Development of a dental pocket drug delivery system based on temperature responsive polymer by the hot melt extrusion method.

Controlled delivery systems are used to improve therapeutic efficacy and safety of drugs by delivering them at a rate dictated by the need of the physiologi- cal environment over a period of treatment to the site of action. A wide variety of polymeric materials, either biodegradable or non-biodegradable but biocompatible, can be used as drug delivery matrices, and the choice of polymer is dictated by the requirements of the specific application. Hot-melt extrusion (HME) is a continuous process of converting a raw material into a product of uniform shape and density by forcing it through a die under high temperature and pressure, thereby making possible to extrude solids resistant to shear forces 1–3). By selecting a suitable exit die, a variety of solid dosage forms including granules, pellets, tablets, supposito- ries, implants, stents, trans- dermal and transmucosal systems, and ophthalmic inserts can be produced 2). HME does not require the use of solvents and for this reason it was first introduced in the pharmaceutical industry as an alternative to solvent-dependent processes 4). It has certain advantages over traditional pharmaceutical manufacturing techniques. Being a solvent and dust-free process, it is environmentally friendly, and since it is a continuous process, fewer steps are involved, which reduces the production cost and makes scaling-up easier 3,4).

The basic HME materials are thermoplastic ma- trix forming polymeric binders, the properties of which influence both the processing conditions and the characteristics of the extruded dosage form, such as dispersibility of active ingredient, its stability and release rate. All components of the hot-melt extruded formulation must be thermally stable at the process- ing temperature, which is usually around 20-30°C lower than the melting point of the drug 5). Due to the intense mixing during the hot-melt processing, and depending on the miscibility of the drug with the polymer, different types of solid dispersions may be formed, including eutectic mixtures, microfine crys- talline dispersions or solid solutions (substitutional, interstitial or amorphous) 6). In this dispersed state, the dissolution of drug can be improved or modified and bad taste can be masked by appropriate selection of polymer 5).
Soluplus® (SP) is a novel amphiphilic polymer ap- plicable for poorly soluble drugs because these drugs can be trapped inside micelles 7). Other techniques for improving the water solubility of drugs include hot melt extrusion techniques, solvent evaporation 8), and spray-drying techniques 9).

Metronidazole (MTZ) is a nitroimidazole derivative and it is the drug of option for intestinal amoebiasis 10). Due to its activity against anaerobic bacteria, met- ronidazole may be useful in the treatment of peri- odontal disease 11). Depending upon the indication the dosage regimen of MTZ can vary from 250 mg three times daily for 7 days to 750 mg three times daily for 10 days. MTZ is Biopharmaceutics Classification System (BCS) Class I (high permeability, high solubility) drug and it is rapidly absorbed with a bioavailability higher than 90% 12). However, MTZ bulk is supplied as a crystalline solid and the solubility in PBS, pH 7.2, is approximately 2 mg/ml 13), indicating that aque- ous formulations containing MTZ are restricted be- cause apparent solubility in water of this drug is low. MTZ is metabolized primarily in liver by oxidation and glucoronide conjugation and excreted in urine. It has the elimination half-life 8 h 14). Application of MTZ-loaded hydrophobic polymer cylindrical shape of filaments would help to release of MTZ in the peri- odontal pocket while targeting the periodontopathic bacteria. Numerous matrix-type and polymer coated MTZ formulations have been widely explored for use as local drug delivery system such as gel, film, fiber 15) but no attempts have been made to formulate fila- ments of SP or HPC. The aim of this study was to develop a new local drug delivery dosage form of MTZ, antibacterial drug, and salicylic acid (SA), analgesic drug, as an intra-pocket dental filament for periodontitis treatment.

Methods: The filaments were prepared by physical mixing of 10 wt% of hydrophilic drug (SA) or hydrophobic drug (MTZ) with different kinds of polymers including Soluplus® (SP), and Hydroxypropyl cellulose (HPC). Then the filaments were fabricated by the hot melt extrusion (HME) method. We obtained a filament with two kinds of shapes in the same weight which are 10 mm length/500 μm diameter and 1.5 mm length/1500 μm diameter. Both SA and MTZ were release from filament in simulated saliva was determined by UV-spectrometer. The scanning electron microscope (SEM) was used for observed the shape and determined the distribution of the drugs on the surface of the filaments.

Results: According to in vitro study, the mechanism of drug release which followed Korsmeyer-Peppas kinetics model mostly indicated anomalous (non-Fickian) diffusion. While release kinetic profile which explained the drug release rate was followed Higuchi’s kinetics model. The results shown SP made drugs release faster than HPC. Comparison between short/thick and long/thin filaments containing MTZ showed the short/thick had slower MTZ release than long/thin filament. The SEM images shown some particles of drug distributed thoroughly filament which confirmed a solid dispersion dosage form.

Conclusion: Intra-pocket dental filament of SA and MTZ were achieved from different polymer formulations includ- ing SP and HPC with P407 fabricated by HME. The release mechanism most likely was anomalous (non- Fickian) diffusion, indicating the swelling and erosion of polymer were involved in drugs release process. Drug release kinetic profile was adjusted to deter- mine the release rate from filaments, it shown the best fitted to Higuchi’s kinetics model. This was sug- gested that drugs released related to square root time. And drug releasing from SP was faster than HPC ac- cording to its solubility and swelling ability. Filament shape was also affected a release rate of drugs. Long and thin filament led to increase of surface area and faster of dissolution rate. To confirm their therapeu- tic effect for periodontal treatment, both in vivo and clinical studies are needed for further investigation. More on dental pocket delivery systems – full publication

Keywords: Dental pocket drug delivery system, Soluplus©, Hydroxypropyl cellulose, Hot melt extrusion