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PubMed1996

Optima: a windows-based program for computer-aided optimization of controlled-release dosage forms.

The purpose of this work was to develop a computer program that assists optimization of controlled-release devices, both visually and mathematically, using response surface methodology (RSM). A Windows-based computer program, Optima, which interactively implemented a number of subroutines for the optimization procedure, was developed. Optima is an integrated, user-friendly, and graphically oriented program for pharmaceutical dosage form optimization. Central composite design is implemented in the program. First- and second-order models containing up to five variables can be fitted to the data. The user can also choose between linear and exponential individual desirability functions, and use them to construct an overall desirability function that combines all the response variables in a single response. The program can predict the optimum levels of experimental variables, with respect to individual responses and/or the overall desirability. Optima has been successfully used in the development of sustained-release AZT-loaded microspheres. During the optimization process, three experimental variables were investigated and four responses were measured. The experimental design was a central composite design that was generated by the program. The response values were used by the program to calculate the individual desirability functions, which were then combined into an overall desirability function. The individual responses as well as the overall desirability function were optimized by fitting to a second-order polynomial equation. The response surfaces were generated and optimum levels of the experimental variables were predicted. The observed responses of the optimized formulation were very close to those predicted by Optima. The program proved to be a very useful, integrated tool for optimization of the controlled-release microspheres.

Computer Graphics↗
PubMed1997

Colonic spread of three rectally administered mesalazine (Pentasa) dosage forms in healthy volunteers as assessed by gamma scintigraphy.

BACKGROUND: Rectal administration of enemas, foams and suppositories is the most efficient method of delivering locally-acting drugs to the distal colon, sigmoid colon and rectum. Healthy volunteers provide an effective population to compare different formulations for rectal drug delivery. However, there is still only limited comparative information available on the dispersion of such dosage forms in human subjects. Therefore, the objective of this scintigraphic study was to compare colonic spread of an enema, a rectal foam and a suppository formulation in healthy volunteers. METHODS: This was a randomized, crossover study in eight healthy male volunteers. Each received Pentasa rectal formulations as either a 100 mL suspension enema (1 g mesalazine), one actuation of a non-CFC propellant rectal foam (1 g mesalazine in 5 mL concentrate, expanding to 40 mL on actuation), or one suppository (1 g mesalazine) on three separate occasions. The spread of the radiolabelled formulations was assessed over a 4-h period by gamma scintigraphy. RESULTS: The formulations were retained by all subjects for the whole of the 4-h imaging period. The enema spread to the splenic flexure in 7 out of 8 subjects, but was retained in the rectum and sigmoid colon in one individual. The foam spread as far as the descending colon in four subjects. In the remaining individuals the foam was retained in the rectum and sigmoid colon. The spread of the suppository was limited and confined to the rectum. CONCLUSIONS: The findings of this study are consistent with previous research and support the intended clinical uses of the enema, foam and suppository formulations to treat distal ulcerative colitis, proctosigmoiditis and proctitis, respectively. The results highlight the potential of gamma scintigraphy in providing in vivo 'proof of concept' data to help verify the targeting of pharmaceutical products to their intended site of delivery.

Administration, Rectal↗
PubMed1989

Pharmacokinetics of a 5-aminosalicylic acid enteric-coated tablet and suppository dosage form.

An Eudragit-L coated oral 5-aminosalicylic acid (5-ASA; mesalazine) product (Mesasal), has been formulated to deliver 5-ASA to the distal small intestine and colon for the treatment of inflammatory bowel disease. The purpose of this study was to compare the pharmacokinetic profile of this product to sulphasalazine (SASP; Salazopyrin) and to assess the pharmacokinetics of a suppository 5-ASA dosage form. Twelve healthy volunteers randomly received four single doses of 5-ASA delivering formulations not less than 1 week apart. (a) Mesasal tablets, 2 x 250 mg, fasting; (b) Mesasal tablets, 2 x 250 mg, fed; (c) Salazopyrin tablets, 3 x 500 mg (corresponding to 576 mg 5-ASA), fasting; and (d) Mesasal suppository, 1 x 500 mg, fasting. Plasma 5-ASA and acetyl-5-ASA (Ac-5-ASA) concentrations were followed for 48 h and urine and faecal concentrations for 72 h. Mesasal tablets (fasting) produced a greater area under the concentration-time curve (AUC), peak and time to peak for both plasma 5-ASA and Ac-5-ASA than Salazopyrin. Median urinary recovery values were 21.7% for Salazopyrin and 35.5% for Mesasal (fasting) (P less than 0.01). This means that the systemic absorption was higher after Mesasal than after Salazopyrin. The total faecal recovery values were 38.3 and 26.5%, respectively (NS). Except for a delay of 1.5-.3 h in the time to peak of 5-ASA and Ac-5-ASA plasma levels, the pharmacokinetics of Mesasal tablets were essentially the same in fasting or fed subjects. Suppository administration of 5-ASA resulted in a low median urinary recovery of 10.8%.

Adult↗
PubMed2004

Drug polymorphism and dosage form design: a practical perspective.

Formulators are charged with the responsibility to formulate a product which is physically and chemically stable, manufacturable, and bioavailable. Most drugs exhibit structural polymorphism, and it is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf life under a variety of real-world storage conditions. There are occasional situations in which the development of a metastable crystalline or amorphous form is justified because a medical benefit is achieved. Such situations include those in which a faster dissolution rate or higher concentration are desired, in order to achieve rapid absorption and efficacy, or to achieve acceptable systemic exposure for a low-solubility drug. Another such situation is one in which the drug remains amorphous despite extensive efforts to crystallize it. If there is no particular medical benefit, there is less justification for accepting the risks of intentional development of a metastable crystalline or amorphous form. Whether or not there is medical benefit, the risks associated with development of a metastable form must be mitigated by laboratory work which provides assurance that (a) the largest possible form change will have no substantive effect on product quality or bioavailability, and/or (b) a change will not occur under all reasonable real-world storage conditions, and/or (c) analytical methodology and sampling procedures are in place which assure that a problem will be detected before dosage forms which have compromised quality or bioavailability can reach patients.

Administration, Oral↗
PubMed1977

Comparative bioavailability of oral dosage forms of oxazepam--correlation with in vitro dissolution rate.

Four oxazepam tablet preparations and a suspension of micronized oxazepam in water were given to healthy, fasting volunteers in a comparative bioavailability study using a partial cross-over design. Urinary recovery (0-72 hours) was used as a measure of extent of absorption. Peak serum concentration was used as a measure of rate of absorption. The three dosage forms having the highest dissolution rate in vitro were absorbed to the same extent, while slower dissolving tablets were not as fully absorbed. Peak serum concentration correlated linearly with in vitro dissolution rate. Single oral doses of oxazepam tablets containing 10, 15 and 25 mg showed equal rates and extents of absorption and produced serum concentrations linearly correlated with dose.

Administration, Oral↗
PubMed1979

Bioavailability study of gitoxin in a solid dosage form.

Although the cardiotonic activity of gitoxin is known for almost half a century, this digitalis glycoside has never been used in therapy, due to its apparent lack of resorption after administration by oral route. Recent studies have demonstrated that the bioavailability of gitoxin could be upraised to 100% provided it be given as a hydroalcoholic solution. The present paper deals with the development of a solid dosage form (tablets) using a physical association of gitoxin and sodium escinate.

Adult↗
PubMed1979

Dihydroquinidine contamination of quinidine raw materials and dosage forms: rapid estimation by high-performance liquid chromatography.

Dihydroquinidine is a commonly encountered contaminant in quinidine raw materials. The USP allows 0-20% dihydroquinidine in quinidine products, but the assays used to quantitate dihydroquinidine have been lengthy or have required sophisticated equipment. The present method separates dihydroquinidine from quinidine and provides rapid, precise quantitation of both dihydroquinidine and quinidine. The clinical importance of dihydroquinidine contamination of quinidine dosage forms remains unanswered.

Chromatography, High Pressure Liquid↗
PubMed2002

Simple spectrophotometric determination of cinnarizine in its dosage forms.

A direct, extraction-free spectrophotometric method has been developed for the determination of cinnarizine in pharmaceutical preparations. The method is based on ion-pair formation between the drug and three acidic (sulphonphthalein) dyes; namely bromocresol green (BCG), bromocresol purple (BCP) and bromophenol blue (BPB) which induces an instantaneous bathochromic shift of the maximum in the drug spectrum. Conformity to Beer's law enabled the assay of dosage forms of the drug. Compared with a reference method, the results obtained were of equal accuracy and precision. A more detailed investigation of the cinnarizine-BCG ion pair complex was made with respect to its composition, association constant and free energy change. In addition, this method was also found to be specific for the analysis of cinnarizine in the presence of some of the co-formulated drugs, such as pyridoxine hydrochloride and digoxin.

Bromcresol Green↗
PubMed2006

Novel dosage forms and regimens for sevelamer-based phosphate binders.

Sevelamer, a nonabsorbed, calcium- and metal-free dietary phosphate binder, consists of a polyallylamine polymer backbone with a cationic charge that shows a high capacity for binding anionically charged compounds such as phosphate. The currently licensed form of sevelamer, Renagel, exists as sevelamer hydrochloride, which disassociates in the acidic environment of the stomach and early gastrointestinal tract, exchanging the chloride ions attached to the polymer backbone for phosphate ions. The resulting absorption of these chloride ions has been reported to be accompanied by a reduction in serum levels of bicarbonate in some patients. To minimize the possibility of this effect, a new salt form of sevelamer has been developed in which carbonate replaces the chloride counter ion, thereby providing a source of buffer. The majority of phosphate binders exist only in tablet form and are dosed three times per day with meals. Genzyme has developed sevelamer carbonate in tablet form and also as a powder formulation that can be taken after mixing with water. This allows for an alternate and potentially more palatable way of dosing. Preliminary data exist suggesting that once daily dosing with sevelamer hydrochloride tablets provides similar phosphate control to three times daily dosing. By providing novel dosage forms and regimens for sevelamer-based phosphate binders, Genzyme will be providing patients and health care providers additional choices and flexibility in controlling phosphorus levels in chronic kidney disease. This should translate to increased compliance and improved rates of phosphate control.

Animals↗
PubMed1988

Analysis of some dosage forms containing pyridine derivatives using a cyclodextrin bonded stationary phase in HPLC.

The high performance liquid chromatography of some pyridine derivatives using a silica column to which beta-cyclodextrin has been bonded, has been investigated. In spite of the low affinity constants of the drugs for cyclodextrin (of the order of 10(2) M(-1)) good separations can be achieved using a mobile phase of methanol and pH 7.0 phosphate. Good analysis of some dosage forms are achieved, including one on a tablet containing pheniramine maleate, pyrilamine maleate and phenylpropanolamine hydrochloride. Extractions and chromatography are quick and simple.

Journal Article↗
PubMed2006

Biocompatibility of solid-dosage forms of anti-human immunodeficiency virus type 1 microbicides with the human cervicovaginal mucosa modeled ex vivo.

Topical anti-human immunodeficiency virus (HIV) microbicides are being sought to reduce the spread of HIV type 1 (HIV-1) during sexual intercourse. The success of this strategy depends upon the selection of formulations compatible with the natural vaginal mucosal barrier. This study applied ex vivo-modeled human cervicovaginal epithelium to evaluate experimental solid-dosage forms of the anti-HIV-1 microbicide cellulose acetate 1,2-benzenedicarboxylate (CAP) and over-the-counter (OTC) vaginal products for their impact on inflammatory mediators regarded as potential HIV-1-enhancing risk factors. We assessed product-induced imbalances between interleukin-1alpha (IL-1alpha) and IL-1beta and the natural IL-1 receptor antagonist (IL-1RA) and changes in levels of IL-6, tumor necrosis factor alpha, IL-8, gamma interferon inducible protein 10 (IP-10), and macrophage inflammatory protein 3alpha (MIP-3alpha), known to recruit and activate monocytes, dendritic cells, and T cells to the inflamed mucosa. CAP film and gel formulation, similarly to the hydroxyethylcellulose universal vaginal placebo gel and the OTC K-Y moisturizing gel, were nontoxic and caused no significant changes in any inflammatory biomarker. In contrast, OTC vaginal cleansing and contraceptive films containing octoxynol-9 or nonoxynol-9 (N-9) demonstrated similar levels of toxicity but distinct immunoinflammatory profiles. IL-1alpha, IL-1beta, IL-8, and IP-10 were increased after treatment with both OTC vaginal cleansing and contraceptive films; however, MIP-3alpha was significantly elevated by the N-9-based film only (P < 0.01). Although both films increased extracellular IL-1RA, the cleansing film only significantly elevated the IL-1RA/IL-1 ratio (P < 0.001). The N-9-based film decreased intracellular IL-1RA (P < 0.05), which has anti-inflammatory intracrine functions. This study identifies immunoinflammatory biomarkers that can discriminate between formulations better than toxicity assays and should be clinically validated in relevance to the risk of HIV-1 acquisition.

Administration, Intravaginal↗
PubMed1989

Effect of absorption promoters in intranasal administration of human fibroblast interferon as a powder dosage form in rabbits.

The utility of the absorption promoters, sodium glycocholate (GC-Na), ethylenediamine dihydrochloride (EDTA-2Na), sodium caprylate (Cap-Na) and sodium salicylate (Sal-Na), in the intranasal administration of human fibroblast interferon-beta (HuIFN-beta) in rabbits was investigated. The optimal amount of added EDTA-2Na, Cap-Na and Sal-Na with respect to HuIFN-beta was examined for nasal absorption in the powder dosage form. Formulations of HuIFN-beta with GC-Na showed greatly enhanced intranasal HuIFN-beta absorption, as compared to the other absorption promoters. The results of a stability study on HuIFN-beta in homogenates of nasal mucosa suggested that GC-Na behaved as a hydrolysis inhibitor in the nasal mucosa and maintained the activity of HuIFN-beta.

Absorption↗
PubMed1981

Pilot study on bioavailability of coumarin and 7-hydroxycoumarin upon peroral administration of coumarin in a sustained-release dosage form.

Prolonged-release tablets containing coumarin were compared to intravenous and peroral administration of coumarin solution in man. Unchanged coumarin, the Phase 1 metabolite 7-hydroxycoumarin, and the Phase II metabolite 7-hydroxycoumarin glucuronide were determined in whole blood. Upon peroral administration, only approximately 1 per cent coumarin was found unchanged in the systemic circulation. However, the amount of the glucuronide found indicates complete absorption with extensive first-pass effect. When the prolonged-release dosage form was compared to the peroral solution, the extent of bioavailability of coumarin was 35 per cent, whereas the 7-hydroxycoumarin glucuronide was totally available. This supports the hypothesis that coumarin might be a prodrug and 7-hydroxycoumarin the active moiety. The drug liberation of coumarin from the sustained-release tablets follows first-order kinetics. A linear correlation was found between per-cent of drug released in vitro and the area under the concentration-time curve, AUC (O-t), of total 7-hydroxycoumarin (7HC + 7HCG).

Biological Availability↗
PubMed1981

Bioavailability, efficacy, and tolerance of two sustained-release theophylline dosage forms in adult patients with bronchial asthma.

Twenty otherwise health adults with a diagnosis of reversible obstructive airways disease were treated for one month in a single-blind crossover study with approximately equivalent doses of Elixophyllin SR capsules or Theo-Dur tablets. Both products provided evidence of efficacy by improvement in pulmonary function tests, and both were well tolerated. There were no significant differences between the two products with regard to bioavailability, efficacy, or tolerance. Both dosage forms appeared to have similar kinetic properties within the context of the study.

Adolescent↗
PubMed1988

[Pharmacokinetics and laxative effect of bisacodyl following administration of various dosage forms].

Since its introduction into the market in 1952, bisacodyl has been successfully used worldwide as a laxative. In discussions on the kinetics and the laxative effect, it is often neglected that results obtained after the administration of the pure compound bisacodyl cannot be transferred to distinctive bisacodyl formulations. The aim of the present investigation is therefore to study the absorption and the plasma level profile and to correlate plasma level profile and laxative effect after the administration of various dosage forms. 12 healthy volunteers were administered with 10 mg bisacodyl as an experimental solution, with an acid resistant, commercially available Dulcolax Dragees (2 x 5 mg) and with a 10 mg Dulcolax suppository. Following glucuronidase cleavage, mean maximum plasma levels of 236.5 +/- 59.2 ng/ml of bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM) were reached after the administration of the solution 1.7 h post administration (p.a.), however, the laxative effect did not occur until 5.7 h +/- 0.7 h p.a. The dominant biological half-life of deconjugated BHPM, the diphenol of bisacodyl which circulated as BHPM-glucuronide, was about 16.5 +/- 4.2 h. The dragee yielded the desired low plasma levels which were between 7 and 47 ng/ml at 4-10 h p.a. In comparison to the solution only 16% were absorbed after the administration of the dragee. The laxative effect started 7.7 h +/- 1.7 h p.a. with no apparent relationship between effect and plasma level. The administration of the suppository resulted 20 +/- 10 min p.a. in a prompt laxative effect, although in 6 out 12 subjects, the plasma levels were below the detection limit.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Liquid chromatographic determination of methyldopa and methyldopa-thiazide combinations in dosage forms.

A liquid chromatographic (LC) method, using a reverse phase C18 column, an acetic acid-methanol-water mobile phase, and detection at 280 nm, was developed for the determination of methyldopa in tablets and oral suspensions and combinations of methyldopa with hydrochlorothiazide or chlorothiazide in tablets. A mixture of these 3 drugs was resolved in less than 8 min. Detector responses were linear for the following amounts (mg/mL) of drug injected: methyldopa 0.031-0.393, chlorothiazide 0.019-0.114, and hydrochlorothiazide 0.004-0.083. Recoveries from commercial dosage forms ranged from 99.1 to 100.9% for methyldopa, 99.2-100.4% for chlorothiazide, and 100.0-101.2% for hydrochlorothiazide. Replicate injections of methyldopa, chlorothiazide, and hydrochlorothiazide standard preparations alone or in combination gave overall relative standard deviations of less than 1.6% (n = 10). The results for methyldopa tablets by the proposed method were in agreement with those obtained by the USP XX method. The LC method detected as little as 0.6 micrograms 3-O-methylmethyldopa/mL and 0.5 micrograms 4-amino-6-chloro-1,3-benzenedisulfonamide/mL, which are sometimes found as contaminants of methyldopa and thiazides, respectively, and resolved methyldopa from its methyldopa glucose adduct, a substance found in methyldopa oral suspensions.

Chlorothiazide↗
PubMed1992

Differential pulse voltammetric determination of sumatriptan succinate (1:1) in a tablet dosage form.

A voltammetric study of the oxidation of sumatriptan succinate (1:1) has been carried out at the glassy carbon electrode. This compound exhibited a single wave in Britton-Robinson buffer solutions of pH 2-11, with a maximum current at pH 5.0. The mechanism of oxidation was shown to be due to oxidation of the N-H group in the indole ring. Based on this study, a simple, rapid and sensitive voltammetric method was developed for the determination of the drug in a tablet dosage form.

Electrochemistry↗
PubMed2006

Degradation studies of azithromycin and its spectrophotometric determination in pharmaceutical dosage forms.

A simple, accurate and rapid spectrophotometric method for the estimation of azithromycin has been developed by the acidic hydrolysis of the drug with sulfuric acid and monitoring the absorbance at 482 nm. All variables affecting the reaction conditions such as sulfuric acid concentration, heating time, temperature and dilution solvents were carefully studied. Analytical parameters such as stability, selectivity, accuracy and precision have been established for the method and evaluated statistically to assess the application of the method. The method was applied successfully for the assay of azithromycin dihydrate in pure and pharmaceutical dosage forms as tablets, capsules and suspensions. The method was found to have the advantages for simplicity, stability, sensitivity, reproducibility and accuracy for using as an alternate to the existing non-spectrophotometric methods for the routine analysis of the drug in pharmaceutical formulations and also in pharmaceutical investigations involving azithromycin dihydrate.

Anti-Bacterial Agents↗