Optimization of Diltiazem hydrochloride osmotic formulation using QBD approach

Abstract Diltiazem hydrochloride (DLH) is a calcium channel blocker useful for the treatment of angina pectoris, arrhythmia, and hypertension. DLH having a short half-life needs frequent administration for successful treatment but this poses a problem of poor patient compliance. These requirements are served by elementary osmotic pump tablets (EOP) based controlled-release (CR) systems. Quality by design (QbD) approach assists in screening various factors with subsequent assessment of critical parameters that can have a major impact on the scalability of EOP. Tablets were formulated using wet granulation method followed by osmotic coating. Factorial design based QbD strategy aided in defining the risk assessment of influential variables such as hydrophilic polymers and osmotic coat component on the in-vitro release kinetics of the designed EOP tablets. These formulated EOP systems followed zero-order kinetics, a characteristic feature of EOPs. EOP tablets were formulated applying a systematic QbD statistical approach. The formulated DLH EOP systems with improved concentration-independent behavior helped to address the challenges of IR formulation. Application of QbD strategy in ascertaining the scalability of DLH EOP formulation would help pharmaceutical industries in the translation of EOP based drug delivery systems from R&D to market.

Development Of Water Transplant Based Single Core Osmotic Pump For Fluvoxamine Maleate Employing Quality By Design Principles

The present study draw a bead on preparing single core osmotic pump with improved water transplant by employing Quality by Design (QbD) principles to achieve zero order drug release for prolonged period of time. QbD principles were employed in preparing single core osmotic pump by deriving quality target product profile (QTPP), critical quality attributes (CQA) followed by risk assessment using ishikawa diagram and risk estimation matrix. Box-Behnken Design was employed to study the effect of various independent parameters like concentration of Natrosol 250 HX (X1) and concentration of Xylitab (X2) no. of orifice (X3), on various dependent parameters like lag time (Y1) and time required for release 25%, 50%, 75% and 100% drug (Y2, Y3, Y4 and Y5). A controlled space was designed where each criteria or CQA was satisfied. Optimized formulation was further characterized for its efficiency. The results of design suggest the suitability of design for optimization of single core osmotic pump. In the initial period, drug release was driven by no. of orifice which on later stage depends on concentration of swellable polymer and concentration of osmogen. Optimized design was validated by preparing check point batch having less than 5% predicted error. Model fitting with drug release kinetics showed that optimized single core osmotic pump released drug in zero order. Stability data suggested that prepared formulation was stable for 3 month period without significant changes in the CQA. Single core osmotic pump using water transplant was successfully developed for a poorly soluble drug using QbD principles.

Preparation and in vitro evaluation of pregabalin controlled porosity osmotic pump tablets / 中国药科大学学报

@#In this study, pregabalin controlled porosity osmotic pump tablets which are taken once a day were prepared. Single-factor tests were carried out to investigate the influence of excipients and manufacturing process. The formulation was optimized through orthogonal experiment on three levels of three significant factors including the amount of sodium citrate, and polyethylene glycol 400 and coating weight gain. On the basis of the results of the single-factor tests and the orthogonal experiment, optimal formulation and manufacturing process were obtained. The final tablet formulation contained pregabalin(82. 5 mg), microcrystalline cellulose(40%), sodium citrate(27. 5%), magnesium stearate(0. 5%)and 5% povidone K30 solution as the tablet binder; the coating formulation consisted of cellulose acetrate and 60% of polyethylene glycol 400 as a porogen; the coating weight gain was 3%. In vitro drug release kinetic study suggested that the drug release from controlled porosity osmotic pump tablets was mainly driven by osmotic pressure, which was barely affected by the pH of the release medium. The drug release behavior of the tablets within 12 hours complied with zero-order release rule and the linear correlation coefficient was 0. 991 6. The obtained porosity osmotic pump tablets could effectively slow the drug release rate, reduce concentration fluctuation and improve the safety and convenience for the patients, hence with broad prospects.

Preparation and Pharmacokinetics of Huperzine A Micro-porous Osmotic Pump Pellets / 中国药学杂志

OBJECTIVE: To prepare huperzine A micro-porous osmotic pump pellets and to investigate the pharmacokinetic properties in Beagle dogs. METHODS: The extrusion-spheronisation method was used to prepare the core of huperzine A pellets which then coated by fluid-bed coating technology. Central composite design-response surface method was used to optimize the prescription of coating layer.Then Zero-order, First-order and Higuchi equation of cumulative release with time were fitted to study its release characteristics.The commercially available huperzine A tablets were used as reference preparations to investigate the in vivo pharmacokinetics of huperzine A micro-porous osmotic pump pellets, and the bioequivalence of the two preparations were compared. RESULTS: The formula of coating was optimized as followsEC of 61.5%, PEG400 of 10.5%. Zero-order kinetics existed in the release of the pellets in 24 h. Moreover, the osmotic pressure-controlled delivery was greatly responsible for drug release. In vivo study showed that tmax and ρmax of huperzine A micro-porous osmotic pump pellets were significantly lower than that of the reference preparation, and its t1/2 was significantly prolonged compared with the reference preparation, the relative bioavailability was 95.8%. CONCLUSION: Huperzine A micro-porous osmotic pump pellets had a better sustained release effect in the Beagle dog and have a good correlation in vivo.

Novel core in cup (In-lay) tablets of lamotrigine for mucoadhesive drug delivery system.

Lamotrigine a BCS class II drug used in treatment of epilepsy has several disadvantages when taken orally (first pass metabolism and increased Cmax). The aim of the study is to design core in cup (In lay) buccoadhesive tablets which aims for controlled, unidirectional release, increased patient compliance and decreased side effects. The present study involves the preparation of core in cup tablets containing release retarding polymers like sodium alginate, xanthan gum and HPMC E 15LV in core and HPMC K 15M in cup for mucoadhesion. L9 orthogonal array Taguchi design was constructed for the study. The dependent variable studied for L9 orthogonal array Taguchi runs include % drug release from which the formulation with highest S/N ratio was optimized. All the runs were evaluated for physical parameters, drug release, mucoadhesive studies and assay. L1, L2, L4 and L8 formulations showed controlled release for up-to 8 hours with good assay values. The model dependent kinetics showed zero order kinetics with super case II transport and Hixson Crowell mechanism which indicates unidirectional drug release.

Preparation and Release Behavior in vitro of Memantine Hydrochloride Sustained-release Pellets / 中国药师

Objective:To prepare sustained-release pellets of memantine hydrochloride and investigate the in vitro drug release be-havior. Methods:The drug-loaded pellets were prepared by a fluid bed coating technology, the sustained-release pellets were prepared with Eudragit RL 30D and Eudragit RS 30D as the coating materials, and in vitro drug release behavior of the sustained-release pellets was studied. Results:The in vitro drug release was steady and complete in 24h, which fit a zero-order kinetics model. Conclusion:The memantine hydrochloride sustained-release pellets has the sustained-release property.

A review on recent innovation in osmotically controlled drug delivery system.

In recent years, oral controlled release (CR) system is most acceptable dosage form by the patients. Drugs having short biological half-life and poor water solubility are the suitable candidate for development of CR system. They include dosage forms for oral and transdermal administration as well as injectable and implantable systems. For most of drugs, oral route remains as the most acceptable route of administration. Certain molecules may have low oral bioavailability because of solubility or permeability limitations. Development of an extended release dosage form also requires reasonable absorption throughout the gastro-intestinal tract (GIT). Among the available techniques to improve the bioavailability of these drugs fabrication of osmotic drug delivery system is the most appropriate one. The release of drug(s) from osmotic systems follows zero order. It is mainly governed by various formulation factors such as solubility and osmotic pressure of the core component(s), size of the delivery orifice, and nature of the rate-controlling membrane. The present review highlights an overview of OCDDS. And new technologies, fabrication and recent clinical research in osmotic drug delivery. Further, the challenges of these technologies and its future perspective are also discussed at length.

Development of UV spectrophotometer method of cefixim in bulk and pharmaceutical tablet dosage formulation.

The simple, precise and economic UV methods have been developed for estimation of Cefixime in single component. Cefixime has the absorbance maxima in zero order spectra in 230 nm (method A). Method B applied was first order derivative for the analysis of Cefixime at 238.5 nm .Method C applied was area under curve in the wavelength range of 234-228 nm. Drug followed Beer-Lamberts law in the concentration range of 503.5 μg/ml for zero order, 10-60 μg for area under curve methods and first order derivative spectrum. The percentage recovery of Cefixim ranged from 98.05 to 101.075 in pharmaceutical dosage from result of analysis was validated statistically and by recovered study.

Design and evaluation of rectal drug delivery systems of non-steroidal anti-inflammatory drug.

The aim of the present study was to design and evaluate the suppositories of aceclofenac a non-steroidal anti inflammatory drug (NSAID). Aceclofenac, rectal suppositories were developed by employing various hydrophilic and hydrophobic polymeric bases like gelatin, PEG-400 and hydrogenated vegetable oil using propylene glycol as plasticizer and beeswax as hardening agent. The in-vitro release rate data was evaluated statistically and was found that from all the formulations the drug release is by diffusion mechanism (r = 0.9547 to 0.9967) according to Higuchi’s equation. All the prepared formulations have shown zero-order release kinetics except those prepared by utilizing 15% and 20 % of PEG-400. The formulation prepared using 7.5% beeswax in hydrogenated vegetable oil has dis-played zero-order drug release (r = 0.9927) and has released 99.18% of the aceclofenac within 4h, hence, this formulation is considered as a promising formulation. The stability study on the promising formulation was con-ducted over a period of 6 months and found that there are no significant changes in the drug content and in-vitro drug release rate (p<0.05). The result suggests that the suppositories can be prepared by employing hydrophilic and hydrophobic polymers.

Design and evaluation of rectal drug delivery systems of non-steroidal anti-inflammatory drug.

The aim of the present study was to design and evaluate the suppositories of aceclofenac a non-steroidal anti inflammatory drug (NSAID). Aceclofenac, rectal suppositories were developed by employing various hydrophilic and hydrophobic polymeric bases like gelatin, PEG-400 and hydrogenated vegetable oil using propylene glycol as plasticizer and beeswax as hardening agent. The in-vitro release rate data was evaluated statistically and was found that from all the formulations the drug release is by diffusion mechanism (r = 0.9547 to 0.9967) according to Higuchi’s equation. All the prepared formulations have shown zero-order release kinetics except those prepared by utilizing 15% and 20 % of PEG-400. The formulation prepared using 7.5% beeswax in hydrogenated vegetable oil has dis-played zero-order drug release (r = 0.9927) and has released 99.18% of the aceclofenac within 4h, hence, this formulation is considered as a promising formulation. The stability study on the promising formulation was con-ducted over a period of 6 months and found that there are no significant changes in the drug content and in-vitro drug release rate (p<0.05). The result suggests that the suppositories can be prepared by employing hydrophilic and hydrophobic polymers.

Preparation of microporous osmotic pump tablets of marine / 中国药科大学学报

Aim: To develop marine microporous osmotic pump tablets and to investigate drug release in vitro of the optimized formulation and the release mechanism.Methods: Wet granulation and film-coating were used to develop marine micro-osmotic pump tablets.In vitro release studies were applied to evaluate the impacts of various factors on the release of the formulation.Central-composite design was exploited to aid the optimization of the formulation,and the mechanism of in vitro release was characterized.Results: There existed fairly good reproducibility in the preparation of marine micro-osmotic pump tablets.It was found that no change in the release rate of the tablets were elicited by the pH of the release media,the rotating speed selected,the hardness of the tablet core,and the amount of the plasticizer incorporated into the coating formulation.It was proved that the release of marine micro-osmotic pump tablets was closely related to the magnitudes of NaCl amount in the tablet core and the pore former in the coating formulation as well as the coating level.In addition,there existed 12-hr zero-order kinetics in the in vitro release study of the tablets.Moreover,it was shown that the osmotic pressure-controlled delivery is greatly responsi-ble for the release of the developed tablets.Conclusion: The prepared marine microporons osmotic pump tablets are expected to be a new sustained-release medication.

Preparation and Drug Release Mechanism of Tetramethylpyrazine Phosphate Porosity Osmotic Tablet / 中国药房

OBJECTIVE:To prepare Tetramethylpyrazine phosphate porosity osmotic tablet (TMPP) and to optimize its formulation and investigate its mechanism of drug release. METHODS: The formulation was optimized by the orthogonal experiment design through investigation of one factor; the accumulative drug release rates of preparations of different formulation were measured, and the mechanism of drug release of the tablets was discussed. RESULTS: The dosage of PEG 400 in coating solution, the content of hydroxy-propyl methyl cellulose (HPMC) in tablet core, the dosage of dibutylphthalate as plasticizer, and the weight gain of coating membrane were four important factors influencing drug release. The optimal formulation was to use 10% of PEG400, 5% of HPMC, 10% of dibutylphthalate and 12 mg coating membrane. The release behavior in vitro of the porosity osmotic tablets prepared in the above condition within 10 h complied with zero order release rule(r=0.999 81), with accumulative release rate of 94.2%. The tablets had good reproducibility in interassay and which was independent of the influence of gastrointestinal condition. The mechanism of drug release included osmotic pump mechanism and diffusion mechanism, but osmotic pump one was the main type. CONCLUSION: The formulation and preparation technology of the porosity osmotic tablets were simple but effective, showing an obvious zero order release within 12 h and good reproducibility, thus suitable for the industrial production of porosity osmotic tablets.

Pharmacokinetics of zero-order release and first-order release of mono-compar tment drugs administered by non-parenteral route / 中国药理学通报

Aim To establish the pharmacokinetic principles of the zero-order release and the first-order release of mono-compartment drugs administered by non-parenteral route based on the release kinetics of the dosage forms and the intrinsic pharmacokinetic parameters of the active drug, such as the rate constants of the absorption and elimination, and the distribution volume of the drug. Methods By the Laplace transform and the compartmental analysis method, the pharmacokinetic behaviors of the zero-order release and the first-order release of mono-compartment drugs administered by non-parenteral routes were deduced with divisions of the dose being absorbed during the release phase and after the release has terminated. Results The pharmacokinetics of the non-parenteral administration of the zero-order release and the first-order release of mono-compartment drugs were established. Conclusion The pharmacokinetic theories of the zero-order release and the first-order release of mono-compartment drugs administered by non-parenteral route have been established. Since the zero-order release and the first-order release are the primary release patterns, the theory should be a key to explore the pharmacokinetics of the controlled/sustained release dosage forms.