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The effect of moxibustion on the in vitro and in vivo skin permeation of salicylate was evaluated in rats.First, the effect of moxibustion pretreatment on the elimination pharmacokinetics of salicylate after i.v.injection in rats was determined: no clear difference was observed in the plasma profiles of salicylate (SA)with or without moxibustion pretreatment. However, much higher skin and muscle concentrations ofsalicylate were observed after its i.v. injection. Next, an in vitro skin permeation study of SA was performedafter moxibustion pretreatment. Moxibustion pretreatment increased the skin permeation of SA, andthe extent of the increase in SA skin permeation was related to the strength of moxibustion ignition.More intense treatments produced higher skin permeation. A similar enhancement effect on the skinpermeation of SA was observed in in vivo studies. Interestingly, the skin/plasma and muscle/plasma ratiosof SA were markedly increased by moxibustion pretreatment. These results were due to the inductionof enhanced skin permeation and lower clearance into the cutaneous vessels by moxibustion ignition.Combination treatment involving moxibustion and the topical application of drugs such as NSAID maybe useful for increasing local pharmaceutical effects by enhancing the drug concentration in the skin andmuscle underneath the topical application site., Research paper

The presence of endogenous competing counterions is a main reason for the generally low efficiency of transdermal iontophoretic drug delivery. The objective of the present study was to test the hypothesis that the incorporation of an ion-exchange membrane (Ionac) in an iontophoresis system to hinder transdermal transport of these counterions can enhance iontophoretic delivery. The properties of Ionac were characterized in passive and iontophoretic transport experiments. Iontophoretic transport across human epidermal membrane (HEM) and across HEM in series with Ionac was then studied. To assess the effect of HEM electrical resistance upon Ionac-assisted iontophoresis, HEM resistance was reduced in the iontophoresis experiments with alternating current (AC). Salicylate (SA) was the negatively charged permeant first tested in this study. Mannitol was the model permeant to examine the effects of electroosmosis. At the completion of the SA study, experiments were performed with acyclovir (ACV), an antiviral drug with limited water solubility. When Ionac was used to enhance SA transdermal fluxes, higher SA fluxes were observed with HEM of lower resistances in Ionac-assisted iontophoresis. Up to a four-fold flux enhancement was achieved when the electrical resistance of HEM was reduced using an AC iontophoresis method. For ACV, two-fold flux enhancement was observed in Ionac-assisted iontophoresis compared with the conventional iontophoresis baseline. In all experiments, the contribution of electroosmosis to drug transport was less than 10%. The present study has demonstrated the potential of a new approach using a positively charged ion-exchange membrane to enhance transdermal iontophoretic transport of negatively charged drugs.

This study evaluated and optimised the ninhydrin assay as a tool for measuring the in vitro release and dissolution of chitosan from solid dosage forms. The precision and accuracy of the assay for the type of chitosan used in the study were examined by measuring the inter- and intra-sample variation and found to be within acceptable limits. The assay was applied practically to construct a pH/solubility profile for chitosan and subsequently to measure the release and dissolution of chitosan from dosage forms in the presence and absence of a model drug, sodium salicylate. Assay performance was found to be satisfactory over a wide range of physiologically relevant pH values. It is concluded that the ninhydrin assay is an essential aid in the design and testing of solid dosage forms with different chitosan-drug release profiles.

The hypoglycemic effect of Eudragit S100 enteric-coated capsules containing sodium salicylate as an absorption promoter formulated with insulin in various ways: as physical mixture, by wet granulation or in suppository bases (polyethylene glycol 4000 or Witepsol W35) was studied in hyperglycemic beagle dogs. The capsules containing insulin formulated with sodium salicylate (50 mg) and prepared by either physical mixing or wet granulation using 10% polyvinyl pyrollidone gave almost the same results producing a maximum reduction in plasma glucose level (C(max)) of 81.53+/-8.21 and 79.59+/-5.75%, T(max) of 6 and 5 h, area under the curve (AUC) of 69.37+/-48.64 and 57.98+/-23.15% reduction hour (% red. h) and resulting in relative hypoglycemia (RH) of 8.73+/-6.12 and 7.29+/-2.91%, respectively. Formulation of insulin with sodium salicylate in PEG 4000 produced a lower AUC of 37.30+/-10.36% red. h and RH of 4.69+/-1.3%. While, formulation in Witepsol W35 (0.5, 1.0 and 2.0 g) that was sieved to produce particle size of 180-315 microm and filled in enteric-coated capsules showed that formulating insulin and sodium salicylate in 1 g base is the best formulation. It produced 25% reduction in plasma glucose levels of the hyperglycemic beagle dogs at T(max) of 4 h and the largest AUC of 100.10+/-25.72% red. h, resulting in the highest RH of 12.59+/-3.23%. In conclusion, 25-30% reduction in plasma glucose levels and RH of about 12.5% relative to subcutaneous injection of regular soluble insulin can be achieved by formulating insulin in Witepsol W35 (1 g) with sodium salicylate (50 mg) as an absorption promoter, reducing the resulting mass into particle size 180-315 microm, packing into hard gelatin capsules and coating with Eudragit S100.

The process of systemic absorption and tissue targeting efficacy of salicylate (SA) following intracutaneous (i.c.), subcutaneous (s.c.) and intramuscular (i.m.) injections of its sodium salt in rats were evaluated by determining the drug concentration at the injection site and surrounding tissues. After i.c. and s.c. injections, SA was absorbed into the systemic circulation from the muscular vessels as well as the cutaneous or subcutaneous vessels beneath the injection site, and the AUC of the drug in the muscle was extremely high. Following i.m. injection, SA was rapidly absorbed into the systemic circulation mostly from the muscular vein. These results suggested that i.c. and s.c. injections have high degrees of targeting efficacy to the muscle, whereas i.m. injection is not appropriate for drug retention in muscle. In contrast, most of the topically applied drug was absorbed from the cutaneous vessels, and little drug migration to the muscle was observed. Thus, the skin pharmacokinetics of SA after i.c. injection was also markedly different from those after topical application on the skin. These results suggested that the i.c. and s.c. injections may be a good means to improve the targeting ability of drugs to the muscle as well as the skin.

The purpose of this work is to develop a thermo-reversible insulin liquid suppository, which undergoes a phase transition to bioadhesive gels at body temperature and enhances the bioavailability of insulin. The effects of insulin and sodium salicylate on the physicochemical properties of a liquid suppository composed of poloxamer P 407, P 188 and polycarbophil were investigated. The pharmacodynamic study and quantitative histological assessment of the rectal mucosa of rats were carried out after the dose of insulin-loaded liquid suppositories with different amounts of sodium salicylate into streptozotocin-treated rats. Only thermo-reversible insulin liquid suppository [insulin/P407/P188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%)] showed the optimal physicochemical properties and good safety in rats. It gave significantly lower plasma glucose levels, AUC0→4h (the area below basal glucose level) and Cnadir (the plasma glucose levels at the nadir) than did the solid and liquid suppositories without sodium salicylate in rats, indicating that the insulin from liquid suppository with sodium salicylate could be well absorbed in rats due to the absorption enhancing effect of sodium salicylate. It is concluded that thermo-reversible insulin liquid suppository [insulin/P 407/P 188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%)], which was easy to administer without any pain during insertion and remained at the administered sites, could have a potential to be developed as a more convenient, safe and effective rectal delivery system of insulin.

To improve the intestinal absorption of human calcitonin (hCT), novel lipophilic derivatives of hCT were synthesized by chemical modification with short-chain length fatty acids such as acetic acid and caproic acid, and the intestinal absorption and stability of these derivatives were examined in rats. The intestinal absorption properties of hCT and its acyl derivatives, acetylated hCT (Ac-hCT) and caproylated hCT (Cap-hCT), were estimated by measuring its hypocalcemic effects. Their intestinal absorption and stability in the intestinal mucosal homogenates were improved by increasing the carbon number of the fatty acid. Furthermore, we investigated the effects of co-administered absorption enhancers, sodium glycocholate (Na-GC), N-lauryl-β-D-maltoside (LM), sodium deoxycholate (Na-DC) and sodium salicylate (Na-Sal), on the intestinal absorption of hCT and its acyl derivatives. Their intestinal absorption was slightly enhanced by the addition of various absorption enhancers except for Na-Sal. However, the extent of the promoting effect was a little higher for a native hCT rather than for acyl-hCT derivatives. These results suggested that it may be possible to achieve the further absorption enhancement of hCT by using a combination of acylation and absorption enhancers.

Matrix pellets were produced combining microcrystalline waxes, pregelatinized starches and hydrolysed starches. Ibuprofen, sodium salicylate, benzoic acid, sodium benzoate and chloroquine phosphate were used as model drugs. Using a wax with a melting range between 68 and 72°C and increasing the wax concentration decreased the drug release rate. Pellets containing drum-dried corn starch failed to form matrix pellets. The slowest drug release was obtained for formulations containing waxy maltodextrin, releasing 95% of the incorporated ibuprofen after 48 h in vitro. Increasing the ibuprofen concentration decreased the drug release rate. Drug release was controlled by pore and matrix diffusion. The release of sodium salicylate and sodium benzoate from the wax-starch matrix pellets was characterised by an initial burst release followed by a block of the drug release.

The clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) (such as sodium salicylate (NaSA)) for the treatment of chronic arthritis is limited due to the adverse effects and patient non-compliance. In order to solve these problems, anion exchange hollow fiber membranes (AEHFMs) are proposed for the first time here as potential drug carriers. Brominated poly(2,6-dimethyl-1,4-phenylene oxide) (BPPO) is used as the starting membrane material. In-situ sol–gel process of γ-methacryloxypropyl trimethoxysilane (γ-MPS) in BPPO matrix is operated so as to enhance the membranes’ thermal and dimensional stability. The performances of the membranes in controlled release of the drug (NaSA as the model drug) are improved accordingly. Loading and release experiments illustrate that the hybrid AEHFM can bind salicylate (SA − ) at a high loading efficiency (28.4%), and the retention of the drug on the membrane matrix is significantly prolonged (drug released in 7 days under physiological condition: 51.9%, neglecting the drug bound by protein). Meanwhile, the membrane is biocompatible and can support the adherence, growth, and survival of human cells. Overall, the prepared AEHFM is a promising scaffolding material for drug delivery and tissue engineering.

The combined effect of pH and vehicle composition on the buccal absorption of propranolol has been evaluated in vitro using hamster cheek pouch. Ethanol was used as cosolvent in various binary-water mixtures. Lauric acid, 1-menthol, sodium salicylate and phosphatidylcholine were evaluated as penetration enhancers. Isopropyl myristate was used as a model of the mucosal lipid phase in partitioning experiments. Permeation of propranolol increased in extent with increasing pH of the vehicle, as compared with the unionized lipophilic fraction of the drug. Permeation of propranolol was decreased at pH 9.4 and increased at pH 6.8 on the addition of ethanol. Ethanol increases the solubility of propranolol in the aqueous vehicle and reduces the oil/vehicle partitioning of the drug through a thermodynamic effect. In addition, at low concentration, ethanol is assumed to increase the permeability of the buccal mucosa to the polar ionized form of propranolol, while higher concentration is required to enhance the diffusivity of the nonpolar unionized form. Menthol and lauric acid were effective at promoting the buccal absorption of propranolol only when the drug was ionized. It was assumed that the mechanism of permeation enhancement was an interaction with the membrane components for 1-menthol, increasing the diffusibility of propranolol, whereas lauric acid may form a more partitionable complex with the drug without any action on membrane permeability.

The effect of sodium salicylate at low and high concentration levels on some solution properties of sodium dodecyl sulphate (SDS), namely critical micelle temperature (CMT), critical micelle concentration (CMC) and micellar solubilisation, was investigated. Sodium salicylate (SS) exerts a dual effect on these properties depending on the concentration. Relatively low salicylate concentrations result in an increase in CMT, lowering of CMC and enhancement of dye solubilization, probably due to decreased monomer solubility and micellization at lower surfactant concentration. Within the higher concentration range, where the hydrotropic activity of salicylate is displayed, the effect of SS on the above properties is reversed. Increased surfactant solubility and interference with micelle formation account for the results obtained. The effect of SS on the properties of anionic surfactants at a given salicylate concentration may be considered as a consequence of the electrolytic and hydrotropic properties of sodium salicylate.

A starch gel has been prepared without heat treatment or chemical modification, using a typical hydrotropic salt (sodium salicylate) as a gelling agent. This gel has the advantage of retaining the marked solubilizing capacity of sodium salicylate. Swelling of dried starch-sodium salicylate gels is affected by the concentration of both starch and sodium salicylate as well as the presence of additives in the swelling medium. Study of the release characteristics of the gel using riboflavin as a model solubilized drug indicated consistent diffusion-controlled kinetics. Drug release is influenced by initial loading levels, starch content of the gel and, to a lesser extent, concentration of the gelling agent. Hydrotrope-gelled starch offers promise as a vehicle for topical drug delivery.

An interfacial cross-linking process was applied to hydrosoluble starch derivatives: hydroxyethylstarch (HES) and carboxymethylstarch (CMS). It resulted in stable microcapsules, which could be easily lyophilized and gave free-flowing powders. Sodium salicylate was encapsulated in HES microcapsules. In vitro dissolution studies indicated that these walls allow a prolonged release of the tracer. CMS microcapsules exhibited hydrophilic properties, as shown by water-induced swelling and gel formation. All cross-linked polysaccharide microcapsules were characterized by a total resistance to digestive media. However, when a protein, human serum albumin (HSA) or gelatin, was added to the starch derivatives in the aqueous phase, the process provided biodegradable microcapsules.

In order to obtain a controlled rate of delivery of sodium salicylate, spherical oral devices have been prepared and studied by using synthetic gastric liquid and in vitro tests. These devices have been prepared by dispersing the drug into Gelucire. The kinetics of release of drug has been found to be controlled by the erosion of Gelucire. The rate of drug delivery is then proportional to the actual area of the device, and a relationship between the time and the remaining weight of the device to the power one-third has been obtained. The effect of the (liquid volume)/(device weight) ratio on the rate of transfer has also been examined, and a decrease in this ratio provokes a decrease in the rate of transfer.

Using advanced topical formulations containing potential chemical enhancer(s) or physical penetration-enhancing tools capable of delivering entrapped drug(s) directly into skin tissues with little influence of the stratum corneum barrier, local and systemic drug disposition may be markedly similar to direct injection into the skin and muscle. The objective of this study is to investigate the dermatopharmacokinetics and systemic drug disposition after topical application and topical injection. Salicylate (SA) disposition in the skin and muscle as administration sites, and in the systemic circulation were evaluated following intracutaneous (i.c.) injection of an isotonic solution of SA-Na (dose; 3.08 micromol). Subcutaneous (s.c.) and intramuscular (i.m.) injection were also evaluated for comparison. Dermatopharmacokinetics and systemic disposition of SA after i.c. and s.c. injections were analyzed using a 4-compartment model consisting of skin, muscle, and central and peripheral compartments, whereas SA disposition after i.m. injection was analyzed using a 3-compartment model consisting of muscle, and central and peripheral compartments. Moreover, the absorption rate constant of SA after i.c. injection (0.073 min(-1)) was slightly lower than that after s.c. injection (0.083 min(-1)), and much lower than that after i.m. injection (0.327 min(-1)). In addition, higher osmolarity and a larger volume of SA-Na injectant increased the retention of SA in the skin and decreased the absorption rate to the systemic circulation after i.c. injection. The effect of injection volume on SA disposition after i.c. injection was not so marked compared with that of osmotic pressure. These results are useful to design an injection-type topical delivery system.

The pharmacokinetic parameters, i.e. peak concentration (cmax); peak time (tmax); area under the curve (AUC); elimination rate constant (k); absorption rate constant (ka); Drug clearance (clt), and the volume of distribution ( v d ) of sodium salicylate administered in fractionated coconut oil (FCO) have been compared with that from an aqueous and glycerin vehicles using a three-way crossover study in 12 rabbits. The results of the study show that all of the pharmacokinetic parameters tested differ significantly when administered in oily rather than aqueous or glycerin vehicles. No statistically significant difference was found between any of the above mentioned parameters when comparison was made between aqueous and glycerin formulations. The results indicate that sodium salicylate is absorbed at a lower rate but to a greater extent from oily formulation. Possible reasons for these differences are discussed and is suggested, therefore, that the oily formulation might be used as a sustained release preparation.

Earlier studies have indicated that the degradation rate of poly(lactic acid) (PDLLA) can be modified by using 2,2'-bis(2-oxazoline) as a chain extender in polymer synthesis to form a lactic acid-based poly(ester-amide) (PEA). In the present study, the effect of an incorporated drug on the degradation rate of the PEA was evaluated. The model drugs, neutral guaifenesin, acidic sodium salicylate (pK(a) 3.0) and basic timolol (pK(a) 9.2), were incorporated into solvent cast PDLLA and PEA films. The drug content in the films was 2% (w/w). The degradation studies were carried out in PBS (pH 7.4, 37 degrees C); the resulting decrease in molecular weight of polymers was determined by size exclusion chromatography and the weight loss of films was measured. In addition, the drug release from the films in PBS (pH 7.4, 37 degrees C) was studied. The model drugs were released from the PDLLA and PEA films in a biphasic or triphasic manner. The final fast release phase of the drugs from both PDLLA and PEA films started when the molecular weight (M(n)) of the polymer had decreased close to 15,000 g/mol. The degradation rate of the PDLLA films was clearly enhanced by incorporated sodium salicylate or timolol. Whereas, the degradation rate of the PEA film was not enhanced by the incorporated drugs. The present results indicate that when compared to the PDLLA film, degradation rate of the PEA film in the presence of the drug is more predictable.

In general, absorption enhancing effects of various absorption enhancers were greater in the large intestine than those in the small intestinal regions. Therefore, the effectiveness of absorption enhancers is expected to be remarkably observed, if these enhancers can be delivered to the large intestine with some poorly absorbable drugs after oral administration. In this study, therefore, we examined whether chitosan capsules were effective for the colon-specific delivery of a certain absorption enhancer and can improve the absorption enhancing action of the absorption enhancer after oral administration. 5(6)-Carboxyfluorescein (CF) was used as a model drug to investigate the site-dependent effectiveness of various absorption enhancers by an in situ closed loop method. Sodium glycocholate (NaGC), n-dodecyl-β- d -maltopyranoside (LM), sodium salicylate (NaSal) and sodium caprate (NaCap) were used as models of absorption enhancers in this study. Overall, the absorption enhancing effects of these enhancers for intestinal absorption of CF were greater in the colon than those in the jejunum and the ileum. Especially, among these enhancers tested in this study, LM showed much greater absorption enhancing effect in the colon than in the jejunum and the ileum. Therefore, LM was selected as a model absorption enhancer to examine the effect of chitosan capsules on the absorption enhancing effect of LM. When CF and LM were orally administered to rats using chitosan capsules, the plasma concentration of CF was much higher than those in other dosage forms including solution and gelatin capsules. Therefore, chitosan capsules may be useful carriers for colon-specific delivery of LM, thereby increasing its absorption enhancing effect from the intestinal membranes.

Previous studies have indicated that conventional description of drug/cyclodextrin complexes in aqueous solutions as inclusion complexes are not as unambiguous as one might think. It has been shown that in some cases drug/cyclodextrin complexes consist of a mixture of inclusion and non-inclusion complexes. Furthermore it has been shown that drug/cyclodextrin complexes can form aggregates containing up to couple of hundred complexes. In this present study β-cyclodextrin (βCD) solubilization of hydrocortisone is enhanced by including short-chain anionic and cationic species in the aqueous complexation medium. For example, maximum hydrocortisone solubility in pure aqueous βCD solutions or suspensions is 2.2 mg/ml. Addition of 1% (w/v) sodium acetate to the complexation medium increases this value to 7.1 mg/ml (or over 220%). Further addition of 0.25% (w/v) hydroxypropyl methylcellulose to the medium increased the hydrocortisone solubility to over 9 mg/ml. Similar results were obtained when sodium salicylate or benzalkonium chloride were added to the complexation medium. It is also shown that cyclodextrin complexes of lipophilic compounds that have good affinity for the cyclodextrin cavity can be used to enhance cyclodextrin solubilization of drugs that have low affinity for the cavity. All these observations can be explained by formation of drug/cyclodextrin complex aggregates.

The effect of sodium cromoglycate and sodium salicylate and a range of diverse pharmaceutical adjuvants: lactose, sodium dodecyl sulphate (SDS), sodium chloride, ammonium sulphate, including sodium benzoate and sodium salicylate as hydrotropic solubilisers, was studied on the cross-linking of bovine serum albumin (BSA) by glutaraldehyde. Photon correlation spectroscopic data indicated that the substances tested affected to different degrees the rate and extent of cross-linking, the effect being most pronounced in the presence of the inorganic salts. The results have been attributed to possible denaturation of BSA and the dehydrating properties of the inorganic salts, as both exposure of additional lysine moieties upon denaturation and dehydration are important factors in the mechanism of cross-linking. Polyacrylamide gel electrophoresis of BSA subjected to cross-linking in the presence of sodium benzoate and sodium salicylate at hydrotropic concentrations indicated a change in the nature of the cross-linked product. The possible effect of drugs and additives on the cross-linking of albumin is a factor that should be taken into consideration in the formulation of albumin microspheres as drug carriers.

The solubilisation of temazepam by hydrotropic complexation has been investigated. Sodium salicyate and nicotinamide were used as hydrotropes. The former allowed appreciable solubilisation of temazepam but the effect was less marked in the case of diazepam. Increased solubilisation with temazepam was attributed to an increase in hydrogen bonding between drug and hydrotrope. Solutions of temazepam solubilised with sodium salicylate developed an unacceptable yellow colour on storage. This problem was overcome by lyophilisation. Lyophilised injections were readily reconstituted and initial assessment in rabbits indicated a satisfactory pharmacological response. Lyophilisation resulted in a preparation with excellent storage characteristics.

Administration of an insulin suppository containing adjuvant such as sodium salicylate and l -phenylalanine enamine ethylacetoacetate (enamine) to healthy male human subjects increased serum immunoreactive insulin (IRI) levels significantly. However, to decrease serum glucose concentrations significantly in humans, high serum IRI levels have to be maintained for at least about one hour in humans, rather than being transient. In comparison with enamine, sodium salicylate seems to be feasible as adjuvant in the insulin suppository since its administration to human subjects resulted in high IRI serum levels for a period long enough to lower serum glucose concentrations significantly.

Microcapsules of sodium salicylate and potassium dichromate were prepared by the temperature reduction ethyl cellulose coacervation method using polyisobutylene as a protective colloid. Film-coated microcapsules were obtained. Minute empty wall polymer spheres were also formed in amounts increasing with protective colloid concentration or core particle size and decreasing with ethylcellulose concentration, in conformity with the mechanism previously proposed. Neither matrix diffusion nor first-order kinetics was observed by sodium salicylate experimental release data. Since small pores not initially present were formed, a dissolution model was applied; release conformed with the Hixson-Crowell cube-root law and was influenced by agitation rate in the sink solution. The effective diffusion coefficients from dissolution rate constants were near to the theoretical water value but several orders higher than the measured permeability constant through ethylcellulose cast films. In support of a hypothesis that pore-formation was caused by the high “internal osmotic pressure developed by water-soluble core material”, the release rate fell on increasing external osmotic pressure, which ultimately prevented pore-formation at 7M LiCl. This is the first case in which a dissolution model has been shown applicable to film-coated core materials.

Tablets containing different concentrations of sodium salicylate in a (hydroxyethyl)methylcellulose matrix swelled without disintegration or attrition. The release rate of the drug from the whole tablet was shown to conform with a model diffusional equation for two-sided release from a slab maintaining a constant surface-volume ratio on swelling, and the rate constant was linearly dependent on the drug dosage, as predicted by this equation, when the polymer concentration was kept constant. With varying polymer concentration, correction of the rate constants for their dependence on drug content of the matrix yielded constants dependent on the polymer concentration only. Such rate constants observed a semi-logarithmic relation to polymer content and extrapolated to give reasonable diffusion coefficient values for hypothetical low and high polymer content matrices. The temperature coefficient yielded a high value (9.15 kcal . mol−1) for the activation energy of the diffusion process, consistent with the energy barrie in a polymer matrix. Such treatment of rate constants and component concentration variables offers a valuable method of correlating formulation and release parameters in non-disintegrating hydrophilic matrices.

There is increasing evidence to suggest that the systematic availability of drugs, particularly those that show significant first-pass metabolism, when administered rectally is dependent upon the site of absorption within the rectum (de Leede et al., 1983). The closer to the anus the drug resides the greater the systemic availability. This observation is usually explained in terms of the venous blood drainage within the rectum; the lower rectal area blood drains directly into the general circulation whereas the upper and middle rectal area blood drains directly into the portal system and undergoes first-pass hepatic metabolism. The role of the lymphatic system in drug dissemination and avoidance of first-pass metabolism from the rectum appears to have received little attention. Liversidge et al. (1985) have found that increasing surface area for absorption by increasing suppository size causes a decrease in systemic availability of rectally administered suppositories containing insulin and sodium salicylate. This observation

A solid dispersion of insulin with sodium salicylate or mannitol could result in the rapid release of insulin from suppositories and a significant decrease in plasma glucose concentrations in dogs after the administration of the insulin suppository even at doses as low as 0.5 U/kg or less in dogs. Furthermore, it has been shown that high plasma insulin concentrations can be maintained for more than 1 h. This results in a decrease of plasma glucose concentrations in normal dogs for more than 1.5 h, which was required for effective treatment in decreasing plasma glucose concentrations in depancreatized dogs (Nishihata et al, 1985a; Okamura et al., 1985). The addition of lecithin to the suppository base resulted in a prolonged effect of salicylate as an adjuvant in suppositories (i.e. 1.5 h.), due to the slow release of sodium salicylate. Thus, a preparation of a solid dispersion of insulin and a triglyceride base containing lecithin seems to be an effective suppository for lowering blood glucose.

The compatibility and stability of diazepam 5 mg/ml in 30% sodium salicylate, following dilution with 5% dextrose and normal saline, was investigated. Test dilutions ranging from 1 : 1 to 1 : 100 did not result in immediate precipitation and remained clear for at least 1h and 3h after dilution with 5% dextrose, normal saline or human plasma respectively. However, microcrystal precipitation was noted in some solutions thereafter. No precipitation was observed when diazepam-sodium salicylate solution was injected at varying rates into the tubing of 5% dextrose and saline infusions moving at low rates. Diazepam-sodium salicylate solution induced a higher degree of haemolysis in vitro and was less bound to bovine serum albumin than a commercial diazepam injection. Sodium salicylate competitively inhibited the binding of diazepam to bovine serum albumin. Further studies are necessary for the clinical evaluation of this diazepam-sodium salicylate combination.

The influence of simple structural modification on the solubility of a series of poorly soluble benzodiazepines in sodium salicylate solution was investigated. Results of solubility and spectral studies indicate that an electrostatic force of the donor—acceptor type plays an important role in the solubilization of these compounds by hydrotropy. In an attempt to explain the characteristic positive deviation in hydrotropic solubilization diagrams, the solution properties of sodium salicylate were studied. Conductivity experiments indicate molecular aggregation of sodium salicylate at a concentration of 0.67 M at 25°C. The aggregation concentration increases as a function of temperature. Results obtained from density, viscosity and diffusion studies are consistent with those of conductivity measurements. The remarkable increase in the solubilizing effect of sodium salicylate is probably associated with aggregate formation. Inclusion of the benzodiazepine molecules in the sodium salicylate aggregates is thought to be the mechanism responsible for the solubilization of these drugs. A donor-acceptor interaction between sodium salicylate and benzodiazepine molecules is assumed to stabilize such an inclusion and determine the degree of solubility of the benzodiazepines in sodium salicylate solution. Nevertheless, further studies are necessary to substantiate these results.

An increased interest in non-injectable dosage forms for polypeptides has led to identification of some compounds which can increase absorption of these drugs. Sodium salicylate administered in rectal suppositories with recombinant methionyl human growth hormone (met-hGH) lead to measurable serum concentrations and demonstratable biological activity of the polypeptide. Sodium salicylate and mineral oil were tested in the ligated stomach, duodenum, ileum and colon of rats for their ability to enhance absorption of met-hGH. Rats were injected in one of the segments of the gastrointestinal tract with 3 mg kg of met-hGH with or without sodium salicylate in aqueous buffer or mineral oil vehicle. Blood samples were collected at various time points and assayed for hGH. Absolute bioavailabilities calculated for each formulation in each intestinal segment indicated that the only treatment with greater than 3% bioavailability was injection of sodium salicylate in mineral oil into the ileum (7%) and colon (9.5%). Statistical analysis proved the surprising interaction of salicylate and mineral oil to be synergistic in absorption enhancement. This is a promising finding but several issues must be addressed and pharmaceutical formulations must be optimized before it can be developed into an oral dosage form for polypeptide drugs.

In order to attain a constant rate of delivery of sodium salicylate as a drug, spherical oral devices were prepared and studied. They were obtained by following this two-stop process: (i) the drug was dispersed in Eudragit as polymer, with the help of a little alcohol, and the mixture was pressed into calibrated spheres; and (ii) the spheres, previously dried, were surrounded with a thin layer of constant thickness of gelucire. These devices exhibited a constant rate of delivery of the drug when soaked in a synthetic gastric liquid. A model built for the study of membranes in spherical form was successfully tested. As a result, the rate of delivery was shown to be inversely proportional to the thickness of the layer of Gelucire.

The effect of two fatty acids (oleic and lauric) on the transport of the cationic drug naphazoline, neutral caffeine, and an anionic model drug salicylate, across excised human skin was studied using Franz diffusion cells. Oleic and lauric acids both increased the in vitro skin permeation of all penetrants. Oil/water partitioning data and rotating diffusion cell measurements, in the presence of the fatty acids, suggested that the enhanced flux of the cationic naphazoline could be accounted for by an increase in lipophilicity through ion pairing with the carboxylate anion of the acid. Caffeine and sodium salicylate were incapable of forming ion pairs consequently, increases in skin permeability are also due to a disruption of the stratum corneum. This conclusion was further supported by (a) increased transepidermal water loss, and (b) increased in-vivo skin permeation of the non ion-pairing methyl nicotinate, at skin sites pretreated with the fatty acids.

Studies have been conducted in a model system for percutaneous absorption, the rotating diffusion cell, using an artificial membrane representative of the epidermal barrier. An ethoxylated amine, Ethomeen S12 (bis-(2-hydroxyethyl)oleylamine), was investigated for its ability to promote the percutaneous absorption of the salicylate anion, by a facilitated transport process, using a pH gradient of 5–7.4 across the membrane to provide the free energy required for the co-transport mechanism. The transport of caffeine, a cationic drug, across the model membrane was not enhanced using this system. In vitro skin studies were conducted to establish a facilitated transport mechanism within the stratum corneum. The transdermal penetration of sodium salicylate was enhanced, but so too was that of caffeine, indicating that this type of compound may reduce the skin barrier by a mechanism independent of observed carrier properties in the model system.

A model for drug release from fatty suppository bases is presented that explains in vitro measurements on drugs with various physicochemical characteristics, such as paracetamol (slowly dissolving in water) sodium salicylate (rapidly dissolving in water) and salicylic acid (soluble in lipid). The in vitro results are compared with in vivo experiments on rectal absorption in man. Results indicated that for suspensions of all the drugs investigated, dissolution takes place at the interface between the suppository base and the surrounding fluid. The release process therefore includes a flow of particles in the suppository base into the direction of the interface and a flow of solute away from the interface. Either of these flows may be rate limiting dependent on the water solubility of the drug, and may determine the effect of concentration and particle size on release rate.

Tablets comprising a compressed matrix of a methylcellulose (MC) derivative mixed with various drugs and additives show 3 distinct types of behaviour in a disintegration test: rapid disintegration (D), gradual attrition (A) and maintenance of integrity (ND). Kinetic studies showed that ND matrices gave drug release related to square-root of time (i.e. matrix diffusional model) whereas a typical A matrix (salicylic acid-MC) deviated positively but observed the Hixson-Crowell cube-root equation for dissolutional control, as applicable to polyphase mixtures. In Une with these models, the matrix-controlled system was unaffected by and the dissolution one dependent on stirring conditions. For clarifying the mechanism of matrix behaviour, gelation temperature and viscosity were studied using dilute aqueous systems. Gelation temperature was raised by ND additives, salts containing large organic ions (including sodium benzoate, octanoate, salicylate, tetracaine-HCl. potassium phenoxypenicillin, chlorpheniramine maleate) thiocyanate and iodide. It was lowered by inorganic and small organic ions, lactose and some free organic acids causing A and D behaviour. The elevation, which has not hitherto been noted, is especially interesting. Intrinsic viscosity was raised by sodium salicylate and lowered by sodium chloride, the Huggins' constant being lowered by the former and raised by the latter. These gel point and viscosity changes reflect increased hydration and extension of the macromolecule chain in the former system and dehydration in the latter, such changes being associated with increased or decreased polymer cohesion in the compressed matrix.

The application of an in situ loop technique to the determination of rectal water flux and drug absorption in the rat is described. The procedure requires minimal surgical skill and allows rapid sampling of luminal fluid. The method was assessed by studies on: (a) the effect of sodium salicylate solutions (1% and 5% w/v) and equiosmotic solutions of mannitol (2.5% and 11.8% w/v) on rectal water flux and tissue morphology; and (b) the rectal uptake of [3H]prednisolone from aqueous solution. The 1% sodium salicylate and 2.5% mannitol solutions induced water movement into the lumen but caused no apparent change in the tissue morphology. The more hypertonic 5% salicylate solution and the equiosmotic mannitol solution induced water flux into the lumen and resulted in extensive cell loss. The uptake of [3H]prednisolone from the loop was confirmed by a simultaneous increase in plasma tritium levels.

Rat colonie absorption of cefmetazole and [Asu1,7]-eel calcitonin was enhanced by coadministration of sodium salicylate, disodium ethylenediaminetetraacetic acid, diethyl ethoxymethylenemalonate or trifluoperazine. Colonie absorption of cefmetazole and eel calcitonin, enhanced by various concentrations of either EDTA or trifluoperazine, appeared to occur via a paracellular pathway. Diethyl maleate did not enhance colonie absorption of eel calcitonin, but it did significantly enhance colonie absorption of cefmetazole, demonstrating the importance of a paracellular absorption pathway for eel calcitonin. Although low concentrations of DEEMM and salicylate enhanced the colonie absorption of only cefmetazole (having a low molecular weight of 471), those adjuvants at high concentrations remarkably enhanced the colonie absorption of both cefmetazole and the macromolecular peptide, eel calcitonin (mol. wt. 3363). This observation suggests two different adjuvant mechanisms, depending on the concentration of the adjuvant.

Drug release in synthetic gastric liquid has been studied by using sheets made of sodium salicylate and Eudragit, this component playing the role of a polymer matrix. A double transfer has been observed as follows: the liquid entered the matrix, dissolved the drug which then diffused out into the gastric liquid. Both these transfers have been found to obey Fickian laws of transient diffusion, with a constant diffusivity for the drug and a concentration-dependent diffusivity for the liquid. A model, using an explicit method with finite differences has been described, taking into account both transfers of material (drug and liquid), as well as the values of matter transferred at equilibrium. The model has been verified on tablets containing various concentrations of sodium salicylate in the polymer ranging from 15 to 50 (weight%), and calculated values were in substantial agreement with experiments.

The effect of the pH of synthetic gastric liquid on drug release has been studied by soaking sheets made of sodium salicylate previously dispersed in a polymer matrix. Eudragit RS plays the role of polymer and binder. The liquid enters the polymer and dissolves the drug, and then the drug is released into the liquid. Both these transfers are controlled by diffusion under transient conditions, and diffusivity is concentration-dependent. The value of the pH of the synthetic gastric liquid was found to be of great importance for the diffusivities and the amount of matter transferred at equilibrium. The model described was used verify the rate of matter transferred for various values of pH ranging from 1.2 to 7. A law accurately described variation of diffusivity with the pH of the liquid. Profiles of concentration of drug and liquid were calculated for various pH values.

The effects of temperature, concentration, hydration, and sodium salicylate (SA) on the permeability of isopropamide iodide (ISP) through the excised abdominal mouse skin were investigated using the in vitro diffusion cell technique. The permeability of ISP was increased as the temperature of the diffusion medium increased, but was independent of ISP concentration, which suggests a simple diffusion process of ISP through the skin. It was increased about 2-fold by hydration of the skin for 3 days in normal saline. The permeability of ISP through the hydrated skin increased in the presence of SA. SA itself did not seem to affect the permeability of the skin for ISP in an irreversible manner, since the increase of the permeability was not seen after SA pretreatment of the skin followed by repeated washing. The apparent n-octanol/water partition coefficient (APC) of ISP increased as the concentration of SA in the aqueous phase increased. The permeability of ISP through the skin increased as the APC of it increased. The increase of the permeability in the presence of SA might be due to the formation of lipophilic ion-pair complex between ISP and SA.

A galenic form made of a dry emulsion was described and tested by considering the drug release in synthetic liquids. It was obtained by mixing the two following phases: the one with water, sodium salicylate as drug and hydrophilic silica in powder form; the other being a lipidic phase with oil and hydrophobic silica. A model, based on a numerical method with finite differences, was applied to the case of spherical samples. The theoretical results for the kinetics of drug release were in good agreement with the corresponding experimental ones. Dry emulsion exhibited a significant sustained drug release, controlled by diffusion with a constant diffusivity and a coefficient of matter transfer characterizing the retardation in the transfer on the surface.

The effects of formulation such as acetic acid content and suppository size on the plasma levels of glucose and sodium salicylate after rectal administration of a suppository containing insulin and sodium salicylate were studied. An HPLC method is described for measuring insulin content in suppositories. Mechanisms are proposed that account for the differences observed in plasma levels of glucose and sodium salicylate from the various formulations.

Sodium chloride facilitated the adjuvant action of sodium salicylate in enhancing rectal ampicillin absorption in rats. This action of sodium chloride involves facilitated absorption of salicylate by sodium ion. That is, enhancement of ampicillin absorption in the presence of salicylate correlated well with the increase of salicylate absortion with increasing concentration of sodium ion. The effect of sodium ion on the action of salicylate was confirmed using the sodium salts of ascorbate instead of sodium chloride. Since a mixture of sodium ascorbate and sodium salicylate showed less disruption of the rectal mucosal surface compared to a mixture of sodium chloride and sodium salicylate, sodium ascorbate seems to be suitable additive for inclusion with sodium salicylate for the formulation of rectal dosage forms of ampicillin.

In this report the effect of particle size on the release rate of sodium salicylate (a highly water-soluble drug) from fatty suppository bases is studied. In vitro it could be shown by comparing sedimentation measurements and release measurements that a rate-limiting process which is operating on the lipid side of the interface is causing the particle size effect. An equation is proposed describing the release flow as a function of particle size. It is shown that the time needed for the drainage of liquified lipid between a particle and the interface, a process which is essential for the drug to arrive at its dissolution site, is of the same order of magnitude as the time required for a wetted particle of a highly water-soluble drug to dissolve in an aqueous phase. This may imply that, in addition to the dissolution process, the drainage effect under certain conditions could become rate-limiting in the release of drugs from suppositories and thus for rectal absorption rate. Although the drainage time for a single particle layer appeared to be rather independent of particle size, reduction of particle size leads to an increase in the number of layers and consequently to a summation of drainage times for the same weight of drug. In vivo it is shown that probably an increase in ‘concentration viscosity’ (increasing the concentration of particles in the base) does not have a negative effect on absorption rate from the rectum, whereas an increase in the ‘fluid viscosity’, does have a negative effect on absorption rate for suppository bases and liquid-paraffin enemas. Since the drainage time is not influenced by the concentration of particles in the base but only by the viscosity of the lipid phase while the bulk transport of particles through the base is influenced by both effects, it is concluded that in line with in vitro data the drainage time of particles determines the release flow of highly water-soluble drugs also in vivo.

A model of ulcerated bowel was produced in the rat rectum by treatment with Brij 35 suppositories. Prednisolone absorption from enemas in normal and damaged bowel was assessed using an in situ rectal loop. In animals 20 h after damage drug absorption was reduced but returned to normal levels after one week. Co-administration of equiosmolar sodium salicylate (1 and 2% w/v) and mannitol (2.5 and 4.1% w/v) solutions in normal bowel induced a significant water flux into the lumen and changed the plasma tritium profile compared to the control. In damaged bowel plasma tritium levels remained low following co-administration of mannitol (2.5% w/v) but were restored to normal control levels by co-administration of salicylate (1% w/v). The altered absorption in normal bowel can be attributed in part to osmotic stress but in damaged bowel the difference between the effect of equiosmotic solutions of salicylate and mannitol suggests that a different mechanism is operating.