Site-specific drug delivery in the dog using flexible fiberoptic endoscopy.

The development of a nonsurgical repeatable method of site-specific delivery to the gastrointestinal tract in the canine is described. Studies to characterize and validate this method were performed utilizing propranolol and etodolac due to their well-known pharmacokinetic properties. Using a catheter placed through the auxiliary port of a flexible fiberoptic endoscope, liquid dosage formulations were consistently delivered to the canine stomach, duodenum, ileum, and colon. It was shown that differences in site-specific delivery could be demonstrated with this model. Propranolol tended to have the highest exposure following dosing to the ileum as compared to other sites. The anesthetic regimen used to perform endoscopy affected certain pharmacokinetic parameters of the compounds being tested including decreasing the intrinsic clearance of propranolol. However, since decreased intrinsic clearance should similarly affect AUCo regardless of the site of delivery, this does not preclude site-specific comparisons to be made. Further, no evidence has been reported for the effect of anesthesia on one GI segment but not another. Thus for other compounds, assuming there are either no anesthetic effects on intestinal pharmacokinetic parameters (absorption, intestinal metabolism, etc.) or that they are consistent and uniform throughout the intestinal tract, this model allows comparisons of the exposure following delivery to differing intestinal sites.

Long-acting contraceptive agents: structure activity relationships in a series of norethisterone and levonorgestrel esters.

A large number of esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) were synthesized and tested for biological activity. The test employed in these studies was the duration of estrus suppression in cycling mature rats. In the norethisterone series several esters exhibited duration of activity comparable to that of norethisterone enanthate. In the levonorgestrel series the butanoic, cyclobutylcarboxylic and cyclopropylcarboxylic esters were longer acting than medroxyprogesterone acetate (17 alpha-acetoxy-6 alpha-methylpregn-4-ene-3,20-dione) when prepared as aqueous microcrystalline suspensions.

PIP: A large number of esters of norethisterone (17alpha-ethynyl-17beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13beta-ethyl-17alpha-ethynyl-17beta-hydroxygon-4-en-3-one) were synthesized and tested for biological activity. The test employed in these studies was the duration of estrus suppression in cycling in mature rats. In the norethisterone series, several esters exhibited duration of activity comparable to that of norethisterone enanthate. In the levonorgestrel series, the butanoic, cyclobutylcarboxylic, and cyclopropylcarboxylic esters were longer acting than medroxyprogesterone acetate (17alpha-acetoxy-6alpha-methylpregn-4-ene-3,20-dione) when prepared as aqueous microcrystalline suspensions.

Long-acting contraceptive agents: the influence of pharmaceutical formulation upon biological activity of esters of norethisterone.

17 beta-esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) have been formulated as aqueous microcrystalline suspensions and oily solutions for administration to rats to assess the length of progestogenic activity. Results show that, for some of the esters, the rate-controlling step in prolonging activity is the rate of drug release from the injected formulation. For these esters, when formulated as suspensions, it is proposed that crystal size and form will have a critical effect upon duration of estrus suppression. The influence of crystal form has been demonstrated with the 4-(butoxy)phenylacetate ester for which two different crystal forms have been identified. The lower melting point, more soluble crystal form shows marked prolongation of action, whereas the other form is ineffective.

Long-acting contraceptive agents: the influence of physico-chemical properties of some esters of norethisterone upon the plasma levels of free norethisterone.

Four 17 beta-esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one), formulated both as oily solutions and aqueous suspensions, were administered intramuscularly to rabbits and free plasma levels measured for periods up to 9 weeks. For all formulations of the compounds, the disappearance of norethisterone following peak plasma levels obeyed first-order kinetics. Since different slope values were obtained for different formulations of the same compound, the values reflected the release rates of the esters from the formulations. Fusion data, partition coefficients and solubilities of the compounds in 2,2,4-trimethylpentane and water were obtained and these properties were related to the biological activity of the formulations. For oily solutions, the differences in plasma levels were ascribed to the different partition coefficients of the esters between the oil and tissue fluids. For suspensions, the different activity in relation to an oily solution of an ester was related to the strength of intermolecular forces in the crystal lattice and to the relative thermodynamic activity in the two formulations. The results demonstrate that microcrystalline suspensions do not always have a longer duration of activity than oily solutions of the same compound after intramuscular injection.

Formulation and evaluation of sustained release paracetamol tablets.

Slow-releasing paracetamol tablet formulations were produced and their in vitro dissolution profiles and in vivo absorption characteristics were determined and compared with a conventional rapidly-disintegrating commercial formulation. A correlation between saliva and plasma levels of the drug was confirmed and this allowed estimation of some simple pharmacokinetic parameters from the saliva paracetamol data. The in vitro data correlated with the in vivo parameters and this enabled the dissolution test results to be used in predictive manner in the development of a compression-coated slow release formulation which produced therapeutic levels of the drug for up to 5 h.

Rheological and drug release properties of oil gels containing colloidal silicon dioxide.

The rheological properties of oil gels prepared by dispersing colloidal silica in n-dodecane and 1-dodecanol were examined. The differences in gel strength using these two media were accounted for by the difference in the extent of hydrogen bond formation between the silanol groups on the silica surface. The incorporation of methyl salicylate further modified the rheological properties of the gels. The drug was capable of hydrogen bonding with silanol groups in the n-dodecane gels, which increase gel strength at low concentrations; at high concentrations, the drug acted as a plasticizer. In 1-dodecanol systems, the drug acted solely as a plasticizer. Adsorption studies showed that methyl salicylate was adsorbed only on the silica particles in the n-dodecane medium. Interaction of the drug with the silanol groups in the n-dodecane systems did not appear to effect methyl salicylate release from the gels.

Flupenthixol dihydrochloride decomposition in aqueous solution.

Flupenthixol dihydrochloride in aqueous solution oxidized to trifluoromethylthioxanthone, ethanol, and piperazine via aldehydic and epoxidic intermediates in the presence of air. The formation rate of trifluoromethylthioxanthone increased with increases in pH and oxygen concentration. Buffer ions also affected the decomposition rate. Micelle formation by the drug markedly influenced its oxidation rate.

A model for short term drug absorption studies; comparison of sulphadiazine tablets.

The four parameter equation, applicable to drug absorption kinetics over a limited time period, has been used to interpret plasma concentration, time results following oral dosage with three different formulations of sulphadiazine tablets, to each of five subjects. Assessment parameters for the formulations, the time for ten percent absorption, the time interval between 10-90% absorption and the plasma concentration with no disposition (relative availability) have been estimated. Intersubject variation obscured many of the differences between formulations. To blank off this variation, plasma concentrations at each time were averaged and then random variation corresponding to the error of the assay method was applied so as to generate a number of sets of data which including the mean concentrations was equal to the number of sets in the original measurements. Kinetic analysis of these sets indicated a number of significant differences between the formulations.

Factors influencing decomposition rate of amitriptyline hydrochloride in aqueous solution.

The degradation rate of amitriptyline hydrochloride in buffered aqueous solution containing various additives was determined. The oxidation was a free radical-mediated process, and the rate was accelerated by the presence of metal-ion contaminants. Glass ampuls, particularly amber ones, in which the solutions were stored were the major source of these contaminants. Edetate disodium stabilized the solution, but the primary antioxidants propyl gallate and hydroquinone were less effective. Sodium metabisulfite accelerated the decomposition, and it is postulated that there was direct attack by metabisulfite at the olefinic double bond in the drug molecule.

Influence of crystal form on tensile strength of compacts of pharmaceutical materials.

The tensile strengths of compacts of different crystal forms of aspirin, sulfathiazole, and barbital were determined with a modified tablet hardness tester. For each material, the tensile strength could be correlated with the amount of plastic flow and/or crushing undergone by each crystal form during compression.

Effect of primidone concentration on glass transition temperature and dissolution of solid dispersion systems containing primidone and citric acid.

The glass transition temperatures of glasses containing various concentrations of primidone in citric acid were measured and found to increase as the primidone concentration increased. Dissolution studies of these systems and particle-size measurements of primidone precipitated during dissolution of devitrified glasses suggest that the increase in the dissolution rate of the devitrified systems is due to both the small size of the precipitated crystals and the excellent wettability of these systems.

Preparation and properties of solid dispersion system containing citric acid and primidone.

Solid dispersions containing 1--32% (w/w) primidone were prepared by fusing the drug with citric acid and rapidly cooling the melt. The solidified dispersions were clear glasses which devitrified on aging or when stored at 60 degrees for up to 3 days. The phase diagram of the devitrified system indicated that the drug may exist as a solid solution at 1--3% (w/w) concentrations but that a eutectic mixture is formed at higher concentrations. The solubility of primidone increased in the presence of citric acid. Preliminary dissolution studies showed that the dissolution rate from the solid dispersion was greater than that of the pure drug or the physical mixture.

Correlation of phase inversion temperature with kinetics of globule coalescence for emulsions stabilized by a polyoxyethylene alkyl ether.

The phase inversion temperatures, globule coalescence rates, and long-term stability of oil-in-water emulsions stabilized by polyoxyethylene 4 cetyl ether were measured. Addition of sodium chloride to the aqueous phase depressed the phase inversion temperatures of the emulsions and the cloud point of the surfactant. Linear correlations were obtained between phase inversion temperature and cloud point and also between phase inversion temperature and the logarithm of the globule coalescence rate at constant temperature. This latter finding is consistent with a theory of emulsion type based upon the kinetics of coalescence. The programmed viscometric technique of determining inversion revealed the presence of a liquid crystalline phase below 35 degrees, which contributes significantly to emulsion stability.

The influence of crystal form on the radial stress transmission characteristics of pharmaceutical materials.

Various crystal forms of sulphathiazole, barbitone and aspirin were compressed in a single-punch tablet machine instrumented to monitor axially applied and radially transmitted forces, and upper punch movement. The changes in radial stress during the compression cycle depended upon the polymorphic form of the compressed material. The results were rationalized in terms of the degree of plastic flow/crushing that occurred with each material, and the degree to which the final compact underwent elastic compression. It is postulated that the reduction in the transition temperature of polymorphic forms of sulphathiazole and barbitone and the polymorphic transition of sulphathiazole Form II was due to the production of dislocations in the crystal and the crystals at crystal boundaries formed in the compressed materials.

Decomposition of amitriptyline hydrochloride in aqueous solution: identification of decomposition products.

The decomposition of amitriptyline hydrochloride upon autoclaving in a buffered solution (pH 6.8) was investigated. Three major decomposition products [3-(propa-1,3-dienyl)-1,2:4,5-dibenzocyclohepta-1,4-diene, dibenzosuberone, and 3-(2-oxoethylidene)-1,2:4,5-dibenzocyclohepta-1,4-diene] were detected and identified by chromatographic and spectroscopic techniques. Evidence is presented that the latter two compounds are formed by further oxidation of 3-(propa-1,3-dienyl)-1,2:4,5-dibenzocyclohepta-1,4-diene, and a possible decomposition pathway is outlined.