Chronomodulated Delivery System Research Articles

Design and assessment of pulsatile technology based chronomodulated delivery systems of nifedipine

Nifedipine has poor aqueous solubility which limits its oral absorption as unit formulation. This limitation was acted through multiparticulate pulsatile systems for the treatment of angina pectoris. Initially, solid dispersions of nifedipine (NF) using sodium starch glycolate (SSG) and guar gum (GG) in 1:1 and 1:2 ratios were processed by kneading technique. Solution layering technique was employed to coat the solid dispersions on non-pareil sugar spheres (∼450 µm) to obtain immediate (NMP 1 and 2) and controlled release pellets (NMP-3 and 4). Controlled release pellets were further coated with Eudragit L100 and RS100 to achieve pulsatile pellets (NMPP-1 to 5). Pellets were subjected to saturation solubility, FTIR, DSC, micromeritics, SEM, drug content, drug release, pharmacokinetic and stability studies. By means of solid dispersions, solubility of NF was increased by 130-folds due to encompassing ordered interparticle mixing of NF and carriers. Significant interactions between NF and carriers were not demonstrated in FTIR spectra as well as in DSC thermograms. Fluidization process again proved its supremacy in producing defined spherical shaped pellets with desired micromeritics. Solution layering process resulted with high drug content (81–94.2%) and maximum drug was released by end of 12 h with 6 h lag phase. Suitable pharmacokinetic parameters were moderated by immediate (NMP) and pulsatile pellets (NMPP) as Cmax of 820 ng/mL for NMP-2 and 360.8 ng/mL for NMPP-5 at 5 and 16 h respectively. Increased pharmacokinetics and bioavailability were the result of linear increase in solubility of NF with solid dispersions. The pulsatile formulations were physicochemically intact over a period of time. Thus, multiparticulate systems of NF had demonstrated their applicability in chronotherapy of circadian based ailments.

Development and Evaluation of a Chronomodulated Delivery System of Metoclopramide Hydrochloride

Chronomodulated delivery system of metoclopramide hydrochloride was developed for the treatment of morning sickness and diabetic gastroparesis. Drug-excipient compatibility studies revealed no significant degradation of metoclopramide hydrochloride in presence of selected tabletting and compression coating excipients. Immediate release core tablets of metoclopramide hydrochloride were prepared using direct compression technique and various physico-chemical parameters were evaluated. The core tablets were subjected to compression coating with a mixture of glyceryl dibehenate, hydrogenated castor oil and dicalcium phosphate; the levels of which were optimized statistically using face-centred cube design to achieve desired in vitro drug release profile of not more than 10% at 4 h, not less than 50% at 4.5 h and not less than 85 % at 5 h interval. Increase in the concentration of glyceryl dibehenate and hydrogenated castor oil in the formulation significantly decreased drug release at 4.5 and 5 h time intervals in distilled water as dissolution medium whereas quantity of dicalcium phosphate was found to have no influence on drug release characteristics. A quadratic model was suggested for the release profile at 4 h whereas linear model signified the release at 4.5 and 5 h. Formulation containing 100, 92 and 150 mg of glyceryl dibehenate, hydrogenated castor oil and dicalcium phosphate respectively per tablet was considered optimum since it showed the desired release profile. As the formulation showed the desired lag time during in vitro drug release, night time administration of the formulation could be expected to prevent the symptoms of morning sickness among pregnant women and hypoglycaemia upon administration of antidiabetic medication in gastroparetic patients.

DESIGN, IN VITRO AND IN VIVO EVALUATION OF CHRONOMODULATED DELIVERY SYSTEMS OF TERBUTALINE SULPHATE FOR NOCTURNAL ASTHAMA

The present study deals with the design and evaluation of chronomodulated delivery of terbutaline sulphate as a chronotherapeutic approach in the treatment of nocturnal asthma. The basic design is based on the Pulsincap technology and consisted of formaldehyde treated insoluble hard gelatin capsule body filled with glutaraldehyde cross-linked carboxymethyl chitosan microspheres of terbutaline sulphate and sealed with a hydrogel tablet plug. The entire device was enteric coated, so as to prevent the variable gastric emptying time. The glutaraldehyde cross-linked carboxymethyl chitosan microspheres appeared to be roughly spherical with the size range of 4.63±0.48 to 11.75±0.92µm. The prepared microspheres possessed good yield and high encapsulation efficiency. Particle size, encapsulation efficiency and release rate are dependent on the fabrication conditions of the microspheres. Drug release from the microspheres depended on the core: coat ratio, reaction time and the rotational speed used in the preparation of microspheres. Formaldehyde treatment efficiently rendered the hard gelatine capsule bodies water insoluble. The ejection of the plug from the chrnomodulated delivery system depended on the nature and concentration of polymer used in the preparation of table plug. A lag time of 3-8hrs was observed for the chronomodulated delivery systems prepared with different hydrogel plugging materials. Among the different polymers studied, HPC showed highest lag time compared to HPMC K4 M and sodium alginate. The Roentgenographic studies revealed the predicted in vivo performance of the developed chronomodulated delivery systems of terbutaline sulphate. Pharmacokinetic analysis revealed the significant increase in tmax, AUC and MRT of optimized chronomodulated system of terbutaline sulphate compared to that of pure drug. The results of the study conclusively proved the suitability of carboxymethyl chitosan microspheres and the adopted Pulsincap technology in the development of chronomodulated delivery systems for terbutaline sulphate in the treatment of nocturnal asthma. Key words: Nocturnal asthma; Terbutaline sulphate; Chronomodulated systems; Lag time; Roentgenography; In vivo pharmacokinetics

DESIGN AND IN VITRO EVALUATION OF MULTIPARTICULATE SYSTEM FOR THE CHRONOMODULATED DELIVERY OF LORNOXICAM

In view of chronobiological considerations of rheumatoid arthritis, the present study deals with the design and evaluation of multiparticulate system for the chronomodulated delivery of lornoxicam. The basic design is based on the Pulsincap technology and consisted of formaldehyde treated insoluble hard gelatin capsule body filled with tripolyphosphate cross-linked chitosan microspheres of lornoxicam and sealed with a hydrogel tablet plug. The entire device was enteric coated, so as to prevent the variable gastric emptying time. The microspheres were found to be discrete, nearly spherical with rough surface characteristics. Particle size, encapsulation efficiency and release rate of lornoxicam from the microspheres are dependent on the fabrication conditions of the microencapsulation. FT-IR, DSC and XRD studies revealed the compatibility of the drug with the excipients used. The exposure of hard gelatine capsule bodies with formaldehyde for a period of 12 hrs was found to be optimum in maintaining the intactness of the capsule bodies in the simulated GI fluids. The lag time of the designed delivery system varied from 4-8 hrs and depended on the nature and concentration of the plugging material. The ejection of the plug was delayed with increase in the polymer concentration. Among the two polymers studied as plugging materials, guar gum exhibited better control in maintaining the lag time compared to xanthan gum. From the study it can be concluded that, the lag time be efficiently tailored by varying the concentrations of the polymers in the hydrogel plug for the chronomodulated delivery of lornoxicam. Key Words: Rheumatoid arthritis; Lornoxicam; Microspheres; Chronomodulated delivery systems; Hydrogel plug; Lag time;

Chronomodulated drug delivery system of urapidil for the treatment of hypertension.

Introduction:Hypertension is a disease which shows circadian rhythm in the pattern of two peaks, one in the evening at about 7pm and other in the early morning between 4 am to 8 am. Conventional therapies are incapable to target those time points when actually the symptoms get worsened. To achieve drug release at two time points, chronomodulated delivery system may offer greater benefits.Materials and methods:The chronomodulated system comprised of dual approach; immediate release granules (IRG) and pulsatile release mini-tablets (PRM) filled in the hard gelatin capsule. The mini-tablets were coated using Eudragit S-100 which provided the lag time. To achieve the desired release, various parameters like coating duration and coat thickness were studied. The immediate release granules were evaluated for micromeritical properties and drug release, while mini-tablets were evaluated for various parameters such as hardness, thickness, friability, weight variation, drug content, and disintegration time and in-vitro drug release. Compatibility of drug-excipient was checked by fourier transform infrared spectroscopy and Differential scanning calorimetry studies and pellets morphology was done by Scanning electron microscopy studies.Results:The in-vitro release profile suggested that immediate release granules gives drug release within 20 min at the time of evening attack while the programmed pulsatile release was achieved from coated mini-tablets after a lag time of 9hrs, which was consistent with the demand of drug during early morning hour attack. Pellets found to be spherical in shape with smooth surface. Moreover compatibility studies illustrated no deleterious reaction between drug and polymers used in the study.Conclusions:The dual approach of developed chronomodulated formulation found to be satisfactory in the treatment of hypertension.

Optimization of Chronomodulated Delivery System Coated with a Blend of Ethyl Cellulose and Eudragit L100 by Central Composite Design: In Vitro and In Vivo Evaluation

Introduction In this study, we present the development of a chronomodulated delivery system consisting of a fast-swelling tablet core containing montelukast sodium coated with a blend of different ratios of ethyl cellulose (gastrointestinal tract (GIT)-insoluble polymer) and Eudragit L100 (enteric polymer). Montelukast sodium is a leukotriene receptor antagonist commonly prescribed for patients of asthma and allergic rhinitis. Asthma and allergic rhinitis share a common core pathophysiology and have almost similar temporal pattern in their occurrence or exacerbation of their respective symptoms, suggesting a role for chronotherapy.

Chronomodulated Delivery System: a Tailored Cap to Fit Different Heads

"Blind race ends in a pit". A similar scenario is observed with the use of conventional dosage forms for different pathological conditions. Of late various disease states had regularly been reported to bear direct concurrence to the body's secretions that bear a constant rotationary cycle. Moreover the pharmacokinetic as well as pharmacodynamic responsiveness of various drugs had been reported to bear constant swings with the changing hours of the day. Thus, usage of the conventional zero order dosage form for every disease state or every active moiety developed, will only leave the researchers as well as the consumers in doldrums. Chronomodulated dosage forms are a silver lining in these overshadowed clouds. They are the dosage forms that spearhead the innovative researches because of their pre-programmed and pre-regulated pulsed release of the drug, at desired sites. Drug release pattern from these dosage forms considerably mimics the circadian timing of the body's secretion which are held responsible for the symptoms of the pathological irregularities arising in one's body. Thus, in a way these dosage forms are a shield against the inducers of the disease symptoms. Current review enlists the pathological states for which the chronomodulated delivery systems can prove to be a miraculous cure. This review emphasizes to summarize the patents granted as well as the novel researches undertaken by various researchers to upgrade the previously existing dosage form scenario. Moreover, this work is an attempt to summarize the various proprietary techniques and marketed formulations, thus trying to help the researchers to fabricate a better and novel dosage form from previously existing ones.

Design and In Vitro Evaluation of Chrono Modulated Theophylline Tablets

The objective of this research work was to prepare a chrono modulated delivery system to meet chronopharmacological needs of asthma. In this study theophylline was selected as a model drug. To meet this objective we considered an initial lag phase of release for 3-5 hrs and later a rapid (surge) release phase. To achieve surge release a rapidly releasing core tablet of theophylline was developed by admixing theophylline with effervescent granules and super disintegrants. The lag phase in release was achieved by coating the EV core tablets with release retarding polymer EUDRAGIT RS-100 containing HPMC, further over coated with enteric polymer CAP. The results indicate that a rapidly releasing EV tablet of theophylline cab be developed which when coated with the polymers a lag phase of 2 hrs was achievable followed by a surge release. Key Words: Theophylline, Chrono Modulated Drug Delivery, Asthma. doi:10.3329/sjps.v1i1.1782 S. J. Pharm. Sci. 1(1&2): 25-28