Controlled-release Drug Formulations Research Articles

Crystal structure determination and DFT analysis of doxorubicin hydrochloride for controlled-release drug formulations

Doxorubicin hydrochloride (DOX) is a widely used chemotherapeutic drug that inhibits the growth of cancer cells. Many DOX-based controlled-release systems have been proposed to reduce toxicity. However, knowledge of its crystal structure is essential for optimizing drug release processes and designing co-crystals or salts with different release properties. Although DOX has been extensively studied, no crystal structure is available in the Cambridge Structural Database or literature. In this work, we determine the crystal structure of DOX using a simulated annealing approach based on powder X-ray diffraction data. We confirm its validation by Rietveld refinement and molecular cohesion by using a molecular geometry check tool. We also use density functional theory to optimize the DOX structure and obtain the minimum energy conformation, H-bond donor/acceptor species, charge localization, and crystal structure parameters. This study provides essential structural information on DOX that can be used to rationalize new modified-release dosage forms and to design co-crystals or salts with different release properties.

Comparative pharmacokinetics of osmotic-controlled and immediate-release Eperisone tablet formulation in healthy human subjects using a sensitive plasma LC-ESI-MS/MS method

To evaluate and compare the pharmacokinetic (PK) characteristics of a newly developed oral osmotically controlled drug delivery system of Eperisone 150 mg tablets with Eperisone immediate release (IR) marketed tablet brand as a reference formulation. It was a single dose, two treatment, two sequence, randomized, crossover study, involving 12 healthy human subjects. A modified, sensitive LC-ESI-MS/MS method was developed and validated as per FDA guidelines for estimation of Eperisone in plasma using a simple extraction and quick protein precipitation method. Non-compartmental pharmacokinetic model was used for PK analysis. Results were statistically compared using logarithmically transformed data, where p > 0.05 was considered as non-significant with 90% CI limit of 0.8–1.25. The bio-analytical method used for estimating drug plasma concentration was found to be simple, selective, linear, accurate and precise with 0.01 ng/ml as limit of detection. The comparative PK analysis revealed an insignificant difference in AUC0-∞, AUC0-t, Vz/F, Cl/F and t1/2λz, whereas a significant difference in Cmax, Tmax and MTTs were found. The relative bioavailability of Eperisone osmotic tablet was 109.7%. The osmotic controlled release drug formulation was found to release Eperisone for an extended period with less inter individual fluctuation in pharmacokinetic variables.

Slow release anti-fungal skin formulations based on citric acid intercalated layered double hydroxides nanohybrids.

BackgroundDuring the past few decades, the occurrence of superficial fungal infections has rapidly increased. As the fungal infections take longer time to get cured, concepts such as designing drugs with extended persistence and controlled release have gained attention. In this context, nanotechnology has been identified as the latest technological revolution which has opened up new pathways for designing new therapeutic materials. Out of the many available nano-structures layered double hydroxides have gained increased scientific attention in applications as slow and controlled release drug formulations. This study focuses on the encapsulation of citric acid which has anti-fungal properties into a Mg-Al- layered double hydroxide (LDH) in order to be used as slow release topical skin formulations.ResultsCitrate ions were encapsulated into Mg-Al LDH using one step co-precipitation reaction. The successful intercalation of citrate ions into the layered structure has been proved referring to the expansion in the interlayer spacing as observed by the shift in the basal peak of the powder X-ray diffraction pattern. Fourier transform infra-red spectroscopy data suggests the change in the electron density around the carboxylate groups of the citrate ion thus providing evidences for formation of encapsulated hybrid composite. The resulting nanohybrid has been then, introduced into a general body cream formulation containing cocoa-butter. Both citrate LDH and the resulting body cream formulations demonstrated prolonged slow release characteristics up to 8 h in aqueous medium under different pH values (3, 4, and 5) compared to quick and fast release of pure citric acid. It was observed that the slow reelase was most efficient at low pH values. The encapsulation between the nano-layers and citrate ions are the key to the slow release characteristics. The body cream has been tested for the anti-fungal activity against three common Candida species (C. albicans, C. glabrata, C. tropicalis). The novel nanohybrid has shown an improved activity and slow release characteristics up to 48 h against the C. albicans and C. glabrata but not for C. tropicalis.ConclusionThe study confirms that the citrate ion intercalated LDHs have the potential for use in future slow release antifungal drug formulation.Graphical Slow release nanohybrids based on citrate intercalated layered double hydroxides

Formulation of propranolol hydrochloride controlled release tablets: Effect of surfactant charge and mechanisms of drug release

Controlled release drug formulation is a very important branch in pharmaceutical industry and attracts a lot of research and investments. Eudragit RL100 and sodium carboxymethylcellulose (NaCMC) are used in drug formulation due to their good coating properties. Here, we studied propranolol hydrochloride formulation with anionic polymer Eudragit RL100 alone and with other additives (lactose, sorbitol, dextrose). The formulation was also studied with Eudragit RL 100 and sodium carboxymethyl cellulose (NaCMC) with different concentrations and with other surfactants (Sodium lauryl sulfate, Sodium taurcholate, Cetrimide, Cetylpiridiniumc chloride and Betaine). The results showed that propranolol hydrochloride was completely released in less than four hours when the tablets were prepared from Eudragit RL100 alone or with lactose, sorbitol or dextrose. In contrast, when the tablets were prepared with Eudragit RL100 and NaCMC, a controlled release rate of the drug was observed. The kinetics and mechanism(s) of the drug release were discussed. Key words: Propranolol hydrochloride, surfactant solubility, controlled-release, surfactant charge, drug release rate.

Semi-solid materials for controlled release drug formulation: current status and future prospects

Semi-solid materials represent an important category of inactive ingredients (excipients) of pharmaceutical products. Here we review several common semisolid polymers currently used in the controlled release formulations of many drugs. These polymers are selected based on their importance and broad scope of application in FDA-approved drug products and include several polysaccharides (cellulose, starch, chitosan, alginate) and carbomers, a group of mucoadhesive synthetic polymers. Glyceride-based polymers used in self-emulsifying drug delivery systems (SEDDS) will also be discussed for its importance in formulating poorly water-soluble drugs. Unique features and advantages of each type of semi-solid materials are discussed and examples of their use in oral delivery of drugs are provided. Finally, future prospects of developing new and better semi-solid excipients are discussed with the objective of facilitating clinical translation.

Effect of Chitosan on the Enantioselective Bioavailability of the Herbicide Dichlorprop to Chlorella pyrenoidosa

Chitosan, a natural polysaccharide, is widely regarded as a biocompatible and potential carrier for controlled-release drug formulations. However, the potential effect of chitosan on the environmental behavior of contaminants is poorly understood, especially on chiral chemicals. In this study, the changes in bioavailability of the chiral herbicide dichlorprop to Chlorella pyrenoidosa by chitosan were investigated. The dissipation of (S)-enantiomer in Chlorella pyrenoidosa culture media without chitosan was faster than that of the herbicidally active (R)-enantiomer, whereas it was inversed to (R)-enantiomer being faster than (S)-enantiomer when chitosan was added into the media. In the absence of chitosan, the toxicity of (R)-enantiomer to Chlorella pyrenoidosa was more potent than that of the (S)-enantiomer. On the contrary, in the presence of chitosan, (R)-enantiomer was less toxic than (S)-enantiomer. These observations clearly suggest that chitosan changed the enantioselective bioavailability of dichlorprop. Fluorescence spectroscopic analysis showed that the interaction between chitosan and dichlorprop enantiomers depended greatly on the steric structure of dichlorprop, which offers a possible explanation as to why the addition of chitosan changed the enantioselective dissipation of dichlorprop by Chlorella pyrenoidosa. This work suggests that the enantioselective behaviors of chiral compounds in the environment might be shifted when interactions with other chiral receptors coexist.

Poly(ortho ester amides): Acid-Labile Temperature-Responsive Copolymers for Potential Biomedical Applications

A new, convenient pathway is developed to synthesize highly hydrolytically labile poly(ortho ester amide) (POEA) copolymers that overcomes some of the major weaknesses of the traditional methods of synthesizing poly(ortho esters) and their derivatives. A diamine monomer containing a built-in, stabilized ortho ester group was synthesized and was used for polycondensation with diacid esters, giving rise to a series of POEA copolymers with unique stimuli-responsive properties. The POEA undergoes temperature-responsive, reversible sol-gel phase transition in water. Phase diagrams of the POEA/H(2)O mixture reveal the concentration-dependent existence of different phases, including hydrogel and opaque or clear solution. Such behavior may be attributed to the temperature-dependent hydrogen-bonding involving the amide groups in the POEA backbone and hydrophobic interactions between POEA chains, and it is tunable by selecting diacid monomers with different chemical structures. The kinetics of POEA mass loss in physiological aqueous buffers and release of a model macromolecular drug, fluorescently labeled dextran, are nearly zero-order, suggesting predominantly surface-restricted polymer erosion. The rates of polymer erosion and drug release are much faster at pH 5.0 than pH 7.4. No cytotoxicity was found for the polymer extracts and the polymer degradation products at concentrations as high as 1 mg/mL. The normal morphology of fibroblasts cultured directly in contact with POEA films was not altered. These novel acid-labile temperature-responsive POEA copolymers may be potentially useful for a wide range of biomedical applications such as minimal invasive delivery of controlled-release drug formulations that respond to biological temperature and acidic-pH environments in cells and tissues.

Microbiological and clinical comparison of chlorhexidine buccoadhesive tablet and chlorhexidine mouthrinse

Abstract Chlorhexidine, which is a gold standard for antiplaque agents, was prepared as a buccoadhesive controlled-release drug formulation. The released amount and effectiveness of the antibacterial properties of the formulations were determined in in vivo and in vitro studies. In laboratory studies, nearly 40% of the total amount of the drug was released over 4 h. Clinically, first day results up to 4 h showed a statistically significant reduction of the bacterial amount in the drug-loaded side of oral mucosa. The results for 1 and 4 days were not statistically significant in the tablet group. The usefulness of the tablet dosage form was also assessed in the subjects.

Formulation of Ibuprofen Beads by Ionotropic Gelation

Microencapsulation has become a common technique in the production of controlled release dosage forms. Many results have been reported, concerning the use of alginate beads as controlled release drug formulations. Alginate has a unique gel-forming property in the presence of multivalent cations, in an aqueous medium. Ibuprofen is an excellent analgesic and antipyretic, non-steroidal anti-inflammatory agent with a high therapeutic index. Formulation of ibuprofen in beads could reduce its gastric ulcerogenicity. Hence, in this study the formation of Ca-alginate ibuprofen beads, through ionotropic gelation has been investigated. For this purpose, different cross- linking agents including: Ca 2+ , Ba 2+ , Mn 2+ , Co 2+ , Sn 2+ and Pb 2+ , were used for bead preparation. Next, characterization of the beads, size distribution, encapsulation efficiency of ibuprofen within the beads, the bead swelling and the drug release kinetic were investigated. Results showed that only Ca ion is suitable for the formation of ibuprofen beads. A good swelling profile for beads in phosphate buffer (pH=7.4) and the lack of swelling in hydrochloric acid (pH= 1.2), show the suitable nature of the beads. In addition, formulation of Na-alginate (2%) and Ca-chloride (2%) beads,resulted in an encapsulation efficacy of around 90%. The drug release studies showed a rapid and complete ibuprofen release from the beads, specially those prepared from Na-alginate (2%) and Ca-chloride (2%), in phosphate buffer medium. However, no detectable drug release was observed within the acidic medium. In conclusion, ibuprofen is capable of being n be microencapsulated as a bead formulation, with suitable properties and release profile.

Drug Transport in Responding Lipid Membranes Can Be Regulated by an External Osmotic Gradient

In this paper, we demonstrate, for the first time, how an external osmotic gradient can be used to regulate diffusion of solutes across a lipid membrane. We present experimental and theoretical studies of the transport of different solutes across a monoolein membrane in the presence of an external osmotic gradient. The osmotic gradient introduces phase transformations in the membrane, and it causes nonlinear transport behavior. The external gradient can thus act as a kind of switch for diffusive transport in the skin and in controlled release drug formulations.

Supercritical CO2 Based Production of Magnetically Responsive Micro- and Nanoparticles for Drug Targeting

Magnetically responsive, controlled-release drug formulations are needed for targeted drug delivery, especially for toxic drugs. A supercritical antisolvent (SAS) technique is used to produce magnetically responsive poly(methyl methacrylate), 50/50 dl-poly(lactide-co-glycolide), and Eudragit RS polymer particles via coprecipitation of the polymer with a suspension of magnetite particles in mineral oil and a fatty acid surfactant, using dichloromethane as the solvent. The SAS technique is again used to precipitate drug-loaded magnetically responsive polymer particles. A modification of the SAS process, the SAS-EM technique developed at Auburn University, is used to produce magnetite-encapsulated polymer nanoparticles of controllable sizes. In SAS-EM, atomization and increased mixing within the supercritical phase is brought about using a surface vibrating at an ultrasonic frequency. Size, morphology, and drug-release kinetics of the obtained particles are studied.

Optimized pharmacokinetic and pharmacodynamic profiles in cardiovascular disease therapy

Desirable pharmacokinetic effects for β-blockers and calcium antagonists Desirable pharmacokinetic properties of β-blockers and calcium antagonists include predictable absorption leading to a gradual onset of action and sustained presence of the drug and its effect over a 24-h dosing interval. The former can be achieved either pharmaceutically by a controlled-release drug formulation or pharmacodynamically with a slow onset of action due to the physiological characteristics of the drug target. The latter is achieved either by developing drug molecules with a low intrinsic clearance or, again, pharmaceutically by controlling the rate of drug input with a controlled-release drug formulation. Both of these approaches to β-adrenoceptor blockers and calcium antagonists have been effectively exploited to improve the therapy of hypertension. The clinical pharmacodynamic profile should include substantial and sustained antihypertensive or antianginal effects over a 24-h period. New calcium antagonists In the case of calcium antagonists, efforts to achieve an optimal profile have been primarily pharmacokinetic until recently, with the development of increasingly complex sustained-release formulations and efforts to develop low-clearance drugs. More recently, extension of the pharmacodynamic target with blockade of T-type calcium channels has been explored in an attempt to further optimize the clinical pharmacodynamic profile of this drug class.

The nifedipine gastrointestinal therapeutic system (GITS). Evaluation of pharmaceutical, pharmacokinetic and pharmacological properties.

Nifedipine is a short-acting calcium antagonist formulated into several different oral preparations, each of which offers a distinct drug release profile. Of these, the nifedipine gastrointestinal therapeutic system (GITS) affords (rate)-controlled-release (CR) and once-daily administration. Although it is recognised that CR drug formulations may enhance the treatment compliance of patients by reducing the number of daily doses, there are several pharmaceutical, pharmacokinetic and pharmacological considerations which may influence the ultimate selection of a particular dosage form. The formulation design of the nifedipine GITS involves an osmotic pump process which provides approximately zero-order delivery of the drug. This mechanism serves to prevent the possibility of dose dumping, but more importantly allows for maintenance of the relatively constant plasma drug concentrations assumed necessary to maintain smooth control of blood pressure. The pharmacokinetic characteristics of the nifedipine GITS have been evaluated in both single- and multiple-dose studies. The GITS formulation provides drug concentrations which reach a plateau within 6 hours after administration of a single dose, and continue at that concentration until at least 24 hours after administration. In this way large fluctuations in plasma drug concentrations are avoided, which may improve the efficacy and tolerability of the drug. Although a trend showing a small increase in the 24-hour plasma nifedipine concentrations has been observed by our group from some single-dose studies, it does not appear to be clinically relevant. One potentially important disadvantage of the GITS compared with 'naturally' long-acting agents is that the 'intrinsic' pharmacokinetic properties of nifedipine may be exposed in poorly compliant patients, leading to extended periods of subtherapeutic drug concentrations. Drug delivery by the nifedipine GITS is unaffected by changes in pH and gastrointestinal (GI) motility, but the rate of drug release can increase slightly with food intake (although absolute bioavailability remains unchanged). No studies have been conducted to determine the average GI transit time of this particular dosage form, but it is possible that inadequate retention may occur in some patients, perhaps leading to less optimal clinical outcomes. For example, the median GI transit time for both oxprenolol and metoprolol Oros drug delivery systems has been reported as 27.4 hours, with individual times ranging from 5.1 to 58.3 hours. The possibility of inadequate GI retention of the nifedipine GITS is perhaps more likely in patients who have pre-existing GI motility disorders or who are taking other medications that enhance GI motility. The interaction between grapefruit juice and nifedipine is interesting, considering that the exact mechanism involved has yet to be determined. Nonetheless, inhibition of presystemic metabolic processes (probably involving liver enzymes but possibly also enzymes contained within the wall of the small intestine) is likely to be a factor in the increased bioavailability of nifedipine observed in individuals coingesting grapefruit juice. Thus, potential nifedipine formulation differences with respect to the degree of interaction with grapefruit juice may occur if a significant degree of extrahepatic metabolism is involved. The majority of clinical trials with the nifedipine GITS have assessed its efficacy in patients with mild-to-moderate essential hypertension, and have found it to be at least equivalent to other dosage forms of the drug. Since there is limited information available directly comparing the efficacy and adverse effects of the different types of nifedipine formulation, little attention has been focused on this subject. However, modifying the rate and duration of nifedipine release may profoundly affect the clinical performance of this drug. A slower rate of intravenous nifedipine infusion has been shown to reduce the incide

Supercritical fluid extraction-liquid chromatography method development for a polymeric controlled-release drug formulation

We have recently been involved in the development of a method for assaying the active component in a controlled-release drug formulation, which is composed of a drug substance covalently bonded to polymer matrix. The drug substance in the formulation is the active enantiomer of misoprostol, a synthetic analog of natural prostaglandins and the active ingredient in Cytotec ®. Our method development consisted of a systematic evaluation of dynamic, off-line supercritical fluid extraction (SFE) as sample preparation for the formulation assay. Extracts were analyzed with normal phase and reversed-phase HPLC methods. The reversed-phase system utilized postcolumn reaction to provide selective detection of the extracted prostaglandin sample components. Several SFE parameters were investigated to optimize the recovery of the drug substance from the formulation, including sample quantity, extraction cell volume, extraction duration, supercritical carbon dioxide modifier, temperature, pressure, and collection solvent. The SFE experiments were completed with a commercially available multicell extractor. Preliminary validation studies utilized a formulation made with radiolabeled drug to determine the recovery achieved under the optimized SFE conditions and assessed the precision of replicate determinations. Analysis was completed under the optimized conditions to quantitate levels of the active component and related compounds in lots of the experimental polymeric formulation and to determine the total weight per cent extracted.

Supercritical fluid extraction—Supercritical fluid chroomatography for analysts of a prostglandin: HPMC dispersion

AbstractAn on-line SFE-SFC system was used to extract and chromatograph a synthetic prostaglandin from hydroxypropyl methylcellulose (HPMC), which is a widely used material in controlled-release drug formulations. The only sample preparation for the on-line SFE-SFC analysis of the dispersion was weighing the sample into the extraction vessel insert. The extraction efficiency for a four-minute extraction was approximately 65%.

Controlled-release new animal drugs

Abstract Economic pressures and technological progress have been major factors in spurring development of novel and improved drug delivery systems in recent years. These specially designed systems may be found in such forms as microcapsules, erodible or diffusion-controlled devices, or liposomes. Antibodies, magnetic microspheres, receptor-binding proteins, and pro-drugs are also examples of some systems that provide enhanced or directed drug delivery. Other systems delay delivery of the drug until it has reached the appropriate portion of the digestive system. The stabilization of the active ingredient to achieve a desired shelf life under expected environmental conditions prior to use may also be achieved by the use of a microencapsulated drug system. A description of the sequence of the approval process for a new animal drug application will be delineated. Some agency suggestions to aid the process of approval for a New Animal Drug Application (NADA) using a microencapsulated or controlled release drug formulation will be given.

Modified release of drug: a way to its quantification

Modified release of drug from a delivery system may be quantified by determining the area deviation of an experimental curve from a standard curve; the latter being the transformation of the individual experimental plasma concentration-time profile to a rectangle of equal area (internal standard) or the plasma concentration-time curve required for adequate effect (external standard). The advantage of this method is the precise characterization of the plasma drug profile over any required time interval. Taking an injectable controlled release drug formulation with bromocriptine (= 2-bromo- α-ergokryptine) as an example, it has been shown how controlled release from such delivery system can be quantified satisfactorily.

Biodegradation of gelatin‐g‐poly(methyl acrylate)

Considerable interest has been focused on the synthesis of biodegradable polymers in specialized applications such as controlled release drug formulations, insecticide and pesticide carriers, and nontoxic surgical implant materials. For many agricultural and ecological uses it is desirable to have a biodegradable polymer that will degrade in a physiological environment or by microbial action in the soil.