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Injectable long-acting systems for Radix Ophiopogonis polysaccharide based on mono-PEGylation and in situ formation of a PLGA depot.

Shi X, Lin X, Zheng X, Feng Y, Shen L - Int J Nanomedicine (2014)

Bottom Line: Relative to ROP, the half-life of which was only 0.5 hours, the conjugate alone, following subcutaneous administration, showed markedly prolonged retention in the systemic circulation, with a mean residence time in vivo of approximately 2.76 days.In combination with in situ-forming PLGA depots, the residence time of the conjugate in vivo was prolonged further.For high-dose and highly hydrophilic macromolecular drugs like ROP, more than one preparation technology might be needed to achieve week-long or month-long delivery per dosing.

View Article: PubMed Central - PubMed

Affiliation: College of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.

ABSTRACT

Background: Radix Ophiopogonis polysaccharide (ROP), a highly hydrophilic macromolecule, has a unique anti-ischemic action in the myocardium. One of the main problems with its use is its relatively short half-life in vivo. To solve this problem, injectable long-acting drug delivery systems, which combine mono-PEGylation (PEG, polyethylene glycol) with the in situ formation of poly(D,L-lactide-co-glycolide) copolymer (PLGA) depots, were tested in this study.

Methods: Through a moderate coupling reaction between 20 kDa amino-terminated methoxy-PEG and excessive ROP with activated hydroxyls, a long-circulating and bioactive mono-PEGylated ROP was prepared and characterized. A reasonable and applicable range of PLGA formulations loaded with the mono-PEGylated ROP were prepared, characterized, and evaluated in vivo.

Results: Relative to ROP, the half-life of which was only 0.5 hours, the conjugate alone, following subcutaneous administration, showed markedly prolonged retention in the systemic circulation, with a mean residence time in vivo of approximately 2.76 days. In combination with in situ-forming PLGA depots, the residence time of the conjugate in vivo was prolonged further. In particular, a long-lasting and steady plasma exposure for nearly a month was achieved by the formulation comprising 40% 30 kDa PLGA in N-methyl-2-pyrrolidone.

Conclusion: Long-lasting and steady drug exposure could be achieved using mono-PEGylation in combination with in situ formation of PLGA depots. Such a combination with ROP would be promising for long-term prophylaxis and/or treatment of myocardial ischemia. For high-dose and highly hydrophilic macromolecular drugs like ROP, more than one preparation technology might be needed to achieve week-long or month-long delivery per dosing.

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Related in: MedlinePlus

Changes in viscosity of blank and drug-containing PLGA formulations with decreases in temperature of 1°C per minute.Notes: □, 40% PLGA30k/NMP alone; ○, 40% PLGA30k/NMP +12.5% drug; Δ, 40% PLGA30k/NMP +20% drug.Abbreviations: NMP, N-methyl-2-pyrrolidone; PGLA, poly(d,l-lactide-co-glycolide); 30k, 30 kDa.
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f4-ijn-9-5555: Changes in viscosity of blank and drug-containing PLGA formulations with decreases in temperature of 1°C per minute.Notes: □, 40% PLGA30k/NMP alone; ○, 40% PLGA30k/NMP +12.5% drug; Δ, 40% PLGA30k/NMP +20% drug.Abbreviations: NMP, N-methyl-2-pyrrolidone; PGLA, poly(d,l-lactide-co-glycolide); 30k, 30 kDa.

Mentions: As shown in Figure 2, the viscosities of PLGA30k sols at 37°C increased nonlinearly with increasing concentrations of PLGA in NMP and an abrupt change occurred at the concentration of 30% (w/w). The addition of mPEG20k-NH2 led to increased viscosity. The effect of the molecular weight of PLGA on viscosity was similar to that of concentration. Namely, viscosity increased nonlinearly with increasing molecular weight of PLGA and an abrupt change happened at 30 kDa, while addition of mPEG20k-NH2 also increased the viscosity (Figure 3). Decreasing the temperature from 42°C to 37°C and increasing mPEG20k-NH2 loading in the 40% PLGA30k/NMP formulation from 12.5% (125 mg/mL) to 20% (200 mg/mL) significantly enhanced the viscosity of the formulation (Figure 4). Thus, the 20% PLGA30k/NMP, 30% PLGA30k/NMP, 40% PLGA30k/NMP, and 30% PLGA50k/NMP formulations were chosen for in vivo studies to determine the applicability of in situ-forming PLGA depots for PEGylated polysaccharides.


Injectable long-acting systems for Radix Ophiopogonis polysaccharide based on mono-PEGylation and in situ formation of a PLGA depot.

Shi X, Lin X, Zheng X, Feng Y, Shen L - Int J Nanomedicine (2014)

Changes in viscosity of blank and drug-containing PLGA formulations with decreases in temperature of 1°C per minute.Notes: □, 40% PLGA30k/NMP alone; ○, 40% PLGA30k/NMP +12.5% drug; Δ, 40% PLGA30k/NMP +20% drug.Abbreviations: NMP, N-methyl-2-pyrrolidone; PGLA, poly(d,l-lactide-co-glycolide); 30k, 30 kDa.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257019&req=5

f4-ijn-9-5555: Changes in viscosity of blank and drug-containing PLGA formulations with decreases in temperature of 1°C per minute.Notes: □, 40% PLGA30k/NMP alone; ○, 40% PLGA30k/NMP +12.5% drug; Δ, 40% PLGA30k/NMP +20% drug.Abbreviations: NMP, N-methyl-2-pyrrolidone; PGLA, poly(d,l-lactide-co-glycolide); 30k, 30 kDa.
Mentions: As shown in Figure 2, the viscosities of PLGA30k sols at 37°C increased nonlinearly with increasing concentrations of PLGA in NMP and an abrupt change occurred at the concentration of 30% (w/w). The addition of mPEG20k-NH2 led to increased viscosity. The effect of the molecular weight of PLGA on viscosity was similar to that of concentration. Namely, viscosity increased nonlinearly with increasing molecular weight of PLGA and an abrupt change happened at 30 kDa, while addition of mPEG20k-NH2 also increased the viscosity (Figure 3). Decreasing the temperature from 42°C to 37°C and increasing mPEG20k-NH2 loading in the 40% PLGA30k/NMP formulation from 12.5% (125 mg/mL) to 20% (200 mg/mL) significantly enhanced the viscosity of the formulation (Figure 4). Thus, the 20% PLGA30k/NMP, 30% PLGA30k/NMP, 40% PLGA30k/NMP, and 30% PLGA50k/NMP formulations were chosen for in vivo studies to determine the applicability of in situ-forming PLGA depots for PEGylated polysaccharides.

Bottom Line: Relative to ROP, the half-life of which was only 0.5 hours, the conjugate alone, following subcutaneous administration, showed markedly prolonged retention in the systemic circulation, with a mean residence time in vivo of approximately 2.76 days.In combination with in situ-forming PLGA depots, the residence time of the conjugate in vivo was prolonged further.For high-dose and highly hydrophilic macromolecular drugs like ROP, more than one preparation technology might be needed to achieve week-long or month-long delivery per dosing.

View Article: PubMed Central - PubMed

Affiliation: College of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.

ABSTRACT

Background: Radix Ophiopogonis polysaccharide (ROP), a highly hydrophilic macromolecule, has a unique anti-ischemic action in the myocardium. One of the main problems with its use is its relatively short half-life in vivo. To solve this problem, injectable long-acting drug delivery systems, which combine mono-PEGylation (PEG, polyethylene glycol) with the in situ formation of poly(D,L-lactide-co-glycolide) copolymer (PLGA) depots, were tested in this study.

Methods: Through a moderate coupling reaction between 20 kDa amino-terminated methoxy-PEG and excessive ROP with activated hydroxyls, a long-circulating and bioactive mono-PEGylated ROP was prepared and characterized. A reasonable and applicable range of PLGA formulations loaded with the mono-PEGylated ROP were prepared, characterized, and evaluated in vivo.

Results: Relative to ROP, the half-life of which was only 0.5 hours, the conjugate alone, following subcutaneous administration, showed markedly prolonged retention in the systemic circulation, with a mean residence time in vivo of approximately 2.76 days. In combination with in situ-forming PLGA depots, the residence time of the conjugate in vivo was prolonged further. In particular, a long-lasting and steady plasma exposure for nearly a month was achieved by the formulation comprising 40% 30 kDa PLGA in N-methyl-2-pyrrolidone.

Conclusion: Long-lasting and steady drug exposure could be achieved using mono-PEGylation in combination with in situ formation of PLGA depots. Such a combination with ROP would be promising for long-term prophylaxis and/or treatment of myocardial ischemia. For high-dose and highly hydrophilic macromolecular drugs like ROP, more than one preparation technology might be needed to achieve week-long or month-long delivery per dosing.

Show MeSH
Related in: MedlinePlus