miniature pump).We have been unable to find any reports describing the time-dependent stability of octreotide in amino acid infusions under different pH, temperature and ingredient such as sodium bisulfite. Especially, we have been unable to find reports evaluating such time-dependent stability of octreotide in amino acid infusions quantitatively.Hanamura et al. 8) report on the stability of octreotide in glucose and saline infusions, but its stability in amino acid infusion fluids was not investigated in detail. We have been unable to find any reports describing the stability of octreotide in amino acid infusions. Sodium bisulfite (SBS), which is used as a stabilizer in injectable preparations, is known to degrade various drugs, including thiamine, 9) epinephrine, 10) gabexate mesilate, 11) nafamostat mesilate, 12) urokinase, 13) morphine, 14)fluorouracil 15) and imipenem. 16) However, there ...

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“…In the previous studies, we demonstrated that the acylated peptides are formed as a result of reaction of primary amino groups of peptide (N-terminal and lysine's amines) with ester backbone of PLGA (Na et al, 2005). The mechanism of acylated peptide formation has been proposed to involve an initial ionic interaction between cationic peptide and carboxylate endgroup of PLGA, followed by a nucleophilic attack of peptide's amines to ester groups of PLGA and subsequent release of acylated peptides by PLGA hydrolysis.…”

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confidence: 99%

Effect of Peptide Charge on the Formation of Acylated Peptide Impurities in PLGA Formulations

Na¹

2011

Journal of Pharmaceutical Investigation

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− The purpose of this study was to investigate the effect of peptide charge on the interaction between peptide and poly(D,L-lactide-co-glycolide) (PLGA) for evaluating mechanism of acylated peptide formation in PLGA matrix. As a model peptide, octreotide, a synthetic somatostatin analogue and active ingredient of commercial PLGA product, was used. The disulfide group of octreotide was reduced with dithiothreitol and the sulfhydryl groups were modified with N-β-maleimidopropionic acid (BMPA) to neutralize octreotide with positive charge in physiological conditions. The BMPA-conjugated octreotide was identified by measuring the molecular mass with liquid chromatography-mass spectrometry. In the interaction study with PLGA, native octreotide showed initial adsorption to PLGA and substantial production of acylated peptides (56% of overall peptide), whereas BMPA-conjugated octreotide showed minimal adsorption to PLGA and no acylation products for 42 days. Consequently, the neutralization of octreotide completely inhibited the peptide acylation by preventing interaction of peptide with PLGA. In conclusion, this study demonstrates that the initial polymer interaction of peptide is important step for peptide acylation in PLGA matrix and suggests the modulation of peptide charge as strategy for inhibiting the formation of acylated peptide impurities.

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PEGylation of Octreotide: I. Separation of Positional Isomers and Stability Against Acylation by Poly(D,L-lactide-co-glycolide)

Abstract: This study shows that the N-terminus of octreotide is the preferred PEGylation site to prevent acylation in degrading PLGA microspheres. The mono-N-terminally PEGylated octreotide may possibly serve as a new source for somatostatin microsphere formulation.

Cited by 84 publications

References 23 publications

Reversible Blocking of Amino Groups of Octreotide for the Inhibition of Formation of Acylated Peptide Impurities in Poly(Lactide-co-Glycolide) Delivery Systems

Reversible Blocking of Amino Groups of Octreotide for the Inhibition of Formation of Acylated Peptide Impurities in Poly(Lactide-co-Glycolide) Delivery Systems

Prediction of the Stability of Octreotide in a Mixed Infusion

Effect of Peptide Charge on the Formation of Acylated Peptide Impurities in PLGA Formulations

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