Dissolution Rate Limited Absorption Research Articles

Predictive computational models for assessing the impact of co-milling on drug dissolution

Co-milling is an effective technique for improving dissolution rate limited absorption characteristics of poorly water soluble drugs. However, there is a scarcity of models available to forecast the magnitude of dissolution rate improvement caused by co-milling. Therefore, this study endeavoured to quantitatively predict the increase in dissolution by co-milling based on drug properties. Using a biorelevant dissolution setup, a series of 29 structurally diverse and crystalline drugs were screened in co-milled and physically blended mixtures with Polyvinylpyrrolidone K25. Co-Milling Dissolution Ratios after 15 min (COMDR15 min) and 60 min (COMDR60 min) drug release were predicted by variable selection in the framework of a partial least squares (PLS) regression. The model forecasts the COMDR15 min (R2 = 0.82 and Q2 = 0.77) and COMDR60 min (R2 = 0.87 and Q2 = 0.84) with small differences in root mean square errors of training and test sets by selecting four drug properties. Based on three of these selected variables, applicable multiple linear regression equations were developed with a high predictive power of R2 = 0.83 (COMDR15 min) and R2 = 0.84 (COMDR60 min). The most influential predictor variable was the median particle size of the pure drug, followed by the calculated drug logD6.5 value, the calculated molecular descriptor Kappa 3 and the apparent solubility of pure drug after 24 h dissolution. The study demonstrates the feasibility of forecasting the dissolution rate improvements of poorly water solube drugs through co-milling. These models can be applied as computational tools to guide formulation in early stage development.

Dissolution-Hollow Fiber Membrane (D-HFM) System to Anticipate Biopharmaceutics Risk of Tablets and Capsules

A dissolution-hollow fiber membrane (D-HFM) system with relatively high area/volume ratio was previously characterized and showed favorably high percent drug absorption. Also, it's in vitro permeation constant (Kp.Ç.) was close to in vivo human permeation constant (kp). The objective of the current study was to predict the in vivo human absorption profile and biopharmaceutic performance of five drug products using the D-HFM system. Four immediate-release (IR) and one extended-release (ER) solid oral dosage form were subjected to the D-HFM system. Tablets and capsule dissolution were also measured using USP apparatus II. Drug solutions were also subjected to D-HFM testing. Predicted and observed absorption profiles in D-HFM system showed close agreement for each solid oral dosage form. Levy-Polli plots from D-HFM system successfully predicted the four IR products to be low biopharmaceutic risk due to permeation rate limited or mixed dissolution/permeation rate limited absorption, and successfully predicted metoprolol ER product to be high biopharmaceutic risk due to dissolution rate limited absorption. These observations showed potential of the in vitro D-HFM system to be utilized in biopharmaceutics risk assessment of in vivo tablet and capsule performance.

Biopharmaceutical evaluation of kavain in Piper methysticum G. Forst dried extract: Equilibrium solubility and intestinal permeability in Caco-2 cell model

Ethnopharmacological relevancePiper methysticum G. Forst, popularly known as kava, is a traditional medicinal plant native from South Pacific islands and widely used to treat anxiety, depression and stress. The psychoactive properties are related to the kavalactones, mainly kavain. Aim of the studyTo evaluate the biopharmaceutical properties of synthetic kavain and when present in kava dried extracts by means of equilibrium solubility and intestinal permeability studies in the Caco-2 cell model. Materials and methodsThe equilibrium solubility of kavain was performed using a shake flask incubator at 37 °C in different media at physiological pH range (1.2–6.8). The intestinal permeability of kavain evaluated in Caco-2 cells in the presence and absence of the P-glycoprotein inhibitor verapamil. Kavain concentrations were determined by reversed phase high performance liquid chromatography (HPLC). ResultsHPLC methods were developed and fully validated for kavain quantitation. Kavain demonstrated low solubility and the pH of the aqueous media did not affect its solubility. Kavain was found to be highly permeable and efflux of kavain mediated by P-glycoprotein was not significant during intestinal permeation. ConclusionThe results of biopharmaceutical studies provided useful information for predicting availability of kavain from the gastrointestinal tract and this compound was ranked as BCS Class II, exhibiting dissolution rate-limited absorption.

Development, Characterization and Analysis of Azelnidipine Co-Crystals

Azelnidipine, an anti-hypertensive drug of dihydropyridine class, has low solubility and high permeability drug (class-2) and thus often shows dissolution rate-limited oral absorption and high variability in pharmacological effects. The purpose of study was to prepare co-crystals of AZL to enhance its solubility. Co-crystals were prepared by solvent evaporation method using different co-crystal formers. The prepared co-crystals were evaluated for solubility. The solid state property was characterized by microscopy, differential scanning calorimetry (DSC) and Fourier transfer infrared spectroscopy (FTIR). It was observed that the solubility of AZL co-crystals was significantly more than AZL. Co-crystal using succinic acid and saccharine gave maximum solubility. The microscopy, FTIR and DSC and studies of cocrystal confirmed the formation of co-crystals and indicated that new interactions were formed. In conclusion, co-crystals of AZL lead to the solubility enhancement and this can be further explored to study the impact of increased solubility on the bioavailability of AZL.

A Systemic Review on the Self Micro Emulsifying Drug Delivery System

Comfort direction and painless method made oral route the most favored. Mainstream of recent active constituents have less oral bioavailability because of dissolution rate limited absorption. While many inventive methods like complexation, cocrystals exist, solid dispersions, pH modification and, lipid-based delivery systems conclusively improved appliance with the seeming rise in drug absorption. Among lipid-based formulations, self-micro emulsifying formulations (SMEDDS) (droplet size < 100 nm) are evident to enhance permeation across intestinal membrane, protection of drug against gastric effect, unit dosage is possible, increased bioavailability of drug, reduces the dose of drug etc. Numerous components are used to formulate these dosage forms like Oil, surfactants, Co-surfactant and lipids mixture contribute to the enhancement in oral bioavailability through promoting the lymphatic passage; thus, hepatic first pass metabolism can be overcoming. The present review highlights comprehensive information on the formulation design, probable mechanisms and characterization of SMEDDS

Formulation, Design and In-Vitro Characterization of Clopidogrel Bisulphate Nanosponge Tablets for Oral Administration

Poor bioavailability by the oral route is noticeable with the majority of new active pharmaceutical ingredients due to its dissolution rate limited absorption. A second-generation thienopyridine antiplatelet drug, though, it is BCS class II drug results in poor oral bioavailability. The present investigation was undertaken to prepare polymeric nanosponges to achieve improved solubility of clopidogrel bisulphate. Nanosponges using ethyl cellulose as a polymer and glutarldehyde as a cross-linker were prepared successfully by emulsion solvent diffusion method. Drug polymer compatibility study were performed by FTIR and DSC. To obtain optimized batch, 32 factorial designs were performed and all batches were evaluated. C1-C9 batches yields particle size (nm) between 87.28-183(nm), % drug content between 71.073±1.066 -88.663 ±0.549, % entrapment efficiency between 51.719±0.775- 81.765±0.506, % drug release 75.120±0.407-97.416±0.336. Optimized batch exhibited particle size 87.28nm, % drug content 88.663 ±0.549, % entrapment efficiency 81.765±0.506, % drug release 97.416±0.336. An SEM and TEM image of optimized batch shows spongy and spherical nature of nanosponges. The optimized nanosponge formulations were converted into tablets to achieve immediate release drug delivery for oral route. These tablets were prepared using crospovidone and pregelatinised starch. All nine tablet batches were evaluated and F3 batch shows good results i.e. hardness (kg/cm2) 3.71±0.04, in- vitro disintegration time (min) 3.21±0.025 and % drug release 99.18±1.38. In vitro dissolution studies indicate that percent cumulative drug release follows zero order kinetics. Accelerated and long term stability data revealed no significant change in drug content and drug release at the end of 6 months. In conclusion, nanosponges could be a newly emerging approach to enhance aqueous solubility of BCS Class II drugs.

Enhancement of in vivo hypoglycemic effect of gliclazide by developing self-microemulsifying pellet dosage form

BackgroundThe present research was aimed to develop a self-microemulsifying drug delivery system (SMEDDS) pellet to increase the dissolution rate and in vivo hypoglycemic effect of gliclazide. Gliclazide belongs to BCS class 2 and it exhibits dissolution rate-limited absorption. Thus, dissolution enhancement of gliclazide from its dosage form is a prime requirement to achieve a better therapeutic effect. The solubility of gliclazide was estimated in oils, surfactants, and co-surfactants. A most effective self-emulsification region was identified using pseudoternary phase diagrams. The optimized liquid SMEDDS gliclazide formulation was converted to SMEDDS pellets using the extrusion-spheronization technique. The in vitro release and hypoglycemic effect of SMEDDS was compared with the marketed product.ResultsThe optimized liquid gliclazide SMEDDS formulations contained mixtures of Tween 80 and PEG 400 and Capmul MCM C8. The gliclazide SMEDDS in liquid preparation quickly formed a fine oil-in-water microemulsion having a globule size of 31.50 nm. In vitro release of gliclazide from SMEDDS pellets was 100.9% within 20 min. SMEDDS pellets exhibited a significant reduction in plasma glucose levels in albino mice compared to the marketed product.ConclusionThe results indicated that SMEDDS pellets could be effectively used to improve the oral delivery of gliclazide.

Formulation and in vitro Evaluation of Fast Dissolving Tablets of Febuxostat Using Co-Processed Excipients.

BackgroundFebuxostat is a novel, orally-administered, powerful, non-purine, xanthine oxidase inhibitor used for treating gout and ceaseless tophaceous gout. The drug exhibits low bioavailability (about 49%) which is ascribed to its dissolution rate-limited absorption.ObjectiveThe current work is aimed to provide a novel strategy to improve the dissolution profile and thus, the bioavailability of Febuxostat.MethodsFormulation of Fast Dissolving Tablets (FDT) is anticipated to provide immediate release of the drug, which in turn, will improve its dissolution profile to provide the initial surge in plasma concentration required in an acute gout attack. Incorporation of co-processed excipients in a tablet is known to improve the compressibility and disintegration characteristics of the tablets, which, in turn, result in enhanced in vitro drug release and improved bioavailability. A combination of crospovidone (it rapidly wicks saliva into the tablet to create the volume development and hydrostatic weight important to give quick disintegration) and microcrystalline cellulose (a highly compressible ingredient with good wicking and absorbing capacity) was, therefore, used as co-processed excipients.ResultsThe tablets were prepared by direct compression technique with the application of a 32 randomized full factorial design. The prepared tablets were able to release more than 80% of the drug within 10 minutes of the start of dissolution testing and were able to show a better drug release profile in comparison to available marketed formulation.ConclusionSo, it can be concluded that the developed fast release formulation was found to exhibit convincing in vitro results and may prove a boon in the treatment of acute gout attack after establishing in vivo potential.

Potential of Lipid Nanoparticles (SLNs and NLCs) in Enhancing Oral Bioavailability of Drugs with Poor Intestinal Permeability.

Lipid-based drug delivery systems has become a popular choice for oral delivery of lipophilic drugs with dissolution rate limited oral absorption. Lipids are known to enhance oral bioavailability of poorly water-soluble drugs in multiple ways like facilitating dissolution as micellar solution, enhancing the lymphatic uptake and acting as inhibitors of efflux transporters. Lipid nanoparticles are matrix type lipid-based carrier systems which can effectively encapsulate both lipophilic and hydrophilic drugs. Lipid nanoparticles namely solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are versatile drug delivery system and can be used for multiple routes of delivery like parenteral, topical, ocular, transdermal, and oral. Lipid nanoparticles are particularly attractive vehicles for peroral delivery of drugs with oral bioavailability problems as they are composed of lipid excipients which are cheap, easily available, and non-toxic; manufacturing technique is simple and readily scalable for large-scale production; the formulations provide controlled release of active components and have no stability issue. A large number of drugs have been incorporated into lipid nanoparticles with the objective of overcoming their poor oral bioavailability. This review tries to assess the potential of lipid nanoparticles for enhancing the oral bioavailability of drugs with permeability limited oral absorption such as drugs belonging to class IV of Biopharmaceutic Classification System (BCS) and protein and peptide drugs and also discusses the mechanism behind the bioavailability enhancement and safety issues related to such delivery systems.

Enhanced dissolution of solid dispersions containing bicalutamide subjected to mechanical stress

The anticancer drug bicalutamide was co-milled with either Macrogol 6000 or Poloxamer 407, and the physicochemical parameters that drive the phase transition of binary systems and influence the dissolution modification of bicalutamide were studied. Milled binary systems with reduced particle size were assessed by scanning electron microscopy and laser diffraction measurements. The results of thermal analysis supported by X-ray diffractometry confirmed the reduction of the crystallinity of bicalutamide co-milled with Macrogol 6000. Infrared spectroscopy was used to determine the molecular structure of the samples and indicated weak interactions between drug and polymer molecules. Two mechanisms were identified and were involved in up to 11-fold enhanced dissolution. The first one was based on improved wettability due to a decreased contact angle in samples containing Macrogol 6000. The second one relied on the solubilization of bicalutamide within nanoaggregates formed by Poloxamer 407 that resulted from its surface activity. This finding was confirmed with fluorescence spectroscopy, dynamic light scattering and cryogenic transmission electron microscopy assays. Given the dissolution rate-limited absorption combined with the reduced bioavailability of bicalutamide as a BCS class II drug, the assessment of the mechanisms driving the increase in drug dissolution is of particular importance in drug development.

Enhancement of Solubility of Rilpivirine by Inclusion Complexation with Cyclodextrins

Rilpivirine having lowest water solubility indicates class II drugs of BCS. These classes of drugs could potentially exhibit dissolution rate limited absorption. The objective of the present study is to improve the solubility and dissolution of Rilpivirine through inclusion complexation with βCD and HPβCD. Solid binary systems of Rilpivirine with βCD and HPβCD were prepared by solvent evaporation and kneading methods at 1:1 and 1:2 M ratios. The prepared solid binary systems were studied in solution state by phase solubility, in vitro dissolution rate and solid state by FTIR and XRD. The dissolution parameters were studied by using dissolution software PCP Disso V3. The drug content was uniform in all the solid binary systems with low SD and CV values. The apparent stability constant indicates there is a 1:1 stochiometric complex with βCD and HPβCD. The formation of inclusion complexes with βCD and HPβCD in the solid state were confirmed by FTIR, XRD. The dissolution data clearly suggest drug release was method dependent and type of cyclodextrin. The dissolution of solid binary systems obeyed first-order kinetics and model fitted with Hixon crowel. A true inclusion complex of Rilpivirine was observed with βCD and HPβCD. Dissolution properties of solid binary systems were superior then rilpivirine alone and its corresponding physical mixtures. Overall dissolution rate was solvent evaporation > kneaded binary systems > physical mixture > pure drug. One-way ANOVA results suggest the DE30 and DE60 values were significantly higher (P less than 0.05) in solid binary systems when compared to physical mixture and pure drug.

Studies on Solubility Enhancement of Poorly Soluble NSAID Using Dual Approach of Micro-environmental pH Modulation and Melt Granulation.

The present work describes the role of melt granulation and microenviron-mental pH modulation technique in solubility enhancement of a poorly water soluble NSAID, Aceclofenac (ACL). ACL is a BCS Class II drug showing dissolution rate limited absorption and pH dependent solubility, with higher solubility at alkaline pH. The limited solubility of ACL affects drug absorption and hence, therapeutic effect as the drug is indicated in conditions of pain where rapid onset of action is desired. Solubility enhancement of ACL was carried out by melt granulation technique using Gelucire 50/13 as molten carrier. The solubility of ACL was improved further by incorporating sodium hydrogen carbonate as pH modifier. The granules of ACL thus developed, were compressed into tablets using adsorbing carriers and other tableting excipients. This dual approach not only enhanced ACL solubility but also aided in achieving a pH independent release. The developed tablets exhibited pH independent release as well as enhanced rate of dissolution which is indicated by in vitro dissolution studies and ex-vivo intestinal permeation studies. The pH independent release would ensure absorption of drug throughout the gastrointestinal tract. The solubility enhancement of ACL was further confirmed by characterization studies such as DSC and XRD. Thus, the dual approach of melt granulation and micro-environmental pH modulation can be simple and scalable method for solubility enhancement of poorly soluble drugs showing pH dependent dissolution rate limited absorption.

Preparation, characterization, and cytotoxicity studies of niclosamide loaded mesoporous drug delivery systems

Recent reports on the anticancer potential of niclosamide have opened new avenues for anticancer treatment. Niclosamide belongs to the BCS class II, which is indicative of poor solubility and dissolution rate limited absorption. The aim of this study was to improve the dissolution rate of the drug by mesoporous drug delivery system. Porous silica grades (ordered and nonordered) with different pore size, pore volume and surface area were used in the study. The drug was loaded on silica carriers by the solvent evaporation method and characterized by BET surface area analysis, SEM, P-XRD, DSC, and FTIR. A discriminatory dissolution medium was developed for performing the in vitro dissolution of niclosamide. In comparison to the plain drug, all silica based formulations showed improvement in the dissolution rate. Maximum enhancement in the dissolution rate was observed in 1:2 drug:carrier loading ratio when compared to 1:1 ratio. Different properties of mesoporous silica like structural geometry, pore size and microenvironment pH demonstrated a significant impact on drug release from the formulations. Cytotoxicity of the optimized mesoporous formulations of niclosamide was explored in HCT-116, HCT-15, NCI, MDA-MB-231 and A549 cancer cell lines. Nearly 3 fold and 2 fold increase in% cytotoxicity of drug loaded Syloid-244 and Sylysia 350 at 1:2 ratio respectively, were observed when compared to the plain drug.

Review on the formulation considerations needed to produce a stable Self micro Emulsifying Drug Delivery System (SMEDDS)

Ease of administration and painless approach made oral route the most preferred. Poor oral bioavailability is pronounced with the majority of recent active ingredients because of dissolution rate limited absorption. Failure to attain intended therapeutic effect of the poor water soluble drugs by this route led to development of novel drug delivery systems which will fulfill therapeutic needs with minimum dose. Although many formulation approaches like solid dispersions, complexation, pH modifications and lipid based delivery systems finding increased appliance with the apparent increase in absorption of drug. Among lipid based formulations, self-micro emulsifying formulations (droplet size < 100 nm) are evident to improve the oral bioavailability of hydrophobic drugs primarily due to their efficiency in facilitating solubilization and in presenting the hydrophobic drug in solubilized form whereby dissolution process can be circumvented. Various components that are used to formulate these dosage forms like surfactants and lipids contribute to the overall improvement in oral bioavailability via promoting the lymphatic transport; thereby hepatic first pass metabolism can be surmounted. The present article gives exhaustive information on the formulation design and characterization of SMEDDS by which the bioavailability can be improved. In this review article, the various aspects of pharmaceutical SMEDDS where compiled together and target audience are specifically the B. Pharm and M. Pharm students so that their knowledge towards the subject concern can be enhanced and also at the same time can be motivated towards the publication.

A Review on Self Emulsified Drug Delivery System: A Promising Approach for Drug Delivery of BCS Class II and IV Drugs

Purpose: The oral delivery of drugs having poor aqueous solubility presents a major challenge. Selfemulsifying drug delivery systems (SEDDS), which are isotropic mixtures of oils, surfactants, solvents and cosolvents/surfactants, can improve the oral absorption of highly lipophilic drug compounds. The current review summarizes the latest research in the field of SEDDS and we emphasize basically the type of excipients used by current researcher. Approaches : SEDDS can be orally administered in soft or hard gelatin capsules and form fine relatively stable oil- in- water (o/w) emulsions upon aqueous dilution owing to the gentle agitation of the gastrointestinal fluids. Findings : Lipophilic drug compounds exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible plasma drug profiles. Conclusion : Almost 40% of the new drug compounds are hydrophobic in nature which draws attention towards SEDDS to improve the oral bioavailability of such drugs.

Production of nano-solid dispersions using a novel solvent-controlled precipitation process — Benchmarking their in vivo performance with an amorphous micro-sized solid dispersion produced by spray drying

A novel solvent controlled precipitation (SCP) process based on microfluidization was assessed to produce solid dispersions of carbamazepine, a poorly water-soluble drug with dissolution-rate limited absorption. A half-factorial design (23–1+2 central points) was conducted to study the effect of different formulation variables (viz. polymer type, drug load, and feed solids' concentration) on the particle size and morphology, drug's solid state and drug's molecular distribution within the carrier of the co-precipitated materials produced. Co-precipitated powders were isolated via spray drying (SD). Nano-composite aggregated particles were obtained among all the tests. The particle size of the aggregates was dependent on the feed solids' concentration, while the level of aggregation between nanoparticles was dependent on the drug-polymer ratio. Both amorphous and crystalline nano-solid dispersions were produced using the proposed SCP process. The solid dispersion produced was dependent on both the type of polymeric stabilizer chosen and the drug load. Controls of amorphous and crystalline nano-solid dispersions produced by SCP and an amorphous micro-solid dispersion produced by SD were tested for: in vitro dissolution, in vivo pharmacokinetics in mice, and long-term storage physical stability. Both nano-amorphous and nano-crystalline presented faster dissolution rates and enhanced bioavailabilities than the micro-sized amorphous powder. The reduction of particle size to the nano-scale was found to be more important than the amorphization of the drug. The long-term physical stability of the amorphous nano-solid dispersion and the amorphous micro-solid dispersion were comparable.

Steep improvement in dissolution profile of ezetimibe through co-inclusion in urea

The main objective of the present study was to simultaneously improve the dissolution profile and content uniformity of ezetimibe (EZ), a low dose poorly soluble drug, through co-inclusion in urea. EZ, a new category of cholesterol absorption inhibitor used in the treatment of primary hypercholesterolemia and sitosterolemia, reveals extremely poor solubility in water and dissolution rate limited absorption resulting in its low bioavailability. In the current study, EZ—a highly substituted potent compound which is normally non-complexing guest (NNCG) was successfully incorporated in urea lattice in the presence of readily complexing guest (RCG). The modified Zimmerschied calorimetric method was used for the estimation of the minimum amount of RCG required per unit weight of drug for co-inclusion in urea. Ezetimibe urea co-inclusion complexes (EZUCIC) containing varying proportions of RCG and NNCG were prepared and subjected to thermal analysis using DSC. The formation of EZUCIC was confirmed by FTIR, DSC, XRD and 1H-NMR studies. The thermal data was subjected to the regression studies to study the effect of the relative molar fraction of RCG on the heat of decomposition of EZUCIC. Study exhibited improved content uniformity of EZ in EZUCIC. In vitro dissolution rate studies exhibited steep improvement in the dissolution profile of EZ, a BCS class II drug. The dissolution data was subjected to various release kinetic models. Steep improvement in the dissolution profile offer urea co-inclusion technique a promising alternative for formulation of poorly soluble potent drug candidates into immediate release products with improved content uniformity.

Formulation and Pharmacokinetic Evaluation of Polymeric Dispersions Containing Valsartan.

Valsartan exhibits poor aqueous solubility and dissolution rate limited absorption. The lower solubility in the upper part of gastrointestinal tract (pH-dependant solubility) where its absorption window exists further contributes to the low oral bioavailability of valsartan. The present work was aimed to improve the in vivo pharmacokinetics of valsartan by preparing amorphous polymeric dispersions using Eudragit E 100 as carrier. Eudragit E 100 is a cationic polymer soluble in gastric fluid up to pH 5.0 and exhibits pH-dependent release. Hence, the dispersions prepared using Eudragit E 100 rapidly dissolves at lower pH presenting drug in molecularly dispersed and soluble form at its absorption site. Polymeric solid dispersions were prepared in different drug-to-carrier ratios. The prepared dispersions were evaluated for drug-carrier interactions, solid-state transitions and drug-release properties with the help of Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and in vitro dissolution studies. The optimized formulation containing valsartan was tested in rats for bioavailability and pharmacokinetic parameters and compared with that of valsartan pure drug. The results from FTIR studies indicated no interactions between drug and excipients. DSC studies confirmed reduction in crystallinity of drug. The dissolution studies performed in 0.1N HCl showed significant improvement (p<0.05) in the dissolution of valsartan. In vivo pharmacokinetic studies showed 199% relative bioavailability with significant improvement (p<0.05) in area under the curve compared to valsartan pure drug. Eudragit E 100 can be used to improve the dissolution of drugs that show low solubility at lower pH and thereby enhancing the bioavailability.

Simultaneous improvement in dissolution profile and content uniformity of lafutidine through co-inclusion in urea

In the present study, simultaneous improvement in dissolution profile and content uniformity of Lafutidine (LAF) has been achieved through co-inclusion in urea. LAF, a recently reported histamine H2 receptor antagonist used in the treatment of peptic ulcer, exhibits low aqueous solubility and dissolution rate limited absorption leading to its poor bioavailability. LAF is a potent and normally non-complexing substituted cyclic organic compound. Urea, a well known host for forming inclusion complexes with linear organic compounds was successfully employed for co-inclusion of LAF in the presence of readily complexing guest (RCG). The modified Zimmerschied calorimetric method was employed for the estimation of the minimum amount of RCG required for co-inclusion of lafutidine in urea. The formation of lafutidine urea co-inclusion complexes (LUCIC) was confirmed by DSC, FTIR, XRD and 1H-NMR studies. LUCIC complexes containing varying proportions of guests were prepared and subjected to thermal analysis using DSC. The thermal data was subjected to the regression analysis to study the influence of the relative molar proportion of RCG on the heat of decomposition of LUCIC. Study revealed good content uniformity of lafutidine in LUCIC. In vitro dissolution rate studies demonstrated steep improvement in dissolution profile of LAF—a BCS class II drug. The resulting dissolution data was subjected to various release kinetic models. Studies reveal that urea co-inclusion complex formation may be a promising technique for the formulation of potent poorly soluble drugs into immediate release products with improved content uniformity.

Self-Microemulsifying Drug Delivery Systems: An Attractive Strategy for Enhanced Therapeutic Profile.

Ease of administration and painless approach made oral route the most preferred. Poor oral bioavailability is pronounced with the majority of recent active ingredients because of dissolution rate limited absorption. Failure to attain intended therapeutic effect of the poor water soluble drugs by this route led to development of novel drug delivery systems which will fulfill therapeutic needs with minimum dose. Although many formulation approaches like solid dispersions, complexation, pH modification, and cocrystals exist, lipid based delivery systems finding increased appliance with the apparent increase in absorption of drug. Among lipid based formulations, self-microemulsifying formulations (droplet size < 100 nm) are evident to improve the oral bioavailability of hydrophobic drugs primarily due to their efficiency in facilitating solubilization and in presenting the hydrophobic drug in solubilized form whereby dissolution process can be circumvented. Various components that are used to formulate these dosage forms like surfactants and lipids contribute to the overall improvement in oral bioavailability via promoting the lymphatic transport; thereby hepatic first pass metabolism can be surmounted. The present paper gives exhaustive information on the formulation design and characterization of SMEDDS along with the probable mechanisms by which the bioavailability can be improved with SMEDDS.