Madhabhai M. Patel is a professor in the Department of Pharmaceutics, Kalol Pharmacy College, Kalol, Gujarat, India.

Madhabhai M. Patel

Chronotherapeutic drug delivery systems (CRDDS) have been recognized as potentially beneficial to the chronotherapy (timeoptimized therapy) of widespread chronic diseases that display time-dependent symptoms, such as ulcers, asthma, cardiovascular diseases and arthritis. CRDDS control drug release according to circadian rhythms and the timing of symptoms.

  A number of CRDDS have been developed to synchronize medication with the intrinsic biorhythm of the disease; with conventional and modifiedrelease formulations being administered at different times of the day in accordance with the circadian onset of the disease.

People with rheumatoid arthritis (RA), usually experience peak pain in the morning, which decreases throughout the day. In this scenario, an evening once-a-day nonsteroidal anti-inflammatory drug (NSAID) schedule is recommended. If pain is worse during early afternoon or at night, however, a morning or an evening onceaday NSAID schedule may be recommended. The exact dose depends on the severity of the patient's pain and their individual physiology.

  Most newly developed antiRA agents are now available as oncedaily dosage forms; the absorption kinetics of conventional dosage forms are inadequate in the morning, which is when the need of patient is greatest, and drug levels of once-a-day formulations that have nighttime dosing indication tend to fall off towards the end of the 24h dosing interval, resulting in reduced protection against the pain when the need is more. 

Diclofenac sodium (DS) is a potent NSAID frequently used to treat RA; however, oral administration of DS as a conventional formulation generally fails to achieve the desired clinical effect because it elicits patient incompliance — many fail to take the dosage early enough in the morning to coordinate with the rhythm of RA. Therefore, the development of oral controlledrelease formulations of this drug is highly desirable.  

The Pulsincap system, developed and registered by R.P. Scherer International Corp. (MI, USA), is a special dosage form comprising a waterinsoluble capsule body enclosing a drug reservoir. The body is closed at the open end with a swellable hydrogel plug, which consists of insoluble, but permeable and swellable polymers (e.g., polymethacrylates), erodible compressed polymers (e.g., hydroxypropylmethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide), congealed melted polymers (e.g., saturated polyglycolated glycerides, glyceryl monooleate) and/or enzymatically controlled erodible polymers (e.g., pectin). When this capsule comes in to contact with the dissolution fluid, it swells and, after a lag time, the plug pushes itself outside the capsule and rapidly releases the drug. The length of the plug and its position of insertion into the capsule controls the lag time.

In our study, a modified Pulsincap device containing DS was developed to target drug release in the colon. This is a sitespecific and timedependent formulation; by administering the formulation at 10.00 pm, symptoms that are experienced early in the morning are avoided. This therapeutic effect is prolonged by continuously releasing the medication over an extended period of time after administering a single dose. The study objective was to explore the time-and pHdependent controlled drug delivery of DS using the pulsincap system. 

DS was obtained as gift sample from Welable Parma Ltd (India). pHsensitive methacrylic acid copolymers (Acrycoat L 100 and S 100) were supplied as gifts by Corel Pharma Ltd (India). Hydroxypropylmethyl celluloseK4M (HPMC) and hydroxypropyl cellulose (HPCH) were obtained as a gift from Colorcon (India). Sodium carboxymethyl cellulose (NaCMC), cellulose acetate phthalate (CAP), guar gum (GG) and sodium alginate (NaAlg) were purchased from S.D. Fine Chem. Ltd (India). All other chemicals used were of analytical grade. 

Step 1: preformulation study for polymer selection

According to the literature reviewed, the pH in the proximal colon ranges from 6.6 to 7.0 (~6.8).

  A combination of acrycoat L 100 and S 100 was therefore designed to maintain the optimum pH. Accordingly, acrycoat L 100 (soluble in pH 6 and above) and acrycoat S 100 (soluble in pH 7 and above) were mixed in different ratios (1:1, 1:1.5, 1:2 and 1:3) and the final mixtures underwent solubility studies at pH 6.8. Based on the solubility parameters, we ascertained that acrycoat L 100 and acrycoat S 100 at a ratio of 1:2 was highly soluble in pH 6.8. This combination was therefore selected for the preparation of microcapsules.

The acrycoat microcapsules containing DS were prepared using emulsification-solvent evaporation in an oily phase. Accurately weighed acrycoat L 100 and acrycoat S 100 in the ratio of 1:2 were dissolved in 10 mL of acetone to form a homogenous polymer solution. Drug was separately suspended in the polymer solution, which was maintained in a continuous phase consisting of 70 mL of liquid paraffin, 1% (w/w) of span 80 and 0.01% (v/v) simethicon (as antifoaming agent) and was stirred constantly at 1000 rpm using a variable speed propeller stirrer to form a uniform emulsion. Approximately 5–10 mL of acetone was added to the external continuous phase to produce a stable oil/oil emulsion and then stirring was continued (3–4 h) until residual acetone had evaporated. The microcapsules formed were separated by filtration, washed three to four times with nhexane to remove adhering liquid paraffin, and dried for 48 h in a vacuum desiccator.  

Four batches were prepared by varying the drug to polymer ratio (D:P=1:0.5, 1:1, 1:1.5 and 1:2 (w/w) named DM 1 to 4, respectively) and evaluated for their flowability, particle size, drug content, surface morphology, compatibility and 

The body and the cap of the hard gelatin capsules were separated. The body portion of the capsules was placed on a wire mesh into a desiccator, which was then exposed to formaldehyde vapours for 6 h at room temperature and dried at 50 °C for 48 h in a hot air oven. The treated capsule bodies were capped with untreated caps and stored at ambient conditions in a sealed glass container.

The microcapsule formulation that had shown good drug content and release characteristics was placed into the capsule manually. Microcapsules (D:P=1:1.5) equivalent to 100 mg of DS were incorporated into treated bodies of empty capsule shells and plugged with different amounts (10, 15 and 20%) of hydrogel polymers; that is, NaCMC, GG, HPMC, HPCH and NaAlg.  

The joint of the treated body and cap of the capsule was sealed with a small amount of the 5% w/v ethyl cellulose ethanolic solution, and the filled and sealed capsules were then coated with CAP to ensure that drug release occurred in the colon rather than in the stomach. The various parameters of coating conditions were standardized, such as dipping time (5 s), coating solution concentration, temperature (25±10 °C) and drying time (5 min) at 500 °C. Coating was repeated until a 6–8% increase in weight was obtained. The percentage weight gain of the capsules before and after coating was determined using 

is the weight of the capsules after coating, Wo is the initial weight of capsules. The capsules were dried in an oven at 50 °C for 12 h. 

Determination of drug entrapment efficiency

  for each batch was calculated in terms of percentage drug entrapment (PDE) using the formula in 

Theoretical drug loading was calculated on the assumption that all of the drug in the polymer solution used was entrapped in the microcapsules and that none was lost during the preparation of the microcapsules. 

Practical drug loading was determined by taking accurately weighed microcapsules equivalent to 100 mg of drug and crushed using a glass pestle and mortar. Methanol was added in small quantities to the mortar and transferred to a 50mL volumetric flask. The mortar was washed with methanol to remove all traces of drug and transferred to the flask. The volume was then increased to 50 mL with the same solvent. The flasks were kept on a sonicator for 5 min. The solution was then filtered using a Whatman filter paper and a suitable dilution was made. Absorbance was read at 281 nm against methanol as a blank. The PDEs of DM1 to DM4 are reported in 

Micromeritic properties of prepared microcapsules

The micromeritic properties of the microcapsules

  were determined by the angle of repose (using the fixedbase funnel method), bulk density, tapped density and Carr's index. Bulk and tapped densities were measured in 10 mL of a graduated glass cylinder. The sample contained in the cylinder was tapped mechanically by a constantvelocity rotating cam. The results are shown in 

Table 1: Physical characteristics of DS microcapsules.			

Particle size and morphology study of microcapsules

The average particle size and morphology of the drugloaded microcapsules

 (n=100) of batches DM1 to DM4 were assessed by using a digital optical microscope (Labomed CX RIII, Ambala, India) and SEM microscopy, respectively. The microcapsules' morphology was characterized by their sphericity and clumping. The results are reported in 

In vitro release profile of microcapsules

  was determined using the USP Dissolution Apparatus 1 Basket method (900 mL of pH 6.8phosphate buffer, 100 rpm, 37±0.5 °C). Microcapsules equivalent to 100 mg of drug were loaded into the basket (covered with Teflon cloth [porous polytetrafluoroethylene (PTFE) cloth]) of the dissolution apparatus. Ten millilitres of the sample were withdrawn from the dissolution media at suitable time intervals and the same amount was replaced with fresh buffer. Samples were filtered though a Whatman filter paper and suitable dilutions were made when required. The absorbance of the samples was determined at the wavelength of 276 nm using UV–Vis spectrophotometer, against pH 6.8 phosphate buffer as a blank. The amount of drug present in the filtrate was then determined from the calibration curve, and cumulative percent of drug release was calculated.  

A compatibility study was employed to assess the physicochemical compatibility between drug and the various excipients used in the formulation.

  FTIR spectrums of drug, acrycoat S 100 and L 100polymer mixture, drug–polymer physical mixture and formulation were taken and are reported in 

The polymer used in the Pulsincap dosage form should be able to swell to its maximum and eject from the capsule body in intestinal fluid. The body portion of the capsules was subjected to disintegration studies at room temperature in a buffer solution of pH 1.2, 7.4 and 6.8.  

Ten capsules were selected randomly from each batch and weighed individually for weight variation.  

In vitro release profile of the pulsatile capsule

Dissolution studies were performed using the USP Dissolution Apparatus 2 Paddle Method (900 mL of dissolution medium, 100 rpm, 37±0.5 °C). Capsules were tied to the paddle with a cotton thread in each dissolution vessel to prevent floating.

To simulate the pH changes along the gastrointestinal tract, three dissolution media with pH 1.2 (simulated gastric fluid (SGF) prepared by dissolving 2 g of NaCl and 3.2 g pepsin in 7 mL of HCl, and then adding deionized water (DW) to 1000 mL, used for 2 h), 7.4 (simulated intestinal fluid (SIF) prepared by dissolving 6.8 g of monobasic potassium phosphate in 250 mL of DW, then adding 190 mL of 0.2 N NaOH, 400 mL of DW and 10 g of pancreatin, and finally adding 0.2 N NaOH to adjust the pH to 7.4, and then diluting with DW to 1000 mL, used for 3 h) and 6.8 (simulated colonic fluid (SCF) prepared by adding 170 mL 1M acetic acid and 160 mL 1M NaOH in DW to 1000 mL, used for subsequent h) were used sequentially.

  Nine hundred millilitres of the dissolution medium was used at each time. Ten millilitres of the sample was withdrawn from the dissolution media at suitable time intervals and the same amount was replaced with fresh buffer. Samples were filtered though a Whatman filter paper and suitable dilutions were made when required. The absorbance of the samples was determined at a wavelength of 276 nm using a UV–Vis spectrophotometer, against a respective buffer as a blank. The amount of drug present in the filtrate was then determined from the calibration curve, and the cumulative percent of drug release was calculated.  

Physicochemical properties of DS microcapsules

The microcapsules of DM1 had a rough surface and the visible drug crystals on the surface indicated that the concentration of the polymeric solution was insufficient for complete encapsulation. DM2 also had rough-surfaced microcrystals, but were less crystalline than DM1. Some clumping of the microcapsules was observed in DM1 and DM2. DM3 and DM4 microcapsules were uniform, spherical, smooth and discrete.  

Articles

Chronotherapeutic drug delivery systems (CRDDS) have been recognized as potentially beneficial to the chronotherapy (timeoptimized therapy) of widespread chronic diseases that display time-dependent symptoms.

Developing a modified Pulsincap system

Self-emulsifying drug delivery systems (SEDDSs) have gained exposure for their ability to increase solubility and bioavailability of poorly soluble drugs. SEDDSs are isotropic mixtures of oils and surfactants, sometimes containing cosolvents, and can be used for the design of formulations in order to improve the oral absorption of highly lipophilic compounds. SEDDSs emulsify spontaneously to produce fine oil-in-water emulsions when introduced into an aqueous phase under gentle agitation. SEDDS can be orally administered in soft or hard gelatine capsules and form fine, relatively stable oil-in-water emulsions upon aqueous dilution. This article presents an overview of SEDDSs and their applications.

In recent years, the formulation of poorly soluble compoundspresented interesting challenges for formulationscientists in the pharmaceutical industry. Up to 40% of newchemical entities discovered by the pharmaceutical industryare poorly soluble or lipophilic compounds, which leads topoor oral bioavailability, high intra- and inter-subject variability,and lack of dose proportionality (1).

In the oral formulation of such compounds, a number ofattempts-such as decreasing particle size, use of wettingagents, coprecipitation, and preparation of solid dispersions-have been made to modify the dissolution profile andthereby improve the absorption rate. Recently, much attentionhas focused on lipid-based formulations to improve thebioavailability of poorly water soluble drugs. Among manysuch delivery options, like incorporation of drugs in oils (2),surfactant dispersion (3), emulsions (4) and liposomes (5),one of the most popular approaches are the self-emulsifyingdrug delivery systems (SEDDSs).

SEDDSs are mixtures of oils and surfactants, ideally isotropicand sometimes containing cosolvents, which emulsify spontaneously to produce fine oil-in-water emulsions whenintroduced into an aqueous phase under gentle agitation. Self-emulsifying formulations spread readily in the gastrointestinal (GI) tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for selfemulsification.These systems advantageously present the drug in dissolved form and the small droplet size provides a large interfacial area for the drug absorption (6). SEDDSs typically produce emulsions with a droplet size between 100–300 nm while self-microemulsifying drug delivery systems (SMEDDSs) form transparent microemulsions with adroplet size of less than 50 nm. When compared with emulsions,which are sensitive and metastable dispersed forms, SEDDSs are physically stable formulations that are easy tomanufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems mayoffer an improvement in the rate and extent of absorption and result in more reproducible blood-time profiles (7).

The self-emulsifying process is depends on: (7)

The nature of the oilâsurfactant pair 

The temperature at which self-emulsification occurs. 

 Oils can solubilize the lipophilic drug in a specificamount. It is the most important excipient because it canfacilitate self-emulsification and increase the fraction of lipophilicdrug transported via the intestinal lymphatic system,thereby increasing absorption from the GI tract (9).Long-chain triglyceride and medium-chain triglyceride oilswith different degrees of saturation have been used in thedesign of SEDDSs. Modified or hydrolyzed vegetable oilshave contributed widely to the success of SEDDSs owing totheir formulation and physiological advantages (8). Novelsemisynthetic medium-chain triglyceride oils have surfactantproperties and are widely replacing the regular medium-chain triglyceride (9).

 Nonionic surfactants with high hydrophilic–lipophilic balance (HLB) values are used in formulation of SEDDSs (e.g., Tween, Labrasol, Labrafac CM 10, Cremophore,etc.). The usual surfactant strength ranges between30–60% w/w of the formulation in order to form a stable SEDDS. Surfactants have a high HLB and hydrophilicity, which assists the immediate formation of o/w dropletsand/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they candissolve or solubilize relatively high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules (10).

 Cosolvents like diehylene glycol monoethyleether (transcutol), propylene glycol, polyethylene glycol,polyoxyethylene, propylene carbonate, tetrahydrofurfurylalcohol polyethylene glycol ether (Glycofurol), etc., mayhelp to dissolve large amounts of hydrophilic surfactantsor the hydrophobic drug in the lipid base. These solventssometimes play the role of the cosurfactant in the microemulsionsystems.

With a large variety of liquid or waxy excipients available,ranging from oils through biological lipids, hydrophobic andhydrophilic surfactants, to water-soluble cosolvents, thereare many different combinations that could be formulatedfor encapsulation in hard or soft gelatin or mixtures whichdisperse to give fine colloidal emulsions (11).The following should be considered in the formulation ofa SEDDS:

The solubility of the drug in different oil, surfactantsand cosolvents. 

The selection of oil, surfactant and cosolvent based onthe solubility of the drug and the preparation of thephase diagram (12). 

The preparation of SEDDS formulation by dissolvingthe drug in a mix of oil, surfactant and cosolvent. 

The addition of a drug to a SEDDS is critical because thedrug interferes with the self-emulsification process to a certainextent, which leads to a change in the optimal oil–surfactant ratio. So, the design of an optimal SEDDS requirespreformulation-solubility and phase-diagram studies. In thecase of prolonged SEDDS, formulation is made by adding the polymer or gelling agent (13).

According to Reiss, self-emulsification occurs when theentropy change that favors dispersion is greater than theenergy required to increase the surface area of the dispersion.The free energy of the conventional emulsion is a directfunction of the energy required to create a new surfacebetween the oil and water phases and can be described bythe equation:

Where, DG is the free energy associated with the process(ignoring the free energy of mixing), N is the number ofdroplets of radius r and s represents the interfacial energy.The two phases of emulsion tend to separate with time toreduce the interfacial area, and subsequently, the emulsion isstabilized by emulsifying agents, which form a monolayer ofemulsion droplets, and hence reduces the interfacial energy,as well as providing a barrier to prevent coalescence (14).

The primary means of self-emulsification assessment is visualevaluation. The efficiency of self-emulsification couldbe estimated by determining the rate of emulsification,droplet-size distribution and turbidity measurements.

 This may provide important informationabout the self-emulsifying and microemulsifying property of the mixture and about the resulting dispersion (15,16,17).

 This is to identify efficient self-emulsificationby establishing whether the dispersion reachesequilibrium rapidly and in a reproducible time.

 This is a crucial factor in self-emulsificationperformance because it determines the rate and extent of drug release as well as the stability of the emulsion (10,18). Photon correlation spectroscopy, microscopic techniques ora Coulter Nanosizer are mainly used for the determinationof the emulsion droplet size (10,19,20). The reduction of the droplet size to values below 50 µm leads to the formationof SMEDDSs, which are stable, isotropic and clear o/wdispersions (6).

 This is used to identify the chargeof the droplets. In conventional SEDDSs, the charge on anoil droplet is negative due to presence of free fatty acids(17).

 Self-emulsification time, dispersibility, appearance and flowability was observed andscored according to techniques described in H. Shen 

(21) used for the grading of formulations.

SEDDS formulation is composed of lipids, surfactants, andcosolvents. The system has the ability to form an oil-in-wateremulsion when dispersed by an aqueous phase under gentleagitation. SEDDSs present drugs in a small droplet size andwell-proportioned distribution, and increase the dissolutionand permeability. Furthermore, because drugs can beloaded in the inner phase and delivered by lymphatic bypassshare, SEDDSs protect drugs against hydrolysis by enzymesin the GI tract and reduce the presystemic clearance in theGI mucosa and hepatic first-pass metabolism. Table I showsthe SEDDSs prepared for oral delivery of lipophilic drugsin recent years.

Self-emulsifying drug delivery systems are a promising approachfor the formulation of drug compounds with pooraqueous solubility. The oral delivery of hydrophobic drugscan be made possible by SEDDSs, which have been shownto substantially improve oral bioavailability. With futuredevelopment of this technology, SEDDSs will continue toenable novel applications in drug delivery and solve problemsassociated with the delivery of poorly soluble drugs.

1. P.P. Bhatt, "Osmotic drug delivery systems for poorly solubledrugs," 

The Drug Delivery Companies Report Autumn/Winter 2004

2. D.L. Burcham et al., "Improved oral bioavailability of the hypocholesterolemicDMP 565 in dogs following oral dosing in oil and glycol solutions," 

3. T.M. Serajuddin et al., "Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug fromsolid dispersion," 

4. R.A. Myers and V.J. Stella, "Systemic bioavailability of penclomedine(NSC-338720) from oil-in-water emulsions administeredintraduodenally to rats," 

5. R.A. Schwendener and H. Schott, "Lipophilic 1-beta-d -arabinofuranosylcytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemiamodel," 

6. N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS)with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs," 

7. R.N. Gursoy and S. Benita, "Self-emulsifying drug delivery systemsfor improved oral delivery of lipophilic drugs," 

8. P.P. Constantinides, "Lipid microemulsion for improving drugsdissolution and oral absorption: physical and biopharmaceuticalaspects," 

9. S.M. Khoo et al., "Formulation design and bioavailability assessmentof lipidic silf-emulsifying formulation of halofanitrine,"

10. N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS)with polyglycolized glycerides for improving in vitro dissolutionand oral absorption of lipophilic drugs." 

11. J.R. Crison and G.L. Amidon, "Method and formulation for increasingthe bioavailability of poorly water-soluble drugs," USPatent No. 5,993,858, issued November 30, 1999.

12. N. Farah, J.P. Laforet and J. Denis, "Self Micro Emulsifying DrugDelivery Systems for improving dissolution of drugs: In vitroevaluations," presented by Gattefosse Patented Technology atthe AAPS Annual Meeting in San Diego, November 1994.

13. S. Nazzal and M.A. Khan, "Controlled release of a self-emulsifyingformulation from a tablet dosage form: Stability assessmentand optimization of some processing parameters," 

14. P.P. Constantinides, "Lipid microemulsions for improving drugdissolution and oral absorption: physical and biopharmaceuticalaspects," 

15. D.Q.M. Craig et al., "An investigation into the mechanisms ofself-emulsification using particle size analysis and low frequencydielectric spectroscopy," 

16. N. Gursoy et al., "Excipient effects on in vitro cytotoxicity of anovel paclitaxel selfemulsifying drug delivery system," 

17. T. Gershanik and S. Benita, "Positively-charged self-emulsifyingoil formulation for improving oral bioavailability of progesterone,"

18. B.D. Tarr and S.H. Yalkowsky, "Enhanced intestinal absorptionof cyclosporine in rats through the reduction of emulsion dropletsize," 

19. S.A. Charman et al., "Self-emulsifying drug delivery system: Formulationand biopharmaceutic evaluation of an investigational lipophilic compound," 

20. R. Holm, I.H.M. Jensen, and J. Sonnergaard, "Optimization ofself-microemulsifying drug delivery system using D-optimaldesign and the desirability function," 

Drug Development and Industrial Pharmacy 

21. H. Shen and M. Zhong, "Preparation and evaluation of self-microemulsifyingdrug delivery system containing atorvastatin,"

22. P. Patil, P. Joshi, and A. Paradkar, "Effect of formulation variableson preparation and evaluation of gelled self emulsifyingdrug delivery systems of ketoprofen," 

23. H.R. Shen and M.K. Zhong, "Preparation and evaluation of selfmicroemulsifyingdrug delivery systems containing atorvastatin,"

24. Wei Ianlan et al., "Preparation and evaluation of SEDDS andSMEDDS containing Carvedilol," 

25. B.K. Kang et al., "Development of self-microemulsifying drug delivery systems for oral bioavailability enhancement of simvastatinin beagle dogs," 

26. J.Y. Hong et al., "A new self-emulsifying formulation of itraconazolewith improved dissolution and oral absorption," 

27. G.S. Chaea et al., "Enhancement of the stability of BCNU using self-emulsifying drug delivery systems (SEDDS) and in vitro antitumoractivity of self-emulsified BCNU-loaded PLGA wafer,"

28. T.R. Kommuru et al., "Self-emulsifying drug delivery systems(SEDDS) of coenzyme Q10: formulation development and bioavailabilityassessment," 

29. A.A. Attama et al., "The use of solid self-emulsifying systems inthe delivery of diclofenac," 

30. Mauro Serratoni et al., "Controlled drug release from pellets containingwater-insoluble drugs dissolved in a self-emulsifying system,"

European Journal of Pharmaceutics and Biopharmaceutics 

31. Mette Grovea et al., "Bioavailability of seocalcitol II: Developmentand characterisation of self-microemulsifying drug delivery systems(SMEDDS) for oral administration containing medium andlong chain triglycerides," 

European Journal of Pharmaceutical Sciences 

32. Wei Wu, Yang Wang and Li Que, "Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system," 

33. A.A. Date and M.S. Nagarsenker, Design and evaluation of self nanoemulsifying drug delivery systems (SNEDDS) for cefpodoximeproxetil," 

34. E.I. Taha et al., "Preparation and in vitro characterization of self nanoemulsified drug delivery system (SNEDDS) of all-trans-retinolacetate," 

 is an assistant professor, both in the Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Gujarat, India, 

 is a professor in the Department of Pharmaceutics, Kalol Pharmacy College, Kalol, Gujarat, India.

*To whom all correspondence should be addressed.

This review article explains how self-emulsifying drug delivery systems can increase the solubility and bioavailability of poorly soluble drug.

Self-Emulsifying Drug Delivery Systems

Lovastatin (LVS) is a well-known compound for lowering plasma cholesterol levels. After oral administration, the inactive parent lactone is hydrolyzed to the corresponding hydroxyacid form. The hydroxyacid is the principal metabolite and a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase. This enzyme catalyzes the conversion of hydroxymethylglutarate to mevalonate, which is an early and rate-limiting step in cholesterol biosynthesis (1, 2).  

LVS is white crystalline powder that is insoluble in water (0.4 g/mL). At room temperature, the partition coefficient of LVS in n-octanol/water system is approximately: K

  (3). Low aqueous solubility of LVS leads to inadequate dissolution in gastrointestinal fluids and, hence, poor absorption, distribution, and targeted organ delivery. The improvement of aqueous solubility in such a case is a valuable goal to improve therapeutic efficacy. 

Cyclodextrin (CD) is a cyclic (α-1, 4)-linked oligosaccharide made of α-D-gluco-pyranose units (see Figure 1). Hydroxypropyl-β-cyclodextrin (HPβ-CD) is more water soluble than the parent molecule and has hydroxypropylester groups attached to the hydroxyl groups in position 2. The molecule has a cone-like configuration with a hydrophilic surface and a lipophilic cavity. In this cavity, hydrophobic molecules interact with lipophilic molecules without forming any covalent bonds and can produce so-called "inclusion complexes," which increase the water solubility and stability of the drug substance (4–6). Complexation with CDs has been reported to enhance the solubility, dissolution rate,  and bioavailability of poorly water-soluble drugs. CDs first gained attention in marketed products as drug delivery technologies that enabled the development of various prostaglandins (7). The inclusion complex of rofecoxib/HPβ-CD (1:1 molar ratio) was prepared by Baboota 

 using a kneading method with a subsequent improvement in dissolution caused by amorphization (8). Several other drugs such as ganciclovir, nimesulide, itraconazole, and tolbutamide have been tested for CD inclusion to enhance solubility (9–12). 

 Figure 1: The structure formula for the Î²-cyclodextrin molecule.			

β-CD has ideal dimensions to complex a range of commonly used drugs. Unfortunately, it has the limitation of a high affinity for cholesterol, which may lead to crystallization of a poorly water-soluble β-CD–cholesterol complex in the kidney. This complex could cause nephrotoxicity. HPβ-CD, a chemical derivative of β-CD, similarly improves the aqueous solubility of many drugs, but it is more hydrophilic than β-CD, forms a less-stable complex with cholesterol, and, therefore, is less toxic (13). 

In this study, the authors compare the similarities of 

dissolution profiles of LVS from complexes, physical mixture, and pure LVS. Dissolution profiles can be compared by calculating a similarity factor (

) and the mean dissolution time (MDT). The method for calculating the similarity factor was first reported by Moore and Flanner (14). It also has been adopted by the US Food and Drug Administration's Center for Drug Evaluation and Research (15) and by the Human Medicines Evaluation Unit of the European Medicines Agency (16) as a criterion for assessing the similarity of two dissolution profiles (17, 18). A similarity factor of 100% suggests that the test and reference profiles are identical. Values between 50 and 100 indicate that the dissolution profiles are similar, whereas smaller values imply an increase in dissimilarity between release profiles (14). MDT reflects the time for the drug to dissolve and is the first statistical moment for the cumulative dissolution process that provides an accurate drug-release rate (15). A higher MDT value indicates greater drug-retarding ability (16).  

The present study was intended to improve the aqueous solubility and dissolution rate of LVS by preparing its complexes with HPβ-CD using various methods such as kneading, coevaporation, and physical mixing. The study further aimed to characterize the interaction between LVS and HPβ-CD. 

HPβ-CD was a gift sample from Roquette Frères, (Lestrem, France). LVS was received as a gift sample from Lincoln Pharmaceuticals Ltd. (Ahmedabad, India). The samples of sodium lauryl sulfate (SLS) were purchased from S.D. Fine Chemicals, (Vadodara, India). Directly compressible lactose, maize starch, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were received as gift samples from Maan Pharmaceuticals Ltd. (Ahmedabad, India). All chemicals and solvents used in this study were of analytical reagent grade. Freshly distilled water was used throughout the work. 

Phase-solubility studies were performed according to the method reported by Higuchi and Connors (19). LVS, in amounts that exceeded its solubility, was transferred to screw-capped vials containing 25 mL of  an aqueous solution of HPβ-CD (molecular weight = 1500 g/mol) in various molar concentrations (0, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, and 14.0 mM/L). The contents were stirred with an electromagnetic stirrer (Remi, Mumbai, India) for 36 h at 37 °C ± 0.1 °C and 350 rpm (this duration was previously tested to be sufficient to reach equilibrium). After reaching equilibrium, samples were filtered through a 0.22-μm membrane filter, suitably diluted, and analyzed spectrophotometrically for drug content at the wavelength of 238.2 nm using a spectrophotometer (Shimadzu-1601, ultraviolet-vis spectrophotometer, Shimadzu Corp., Kyoto, Japan). Solubility studies were performed in triplicate (

 = 3). The apparent stability constant (Kc), according to the hypothesis of 1:1 stoichiometric ratio of complexes, was calculated from the phase-solubility diagrams using the following equation: 

in which the slope is obtained from the initial straight-line portion of the plot of LVS concentration against HPβ-CD concentration, and S0 is the equilibrium solubility of LVS in water. 

Complexes of HPβ-CD and LVS were prepared in the molar ratio of 1:1 (on the basis of the phase solubility study) by various methods such as physical mixture, coevaporation, and kneading.  

A physical mixture of HPβ-CD and LVS was prepared by mixing the powders with a spatula for 15 minutes.  

Methanol and water were used as solvents to prepare the complex by a coevaporation method. The required quantities of LVS and HPβ-CD were dissolved in methanol and water, respectively. Both the solutions were mixed and solvents were evaporated by controlled heating at 45–50 °C. The resultant solid was pulverized and then put through a 120 # sieve.  

The required quantities of HPβ-CD and distilled water were mixed together in a motor to obtain a homogeneous paste. Then, LVS was added slowly; while grinding, a small quantity of methanol was added to assist the dissolution of LVS. The mixture was then ground for 1 h. During this process, an appropriate quantity of water was added to the mixture to maintain a suitable consistency. The paste was dried in an oven at 45–50 °C for 24 h. The dried complex was pulverized and then put through a 120 # sieve.   

The complexes prepared by kneading, coevaporation, and physical mixture were assayed for LVS content by dissolving a specific amount of the complex in methanol and analyzing for the LVS content spectrophotometrically at 238.2 nm on spectrophotometer (ultraviolet-vis spectrophotometer, Shimazdu-1601). The final moisture contents of all samples were measured with an electronic moisture balance (Sartorius, model MA-45, Goettingen, Germany). 

 The IR spectra of moisture-free powdered samples of LVS, HPβ-CD, the physical mixture

 and the complex prepared by the coevaporation and the kneading methods were obtained using a spectrometer (FTIR-8300, Shimadzu Co., Kyoto, Japan) with a potassium bromide (KBr) pellet method.  

Powder X-ray diffraction (PXRD) analysis. 

PXRD patterns of LVS, HPβ-CD, the physical mixture, and complexes prepared by the coevaporation and the kneading methods were determined using a scanner (Phillips PW 3710) and a generator (IW 1830) with a CuK α anode at 40 kV and 30 mA at a scan rate of 1° min

Differential scanning calorimetry (DSC) analysis. 

DSC scans of the powdered sample of LVS, β-CD, the physical mixture, and complexes prepared by the coevaporation and the kneading methods were recorded using a DSC instrument (Shimadzu 60) with TDA trend-line software. The samples (6–7 mg) were weighed accurately in crimped aluminum pans and heated from 50 °C to 300 °C at a scanning rate of 10 °C /min under dry nitrogen flow (100 mL/min). 

The wettability study was performed using open tubes containing LVS, the physical mixture, and complexes prepared by the coevaporation and the kneading methods. The tubes were placed with their lower capillary ends dipped into colored water (0.01% eosin in water). The upward migration of the colored front was registered as a function of time. The porosity of all samples also was measured using a mercury porosimeter (PoreMaster 60, Quantachrome Instruments,  Boynton Beach, FL). 

 is defined as the percentage of void space in a solid. Mercury density (ρ

) values often are used to evaluate % porosity (€) (20). Each test was repeated four times and the mean was calculated. 

Dissolution studies of LVS in powder form, the physical mixture, and complexes prepared by the coevaporation and the kneading methods were performed to evaluate the 

 drug-release profile. Dissolution studies were carried out using a 

 dissolution apparatus type II with a 500-mL dissolution medium at 37 °C ± 0.5 °C and 50 rpm for 3 h. In addition, 0.1 N HCl and a phosphate buffer (pH 6.8) containing 0.25% (weight/volune [w/v]) of sodium lauryl sulfate were used as other dissolution mediums. At fixed time intervals, 5-mL aliquots were withdrawn, filtered, suitably diluted, and assayed for LVS content by measuring the absorbance at 238.2 nm using a spectrophotometer. An equal volume of fresh medium at the same temperature was placed into the dissolution medium after each sampling to maintain its constant volume throughout the test. 

Table I: Tablet formulations of plain lovastatin (LVS), the physical mixture (PM), and complexes made with the coevaporation (CPC) and the kneading methods (CPK).			

Pure drug, the physical mixture, and complexes prepared by the coevaporation and the kneading methods were evaluated in dissolution-rate studies. Dissolution studies were performed in triplicate (

 = 3) and the calculated mean values of cumulative drug release were used while plotting the release curves. MDT values were calculated to compare the extent of improvement in the dissolution rate of the physical mixture, and the complexes prepared by the coevaporation and the kneading methods. Preliminary tests demonstrated that there was no change in the λmax of LVS because of the presence of HPβ-CD dissolved in the dissolution medium. 

Table II:  Gibbs free energy of transfer (ÎGtrÃÂ°) for the solubilization process of lovastatin in aqueous solutions of hydroxypropyl-Î²-cyclodextrin (HP-Î²CD) at 37 8C.			

Formulation excipients were selected on the basis of preliminary tests that demonstrated the excipients did not interfere with the λmax of LVS. The % compressibility and the angle of repose were measured to assess the tableting ability of the kneading method.  

The % compressibility was calculated using the following equation: 

 is the powder volume before tapping and V

 is powder volume after tapping infinitely. The powder volume was calculated from Kawakita's equation (21) using data from 200 tapping points obtained with a tapping density analyzer (bulk density test apparatus, DBK Instruments, Mumbai, India) equipped with a 20-mL cylinder. 

For the angle of repose measurement, a pile of powder was carefully made by dropping the powder material through a funnel tip from a height of 2 cm (22). The angle of repose was calculated by tangentially inverting the ratio of the formed pile's height and radius. 

Tablets containing 10 mg of LVS were made by direct compression using various formulation excipients such as directly compressible lactose, colloidal silicon dioxide, and magnesium stearate (see Table I). Tablets equivalent to 10 mg LVS were made similarly using the kneading method, but using less lactose. The blend was compressed on an eight-station, single-rotary machine (Cadmach, India) using round-shaped, flat punches to obtain tablets of 4–7 kg/cm

  hardness and 3.5–3.7 mm thickness (see Table I). For the assay, three tablets were crushed and a blend equivalent to 10 mg of LVS was weighed and dissolved in dissolution mediums. The tablets were studied in triplicate (

 = 3) for the drug-release profile using the same methodology described for the 

Figure 2: The phase solubility curve of lovastatin in an aqueous solution of hydroxypropyl-Î²-cyclodextrin (HP-Î²CD) at 37 8C.			

A model-independent, mathematical approach proposed by Moore and Flanner (14) for calculating  

 was used for comparison among the dissolution profiles of various samples. The 

 is a measure of similarity in the percentage dissolution between two dissolution curves and is defined by following equation:  

 is the percentage dissolved of reference at the time point 

 is the percentage dissolved of test at the time point 

 suggests that the test and reference profiles are identical. Values between 50 and 100 indicate that the dissolution profiles are similar, whereas smaller values imply an increase in dissimilarity between release profiles (14).  

The objectives of this study were to prepare and characterize inclusion complexes of lovastatin with hydroxypropyl-β-cyclodextrin (HPβ-CD) and to study the effect of the complexes on the dissolution rate of lovastatin (LVS). The findings suggest that LVS's poor dissolution profile can be overcome by preparing its inclusion complex with HPβ-CD.