International Journal of Pharmaceutics (v.381, #1)

Biodegradable poly(ɛ-caprolactone)–poly(ethylene glycol) copolymers as drug delivery system by XiaWei Wei; ChangYang Gong; MaLing Gou; ShaoZhi Fu; QingFa Guo; Shuai Shi; Feng Luo; Gang Guo; LiYan Qiu; ZhiYong Qian (1-18).
Poly(ɛ-caprolactone)–poly(ethylene glycol) (PCL–PEG) copolymers are important synthetic biomedical materials with amphiphilicity, controlled biodegradability, and great biocompatibility. They have great potential application in the fields of nanotechnology, tissue engineering, pharmaceutics, and medicinal chemistry. This review introduced several aspects of PCL–PEG copolymers, including synthetic chemistry, PCL–PEG micro/nanoparticles, PCL–PEG hydrogels, and physicochemical and toxicological properties.
Keywords: Poly(ɛ-caprolactone)–poly(ethylene glycol) copolymer; Microparticles; Nanoparticles; Polymeric drug delivery systems; Hydrogels;

Systemic drug delivery through intraoral membranes may offer a promising administration route for lipophilic peptide drugs. The aim of the present study was to investigate the effect of α-cyclodextrin (α-CD) and a novel chitosan derivative, chitosan N-betainate (CH), on sublingual absorption of a hydrophobic model peptide cyclosporin A (CsA), and the effect of temperature on the complexation of CsA with α-CD.Complexation of CsA with α-CD was studied using the phase-solubility method.Sublingual absorption of CsA was studied by administration of solid CsA/α-CD complex (with and without CH solution), solid CsA/α-CD/CH formulation and solid plain CsA to rabbits.The solubility of CsA in aqueous α-CD solution (14%) increased with decreasing temperature; the solubility of CsA at room temperature, +5 and +1 °C was 1.2, 12 and 19 mg/ml, respectively. The bioavailability of CsA after administration of plain CsA, solid CsA/α-CD and solid CsA/α-CD/CH (0.6 ± 0.5, 1.4 ± 0.7 and 1.7 ± 0.8%, respectively; mean ± S.D.) was further increased when solid CsA/α-CD was administered together with CH solution (3.2 ± 2.2%).The present study shows that decreased temperature can be effectively utilized to produce CsA/α-CD complexes. It was also shown that α-CD and CH may be advantageous in sublingual delivery of lipophilic peptides, although the absolute bioavailability remains low.
Keywords: Absorption enhancer; Bioavailability; Buccal; Cyclodextrins; Peptide delivery; Transmucosal drug delivery;

Controlled transdermal iontophoresis of sulfosalicylic acid from polypyrrole/poly(acrylic acid) hydrogel by Phithupha Chansai; Anuvat Sirivat; Sumonman Niamlang; Datchanee Chotpattananont; Kwanchanok Viravaidya-Pasuwat (25-33).
A conductive polymer–hydrogel blend between sulfosalicylic acid-doped polypyrrole (PPy) and poly(acrylic acid) (PAA) was used as a carrier/matrix for the transdermal drug delivery under applied electrical field. PAA films and the blend films were prepared by solution casting with ethylene glycol dimethacrylate (EGDMA) as a cross-linking agent, followed by the blending of PPy particles and the PAA matrix. The effects of cross-linking ratio and electric field strength on the diffusion of the drug from PAA and PPy/PAA hydrogels were investigated using a modified Franz-diffusion cell with an acetate buffer of pH 5.5 and at 37 °C, for a period of 48 h. The diffusion coefficient of the drug is calculated using the Higuchi equation, with and without an electric field, at various cross-linking ratios. The drug diffusion coefficient decreases with increasing drug size/mesh size ratio, irrespective of the presence of the conductive polymer as the drug carrier. The diffusion coefficient, at the applied electric field of 1.0 V, becomes larger by an order of magnitude relative to those without the electric field.
Keywords: Poly(acrylic acid) hydrogels; Polypyrrole; Sulfosalicylic acid; Diffusion coefficient; Electrically controlled drug release;

Synthesis of composites of sodium oleate/Mg–Al-ascorbic acid-layered double hydroxides for drug delivery applications by Yoshikazu Kameshima; Hirokazu Sasaki; Toshihiro Isobe; Akira Nakajima; Kiyoshi Okada (34-39).
Mg–Al-ascorbic acid (ASA)-layered double hydroxides (ASA-LDHs) with Mg/Al = 3 were synthesized by ion-exchange, coprecipitation and reconstruction methods. Composites with sodium oleate (SOA)/ASA-LDH were prepared by an ion-exchange method using various concentrations of SOA solutions. The (0 0 3) basal spacing of the ASA-LDHs changed from 0.76 nm in the CO3-LDH to 0.78 and 0.86 nm after intercalation of the ASA ions and these basal spacings are in good agreement with models based on the assumption as mono layers and double layers of ASA ions in the LDH interlayers, respectively. The amounts of ASA in the LDHs prepared by the reconstruction method were higher than those by the ion-exchange and coprecipitation methods. In the preparation of composites of SOA/ASA-LDH, an ion-exchange method was more suitable than a reconstruction method to cause surface sorption of the SOA molecules with maintaining intercalated ASA ions in the LDH interlayers. The acid-resistant properties of the composites of SOA/ASA-LDH were found to be much higher than for the pure ASA-LDH and mixture of CO3-LDH and ASA. The surfaces of the LDH particles in the composites are, thus, mostly covered with sorbed SOA molecules and they are good candidates as drug delivery materials for intestines through the stomach.
Keywords: Layered double hydroxide; Ascorbic acid; Oleic acid; Composite; Drug delivery material;

Self-assembled drug delivery systems. Part 4. In vitro/in vivo studies of the self-assemblies of cholesteryl-phosphonyl zidovudine by Yiguang Jin; Lei Xing; Ying Tian; Miao Li; Chunsheng Gao; Lina Du; Junxing Dong; Hongxuan Chen (40-48).
An amphiphilic prodrug of anti-HIV nucleoside analogue, cholesteryl-phosphonyl zidovudine (CPNZ) was synthesized. An aqueous suspension containing CPNZ self-assemblies was obtained through injecting the ethanol solution of CPNZ and cholesteryl succinyl poly(ethylene glycol) 1500 (20:1, mol/mol) into water under agitation. Hydrophobic interaction may be the driving force of molecular self-assembly. The self-assemblies were nanoscale with ∼100 nm in size, and remained stable for a long time. Degradation of CPNZ self-assemblies was investigated in various environments including buffered solutions, plasma and rabbit tissue homogenates. CPNZ was degraded very slowly in neutral solutions but rapidly in various plasma with the half-lives (t 1/2) of less than 20 h. Tissue homogenates degraded CPNZ with varied rates depending on enzyme activity. CPNZ self-assemblies showed potent anti-HIV activity on MT4 cell model, the anti-HIV 50% effective concentration (EC50) of which was 1 nM, only equal to 1/5 of AZT EC50. CPNZ was rapidly eliminated from circulation and distributed into the mononuclear phagocyte system (MPS) including liver, spleen and lung after bolus intravenous administration of CPNZ self-assemblies followed slowly elimination. The possible products include AZT-5′-H-phosphonate, AZT and their derivatives. The MPS-targeted effect and high anti-HIV activity of CPNZ self-assemblies make them become a promising self-assembled drug delivery system (SADDS).
Keywords: Anti-HIV; Cholesterol; Phosphonate; Prodrugs; Self-assembly; Zidovudine;

Efficiency of cell-penetrating peptides on the nasal and intestinal absorption of therapeutic peptides and proteins by El-Sayed Khafagy; Mariko Morishita; Noriyasu Kamei; Yoshimi Eda; Yohei Ikeno; Kozo Takayama (49-55).
The purpose of our study was to investigate the potential of cell-penetrating peptides; penetratin as novel delivery vector, on the systemic absorption of therapeutic peptides and proteins across different mucosal administration sites. The absorption-enhancing feasibility of l- and d-penetratin (0.5 mM) was used for glucagon-like peptide-1 (GLP-1), and exendin-4 as novel antidiabetic therapy, in addition to interferon-β (IFN-β) as protein biotherapeutic model from nasal and intestinal route of administration was evaluated as first time in rats. Nasal route is the most feasible for the delivery of therapeutic peptides coadministered with penetratin whereas the intestinal route appears to be more restricted. The absolute bioavailability (BA (%)) values depend on the physichochemical characters of drugs, stereoisomer character of penetratin, and site of administration. Penetratin significantly increased the nasal more than intestinal absorption of GLP-1 and exendin-4, as the BA for nasal and intestinal administration of GLP-1 was 15.9% and 5%, and for exendin-4 were 7.7% and 1.8%, respectively. Moreover, the BA of IFN-β coadministered with penetratin was 11.1% and 0.17% for nasal and intestinal administration, respectively. From these findings, penetratin is a promising carrier for transmucosal delivery of therapeutic peptides and macromolecules as an alternative to conventional parenteral routes.
Keywords: Cell-penetrating peptides; Penetratin; Nasal and intestinal absorption; Therapeutic peptides and proteins;

Application of melt granulation technology to enhance stability of a moisture sensitive immediate-release drug product by James Kowalski; Oskar Kalb; Yatindra M. Joshi; Abu T.M. Serajuddin (56-61).
The preparation of tablets by the melt granulation process was investigated to enhance chemical stability of a highly water-soluble drug substance, dipeptidylpeptidase IV (DPP-IV) inhibitor (Compound I), that is susceptible to degradation in presence of moisture. Melt granulation with a lipophilic binder (hydrogenated castor oil; Cutina HR®) improved the stability of the drug, while still maintaining immediate-release characteristics of the drug product. The drug to binder ratio was shown to impact the degradation behavior of the drug product. With higher binder levels, the sensitivity of the drug to degradation under humidity conditions decreased. It is postulated that the lipophilic binder coated drug particles at the surface protecting them from the influence of moisture. The granules had good flow properties and good compressibility and tablets prepared from them exhibited low weight variation and low friability.
Keywords: Melt granulation; Hydrolytic degradation; Moisture sorption; Lipophilic binder; Hydrogenated castor oil; Tablet; Stabilization;

Oil-in-water (o/w) type nanosized emulsions (NE) have been widely investigated as vehicles/carrier for the formulation and delivery of drugs with a broad range of applications. A comprehensive summary is presented on how to formulate the multifunctional o/w NE for active and passive targeting of drugs to otherwise inaccessible internal organs of the human body. The NE is classified into three generations based on its development over the last couple of decades to make ultimately a better colloidal carrier for a target site within the internal and external organs/parts of the body, thus allowing site-specific drug delivery and/or enhanced drug absorption. The third generation NE has tremendous application for drug absorption enhancement and for ‘ferrying’ compounds across cell membranes in comparison to its first and second generation counterparts. Furthermore, the third generation NE provides an interesting opportunity for use as drug delivery vehicles for numerous therapeutics that can range in size from small molecules to macromolecules.
Keywords: Nanosized emulsion; Multifunctional; Generations of emulsion; Pharmacopoeial and safety issues; Opsonization; Unique property;

Formation of ion pairing as an alternative to improve encapsulation and stability and to reduce skin irritation of retinoic acid loaded in solid lipid nanoparticles by Gisele A. Castro; Anna Luíza L.R. Coelho; Cleida A. Oliveira; Germán A.B. Mahecha; Rodrigo L. Oréfice; Lucas A.M. Ferreira (77-83).
This work aims to investigate the influence of the formation of ion pairing between all-trans retinoic acid (RA) and a lipophilic amine (stearylamine; STE) on the drug encapsulation efficiency (EE) and stability of solid lipid nanoparticles (SLNs). The SLNs were characterized for EE and size. The EE and particle size were significantly improved and reduced, respectively, when the surfactant or co-surfactant concentration increased. However, while the formulation without STE allowed only 13% of RA encapsulation, the EE for RA–STE-loaded SLNs was 94%. The stability studies showed a significant decrease in EE for the SLNs without STE, while, for SLNs loaded with RA and STE, the EE remained constant after 360 days. The interactions among ion pairing components and the lipid matrix were investigated through small-angle X-ray scattering (SAXS). The SAXS analysis revealed the presence of RA in the crystalline form in SLNs without ion pairing, while crystalline RA was not observed in SLNs loaded with RA/amine. Skin irritation studies showed that the SLNs loaded with the ion pairing were significantly less irritating when compared to the marketed RA-cream. This novel SLN formulation represents a promising alternative for topical treatment of acne with RA.
Keywords: Solid lipid nanoparticles; Retinoic acid; Acne; Topical treatment; Ion pairing; Skin irritation;

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