Intragastric distribution of ion-exchange resins: a drug delivery system for the topical treatment of the gastric mucosa

Previous studies by this group on freeze-dried oral dosage forms containing finely-divided ion-exchange resins revealed prolonged gastric residence and uniform distribution within the stomach. The present study was carried out to ascertain whether this was due to freeze-drying, properties of the radiolabelled ionic exchange resin, or the small dosing volume used. 99mTc-labelled cholestyramine resin was administered in two dosage forms, a freeze-dried tablet which dissolved in the oral cavity (orally dissolving tablet; ODT) and a 1.5 mL aqueous suspension. Two resin particle sizes (20-40 and 90-125 microns) were studied. Oesophageal transit and intragastric distribution and residence were followed by gamma scintigraphy. In a second study, in six subjects, gastric emptying of the water-soluble fraction of the ODT and 1.5 mL of water, was measured using 99mTc diethylenetriaminepentaacetic acid. Oesophageal transit of a water-soluble marker and resin in suspension was rapid, but the transit of the resin in the ODTs was significantly prolonged. Regardless of particle size or dosage form, the resin was evenly distributed throughout the stomach with 20-25% remaining for 5.5 h. In contrast, the water-soluble marker cleared from the stomach rapidly from both dosage forms. We suggest that oral dose forms containing finely-divided ion-exchange resins may form a useful system for topical treatment of the gastric mucosa, for example in targeting to Helicobacter pylori infection.     

Cardiac rhabdomyosarcoma: a clinicopathologic and electron microscopy study

The use of imaging techniques including gamma scintigraphy to follow the behaviour of drug formulations has revolutionized our knowledge of absorption and distribution in drug delivery. The development of gamma camera techniques as physiological tools to explore organ function became routine by the mid-seventies. Several research groups started to explore the applications of technique in drug delivery. Within 5 years, the utility of the technique became obvious and scintigraphy is now widely accepted as an important investigation tool in formulation research. Gamma scintigraphy is especially useful in exploring sources of inter-subject variation, especially in examining food effects in pharmacokinetic estimations and establishing windows of absorption for oral delivery. As a tool to examine drug delivery to the lung and to the eye, scintigraphy is the method of choice. Magnetic Resonance Imaging (MRI) became more generally employed in medicine two decades after the gamma camera. The superior soft-tissue contrast and resolution compared to computed X-ray tomography rapidly established MRI in clinical investigation. Recent applications in oral drug research has allowed the pharmaceutical scientist to explore new facets of delivery and ultimately combine MRI and scintigraphy in human clinical trials.     

Oral solid controlled release dosage forms: role of GI-mechanical destructive forces and colonic release in drug absorption under fasted and fed conditions in humans

PURPOSE: This study was undertaken to examine the effects of mechanical destructive forces on drug release from controlled release (CR) dosage forms in vitro and in vivo and their colonic release, using two CR tablets of acetaminophen A and B, showing slower and faster erosion rates, respectively. METHODS: In vitro release rates were determined by several official methods. Tablets were administered to healthy volunteers under fasting and fed conditions. RESULTS: Both tablets showed similar release rates under mild destructive conditions (e.g., paddle method at 10 rpm) but CR-B showed faster release under highly destructive conditions (e.g., rotating basket method at 150 rpm), where the tablet was eroded. The in vivo release from CR-B was faster than from CR-A, possibly because of enhanced erosion. The variable in vivo release from CR-B indicated large inter-subject differences in destructive GI forces. The fastest in vivo release from CR-B among individuals was approximated by the in vitro dissolution determined by destructive methods such as the rotating basket at 150 rpm. The slowest in vivo release from tablets A and B was lower than the dissolution by the paddle method at 10 rpm. The release from both tablets was markedly reduced at 3-4 hrs after dosing irrespective of feeding conditions which can be attributed to release inhibition in the colon. CONCLUSIONS: Effects of GI destructive forces on the tablet erosion and the release inhibition in the colon must be considered in the development of CR dosage forms.     

Therapeutic delivery of proteins to macrophages: implications for treatment of Gaucher's disease

BACKGROUND: The primary defect in Gaucher's disease, a lysosomal disorder affecting macrophages, is in the activity of glucocerebrosidase. Treatment with exogenous enzyme (modified to increase its affinity for macrophage glycoprotein receptors) aims to restore this activity. However, the fate of the exogenous enzyme in vivo is unknown. We used radiolabelled enzyme to assess macrophage receptor activity for mannosylated ligands in vivo. METHODS: We examined the uptake and tissue distribution of radiolabelled enzyme molecules by gamma scintigraphy after bolus injection of iodine-123-labelled recombinant or placental enzyme (imiglucerase and alglucerase, respectively) in eight patients with type 1 Gaucher's disease, and in one healthy individual. The metabolism of the tracer enzyme was followed by scintigraphy and by analysis of blood, urine, and faeces. RESULTS: The tracer enzyme was rapidly cleared from blood (half-life 4.7 min [SD 1.0]). Concomitantly, there was avid uptake by the liver (about 30% of the injected dose), the spleen (about 15%), and the bone marrow. 40-55% of the tracer was cleared rapidly from the viscera (half-life 1-2 h) and 45-60% was cleared slowly (half-life 34-42 h). The half-life in the bone marrow was 14.1 h. Infusion of alglucerase at dose of 5 U/kg bodyweight normalised acid beta-glucosidase activity of splenic Gaucher's cells in vivo. When the enzyme was administered at a seven-fold higher dose (35 U/kg over 1 h), the receptor-mediated uptake in vivo was saturated, as shown by the increase in blood-clearance half-life of tracer enzyme from 4.5 min to 12 min. INTERPRETATION: Avid and saturable uptake of modified glucocerebrosidase was found, which indicates high-affinity targeting to the macrophage system in vivo. The rate of enzyme turnover suggests a rational basis for use of this therapy in treatment of Gaucher's disease.     

High-performance liquid chromatographic analysis of isoniazid and its dosage forms

A high-performance liquid chromatographic analysis is described for isoniazid as a drug entity and in its tablet and injectable dosage forms. After incorporation of the drug or dosage form in a solvent mixture and addition of an internal standard, tribenzylamine, an aliquot is chromatographed using a pellicular silica gel medium followed by UV spectrophotometric detection at 254 nm. The response of the chromatographic system was linear over a concentration range corresponding to 20-200% of the labelled amount of isoniazid. Comparison of the results with those obtained by the official USP XIX method indicates similar accuracy and precision. The advantages of the proposed method are its simplicity and rapidity, its potential for automation, and its specificity. The specificity was demonstrated in the presence of potential degradation products of isoniazid, other drugs used with isoniazid in combination dosage forms, and an adduct formed by the reaction of isoniazid with lactose in the tablet.     

Acyclovir-resistant chronic cutaneous herpes simplex in Wiskott-Aldrich syndrome

A 28-year-old man with Wiskott-Aldrich syndrome presented with ulcerative-proliferative lesions on his face from which herpes simplex type 1 (HSV-1) was isolated. He was initially treated with 10 mg/kg of acyclovir (Zovirax) intravenously every 8 h, but his skin lesions worsened. Clinical resistance to acyclovir was suspected, and therapy with this drug was intensified. The dosage of acyclovir was increased to 45 mg/kg, administered by continuous infusion, and the lesions subsequently resolved. The strain of HSV recovered from the patient showed acyclovir-resistance in vitro, using the colorimetric method with neutral red. Herpes simplex virus resistance to acyclovir is rare. It is more common in immunocompromised patients if subtherapeutic doses are administered in the treatment of chronic persistent forms of infection. Whenever clinical resistance to acyclovir is suspected, the dosage should be increased to 2 mg/kg per h administered via an infusion pump. If no improvement is observed in the patient's condition with this regimen, a phosphorylated medication whose mechanism of action is not dependent on viral thymidine kinase, such as foscarnet (phosphonoformic acid), should be substituted.     

FDA perspective on peptide formulation and stability issues

Traditionally, peptide drugs are prepared as sterile solutions and administered to patients by daily injection. However, this form of drug delivery causes pain and inconvenience to patients and thus has been poorly accepted. In addition to improving patient compliance, many novel delivery systems have been developed to address the need for prolonged, localized (targeted), or pulsatile drug action. Examples include, but are not limited to oral, nasal, or long-acting controlled release injectable dosage forms; a number of them have been approved by FDA recently. The unique characteristics and the relevant regulatory issues with respect to each type of delivery system are presented.     

Influence of pH on release of phenytoin sodium from slow-release dosage forms

Physicochemical factors influencing the release of phenytoin sodium from slow-release dosage forms were studied. Some of these factors were solubility and intrinsic dissolution rate as functions of pH, type of dosage form, pH of dissolution medium used, and conversion of the sodium salt to free acid (phenytoin). The innovator's product, Extended Phenytoin Sodium Capsule (Dilantin Kapseal, 100 mg, Parke-Davis), and two experimental formulations (one nondisintegrating tablet containing polymeric materials and the other a solid dispersion in an erodible matrix) served as the slow-release dosage forms. The sodium salt converts to practically insoluble phenytoin in the gastrointestinal pH range of 1 to 8. Due to such a conversion inside or at the surface of slow-release dosage forms, the release of drug in this pH range was incomplete. The extent of drug release also varied with the type of formulation used. In contrast, complete dissolution could be obtained in water because the pH of the medium gradually rose from approximately 6 to approximately 9.2 where the drug solubility was higher. Although several phenytoin sodium products might have similar dissolution rates in water, the extents of drug release under gastrointestinal pH conditions (pH 1-8) could differ greatly, thus supporting the Food and Drug Administration recognition that the similarity in dissolution profiles in water does not assure that the products are bioequivalent. The reported lower steady-state level of phenytoin in human plasma following oral administration of a slow-release dosage form may be related to incomplete drug release.     

Effect of venlafaxine on the pharmacokinetics of terfenadine

Prediction of the drug level in the volume of distribution was made using a numerical model taking into account the following facts: the kinetics of drug release out of the dosage form along the gastrointestinal tract, the kinetics of absorption in the blood compartment and the kinetics of elimination. Various parameters intervene significantly for a given dosage form. Some emphasis was placed upon the rate of elimination of the drug which appears to be the main characteristic for the drug, especially when it is delivered through controlled release dosage forms. The rate of release of the drug out of the dosage form, as well as the dose frequency and the gastrointestinal transit time were also considered. The drug level in the plasma was expressed by the amount of drug as a fraction of the amount of drug initially located in the dosage form.     

High sensitivity of the in vivo detection of somatostatin receptors by 111indium (DTPA-octreotide)-scintigraphy in meningioma patients

The recent availability of isotope-labelled somatostatin analogues has allowed one to detect somatostatin receptors in normal tissue as well as in endocrine or non-endocrine cranial tumours. The purpose of the present study was to establish the value of somatostatin receptor scintigraphy using an 111Indium-labelled somatostatin analogue, octreotide, in the diagnostic work-up of meningioma patients. Twenty-two patients (16 women, 6 men, aged from 19-70 years) with newly diagnosed, residual or recurrent cranial meningiomas were examined. 111Indium-labelled DTPA-octreotide was injected i.v.. Planar and tomographic images were obtained with a gamma camera 4-6, and 24 hours after injection. In all of the meningiomas studied a high density of somatostatin receptors was detected by scintigraphy. No false negative test result was found. Due to this, a 100% predictive value of a negative test was calculated. However, when the tumours were taken in culture differing staining intensity could be seen in the light- and electron microscopic level even on individual cells of a single culture when silver intensified somatostatin-gold was used as ligand. We conclude, that in vivo somatostatin receptor scintigraphy may aid in the pre-operative differential diagnosis of skull base tumours.     

Cervical ripening

Electrostatic charge in plastic spacer devices has been shown in vitro to reduce delivery of asthma medications intended for inhalation, but the effect of static charge on in vivo drug deposition is unknown. A six-way randomized crossover study was conducted in 10 mild asthmatic patients. Two plastic spacers (Nebuhaler and Volumatic) and one metal spacer (Nebuchamber) were tested. The spacers were used either "primed" or "unprimed". Priming was performed by firing 20 doses of placebo aerosol into a new spacer, hence coating the inner surface with surfactant and minimizing static charge. Unprimed spacers were new and were not treated. Pressurized aerosol canisters delivering budesonide (200 microg Pulmicort) were radiolabelled with the radionuclide 99mTc and lung deposition was measured by gamma scintigraphy. The radiolabel was shown to be a valid marker for the drug substance prior to the clinical phase of the study. Priming significantly increased mean whole lung deposition following inhalation from plastic spacers (Nebuhaler primed 37.7% and unprimed 26.7%, p=0.01; Volumatic primed 32.0% and unprimed 22.1%, p=0.02). Priming had no effect on the mean whole lung deposition following inhalation from the Nebuchamber (primed 33.5% and unprimed 32.9%). Lung deposition in vivo from plastic spacer devices will vary according to the electrostatic charge on the spacer walls. Priming reduces retention of drug on plastic spacer devices and increases lung deposition. Metal spacers are not susceptible to static charge, which should result in more predictable lung deposition.     

Brain scanning with the Anger multiplane tomographic scanner as a second examination evaluation by the ROC method

The disposition kinetics and systemic availability of ketamine, a dissociative anaesthetic agent, was studied in normal domestic cats. A similar dose (25 mg/kg) of ketamine hydrochloride was administered by the i.v. and i.m. routes; drug concentrations in plasma were measured by a gas-liquid chromatographic procedure. A rapid distribution phase (t1/2 (alpha) = 3 min) was followed by a slower first-order elimination phase. The half-life of the drug (66.9 +/- 24.1 min) was independent of the route of parenteral administration. Absorption from i.m. site of administration was rapid, with peak plasma level at 10 min, and ca. 92 per cent of the dose was available systemically. Extent of plasma protein binding, measured in vitro at 5 and 20 mug/ml by equilibrium dialysis technique, was 53 per cent and independent of ketamine concentration. Simulated plasma and tissue level curves, which were generated by an analogue computer programmed with the individual rate constants of the two-compartment open model, showed that 10 and 15 per cent of the dose were present in the central and peripheral compartments, respectively, at 90 min after i.v. administration of the drug. Peak tissue level of 42 per cent of the dose was reached at 12 to 15 min. Parenteral administration of ketamine, at the dosage rate studied, quickly produced an immobilizing effect of variable duration (0.75 to 1.75 hr) in normal cats.     

Sustained relief of chronic pain. Pharmacokinetics of sustained release morphine

There are a number of modified release formulations of morphine with recommended dosage intervals of either 12 or 24 hours, including tablets (MS Contin, Oramorph SR), capsules (Kapanol, Skenan), suspension and suppositories. Orally administered solid dosage forms are most popular but significant differences exist in the resultant pharmacokinetics and bioequivalence status of morphine after both single doses and at steady state. Following single doses, the plasma morphine concentrations showed pronounced differences in the 0- to 12-hour period with a 4- to 5-fold difference in the mean peak concentration (Cmax) for morphine and the time to Cmax (tmax) The area under the concentration-time curve (AUC) from 0 to 24 hours for the 4 formulations show greater similarity. None of the formulations were shown to be bioequivalent according to US Food and Drug Administration (FDA) criteria. At steady state, fluctuations in plasma morphine concentrations throughout a 12-hour dosage interval were greatest for MS Contin and least for Kapanol. In fact, the relatively small fluctuations in plasma morphine concentrations following Kapanol administration suggested the same formulation could successfully be used with a 24-hour dosage interval. The pharmacokinetic parameters of morphine following Kapanol once daily were similar to MS Contin (12 hours) with the obvious exception of the longer tmax. There is also another once daily oral morphine preparation (MXL) which has been shown to be bioequivalent to Kapanol under fasting conditions only in a single dose study in volunteers. Food has been shown to have an effect on the pharmacokinetics of morphine following doses of immediate release solution and the modified release preparations. However, bioequivalence is generally maintained between the fed and fasting states for most preparations. MS Contin tablets have been administered rectally, but morphine pharmacokinetic parameters show greater variability compared with oral administration and the 2 routes are not bioequivalent. The results suggest a slower rate but greater extent of morphine adsorption. Somewhat similar results were obtained when Kapanol granules are administered rectally. The morphine pharmacokinetics following administration of a specifically formulated controlled release suppository showed less variability (rectal bioavailability was 42%). The pronounced differences in morphine pharmacokinetics between the various formulations are not translated into measurable differences in the pharmacodynamic effects of pain relief and adverse effects. The lack of bioequivalence between some of the formulations suggests that care should be exercised if physicians change modified release formulations as dosage adjustments may be necessary in some patients.     

Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models

Considerable effort has been placed into the identification of new antineoplastic agents to treat breast cancer and other malignant diseases. The basic approaches, in terms of model selection, endpoints, and data analysis, have changed in the previous few decades. This article deals with many of the issues associated with designing in vivo studies to investigate the activity of experimental and established compounds and their potential interactions. Endpoints for both in situ and excision assays are described, including approaches for determining cell kill, tumor growth delay, survival, and other estimates of activity. Suggestions for approaches that may limit the number of animals also are included, as are possible alternatives for death as an experimental endpoint. Other concerns, such routes for drug administration, drug dosage, and preliminary assessments of toxicity also are addressed. Statistical considerations are only briefly discussed, since these are addressed in detail in the accompanying article by Hanfelt (Hanfelt JJ, Breast Cancer Res Treat 46:279-302, 1997). The approaches suggested within this article are presented to draw attention to many of the key issues in experimental design and are not intended to exclude other approaches.     

Labelled polycyanoacrylate nanoparticles for human in vivo use

Isobutyl and isohexyl cyanoacrylate nanoparticles are used as drug carriers, particularly for some anti-cancer drugs. Body distribution as well as pharmacokinetics have been well studied in animal and partially in man. Labelling of the monomer itself or of the carried drug with beta-emitters allowed such studies. In man, however, organ distribution and uptake could easily be done and followed by means of scintigraphy (imaging) techniques if one could achieve nanoparticle labelling with gamma-emitting isotopes. We have developed labelling methods able to supply such carriers using gamma-emitters like radioactive iodine (125I or 131I), indium or technetium. We used DTPA as a spacer in order to fix the last two isotopes. This would mean that any other gamma-emitting cation can theoretically be tried pending on its ability to be chelated by DTPA. The preparations were obtained with high labelling yields, usually > 80% and were relatively stable in human plasma over the whole period of investigation. 111In and 99mTc labelled forms have been administered to rabbit and then to man with 60-75% accumulation in the reticulo-endothelial system.     

Quantifying the radiation dosage to individual skeletal lesions treated with samarium-153-EDTMP

Samarium-153ethylenediaminetetramethylenephosphonate (EDTMP) is used in the treatment of painful skeletal lesions. This study attempted to quantify the radiation dosage to individual lesions on both the macroscopic and microscopic level. METHODS: A gamma camera-based quantification technique was adapted and refined for 153Sm. The accuracy of the technique was determined by using a realistic phantom. The activity and volume of lesions as well as normal bone were determined and used to estimate the radiation dosages to these regions. Two patients died of unrelated causes shortly after receiving 153Sm-EDTMP. This made it possible to compare the gamma camera results with direct measurements. It also allowed for autoradiographic examination of the lesions. Finally, the microscopic radiation dosages were estimated. RESULTS: The phantom study indicated that the quantification technique was off, on average, by 4.1% (s.d. = 8.1%). The absolute activity concentration of trabecular bone was found to be approximately 0.22 MBq/g, and that of cortical bone was found to be approximately 0.1 MBq/g, regardless of the dosage administered. The corresponding concentrations for lesions were between 3 and 7 times higher than that of normal bone, with no apparent ceiling. From these results, the macroscopic radiation dosage could be estimated. The dosage to normal bone varied between 0.9 and 3.9 cGy x kg/MBq, and that of the lesions varied between 5.2 and 27.1 cGy x kg/MBq. The autopsy results confirmed that the gamma camera technique was accurate. The autoradiography showed clearly that the activity was associated with the surface of the bone. From these findings, the microscopic radiation dosage distribution was estimated for cortical and trabecular bone as well as osteoblastic lesions. The variation in the microscopic dosage compared to the macroscopic dosage was quite large. Microscopic dosages, when compared to the macroscopic dosages, were as high as 965% and as low as 14.9%. CONCLUSION: The techniques used have been proven to be accurate. The activity in normal bone may be at a ceiling value for all the administered doses, which could explain the small variation. This is not true for the lesions. The large variation in dosages on a microscopic scale, combined with the ceiling in normal bone, may explain the lower than expected toxicity and relatively quick relapse of the patients.     

Use of food nutrition labels is associated with lower fat intake

The colon-targeted delivery capsule (CTDC), a new capsule-type dosage form for colonic delivery of drugs, was investigated for the in vivo drug release behavior in dogs. A CTDC formulation with prednisolone as a model drug and theophylline as a marker substance for gastric emptying was prepared for this study. The enteric-coated capsule (ECC) formulation with a similar composition was also prepared as the reference. Both formulations were administered to four beagle dogs, and the drug release behavior thereof was compared. Under fasted condition, ECC released prednisolone and theophylline at the same time within 1 h after the gastric emptying. On the other hand the CTDC released prednisolone at 3.2 h after the gastric emptying. Such release behavior of CTDC was approximately consistent with the results obtained from the in vitro dissolution study, suggesting that the pH-sensing and timed-release functions imparted to the CTDC can work in the gastrointestinal tract of dogs as programmed. Under non-fasted condition, however, the gastric emptying of CTDC was found to be considerably delayed, up to about 14 h, and in this case the in vivo dissolution lag time of prednisolone at the small intestine was shortened to about 1.5 h.     

An evaluation of the efficacy of Pimafucin in candidiasis of the skin and mucous membranes

Results were studied of use of different dosage forms of pimafucin in candidiases in children. It was found out that the above medicinal agent is an effective anticandidiasis drug that can easily be tolerated by children. A beneficial clinical effect was noted in treatment of candidiasis complications in those children suffering from atopic dermatitis. The above drug can, we believe, come into widespread use in pediatric dermatovenereology.     

Relative biological effectiveness of negative pi mesons for the immune response in mice

Immunologically competent mouse spleen cells were exposed to negative pi mesons in the entrance plateau or at the peak of the dose distribution at a maximum dosage of 5 rads/min. or to 60Co gamma rays at 4.96 rads/min. Survival curves from cells irradiated in vitro but incubated in vivo yielded RBE values of 2.15 for the peak and 1.84 for the entrance plateau at a surviving fraction of 0.1. The dose-rate dependence of antibody-forming spleen cells for both 60Co gamma rays and the lot-LET components of the pion beam is discussed. The authors suggest that these RBE values constitute an upper limit for normal mammalian cells exposed to pions and tha the RBE with clinically useful dose rates may be significantly lower than those reported here.     

Ocular contact time of a carbomer gel (GelTears) in humans

BACKGROUND/AIMS: Carbomers are widely used in products for the treatment of dry eye; however, the polymer gel thins on addition of probes (for example, fluorescein salt) confounding the comparison of products by objective clinical tests such as spectrophotofluorimetry or scintigraphy. A novel method of radiolabelling carbomer gels, with minimum change to their rheology, has permitted the non-invasive evaluation of precorneal residence of the gel in volunteers using gamma scintigraphy. The technique was used to evaluate the precorneal clearance of the liquid phase and of a suspended particulate in GelTears. METHODS: Low sodium technetium-99m labelled diethylenetriaminepentacetic acid (99mTc-DTPA) was used to label carbomer 940 gel, either adsorbed onto sterile charcoal to model an entrapped drug, or added directly to the gel to a final activity of 1 MBq per 25 microliters dose. The clearance of the labelled gels was then compared with 99mTc-DTPA labelled saline in 12 volunteers. RESULTS: The addition of the low sodium radiopharmaceutical produced insignificant rheological changes in the gel compared with conventional 99mTc-DTPA labelling. The residence times on the eye of the gel formulations were significantly greater than that of the saline control. At 8 minutes postdosing, the label levels retained (mean (SD)) on the ocular surface were: saline, 7% (7%); 99mTc-DTPA gel, 42% (27%); and 99mTc-carbon gel, 42% (20%) of administered dose. There was no difference observed in the precorneal distribution between 99mTc-DTPA solution and particulate markers. CONCLUSIONS: These data demonstrate that carbomer based gels significantly extend contact of solutes or suspended solids with the corneal surface. The method of labelling does not significantly change the initial viscosity and is superior to previous methods which have used sodium salts (for example, sodium fluorescein) and therefore underestimate contact time.