Mechanochemical solid-state polymerization (XI): effect of water-insoluble pharmaceutical aids on drug release from mechanically synthesized polymeric prodrugs

We discuss here the effect of water-insoluble pharmaceutical aids on the nature of drug release from composite polymeric prodrugs synthesized by mechanochemical solid-state polymerization. Magnesium stearate (Mgst) and hydrogen castor oil (HCO) were used as water-insoluble pharmaceutical aids. Composite polymeric prodrugs were synthesized by the mechanochemical solid-state polymerization of a vinyl monomer of 5-fluorouracil (I) in the presence of Mgst or HCO. The molecular weight of the resulting polymeric prodrugs increased with increasing the content of Mgst or HCO. Prodrug hydrolysis was carried out in a heterogeneous system in phosphate buffer at pH 6.8 and 37 degrees C. The rate of drug release from the composite polymeric prodrug containing Mgst (Poly-Mgst) was faster than that from polymeric prodrug containing no pharmaceutical aids (Poly-Non), while hydrolysis of the composite polymeric prodrug containing HCO (Poly-HCO) was slower than Poly-Non. Scanning electron microscope (SEM) photos showed the surface of Poly-HCO was smoother than that of Poly-Non and Poly-Mgst. It was suggested that the slower drug release from Poly-HCO may be responsible for the smaller specific surface area than that of Poly-Non. It was also shown that the rate of drug release from the composite polymeric prodrugs decreases with increasing the content of Mgst or HCO. Hence, novel composite polymeric prodrugs with a variety of drug release rates can be prepared by mechanochemical solid-state polymerization in a totally dry process.     

Mechanochemical solid-state polymerization (X): the influence of copolymer structure in copolymeric prodrugs on the nature of drug release

From the standpoint of the mechanism of mechanochemical polymerization, two kinds of copolymeric prodrug, whose monomer sequence distribution (MSD) is different from each other, can be prepared by this polymerization under appropriate operational conditions: one is a random copolymer abundant in the longer block consisting of the same repeating units (multi-block copolymer), and the other is a block copolymer. To confirm the difference of MSD, the 13C-NMR spectra of poly(acrylamide-co-sodium acrylate) prepared by mechanochemical polymerization were measured and compared with the spectrum of that synthesized by a conventional radical-initiated solution polymerization, which produces the random copolymer normally. The results show that MSD in copolymers depends on the polymerization method (operational condition). We prepared three kinds of copolymeric prodrug consisting of acrylamide and vinyl monomer of 5-fluorouracil, whose MSD is different from one another. These copolymeric prodrugs had almost the same number average molecular weight, particle diameter and composition, and differed only in MSD. We compared the rate of drug release of these copolymeric prodrugs. The rate of drug release was the highest with the random copolymer, followed by the mechanochemically produced multi-block copolymer and the block copolymer. This result suggests that the rate of drug release depends on MSD of copolymeric prodrugs. These results are useful as they give a fundamental insight into the synthesis of copolymeric prodrugs having the desired rate of drug release.     

Synthesis of polymeric derivatives of isoniazid: characterization and in vitro release from a water-soluble adduct with polysuccinimide

Coupling of isoniazid with polysuccinimide afforded a water-insoluble polymeric pro-drug; by reaction with ethanolamine it was chemically transformed in a water-soluble adduct. The in vitro release of isoniazid from the drug-polymer adduct was studied by using an artificial stomach wall lipid membrane. The transfer rate constant from simulated gastric juice to simulated plasma was defined and compared with that of an equivalent dose of pure drug.     

Conventional synthesis of amphiphilic block copolymer utilized for polymeric micelle by mechanochemical solid-state polymerization

The first example is presented here of an amiphiphilic block copolymer synthesized by mechanochemical solid-state polymerization and used to form polymeric micelles. A model amphiphilic block copolymer was synthesized first, possessing galactose as a hydrophilic side chain and theophylline as a hydrophobic side chain, by mechanochemical solid-state polymerization. The resulting copolymer had a narrow molecular weight distribution. Polymeric micelle formation was subsequently carried out with the copolymer by a dialysis method. To gain insight into the physicochemical properties of the polymeric micelle, dynamic light scattering (DLS) measurements were performed. A narrow distribution of diameters was observed in the polymeric micelle solution, and these micelles were disrupted by the addition of sodium dodecyl sulfate (SDS). It was also confirmed by DLS measurements that the polymeric micelles were spherical. These results suggested that the block copolymer synthesized by mechanochemical solid-state polymerization was as suitable for the preparation of polymeric micelles as materials obtained by living polymerization.     

Characterization of novel pH-sensitive polymeric micelles prepared by the self-assembly of amphiphilic block copolymer with poly-4-vinylpyridine block synthesized by mechanochemical solid-state polymerization

We fabricated novel pH-sensitive polymeric micelles consisting of amphiphilic block copolymer containing pyridyl groups as side chains in the hydrophobic block. The number average particle diameter of the polymeric micelles at pH 7 was approximately 200 nm. A decrease in pH resulted in deformation of the polymeric micelles over a very narrow pH range (between pH 5.7 and 5.6). Interestingly, micellization and demicellization occurred reversibly in this narrow pH range. Polymeric micelles incorporating 5-fluorouracil (5FU) were also prepared. Decreasing the pH of this polymeric micelle solution from 7 to 5.5 resulted in the rapid release of 5FU at pH 5.6; the drug was completely released within 30 min. These results suggest that deformation of the polymeric micelles caused the rapid release of 5FU.     

Synthesis and characterization of water-soluble amino fullerene derivatives

[formula: see text] A series of amino-substituted methanofullerene derivatives were prepared by mono-, tris-, and hexa-Bingel-Hirsch reactions using an N-protected malonate derivative. Upon scission of the protecting groups, the e,e,e-tris- and octahedral Th hexa-methano amino fullerenes were found to be among the most water-soluble fullerene derivatives yet prepared. 3He NMR data on corresponding adducts of 3He/C60 helped verify the assigned structures. UV spectral studies confirmed the influence of aggregation on solubility of these adducts in water.     

Microporous structure and drug release kinetics of polymeric nanoparticles

The aim of the present study was to characterize pegylated nanoparticles (NPs) for their microporosity and study the effect of microporosity on drug release kinetics. Blank and drug-loaded NPs were prepared from three different pegylated polymers, namely, poly(ethylene glycol)1%-graft-poly(D,L)-lactide, poly(ethylene glycol)5%-graft-poly(D,L)-lactide, and the multiblock copolymer (poly(D,L)-lactide-block-poly(ethylene glycol)-block-poly(D,L)-lactide)n. These NPs were characterized for their microporosity using nitrogen adsorption isotherms. NPs of the multiblock copolymer showed the least microporosity and Brunauer-Emmett-Teller (BET) surface area, and that of PEG1%-g-PLA showed the maximum. Based on these results, the structural organization of poly(D,L)-lactide (PLA) and poly(ethylene glycol) (PEG) chains inside the NPs was proposed and was validated with differential scanning calorimetry (DSC) and X-ray photoelectron spectroscopy (XPS) surface analysis. An in vitro drug release study revealed that PEG1%-g-PLA NPs exhibited slower release despite their higher surface area and microporosity. This was attributed to the presence of increased microporosity forming tortuous internal structures, thereby hindering drug diffusion from the matrix. Thus, it was concluded that the microporous structure of NPs, which is affected by the molecular architecture of polymers, determines the release rate of the encapsulated drug.     

Synthesis and antineoplastic activity of novel water-soluble curcumol derivatives

6-Succinyl curcumol sodium salt was synthesized by reaction of curcumol with succinic acid. The structure of the derivative was confirmed by NMR spectroscopy and mass spectrometry. Furthermore, the derivative showed antitumor activity, which makes it a promising antitumor drug candidate that overcomes the insolubility in water.     

Synthesis and spectroscopic properties of highly water-soluble perylene derivatives

Most known perylene diimides are lipophilic, with few exceptions of hydrophilic derivatives. Even in the latter case, the compounds have limited water solubility and show a strong tendency to self-aggregation. In this paper we present the synthesis of four new perylene derivatives with three and four basic side chains, obtained by functionalizing the bay-area of perylene. These molecules show great solubility in aqueous media as hydrochlorides and their tendency to self-aggregate is remarkably reduced with respect to the previously synthesized two-chained perylene diimides. Their different spectroscopic properties in various solvents and conditions are reported and discussed.     

Synthesis of DNA conjugate by mechanochemical solid-state polymerization and its affinity separation of oligonucleotides having single-base difference by capillary electrophoresis

In this communication, we discuss the characterization of DNA conjugate synthesized by mechanochemical polymerization, Con-M, on the separation of model oligo-DNA and its single nucleotide polymorphisms (SNPs) by affinity capillary electrophoresis, compared with that prepared by radical-initiated solution polymerization, Con-RL. The average molecular weight of Con-M was similar to that of Con-RL, although the molecular weight distribution of Con-M was narrower than that of Con-RL. Capillary electrophoresis of oligo-DNA was performed using the capillary filled with DNA conjugate. The resolution of the capillary filled with Con-M was apparently higher than with Con-RL. It is considered that higher resolution using the capillary filled with Con-M could be ascribed not only to the narrow molecular weight distribution but also to the difference of copolymer structure.     

Syntheses,electrochemistry and cytotoxicity of ferrocene-containing polyaspartamides as water-soluble polymeric drug carrier/drug conjugates

A general strategy towards the syntheses of water-soluble polymeric drug carriers and their drug conjugates is described. Methods of drug uptake by cells, drug release from the polymeric carrier and the relevance of electrochemistry to drug activity of the ferrocenyl group are highlighted. The advantages of these polymeric systems are demonstrated utilising cytotoxicity results of a polyaspartamide-ferrocenyl conjugate.     

Preparation of thermosensitive polymeric organogels and their drug release behaviors

Stimuli-sensitive drug delivery systems—in particular, stimuli-sensitive polymeric hydrogels swollen with water—have attracted considerable attention in medical and pharmaceutical fields. This study concerns with the synthesis of thermosensitive polymeric organogels for controlled drug release; a copolymerization of stearyl acrylate (SA) with a cross-linker and the loading of indomethacin as a model lipophilic drug were accomplished in oleyl alcohol. The pulsatile (on-off) drug release was successfully conducted: release was halted at 36 °C and release occurred at over ca. 40 °C. This drug release pattern is suitable for thermochemotherapy combined with hyperthermia. The differential scanning calorimetric measurement suggests the following mechanism: the ordered crystalline structure, i.e., the alignment of hydrophobic alkyl side chains, works to prevent indomethacin diffusion from the organogel below the crystallization temperature, while the disordered amorphous structure above the melting temperature allows indomethacin to diffuse.     

Synthesis and properties of water-soluble derivatives of fullerene C60

Procedures for synthesized of water-soluble forms of fullerene C₆₀ and its derivatives were developed.     

Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives

A peptidic CXCR4 antagonist T140 efficiently blocks the entry of T cell line-tropic strains of HIV-1 (X4-HIV-1) into target cells. In this study, a series of T140 derivatives, replacing the basic amino acid residues with Glu (D-Glu) and/or L-citrulline (Cit), were synthesized in order to reduce non-specific binding and cytotoxicity. Among them, TE14011 ([Cit6, D-Glu8]-T140 with the C-terminal amide) exhibited strong anti-HIV activity and low cytotoxicity. TE14011 was found to be stable in mouse serum, but unstable in rat liver homogenate due to the deletion of the N-terminal Arg1-Arg2-L-3-(2-naphthyl)alanine (Nal)3 residues from the parent peptide. N-Terminal acetylation of TE14011 led to the development of a novel lead compound, Ac-TE 14011, which possesses a high selectivity index as well as increased stability in serum and liver homogenate.     

Synthesis of stereoregular heteropolysaccharides having amino-groups by ring-opening copolymerization of 1,6-anhydro-azido-sugar derivatives

The cationic, ring-opening copolymerization of 1,6-anhydro-2-azido-3,4-di-0-benzyl-2-deoxy-(2-ABG), -3-azido-2,4-di-0-benzyl-3-deoxy- (3-ABG), -4-azido-2,3-di-0-benzyl-4-deoxy-β-D -glucopyranose (4-ABG) with 1,6-anhydro-2,3,4-tri-0-benzyl-β-D -glucopyranose (LGTBE) was investigated with phosphorus pentafluoride as catalyst at low temperatures, giving highly stereoregular, (1→6)-α-linked copolymers with number-average molecular weights of 3.90 × 10⁴?9.27 × 10⁴. Structure and composition of the copolymers were determined by ¹H- and ¹³C-NMR spectroscopies and elemental analysis, which indicated that copolymerization occurred in a stereoregular manner to give azido groups containing (1→6)-α-linked glucopyranan derivatives. The differences in polymerizability among the three azido monomers are discussed. Regioselective reduction of three kinds of heteropolysacharide derivatives which had different quantities of azido groups at C-2, -3, or -4 position with lithium aluminum hydride and subsequent debenzylation of the copolymers with sodium in liquid ammonia produced amino-group-containing heteropolysaccharides.     

Photochemical release of bases from nucleosides and their derivatives by water-soluble iron(III) porphyrins.

The compounds [meso-tetrakis(1-methyl-4-pyridiniumyl)porphyrinato]iron(III ) (FeIIITMPyP) and [meso-tetrakis(3,5-dichloro-1-methyl-4-pyridiniumyl)porphyrinat o]iron(III) (FeIIITCl2MPyP) photocatalysed the release of bases from nucleosides and their derivatives. The ribonucleosides, of which cytidine (C) gave the highest yield, produced much higher yields of free base than the corresponding deoxyribonucleosides. Under an argon atmosphere, virtually quantitative reduction of FeIIITMPyP into FeIITMPyP by C or 2'-deoxycytidine (dC) was observed and the reduction by C was much more effective than by dC. The increased reactivity of ribonucleosides relative to deoxyribonucleosides was ascribed to a difference in the binding properties of the porphyrin-nucleoside interactions and to base-releasing degradation of ribonucleosides from their C-2' carbon radical.     

Synthesis and emulsion copolymerization of amphiphilic poly(2-oxazoline) macromonomer possessing a vinyl ester group

The present article describes the synthesis and emulsion copolymerization of a block-type amphiphilic poly(2-oxazoline) macromonomer possessing a polymerizable vinyl ester group. The macromonomer was synthesized by one-pot two-stage block copolymerization of 2-oxazolines using vinyl iodoacetate as initiator. 2-Methyl- and 2-n-butyl-2-oxazolines were employed for the construction of hydrophilic and hydrophobic segments, respectively. The surface activities evaluated by the surface tension of the macromonomer in water were fairly good. Emulsion copolymerization of vinyl acetate with the macromonomer was carried out. The macromonomer acted as a polymeric surfactant, as well as a comonomer. The resulting copolymer latex particles were spherical and their diameter was in the sub-micron range. The effects of the composition of the macromonomer on the emulsion copolymerization and the resulting latex particles were examined. © 1993 John Wiley & Sons, Inc.