Rational Design of Self-Emulsifying Pellet Formulation of Thymol: Technology Development Guided by Molecular-Level Structure Characterization and Ex Vivo Testing.

The growing need for processing natural lipophilic and often volatile substances such as thymol, a promising candidate for topical treatment of intestinal mucosa, led us to the utilization of solid-state nuclear magnetic resonance (ss-NMR) spectroscopy for the rational design of enteric pellets with a thymol self-emulsifying system (SES). The SES (triacylglycerol, Labrasol®, and propylene glycol) provided a stable o/w emulsion with particle size between 1 and 7 µm. The ex vivo experiment confirmed the SES mucosal permeation and thymol delivery to enterocytes. Pellets W90 (MCC, Neusilin®US2, chitosan) were prepared using distilled water (90 g) by the M1−M3 extrusion/spheronisation methods varying in steps number and/or cumulative time. The pellets (705−740 µm) showed mostly comparable properties­zero friability, low intraparticular porosity (0−0.71%), and relatively high density (1.43−1.45%). They exhibited similar thymol release for 6 h (burst effect in 15th min ca. 60%), but its content increased (30−39.6 mg/g) with a shorter process time. The M3-W90 fluid-bed coated pellets (Eudragit®L) prevented undesirable thymol release in stomach conditions (<10% for 3 h). A detailed, ss-NMR investigation revealed structural differences across samples prepared by M1−M3 methods concerning system stability and internal interactions. The suggested formulation and methodology are promising for other lipophilic volatiles in treating intestinal diseases.

Exploration of Neusilin® US2 as an Acceptable Filler in HPMC Matrix Systems-Comparison of Pharmacopoeial and Dynamic Biorelevant Dissolution Study.

Modern pharmaceutical technology still seeks new excipients and investigates the further use in already known ones. An example is magnesium aluminometasilicate Neusilin® US2 (NEU), a commonly used inert filler with unique properties that are usable in various pharmaceutical fields of interest. We aimed to explore its application in hypromellose matrix systems (HPMC content 10-30%) compared to the traditionally used microcrystalline cellulose (MCC) PH 102. The properties of powder mixtures and directly compressed tablets containing individual fillers NEU or MCC, or their blend with ratios of 1.5:1, 1:1, and 0.5:1 were investigated. Besides the routine pharmaceutical testing, we have enriched the matrices' evaluation with a biorelevant dynamic dissolution study and advanced statistical analysis. Under the USP apparatus 2 dissolution test, NEU, individually, did not provide advantages compared to MCC. The primary limitations were the burst effect increase followed by faster drug release at the 10-20% HPMC concentrations. However, the biorelevant dynamic dissolution study did not confirm these findings and showed similarities in dissolution profiles. It indicates the limitations of pharmacopoeial methods in matrix tablet development. Surprisingly, the NEU/MCC blend matrices at the same HPMC concentration showed technologically advantageous properties. Besides improved flowability, tablet hardness, and a positive impact on the in vitro drug dissolution profile toward zero-order kinetics, the USP 2 dissolution data of the samples N75M50 and N50M50 showed a similarity to those obtained from the dynamic biorelevant apparatus with multi-compartment structure. This finding demonstrates the more predictable in vivo behaviour of the developed matrix systems in human organisms.

A Critical Overview of FDA and EMA Statistical Methods to Compare In Vitro Drug Dissolution Profiles of Pharmaceutical Products.

A drug dissolution profile is one of the most critical dosage form characteristics with immediate and controlled drug release. Comparing the dissolution profiles of different pharmaceutical products plays a key role before starting the bioequivalence or stability studies. General recommendations for dissolution profile comparison are mentioned by the EMA and FDA guidelines. However, neither the EMA nor the FDA provides unambiguous instructions for comparing the dissolution curves, except for calculating the similarity factor f2. In agreement with the EMA and FDA strategy for comparing the dissolution profiles, this manuscript provides an overview of suitable statistical methods (CI derivation for f2 based on bootstrap, CI derivation for the difference between reference and test samples, Mahalanobis distance, model-dependent approach and maximum deviation method), their procedures and limitations. However, usage of statistical approaches for the above-described methods can be met with difficulties, especially when combined with the requirement of practice for robust and straightforward techniques for data evaluation. Therefore, the bootstrap to derive the CI for f2 or CI derivation for the difference between reference and test samples was selected as the method of choice.

Structural Changes of Sodium Warfarin in Tablets Affecting the Dissolution Profiles and Potential Safety of Generic Substitution.

At present, the risk of generic substitutions in warfarin tablets is still being discussed. The aim of this study was to assess whether API interactions with commonly used excipients may affect the safety of generic replacement of warfarin sodium tablets. These interactions were observed during an accelerated stability study, and the effect of the warfarin solid phase (crystalline/amorphous form) as well as the API particle size distribution was studied. Commercial tablets and prepared tablets containing crystalline warfarin or amorphous warfarin were used. In addition, binary mixtures of warfarin with various excipients were prepared. The structural changes before and after the stability study were monitored by dissolution test in different media, solid-state NMR spectroscopy and Raman microscopy. During the stability study, the conversion of the sodium in warfarin to its acid form was demonstrated by some excipients (e.g., calcium phosphate). This change in the solid phase of warfarin leads to significant changes in dissolution, especially with the different particle sizes of the APIs in the tablet. Thus, the choice of suitable excipients and particle sizes are critical factors influencing the safety of generic warfarin sodium tablets.

Preformulation design of PLGA particulate system for multi-day drug delivery of the antidepressant mirtazapine.

In this experimental study, the biodegradable polylactide-co-glycolide (PLGA) microparticles (MP) loaded with the insoluble antidepressant mirtazapine were prepared by the simple o/w solvent evaporation method. The formation involved intrinsic variables, such as the content of polymer (700, 900 or 1200 mg), dichloromethane (5 or 10 ml) and/or drug (200 or 400 or 600 mg), and the volume of the aqueous emulsion phase (400, 600 or 800 ml). The influence of these parameters on the size and morphology of microparticles, encapsulation efficiency, and drug release behavior was observed. All MP were successfully prepared, and their size ranged between 165.34 ± 42.88 and 360.17 ± 121.59 μm. MP exhibited prolonged drug release (days), and some profiles had multiphasic character. It was found that the samples prepared with a  higher initial amount of PLGA were bigger with prolonged lag time up to 34.3 hours. On the other hand, higher drug concentrations reduced the lag time. The external phase volume reduction and multiplication of dichloromethane amount prolonged the mirtazapine release and decreased the encapsulation efficiency. These observations were further confirmed by multivariate data analysis.

Bilayer mucoadhesive buccal films with prolonged release of ciclopirox olamine for the treatment of oral candidiasis: In vitro development, ex vivo permeation testing, pharmacokinetic and efficacy study in rabbits.

The incidence of fungal infections has increased in recent decades not only in patients with predisposing and risk factors, but it has also spread up due to the widespread use of broad-spectrum antibiotics, immunosuppressants and corticosteroids. A limited number of drugs are currently used to treat oral candidiasis (OC). There is an emerging need to look for new antifungals, to rework or to explore the already known molecules. Ciclopirox olamine (CPX), a broad-spectrum antifungal agent, is currently used for topical dermatologic treatment. In this study, bilayer mucoadhesive buccal films (MBFs) containing poly(ethylene oxide) (PEO) and Eudragit® NM 30D (EU) with the prolonged release of ciclopirox olamine, were developed for the treatment of oral candidiasis. During ex vivo testing it was found that CPX does not pass through the porcine buccal tissue but it accumulates in it, which may be beneficial for the treatment of candidiasis in the oral cavity. In a pharmacokinetic study, the drug release from mucoadhesive films was prolonged with the maximum plasma concentration at 3.4 (1.4; 5.5) h. All rabbits with stomatitis showed progressive healing after the treatment with CPX bilayer mucoadhesive buccal films without organ pathologies.

Diazepam filled hard capsules intended for detoxification of patients addicted to benzodiazepines and Z-drugs.

OBJECTIVES: The abuse of benzodiazepines and Z-drugs reduces the quality of life of millions of addicted people worldwide. They cannot be discontinued abruptly due to harmful withdrawal symptoms. Detoxification is usually based on replacement of short/middle acting benzodiazepines or Z-drugs by diazepam and tapering the dose over time. In order to enhance patient adherence to an individual withdrawal plan, suitable diazepam dosage forms have to be available. Hard capsules containing an exact and uniform dose could be used for the relief of symptoms caused by altering the plasma level and overcoming psychogenic stress from the dose reduction. METHODS: This work demonstrates that capsules with a content of diazepam ranging from 2.125mg to 0.492 mg (dose decreasing always by 15%) cannot be easily prepared by standard mortar technology in a pharmacy. To meet mass and content uniformity European Pharmacopoeia criteria, capsules were prepared by improved technology based on the preparation of binary blends of calcium phosphate anhydrous and diazepam in descending concentrations in a high-speed mixer (time 30 s) and densification of about 10% during filling of the capsules. RESULTS: All batches (n=20) prepared by improved technology met the requirement for content uniformity compared with only nine batches prepared by standard mortar blender technology. Based on the process capability index, none of the samples prepared by standard technology fitted pharmacopeia limits at the statistically acceptable level. On the other hand, all batches prepared by improved technology exhibited acceptable process capability index. CONCLUSIONS: We have shown that at least 99.73% of batches prepared by our improved technology would meet the pharmacopoeia limits for content uniformity and are suitable for treatment of this type of addiction.

The development of a silicone vaginal ring with a prostaglandin analogue for potential use in the treatment of canine reproductive disorders.

In veterinary medicine, vaginal rings (VRs) are rarely used. However, there are diseases of female dogs' reproductive system which represent a suitable possibility for their usage. An example of such a disease is canine pyometra which can be treated by lipophilic prostaglandin drugs, unfortunately with harmful side effects after systemic administration. The aim of the study was to prove that the matrix VR based on silicone and channel-forming substance can be successfully used as a carrier for a three-day delivery of prostaglandin E2 (PGE2). Based on an in-vitro release study, an optimum channel-forming substance and its concentration were selected. The results were implemented during the construction of VR from the medical grade silicone DDU-4840 with PGE2 (5 mg). Glucose anhydrous in the 30% concentration was chosen as the most functional channel-forming substance due to synergism of osmotic activity and solubility. The DDU-VR containing PGE2 and 30% of glucose anhydrous exhibited excellent mechanical characteristics and ensured 29% drug release through water-filled channels in first-order kinetic manner. This is eight times higher than a sample without glucose where molecular diffusion through the silicone matrix was dominating the release mechanism. Moreover, drug-free VRs were tested for mechanical resistance and the design of removal thread.

The effects of the treatment conditions on the dissolution profile of ethylcellulose coated pellets.

Due to the additional particle coalescence in the coating, changes in the dissolution profile occur over time in the formulations coated by aqueous ethylcellulose latex. Dry thermal treatment (DT) of the coating can be used as a prevention of this process. Alternatively, it is advisable to take advantage of the synergistic effect of high humidity during wet treatment (WT), which substantially accelerates the film formation. This can be a problem for time-controlled systems, which are based on the coating rupture due to the penetration of water into the core causing the increase in the system volume. This process can begin already during the WT, which may affect the coating adversely. The submitted work was focused on the stability testing of two pellet core compositions: pellets containing swelling superdisintegrant sodium carboxymethyl starch (CMS) and pellets containing osmotically active polyethylene glycol (PEG). Another objective was to identify the treatment/storage condition effects on the pellet dissolution profiles. These pellets are intended to prevent hypoglycemia for patients with diabetes mellitus and therefore, besides the excipients, pellet cores contain 75% or 80% of glucose. The pellet coating is formed by ethylcellulose-based latex, which provides the required lag time (120-360 min). The sample stability was evaluated depending on the pellet core composition (PEG, CMS) for two types of final pellet coating treatment (DT or WT). Scanning electron microscopy and Raman microspectroscopy revealed the penetration of glucose and polyethylene glycol from the core to the PEG pellet surface after WT. For the CMS sample, significant pellet swelling after WT (under the conditions of elevated humidity) was statistically confirmed by the means of stereomicroscopic data evaluation. Therefore, the acceleration of dissolution rate during the stress tests is caused by the soluble substance penetration through the coating in the case of PEG pellets or by dosage form volume increase in the case of CMS pellets. The observed mechanisms can be generally anticipated during the stability testing of the ethylcellulose coated dosage forms. The aforementioned processes do not occur after DT and the pellets are stable in the environment without increased humidity.

The effect of amorphous and crystal sodium warfarin and its content uniformity on bioequivalence of tablets.

Warfarin is intensively discussed in terms of generic substitution due to particular cases of bleeding, which are attributable to fluctuations in API content or the substitution of crystalline (WSC) for amorphous (WSA) warfarin. The aim of this study was to assess to what extent the in vitro release was affected by the form of API depending on the composition and technology. Bioequivalent tablets containing 5 mg of WSA or WSC prepared by wet granulation or direct compression were used. Furthermore, tablets of the same composition with WSC or WSA prepared by direct compression were evaluated. Raman spectroscopy was used to confirm the presence of WSA or WSC. The dissolution was more influenced by the technology than by the form of API but even tablets with dissimilar profiles were bioequivalent. This is probably due to the precipitation of WSA and WSC in the stomach on a poorly soluble acidic form, which subsequently dissolves in the neutral environment of the small intestine. Recrystallization was demonstrated in the in vitro assay at a pH of 1.2 and 4.5 using Raman spectroscopy and X-ray diffraction. In summary, the content uniformity appears to be the main factor affecting the safety of the treatment.

Evaluation and Comparison of Three Types of Spray Dried Coprocessed Excipient Avicel® for Direct Compression.

As coprocessed excipients (CPE) gain a lot of focus recently, this article compares three commercially available CPE of Avicel brand, namely, CE 15, DG, and HFE 102. Comparison is based on measured physical properties of coprocessed mixtures, respectively, flow properties, pycnometric density, mean particle size, specific surface area, moisture content, hygroscopicity, solubility, pH leaching, electrostatic charge, SEM images, and DSC. Tablets were made employing three pressure sets. Viscoelastic properties and ejection force were assessed during compression, as well as pycnometric density, mass uniformity, height, tensile strength, friability, disintegration, and wetting times. Avicel CE 15 is of mid-range flow properties, contains mid-size and nonspherical particles, and has high hygroscopicity, growing negative charge, best lubricity, lowest tensile strength, and mid-long disintegration times. Avicel DG possesses the worst flow properties, small asymmetrical particles, lowest hygroscopicity, stable charge, intermediate lubricity, and tensile strength and exhibits fast disintegration of tablets. Finally, Avicel HFE 102 has the best flow properties, large symmetrical particles, and middle hygroscopicity and its charge fluctuates throughout blending. It also exhibits inferior lubricity, the highest tensile strength, and slow disintegration of tablets. Generally, it is impossible to select the best CPE, as their different properties fit versatile needs of countless manufacturers and final products.

Development of Orodispersible Films Containing Benzydamine Hydrochloride Using a Modified Solvent Casting Method.

The aim of this study was to develop benzydamine hydrochloride-loaded orodispersible films using the modification of a solvent casting method. An innovative approach was developed when the drying process of a small-scale production was used based on a heated inert base for casting the film. During this process, two types of film-forming maltodextrins for rapid drug delivery were used. They were plasticized with two different polyols (xylitol and sorbitol). Superdisintegrant Kollidon® CL-F was tested as an excipient that can induce faster disintegration of the prepared films. The influence of the formulation parameters (dextrose equivalent of film-forming maltodextrins, a type of plasticizer, and the presence of superdisintegrant) on the disintegration time, mechanical properties, and moisture content of films was statistically evaluated using a multivariate data analysis. Orodispersible films containing maltodextrin with lower dextrose equivalent value showed better mechanical properties (tensile strength ranged from 886.6 ± 30.2 to 1484.2 ± 226.9 N cm-2), lower moisture content (0.5 ± 0.0 to 1.2 ± 0.2%), and shorter disintegration time (17.6 ± 2.9 to 27.8 ± 2.8 s). Films plasticized with xylitol showed shorter disintegration time (17.6 ± 2.9 to 29.2 ± 3.8 s) than films containing sorbitol (23.8 ± 2.9 to 31.7 ± 3.9 s). With the addition of superdisintegrant Kollidon® CL-F, a significant influence on disintegration time was not observed. The modified solvent casting method shows great promise in a small-scale laboratory production of orodispersible films, e.g., in a pharmacy lab.

[Development of dissolution method for warfarin sodium tablets]. / Vývoj disolucnej metódy pre tablety s obsahom warfarínu sodného.

Warfarin is intensively discussed drug with narrow therapeutic index. In the past, its generic substitution was identified as a cause of bleeding. Altered quality of the active substance or varying drug content was discussed. The substance quality can be evaluated with adequate dissolution method. An official dissolution method with aqueous medium exists, however this method is non-discriminatory. In the first 15 minutes the whole amount of the active pharmaceutical ingredient is released from a tested dosage form, which does not allow comparison between tablets from different producers and it also makes difficult to track the changes throughout stability testing. In the literature, there is a well known method using pH 6.8 buffer, which seems to be a suitable alternative to water. The aim of this study was to prove, that this alternative medium, when two stirring speeds for dissolution (50 or 25 rpm) are used, will be suitable for calculation of similarity and difference factor and if it will be eventually discriminatory with regard to particle size and radial hardness. For this purpose we prepared tablets with 10 mg of warfarin sodium in form of crystalline clathrate with isopropanol. Tablets differed by particle size of active pharmaceutical ingredient (d50 = 4.8, or d50 = 22.5 µm respectively) and by radial hardness (30, or 100 N respectively). The content uniformity of the tablets was determined using process capability index (Cpk) and Bergum method. It was confirmed that the dissolution medium with pH of 6.8 allows comparison of dissolution profiles by similarity and difference factors but under given conditions it is not discriminatory.Key words: warfarin dissolution method particle size distribution radial hardness similarity factor difference factor.

Beer with reduced carbohydrates and alcohol content suitable for diabetics.

eer is for its glycemic index and for alcohol content inappropriate drink for patients with diabetes mellitus. Traditional social habits, however, lead diabetics to drinking the beer and it has negative health effects in these patients. On the other hand, beer contains substances with a beneficial health effect, such as flavionoids, saponins, prebiotics, vitamin B complex and others. Also, for its isotonicity with blood and a suitable pH value the beer is appropriate for supplementation of liquids during physical activities. Therefore, the beer with reduced content of sugar and alcohol could be a desirable functional food not only for diabetics. While there are both low-sugar beers and low-alcohol beers on the market, “non-alcoholic diabetic” is not yet commercially available. In this research we present the method of beer production by vacuum distillation with an alcohol content less than 1.2 vol % and with a maximum of sugar content not more than 0.75 g/100 ml.

Factor analysis in optimization of formulation of high content uniformity tablets containing low dose active substance.

Warfarin is intensively discussed drug with narrow therapeutic range. There have been cases of bleeding attributed to varying content or altered quality of the active substance. Factor analysis is useful for finding suitable technological parameters leading to high content uniformity of tablets containing low amount of active substance. The composition of tabletting blend and technological procedure were set with respect to factor analysis of previously published results. The correctness of set parameters was checked by manufacturing and evaluation of tablets containing 1-10mg of warfarin sodium. The robustness of suggested technology was checked by using "worst case scenario" and statistical evaluation of European Pharmacopoeia (EP) content uniformity limits with respect to Bergum division and process capability index (Cpk). To evaluate the quality of active substance and tablets, dissolution method was developed (water; EP apparatus II; 25rpm), allowing for statistical comparison of dissolution profiles. Obtained results prove the suitability of factor analysis to optimize the composition with respect to batches manufactured previously and thus the use of metaanalysis under industrial conditions is feasible.

Clinical assessment of the lag-time and tmax of pellets with controlled release of glucose: in vitro/in vivo comparison using 13 C-breath test.

Maintaining a stable glycaemia in diabetes mellitus type 1 requires flexible insulin administration and carbohydrate intake to affected individuals. In real life, there might be some situations limiting the insulin-sugar balance control, e.g. night sleep or prolonged sporting activities. Glucose pellets with a pre-determined time lag between the pellet administration and glucose release were developed to mimic a 'snack eaten in advance'. In this article, a 13 C-glucose breath test was introduced to translate laboratory dissolution testing to clinical confirmation of the glucose release pattern using 5% δ abundance to differentiate the appearance of in 13 C exhaled breath. An independent two-sample t-test (p = 0.20) confirmed an average clinical lag time of 300 min and an in vitro time of 338 min to be identical at a level of significance of α = 0.05. Moreover, using the same statistical method, the clinical tmax (564 min) and the in vitro t50 (594 min) were also considered identical (p = 0.34). It was concluded that dissolution testing is a relevant method to determine the time lags of dosage forms with controlled release of glucose and that the 13 C-glucose breath test is a suitable clinical tool for lag time verification in clinical studies.

Influence of concentration and type of microcrystalline cellulose on the physical properties of tablets containing Cornelian cherry fruits.

The aim of this study was to find the optimal tablet composition with maximum content of dried fruits (Cornus mas L.). The effect of three different concentrations (12.5, 25 and 50 %) of two types of microcrystalline cellulose (Avicel® PH 101 and Avicel® PH 200) and three different compression pressures (20, 60 and 100 MPa) on the physical properties of tablet blends and tablets was studied. Tablets containing 50 % Avicel® PH 101 compressed under 100 MPa were found to have the best physical properties. This combination of composition and compression pressure resulted in stable tablets even after storage under accelerated stability conditions (6 months, 40 °C and 75 % RH).

The influence of thermal treatment and type of insoluble poly(meth)acrylates on dissolution behavior of very soluble drug from hypromellose matrix tablets evaluated by multivariate data analysis.

Hypromellose matrices exhibit extended burst effect immediately after contact with aqueous medium, especially when a water-soluble drug is incorporated. The objective of this study was to reduce burst effect and maintain complete dissolution of a very soluble levetiracetam over 12 h period from hypromellose K4M matrices to obtain zero-order kinetics. Desired changes were achieved by applying water dispersions of insoluble Eudragits® (NE, NM, RL, RS) as a granulation liquid to the drug/microcrystalline cellulose mixture during high-shear granulation (non-thermal treated set) and consequently by thermally treating granules or final tablets (TT), respectively. Applying Eudragit® water dispersions to the drug/microcrystalline cellulose mixture was recognized as an effective method of significantly reducing the burst release (25.4-33.7%) of levetiracetam in comparison with a reference sample without Eudragit®. Multivariate data analysis showed that the addition of Eudragit® reduced burst effect, increased fitting with zero-order kinetics, and supported matrix erosion as the supplementary mechanism to predominant diffusion. Moreover, resulting PCA sub-model revealed the addition of Eudragit® RL and thermal treatment of tablets to be the most suitable method of all. For a 12 h dissolution profile, characterized by low burst effect and drug release close to 100% at the 12th hour, sample RL_TT was the most suitable.

Pharmacokinetics of Ciclopirox Olamine after Buccal Administration in Rabbits.

BACKGROUND: Prevalence of oral mucosal fungal infections increases with the frequent administration of antibiotics, corticosteroids and immunosuppressive drugs. Therapeutically used antifungals are usually associated with a variety of drug interactions. Furthermore, there has been a noticeable increase in microorganisms resistant to these preparations. Mucoadhesive buccal films represent a modern therapeutic system for the treatment of oral mucosal fungal infection paired with a high degree of patient compliance. Ciclopirox olamine applied directly onto the oral mucosa offers an attractive alternative to treatment with systemic antifungals thanks to its low incidence of resistance and side effects. OBJECTIVE: The aim of this work was to evaluate the pharmacokinetic parameters of ciclopirox olamine after the buccal application of mucoadhesive film prepared by the solvent casting method. METHOD: A chromatographic method using an internal standard was developed and validated for evaluation of ciclopirox olamine plasma concentrations. Method accuracy was 88.5-104.6% and 89.5-99.7% for interday and intraday assays, respectively. RESULTS: The pharmacokinetic properties of ciclopirox olamine were studied in New Zealand White rabbits. The mucoadhesive films containing ciclopirox olamine in a total dose of 34.4 (33.0; 35.9) mg kg-1 were applied to all the rabbits. Plasma ciclopirox olamine concentrations were determined during the 12 h following application. The time taken to reach maximum plasma concentration was 1.7 (1.1; 2.2) h after the drug administration with cmax 5.73 (4.18; 7.28) µg mL-1. Overall elimination half-life was 3.8 (1.9; 10.8) h. CONCLUSION: The experiment suggests that oral mucoadhesive film may be a valuable alternative ciclopirox olamine administration.

Coated pellets with delayed-release glucose for prevention of hypoglycemic episodes.

Patients tend to prevent hypoglycemia by excessive saccharide intake leading to poorer glycemic control with potentially fatal consequences. This problem could be resolved by means of pellets with glucose release delayed by 120-360 min as a compensation of the antidiabetic drug peak effect. No glucose is released before; hence there is no risk of hyperglycemia and secondary complications. The pellets contain glucose in combination with an osmotically active ingredient and are coated with an ethylcellulose dispersion, which forms an insoluble semipermeable membrane and ensures delayed release. The release of glucose was assessed using dissolution and high-performance liquid chromatography. Dissolution profiles indicated the possibility of achieving the requested lag time using a combination of adequate compositions and coating concentrations. Lag times of 60, 240 and 360 min were achieved. The sample containing carboxymethyl starch was found to be most suitable for the intent of this work.