Willi Paul

Ceramic drug delivery: a perspective.

Different ceramic substances are offered in the market as bone substitute materials. These include monophasic calcium phosphate ceramics of tricalciumphosphate (TCP) or hydroxyapatite (HA), biphasic calcium phosphate ceramics and multiphasic bio-glasses synthetic calcium phosphate cements. Ceramics with appropriate three-dimensional geometry are able to bind and concentrate bone morphogenetic proteins in circulation and may become osteoinductive (capable of osteogenesis) and can be effective carriers of bioactive peptide or bone cell seeds and are therefore potentially useful in tissue engineering and drug delivery. An attempt has been made to review various drug delivery applications of ceramics.

Synthesis and characterization of PEGylated calcium phosphate nanoparticles for oral insulin delivery

The inconvenience of subcutaneous insulin delivery leads to low patient compliance with the dosage regimens. The most desirable form of administration seems to be through the oral route. This work investigates the utility of PEGylated calcium phosphate nanoparticles as oral carriers for insulin. Calcium phosphate nanoparticles (CaP) with an average particle size of 47.9 nm (D50) were synthesized and surface modified by conjugating it with poly(ethylene glycol) (PEG). These modified nanoparticles were having a near zero zeta potential. Protection of insulin from the gastric environment has been achieved by coating the nanoparticles with a pH sensitive polymer that will dissolve in the mildly alkaline pH environment of the intestine. The release profiles of coated nanoparticles exhibited negligible release in acidic (gastric) pH, i.e., only 2% for CaP and 6.5% for PEGylated CaP. However, a sustained release of insulin was observed at neutral (intestinal) pH for over 8 h. The conformation of the released insulin, studied using circular dichroism, was unaltered when compared with native insulin. The released insulin was also stable as it was studied using dynamic light scattering. Radioimmunoassay was performed and the immunoreactivity of the released insulin was found to be intact. These results suggest PEGylated calcium phosphate nanoparticles as an excellent carrier system for insulin toward the development of an oral insulin delivery system.

Adsorption of human IgG on Cu2+-immobilized cellulose affinity membrane: Preliminary study

Immobilized metal ion affinity chromatography (IMAC) is widely used. Transition metal ions have a high affinity to some peptide sequences. We have studied the selective adsorption of human IgG from a mixture of albumin, gamma-globulin, fibrinogen, and IgG onto Cu(2+) ion-immobilized cellulose membrane. Although Cu(2+) ligand is selective to IgG, in general gamma-globulins also are adsorbed. The simplicity and lower cost of Cu(2+) ion-immobilized cellulose membranes may be useful for removing IgG from blood.

PEGylated starch acetate nanoparticles and its potential use for oral insulin delivery

A novel controlled release formulation has been developed with PEGylated starch acetate nanoparticles. Biodegradable polymers, such as starch, have been studied for various pharmaceutical applications because of their biocompatibility and biodegradability. Starch acetate is one of the hydrophobic biodegradable polymers currently being used or studied for controlled drug delivery. Polyethylene glycol was conjugated with starch acetate, to obtain an amphiphilic polymeric derivative. On its incubation with insulin solution at the critical micelle concentration, self-aggregated nanoparticles with mean particle size of 32 nm are formed. These self-aggregated nanoparticles with associated insulin have enhanced encapsulation efficiency. The mean particle size of these nanoparticles increased with the increase in the molecular weight of PEG. Present study indicated that PEGylated starch acetate nanoparticles are highly bioadhesive and can be utilized as a carrier system for controlled delivery of insulin or other proteins for various therapeutic applications.

Alginate encapsulated bioadhesive chitosan microspheres for intestinal drug delivery.

Sustained intestinal delivery of drugs such as 5-fluorouracil (choice for colon carcinomas) and insulin (for diabetes mellitus) seems to be a feasible alternative to injection therapy. For successful therapy, the drug should be delivered at proper sites (here, the intestine) for long duration, for producing maximum pharmacological activity. We have attempted to develop a formulation that can bypass the acidity of the stomach and release the loaded drug for long periods into the intestine by using the bioadhesiveness of polyacrylic acid, alginate, and chitosan. Bromothymol blue was taken as a model drug. The formulation exhibited bioadhesive property and released the drug for an eight-day period in vitro.

Acetylsalicylic acid loaded poly(vinyl alcohol) hemodialysis membranes: effect of drug release on blood compatibility and permeability.

Membranes developed from poly(vinyl alcohol) (PVA) have superior permeability because of the highly hydrophilic character of PVA. However, its blood compatibility needs to be further improved. For this we have developed acetylsalicylic acid (ASA, aspirin) loaded PVA membranes. It seems that the slow release of aspirin from the membrane provides a surface concentration of aspirin sufficient for partially inhibiting platelet adhesion. PVA membrane with 531 micrograms cm-2 of ASA loaded, may be selected for hemodialysis applications. This may help to reduce the amount of heparin infused during hemodialysis, thereby reducing the side-effects associated with the systemic administration of heparin.

Supramolecular hydroxyapatite complexes as theranostic near-infrared luminescent drug carriers

The facile synthesis of luminescent, multifunctional, needle-like hydroxyapatite (HA) nanoparticle complexes containing cyclodextrin has been reported. The in vitro loading and release studies using doxorubicin hydrochloride (DOX) demonstrate that the nanoparticle complexes show high drug adsorption capacity and sustained drug release profiles. Moreover, they exhibit strong photoluminescence even after loading of DOX molecules and permit the monitoring of the photoluminescence intensity. The nanocomplexes further reveal excellent blood compatibility, inappreciable toxicity and cellular internalization properties. Upon excitation at 420 nm, these complexes exhibit strong near-infrared emission at 680 nm. The photoluminescence intensity of the nanoparticles can be adjusted by varying the concentration of neodymium. Thus, the nanoparticle complexes obtained in the present study are promising for applications in the biomedical field as multifunctional drug delivery systems for simultaneous targeted drug delivery and near-infrared fluorescence imaging guidance.

Blood compatibility studies of Swarna bhasma (gold bhasma), an Ayurvedic drug.

Swarna bhasma (gold bhasma) preparations are widely utilized as therapeutic agents. However, in vitro biological evaluations of bhasma preparations are needed along with the physicochemical characterization for present day standardization of metallic bhasma preparations to meet the criteria that supports its use. Therefore, an attempt has been made to evaluate the protein adsorption, blood compatibility and complement activation potential of two batches of Swarna bhasma preparation, along with its physicochemical characterization. The particle size, morphology, elemental analysis, and in vitro cytotoxicity were evaluated initially. Red blood cell hemolysis, aggregation studies with blood cells, protein adsorption, complement C3 adsorption, platelet activation and tight junction permeability in Caco-2 cell line were investigated. The Swarna bhasma preparations with a crystallite size of 28–35 nm did not induce any blood cell aggregation or protein adsorption. Activation potential of these preparations towards complement system or platelets was negligible. These particles were also non-cytotoxic. Swarna bhasma particles opened the tight junctions in Caco-2 cell experiments. The results suggest the application of Swarna bhasma preparations as a therapeutic agent in clinical medicine from the biological safety point of view.

Polyethylene Glycol (PEG) Modified Bovine Pericardiuim as a Biomaterial: A Comparative Study on Immunogenicity

Bioprosthetic heart valves made from glutaraldehyde (GA)-fixed porcine aortic valves or bovine pericardium (BP) are having some advantages over mechanical valves. However, their durability is low due to the calcification and immunological rejection. Study on immunogenicity is an important part in understanding the biocompatibility of materials. Polyethylene glycol (PEG) on pericardium can control biodegradation and calcification. Also, PEG exhibits low immunogenicity. We have studied the complement activation potential and the contribution of complement factors (biologic factors) on the calcification of PEG grafted pericardium samples and compared with standard (control) glutaraldehyde-treated pericardium samples. PEG-grafted BP activated using GA and carbodiimide (EDC) could be selected for further studies since complement activation and calcification observed on these samples has been relatively low.

Cucurbituril/hydroxyapatite based nanoparticles for potential use in theranostic applications

We present the engineering of cucurbituril/hydroxyapatite based theranostic nanoparticles with a high aspect ratio and a needle shaped morphology. These particles with varying sizes, surface charges and tunable degradation profiles manifested the advantages of the presence of cucurbituril with respect to drug loading, encapsulation efficacy and release kinetics. In vitro release profiles with two model drugs, Doxorubicin hydrochloride (Dox, hydrophilic) and Nile Red dye (NR, hydrophobic), were evaluated. It was ascertained that hydrophilic Dox was released at a faster rate compared to hydrophobic NR over similar time periods. The concomitant presence of samarium (Sm3+) and CB[7] confers theranostic potential to the synthesized nanoparticles. Cellular toxicity effects systematically assessed using MTT and live/dead assay protocols indicate inappreciable toxicity. The nanoparticles further reveal excellent blood compatibility and cellular internalization properties as visualized by fluorescence microscopy. Particles excited at 300 nm revealed Dox emission in the green channel (470 nm) as well as Sm3+ emission in the red channel (590 nm). These studies unravel the potential of these nanoparticles for effective theranostic applications.