Transforming Liquid SEDDS into Solid Oral Dosage Forms

Jasmine Musakhanian,¹ Inayet Ellis,² and Masumi Dave³

¹Scientific and Marketing Director

²Scientific Affairs Director

³Application Laboratory Manager

Gattefossé USA, Pharmaceutical Division, Paramus, NJ

Introduction 

Self-emulsifying drug delivery systems (SEDDS) help solubilize poorly soluble drugs in the dosage form and more importantly facilitate drug dispersion and dissolution in vivo because of their ability to readily disperse in the aqueous environment of the GI tract.^1-3 This self-emulsification capacity is achieved by bringing together the right combination of functional categories: oil, surfactant, cosurfactant and or cosolvent^4,5 In practice, this means screening for drug solubility in a dozen different excipients followed by evaluation of compatibility and miscibility among the binary, ternary, or quaternary combinations, to optimize the eventual formulation.  Such elaborate customization may be appropriate for mid to late-stage formulation development but for early drug discovery and preclinical development, simpler options are needed. 

Another challenge associated with SEDDS formulations is their liquid or semi-solid consistency. A drug substance solubilized or suspended in liquid SEDDS can be readily filled into capsules, ideal for speedy progress in the early phases of development and if desired, carrying the formulation all the way to the market. Given the option, however, the common preference is to reach the finish line with a solid dosage form. This paper focuses on the possible avenues for transforming liquid SEDDS formulations into solid oral tablets or granules. 

An attractive solution to the mentioned challenges lies in screening of drug solubility in lipid excipients that by design, are SEDDS on their own, followed by adsorption of the liquid formulation onto solid carriers. Among the examples of SEDDS forming excipients are Labrasol (caprylocaproyl polyoxyl-8 glycerides), Gelucire 44/14 (lauroyl polyoxyl-32 glycerides), and Labrafil series (oleoyl, linoleoyl, or linolenoyl polyoxyl-6 glycerides NF). Capable of forming micellar dispersions upon contact with aqueous media, these excipients offer significant drug solubilization capacity. In addition, they improve drug absorption by unique mechanisms of their own, based on their fatty acid composition. Labrasol ALF for instance, consists of medium-chain fatty acids associated with transient epithelial tight junction opening. Labrafil series on the other hand, possess long-chain unsaturated (C18:1, C18:2) fatty acids, concomitant with enhanced lymphatic absorption.

Several recent publications^6-10 have demonstrated that it is possible to successfully adsorb a liquid formulation onto the porous, internal structure of a carrier such as microcrystalline cellulose. As a next step, a highly adsorptive coating material, with large surface area such as nanosized amorphous silicon dioxide, may be added to the adsorbed mixture to obtain a free-flowing composition. Note that earlier attempts, where silicates were used as a carrier/adsorbent instead of coating material, had produced less than satisfactory results. In the case of danazol-SEDDS formulation for example, adsorption onto magnesium aluminometasilicate (Neusilin US2) led to 35% lower drug solubility in the dose, and 50% lower bioavailability (rats, in vivo) compared to that observed for the unadsorbed liquid SEDDS.¹¹ The results were explained in part, by the significantly reduced ability of the formulations to desorb out of the porous silicate particles. 

The modified adsorption approach, referred to as “solid dispersion by adsorption”, or “liquisolid technique” however, has produced very satisfactory results for several drug actives, including felodipine6 and risperidone.7 Felodipine is indicated for treatment of hypertension, angina pectoris and congestive heart failure, and its administration warrants a rapid dissolution, immediate release dosage form. Following solubility screening in various excipients, a liquid SEDDS consisting of castor oil, Labrasol and Transcutol (diethylene glycol monoethyl ether) in ratios of 1:2:2 was developed.⁶  The felodipine solubility in the SEDDS (254 drug/mL) was comparable to that in PEG 400 (233.47 mg/mL) solution. These two formulations were converted into solids by blending each with microcrystalline cellulose (Avicel PH 102) as a carrier, followed by addition of nanosized silica (Aerosil 200) as a coating to improve the flow properties of the mixture. Lastly, a super disintegrant (croscarmellose) was added to these formulations before compression into tablets (Table 1). The carrier/coating ratio was 10/1. The tablets varied in total weight, indicative of the significant bulking effect of the adsorption process. The drug loading was fixed at 10mg of felodipine per tablet.

The release profile of felodipine from each of the prepared tablets was compared to those of unprocessed felodipine powder, and liquid SEDDS (Figure 1). As shown, the liquid and liquisolid tablet formulations consisting of the optimized SEDDS performed significantly better in the speed and extent of the felodipine dissolution profile, being >90% in the first 10 minutes. 

In an investigation into the in vitro and in vivo performance of liquisolid formulations, risperidone was selected as the model drug.⁷ Risperidone is an antipsychotic drug indicated for the treatment of schizophrenia. Risperidone was dissolved in various solubilizers at 10% to 30% for preparation of liquid formulations. To obtain liquisolid tablets, the aforesaid liquid formulations were mixed with microcrystalline cellulose (86%) as carrier for the drug solutions, followed by addition of nanosized amorphous silicon dioxide (4%) to adsorb the excess fluid. The liquisolid compacts were subsequently mixed with a disintegrant (9%) and magnesium stearate (1%) prior to compression into tablets. Among the formulations tested, a SEDDS consisting of Labrasol/Labrafi l (1:1) provided liquisolid tablets of a high dissolution rate, i.e., 100% drug release within 25 minutes at the targeted pH of 6.8. The latter was therefore selected for further evaluation in rabbits, where drug bioavailability was significantly increased. As shown in Figure 2 and Table 2, the Cmax and total bioavailability of risperidone SEDDS formulation were 4.5 and 3.5 times higher than that observed for the commercial tablets. These results could correlate with higher solubilization capacity of risperidone in the SEDDS formulation at the main absorption sites, the duodenum and jejunum.⁷ 

Similar results were reported for 10%, 20%, and 30% ritonavir formulations prepared with 1:1 mixture of Labrasol:Labrafil by the liquisolid technique. Similar to the previous reference7 this study8 did not indicate the grade of Labrafi l used. The liquid preparations were transformed into tablets, followed by assessment of tablets for various properties such as hardness, friability, and disintegration time. In this work, Avicel PH 102 served as carrier, and nanometer-sized amorphous silicon dioxide was used for coating the adsorbed solids. The cumulative dissolution of ritonavir from the liquisolid tablets exceeded 80% and up to 100%, compared to that of 34.6% (from ritonavir powder) and 49.8% (conventional tablets) within 90 minutes. More specifically, a rapid drug dissolution and complete (100%) drug release were observed within 35 minutes of testing the 10% ritonavir liquisolid tablets. 

In another study, Labrasol/PEG 200 (1:1) was used as solubilizer for combined delivery of two drugs indicated for male sexual dysfunction, tadalafil and dapoxetine.⁹  Fifteen formulations consisting of 100mg tadalafil and 600mg of dapoxetine combined were prepared by varying amounts of microcrystalline cellulose, fumed silica, magnesium trisilicate, Polyplasdone XL-10, and Methocel ES. After sieving and blending in talc and magnesium stearate, powdered mixes were compressed into tablets. The pharmacokinetic evaluation of the tablets in healthy volunteers revealed significantly reduced Tmax, i.e., faster release, 30% higher Cmax and increased bioavailability of 50% for tadalafil (Table 3). The improvements observed for dapoxetine were not deemed statistically significant.

Reports on application of the technique to produce solid pellets, termed as “liquid-pellets,” have also shown promise.¹⁰ The guiding principles for preparation of liquisolid tablets or pellets have been summarized in Figure 3. As indicated in the previous examples, the process requires selection of an appropriate non-volatile liquid vehicle to disperse or solubilize the drug(s). 

Since the preparation of liquisolid tablets necessitates addition of carrier, coater, and other tableting excipients to render the admixture flowing and compressible, the final dosage form may become larger than desirable. To do away with the bulking challenges of liquisolid tablets, a liquid-pellet approach, which combines the liquisolid concept with pelletization by extrusion-spheronization technology, has been proposed.¹⁰ Naproxen as a model drug was added to different liquid solubilizers, namely PEG 200, propylene glycol, Kolliphor EL (macrogolglycerol ricinoleate 35), polysorbate 80 (Tween 80), linoleoyl polyoxyl-6 glycerides (Labrafi l 2125), and Labrasol. Microcrystalline cellulose (as carrier) was blended with each drug/ solubilizer combination. Once the liquid formulations had been fully adsorbed, a predetermined amount of deionized water was slowly added to the admixture. The optimal amount of water had been determined earlier, establishing a correlation between extrudate plasticity and quantity of water added – up to a level, above which the particles would agglomerate. After addition of the deionized water, the admixture was transferred for additional mixing with fumed silica prior to extrusion spheronization. Whereas the time for spheronization varied for each formulation, the carrier to coating material ratio of 20:1 was maintained. The extrudates were then placed in an oven at 50°C overnight to remove moisture. The dissolution results for the various formulations were compared to that of physical mixtures at pH 1.2 and pH 7.4. Since Naproxen is typically enteric coated to protect against gastric side effects, the results of the drug release at pH 7.4 are shared in Figure 4. As shown, the liquid-pellets had significantly better performance compared to that of the physical mixture. Labrasol provided the fastest drug release i.e., ~75% after two hours.

Summary 

The utility of self-emulsifying formulations in solubility and bioavailability enhancement is well established by way of market references and published works. Polyoxylglycerides like Labrasol or Labrafi l are designed to function as SEDDS on their own. Depending on the drug solubility in the excipient(s), they may be used alone as the primary drug delivery system, as well as in combination with each other or other cosolvents. This provides great savings in time for development of SEDDS formulations. Combined with “liquisolid” techniques, SEDDS offer unique opportunities for the development of solid dosage forms that have high drug solubility properties and are easy to characterize. Conversion of a liquid SEDDS formulation into a solid form may be an interesting approach to development of high potency, poorly soluble drugs.  

References 

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