Oral Controlled Release System Research Articles

Nicotinamide pelletization by fluidized hot melt granulation: L18 Hunter design to screen high risk variables

L18 Hunter design was used to investigate the practicability of applying QbD approaches to fluidized hot melt granulation (FHMG) in preparing oral controlled release systems. Eight high-risk variables obtained from risk analysis were classified into chemical factors (type and percentage of meltable binder, matrix viscosity and percentage and filler type) and process variables (size fraction of meltable binder, inlet air volume and fluidization time). The variables were screened for their impacts on pellets characteristics. The obtained results showed that the meltable binder percentage was the significant variable affecting most responses. Flow properties, size distribution, bulk, and tapped densities were significantly (P<0.05) affected by the filler type, inlet air volume, and fluidization time. On the other hand, the matrix variables were non-significant to the dissolution parameters. Out of eight critical variables, it was found that the meltable binder percentage and size fraction, inlet air volume had the most significant effects and will be optimized in the second part of the study. In conclusion, QbD paradigm not only offered a robust FHMG technique to formulate controlled release formulations of hydrophilic drugs but also provided a time and cost saving advantage to pharmaceutical industry.

Floating Microspheres: Recent Trends in the Development of Gastroretentive Floating Drug Delivery System

Oral controlled release systems are designed to release the drug in-vivo with prediction so as to increase efficacy, minimize adverse effects and increase bioavailability of drugs. Floating drug delivery systems (FDDSs) are expected to remain buoyant in a lasting way upon the gastric contents. The various buoyant preparations include hollow microspheres, granules, powders, tablets, capsules, pills and laminated films. Floating microspheres are especially gaining attention due to their wide applicability in the targeting of drugs to the stomach. These floating microspheres have the advantage that they remain buoyant and distributed uniformly over the gastric fluid to avoid the vagaries of gastric emptying and release the drug for prolonged periods of time. Multiparticulate low-density particles can successfully prolong the gastric retention time of drugs. This article provides an overview of two important approaches utilized to prepare and improve the performance of floating microspheres.

An Oral Colon-Targeting Controlled Release System Based on Resistant Starch Acetate: Synthetization, Characterization, and Preparation of Film-Coating Pellets

An oral colon-targeting controlled release system based on resistant starch acetate (RSA) as a film-coating material was developed. The RSA was successfully synthesized, and its digestion resistibility could be improved by increasing the degree of substitution (DS), which was favorable for the colon-targeting purpose. As a delivery carrier material, the characteristics of RSA were investigated by polarized light microscopy, FTIR spectroscopy, and X-ray diffraction. The results revealed a decrease of the crystallinity of RSA and a change of its crystalline structure from B + V hydrid type to V type. To evaluate the colon-targeting release performance, the RSA film-coated pellets loaded with different bioactive components were prepared by extrusion-spheronization and then by fluid bed coating. The effects of the DS, plasticizer content, and coating thickness of the RSA film and those of the content and molecular weight of the loaded bioactive component on the colon-targeting release performance of the resulting delivery system were investigated. By adjusting the DS, the coating thickness, and the plasticizer content of the RSA film, either the pellets loaded with a small molecular bioactive component such as 5-aminosalicylic acid or those with a macromolecular bioactive peptide or protein such as bovine serum albumin, hepatocyte growth-promoting factor, or insulin showed a desirable colon-targeting release performance. The release percentage was less than 12% in simulated upper gastrointestinal tract and went up to 70% over a period of 40 h in simulated colonic fluid. This suggests that the delivery system based on RSA film has an excellent colon-targeting release performance and the universality for a wide range of bioactive components.

P.7.c.007 Self-injury among Croatian adolescents: important risk factors

Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at high risk for driving accidents. One dose of methylphenidate (MPH) improves simulator driving performances of ADHD-diagnosed adolescents at 1.5 hours post-dose. However, little is known about the effects of different MPH delivery profiles on driving performance throughout the day.This randomized, crossover, single-blind study compared osmotic, controlled-release oral system (OROS) MPH (Concerta) given q.d. to immediate-release MPH (Ritalin) given in equal doses t.i.d. on driving performance among six male ADHD-diagnosed adolescent drivers aged 16 to 19 years. Under each treatment condition, participants were maintained on their medication dosage for 7 days, then drove a sophisticated driving simulator at 2 p.m., 5 p.m., 8 p.m., and 11 p.m. The primary outcome measure was each participant's computer-quantified Impaired Driving Score (IDS).IDS worsened in the evenings for participants receiving MPH t.i.d. but remained stable when they received once-daily OROS MPH. Participants performed significantly better when receiving OROS MPH q.d. compared with MPH t.i.d. (F = 9.3, df = 1, p = .004). When MPH was given t.i.d., IDS significantly worsened beginning at 8 p.m. compared to OROS MPH (p = .01).Participants demonstrated significantly less variability and better driving performance when receiving OROS MPH q.d. compared to MPH t.i.d., particularly in the evenings.

Effectiveness of repeated administration of a new oral naltrexone controlled-release system on morphine analgesia.

Naltrexone hydrochloride, an opioid antagonist used as an adjunct to the maintenance of the opioid-free state for detoxified individuals, was introduced into the polymeric structure of Eudragit L30D, an anionic copolymer based on polymethacrylic acid and ethylacrylate. From the results of a preclinical study, this complexation technique can be considered as a useful tool in the design of oral controlled-release systems (naltrexone-Eudragit L) capable of inducing long-lasting effects in-vivo. The biopharmaceutical characterization of the naltrexone-Eudragit L complex in comparison with naltrexone hydrochloride using the mouse hot-plate model has been previously carried out. The results showed a longer effect, an enhancement of 23.47% of the area under the curve of the inhibition of analgesic activity vs time, and a delay of 51.80% in the t1/2 value induced by the complex, compared with those induced by conventional naltrexone. In this study, a regimen of chronic administration of naltrexone-Eudragit L was established. Thus, in an 8-day treatment (4 doses in alternate days) this oral controlled-release system effectively antagonized the analgesic effect of morphine for 8 h, whereas naltrexone hydrochloride has to be administered over 16 days (8 doses in alternate days) to induce the same effect. In the 16-day schedule the complex-induced antagonism lasted over 14 h after administration.

Preclinical study of an oral controlled release naltrexone complex in mice.

Naltrexone, a long-acting, orally effective, opioid antagonist which blocks opioid effects as well as the development of physical dependence, would appear to be a drug ideally suited to addiction treatment. An optimal dosage regimen is critical for the treatment patient compliance in ambulatory opiate detoxification programs. The ideal dosage regimen would be an oral controlled-release system of naltrexone that allowed once-a-day administration providing stable plasma levels. A naltrexone-Eudragit L complex was produced in aqueous medium from naltrexone hydrochloride solution and Eudragit L30D (30% w/v) previously diluted (6% w/v) and partially neutralized. The antagonistic activity of naltrexone-Eudragit L on morphine-induced thermal antinociception, in comparison with conventional naltrexone, was evaluated, using the mouse hot-plate model. Mice were administered 10 mg kg(-1) morphine subcutaneously, 10 min before test, and the antagonist products, either naltrexone-Eudragit L or naltrexone hydrochloride, were administered orally at 0.5, 1, 2, 4, 6, 8, 10, 12, 14 and 16h before the test. The results showed that the antagonism induced by naltrexone-Eudragit L was effective until 12 h after drug administration, while that induced by naltrexone hydrochloride disappeared 10 h after its administration. A 23.47% increase of the area under curve was obtained when naltrexone-Eudragit L was administered, compared with that induced by conventional naltrexone. The time taken to decrease the inhibition of analgesic activity to 50% was delayed by 51.80%. This complexation technique can be considered as a useful tool in the design of oral controlled-release systems capable of inducing a long-lasting effect in-vivo.

An oral controlled release system for amroxol hydrochloride containing a wax and a water insoluble polymer

This study was carried out to develop and optimize oral sustained-release formulations for Ambroxol hydrochloride matrix pellets using a combination of wax and water-insoluble polymer, glyceryl behenate (Compritol 888 ATO) and Ethylcellulose (EC7 FP). It involved three factors: the content of Compritol 888 ATO (X1), EC7 FP (X2), and the matrix formation methods (X3), as independent variables. The drug release percentages at 1, 2 and 4 h were the target responses and were restricted to 15–45% (Y1), 45–80% (Y2) and 80–100% (Y3), respectively. The final blend formulation prepared by extrusion spheronization, was achieved with 27.00% (w/w) Ambroxol hydrochloride, 48.70% (w/w) Compritol 888 ATO, and 24.30% (w/w) EC7 Fp with 40°C for 12 h. Comparing the single matrix materials consisting of just the wax or water-insoluble in the complex matrix system containing wax and water-insoluble polymer, the release of the drug can be far more retarded, when the formulations have undergone the process of heat treatment. Furthermore, the combination of the two polymers, with flexible matrix formation methods, will offer a very promising way of producing matrix pellets instead of coated controlled-release pellets to meet various demands of drug release.

Formulation of Controlled Release Gellan Gum Macro Beads of Amoxicillin

Gellan gum has been reported to have wide pharmaceutical applications such as tablet binder, disintegrant, gelling agent and as a controlled release polymer. Multiparticulate delivery systems spread out more uniformly in the gastrointestinal tract and reduce the local irritation. The purpose of this study is to explore possible applicability of gellan macro beads as an oral controlled release system of a sparingly soluble drug, amoxicillin. Gellan gum beads were prepared by ionotropic gelation with calcium ions. The effect of drug loading, stirring time, polymer concentration, electrolyte (CaCl2) concentration, curing time etc. influencing the preparation of the gellan gum macro beads and the drug release from gellan gum beads were investigated in this study. Optimal preparation conditions allowed very high incorporation efficiency for amoxicillin (91%) The release kinetics of amoxicillin from gellan beads followed the diffusion model for an inert porous matrix in the order: 0.1 N HCl > phosphate buffer > distilled water. Change in curing time did not significantly affect the release rate constant, but drug concentration, polymer concentration and electrolyte concentration significantly affect the release rate of amoxicillin from the beads. The gellan macro beads may be suitable for gastro retentive controlled delivery of amoxicillin.

An oral controlled release system for amroxol hydrochloride containing a wax and a water insoluble polymer

An oral controlled release system for amroxol hydrochloride containing a wax and a water insoluble polymer

Calcium Pectinate Gel Bead Intended for Oral Protein Delivery: Preparation Improvement and Formulation Development

Calcium pectinate gel (CPG) micrometer-sized beads (microbeads) containing insulin, as a model amphoteric protein, were prepared by ionotropic gelation technique together with an air compressor. The influences of phosphate buffer, pH as well as calcium and pectin concentrations of cross-linking solution on the characteristics and release profiles of microbeads were investigated. With the aid of compressed air flow, the mean diameters of beads were successfully decreased to micron-sized. The results showed that all the factors investigated greatly affected the entrapment efficiencies and release profiles of the microbeads. Suitable formulation concentrations should be considered and great care should be taken to maintain the pH of working solutions at or close to isoelectric point of protein loaded during the whole preparation process. Hence, CPG microbeads of perfect spherical shape, uniform sizes, enhanced mechanical strength, good entrapment efficiencies and delayed release profiles were prepared for a load of amphoteric protein and peptide drugs, without any use of organic solvents or harsh ingredients. Therefore, CPG microbeads could be a promising carrier for oral controlled-release systems of amphoteric protein and peptide drugs.

Design and Evaluation of a Sustained Release Gastroretentive Dosage Form of Captopril: A Technical Note

Development of oral controlled release systems has been a challenge to formulation scientists because of their inability to restrain and localize the system in the targeted area of the gastrointestinal tract. Controlled release preparations using alternative routes have been formulated but the oral route still remains preferable. Amongst the various approaches to target the drug to the stomach or proximal region of small intestine, high density systems have a technical difficulty in formulating a dosage form having a density in the range of 2.4–2.8 g/cm3, swelling systems require an optimum balance between the rate of swelling and rate of erosion of the polymer to avoid unwanted side effects and bio/mucoadhesive systems which can be dislodged from its site of adhesion, may not provide the optimum benefits. When the drug is formulated with a gel forming polymer such as semisynthetic derivatives of cellulose, it swells in the gastric fluid with a bulk density less than one. It then remains buoyant and floats on the gastric fluid, prolonging gastric residence time (GRT). This floating dosage form is well known as a hydrodynamically balanced system (HBS) (1,2,3). It has been suggested for the following instances that an active material can be formulated as an HBS to enhance bioavailability: (1) having a dissolution and/or stability problem in the small intestinal fluids, (2) being locally effective in the stomach, (3) being absorbed only in the stomach and/or upper part of the intestine (4). Floating tablets, capsules, beads, microspheres and chambers have been reported in literature (5). Floating systems can be developed by two approaches. First is the effervescent system which needs a gas generating agent that may alkalinize the microenvironment of the stomach and whose buoyancy would be dependent on the gas generating agent unlike the second which is a non-effervescent approach. CAP, 1-[(2S)-3-mercapto-2-methyl-1-oxopropyl]-l-proline, is an angiotensin converting enzyme inhibitor. It has been widely used for the treatment of hypertension and congestive heart failure. It has been reported that the duration of antihypertensive action after a single oral dose of CAP is only 6–8 h, so clinical use requires a daily dose of 37.5–75 mg to be taken three times (6). It is most stable at pH 1.2 and as the pH increases; it becomes unstable and undergoes a degradation reaction (7). The present investigation aims to develop a sustained release non-effervescent floating matrix tablet of CAP with a view of prolonging GRT as well as avoiding intestinal degradation.

Influence of water soluble additives and HPMCP on drug release from sureleaseê-coated pellets containing tamsulosin hydrochloride

The objective of this study was to investigate the influence of various water-soluble additives and HPMCP as an enteric polymer into Surelease for the developement of oral controlled release system containg tamsulosin hydrochloride. The drug loaded pellets were coated with only Surelease or Surelease containing HPMC, PEG 4000, mannitol and HPMCP (20% w/w). In case of HPMC and PEG 4000 as additives into Surelease film, the rapid drug release was observed in pH 1.2 while the higher drug release was achieved by adding HPMCP into Surelease as well as by increasing the amount of HPMCP (10, 20, and 30% w/w) in pH 7.2. The incorporation of HPMCP into Surelease showed pH-denpendent drug release due to its pH-dependent nature. Therefore, the incorporation of HPMCP into Surelease based on aqueous coating formulation is an effective way to develop oral controlled release delivery systems containing tamsulosin hydrochloride.

Dexamethasone-loaded nanoparticle-coated microparticles: Correlation between in vitro drug release and drug transport across Caco-2 cell monolayers

This work reports the preparation of dexamethasone in nanoparticle-coated microparticles and the study of the influence of such microencapsulation on drug absorption across Caco-2 cell monolayers. Nanoparticle-coated microparticles were prepared by spray-drying using nanocapsules (NC) or nanospheres (NS) in aqueous suspensions as coating material. Drug contents ranged from 64 to 134 mg g −1, yields between 49% and 67% and moisture content below 2.0%. SEM and AFM analysis demonstrated that the nanoparticle-coated microparticles (20–53 μm) show nanostructures on their surface with a similar diameter compared to the aqueous suspensions. The type of nanocoating material had a significant influence on the drug release profile and on the drug permeation across Caco-2 cells: NC-coated microparticles led to a prolonged release and slower transport across Caco-2 cell monolayers, while the NS-coated microparticles showed a faster release and Caco-2 transport compared to uncoated microparticles. The correlation between the amount of drug permeated and the drug released (%) suggests that the drug absorption from such a delivery system is controlled mainly by the release rate rather than by epithelial permeability. Caco-2 transport studies appear to be a useful characterization tool for the development of microparticulate oral controlled release systems.

Diffusion Transport Properties of Polymeric Complex Matrix Systems Based on Eudragit E100 and L100 Copolymers

With a view to application in oral controlled drug release systems, a new interpolyelectrolyte complex (IPEC) between Eudragit E100 and Eudragit L100 has been synthesized. The IPEC structure is characterized by two maxima in the swelling kinetics curve, which occur in the regions of media with different pH values modeling conditions in the gastrointestinal tract. The release of a model drug (ibuprofen) from IPEC-based tablets was significantly retarded as compared to the behavior observed for individual polymers and their physical mixture.

Impact of Methylphenidate Delivery Profiles on Driving Performance of Adolescents With Attention-Deficit/Hyperactivity Disorder: A Pilot Study

Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at high risk for driving accidents. One dose of methylphenidate (MPH) improves simulator driving performances of ADHD-diagnosed adolescents at 1.5 hours post-dose. However, little is known about the effects of different MPH delivery profiles on driving performance throughout the day. This randomized, crossover, single-blind study compared osmotic, controlled-release oral system (OROS) MPH (Concerta) given q.d. to immediate-release MPH (Ritalin) given in equal doses t.i.d. on driving performance among six male ADHD-diagnosed adolescent drivers aged 16 to 19 years. Under each treatment condition, participants were maintained on their medication dosage for 7 days, then drove a sophisticated driving simulator at 2 p.m., 5 p.m., 8 p.m., and 11 p.m. The primary outcome measure was each participant's computer-quantified Impaired Driving Score (IDS). IDS worsened in the evenings for participants receiving MPH t.i.d. but remained stable when they received once-daily OROS MPH. Participants performed significantly better when receiving OROS MPH q.d. compared with MPH t.i.d. (F = 9.3, df = 1, p =.004). When MPH was given t.i.d., IDS significantly worsened beginning at 8 p.m. compared to OROS MPH (p =.01). Participants demonstrated significantly less variability and better driving performance when receiving OROS MPH q.d. compared to MPH t.i.d., particularly in the evenings.

Basic Drug—Enterosoluble Polymer Coevaporates: Development of Oral Controlled Release Systems

Precipitation of basic drugs within oral prolonged release systems, at the higher pH values of the intestine, would affect drug release. Coevaporates of a model basic drug verapamil HCl, in single or mixed polymer systems, containing Eudragit L100 (L100) and ethyl cellulose or Eudragit RS100, were prepared from ethanolic solution. XRD and DSC indicated loss of crystallinity of the drug in the coevaporates. The presence of the enterosoluble polymer in the system was found to aid in faster dissolution of the drug at higher pH values. This was affected by the presence and type of retarding polymer present in the system. Compression of the coevaporates resulted in either very slow release of the drug or undesirable changes in the release profile. Pelletization of a coevaporate containing drug and L100 yielded systems, which released the drug uniformly when studied by the buffer change method in simulated gastric (SGF) and intestinal (SIF) fluids. The presence of L100 in intimate contact with the drug was found to be essential for the desirable drug release properties of the system. The drug release occurred predominantly by diffusion in SGF and by a combination of diffusion and polymer dissolution/erosion in SIF. Appropriate choice of release modifiers and formulation variables and development of suitable formulations can yield systems which compensate for the reduced solubility of the drug in the higher pH environments of the intestine.

Development of Oral Controlled-Release System for Continuous Absorption (OCASTM) Utilizing Colonic Drug Absorption

Development of Oral Controlled-Release System for Continuous Absorption (OCAS^TM) Utilizing Colonic Drug Absorption

Preparation and in-vitro evaluation of alginate beads of flurbiprofen

The purpose of this study was to prep. and evaluate alginate gel beads as an oral controlled release system of flurbiprofen (FLUP)​. FLUP is one of the potent nonsteroidal antiinflammatory drugs (NSAIDs) which has deleterious side effects on the GIT such as irritation, ulceration and hemorrhage. The release of FLUP from alginate beads was strongly affected by pH of the dissoln. medium and drug : polymer ratio. In all cases the drug release front alginate beads showed nearly zero-​order mechanism. The release rate of drug was more rapidly in alk. medium (pH 7.4) than that at pH 5.8. The swelling property of dried alginate beads was of interest. The beads remained unchanged in acidic medium (pH 1.2 and 5.8) but swelled rather rapidly in pH 7.4 phosphate buffer to a size greater than their original size before being dried. Such a pH-​sensitive swelling properties could be advantageous for orally administered drug vehicles, esp. when an acid-​sensitive drug or drug that has adverse-​effects on the GIT is incorporated in the beads. The effect of the intact drug as well as FLUP alginate beads on the ulcerogenic activity of the drug in the stomach of rabbit was carried out. It was obsd. that, the ulcerogenic activity of the intact drug disappeared and the mucosal surface did not show hemorrhage or inflammation when the drug is loaded with alginate beads.

Eudragit® RS-PM and Ethocel® 100 Premium: influence over the behavior of didanosine inert matrix system

Inert matrices of didanosine (ddI) were elaborated as controlled release dosage forms, using two different types of polymers: Eudragit® RS-PM, an anionic acrylic acid copolymer, and Ethocel® 100 Premium, an ethylcellulose. A preformulation study of the drug was designed to address the following points: (a) the development of two alternative methods (high performance liquid chromatography ( HPLC) and UV spectrophotometry) for the analysis and quantifying of ddI; (b) the determination of the aqueous solubility of ddI; and (c) the characterization of ddI from the following points of view: morphological (scanning electronic microscopy (SEM)) and thermal (differential scanning calorimetry (DSC)). Furthermore, some of these techniques were used for the characterization of those components which will be included in the oral controlled release system to be developed. The in vitro release of ddI matrices was studied at pH 7.4, because of the instability of ddI at pH values lower than 3 units. A significant reduction in the release rate of drug from both ddI controlled release systems was found. Furthermore, Ethocel® 100 Premium showed a minor efficiency in the dissolution process, with a reduction of more than double in the final dissolution efficiency (DE) value. This parameter and the fit factors ( f 1 and f 2) have been compared for the characterization of dissolution profiles.

Influence of layer position on in vitro and in vivo release of levodopa methyl ester and carbidopa from three-layer matrix tablets

A versatile oral controlled release system for the simultaneous delivery of levodopa methyl ester and carbidopa, consisting of a three-layer matrix tablet, has been studied and developed. Each individual layer of the matrix exhibited a different release mechanism, i.e. the first layer was swellable (S), the second one was erodible (E) and the third one was disintegrating (D). The three layers have been assembled in the monolithic matrix in different relative positions. It was found that in the monolith the three layers could interact, producing in vitro release profiles depending on their relative position. The monoliths having the configurations DSE and SDE were administered to human volunteers in order to determine the plasma profiles. The pharmacokinetic data showed a significant difference between the early time plasma curves: the monolith DSE, having the fast release profile, gave rise to a rapid appearance of a high levodopa plasma level, whereas the slower releasing monolith SDE produced a smoothed plasma concentration profile.