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PubMedDate not supplied

Softgels: consumer perceptions and market impact relative to other oral dosage forms.

Softgels, which contain a liquid formulation of a drug, often provide clinical benefit over other solid oral dosage forms and may represent an attractive alternative to them. A consumer preference survey of softgels versus other solid forms investigated four areas: (1) identification of various dosage forms; (2) perception of therapeutic benefit (easiest to swallow, faster-acting, work longer); (3) impact of individual product characteristics on overall product selection; and (4) market impact in terms of premiums consumers would pay on the basis of dosage form. The 300 survey participants strongly preferred clear softgels over other dosage forms in virtually every area. Softgels were perceived as easy to swallow and fast-acting, with a duration of action second only to that of a two-piece capsule. Overall preference was driven by ease of swallowing, and softgels were rated first by the majority of respondents. Consumers would be interested in various products if these were available as softgels rather than in their current oral dosage forms and may be willing to pay a premium for softgel products. This survey confirms consumer preferences for particular dosage forms and for softgels over other solid forms. Pharmaceutical scientists and marketers should consider softgels as alternative dosage forms when developing new compounds or considering life-cycle management of existing products.

Administration, Oral↗

PubMed2003

Evaluation of critical formulation factors in the development of a rapidly dispersing captopril oral dosage form.

New methods of manufacture have enabled the creation of novel dosage forms with unique rapid-dispersion properties. This study combines one such technique with a statistical experimental design to develop dosage forms from captopril, an angiotensin-converting enzyme inhibitor used to treat cases of hypertensive emergency. The TheriForm process, a novel microfabrication technique, was used to build the dosage forms in a layer-by-layer fashion. Three key formulation factors were chosen for the design of experiments. A modified central composite design (Box-Behnken design) was used to maximize the efficiency of the experiments. A total of 13 distinct formulations were fabricated and tested, using mannitol as the bulk excipient. In addition, three replicates of the center point were tested to assess variability and experimental error. These formulations were tested for speed of dispersion (flash time), active content, hardness, friability, and moisture absorption. Regression analysis was performed to fit data responses to quadratic equations. Excellent dose accuracy (95% to 102% of target) and content uniformity (between 1.03% to 2.84%) were observed from all experimental formulation batches. As expected, the choice of powder additive (maltitol, maltodextrin, polyvinyl pyrrolidone), level of additive (2.5% to 7.5%), and saturation level of the binder liquid (45% to 65%) were all found to be significant factors for the TheriForm process. The regression analysis suggested that a rapidly dispersing dosage form of optimal physical properties would be obtained when a powder mixture of mannitol (97.5%) and maltitol (2.5%) is used at a saturation level of 45%. In conclusion, rapidly dispersing captopril oral dosage forms were successfully fabricated and tested. A wide range of physical properties, flash time, and hardness, were determined experimentally, and the effects of key formulation factors were identified.

Administration, Oral↗

PubMed1976

Development of an aerosol dosage form containing insulin.

An aerosol dosage form containing insulin was developed by suspending insulin zinc crystals in fluorocarbon propellant and using oleyl alcohol to improve the insulin suspension and to prevent valve clogging. A metered valve was used to control the amount of insulin delivered per actuation. The dose dispensed, sedimentation rate, and particle-size distribution of the aerosol formulation were evaluated. The potency of the insulin delivered from the aerosol containers stored at various temperatures and time intervals was determined using a radioimmunoassay. Based upon preliminary stability data, which were treated kinetically, it was noted that insulin aerosols stored in a refrigerator at 7 degrees would have a predicted shelflife of approximately 19 years, whereas samples stored at 25 and 37 degrees would have shelflives of 11 and 2 months, respectively. Long-term stability studies are indicated to establish this conclusion. On the basis of this study, it was concluded that an insulin-containing aerosol dosage form can be formulated and that a suitable dose of insulin can be dispensed using commercially available metered dose valves. The actual dose of insulin dispensed would have to be related to the degree of absorption of insulin one would normally expect when insulin is administered by the inhalation route.

Aerosols↗

PubMed2006

Formulation and evaluation of mucoadhesive dosage form containing rosiglitazone maleate.

Extending the residence time of a dosage form at a particular site and controlling the release of drug from the dosage form are useful especially for achieving controlled plasma level of the drug as well as improving bioavailability. The objective of this study was to extend the GI residence time of the dosage form and control the release of rosiglitazone using mucoadhesive tablet to achieve controlled plasma level of the drug which is especially useful after 8 to 12 weeks of monotherapy using conventional dosage forms when dose is doubled and plasma level also doubles. Direct compression method using simplex lattice design, followed by optimization of the evaluation parameters was employed to get final optimized formulation. The optimized formulation showed a mucoadhesive strength >40 gm-f, and a mucoadhesion time >12 hours with release profile closer to the target release profile and followed Non-Fickian diffusion mediated release of rosiglitazone maleate.

Adhesives↗

PubMed2002

Gastrointestinal safety of an extended-release, nondeformable, oral dosage form (OROS: a retrospective study.

BACKGROUND: The OROS osmotic (OSM) dosage form optimises extended-release oral administration by controlling the rate of drug release for a predetermined time, providing constant, patterned, or pulsed delivery profiles. OSM products include prescription medications for urology, CNS, and cardiovascular indications, as well as over-the-counter nasal/sinus congestion medications. METHODS: This retrospective study examines US gastrointestinal (GI) safety data for the OROS dosage form following nearly two decades of use. Although GI injury and obstruction are known effects of oral medications, some reports have suggested that extended-release products pose a greater risk of GI injury and obstruction than other oral dosage forms. Products incorporating OROS technology are being prescribed to an expanding range of patients; a review of the GI safety data for this dosage form thus seemed timely and appropriate. US safety information was obtained from three sources: English language literature published from 1982 until June 1, 2000 from five major biomedical databases;postmarketing safety reports from January 1, 1983 until June 1, 2000 available through the Freedom of Information Act; andcommercial safety information obtained directly from ALZA Corporation's in-house safety database for those OSM products for which ALZA has reporting responsibility. US distribution data from IMS National Prescription Audit trade mark Plus data were used to estimate cumulative product distribution totals. These totals were combined with numbers of unique GI events to determine the estimated frequency of events. RESULTS: Nearly 13 billion OSM tablets are estimated to have been distributed in the US. The incidence of all clinically significant GI adverse events for OSM products (including intestinal, gastric, and oesophageal irritation, injury, and obstruction) reported in the US was approximately one case in >76 million tablets distributed. The majority (78%; estimated incidence: one case in 29 million tablets) of cases were reported in patients taking Procardia XL (nifedipine). Oesophageal and lower GI obstruction were reported primarily in patients with pre-existing abnormalities or disease of the GI tract. Among paediatric patients, one obstruction was reported in an estimated 37.7 million tablets distributed. Reports of GI irritation associated with OSM products were consistent with known effects of the same drug substances in other dosage forms. CONCLUSION: A review of long-term safety experience with products using OSM controlled-release technology yields a low incidence of clinically significant GI events. Properly prescribed, extended-release products provide substantial therapeutic and convenience benefits without additional risk.

Administration, Oral↗

PubMed2006

Stability considerations in liquid dosage forms extemporaneously prepared from commercially available products.

The pharmacist, both in community and hospital pharmacy practice, is often challenged with the preparation of a liquid dosage form not available commercially for paediatric patients, those adults unable to swallow tablets or capsules and patients who must receive medications via nasogastric or gastrostomy tubes. Recognising the lack of information available to healthcare professionals, a general discussion of the various parameters that may be modified in preparing these dosage forms and a tabulated summary of the dosage forms presented in the literature is described, which, although not exhaustive, will provide information on the formulation and stability of the most commonly prepared extemporaneous liquid dosage forms. An extensive survey of the literature and investigation of 83 liquid dosage forms revealed that stability considerations were of concern for only 7.2% of these liquid dosage forms, extemporaneously prepared from the following commercially available products: captopril, hydralazine hydrochloride, isoniazid, levothyroxine sodium, phenoxybenzamine hydrochloride and tetracycline hydrochloride. Inclusion of the antioxidant, sodium ascorbate in the liquid dosage form for captopril resulted in improved stability at 4 degrees C. Hydralazine hydrochloride, isoniazid and phenoxybenzamine hydrochloride were adversely affected due to interactions with excipients in the formulation, while the effect of the preservative in lowering the pH in a levothyroxine sodium mixture resulted in decreased stability. Interestingly, the instability in these formulations is primarily due to interactions between the drug substance and the excipients rather than degradation of the active pharmaceutical ingredient by standard routes such as oxidation, hydrolysis, photolysis or thermolysis. This low percentage however illustrates the low risk associated with these dosage forms investigated. It may be concluded that when considering the safety and efficacy of liquid dosage forms prepared extemporaneously, it is thus important to consider not only the stability of the drug substance but the entire formulation.

Dosage Forms↗

PubMed2004

Validated spectrophotometric methods for the determination of amiodarone hydrochloride in commercial dosage forms using p-chloranilic acid and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Two simple, sensitive and economical spectrophotometric methods have been developed for the determination of amiodarone hydrochloride in pure form and commercial dosage form. These methods (A and B) are based on the reaction of amiodarone base as n-electron donor with p-chloranilic acid and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as pi-acceptors to give highly colored complex species which absorb maximally at 535 and 570 nm, respectively. Beer's law is obeyed in the concentration ranges 10.0 - 360.0 and 2.0 - 65.0 microg ml(-1) for methods A and B, respectively. Application of the proposed methods to commercial pharmaceutical tablets are presented.

Amiodarone↗

PubMed2002

Determination of some histamine H1-receptor antagonists in dosage forms.

Three simple and accurate methods are presented for determination of Cetirizine, Fexofenadine, Loratadine and Acrivastine in pure form and commercial dosage forms. The first method is based on the reaction of the above cited drugs with bromocresol purple dye to form ion-pair complex extractable with chloroform and subsequently measured spectrophotometrically. Secondly, eosin gives with these drugs ion-pair complex, measurable directly without extraction both spectrophotometrically and spectrofluorimetrically. The last method involves the base-catalysed condensation of mixed anhydrides of organic acids (citric acid/acetic anhydride) where as the tertiary amino group in the above-cited drugs acts as the basic catalyst. The product of condensation is measured spectrophotometrically. All the reaction conditions for the proposed methods have been studied.

Acetic Anhydrides↗

PubMed2004

Development and validation of an assay for citric acid/citrate and phosphate in pharmaceutical dosage forms using ion chromatography with suppressed conductivity detection.

The paper describes the development and validation of a simple, rapid, accurate, and sensitive ion chromatographic procedure to assay total citrate (citric acid/citrate) and phosphate in nine dosage forms. The dosage forms chosen represent all dosage forms in USP27-NF22 for which the respective monographs require an assay for either citric acid/citrate or citric acid/citrate and phosphate. Citrate and phosphate were separated in <10min by a hydroxide-selective column using anion-exchange chromatography with a 20mM potassium hydroxide eluent and detected by suppressed conductivity. The method showed linear responses over the concentration ranges 0.2-100microg ml(-1) (r(2) > 0.9990) for citrate and 0.2-60microg ml(-1) (r(2) = 0.9999) for phosphate, with limits of quantitation (signal-to-noise (S/N) = 10) of 0.2microg ml(-1) for both analytes. The accuracy of the procedure, determined by spiked recovery measurements, was within 95-105%. The intraday and the interday precision were demonstrated by the relative standard deviations (R.S.D.) of <1 and <2%, respectively, for both analytes. The ruggedness was determined by a full factorial design using analyst, equipment, column lot, and eluent preparation procedure as variables. The results show an overall R.S.D. of <3% and that an electrolytically generated 20mM KOH eluent produces assay results equivalent to a manually prepared 20mM NaOH eluent.

Chromatography, Ion Exchange↗

PubMed1998

[Pellet technology. Sustained-release pellets in hard gelatin capsules--a suitable dosage form for theophylline].

Reproducible gastrointestinal transit times of multiple unit dosage forms result in increasing efficacy and safety of pellets compared to single unit dosage forms. Furthermore, predictable concentration/time profiles can be achieved and local mucosa irritations can be avoided. These pharmacokinetic and clinical advantages compensate the increased investment necessary for development and production of theophylline (CAS 58-55-9) sustained release dosage forms. Several process steps are necessary to obtain the finished dosage form. After manufacturing, the pellet cores are coated and encapsulated in hard gelatine capsules. Manufacturing based on pelletization in an intensive mixer followed by drying of the pellet cores in a fluid-bed dryer and filmcoating according to the direct current principle in a Kugelcoater has become an established manufacturing technology both economically and ecologically.

Animals↗

PubMed2005

Immediate drug release from solid oral dosage forms.

Fast drug release from solid dosage forms requires a very fast contact of the vast majority of the drug particles with the solvent; this, however, is particularly delayed in tablets and granulations. Starch and cellulose substances favor the matrix disintegration during the starting phase and the generation of the effective dissolution surface of the drug substance, thereby. To investigate the very complex interrelation between the functionality of commonly used excipients and the structural effects of the production processes, wettability, porosity, water uptake, and drug release rates of several ketoprofen-excipient preparations (powder blends, granulations, tablets) were measured. Significant linear correlation between these parameters, however, was not achieved; only qualitative tendencies of the effects could be detected. In consequence, a general mathematical model describing the mechanistic steps of drug dissolution from solid dosage forms in a fully correct way was not realized. However, the time-dependent change of the effective dissolution surface follows stochastic models: a new dissolution equation is based on the differential Noyes-Whitney equation combined with a distribution function, e.g. the lognormal distribution, and numerically solved with the software system EASY-FIT by fitting to the observations. This new model coincides with the data to a considerably higher degree of accuracy than the Weibull function alone, particularly during the starting, matrix disintegration, and end phases. In combination with a procedure continuously quantifying the dissolved drug, this mathematical model is suitable for the characterization and optimization of immediate drug release by the choice and modification of excipients and unit operations. The interdependence of some characteristic effects of excipients and production methods is discussed.

Algorithms↗

PubMed1986

Transit of pharmaceutical dosage forms through the small intestine.

The gastrointestinal transit of pharmaceutical dosage forms has been measured in 201 studies in normal subjects using gamma scintigraphy. Solutions, small pellets, and single units (matrix tablets and osmotic pumps) were administered with different amounts of food in the stomach, ranging from fasted state to heavy breakfast. Gastric emptying was affected by the nature of the dosage form and the presence of food in the stomach. Solutions and pellets were emptied even when the stomach was in the digestive mode, while single units were retained for long periods of time, depending on the size of the meal. In contrast, measured intestinal transit times were independent of the dosage form and fed state. The small intestinal transit time of about three hours (mean +/- 1 h SEM) has implications for the design of dosage forms for the sustained release of drugs in specific positions in the gastrointestinal tract.

Adult↗

PubMed2000

Pharmacokinetics of a sustained-release dosage form of clomipramine.

In this study, the pharmacokinetic parameters of the sustained-release (SR) dosage form of clomipramine (CMI) were compared with those obtained after the administration of the immediate-release (IR) dosage form. Two studies were performed. In the first study, a single oral dose of both products was administered in 12 healthy volunteers, and in the second study, multiple doses of both products were administered in 6 patients with depression in which steady-state plasma levels (Css) were determined. Plasma levels were assayed using an HPLC method. In the single-dose study, the mean Cmax and AUC values of CMI were 63.37 ng/mL-1 and 1375.38 ng.h/mL-1 for the reference product and 32.55 ng/mL-1 and 1285.26 ng.h/mL-1 for the test product, respectively. The mean beta and MRT values of CMI were 0.030 h-1 and 47.21 h for the reference product and 0.026 h-1 and 55.63 h for test product, respectively. Results showed that after the multiple-dose study, the mean clomipramine plus demethylclomipramine values of Cavss were 406.2 ng/mL-1 for the reference and 328.6 ng/mL-1 for the sustained-release dosage form. This product also presented less fluctuation in steady-state plasma levels (1.08 vs. 1.23). The values of MRT and tmax were higher for the SR dosage form, showing that the drug was maintained longer in the body. The mean values for the ratio metabolite/drug were 2.06 and 2.41 for the IR and SR dosage forms, respectively. Neither AUC nor elimination half-life was affected significantly after the administration of the sustained-release dosage form.

Adult↗

PubMedDate not supplied

[Research and development of oral controlled-release dosage forms].

Important data concerning the gastrointestinal transit of oral solid dosage forms have been obtained recently by using the technique of gamma scintigraphy. It is now possible to put forward the principal limitations of the oral sustained release dosage forms actually available. The research and development of new controlled release products such as buoyant dosage forms and coevaporates with polymers should permit to decrease the large inter and intrasubject variations of drug plasma levels observed when the actual sustained release dosage forms are administered.

Administration, Oral↗

PubMed1997

Simultaneous in vivo visualization and localization of solid oral dosage forms in the rat gastrointestinal tract by magnetic resonance imaging (MRI).

PURPOSE: Bioavailability of orally administered drugs is much influenced by the behavior, performance and fate of the dosage form within the gastrointestinal (GI) tract. Therefore, MRI in vivo methods that allow for the simultaneous visualization of solid oral dosage forms and anatomical structures of the GI tract have been investigated. METHODS: Oral contrast agents containing Gd-DTPA were used to depict the lumen of the digestive organs. Solid oral dosage forms were visualized in a rat model by a 1H-MRI double contrast technique (magnetite-labelled microtablets) and a combination of 1H- and 19F-MRI (fluorine-labelled minicapsules). RESULTS: Simultaneous visualization of solid oral dosage forms and the GI environment in the rat was possible using MRI. Microtablets could reproducibly be monitored in the rat stomach and in the intestines using a 1H-MRI double contrast technique. Fluorine-labelled minicapsules were detectable in the rat stomach by a combination of 1H- and 19F-MRI in vivo. CONCLUSIONS: The in vivo 1H-MRI double contrast technique described allows solid oral dosage forms in the rat GI tract to be depicted. Solid dosage forms can easily be labelled by incorporating trace amounts of non-toxic iron oxide (magnetite) particles. 1H-MRI is a promising tool for observing such pharmaceutical dosage forms in humans. Combined 1H- and 19F-MRI offer a means of unambiguously localizing solid oral dosage forms in more distal parts of the GI tract. Studies correlating MRI examinations with drug plasma levels could provide valuable information for the development of pharmaceutical dosage forms.

Administration, Oral↗

PubMed1988

Gastric emptying rates of drug preparations. I. Effects of size of dosage forms, food and species on gastric emptying rates.

The gastric emptying rates of oral dosage forms of different sizes were studied in humans and beagle dogs measuring of marker drugs such as acetaminophen, aspirin and pyridoxal phosphate in plasma or urine. The marker drugs, except acetaminophen, were contained in enteric-coated granules or tablets which did not dissolve in the stomach but dissolved rapidly in the upper intestine. The gastric emptying rate of a dosage form of smaller size was faster than that of a larger size. The gastric emptying rates of dosage forms with different sizes did not correlate with each other inter-individually. The gastric emptying rates of dosage forms of any size were delayed when drugs were administered after taking a meal. The gastric emptying rates of dosage forms were extremely prolonged in beagle dogs after drug administration postprandially, and this restricted the use of beagle dogs as an animal model in bioavailability tests.

Acetaminophen↗

PubMed1993

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

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

Chemistry, Pharmaceutical↗

PubMed2003

Approach to the determination of hydrate form conversions of drug compounds and solid dosage forms by near-infrared spectroscopy.

Near-infrared (IR) spectroscopy is used for the rapid, nondestructive identification and quantitation of the hydrate form of drug compounds forming both single and multiple hydration states. Near-IR is shown to be useful in both bulk drug and in finished solid dosage forms. The capability of near-IR to nondestructively analyze samples allows the kinetics of hydrate form conversions to be measured directly in formulated products. In addition, the environmental conditions for stability of the individual hydration states are mapped out using near-IR spectroscopy. Detailed molecular mechanisms are given to account for the near-IR spectral changes that occur upon hydration. The technique is applied in both laboratory studies as well as in a process environment for at-line analysis of active pharmaceutical ingredient hydration state during pharmaceutical processing.

Absorption↗