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PubMed1993

An efficient method for computer-aided dosage form design.

It is desirable to have slow-release dosage form to be taken once daily, or at most twice daily, as compared to three or four times in a single day. However, the existing computer-aided dosage form design method requires a large amount of computer time when applied to nonlinear disposition drugs. This large commitment of computer time makes it inconvenient to study the feasibility for prolonged-release products containing such drugs. Instead of evaluating all possible combinations of the amount of dose and release rates that produce acceptable steady-state plasma concentrations, only the contour of the dose-release rate domain needs to be determined. An image boundary tracking method has been used to determine such contours. When combined with several modifications of the numerical solution process, the acceptable dose and release rate constants can be determined efficiently. When this modified boundary tracking method was applied to phenytoin, which exhibits nonlinear disposition, the required computer time was reduced to about 5% of the previous method, making the dosage form feasibility assessment practical.

Computer Simulation↗

PubMed1986

A comparison of test methods for determining in vitro drug release from transdermal delivery dosage forms.

Three test methods for determining in vitro drug release rate from transdermal delivery dosage forms were tested for equivalency of results, ease of implementation and precision. The 'paddle-over-disk' (POD) method is under consideration by the USP as a standarized method for release-rate testing of all transdermal delivery dosage forms. The 'reciprocating disk' (RD) and 'diffusion cell' (DC) methods are both commonly employed throughout the pharmaceutical industry. The three methods were demonstrated to be equivalent in terms of release rate profile (curve shape) and total drug released over the lifetime of the dosage form tested (Transderm-Scop). The precision for the RD method as measured by the mean relative standard deviation over all time points was 4.6%; the precision of the POD method was 5.4% and that for the DC method was 6.7%. Steady-state flux values derived from the POD and RD methods were equivalent ( approximately 4 microg cm(-2) h(-1)) but were approximately 25% greater than the steady-state flux value derived from the DC method ( approximately 3 microg cm(-2) h(-1)). All three methods gave results which were within the specifications of the manufacturer (CIBA-GEIGY). The POD method was the easiest to use on a routine basis, required the least amount of specialized equipment and most resembled the current test methodology for dissolution testing of other dosage forms such as tablets or capsules.

Journal Article↗

PubMed2006

Development and validation of a stability-indicating analytical method for the quantitation of oxytocin in pharmaceutical dosage forms.

A single stability-indicating assay for oxytocin (OT) in pharmaceutical dosage forms using gradient elution over 21 min has been reported in the literature. Furthermore, published and compendial methods for the analysis of OT containing dosage forms also involve using HPLC with gradient elution and complicated mobile phases that include hydrophobic ion pairing agents. A simple isocratic and stability-indicating assay was developed and validated. The conditions are as follows, column: Phenomenex C18 Hypersil, 5 microm packing, 4.6 mm x 150 mm with acetonitrile-phosphate buffer (pH 5; 0.08 M) (20:80) as the mobile phase with UV detection at 220 nm The method was found to be specific for OT in the presence of degradation products and chlorbutol (preservative) with an overall analytical run time of 16 min. Accuracy was determined to be 0.77-1.18% bias for all samples tested. Intra-assay precision (repeatability) was found to be 0.22-1.04%R.S.D. while the inter-day precision (intermediate precision) was found to be 1.27-1.68%R.S.D. for the samples studied. The calibration curve was found to be linear with the equation y = 1.81x + 0.02 and a linear regression coefficient of 0.9991 over the range 0.4-12.0 IU/ml. The LOD and the LOQ were determined to be 0.1 and 0.4 IU/ml, respectively. Syntocinon, a commercially available dosage form of OT was assayed resulting in 100.5-106.6% recovery of the label claim and an average of 10.04 IU/ml.

Buffers↗

PubMed1998

Bioavailability of intranasal promethazine dosage forms in dogs.

Intramuscular promethazine (PMZ) is used aboard the US Space Shuttle to ameliorate symptoms of space motion sickness. Bioavailability after an oral dose of PMZ during space flight is thought to be impaired because of gastrointestinal disturbances associated with weightlessness and space motion sickness. In an attempt to find an alternative dosage form for use in space, we evaluated two intranasal (i.n.) dosage forms of PMZ in dogs for absorption and bioavailability relative to that of an equivalent intramuscular dose. Promethazine (5 mg kg-1) was administered as two intranasal dosage forms and as an intramuscular (i.m.) dose to three dogs in a randomised cross-over design. Serial blood samples were taken and analysed for PMZ concentrations and the absorption and bioavailability of PMZ were calculated for the three dosage forms. PMZ absorption from the carboxymethyl cellulose microsphere i.n. dosage form was more rapid and complete than from the myverol cubic gel formulation or from an i.m. injection. Bioavailability of the microsphere formulation was also greater than that of the gel formulation (AUC 3009 vs 1727 ng h ml-1). The bioavailability of the two i.n. dosage forms (relative to that of the i.m. injection) were 94% (microsphere) and 54% (gel). The i.n. microsphere formulation of PMZ offers great promise as an effective non-invasive alternative for treating space motion sickness due to its rapid absorption and bioavailability equivalent to the i.m. dose.

Administration, Intranasal↗

PubMed1999

Evaluation of peroral silicone dosage forms in humans by gamma-scintigraphy.

Gastric emptying of oral silicone dosage forms was studied in humans by gamma-scintigraphy. To achieve a constant and predictable residence time in the stomach, three different formulations based on known concepts such as controlled swelling were investigated. The importance of physical parameters such as size or shape were also examined to assess the feasibility of designing a dosage form for gastric retention. Three shapes: minimatrices, extruded rods and moulded slabs were screened. To label the silicone polymer, two isotopes, used routinely in nuclear medicine departments, were selected: iodine-123 and indium-111. To select the most suitable isotope, the yield and the stability of the labelling were determined in vitro on the pharmaceutical dosage forms. The residence time of these silicone formulations, labelled with iodine and administered in hard gelatine capsules, was monitored in 12 subjects with a gamma camera. The study was performed under fed conditions after ingestion of a standardised meal labelled with indium. The minimatrices provided at least 3 h retention, slabs exhibited 4 h 40 min retention. For the rods the mean residence time in the stomach was around 4 h 20 min. In addition, a correlation was established between the gastric emptying of rods and the half-gastric residence time of meal. On the contrary, such a correlation was not observed for the slabs.

Administration, Oral↗

PubMed2000

Studies of floating dosage forms of furosemide: in vitro and in vivo evaluations of bilayer tablet formulations.

For the purpose of enhancement the bioavailability of furosemide (FR), a floating dosage form with controlled release of FR was designed in this study. Because of the lower solubility of active material in the gastric medium, it was first enhanced by preparing an inclusion complex of FR with beta-cyclodextrin (beta-CD) in a 1:1 proportion using the kneading method. Following the design of dosage form, bilayer floating tablets were prepared. After dissolution rate studies were performed using the continuous flow-through cell method, the formulation that provided delivery of active material near the target profile was given to six healthy male volunteer subjects, and in vivo tests were performed. It was determined by radiographs that floating tablets prepared by adding BaSO4 stayed in the stomach for 6 hr. Further, values of the area under the plasma concentration-time curve (AUC) obtained with the floating dosage form were about 1.8 times those of the conventional FR tablet in blood analyses; maximum and minimum plasma concentrations were also found to be between the desired limits. In urine analyses, the peak diuretic effect seen in classical preparations was decreased and prolonged in floating dosage forms. Also, a considerably significant correlation was detected between in vivo results and in vitro data of the dissolution rate, and it was concluded that the modified continuous flow-through cell method is usable for in vitro dissolution rate tests of floating dosage forms.

Biological Availability↗

PubMed1978

Separation and identification of impurities in parenteral methotrexate dosage forms.

Eleven lots of parenteral methotrexate (MTX) dosage forms from two manufactures have been analyzed and found to be 93.4% +/- 2.1% (SD) pure by a new procedure employing a DEAE-cellulose column adapted for high performance liquid chromatography instrumentation. In addition to 4-amino-10-methylpteroic acid and N10-methylpteroylglutamic acid, which were previously identified contaminants, and benzyl alcohol, which was added as a preservative, we have also isolated and identified 2,4-diamino-6-methylpteridine, 2,4-diamino-6-bromomethylpteridine, and p-methylaminobenzoic acid. Another impurity has tentatively been identified as 4-amino-10-methylpteroic acid amide. The individual impurities vary from 0.1% to 4.8% of the ultraviolet absorbing material which elutes from the column. Additional impurities were detected by gas chromatography-mass spectrometry. Since "high-dose" therapy may involve the administration of up to 20 g of MTX/day, the effect of the impurities present in these dosage forms on the course of the patient's therapy should be determined.

Chromatography, High Pressure Liquid↗

PubMed1992

Development of a colonic release capsule dosage form and the absorption of insulin.

Since the colon is relatively low in peptidase activity and drainage into the lymphatics is maximized, a peroral dosage form was developed to deliver insulin to the colon. Microemulsions, used as a vehicle for insulin, were gelled using Cab-O-Sil, and filled into gelatin capsules pretreated with formaldehyde vapor. The capsules were coated with Eudragit NE 30 D, Eudragit S100 and cellulose acetate phthalate polymers of pH-dependent and time-controlled release mechanisms. In vitro dissolution profiles of the capsule coating, using sodium salicylate as the marker, show that dissolution of the capsule begins at 4 h, at pH 5.5, and is completed at 8 h, at pH 7.7, simulating the gastrointestinal transit and pH profile of the dog. An in vivo crossover study in beagle dogs was carried out employing the following treatments: i.v. insulin, p.o. insulin microemulsion and colonic release capsule dosage form without insulin (CRC), were used as controls, a colonic release capsule dosage form with insulin (CRI) and additionally with sodium laurylsulfate (CRIL) or aprotinin (CRIA) as sorption promoter and enzyme inhibitor, respectively. Evaluation was done by measuring the reduction in blood glucose concentration levels. The pharmacological availability (P.A.) is the ratio of the area under the baseline curve (AUC), expressed as percent glucose reduction from baseline vs time, of the p.o. dosage forms to i.v. insulin administration, corrected for body weight and dose size. The P.A. for the p.o. microemulsion, CRC, CRI, CRIL and CRIA were 2.1, 0.4, 5.0, 2.7 and 6.2%, respectively. Insulin release occurred throughout the GI tract, with the exception of the stomach. Tmax occurred at 6.4 h for CRIA; the majority of insulin is taken up after the colonic arrival time is reached in the dog (4-6 h). Duration of the reduction in blood glucose levels occurred for 14 h with the CRIA dosage form.

Animals↗

PubMed1989

[The relative bioavailability of paracetamol following administration of solid and liquid oral preparations and rectal dosage forms].

Determination of the Relative Bioavailability of Paracetamol Following Administration of Solid and Liquid Oral Preparations and Rectal Dosage Forms. The relative bioavailability of paracetamol from two solid and two liquid oral preparations and two rectal dosage forms, each containing 500 mg of the active ingredient, was investigated in 12 healthy male individuals. The plasma concentration-time curves of paracetamol following administration of the oral formulations were very similar; consequently there were only minor differences of the AUC0-12h (21.4, 21.9; 23.0, 22.8 micrograms.h/ml), cmax (8.8, 9.1; 10.0, 10.7 micrograms/ml), tmax (35, 25; 20, 19 min), and the terminal plasma elimination half-life t1/2 beta (2.95, 2.85; 2.86, 2.99 h) for the solid and the liquid test and reference preparations, respectively. The suppositories (test and reference formulation) differed from the oral dosage forms, but were comparable to each other with respect to AUC0-12h (18.2, 18.8 micrograms.h/ml), cmax (3.3, 3.5 micrograms/ml), tmax (1.6, 2.45 h), and t1/2 beta (3.55, 3.54 h). In all test preparations the 95% confidence limits for AUC0-12h completely were enclosed in the range of 80-120% relative bioavailability (independently of whether parametric or non-parametric statistical methods were applied); the limits for the oral formulations were quite narrow, thus indicating a highly consistent release of the active compound from the tablets as well as from the liquid dosage form. A comparison of the mean values of cmax by analysis of variance at the 80% probability level did not reveal any significant differences between the test and the corresponding reference formulations; based on non-parametric statistical methods, the 95% confidence limits for cmax were enclosed in the range of 70-130%.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

PubMed2005

IV-IVC considerations in the development of immediate-release oral dosage form.

Predictive scientific principles and methods to assess in vivo performance of pharmaceutical dosage forms based on in vitro studies are important in order to minimize costly animal and human experiments during drug development. Because of issues related to poor solubility and low permeability of newer drug candidates, there has in recent years been a special focus on in vitro-in vivo correlation (IV-IVC) of drug products, particularly those used orally. Various physicochemical, biopharmaceutical, and physiological factors that need to be considered in successful IV-IVC of immediate-release oral dosage forms are reviewed in this article. The physicochemical factors include drug solubility in water and physiologically relevant aqueous media, pK(a) and drug ionization characteristics, salt formation, drug diffusion-layer pH, particle size, polymorphism of drug substance, and so forth. The biopharmaceutical factors that need to be considered include effects of drug ionization, partition coefficient, polar surface area, etc., on drug permeability, and some of the physiological factors are gastrointestinal (GI) content, GI pH, GI transit time, etc. Various in silico, in vitro, and in vivo methods of estimating drug permeability and absorption are discussed. Additionally, how IV-IVC may be applied to immediate-release oral dosage form design are presented.

Animals↗

PubMed2001

Influence of drug release properties of conventional solid dosage forms on the systemic exposure of highly soluble drugs.

This study was designed to theoretically investigate the influence of drug release properties, characterized by the disintegration of a solid dosage form and dissolution of drug particles, on the systemic exposure of highly soluble drugs in immediate release products. An absorption model was developed by considering disintegration of a solid dosage form, dissolution of drug particles, gastrointestinal transit flow, and intestinal absorption processes. The absorption model was linked to a conventional pharmacokinetic model to evaluate the effect of disintegration and dissolution on the peak exposure (Cmax) and total exposure of area under the curve (AUC). Numerical methods were used to solve the model equations. The simulations show that the effect of disintegration of a dosage form and dissolution of drug particles depend on the permeability of a drug, with a low-permeability drug having a greater effect. To provide similar exposure to an oral solution formulation, a solid dosage form containing a low-permeability drug would need to dissolve more rapidly than a solid dosage form containing a high-permeability drug. It was shown theoretically for poorly permeable drugs that the disintegration rate constant has to be greater than 9 hour(-1)(equivalent to approximately 90% in 30 minutes) to make both AUC and Cmax ratios higher than.9, ensuring the confidence interval of.80 to 1.25. The rapid in vitro release requirement of at least 85% dissolved in 30 minutes is sufficient for highly soluble and highly permeable drugs. However, for highly soluble and poorly permeable drugs, the appropriate in vitro release requirement seems to be 90% dissolved in 30 minutes.

Algorithms↗

PubMed1999

Determination of the nutraceutical, glucosamine hydrochloride, in raw materials, dosage forms and plasma using pre-column derivatization with ultraviolet HPLC.

A selective and specific high performance liquid chromatography method was developed to quantitate glucosamine hydrochloride in raw materials, dosage forms and plasma. Reverse phase chromatography using pre-column derivatization with phenylisothiocyanate, and ultraviolet detection (lambda = 254 nm) was used to quantify the eluate. The mobile phase consisted of MeOH/H2O/CH3COOH (10:89.6:0.04) and was pumped at a flow rate of 1.2 ml/min. The standard curves for glucosamine hydrochloride showed linearity (r > or = 0.99) over the selected concentration range from 6.65 to 16.63 microg/ml for raw materials and dosage forms. The precision of the dosage form assay, expressed as the % relative standard deviation (R.S.D.), was < 5% at all concentrations. The intra-day and inter-day accuracy, as indicated by the relative error (R.E.), ranged from - 2.54 to 2.70% for glucosamine hydrochloride. For the plasma assay, beagle dog plasma was used to prepare standard curves in the concentration range of 1.25-20 microg/ml. Precipitation of plasma proteins was accomplished with acetonitrile to separate interfering endogenous products from the compound of interest. The supernatant was derivatized using phenylisocyanate in phosphate buffer (pH = 8.3) and subsequently evaporated to dryness under a nitrogen stream at 42 degrees C. The residue was dissolved in 250 microl mobile phase and injected onto the chromatographic system. The assay was linear in concentration ranges of 1.25-20 microg/ml (r > or = 0.999). Intra- and inter-day precision was < or = 5.23 and 5.65%, respectively and the intra- and inter-day accuracy, indicated by R.E., ranged from - 8.6 to 10.35%. The method was found to be specific and with excellent linearity, accuracy and precision and is well suited for the quantitation of glucosamine hydrochloride in raw materials, dosage forms, and pharmacokinetic studies.

Acetonitriles↗

PubMed2003

Evaluation of electronic databases used to identify solid oral dosage forms.

The ability of electronic drug identification databases to identify solid oral dosage forms by their imprint codes was studied. The following seven commercially available electronic drug identification databases were selected to identify 500 solid oral dosage forms by their imprint codes: Clinical Pharmacology (Gold Standard Media, Tampa, FL), eFacts (Facts and Comparison, St. Louis, MO), Ident-A-Drug (Therapeutic Research, Stockton, CA), Identidex (Micromedex, Greenwood Village, CO), Clinical Reference Library (Lexi-Comp, Hudson, OH), Physicians' Desk Reference (PDR) Electronic Library (Medical Economics, Montvale, NJ), and RxList (RxList LLC, San Francisco, CA), Chi-square test was used to compare the percentages of medications identified by each of the seven electronic references. The ability of the databases to identify medication by specific characteristics, such as brand name versus generic, prescription versus nonprescription, commercially available for more than one year versus less than one year, colored versus white drug products, and controlled versus noncontrolled substances was evaluated. A logistic regression model was used to determine the probability of a drug product being identified by one of the electronic references based on these characteristics. All seven electronic databases combined identified 95.6% of the unknown medications by imprint code, color, shape, and scoring. Ident-A-Drug and Identidex identified the most drugs. The PDR Electronic Library and Facts and Comparisons Identified the least number of drugs. Solid oral dosage forms more likely to be identified were those that were on the market for more than a year, brand-name products, and prescription medications. Generic products on the market for less than a year and nonprescription products were particularly difficult to identify. A combination of electronic drug identification databases provides the best method of drug identification in an institutional setting.

Capsules↗

PubMed1987

Testing of controlled-release transdermal dosage forms. Product development and clinical trials.

In vitro techniques have been developed that are predictive of drug permeation through skin. Methods also have been developed to determine the skin irritation potential of a drug substance during the preclinical stages of transdermal dosage form development. Clinical studies are performed to test for skin irritation, contact sensitization, plasma levels of drug, and efficacy of the dosage form. In theory, these studies should be predictive of a dosage form's performance in routine clinical use. This may not be the case, however; contact sensitization cannot be predicted with absolute certainty beforehand in animals. This article discusses various aspects of testing transdermal dosage forms and how the results of these tests correlate with what happens when a transdermal dosage form is put into routine clinical use.

Administration, Cutaneous↗

PubMed1978

Plasma levels of clobazam after three oral dosage forms in health subjects.

As can be seen from the tables, the terminal half-life of clobazam is about 50 hours, and from a solid dosage form the peak plasma level occurs approximately 1.5 hours after ingestion. Thus, there is a significant, yet relatively short, dosage form delay effect when the solid dosage forms are compared to the rapidly available solution of the drug. However, based on the areas under the curve, comparison of the solid dosage forms with the solution indicates that the fraction of clobazam absorbed is 1. Pupil diameter measurement at 2, 4, and 6 hours after ingestion of clobazam correlated well with the plasma levels at these times. Pupils were constricted to the highest degree at 2 hours and approached the initial pupillary diameter at the 6-hour measurement.

Administration, Oral↗

PubMed1990

Protein denaturation in dosage forms measured by differential scanning calorimetry.

The stability of beta-galactosidase dosage forms was studied by differential scanning calorimetry (DSC). It was found that the observed enthalpy of thermal denaturation was approximately in proportion to remaining enzyme activity, and denaturation temperature was related to protein stability. These results suggest that DSC can be used to determine native proteins in dosage forms and to clarify the factors affecting protein stability. The DSC method seems to be more convenient than conventional activity assay methods, and useful to follow protein denaturation during the manufacturing process and storage of dosage forms.

Calorimetry, Differential Scanning↗

PubMed1991

Nasal distribution of radioactive drug administered using two dosage forms.

The deposition patterns of 99mtechnetium labelled disodium cromoglycate particles administered either from a metered dose aerosol with a conventional nasal adaptor or from a dry powder nasal inhaler were studied using gamma camera. Disodium cromoglycate particles were firstly labelled with 99mTc using the spray drying technique. Both the metered dose aerosol and the dry powder dosage form were formulated using these radioactive drug particles. Seven healthy volunteers inhaled either three aerosol doses or one dry powder dose unit into one nostril. The drug dose reaching nasal cavity after administration from these two dosage forms was about the same. The deposition patterns as well as the changes in distribution due to the mucociliary transport were monitored by a gamma camera equipped with a low energy all purpose collimator. Initially drug doses deposited in a wider area of the nasal cavity when disodium cromoglycate particles were administered as a dry powder dosage form. In addition, retention index (%) which illustrates the movements of drug particles by mucociliary transport from the initial area of application seemed to be slightly higher for a metered dose aerosol than for a dry powder dosage form. At the end of the 30 minutes measuring period the area of the mucosal layer covered by radioactive drug particles was clearly wider for the dry powder dosage form than for the metered dose aerosol. Thus it is well possible to administer drug particles effectively into the nasal cavity as a dry powder dosage form.

Administration, Inhalation↗

PubMedDate not supplied

The influence of dosage form on papaverine bioavailability.

The bioavailability of sustained-release papaverine HCl dosage forms were compared to equivalent doses of the drug administered as an elixir and conventional compressed tablets to 12 healthy human subjects. Papaverine plasma levels were determined using a gas-chromatographic procedure. The drug was absorbed more rapidly and completely from the two nonsustained-release formulations. There was a large intersubject variability, and the plasma half-life of the drug was esstimated to be 1 hour. The area under the plasma level-time curve for the nine sustained-release products ranged from 18 to 64% relative to the area achieved by the papaverine elixir. It was concluded that the sustained-release dosage forms of papaverine included in each study group could be considered bioequivalent, but they exhibited inadequate bioavailability relative to either the elixir or the compressed tablet dosage form.

Administration, Oral↗