A pharmacokinetic approach to the establishment of biopharmaceutic characteristics of different acetylsalicylic acid formulations in man

Eleven acetylsalicylic acid (ASA) formulations were administered to 26 healthy volunteers in a cross-over design. The properties of the preparations differed from conventional, effervescent, buffered to buccal. The objectives of this study were:

• 1 Consideration of the general aspects of a biopharmaceutical study: which parameter for which biopharmaceutic characteristic?
• 2 Measurement of the kinetic parameters of ASA: first-pass effect, mean residence time, mean appearance time, total body clearance, apparent volume of distribution, half-lives, etc.
• 3 Comparison of the formulations.

Most of the formulations yield mean residence times for ASA of 0.3–1.0h, which do not differ significantly (p > 0.05). For most of the products the first-pass effect is about 40 per cent; the average values of the apparent volume of distribution and whole body clearance, corrected for the first-pass effect, are about 201 and 650 ml min^?1, respectively. Peak levels are reached slowly for the buccal formulations, and rapidly for the buffered products. It is difficult, especially for ASA, to characterize the gastro-intestinal absorption with pharmacokinetic model parameters, because the first-pass effect is large and often elimination of ASA is faster than absorption. The model-independent approach has the special advantages of calculating reliable pharmacokinetic parameters, and creating theoretical possibilities to characterize the absorption patterns of the different formulations in a quantitative way. No significant differences in the values of the parameters are found between most of the formulations. The ASA first-pass effect is reasonably constant and buccal application has no advantage. Enteric coating of the outer layer of ASA formulations causes inconsistent absorption and may be categorized under ‘artificial mistakes’.     

Approaches to reducing toxicity of parenteral anticancer drug formulations using cyclodextrins

Mitomycin C (MMC) is a clinically useful anticancer drug which can cause severe dermatological problems upon injection. It can cause delayed erythema and/or ulceration occurring either at or distant from the injection site for weeks or even months after administration. In an attempt to reduce the skin necrosis, complexation of MMC with cyclodextrins was studied in order to help increase patient compliance and acceptance. The complexation of MMC with 2-Hydroxypropylbetacyclodextrin (HPBCD) in the presence and absence of mannitol was studied and it was found that the mannitol present in the commercial formulation caused an increase in the binding of MMC to HPBCD. Isotonicity adjustment of hypotonic MMC formulations by the addition of normal saline did not change the degree of complexation with MMC. The complexed formulations were then tested to determine their antitumor efficacy using the B-16 melanoma cell model. No difference in antitumor activity between the complexed and uncomplexed MMC formulations was observed. Different MMC formulations were tested for their potential to produce skin irritation and/or toxicity using intradermal injections in a BALB/c mouse model in order to find the most suitable formulation. The skin ulceration studies indicated that there were no significant differences between the isotonic MMC solution and isotonic formulations of MMC complexed with HPBCD.     

Pharmacokinetics of parenteral 13-cis-retinoic acid formulations in rats.

The pharmacokinetics of three 13-cis-retinoic acid formulations were studied after intraperitoneal (ip) administration to rats. Rats were given ip injections of 2.5 mg of 13-cis-retinoic acid per 360 g of body weight; the drug was administered as an alkaline solution, suspended in corn oil, or as a mixture with polysorbate 80. The alkaline solution was also given intravenously (iv) via the tail vein as a control. The mean elimination rate constant, calculated from data from iv administration, was 0.72 +/- 0.088 h-1 (r = 0.988). The peak concentration in plasma and the time to reach this maximum were 14 mg/L and 0.5 h, 22 mg/L and 2 h, and 10 mg/L and 1 h for the drug administered as an alkaline solution, suspended in corn oil, and as a mixture with polysorbate 80, respectively. The areas under the concentration-time curve (concentration in plasma versus time) were 34.9 +/- 8.78 mg.h/L for the iv dose and 34.1 +/- 9.97, 62.4 +/- 32.3, and 25.9 +/- 12.0 mg.h/L for the ip doses of alkaline solution, suspension in oil, and mixture with polysorbate 80, respectively. Because of the rapid increase of concentration in plasma, which is identical to that of the iv profile, and the ease of its handling and preparation, the ip administered alkaline solution is the preferable formulation.     

Development of parenteral formulations and evaluation of the biological activity of the trypanocide drug benznidazole

Chagas disease, caused by Trypanosoma cruzi, is a major public health problem in Latin America. According to the World Health Organization, around 20 million people are infected and another 40 million are at risk of acquiring the disease. One of the drugs most frequently used for the treatment of Chagas disease is benznidazole (BZL). It is practically insoluble in water (0.4 mg/ml), which precludes the preparation of liquid dosage forms, in particular, parenteral formulations. Thus, the aim of this work was to investigate the solubilization of BZL at two pH values using various cosolvents such as ethyl alcohol, propylene glycol, polyethylene glycol 400, benzyl alcohol, diethylene glycol monoethyl ether (Transcutol) and surfactants such as polysorbates (Tween) 40 and 80, and sodium dioctyl sulfosuccinate (AOT). Solvent systems based on PEG 400, with the addition ethyl alcohol and/or potassium biphthalate buffer solution, increased the BZL solubility up to 10 mg/ml. These alcoholic vehicles showed no toxicity against parasite when assayed at 1%. Physical and chemical stability studies showed that the formulations were stable for at least 1.5 years. In agreement with the biological activity results, the selected formulations are suitable for further clinical studies. Moreover, increasing the aqueous solubility of BZL reduced the problems in vitro testing techniques and bioassays leading to more reliable results and/or reproducibility.     

Micellar complexes of all-trans retinoic acid with polyvinylalcohol-nicotinoyl esters as new parenteral formulations in neuroblastoma

All-trans-retinoic acid (ATRA) is now included in many antitumor therapeutic schemes for the treatment of acute promyelocytic leukemia, Kaposi’s sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, bladder cancer, and neuroblastoma. Unfortunately, its poor aqueous solubility hampers its parenteral formulation, whereas oral administration of ATRA is associated with progressively diminishing drug levels in plasma, which is related to induction of retinoic acid-binding proteins and increased drug catabolism by cytochrome P450-mediated reactions. An ATRA formulation, obtained by complexation of the drug into polymeric micelles, might be suitable for parenteral administration overcoming these unwanted effects. To this purpose, amphiphilic polymers were prepared by polyvinylalcohol (PVA) partial esterification with nicotinoyl moieties and their functional properties evaluated with regard to ATRA complexation. The physicochemical characteristics of the polymers and the complexes were analyzed by ¹H-NMR, Dynamic Light Scattering (DLS), Capillary Electophoresis (CE), and were correlated with the complex ability to improve the drug solubilization and release the free drug in an aqueous environment. Subsequently, the best complex, providing the highest ATRA solubilization and release, was evaluated in vitro to test its citotoxicity towards neuroblastoma cell lines. The PVA substitution degree calculated from ¹H-NMR was found to be 5.0%, 8.2%, 15.3% (nicotinoyl moiety:PVA monomer molar ratio), while capillary electrophoresis analysis on the complexes revealed that the drug loadings were 0.95%, 1.20%, 4.76% (ATRA:polymer w:w) for PVA substitution degrees of 5.0%, 8.2%, and 15.3%, respectively. Complexation strongly increased ATRA aqueous solubility, which reached 1.20 ± 0.25 mg/mL. The DLS measurements of the polymers and the complexes in aqueous solutions revealed mean sizes always below 400 nm, low polydispersity (min 0.202 ± 0.013, max 0.450 ± 0.032), and size almost unaffected by concentration. Drug fractional release did not exceed 8% after 48 h. The cytotoxicity studies against neuroblastoma cell lines outlined a significant growth inhibition effect of complexed ATRA with respect to free ATRA. These data suggest that the systems analyzed may be suitable carriers for parenteral administration of ATRA and other hydrophobic antitumor drugs, where the carriers are required to improve drug aqueous solubility and delay drug release almost after their accumulation in solid tumors.     

A clinical sociology approach to treatment of deviants: The case of drug addicts

This paper has three foci. First, it examines the developing area of clinical sociology. Second, it demonstrates how, in reality, deviants in general and drug addicts in particular should be treated using theories of deviance and symbolic interactionism. The treatment itself is based on group experiences and is geared towards coping with problems associated with social position and identity. Third, an evaluation of the treatment is provided.     

In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug

This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide (BUD) as a model drug. The formulations investigated in this study are: (i) commercially available micronized BUD mixed with lactose (BUD-PT), (ii) BUD nanocrystal suspension (BUD-NC), (iii) BUD nanocrystals embedded hyaluronic acid microparticles (BUD-NEM). The deposition patterns of the three inhaled formulations in the rats’ lungs were determined in vivo and in silico predicted, which were used as inputs in GastroPlus™ software to predict drug absorption following aerosolization of the tested formulations. BUD pharmacokinetics, estimated based on intravenous data in rats, was used to establish a drug-specific in silico absorption model. The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM, respectively. In the case of BUD-PT, the in silico model revealed significant gastrointestinal absorption of BUD, which could be overlooked by traditional in vivo experimental observation. This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations, which may facilitate the development of orally inhaled formulations with different drug release/absorption rates.     

Mathematical approach for understanding deagglomeration behaviour of drug powder in formulations with coarse carrier

Deagglomeration of cohesive particles in combination with coarse carrier is a key requirement for inhaled formulations. The aim of the project was to propose a mathematical approach to understand aerosolization behaviour of micronized particles alone and in formulation with carriers. Salbutamol sulphate and salmeterol xinafoate were blended separately with fine lactose (ratio 1:4) and fine and coarse lactose (1:4:63.5). Laser diffraction was employed to characterize the powder median particle size. The deagglomeration of micronized materials followed an asymptotic monoexponential relationship. When the coarse lactose was added, the relationship fitted a bi-exponential equation showing an easily and a poorly dispersed fraction. Using model hydrophobic and hydrophilic APIs, this study has demonstrated the utility of an analytical approach that can parameterize deagglomeration behaviour of carrier-free and carrier-based inhalation formulations. The analytical approach provides the ability to systematically study the effect of material, formulation and processing factors on deagglomeration behaviour.     

Use of transdermal drug formulations in the elderly

Transdermal drug delivery systems are pharmaceutical forms designed to administer a drug through the skin to obtain a systemic effect. They ensure a constant rate of drug administration and a prolonged action. Several different types of transdermal delivery devices are available on the market. They are either matrix or reservoir systems and their main current uses are to treat neurological disorders, pain and coronary artery disease, and as hormone replacement therapy.Transdermal drug administration has a number of advantages compared with the oral route: it avoids gastrointestinal absorption and hepatic first-pass metabolism, minimizes adverse effects arising from peak plasma drug concentrations and improves patient compliance. Compared with the parenteral route, transdermal administration entails no risk of infection. For elderly people, who are often polymedicated, transdermal drug delivery can be a good alternative route of administration.Transdermal absorption depends on passive diffusion through the different layers of the skin. As skin undergoes many structural and functional changes with increasing age, it would be useful to know whether these alterations affect the transdermal diffusion of drugs. Studies have shown that age-related changes in hydration and lipidic structure result in an increased barrier function of the stratum corneum only for relatively hydrophilic compounds. In practice, no significant differences in absorption of drugs from transdermal delivery systems have been demonstrated between young and old individuals. The need for dose adaptation in elderly patients using transdermal drug delivery systems is therefore not related to differences in skin absorption but rather to age-related cardiovascular, cerebral, hepatic and/or renal compromise, and to ensuing geriatric pharmacokinetic and pharmacodynamic changes.     

Application of ninhydrin to spectrophotometric determination of famotidine in drug formulations

A simple and fast spectrophotometric procedure has been developed for the determination of famotidine. The method is based on the interaction of ninhydrin with primary amines present in the famotidine. This reaction produces a blue coloured product which absorbed maximally at 590 nm. The effects of variables such as reagent concentration and reaction time were investigated to optimize the procedure. Beer's law was obeyed in the concentration range of 5-30 microg ml(-1) with molar absorptivity of 6.99 x 10(3) l M(-1) cm(-1). The results were validated statistically. The proposed method has been applied to the determination of famotidine in tablets with satisfactory results.     

Liposomal drug formulations in the treatment of rheumatoid arthritis

Liposomes have been extensively investigated as drug delivery systems in the treatment of rheumatoid arthritis (RA). Low bioavailability, high clearance rates and limited selectivity of several important drugs used for RA treatment require high and frequent dosing to achieve sufficient therapeutic efficacy. However, high doses also increase the risk for systemic side effects. The use of liposomes as drug carriers may increase the therapeutic index of these antirheumatic drugs. Liposomal physicochemical properties can be changed to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to nontarget tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells in RA. This review gives an overview of liposomal drug formulations studied in a preclinical setting as well as in clinical practice. It covers the use of liposomes for existing antirheumatic drugs as well as for new possible treatment strategies for RA. Both local administration of liposomal depot formulations and intravenous administration of passively and actively targeted liposomes are reviewed.     

Modification of in vitro drug release rate from oily parenteral depots using a formulation approach.

Rate constants for transfer of naproxen and lidocaine from different oils and oil mixtures to aqueous buffer, pH 6.00, were determined using the rotating dialysis cell. Significantly different first-order rate constants related to attainment of equilibrium, k(obs), were derived depending on the type of oil/oil mixtures used in the release experiments. For the drugs a linear correlation was found between logk(obs) and the logarithm of the partition coefficient P(app): logk(obs)=-0.68 logP(app)-0.25 (k(obs) in h(-1), n=26). A linear relationship was observed between the calculated and experimentally determined P(app) values for the oil mixtures investigated. The specific rate constants, k(ow) and k(wo), related to the partition process were derived from the determined k(obs) and P(app) values. The rate constant k(ow) representing the rate of transfer of the solute from the oil phase to the aqueous buffer was shown to be strongly dependent on the partition coefficient according to the relationship: logk(ow)=-0.68 logP(app)-log(P(app)+1)-0.25 (k(ow) in h(-1), n=26). In particular, diminished release rates were seen for oil mixtures containing castor oil most likely afforded by hydrogen bonding between the solute and the hydroxy groups of the latter vegetable oil. In this study it has been possible to alter P(app) for a specific compound up to a factor of 10 by variation of the composition of the oil vehicle. Such a span of P(app) values results in in vitro release rates differing a factor of 37. Thus, by proper design of the oil vehicle composition it should be possible to modify the release rate for a specific compound within certain limits.     

Liposomal drug formulations in cancer therapy: 15 years along the road

Liposomes as pharmaceutical drug carriers were developed to increase antitumour efficacy and decrease drug toxicity. Doxorubicin HCl liposomal injection was the first liposomal encapsulated anticancer drug to receive clinical approval. To date, virtually all traditional anticancer drugs have been encapsulated in liposomes. The majority of clinical studies only support the concept of a decreased toxicity and better tolerability of the liposomal anticancer drug. Although liposomal anticancer drugs have grown to maturity in several indications and are now in widespread further development programmes using their theoretical advantages to fulfil the high expectations, further studies are warranted--including the development of novel liposomal formulations.     

Oversaturated solutions of drug in hydroxypropylcyclodextrins: parenteral preparation of pancratistatin

The effect of 15 cyclodextrin derivatives (polar-electroneutral, cationic, anionic, and lipophilic) and of three 2-hydroxypropyldigitonins on the solubility of pancratistatin, an anticancer drug, was evaluated. The direct solubilizations into aqueous solutions were invariably low (0.1-1.2 mg/mL compared with 50 micrograms/mL in water). Complexes of pancratistatin with hydroxypropyl-beta-cyclodextrin were more stable (Kapp 153 M-1) than those with hydroxypropyl-gamma-cyclodextrin (Kapp 108 M-1). Acceptable preparations were made by dissolution of pancratistatin in a large excess (50x) of hydroxypropylcyclodextrin by ammonia and then freeze drying to ammonia-free preparations. In these preparations, both the inclusion and interdispersion phenomena were operative, and the preparations dissolved rapidly forming clear solutions of pancratistatin of concentrations up to 9 mg/mL. These solutions were oversaturated and while those based on hydroxypropyl-beta-cyclodextrin precipitated within 1 h; those based on hydroxypropyl-gamma-cyclodextrin were stable for at least 4 h when kept in a plastic container (i.e., time sufficient for potential use in parenteral preparations).     

A new validation approach applied to the GC determination of impurities in organic solvents

Organic solvents such as methanol, acetone, dichloromethane or toluene are frequently used in the pharmaceutical industry. The manufacturing of new active pharmaceutical ingredients (APIs) under GMP conditions commands to control adequately the quality of the different ingredients happening in the synthesis. Organic solvents have therefore to be controlled and their purity has to be determined before any GMP synthesis. A selective gas chromatography (GC) method has been developed to determine the purity of acetone, dichloromethane, methanol and toluene. Using this method, the main contaminants of each organic solvent can be quantified. Moreover, the developed method allows the simultaneous determination of ethanol, isopropanol, chloroform, benzene, acetone, dichloromethane, methanol and toluene. Propionitrile was used as the internal standard. The separation was obtained on a CP-SIL 8-CB low bleed/MS column (60 m x 0.32 mm i.d.x1.0 microm coating thickness). The GC method was fully validated using a new approach based on the accuracy profile as a decision tool. The determination of beta-expectation tolerance intervals for the estimation of total error - including both bias and precision - is used to better reflect the actual performances of the method, which is definitively the objective of the validation. The different validation criteria such as selectivity, response function, trueness, precision, accuracy, linearity or limits of detection and quantification were considered. The method was found to be able to quantitate with a good accuracy impurities around the 0.1% (v/v) concentration level for the different solvents.     

Liposomal formulations of Cyclosporin A: a biophysical approach to pharmacokinetics and pharmacodynamics

There are about 20 publications about liposomal formulations of Cyclosporin A (CyA) in the pharmaceutical and preclinical literature. Liposomal formulations were developed in order to reduce the nephrotoxicity of CyA and to increase pharmacological effects. However, conflicting results have been published as to the therapeutic properties of these formulations. This is also true for the change in pharmacokinetics and organ distribution of the liposomally encapsulated CyA as compared to conventionally formulated CyA. Using biophysical methods, it could be shown that CyA is not tightly entrapped in liposomal membranes, despite its high lipophilicity. CyA shows retardation only at high lipid concentrations in blood, following a massive injection of liposomes.This effect may diminish nephrotoxicity, as could be demonstrated by in vitro studies using a model tubule system. The results of these studies can be used to predict the formulation behavior in vivo and to optimize liposomal formulations. When applied in an early phase of the drug formulation process, these types of biophysical experiments can also help minimize animal experiments. However, these basic interaction studies cannot cover all physiological, pharmacological, and toxic effects in animals and humans.