Luigi G. Martini

The use of hypromellose in oral drug delivery

Hypromellose, formerly known as hydroxypropylmethylcellulose (HPMC), is by far the most commonly employed cellulose ether used in the fabrication of hydrophilic matrices. Hypromellose provides the release of a drug in a controlled manner, effectively increasing the duration of release of a drug to prolong its therapeutic effect. This review provides a current insight into hypromellose and its applicability to hydrophilic matrices in order to highlight the basic parameters that affect its performance. Topics covered include the chemical, thermal and mechanical properties of hypromellose, hydration of the polymer matrices, the mechanism of drug release and the influence of tablet geometry on drug‐release rate. The inclusion of drug‐release modifiers within hypromellose matrices, the effects of dissolution media and the influence of both the external environment and microenvironment pH within the gel matrix on the properties of the polymer are also discussed.

Developing paediatric medicines: identifying the needs and recognizing the challenges

There is a significant need for research and development into paediatric medicines. Only a small fraction of the drugs marketed and utilized as therapeutic agents in children have been clinically evaluated. The majority of marketed drugs are either not labelled, or inadequately labelled, for use in paediatric patients. The absence of suitable medicines or critical safety and efficacy information poses significant risks to a particularly vulnerable patient population. However, there are many challenges associated with developing medicines for the paediatric population and this review paper is intended to highlight these. The paediatric population is made up of a wide range of individuals of substantially varied physical size, weight and stage of physiological development. Experimentation on children is considered by many to be unethical, resulting in difficulties in obtaining critical safety data. Clinical trials are subject to detailed scrutiny by the various regulatory bodies who have recently recognized the need for pharmaceutical companies to invest in paediatric medicines. The costs associated with paediatric product development could result in poor or negative return on investment and so incentives have been proposed by the EU and US regulatory bodies. Additionally, some commonly used excipients may be unsuitable for use in children; and some dosage forms may be undesirable to the paediatric population.

The effect of hydrophobe chemical structure and chain length on the solubilization of griseofulvin in aqueous micellar solutions of block copoly(oxyalkylene)s

The solubilization capacities of micellar solutions of a series of block copolymers composed of hydrophilic poly(oxyethylene) (E) and hydrophobic poly(oxypropylene) (P), poly(oxybutylene) (B) or poly(oxyphenylethylene) (S, from styrene oxide) have been compared using the poorly water-soluble drug griseofulvin as a model solubilizate. A 1H NMR technique for determining the extent of solubilization has been developed. Considering the optimum result in each case, the amount of griseofulvin solubilized (expressed as moles griseofulvin per mole of hydrophobic units) by ES block copolymers was approximately nine times more than by EP copolymers and three times more than by EB copolymers. The mobility of the S-blocks in the cores of the ES copolymer micelles, as determined by 1H NMR spectroscopy, was sufficient to allow solubilization at ambient temperature.

Solubility parameter and oral absorption

The solubility parameter (delta) for a series of structurally diverse compounds was determined using a group contribution method devised by Fedors, and then related to the degree of oral absorption. Solubility parameter values around 22.5 MPa1/2 were shown to be associated with compounds that were well absorbed, whereas, compounds with a high delta (30-40 MPa1/2) showed poor absorption. A correlation was also evident between the number of H-bonding acceptor groups in a compound and the extent of oral absorption. Surprisingly, when C Log P values were used in comparison, no obvious correlation existed. The conclusion from this work is that the solubility parameter may be a more reasonable predictor of absorption than using C Log P values.

Association properties of a diblock copolymer of ethylene oxide and styrene oxide in aqueous solution studied by light scattering and rheometry

Copolymer S13E60 (E = oxyethylene unit, S = oxyphenylethylene unit) was synthesised and characterised by gel permeation chromatography (for distribution width) and 13C NMR spectroscopy (for absolute molar mass and composition). Dynamic and static light scattering were used to determine micellar properties in dilute aqueous solution at three temperatures (20, 30 and 40°C): i. e. association number, hydrodynamic and thermodynamic radii. Comparison with reported results for related copolymers allowed exploration of the dependence of these properties on hydrophobe block length. The phase behaviour of the copolymer in aqueous solution was defined using tube inversion and rheometry (for yield stress and dynamic modulus). The hard-gel boundary was detected by both methods in satisfactory agreement. Discussion is focused on effects of micelle stability on the shape and extent of the hard-gel region of the phase diagram. A region of soft gel was detected at low concentrations by rheometry, and assigned to a percolation mechanism.

Micellisation and gelation of triblock copolymer of ethylene oxide and ε-caprolactone, CLnEmCLn, in aqueous solution

Three triblock copolymers of ethylene oxide and Iµ-caprolactone, nominally CL2E90CL2, CL4E90CL4 and CL6E90CL6 have been prepared and characterised. The micellar and surface properties in aqueous solution of the copolymers with CL-block lengths of four and six were investigated as a function of temperature and concentration using surface tension and static and dynamic light scattering techniques. Reversible gelation on cooling solutions of CL6E90CL6 was observed at critical concentrations and temperatures ranging from 130 g kg–1 at 25 °C to 300 g kg–1, at 80 °C.

Characterization of polymer adsorption onto drug nanoparticles using depletion measurements and small-angle neutron scattering.

Production of polymer and/or surfactant-coated crystalline nanoparticles of water-insoluble drugs (nanosuspensions) using wet bead milling is an important formulation approach to improve the bioavailability of said compounds. Despite the fact that there are a number of nanosuspensions on the market, there is still a deficiency in the characterization of these nanoparticles where further understanding may lead to the rational selection of polymer/surfactant. To this end small-angle neutron scattering (SANS) measurements were performed on drug nanoparticles milled in the presence of a range of polymers of varying molecular weight. Isotopic substitution of the aqueous solvent to match the scattering length density of the drug nanoparticles (i.e., the technique of contrast matching) meant that neutron scattering resulted only from the adsorbed polymer layer. The layer thickness and amount of hydroxypropylcellulose adsorbed on nabumetone nanoparticles derived from fitting the SANS data to both model-independent and model dependent volume fraction profiles were insensitive to polymer molecular weight over the range Mv = 47-112 kg/mol, indicating that the adsorbed layer is relatively flat but with tails extending up to approximately 23 nm. The constancy of the absorbed amount is in agreement with the adsorption isotherm determined by measuring polymer depletion from solution in the presence of the nanoparticles. Insensitivity to polymer molecular weight was similarly determined using SANS measurements of nabumetone or halofantrine nanoparticles stabilized with hydroxypropylmethylcellulose or poly(vinylpyrrolidone). Additionally SANS studies revealed the amount adsorbed, and the thickness of the polymer layer was dependent on both the nature of the polymer and drug particle surface. The insensitivity of the adsorbed polymer layer to polymer molecular weight has important implications for the production of nanoparticles, suggesting that lower molecular weight polymers should be used when preparing nanoparticles by wet bead milling since nanoparticle formation is more rapid but with no likely consequence on the resultant physical stability of the nanoparticles.

Association properties of ethylene oxide/styrene oxide diblock copolymer E17S8 in aqueous solution

Ethylene oxide and styrene oxide were sequentially polymerized to form the diblock copolymer E(17)S(8) (E = oxyethylene, OCH(2)CH(2); S = oxyphenylethylene, OCH(2)CH(C(6)H(5)); subscripts denote number-average block lengths in repeat units). Light scattering was used to investigate the properties of the micelles formed in dilute solution in the temperature range 15-30 degrees C. The micelles are elongated (probably spheroidal) at the lower temperature and highly elongated (cylindrical, probably wormlike) at the higher temperature. Comparison with results reported for the copolymer E(11)B(8) (B = oxybutylene, OCH(2)CH(C(2)H(5))) allowed exploration of the effect of changing the hydrophobic block. The results provide useful indicators toward the design of ES copolymers with optimal solubilization properties.

The use of small volume ocular sprays to improve the bioavailability of topically applied ophthalmic drugs

Abstract It is accepted that the standard eyedrop volume of 25–50 μl is too large to be accommodated within the conjunctival sac, leading to overspill and to rapid drainage into the nasolacrimal duct. This drainage can lead to unwanted systemic absorption of the active agent, which could be avoided if the dropsize were smaller. In this study, we have evaluated the efficiency of small volume ocular sprays in achieving target corneal drug concentrations. A five-way cross-over pharmacodynamic study was initiated using 10 New Zealand white rabbits as the test subjects. The efficacy of a 30 μl instillate of a 1% w/v pilocarpine hydrochloride solution was compared to 5 μl ocular sprays of 1, 2, 3 and 4% w/v solutions. The efficacy of these treatments was determined by measuring the pupillary miotic responses of the rabbits using video imaging. Analysis of the miotic response showed no significant differences between the treatments, e.g. the area under the miosis-time curve for a 30 μl drop of a 1% pilocarpine hydrochloride solution was 3871 c.f 3827 for a 1% spray despite a six-fold reduction in the administered volume and drug loading. This study demonstrates that the spray delivery of 5 μl volumes of pilocarpine hydrochloride, at concentrations of 1, 2, 3 and 4% achieved an equivalent miotic response to that of a 30 μl volume instillate of a 1% solution.

The Release of 5-Fluorouracil from Microspheres of Poly(ε-Caprolactone-co-ethylene Oxide)

The purpose of this study was to evaluate the in vitro release of 5-fluorouracil from microspheres prepared using a novel triblock copolymer of ε-caprolactone and ethylene oxide as the encapsulating material. Microspheres of poly(ε-caprolactone-co-ethylene oxide) were prepared by employing the “hot-melt” method of microencapsulation. Microspheres were sized using sieve analysis and scanning electron microscopy (SEM). Release studies were performed using a custom-made rotating paddle dissolution apparatus. Copolymer microspheres, fabricated by the hot melt method were shown by electron microscopy to have smooth, nonporous surfaces. Drug-loaded microspheres were found to have a broad distribution of sizes, which was thought to be a consequence of the wide range of crystal sizes of the encapsulated unmilled drug. Nonlinear release kinetics were observed from microspheres in the size fraction 75–250 μm, with a pronounced “burst release” associated with the presence of drug at the surface of the microspheres. A specific delineation of the drug release mechanism was not possible due to rapid gelation, swelling, and subsequent dissolution of the microspheres that occurred on hydration. This work describes the preparation of microspheres that swell rapidly and coalesce together on hydration, accompanied by rapid drug release and copolymer dissolution over a 2-hr period.