Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers.

OBJECTIVES: To compare bioavailability and pharmacokinetics of single doses of 3 different levodopa formulations given orally in healthy volunteers. Two marketed formulations, standard levodopa/carbidopa, 100/25 mg (LC-100), and dispersible levodopa/benserazide, 100/25 mg (LB-100), were used as reference formulations for a newly developed dispersible microtablet formulation of levodopa/carbidopa, 5/1.25 mg (LC-5). The microtablets are intended for individualized dosing of levodopa/carbidopa in Parkinson disease by means of an electronic dose dispenser with a built-in diary for symptom registration. METHODS: A single-dose, open, randomized, 3-way crossover study was performed in 19 healthy subjects. Concentrations of levodopa, carbidopa, and the metabolite 3-O-MD in plasma were determined after intake of 100 mg of levodopa, that is, one tablet of reference formulations and 20 microtablets of the new formulation. RESULTS: The LC-5 microtablets were bioequivalent to the LC-100 tablets in area under the curve (AUC) and maximum concentration in plasma (Cmax) for levodopa, and to the LB-100 tablets in AUC. The dispersible levodopa/benserazide formulation showed earlier time to Cmax and significantly higher Cmax for levodopa in plasma compared to the microtablets. Carbidopa showed larger interindividual variation in AUC and Cmax than levodopa, and the bioequivalence comparison LC-5/LC-100 for this compound did not reach the target. Nevertheless, comparison of 3-O-MD levels for LC-5/LC-100, assuming proportionality to levodopa levels, demonstrated bioequivalence. CONCLUSIONS: The new levodopa/carbidopa microtablets had a pharmacokinetic profile that would allow for a convenient switch of therapy from standard tablets. Frequent dose administration of levodopa/carbidopa microtablets with an electronic dose dispenser might offer an optimal oral drug delivery in Parkinson disease.

Dry mixing transformed micro-particles of a drug from a highly crystalline to a highly amorphous state.

In this paper, the degree of mechanical activation of particles due to mechanical straining without subsequent breakage has been studied. Griseofulvin micro-particles of about 2 microm in size were mixed with glass beads (proportion 1:99) in a tumbling mixer. After a series of mixing times, ranging from 2-96 hours, samples were withdrawn and the particle size and the degree of crystallinity were assessed. The mixing process gave no detectable change in particle size. The degree of disorder of the drug particles increased with mixing time and highly amorphous particles were obtained after about 24 h of mixing. The results thus indicate that particles can be completely activated by mechanical treatment without a parallel size reduction of the particles. It is suggested that the activation is caused by repeated deformation of the particles, gradually transforming the crystalline state into an amorphous state.

Development and characterisation of interactive mixtures with a fine-particulate mucoadhesive carrier for nasal drug delivery.

The aim of this study was to investigate whether mucoadhesive interactive mixtures can be created using carrier particles in a size range appropriate for nasal administration, i.e. 10-50 microm. We also used theoretical models to investigate if homogeneity measurements can be used to evaluate the formation of interactive mixtures containing carrier particles in this size range. Sodium starch glycolate (SSG) was used as carrier material and sodium salicylate (SS) as the model fine-particulate drug. The size ranges of SSG particles and amounts of SS were varied to find the smallest carrier particle size and highest amount of drug that still resulted in an interactive mixture. Visual inspection of the mixtures by scanning electron microscopy showed that interactive mixtures could be formed with carrier particles as small as 30 microm and containing up to 4% (w/w) of SS. Comparisons with theoretical models highlighted the difficulties of using homogeneity measurements to determine if interactive mixtures were formed. The measured coefficients of variation (CV) for the amount of drug in the samples were low and inferior mixtures were associated with only a slight increase. It was thus concluded that mucoadhesive interactive mixtures can be created in an appropriate size range for nasal administration, but that visual inspection of these mixtures is initially necessary to confirm the formation of an interactive mixture.

Evaluation of surface and bulk characteristics of cellulose I powders in relation to compaction behavior and tablet properties.

The particle properties and solid-state characteristics of two celluloses, Avicel PH101 and cellulose obtained from the alga Cladophora sp., were evaluated and related to the compaction behavior and the properties of the tablets made from them. The surface area of the celluloses was measured at different levels of penetration capacity, ranging from external surface area of particles to molecular texture with Blaine permeametry, Kr-gasadsorption, and solid-state NMR. The important cellulose fibril surface area was best reflected by solid-state NMR, although for the Cladophora cellulose, Kr-gas adsorption also resulted in a surface area of the order of what has been suggested earlier on the basis of the cellulose fibril dimensions. The difference in fibril dimension and, thereby, the fibril surface area of the two celluloses was shown to be the primary factor in determining their properties and behavior. Properties such as the crystallinity and the tablet disintegration could be related to the fibril dimensions. The Cladophora cellulose resulted in rather strong compacts that still disintegrated rapidly. The irregular surface morphology of the particles and the fragmenting behavior of Cladophora probably contributed to the strength of the tablets.

In vitro and in vivo evaluation of a new sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as the active substance.

Oromucosal delivery of drugs promotes rapid absorption and high bioavailability, with subsequent almost immediate onset of pharmacological effect. However, many oromucosal delivery systems are compromised by the possibility of the patient swallowing the active substance before it has been released and absorbed locally into the systemic circulation. This paper introduces a new tablet system for sublingual administration and rapid drug absorption. The tablet is based on interactive mixtures of components, consisting of carrier particles partially covered by fine dry particles of the drug, in this case fentanyl citrate. In the interests of increasing retention of the drug at the site of absorption in the oral cavity, a bioadhesive component was also added to the carrier particles. Tablets containing 100, 200 and 400 microg of fentanyl were tested both in vitro and in vivo. The tablets disintegrated rapidly and dissolution tests revealed that fentanyl citrate was dissolved from the formulation almost instantly. Plasma concentrations of fentanyl were obtained within 10 min, with no second peak. These results indicated that the bioadhesive component prevented the fentanyl from being swallowed (the fraction swallowed was considered smaller compared to other mucosal delivery systems), without hindering its release and absorption. This new sublingual tablet formulation may also hold potential for other substances where a rapid onset of effect is desirable.

Apparent solubility of drugs in partially crystalline systems.

Using several griseofulvin samples, representing different solid-state structures, the solubility behavior of drugs in both one-state (totally ordered, semiordered or disordered) and two-state systems was studied. Special attention was directed towards the surface structure of the particles. The partially crystalline samples were obtained by milling the raw material (crystalline standard) or storing the quenched sample (amorphous standard). The solid-state structure of the materials was studied using x-ray diffraction (XRD), differential scanning calorimetry (DSC), isothermal microcalorimetry (IMC), and scanning electron microscopy (SEM). The saturation concentration of the materials was studied in suspensions containing different dispersion concentrations of drug after centrifugation and filtration, using spectrophotometry. In all cases these dispersion concentrations exceeded the solubility of the drug. The solubilities were plotted vs. dispersion concentrations for each sample. Several solubility plateaus were found. The lowest and highest solubility plateaus corresponded to the solubilities of crystalline and amorphous standards. These plateaus were reached at 8 and 44 microg/mL for crystalline and amorphous griseofulvin standards, respectively. An intermediate plateau served as an indication of the existence of a totally semiordered structure. This was reached at 19 microg/mL for griseofulvin. Any deviation from these plateaus was suggested to be indicative of the existence of heterogeneity on the surface structure, which in most cases could be described as a two state system. In such cases, the apparent solubility was a function of dispersion concentration, until at very high dispersion concentrations (4000-20,000 microg/mL) the saturation concentration of the totally disordered (44 microg/mL) or semiordered (19 microg/mL) one-state phase was reached. No reduction in these values was observed during storage for 50 days. It is thus concluded that, in partially crystalline systems, the saturation concentration is an interfacial phenomenon, which depends on the amount, reactivity, and solid-state structure of the exposed solid surfaces in equilibrium with the solution. A simplified solubility model is proposed to qualitatively describe the relationship between established apparent solubilities (saturation concentrations) and different combinations of solid-state structures.

An automatic dose dispenser for microtablets--a new concept for individual dosage of drugs in tablet form.

A new concept for individualising the dosage of drugs in solid form is presented. The principle is based on the use of standardised units (microtablets), each containing a subtherapeutic amount of the active ingredient. The required dose is fine-tuned by counting out a specific number of these units. The microtablets are counted electronically from the attached cassette by the automatic dispensing device. The individual dose is set and the dispenser counts and delivers the correct number of microtablets. The usefulness of the automatic dispenser concept and acceptability of the apparatus were evaluated in patients with Parkinson's disease (PD). After initial instruction on use of the dispenser, 20 patients operated it themselves. All patients were generally satisfied with their management of the automatic dispenser and most would be happy to use the device again. Further technical development is required before use in clinical practice, but the current prototype may be acceptable for some patients. It is concluded that the final version of the automatic dose dispenser concept will offer potential for improvement of drug administration for patients with PD or other diseases requiring individual dosage.

Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets.

Continuous duodenal infusion of carbidopa/levodopa has been shown to control motor fluctuations in advanced Parkinson's disease (PD). The authors compared the pharmacokinetics of levodopa and 3-O-methyldopa in patients with advanced PD after administration of an oral sustained-release levodopa preparation and after continuous intestinal levodopa infusion with a new formulation as a gel suspension. A randomized crossover trial was carried out in 12 patients. Carbidopa/levodopa was administered as an oral sustained-release tablet and by nasoduodenal continuous infusion for 3-week periods for each treatment. Plasma levodopa concentrations and motor performance were evaluated every 30 minutes during 3 test days of each treatment period. The average intraindividual coefficient of variation for the plasma levodopa concentrations after oral therapy was 34% and was significantly lower (14%, p < 0.01) during continuous infusion. Hourly video evaluations showed a significant increase in ON time during infusion and a significant decrease in OFF time and dyskinesia. Continuous intraduodenal delivery of a new carbidopa/levodopa formulation offers a means for markedly improved control of motor fluctuations in late stages of PD.

In-vitro evaluation of bioadhesion in particulate systems and possible improvement using interactive mixtures.

The bioadhesion of tablet components was tested using the fracture method (maximum tensile stress in detaching the sample from mucus membrane) and comparing traditional tablet specimens with powder monolayers. Both nonadhesive excipients and established mucoadhesive materials were investigated. Some nonadhesive materials showed unexpectedly good adhesive properties when tested as tablets but not as powders. Conversely, some bioadhesive materials had unexpectedly low adhesive properties when tested as tablets. Thus, powder specimens of some materials appear to give more realistic results than tablet specimens in this respect. The use of powder specimens seems particularly applicable for testing dispersible tablets intended for transmucosal absorption. Potential for increasing the bioadhesive properties of coarse, nonadhesive carrier particles by coating them with fine particles of bioadhesive materials during dry mixing (forming interactive mixtures) was also studied. The tensile strength of the adhesive bond between the mucosa and the nonadhesive excipients was improved when fine cross-linked carboxymethyl cellulose sodium (Ac-Di-Sol) particles were added. The addition of increased proportions of Ac-Di-Sol initially improved the bioadhesive properties until a plateau was reached. A standardised test of bioadhesive capacity could therefore involve the addition of fine bioadhesive powders to coarse carriers in proportions close to those providing monoparticulate surface coverage. Interactive mixtures such as these may also offer potential as a tool for use in the development of bioadhesive drug formulations.

Characteristics of hydroxypropyl methylcellulose influencing compactibility and prediction of particle and tablet properties by infrared spectroscopy.

Particle characteristics, chemical substitution, compaction behavior, and tablet properties of hydroxypropyl methylcellulose powders from two different suppliers were related using multivariate data analysis. By Principal Component Analysis it was shown that the the degree of substitution of the HPMC powders did not correlate to the particle and compaction properties as strongly as anticipated. Particle shape and powder surface area seem to be more important for the compaction behaviour of the powders than the degree of substitution. In addition, particle and tablet properties were predicted from infrared spectral data. Fourier transform infrared (FTIR) and near infrared (NIR) spectral data of the powders were combined with measured values of the particle characteristics, compaction behavior, and tablet properties using the multivariate data analysis program SIMCA 7.1. Properties like density, particle shape, tablet tensile strength, and drug release characteristics of the HPMC powders and corresponding tablets in this study could be predicted using Partial Least Squares models. In conclusion, the particle shape and powder surface area of HPMC powders seem to be important factors for the quality of tablet attained. Further, this study confirms that NIR and FTIR analysis used in combination with multivariate analysis are powerful tools for predicting the properties of materials and the quality of the end product.