Fluctuations In Drug Concentrations Research Articles

Abstract 7182: Blood brain barrier masks effects of dosing strategy

Abstract The penetration of the blood brain barrier (BBB) presents a significant challenge in the design of drugs targeting brain tumors. The BBB desynchronizes drug concentrations between the body and brain, complicating the relationships between drug dose, effective concentration, and toxicity. In this work, we sought to understand the nature of these relationships in the context of dose schedule, in order to suggest minimally toxic and maximally effective strategies. We developed a two-compartment pharmacokinetic model to simulate the exchange of a drug between the body and the brain. Drug exchange was based on passive diffusion through the barrier and active transport into the brain as described by Michaelis-Menten kinetics. In the model, tumor cells exhibit binary resistance to the drug under a logistic growth model. The drug reduces the growth rate of the sensitive population while the resistant population suffers a small growth penalty because of the mutation conferring resistance. Strategy effectiveness was quantified in terms of survival time, the time until 95% of carrying capacity was reached, and toxicity was evaluated as the peak moving average over 18 days. Although the BBB complicates prediction of drug action, it simplifies drug impact by masking schedule effects. Our work suggests that drug concentrations in the brain increase with initial treatment until equilibrium between active transport, diffusion, and drug metabolism is reached. Fluctuations in drug concentration resulting from breaks between bolus dosing are greatly reduced in the brain relative to the body, and high frequency (daily) dosing results in a nearly constant equilibrium drug concentration. The rate at which equilibrium is reached and the drug concentration in the brain are unaffected by dosing period, as long as the average dose per day is constant. Our model suggests that the impact of dosing cycle length on survival time is negligible. Neutropenia is minimized by schedules with dosing cycle lengths that factor evenly into the 18-day neutrophil recovery period. These schedules have consistent toxicity throughout. Strategies with two, three, six, nine, and eighteen day cycles induce neutropenia least. As fluctuations in drug concentration are small at the equilibrium steady-state, effects of scheduling on drug interactions are predicted to be minimal. As drug concentration in the brain at equilibrium and latency to equilibrium are independent of dosing period, these parameters must be modulated through changes in the amount of drug dosed. The use of a loading dose may compensate for latency. Although this analysis is based on hypothetical drugs, it provides practical insights that are applicable across a wide range of systemically dosed small-molecule therapeutics. Further, the modeling framework derived here can be readily extended to guide the design of dosing schedules for real-world therapeutic interventions. Citation Format: Madison Stoddard, Andrew Chen, Lin Yuan, Debra Van Egeren, Arijit Chakravarty. Blood brain barrier masks effects of dosing strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7182.

The effect of polymeric films of hydroxypropyl methylcellulose (HPMC)/chitosan on ofloxacin release, diffusion, and biological activity

AbstractInfectious diseases caused by resistant bacteria have been investigated by several researchers recently. Ofloxacin is a quinolone antibiotic used against resistant microorganisms and in different routes of administration. Transdermal drug delivery is used to reduce drug toxicity, avoid first‐pass metabolism, and reduce fluctuations in drug concentration in the body. Ofloxacin was formulated in a transdermal polymeric formula using hydroxypropyl methyl cellulose (HPMC) and chitosan at different ratios in the presence of palmitic acid as a permeation enhancer. Physical characterization, drug release and diffusion, drug matrix association, and antimicrobial assay have been investigated using different techniques including HPLC, fourier‐transform infrared spectroscopy (FTIR), Franz cells diffusion, and UV spectroscopy. Ofloxacin release was successfully accomplished in many polymeric formulas containing a high ratio of HPMC with a maximum drug release of 53%. Formulas selected for antimicrobial assay indicate that sustained release patches have successfully inhibited microbial and biofilm growth with a percentage inhibition of more than 90%. In conclusion, antibiotics can be formulated in transdermal polymeric film to target skin infection and reduce drug toxicity and avoid drug first metabolism for drugs reaching systemic circulation which has a direct influence on drug activity.

A Microphysiological Cell-Culturing System for Pharmacokinetic Drug Exposure and High-Resolution Imaging of Arrays of 3D Microtissues.

Understanding the pharmacokinetic/pharmacodynamic (PK/PD)-relationship of a drug candidate is key to determine effective, yet safe treatment regimens for patients. However, current testing strategies are inefficient in characterizing in vivo responses to fluctuating drug concentrations during multi-day treatment cycles. Methods based on animal models are resource-intensive and require time, while traditional in vitro cell-culturing methods usually do not provide temporally-resolved information on the effects of in vivo–like drug exposure scenarios. To address this issue, we developed a microfluidic system to 1) culture arrays of three-dimensional spheroids in vitro, to 2) apply specific dynamic drug exposure profiles, and to 3) in-situ analyze spheroid growth and the invoked drug effects in 3D by means of 2-photon microscopy at tissue and single-cell level. Spheroids of fluorescently-labeled T-47D breast cancer cells were monitored under perfusion-culture conditions at short time intervals over three days and exposed to either three 24 h-PK-cycles or a dose-matched constant concentration of the phosphatidylinositol 3-kinase inhibitor BYL719. While the overall efficacy of the two treatment regimens was similar, spheroids exposed to the PK profile displayed cycle-dependent oscillations between regression and regrowth. Spheroids treated with a constant BYL719 concentration regressed at a steady, albeit slower rate. At a single-cell level, the cell density in BYL719-treated spheroids oscillated in a concentration-dependent manner. Our system represents a versatile tool for in-depth preclinical characterization of PK/PD parameters, as it enables an evaluation of drug efficacy and/or toxicity under realistic exposure conditions.

Mechanisms of a Sustained Anti-inflammatory Drug Response in Alveolar Macrophages Unraveled with Mathematical Modeling.

Both initiation and suppression of inflammation are hallmarks of the immune response. If not balanced, the inflammation may cause extensive tissue damage, which is associated with common diseases, e.g., asthma and atherosclerosis. Anti‐inflammatory drugs come with side effects that may be aggravated by high and fluctuating drug concentrations. To remedy this, an anti‐inflammatory drug should have an appropriate pharmacokinetic half‐life or better still, a sustained anti‐inflammatory drug response. However, we still lack a quantitative mechanistic understanding of such sustained effects. Here, we study the anti‐inflammatory response to a common glucocorticoid drug, dexamethasone. We find a sustained response 22 hours after drug removal. With hypothesis testing using mathematical modeling, we unravel the underlying mechanism—a slow release of dexamethasone from the receptor–drug complex. The developed model is in agreement with time‐resolved training and testing data and is used to simulate hypothetical treatment schemes. This work opens up for a more knowledge‐driven drug development to find sustained anti‐inflammatory responses and fewer side effects.

Formulation and evaluation of transdermal patches containing dexketoprofen trometamol

Dexketoprofen Trometamol is a NSAID, used as an analgesic and anti-inflammatory drug. It works by blocking the action of cyclo-oxygenase in the body. Conventional route of delivery has many drawbacks such as hepatic first-pass metabolism, reduced bioavailability, and fluctuating drug concentrations in the blood. These problems can be overcome by development of transdermal drug delivery system. The objective of this study was to develop and evaluate the transdermal patches of the drug Dexketoprofen Trometamol. The patches were prepared by solvent casting method using polymers; Ethyl cellulose, HPMC and ERS 100 in different ratios.The prepared formulations were uniform in their physical characteristicsThe formulation F6, combination of polymer (HPMC: EC in ratio 4:1) showed maximum release of 85.77% in 24 hours. The resultant data was fitted in to zero, first, Higuchi and Peppas model. The results specify that Dexketoprofen Trometamol transdermal patch can be designed for obtaining better therapeutic benefits.

Wireless, battery-free and wearable device for electrically controlled drug delivery: sodium salicylate released from bilayer polypyrrole by near-field communication on smartphone.

Compared with traditional drug delivery methods, transdermal drug delivery has many advantages in avoiding the side effects in gastrointestinal tract, reducing the fluctuations in drug concentration, and improving patients' compliance. Among them, electrically controlled drug delivery is a promising solution. This work presents a wireless, battery-free and wearable device with electrically controlled drug delivery capability. The electronic component of the device is a flexible circuit board with a temperature sensor and a near-field communication module. With the help of smartphone, the device could wirelessly obtain energy and implement data transmission. The drug delivery component is a paper-based electrode modified with polypyrrole, in which non-steroidal anti-inflammatory drug sodium salicylate was encapsulated. The applied potential for electrically controlled drug delivery was more negative than -0.6V. The drug release dose and release rates could be controlled by applying potentials with different amplitudes and durations through this device. It provided a minimalized wearable transdermal drug delivery platform for monitoring diseases such as gout. This wearable device shows promising potential in develop closed-loop drug delivery and monitoring systems for the treatment of various diseases.

Oral Modified Drug Release Solid Dosage Form with Special Reference to Design; An Overview.

Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form and this oral route provides maximum active surface area among all drug delivery system for administration of various drugs. The attractiveness of these dosage forms is due to awareness of toxicity and ineffectiveness of drugs when administered by oral conventional method in the form of tablets and capsules. Usually, conventional dosage form produces wide range of fluctuation in drug concentration in the bloodstream and tissues with consequent undesirable toxicity and poor efficiency. The maintenance of concentration of drug in plasma within therapeutic index is very critical for effective treatment. These factors as well as factors such as repetitive dosing and unpredictable absorption lead to the concept of oral modified drug delivery systems like Sustained release, prolonged release, modified release, extended release. These formulations are used to identify drug delivery systems that are designed to achieve or extend therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. This review describes the basic information regarding modified release dosage form like designed to release their medication in controlled manner, criteria for selecting modified release dosage form and factors influencing the dosage and release pattern.

Gastro-retentive drug delivery system for treatment of Ulcer

Due to the comfort of administration, economical and extensibility in formulation, the most adopted route to the systemic circulation is the oral route regardless of the astounding elevation in the drug delivery. Oral drug delivery is the most comforting method of delivery due to its comforting method of delivery, due to its better solubility, accurate dosage and simpler production. Approximately 90% of the drugs are administered orally of which solid oral dosage form is the most chosen class of medicaments. Conventional dosage forms usually exhibit the serum drug concentration fluctuations and irregularities in drug concentration in the tissues with resultant toxicity, low bioavailability and thus low therapeutic effects. Accordingly, the concept of the oral sustained release drug delivery system has gained popularity in advancement. Sustained release drug deliveries have steady and consistent drug release over longer time duration. Here, if the drug release is consistent over the time duration, it is supposed to be controlled release system, however if the system doesn’t achieve the constant drug release but shows the drug release over the longer duration compared to the conventional system, it is prolonged release systems. These systems are hot in the recent trend as they offer huge designing and adaptability range during formulation

Impact of dosing schedule in animal experiments on compound progression decisions

Low pipeline output is a major problem for the pharmaceutical industry. Many compounds fail to enter clinical development, owing to toxicities in animals. Using pharmacology principles, this paper argues that the often-infrequent dosing in animal experiments despite a drug's short half-life produces a large fluctuation in drug concentration, which can severely erode the therapeutic index and safety margin for the anticipated clinical dose, consequently preventing potentially effective treatments from entering human trials. Aided by computer simulations under generalised conditions, the analysis was conducted in a quantitative framework with broad relevance. The findings call for more-translatable dosing practices through closer collaboration among scientists in multiple disciplines and better regulatory guidance for animal studies to better inform compound progression decisions.

Biodegradable synthetic polymers and their application in advanced drug delivery systems (DDS)

Natural and synthetic polymers have been used in pharmaceutical industry for many years and have important role in the development of the conventional dosage forms or for manufacturing of various drug packaging materials. In recent years, their important application resides in the development of the most sophisticated drug delivery systems where polymers are used as a drug carrier. Biodegradable polymers are particularly attractive for application in drug delivery systems since, once introduced into the human body, they do not require removal or additional manipulation. Their degradation products are normal metabolites of the body or products that can be metabolized and easily cleared from the body. Among that, synthetic polymers offer a wide variety of compositions with adjustable properties. These materials open the possibility of developing new drug delivery systems with specific properties (chemical, interfacial, mechanical and biological) for a given application, simply by changing the building blocks or the preparation technique. Such designed complex drug delivery systems where polymers are used as functional excipients have numerous advantages such as localized delivery of drug, sustained delivery of drug, stabilization of the drug, prevention of drug’s adverse side-effects, reduction of dosing frequency, minimization of drug concentration fluctuations in plasma level, improved drug utilization and patient compliance. There are range of differently designed drug delivery systems and their description and mechanism of action will be presented in this paper together with the prominent role of the polymers for each particular system. Additionally, most commonly used synthetic biodegradable polymers in drug delivery systems will be presented together with their degradation mechanism.

Indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease

BackgroundVesicular monoamine transporter 2 (VMAT2) inhibitors can improve hyperkinetic movements, and are effective treatment options for chorea of Huntington disease (HD). Tetrabenazine was assessed for treating chorea in the TETRA-HD trial, and while efficacious, there are tolerability concerns possibly due to its pharmacokinetic properties. Deutetrabenazine is a novel VMAT2 inhibitor that contains deuterium, which extends active metabolite half-lives and minimizes drug concentration fluctuations. In the First-HD trial, deutetrabenazine was efficacious in treating chorea and was generally well tolerated. In the absence of a head-to-head trial, we performed an indirect treatment comparison (ITC) of the tolerability of deutetrabenazine and tetrabenazine for the treatment of HD-associated chorea, as observed in the First-HD and TETRA-HD trials, using well-established comparison methods.MethodsData from the Phase III, 12-week, parallel-group, clinical trials First-HD (N = 90) and TETRA-HD (N = 84) were used to conduct an ITC of the tolerability of deutetrabenazine versus tetrabenazine using two anchor-based methods: Bucher comparison for unadjusted ITCs, and matching indirect comparison for adjusted ITCs. Overall adverse events (AEs; mild, moderate, and severe), serious AEs, specific AEs occurring in ≥10% of patients, and discontinuations (all-cause and AE-related) were included in the analysis. The risk differences of these outcomes for deutetrabenazine and tetrabenazine were estimated by subtracting the applicable placebo-adjusted risk in First-HD from that of TETRA-HD. Sensitivity analyses were performed to address differences between trials, and p-values were obtained from z-tests.ResultsCompared with tetrabenazine, deutetrabenazine was associated with a significantly lower risk of moderate to severe AEs and neuropsychiatric AEs including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia, and parkinsonism in both adjusted and unadjusted analyses (p < 0.05 for each). Deutetrabenazine had a significantly lower rate of dose reduction or dose reduction/suspension in the unadjusted and adjusted analyses (p < 0.001 for each). Deutetrabenazine resulted in numerically more mild AEs, such as diarrhea and coughing; however, these results were not statistically significant.ConclusionsThis indirect treatment comparison demonstrates that for the treatment of HD chorea, deutetrabenazine has a favorable tolerability profile compared to tetrabenazine.Trial registrationClinicalTrials.gov NCT01795859 and NCT00219804.

Thioridazine as Chemotherapy for Mycobacterium avium Complex Diseases.

Mycobacterium avium-intracellulare complex (MAC) causes an intractable intracellular infection that presents as chronic pulmonary disease. Currently, therapy consists of ethambutol and macrolides and takes several years to complete. The neuroleptic phenothiazine thioridazine kills mycobacteria by inhibiting the electron transport chain. In several experiments with bacterial populations of up to 1012 CFU/ml, we failed to isolate any bacteria resistant to 3 times the MIC of thioridazine, suggesting the absence of resistant mutants at bacterial burdens severalfold higher than those encountered in patients. In the hollow-fiber model of intracellular MAC (HFS-MAC), thioridazine achieved an extracellular half-life of 16.8 h and an intracellular half-life of 19.7 h. Thioridazine concentrations were >28,000-fold higher inside infected macrophages than in the HFS-MAC central compartment (equivalent to plasma). Thioridazine maximal kill was 5.20 ± 0.75 log10 CFU/ml on day 7 (r2 = 0.96) and 7.19 ± 0.31 log10 CFU/ml on day 14 (r2 = 0.99), the highest seen with any drug in the system. Dose fractionation studies revealed that thioridazine efficacy and acquired drug resistance were driven by the peak concentation-to-MIC ratio, with a 50% effective concentration (EC50) of 2.78 ± 0.44 for microbial killing. Acquired drug resistance was encountered by day 21 with suboptimal doses, demonstrating that fluctuating drug concentrations drive evolution faster than static concentrations in mutation frequency studies. However, the thioridazine EC50 changed 16.14-fold when the concentration of fetal bovine serum was changed from 0% to 50%, suggesting that intracellular potency could be heavily curtailed by protein binding. Efficacy in patients will depend on the balance between trapping of the drug in the pulmonary system and the massive intracellular concentrations versus very high protein binding of thioridazine.

Evaluation of Certain Pharmaceutical Quality Attributes of Lisinopril Split Tablets.

Tablet splitting is an accepted practice for the administration of drugs for a variety of reasons, including dose adjustment, ease of swallowing and cost savings. The purpose of this study was to evaluate the physical properties of lisinopril tablets as a result of splitting the tablets either by hand or with a splitting device. The impact of the splitting technique of lisinopril (Zestril® tablets, 20 mg) on certain physical parameters such as weight variation, friability, disintegration, dissolution and drug content were studied. Splitting the tablets either by hand or with a splitter resulted in a minute but statistically significant average weight loss of <0.25% of the tablet to the surrounding environment. The variability in the weight of the hand-split tablet halves was more pronounced (37 out of 40 tablet halves varied by more than 10% from the mean weight) than when using the tablet splitter (3 out of 40 tablet halves). The dissolution and drug content of the hand-split tablets were therefore affected because of weight differences. However, the pharmacopoeia requirements for friability and disintegration time were met. Hand splitting of tablets can result in an inaccurate dose and may present clinical safety issues, especially for drugs with a narrow therapeutic window in which large fluctuations in drug concentrations are undesirable. It is recommended to use tablets with the exact desired dose, but if this is not an option, then a tablet splitter could be used.

The Impact of Protein Binding on Antibacterial Activities of Antibiotics is more than Predicted by Considering its Numerical Value Alone: Effects of Serum Proteins on Activities of Poorly Penetrating Agents and Inhibition of ß- Lactamase Activity-Part II

Objectives: Protein binding decreases antibacterial activities as the free fraction only crosses membranes thus reaching intracellular targets. However, serum components may increase antibacterial activities. Therefore, the effect of serum proteins on activities of s-lactams and macrolides was examined. Methods: Strains with defined resistance genotypes were selected; MRSA, ermB-, mefA-, gyrA Ser81-Phemutants of S. pneumoniae, and TEM-1 or TEM-3 s-lactamase producing E. coli were used. Ten antibiotics known to penetrate into bacteria either well or poorly and/or known to be labile or stable to inactivation by s-lactamases were used. Strains were incubated in Brain Heart Infusion Broth (BHI), BHI +50% heat inactivated human serum or active serum, or 45 g/L albumin. MICs were determined and Kill-kinetics was recorded following exposure to constant or fluctuating drug concentrations. Kill constants and areas under the bacterial kill curves were calculated. Results: Albumin and inactive serum increased MICs and reduced kill rates of the agents studied in conformity with their protein binding. However, active serum increased the activities of such agents known to penetrate poorly into strains with permeation barriers. In addition, active as well as inactive serum restored the activities of s-lactams against s-lactamase producing strains due to enzyme inhibition. Conclusions: Serum proteins permeabilized bacteria and inhibited s-lactamase activity. The impact of serum proteins on antibacterial activities against specific drug-bug associations is more than predicted by considering the numerical value of protein binding alone.

The Impact of Protein Binding on Antibacterial Activities of Antibiotics is more than Predicted by Considering its Numerical Value Alone: Impact of Preparative and Incubation Methods on Different Pharmacodynamic Endpoints of ß-Lactams, Macrolides, or Fluoroquinolones Against Gram-positive and Gram-negative Bacteria-Part I

Objectives: Protein binding decreases antibacterial activities as the free fraction only crosses membranes thus reaching intracellular targets. However, serum components may also increase antibacterial activities. Therefore, the effect of serum proteins on activities of ß-lactams, macrolides, and fluoroquinolones was examined. Several preparation- and cultivation-conditions were examined as some preparative methods like freeze-thawing of sera may cause artifacts. Furthermore, previous studies have indicated that data may vary depending on the endpoints studied. Therefore, the aim of this study was to avoid an impact of methodological factors on the data generated and to analyse the activities of the study drugs by examining different static- or dynamic endpoints. Methods: Bacteria were grown in Brain Heart Infusion Broth (BHI), plus 50% of either fresh inactivated, pH 7.2, or fresh inactivated- , pH 7.2 or 8.2, frozen inactivated-serum, pH 8.2 as compared to BHI without any supplementations, pH 7.2 or 8.2, and BHI plus 45 g/L albumin. MICs of faropenem, amoxicillin, clarithromycin, azithromycin, moxifloxacin, and levofloxacin were determined and kill-kinetics were recorded following exposure to constant or fluctuating drug concentrations simulating serum pharmacokinetics of the agents. Kill-rates and areas under the bacterial kill curves were calculated. Results: Albumin and inactive serum increased MICs and reduced kill-rates of the agents studied in conformity with their protein binding, whereas active serum increased the activities of the agents. MICs and kill-rates did not change in parallel. The impact of protein binding in decreasing order was: MICs>kill-rates in time-kill experiments>kill-rates in kinetic-simulations. Macrolides and fluoroquinolones but not ß-lactams were more active at an alkaline- than neutral pH. Use of frozen sera caused alkalinization of media, thus generating artifacts. Conclusions: The impact of serum proteins on antibacterial activities is strongly dependent from three factors: the methods applied to prepare the serum pool, the incubation conditions, and the enpoints studied.

Development of Recombinant Human Growth Hormone (rhGH) sustained-release microspheres by a low temperature aqueous phase/aqueous phase emulsion method

A novel method has been developed to protect Recombinant Human Growth Hormone (rhGH) in poly (lactic-co-glycolic acid) (PLGA) microspheres using an aqueous phase/aqueous phase emulsion and S/O/W multi-emulsion method. This method develops a novel rhGH sustained-release system, which is based on the combination of rhGH-loaded dextran microparticles and PLGA microspheres. The process to fabricate rhGH-loaded dextran microparticles involves an aqueous phase/aqueous phase emulsion system formed at the reduced temperature. RhGH was first dissolved in water together with dextran and polyethylene glycol, followed by stirring at the speed of 2000rpm for 20–30s at 0°C, and then a freezing process could enable the dextran phase to separate from the continuous PEG phase and rhGH could preferentially be loaded with dextran. The sample after freezing and phase separation was then lyophilized to powder and washed with dichloromethane to remove the PEG. Once loaded in the dextran microparticles (1–4μm in diameter), rhGH gained resistance to interface tensions and was encapsulated into PLGA microspheres without aggregation thereafter. RhGH released from PLGA microspheres was in a sustained manner with minimal burst and maximally reduced incomplete release in vitro. Single subcutaneous injection of rhGH-loaded PLGA microspheres to rats resulted in a stable plasma concentration for 30days avoiding the drug concentration fluctuations after multiple injections of protein solutions. In a hypophysectomized rat model, the IGF-1 and bodyweight results showed that there were higher than the levels obtained for the sustained release formulation by W/O/W for 40days. These results suggest that the microsphere delivery system had the potential to be an injectable depot for sustained-release of the biocompatible protein of rhGH.

Continuous Drug Delivery in Parkinson’s Disease

Development of motor and non-motor complications during the course of Parkinson's disease (PD) is a major challenge for therapeutic management. At advanced disease stages, patients frequently fluctuate between PD symptoms-such as bradykinesia-and dyskinesias, in response to fluctuations in drug concentrations. Continuous subcutaneous infusion of the dopamine agonist apomorphine or intestinal infusion of levodopa reduce such fluctuations in both pharmacokinetics and motor function. This is the basis for the concept of continuous drug delivery in PD, and the more theoretical concept of continuous dopaminergic stimulation. These expressions are sometimes used to describe a treatment that is more continuous in its pharmacokinetic profile or that produces more sustained effects, compared with immediate-release levodopa, i.e. not only pump treatments. For example, sustained-release formulations of levodopa or dopamine agonists, transdermal delivery of rotigotine, and addition of catechol-O-methyltransferase inhibitors or monoamine oxidase-B inhibitors have been developed with the aim to provide more continuous drug concentrations, sustained benefits and minimized side effects. Progress has been made, but there are still knowledge gaps regarding how these treatment alternatives can be optimally used. New treatments are currently being developed to provide the continuous drug delivery that is known to successfully alleviate motor and non-motor complications. Hopefully, although not yet proven, these new methods may also prevent or postpone some of the late-stage complications.

ORAL CONTROLLED RELEASE DRUG DELIVERY SYSTEM: AN OVERVIEW

Oral drug delivery is the most preferred and con venient option as the oral route provides maximum active surface area among all drug delivery system for administration of various drugs. The attractiveness of these dosage forms is due to awareness to toxicity and ineffectiveness of drugs when administere d by oral conventional method in the form of tablets and capsules. Usually conventional dosage form produces wide range of fluctuation in drug concentration in the bloodstream and tissues with consequent undesirable toxicity and poor efficiency. The mainte nance of concentration of drug in plasma within therapeutic index is very critical for effective treatment. These factors as well as factors such as repetitive dosing and unpredictable absorption lead to the concept of oral controlled release drug delivery systems. Controlled release drug delivery system works on many different mechanisms to control the release rate of drugs. Various mechanisms like osmotic pressure, matrix system, reservoir system, altered density system etc. have been utilized as formulat ion approaches. The present article contains brief review on various formulation approaches for controlled release drug delivery system.

Effect of bases with different solubility on the release behavior of risperidone loaded PLGA microspheres

Poly (D, L-lactide-co-glycolide) (PLGA) microspheres are attractive delivery vehicles due to their excellent sustained release capabilities. One major problem with PLGA microspheres is that the hydrophobic properties of PLGA generally cause a lag period in the process of drug release, leading to fluctuation of drug concentration in the blood and various resulting adverse reactions. Herein, Mg(OH)₂, an inorganic base, and arginine, an organic base, were separately co-encapsulated into risperidone-loaded PLGA microspheres at varying concentration using the solvent evaporation method to improve release profiles from the microspheres. High encapsulation efficiencies were obtained in all formulations. The surface of base-free microspheres was smooth, whereas a few pores formed in base co-encapsulated microspheres. After 7-days degradation, many inter-connecting pores were formed in the interior of the microspheres containing 10 mg Mg(OH)₂. The final pH in the microspheres with Mg(OH)₂ was higher than in those with arginine after 28-days degradation. The initial release of risperidone from microspheres containing Mg(OH)₂ was higher than from those containing arginine, and the latter release exhibited a more uniform pattern. Microspheres with 5mg and 10mg arginine exhibited zero-order release kinetics. However, both bases eliminated the lag phase of release. These results indicate that the incorporation of bases has potential in addressing the problem of the lag period in drug release from PLGA microspheres, and improving release behavior toward an ideal model.

Pharmacokinetics of levodopa

This paper reviews the clinically relevant determinants of levodopa peripheral pharmacokinetics and main observed changes in the levodopa concentration-effect relationship with Parkinson's disease (PD) progression. Available clinically practical strategies to optimise levodopa pharmacokinetics and pharmacodynamics are briefly discussed. Levodopa shows particular pharmacokinetics including an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme L: -amino acid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both intestinal absorption and delivery to the brain, and the clinical effect include standardization of levodopa dosing with respect to meal times and a controlled dietary protein intake. Levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, to swings in the therapeutic response ("wearing-off" phenomena). "Wearing-off" phenomena can also be associated, at the more advanced disease stages, with a "negative", both parkinsonism-exacerbating and dyskinetic effect of levodopa at low, subtherapeutic plasma concentrations. Dyskinesias may also be related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone and simultaneous monitoring of the levodopa concentration-effect relationship may prove useful to disclose the underlying mechanism and in planning the correct management. Clinically practical strategies to optimise levodopa pharmacokinetics, and possibly its therapeutic response, include liquid drug solutions, controlled release formulations and the use of inhibitors of levodopa metabolism. Unfortunately, these attempts have proved so far only partly successful, due to the complex alterations in cerebral levodopa kinetics which accompany the progressive degeneration of the nigrostriatal dopaminergic system in PD patients.