Drug release from liquisolid systems: speed it up, slow it down

INTRODUCTION: Today, the properties of many new chemical entities have shifted towards higher molecular weights and this in turn increases the lipophilicity hence decreasing aqueous solubility. The low solubility of drugs usually has in vivo consequences such as low bioavailability, increased chance of food effect and incomplete release from the dosage form. AREAS COVERED: The present review discusses the advantages of the liquisolid technology in formulation design of poorly water soluble drugs for dissolution enhancement and highly water soluble drugs for slow release pattern. EXPERT OPINION: With the advent of high throughput screening and combinatorial chemistry, it has been shown that most of the new chemical entities have a high lipophilicity and poor aqueous solubility, hence poor bioavailability. In order to improve the bioavailability, the release rate of these drugs should be enhanced. Although there are multiple technologies to tackle this issue, they are not cost effective due to the involvement of sophisticated machinery, advanced preparation techniques and complicated technology. As the liquisolid technology uses a similar production process as the conventional tablets, this technology to improve the release rate of poorly water soluble drugs will be cost effective. This technology also has the capability to slow down drug release and allows preparing sustained release tablets with zero order drug release pattern. The excipients required for this technology are conventional and commonly available in the market. The technology is in the early stages of its development with extensive research currently focused on. It is envisaged that the liquisolid compacts could play a major role in the next generation of tablets.     

难溶性药物新型速崩片的研究进展

摘 要难溶性药物由于其溶解度低,导致吸收差,生物利用度低,临床应用受到很大局限。运用各种增溶技术,增加难溶性药物的溶解度,进而提高其生物利用度十分必要。然而现有的增溶技术常常会造成增溶后含药量低、粘度高等问题,容易造成服用量的增大以及制剂困难。速崩片可通过局部快速释放达到提高患者顺应性以及增溶的目的。本文针对近年来出现的难溶性药物速崩片增溶技术,综述了固体分散体速崩片、包合物速崩片、乳剂冻干片、自微乳分散片、纳米混悬剂冻干片、微丸速崩片、水分散体冻干片等制剂新技术在增加难溶性药物溶解度、改善生物利用度、提高患者用药依从性等方面的应用。     

Potentials and challenges in self-nanoemulsifying drug delivery systems

Introduction: A significant number of new chemical entities (almost 40%), that are outcome of contemporary drug discovery programs, have a potential therapeutic promise for patient, as they are highly potent but poorly water soluble resulting in reduced oral bioavailability. Self-nanoemulsifying drug delivery systems (SNEDDS) have emerged as a vital strategy to formulate these poorly soluble compounds for bioavailability enhancement.

Areas covered: The review gives an insight about potential of SNEDDS with regards to oral drug delivery. The effect of various key constituents on formulation of SNEDDS and their applications in oral drug delivery is also discussed. Various aspects of formulation, characterization and biopharmaceutical aspects of SNEDDS are also been explored. The choice and selection of excipients for development of SNEDDS is also discussed.

Expert opinion: The ability of SNEDDS to present the drug in single unit dosage form either as soft or hard gelatin capsule with enhanced solubility maintaining the uniformity of dose is unique. With the ease of large-scale production, high drug-loading capacity, improvement in release behavior of poorly water-soluble drugs and improvement of oral bioavailability, SNEDDS have emerged as preferable system for the formulation of drug compounds with bioavailability problems due to poor aqueous solubility.     

Liquisolid technology for dissolution rate enhancement or sustained release

Importance of the field: Most of the drugs that have been invented are of BCS Class II. Therefore, dissolution rate enhancement is the key aspect for absorption of these drugs. Liquisolid technology is very efficient in the dissolution rate enhancement of these drugs. Moreover, use of other polymers such as Eudragit and hydroxypropyl methylcellulose in the liquisolid approach can cause sustained release of drugs. This review focuses on the formulation approaches of liquisolid tablets or compacts along with its fundamental principles.

Areas covered in this review: The review focuses on the developments in liquisolid technology from 1998 to 2009 with in vitro and in vivo performance of the dosage forms prepared using this technology.

What the reader will gain: Benefits of this review include a concise evaluation of this technology by focusing on the scope of future developments to be done using this technique.

Take home message: Liquisolid technology, the next generation of powder solution technology, can be helpful for enhancing dissolution rates of poorly water-soluble drugs as well as effective at sustaining drug release.     

Formulation factors affecting the release of ezetimibe from different liquisolid compacts

Context: Liquisolid technique is one of the methods used to improve the dissolution rate of the poorly water soluble drugs utilizing non volatile liquids.Objectives: Enhancement of the release of ezetimibe from different liquisolid formulations.Materials and Methods: Four liquid vehicles were used to prepare the liquid medications with different drug concentrations. The interaction between the drug and the excipients in liquisolid powders were characterized by DSC, X-ray, FTIR and SEM. Furthermore, the powder characteristics were evaluated by Carr’s Index and powder wetting time determinations, respectively. All prepared formulations were compressed at different pressures to end with the same constant porosity and the tablets were evaluated by different tests and compared with conventional formula. Results and Discussion: No interaction had been detected in all liquisolid formulations as shown in the results of XRD, FTIR, DSC and SEM. In addition to that, all liquisolid compacts had expressed faster dissolution profiles compared with that of conventional formula. Conclusion: The dissolution rate was affected by the drug concentration, solubility of the drug in the liquid vehicle and type of carrier. In addition, the presence of the liquid vehicle has been found to affect the mechanical properties of the liquisolid formulations.     

Quality by design approach for oral bioavailability enhancement of Irbesartan by self-nanoemulsifying tablets

Abstract

The present investigation was aimed to develop self-nanoemulsifying tablets (SNETs) as novel nanosized solid oral dosage forms for Irbesartan (IRB). In the first part of the investigation, IRB-loaded self-nanoemulsifying drug delivery systems (SNEDDS) were developed using Capryol 90 – Cremophor RH40 – Transcutol P as three component (oil – surfactant – cosurfactant) SNEDDS system. On the basis of ternary phase diagram IRB-loaded SNEDDS were optimized by using Design of Experiments (DoE) and Principal component analysis (PCA) with amount of oil and surfactant: cosurfactant ratio (K_m) as factors. The optimized batch of IRB-loaded SNEDDS comprised of 31.62% w/w of Capryol 90 as oil phase, 49.90% w/w Cremophor RH40 as surfactant and 18.48% w/w of Transcutol P as cosurfactant exemplified a mean globule size as 23.94?nm. Further, with an aim to provide enhanced patient compliance the optimized batch of liquid SNEDDS was transformed into SNETs by liquisolid compaction technique. Solid state characterization of IRB-loaded liquisolid mixtures revealed a decrease in the magnitude of crystallinity of IRB. The results of in vitro drug release study of optimized batch of IRB-loaded SNET illustrated a remarkable improvement in the dissolution rate as compared to marketed tablets (Avapro® 75). The results of in vivo pharmacokinetic study on Wister rats revealed 1.78-fold enhancement in oral bioavailability for IRB-loaded SNETs against marketed tablets. The present study proposed SNEDDS as one of the suitable approach for developing nanosized solid oral dosage forms of poorly water soluble drugs like Irbesartan.     

Enhancement of griseofulvin release from liquisolid compacts

The potential of hydrophilic aerogel formulations and liquisolid systems to improve the release of poorly soluble drugs was investigated using griseofulvin as model drug. The in vitro release rates of this drug formulated as directly compressed tablets containing crystalline griseofulvin were compared to aerogel tablets with the drug adsorbed onto hydrophilic silica aerogel and to liquisolid compacts containing the drug dissolved or suspended in PEG 300. Furthermore, the commonly used carrier and coating materials in liquisolid systems Avicel® and Aerosil® were replaced by Neusilin®, an amorphous magnesium aluminometasilicate with an extremely high specific surface area of 339 m²/g to improve the liquisolid approach.Both the liquisolid compacts containing the drug dissolved in PEG 300 and the aerogel tablets showed a considerably faster drug release than the directly compressed tablets. With liquisolid compacts containing the drug suspended in PEG 300, the release rate increased with rising fraction of dissolved drug in the liquid portion. It could be shown that Neusilin® with its sevenfold higher liquid adsorption capacity than the commonly used Avicel® and Aerosil® allows the production of liquisolid formulations with lower tablet weights.     

Investigation of the effect of solubility increase at the main absorption site on bioavailability of BCS class II drug (risperidone) using liquisolid technique

BCS class II drugs usually suffer inadequate bioavailability as dissolution step is the absorption rate limiting step. In this work, the effect of solubility increase at the main absorption site for these drugs was investigated using risperidone as a drug model. Liquisolid technique was applied to prepare risperidone per-oral tablets of high dissolution rate at intestinal pH (6.8) using versatile nonionic surfactants of high solubilizing ability [Transcutol HP, Labrasol and Labrasol/Labrafil (1:1) mixture] as liquid vehicles at different drug concentrations (10–30%) and fixed (R). The prepared liquisolid tablets were fully evaluated and the dissolution rate at pH 6.8 was investigated. The formulae that showed significantly different release rate were selected and subjected to mathematical modeling using DE₂₅, MDT and similarity factor (f2). Depending on mathematical modeling results, formula of higher dissolution rate was subjected to solid state characterization using differential scanning calorimetric (DSC), infrared spectroscopy (IR) and X-ray diffraction (XRD). Finally, the drug bioavailability was studied in comparison to conventional tablets in rabbits. Results showed that liquisolid tablet prepared using Labrasol/Labrafil (1:1) mixture as liquid vehicle containing 10% risperidone is a compatible formula with law drug crystallinity and higher dissolution rate (100% in 25?min). The drug bioavailability was significantly increased in comparison to the conventional tablets (1441.711?μg h/mL and 137.518?μg/mL in comparison to 321.011?μg h/mL and 38.673?μg/mL for AUC and Cp_max, respectively). This led to the conclusion that liquisolid technique was efficiently improved drug solubility and solubility increase of BCS class II drugs at their main absorption site significantly increases their bioavailability.     

Liquisolid Tablets for Dissolution Enhancement of a Hypolipidemic Drug

This investigation was aimed to improve the dissolution rate of the poorly soluble drug lovastatin, by formulating it as a liquisolid compact. Different liquisolid compacts were prepared using mathematical formulae to calculate the required quantities of powder and liquid ingredients to produce acceptably flowable and compressible admixture. Avicel PH 200, Cab-O-Sil, sodium starch glycolate and PEG 400 were employed as carrier, coating material, disintegrant and non-volatile liquid vehicle, respectively. The various drug to liquid and carrier to coating ratio were used to prepare liquisolid compacts. The formulated liquisolid tablets were evaluated for weight variation, hardness, drug content, friability and disintegration time. The in vitro release characteristics of the drug from tablets formulated by direct compression and liquisolid technique were compared in two different dissolution media. The tableting properties of the liquisolid compacts were within the acceptable limits and drug release rates were distinctly higher as compared to directly compressed tablets. The FTIR spectra showed no interaction between drug-excipient and disappearance of the characteristic absorption band of lovastatin in liquisolid formulations could be attributed to the formation of hydrogen bonding between the drug and liquid vehicle, which resulted in dissolution enhancement. Thus, the liquisolid technique was found to be a promising approach for improving the dissolution of a poorly soluble drug like lovastatin.     

Self-emulsifying drug delivery system and the applications in herbal drugs

Abstract

Herbal drugs have been used for thousands of years in the east and have had a recent resurgence in popularity among consumers in the west. However, most of herbal drug are poorly soluble and have hydrophobic properties and poor distribution, leading to reduced bioavailability and hence decreased treatment efficacy, requiring repeated administration or increased dose. In the past few decades, considerable attention has been focused on the development of self-emulsifying drug delivery system (SEDDS) for herbal drugs. SEDDS is isotropic and thermodynamically stable solutions consisting of oil, surfactant, co-surfactant and drug that can spontaneously form oil-in-water micro/nanoemulsion when mixed with water under gentle stirring. The formulation can be a viable alternative to classical formulations to take advantage of their lipophilic nature and to solve their problems of poor solubility, poor bioavailability, low oral absorption and instability. The mechanism of self-emulsification, solubility studies, construction of phase diagram, optimization and characterization of herbal drugs-loaded SEDDS formulation and in situ absorption evaluation of herbal drugs in rat intestine are presented in our article.     

Liquisolid systems to improve the dissolution of furosemide

A liquisolid system has the ability to improve the dissolution properties of poorly water soluble drugs. Liquisolid compacts are flowing and compactable powdered forms of liquid medications. The aim of this study was to enhance the in vitro dissolution properties of the practically water insoluble loop diuretic furosemide, by utilising liquisolid technique. Several liquisolid tablets were prepared using microcrystalline cellulose (Avicel® pH-101) and fumed silica (Cab-O-Sil® M-5) as the carrier and coating materials, respectively. Polyoxy-ethylene-polyoxypropylene-polyoxyethylene block copolymer (Synperonic® PE/L 81); 1,2,3-propanetriol, homopolymer, (9Z)-9-octadecenoate (Caprol® PGE-860) and polyethylene glycol 400 (PEG 400) were used as non- volatile water-miscible liquid vehicles. The liquid loading factors for such liquid vehicles were calculated to obtain the optimum amounts of carrier and coating materials necessary to produce acceptable flowing and compactible powder admixtures viable to produce compacts. The ratio of carrier to coating material was kept constant in all formulations at 20 to 1. The formulated liquisolid tablets were evaluated for post compaction parameters such as weight variation, hardness, drug content uniformity, percentage friability and disintegration time. The in-vitro release characteristics of the drug from tablets formulated by direct compression (as reference) and liquisolid technique, were studied in two different dissolution media. Differential scanning calorimetry (DSC) and Fourier-Transform infrared spectroscopy (FT-IR) were performed. The results showed that all formulations exhibited higher percentage of drug dissolved in water (pH 6.4–6.6) compared to that at acidic medium (pH 1.2). Liquisolid compacts containing Synperonic® PE/L 81 demonstrated higher release rate at the different pH values. Formulations with PEG 400 displayed lower drug release rate, compared to conventional and liquisolid tablets. DSC and FT-IR indicated a possible interaction between furosemide and tablet excipients that could explain the dissolution results. Caprol® PGE-860, as a liquid vehicle, failed to produce furosemide liquisolid compacts.     

Pharmaceutical particle technologies: An approach to improve drug solubility,dissolution and bioavailability

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration. The particle technology involves several approaches from the conventional size reduction processes to the newer, novel particle technologies that modify the solubility properties of the drugs and produce solid, powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms. This review highlights the solid particle technologies available for improving solubility, dissolution and bioavailability of drugs with poor aqueous solubility.     

Experimental and Computational Screening Models for Prediction of Aqueous Drug Solubility

Purpose. To devise experimental and computational models to predict aqueous drug solubility. Methods. A simple and reliable modification of the shake flask method to a small-scale format was devised, and the intrinsic solubilities of 17 structurally diverse drugs were determined. The experimental solubility data were used to investigate the accuracy of commonly used theoretical and semiexperimental models for prediction of aqueous drug solubility. Computational models for prediction of intrinsic solubility, based on lipophilicity and molecular surface areas, were developed. Results. The intrinsic solubilities ranged from 0.7 ng/mL to 6.0 mg/mL, covering a range of almost seven log₁₀ units, and the values determined with the new small-scale shake flask method agreed well with published solubility data. Solubility data computed with established theoretical models agreed poorly with the experimentally determined solubilities, but the correlations improved when experimentally determined melting points were included in the models. A new, fast computational model based on lipophilicity and partitioned molecular surface areas, which predicted intrinsic drug solubility with a good accuracy (R ²of 0.91 and RMSE_tr of 0.61) was devised. Conclusions. A small-scale shake flask method for determination of intrinsic drug solubility was developed, and a promising alternative computational model for the theoretical prediction of aqueous drug solubility was proposed.     

Enhancement of famotidine dissolution rate through liquisolid tablets formulation: in vitro and in vivo evaluation

Although famotidine was reported to be 7.5 and 20 times more potent than ranitidine and cimetidine, respectively, its oral bioavailability is low and variable; due mainly to its poor aqueous solubility. The purpose of this study was to improve famotidine dissolution through its formulation into liquisolid systems and then to investigate the in vitro and in vivo performance of the prepared liquisolid tablets. The new mathematical model was utilized to formulate various liquisolid powder systems. Both DSC and XRD suggested loss of famotidine crystallinity upon liquisolid formulation which was further confirmed by SEM indicating that even though the drug existed in a solid dosage form, it is held within the powder substrate in a solubilized, almost molecularly dispersed state, which contributed to the enhanced drug dissolution properties. All the tested liquisolid tablet formulations showed higher drug dissolution rates (DR) than the conventional, directly compressed tables. In addition, the selected optimal formula released 78.36% of its content during the first 10 min which is 39% higher than that of the directly compressed tablets. Further, the bioavailability study indicated that the prepared optimal liquisolid formula did not differ significantly from the marketed famotidine tablets concerning Cmax, tmax, and AUC(0-8) at P<0.05.     

Insoluble drug delivery strategies: review of recent advances and business prospects

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects.KEY WORDS: Bioavailability, Cocrystals, Solubility, Inclusion complexation, Nanoparticles, Self-emulsifying formulations, Proliposomes     

The applicability of sucrose laurate in hot-melt technology

Nowadays, one of the most important task of the pharmaceutical technology is to optimize the dissolution of active ingredients, because most of the drug candidates have a poorly water solubility and hence a slow absorption. According to the latest examinations, the bioavailability of poorly water soluble drugs can be increased significantly by using surfactants or the mixture of surfactants and polymers. Nowadays, surfactants (like polysorbates) are generally used in the production of solid dispersions, so the use of surface-active sucrose esters can be resulted an innovative solution in the pharmaceutical technology. The aim of our investigation was to examine the applicability of sucrose laurate in hot-melt technology in order to influence the crystalline structure and dissolution rate of a poorly water soluble drug (gemfibrosil) having low-melting point. The results of the X-ray powder diffractometry have showed that the sucrose laurate had no significant effect on the crystallization degree of the drug which is important in case of the stability. On the bases of the results of in-vitro dissolution studies, it can be concluded that the sucrose laurate (using minimum 5%) can be well applied in hot-melt technology with carriers having characteristic melting point (e.g. Macrogol) to increase the dissolution rate of poorly soluble drugs.     

Enhancement of dissolution rate of piroxicam using liquisolid compacts

Piroxicam is a poorly soluble, highly permeable drug and the rate of its oral absorption is often controlled by the dissolution rate in the gastrointestinal. The poor dissolution rate of water-insoluble drugs is still a major problem confronting the pharmaceutical industry. There are several techniques to enhance the dissolution of poorly soluble drugs. Among them, the technique of liquisolid compacts is a promising technique towards such a novel aim. In this study, the dissolution behaviour of piroxicam from liquisolid compacts was investigated in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.2). To this end, several liquisolid tablets formulations containing various ratios of drug:Tween 80 (ranging from 10% to 50% w/w) were prepared. The ratio of microcrystalline cellulose (carrier) to silica (coating powder material) was kept constant in all formulations. The results showed that liquisolid compacts demonstrated significantly higher drug release rates than those of conventionally made (capsules and directly compressed tablets containing micronized piroxicam). This was due to an increase in wetting properties and surface of drug available for dissolution.     

Formulation and optimization of liquisolid compact for enhancing dissolution properties of efavirenz by using DoE approach

Efavirenz displays low and variable bioavailability because of its poor aqueous solubility and high log P-value. The present investigation was aimed to improve the dissolution profile of efavirenz by using a simple, scalable and cost-effective technique of liquisolid compact. The drug was dissolved in Trancutol-HP for preparing the liquid medicament which was subsequently mixed with carrier and coating material to make free-flowing and compressible powder. 3² full factorial design was used to optimize the formulation in which the Neusilin US2/Corn starch ratios and carrier/coating material ratio were selected as independent variables. The results of in-vitro dissolution test proved that liquisolid compacts have significantly higher dissolution rate than tablets containing pure drug. Results of DSC and XRD studies suggested that the high dissolution of the drug from the liquisolid compacts was possibly because of the drug either being in an amorphous state or being molecularly dispersed within the internal matrix of compacts.     

Refining stability and dissolution rate of amorphous drug formulations

Introduction: Poor aqueous solubility of active pharmaceutical ingredients (APIs) is one of the main challenges in the development of new small molecular drugs. Additionally, the proportion of poorly soluble drugs among new chemical entities is increasing. The transfer of a crystalline drug to its amorphous counterpart is often seen as a potential solution to increase the solubility. However, amorphous systems are physically unstable. Therefore, pharmaceutical formulations scientists need to find ways to stabilise amorphous forms.

Areas covered: The use of polymer-based solid dispersions is the most established technique for the stabilisation of amorphous forms, and this review will initially focus on new developments in this field. Additionally, newly discovered formulation approaches will be investigated, including approaches based on the physical restriction of crystallisation and crystal growth and on the interaction of APIs with small molecular compounds rather than polymers. Finally, in situ formation of an amorphous form might be an option to avoid storage problems altogether.

Expert opinion: The diversity of poorly soluble APIs formulated in an amorphous drug delivery system will require different approaches for their stabilisation. Thus, increased focus on emerging techniques can be expected and a rational approach to decide the correct formulation is needed.     

Cyclodextrin and phospholipid complexation in solubility and dissolution enhancement: a critical and meta-analysis

Introduction: Poor solubility and dissolution of drugs are the major challenges in drug formulation and delivery. In order to improve the solubility and dissolution profile of drugs, various methods have been investigated so far. The cyclodextrin (CD) complexation and phospholipid (PL) complexation are among the exhaustively investigated methods employed for more precise improvement of the solubility and dissolution of poorly water-soluble drugs.

Areas covered: The article discusses the CD and PL complexation techniques of solubility and dissolution enhancement. Various studies reporting the CD and PL complexation as the potential approaches to improve the dissolution, absorption and the bioavailability of the drugs have been discussed. The article critically reviews the physicochemical properties of CDs and PLs, eligibility of drugs for both the complexation, thermodynamics of complexation, methods of preparation, characterization, advantages, limitation and the meta-analysis of some studies for both the techniques.

Expert opinion: The CD and PL complexation techniques are very useful in improving solubility and dissolution (and hence the bioavailability) of biopharmaceutical classification system Class II and Class IV drugs. The selection of a particular kind of complexation can be made on the basis of eligibility criteria (of drugs) for the individual techniques, cost, stability and effectiveness of the complexes.