Development and application of a radioreceptor assay for scopolamine

6 beta,7 beta-Epoxy-3a(1aH,5aH)-tropanyl-(S)-tropate (scopolamine) has proved to be a very effective drug in the prevention of motion sickness, however, the drug has a small therapeutic window, a low bioavailability and a short half-life. A transdermal drug delivery system (Scopoderm TTS) was developed to circumvent these problems as well as the variability in gastric absorption. In order to study the pharmacokinetics of the drug and its glucuronide, a highly sensitive radioreceptor assay with an absolute detection limit of 15 pg scopolamine was developed. In children undergoing minor surgery, a Scopoderm TTS patch of different sizes (according to the age of the children) was applied to the retro-auricular skin. Urine samples were collected and assayed for free and conjugated scopolamine. Furthermore possible anticholinergic effects on the pupil reaction, salivation, blood pressure and heart rate were monitored. The urine excretion of free and glucuronidated scopolamine showed large intra- and interindividual variations. However, in all age groups relatively high percentages of free scopolamine were found, namely 47.5% (3-6 years), 48.3% (7-12 years) and 36.0% (13-18 years) of the sum of free plus glucuronidated scopolamine. During the application of the patch, a prolonged plateau of scopolamine excretion could be found. Although in general the patches were well tolerated, both locally and systematically, moderate anticholinergic effects were observed in patients.     

Dermal Drug Delivery Systems: A Review

Abstract

Systems that deliver drugs through intact skin at a controlled rate are now in routine clinical use. They include a nitroglycerin system for the prophylaxis of angina, and a scopolamine system for the prevention of motion sickness. In addition, there are also published reports on rate-controlled transdermal forms of clonidine and estradiol. Since the trans-dermal mode of drug administration can provide continuity of delivery and precise control of drug plasma concentrations, it offers particular advantages for drugs with short half-lives or narrow therapeutic indices. It is also useful when the oral route is unsuitable. Transdermal rate-controlled therapy appears on the brink of rapid expansion for the administration of potent, nonirritating, nonallergenic agents with suitable physi-cochemical properties. In the case of new agents, rate-controlled transdermal administration may render some drugs routinely usable that otherwise would produce unacceptable side effects or require impractical regimens. Some older agents will gain an increased margin of safety and convenience—as well as expanded therapeutic usefulness—compared with their administration in conventional dosage forms. Owing to constraints arising from drug potency, skin permeability, and/or topical reactions, however, transdermal administration is not expected to become the preferred dosage form for a high percentage of drugs.     

Effects of transdermal scopolamine on pulmonary function, symptoms and bronchial hyperresponsiveness to methacholine

This study is a result of two consecutive double-blind, placebo-controlled, cross-over studies. In the first study, we evaluated therapeutic effects of a single transdermal scopolamine patch (Scopoderm® TTS, size 2.5 cm², Ciba Geigy) on forced expiratory volume in one second (FEV₁), reversibility, peak expiratory flow (PEF) and symptoms in ten patients with reversible airways disease (ΔFEV₁9% predicted). During the study, blood and urine samples were taken from the patients and analysed for scopolamine levels. The drug was adequately taken up from the patch into the systemic circulation. However, no significant clinical effects, nor correlations between the scopolamine levels and the outcome parameters were observed. Because of the possibility of sub-therapeutic doses in the first study, a second study with two transdermal scopolamine patches was performed in ten patients with bronchial hyperresponsiveness to methacholine. The blood and urine concentrations of free scopolamine were doubled compared to the first study. There were still no statistically significant effects on FEV₁, PEF, symptoms, and bronchial hyperresponsiveness, yet most of the patients now reported adverse side effects. We conclude that transdermal administration of scopolamine is not clinically useful in asthma and chronic obstructive pulmonary disease. Even application of two patches does not result in therapeutically effective levels at the muscarinic receptors in the lung, yet causes several side effects.     

Pharmacokinetics and efficacy of phenazepam after transdermal and enteral administration in rats

The concentration of fenazepam in the blood plasma of rats upon application of the transdermal therapeutic system (TTS) fenapercuten was very low, incomparable to the drug concentration (recalculated to equal input doses) upon intravenous or enteral administration. Nevertheless, the TTS exhibited a pronounced anxiolytic and weak sedative action in the absence of any side myorelaxant effect. The agent responsible for adverse side effects (3-hydroxyfenazepam) was not determined in the blood plasma upon the TTS application. A steady-state concentration of fenazepam in the blood plasma of rats was observed between 2nd and 8th hours upon fenapercuten application, which agrees with the duration of anxiolytic action of the parent drug.     

Pharmacokinetics and pharmacodynamics in clinical use of scopolamine

The alkaloid L-(-)-scopolamine [L-(-)-hyoscine] competitively inhibits muscarinic receptors for acetylcholine and acts as a nonselective muscarinic antagonist, producing both peripheral antimuscarinic properties and central sedative, antiemetic, and amnestic effects. The parasympatholytic scopolamine, structurally very similar to atropine (racemate of hyoscyamine), is used in conditions requiring decreased parasympathetic activity, primarily for its effect on the eye, gastrointestinal tract, heart, and salivary and bronchial secretion glands, and in special circumstances for a CNS action. Therefore, scopolamine is most suitable for premedication before anesthesia and for antiemetic effects. This alkaloid is the most effective single agent to prevent motion sickness. Scopolamine was the first drug to be made commercially available in a transdermal therapeutic system (TTS-patch) delivering alkaloid. Recently, pharmacokinetic data on scopolamine in different biozlogic matrices were obtained most efficiently using liquid chromatographic-tandem mass spectrometric (LC-MS/MS) or gas chromatography online coupled to mass spectrometry. Pharmacokinetic parameters are dependent on the dosage form (oral dose, tablets; parenteral application; IV infusion; SC and IM injection). Scopolamine has a limited bioavailability if orally administered. The maximum drug concentration occurs approximately 0.5 hours after oral administration. Because only 2.6% of nonmetabolized L-(-)-scopolamine is excreted in urine, a first-pass metabolism is suggested to occur after oral administration of scopolamine. Because of its short half-life in plasma and dose-dependent adverse effects (in particular hallucinations and the less serious reactions, eg, vertigo, dry mouth, drowsiness), the clinical use of scopolamine administered orally or parenterally is limited. To minimize the relatively high incidence of side effects, the transdermal dosage form has been developed. The commercially available TTS-patch contains a 1.5-mg drug reservoir and a priming dose (140 microg) to reach the steady-state concentration of scopolamine quickly. The patch releases 0.5 mg alkaloid over a period of 3 days (releasing rate 5 microg/h). Following the transdermal application of scopolamine, the plasma concentrations of the drug indicate major interindividual variations. Peak plasma concentrations (Cmax) of approximately 100 pg/mL (range 11-240 pg/mL) of the alkaloid are reached after about 8 hours and achieve steady state. During a period of 72 hours the plaster releases scopolamine, so constantly high plasma levels (concentration range 56-245 pg/mL) are obtained, followed by a plateau of urinary scopolamine excretion. Although scopolamine has been used in clinical practice for many years, data concerning its metabolism and the renal excretion in man are limited. After incubation with beta-glucuronidase and sulfatase, the recovery of scopolamine in human urine increased from 3% to approximately 30% of the drug dose (intravenously administered). According to these results from enzymatic hydrolysis of scopolamine metabolites, the glucuronide conjugation of scopolamine could be the relevant pathway in healthy volunteers. However, scopolamine metabolism in man has not been verified stringently. An elucidation of the chemical structures of the metabolites extracted from human urine is still lacking. Scopolamine has been shown to undergo an oxidative demethylation during incubation with CYP3A (cytochrome P-450 subfamily). To inhibit the CYP3A located in the intestinal mucosa, components of grapefruit juice are very suitable. When scopolamine was administered together with 150 mL grapefruit juice, the alkaloid concentrations continued to increase, resulting in an evident prolongation of tmax (59.5 +/- 25.0 minutes; P < 0.001). The AUC0-24h values of scopolamine were higher during the grapefruit juice period. They reached approximately 142% of the values associated with the control group (P < 0.005). Consequently, the related absolute bioavailabilities (range 6% to 37%) were significantly higher than the corresponding values of the drug orally administered together with water (range 3% to 27%). The effect of the alkaloid on quantitative electroencephalogram (qEEG) and cognitive performance correlated with pharmacokinetics was shown in studies with healthy volunteers. From pharmacokinetic-pharmacodynamic modeling techniques, a direct correlation between serum concentrations of scopolamine and changes in total power in alpha-frequency band (EEG) in healthy volunteers was provided.The alkaloid readily crosses the placenta. Therefore, scopolamine should be administered to pregnant women only under observation. The drug is compatible with nursing and is considered to be nonteratogenic.In conclusion, scopolamine is used for premedication in anesthesia and for the prevention of nausea and vomiting associated with motion sickness. Pharmacokinetics and pharmacodynamics of scopolamine depend on the dosage form. Effects on different cognitive functions have been extensively documented.     

“Programmed Polymeric Devices” for Pulsed Drug Delivery

Pharmaceutical research strives to design drug delivery systems that respond to therapeutic needs. Considering the facts that physiologic parameters (e.g., heart rate, blood pressure, and plasma concentration of hormones, plasma proteins, and enzymes) display constancy over time, drug delivery systems with a constant release profile have been designed. However, because of circadian rhythms in physiologic parameters and pathologic conditions (e.g., asthma, angina pectoris), the conventional paradigm concerning drug concentrations "the flatter the better" may not be what the organism may need. Instead, to correlate with our biological needs, "precisely timed drug delivery," which could be accomplished with "programmable dosage forms," is required. Precisely timed drug delivery may maximize therapeutic efficacy, may minimize dose frequency, and may reduce toxicity by avoiding side effects and drug tolerance. This paper outlines the concepts that have been proposed to release drugs in a pulsed manner from pharmaceutical devices.     

Transdermal therapeutic systems--actual state and future developments

Modern transdermal therapeutic systems have been marketed since the last decade only. Nitroglycerin, scopolamine, clonidine, estradiol and nicotine are the current prominent representatives that have matched expectations regarding therapeutical benefits based on TTS applications. Although different TTS constructions have been realized, it is nevertheless appropriate to consider the governing role of the skin permanent. As the upper skin barrier limits flux rates, drug uptake has to be improved by the TTS's own occlusion or by flux enhancers. Enhancers act either on the hydrophilic keratin matrix or on the lipophilic intercellular material in the stratum corneum. Improvements in drug diffusion must be balanced carefully with the risk of skin irritation. In the future we should expect, among others, pulsatile systems to avoid tolerance, or systems comprising fixed combinations of transdermal drugs within one TTS, possibly at first in the field of hormones. Other expectations will be discussed. Therapeutic benefits are expected by the administration of highly potent topical drugs by means of TTS-analogous therapeutic systems, enabling a time-controlled drug release for purposes of topical treatment only.     

An insight to osmotic drug delivery

In a typical therapeutic regimen the drug dose and the dosing interval are optimized to maintain drug concentration within the therapeutic window, thus ensuring efficacy while minimizing toxic effects. For many decades treatment of acute disease or a chronic illness has been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms. The immediate release conventional dosage form does not provide the proper plasma concentration of drug for prolonged period. This results in the development of various controlled drug delivery system. Among which the osmotic drug delivery systems (ODDS) are gaining importance as these systems deliver the drug at specific time as per the path physiological need of the disease, resulting in improved patient therapeutic efficacy and compliance. They work on the principle of osmotic pressure for controlling the delivery of the drug. Osmotic drug delivery systems with their versatility and their highly predictable drug release rates offer various biomedical advantages when given parenterally like reduced dose, targeting of site, avoiding gastrointestinal stability, hepatic bypass of drug molecule and follows zero order kinetics. Osmosis is an aristocratic phenomenon that seizes the attention for its exploitation in zero-order drug delivery systems. The release of the drug is independent of pH and physiological factors of the GIT to a large extent. Optimizing semi-permeable membrane characteristics and osmotic agent can modulate delivery of drug from the system. This review highlights the theoretical concept of drug delivery, history, types of oral osmotic drug delivery systems, factors affecting the drug delivery system, advantages and disadvantages of this delivery system, theoretical aspects, applications, and the marketed status.     

Promotion of optimized protein therapy by bioconjugation as a polymeric DDS

In recent years, clinical applications of recombinantly produced bioactive proteins such as cytokines have attracted attention. However, since these recombinant proteins are rather unstable in vivo, their clinical use as therapeutic agents requires frequent administration at a high dosage. This regimen disrupts homeostasis and results in severe side effects. To overcome these problems, bioactive proteins have been conjugated with water-soluble synthetic (WSS) polymeric carriers. Chemical modification of a protein with a WSS polymeric carrier (bioconjugation) regulates tissue distribution, resulting in a selective increase in its desirable therapeutic effects and a decrease in undesirable side effects. Among several drug delivery system (DDS) technologies, bioconjugation has been recognized as one of the most efficient methods for improving therapeutic potency of proteins. However, for further enhancement of the therapeutic potency and safety of conjugated bioactive proteins, more precise regulation of the in vivo behavior of each protein is necessary for selective expression of its therapeutic effect. Therefore, alternative WSS polymeric modifiers in which new functions such as targeting and controlled release of drugs can be added are required for further development of bioconjugated drugs. Recently, we have synthesized a novel polymeric drug carrier, poly(vinylpyrrolidone-co-dimethyl maleic anhydride) [PVD], which was a powerful candidate drug carrier for cancer therapy. In this review, we introduce useful information that enabled us to design polymeric drug carriers and their application for protein therapy.     

Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy

The clonidine transdermal therapeutic system (TTS) is a cutaneous delivery device which provides therapeutically effective doses of clonidine at a constant rate over 7 days. In clinical trials it reduces blood pressure in patients with mild to moderate hypertension as effectively as oral clonidine but with greater stability of blood pressure control. Most patients find the transdermal system more convenient than oral treatments, and compliance may be improved. The side effects known to occur with orally administered clonidine, dry mouth and sedation in particular, are also produced with transdermal administration, but possibly at a lower incidence than during oral treatment. A proportion of patients experience adverse skin reactions with the transdermal system. At this stage of its development, transdermal clonidine has not been adequately compared with other 'standard' antihypertensive treatments such as diuretics or beta-adrenoceptor blocking drugs. However, despite the lack of such comparative studies, transdermal clonidine represents a worthwhile new approach to antihypertensive therapy, particularly in terms of patient convenience.     

Iontophoretic delivery of nonpeptide drugs: formulation optimization for maximum skin permeability

Although the technique of transdermal iontophoretic drug delivery has been known for many years, its use has been limited clinically to those applications for which a brief drug delivery period is adequate (e.g., delivery of pilocarpine in the diagnosis of cystic fibrosis). For most therapeutic applications, however, it is necessary to have an extended, if not continuous, drug delivery regimen. The use of iontophoresis has been limited in these applications by side effects, primarily skin trauma, associated both with the current density and the total amount of current passed. A mechanism for these side effects will be proposed and techniques to mitigate them will be presented. Many of these techniques involve ways in which the drug formulation can be designed to maximize the fraction of current carried by the drug species. These methods include the following: control of the pH in the bulk solution and in the boundary layer without using conventional buffers; taking advantage of polarization effects; and enhancing the permselectivity of skin. In this way, the therapeutic dose or optimal infusion rate of drug can be achieved with the minimum current and, therefore, the minimum number of side effects.     

Nanomedicines for ocular NSAIDs: safety on drug delivery

The eyes are among the most readily accessible organs in terms of location in the body, yet drug delivery to eye tissues is particularly problematic. Poor bioavailability of drugs from ocular dosage forms is mainly due to precorneal loss factors (e.g., tear dynamics, nonproductive absorption, transient residence time in the cul-de-sac, and relative impermeability of the corneal epithelial membrane). There is a clear need for effective topical formulations capable of promoting drug penetration and maintaining therapeutic levels with a reasonable frequency of application—a strategy that can also result in enhancement of side effects that probably would not be acceptable. Delivery of a drug via a nanotechnology-based product fulfills three main objectives: enhancement of drug permeation, controlled release, and targeting. The inflammatory response of the ocular tissues is a common side effect associated with ophthalmic surgery. Together with steroidal agents, nonsteroidal anti-inflammatory drugs are used in eye surgery. In this review we focus on microemulsions, polymeric nanoparticles, liposomes, solid lipid nanoparticles, and drug nanocrystals as formulations incorporating anti-inflammatory drugs for ophthalmic application.From the Clinical EditorThis review focuses on microemulsions, polymeric nanoparticles, liposomes, solid lipid nanoparticles, and drug nanocrystals as novel high efficiency delivery systems of anti-inflammatory drugs in ophthalmic applications.     

Prediction of plasma concentration of GTS-21 in hairless rats following monolithic transdermal delivery

The transdermal therapeutic systems (TTS) usually achieve constant plasma concentration for an extended period of time. This is because a sufficient drug stored in the device can keep the constant concentration on the surface of the stratum corneum during the system application. When the drug molecules are not enough to provide the constant surface concentration, the rate of drug penetration decreases with time because of decreased supply of the drug molecules from the delivery device. This paper has proposed an empirical simple approach to predict the plasma concentration for such a TTS. A novel compound, GTS-21, for Alzheimers' disease currently under development was used as a model drug. In vivo and in vitro experiments were carried out in hairless rats. The in vivo plasma concentration-time profile in hairless rats following the application of TTS well agreed with the predicted profile based on the skin pharmacokinetic model together with the model parameters determined from the in vitro experiment.     

Pharmacokinetics and pharmacodynamics of transdermally administered clonidine

Summary Clonidine was applied to the skin of healthy volunteers once weekly by means of a Transdermal Therapeutic System (TTS). The plasma concentration and renal excretion of clonidine, and its effects on mean arterial blood pressure (MAP) and heart rate (HR) were recorded for 7 days, followed by a three-day observation period when a second TTS was applied. Subjective side effects were semiquantitatively recorded. Four differents TTS formulations were tested; of which TTS-RP 600679 was the most effective. Following application of this formulation, the plasma level of the drug built-up up during the first 2 days and then remained stable for 120 h at therapeutic concentrations between 0.5 and 0.7 ng/ml; MAP was consistently reduced. During the steady state period the daily urinary clonidine excretion was in the same range as during chronic administration of Catapres tablets 0.15 mg every 12 h, or Catapres Perlongets 0.25 mg every 24 h. Transdermal clonidine applications renewed weekly provide the following therapeutic advantages: 1. patients are protected continuously throughout the entire steady state period; 2. daily fluctuations in plasma clonidine concentration are minimized, which may result in a marked reduction in side effects; and, 3. drug compliance should be improved.     

Evaluation of new indomethacin dosage forms

Indomethacin, an indole derivative nonsteroidal anti-inflammatory drug, has been available since the early 1960s in gelatin capsules. In 1982, a sustained release product, Indocin SR, was marketed. Awaiting marketing approval is a unique controlled release form of indomethacin, Indos. The disposition of indomethacin includes enterohepatic cycling and extensive metabolism to inactive metabolites. Enterohepatic cycling makes interpretation of bioavailability estimates of indomethacin dosage forms difficult. The relationship of indomethacin plasma concentration to therapeutic effects and side effects is inconclusive. It appears in vivo prostaglandin inhibition occurs at very low plasma concentrations that are achievable with all available dosage forms. Indocin SR is a sustained release capsule of indomethacin designed to deliver 25 mg of drug immediately and 50 mg gradually. Absolute bioavailability of the product is 80%. The plasma concentration-time curves do not show good sustained release characteristics; after four hours plasma concentrations resemble those seen with a single dose of regular capsule. The cost compared with Indocin is competitive. Indos is a zero-order release form of indomethacin. It is a unique drug delivery system that shows good controlled release characteristics. Bioavailability is 85%. Both Indocin SR and Indos are apparently therapeutically equivalent to indomethacin capsules. In elderly patients, Indos has been shown to be associated with fewer side effects than Indocin. Both Indocin SR and Indos have the advantage of once or twice daily dosing.     

Steroid-coupled liposomes for targeted delivery to tumor

The steroidal receptors play a key role in protein synthesis and maintain the homeostasis in normal and diseased state, including tumorigenesis at the target tissues when overactivated. Thus steroidal receptors may act as potential targets for selective delivery of different therapeutic agents as they are overexpressed by a number of endocrinal tumors. The selective delivery of these agents may be a better treatment strategy for endocrinal cancer as it may also result in cytosolic and nuclear delivery of cytotoxic agents. In this review, the targeting potential of steroidal receptors for the drug or bioactive(s) delivery is discussed. The ligands that have been proven to be effective for specific steroidal receptors can be used as vectors for carrying the drug or drug-delivery system to the desired site of drug action in an optimum concentration. This strategy will not only minimize the undesired side effects associated with nonspecific delivery of drug, but will also maximize the drug utilization. Ligand-conjugated liposomes as a carrier of bioactives prevent passive diffusion of the encapsulated drug to normal cells, increase the time of circulation and reduce the undesirable side effects of a drug.     

Systemic delivery of β-blockers via transdermal route for hypertension

Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later.     

Vaginal Films for Drug Delivery

Vaginal dosage forms have been studied in relation to many drugs as the vagina presents several advantages as a site for drug delivery, such as large surface area, rich blood supply, avoidance of the first-pass effect, relatively high permeability to several drugs, and self-insertion. Traditional vaginal dosage forms have been associated with disadvantages such as low residence time and discomfort and have been surpassed by newly designed drug delivery systems, particularly those based on bioadhesive polymers. Vaginal films are solid dosage forms that rapidly dissolve in contact with vaginal fluids and are unlikely to be associated with leakage and messiness. They have been studied for some female genital problems, aiming either contraceptive, antimicrobial, or microbicide effects. Precise and complex processes of manufacturing and characterization are required to achieve successful film formulation. Although scarce, the available user's acceptability studies show promising results. Vaginal films gather a lack of opportunities for both therapeutic and prophylactic actions, and therefore should be considered when designing and developing new vaginal drug delivery systems. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2069–2081, 2013     

Clinical efficacy of current transdermal drug delivery systems: a retrospective evaluation

In spite of intensive research on transdermal drug delivery systems (TDDSs), only four--nitroglycerin, clonidine, estradiol, and scopolamine--have reached the market, and the clinical effectiveness of these systems has yet to be clearly demonstrated. Ideally, a candidate for transdermal drug delivery should demonstrate clinical significance within a wide therapeutic range for a well-documented indication for use. Continuous administration of a drug should result in better control of the disease with fewer side effects and a marked increase in patient compliance than when traditional dosage forms are used. It appears that nitroglycerin is a poor candidate for transdermal drug delivery by virtue of the ambiguity associated with its clinical pharmacology, substantial interpatient variation in dose-response relationship, and development of tolerance with potential toxicity risks in chronic administration. Clonidine's well-defined indication for use coupled with its high potency and low molecular weight with high lipid solubility is well suited to transdermal therapy. Because estradiol is unsuitable for use in people who smoke and has dermatotoxic potential, it is a marginal candidate for use in TDDSs. Transdermal scopolamine was not reviewed because it is a unique entity (no conventional dosage forms of this product are available) intended for short-term use. Its use is dictated more by the patient's unique circumstances, such as travel requirements, than by physiological condition. Although TDDSs provide a convenient and effective means of administering medications, the aforementioned clinical constraints need to be evaluated in depth before more widespread application of TDDSs can be recommended. In particular; conclusive demonstration of biocompatibility of a TDDS is warranted.