ENHANCEMENT OF SOLUBILITY AND DISSOLUTION PROFILE OF EPLERENONE BY LIQUISOLID COMPACTS USING NOVEL EXCIPIENTS

ENHANCEMENT OF SOLUBILITY AND DISSOLUTION PROFILE OF EPLERENONE BY LIQUISOLID COMPACTS USING NOVEL EXCIPIENTS

G. Narender Naik ^{* 1} and R. Shyam Sunder ²

Jyothishmathi Institute of Pharmaceutical Sciences ¹, Karimnagar - 505527, Telangana, India.

University Institute of Chemical Technology ², Osmania University, Hyderabad - 500007, Telangana, India.

ABSTRACT: Eplerenone is a poorly soluble drug that belongs to class II biopharmaceutical classification system. It is a selective aldosterone receptor antagonist, which binds to the mineralocorticoid receptor and blocks the binding of aldosterone, thereby decreases the sodium resorption and subsequently increasing water outflow. This leads to a decrease in blood pressure and used in congestive heart failure. The aim of the present study was to improve the solubility, dissolution and permeability properties of Eplerenone by liquisolid compacts, thereby enhancing oral bioavailability. Different formulations of Liquisolid were developed by dissolving the drug in mixture of Transcutol HP: Capmul MCM and Cremophor EL: Capmul MCM (Non-volatile liquid; 1:1 ratio), converting this liquid medication using carriers as fujicalin and neusilin and coating material as syloid FP 244. The results showed that Liquisolid formulation exhibited significantly higher drug dissolution rate compared to pure drug as well as marketed formulation. The plasma concentration-time profile of healthy Wister rats indicated that the oral bioavailability of optimized formulation has been significantly improved compared to pure drug and marketed formulation. The enhanced bioavailability might be due to increased wetting properties of drug and permeability of the drug due to lipophilic properties of solvent used for wetting. This study can conclude that Liquisolid technique is a promising alternative method for improving the bioavailability of class-II drugs.

BCS-Class II drug, Liquisolid compact, Non-volatile liquid, Carrier, Coating material

INTRODUCTION: Nowadays, the synthesis of poorly soluble drugs increasing steadily ¹. Around 75% of the new drug candidates are poorly water-soluble ², therefore, there is great interest in developing techniques to improve the solubility and the dissolution rate of drugs ³.

BCS Class II drugs pose challenging problems in their pharmaceutical product development process because of their low solubility and dissolution rates.

Therapeutic effectiveness of a drug depends up on the bioavailability and ultimately up on the solubility and dissolution rates of drug molecules ^{4, 5}. Solubility and dissolution rate are the important parameters to achieve the desired concentration of drug in systemic circulation for pharmacological response to be shown ^{6, 7}. The dissolution rate is one of the rate-determining step in the drug absorption ^{8, 9}.

The challenge for these poorly soluble drugs /class –II drugs is to enhance the solubility and dissolution profile by several techniques such as micronization ¹⁰, solid dispersions ¹¹, salt formation ¹², micellar solubilization ¹³, hydrotrophy ¹⁴, inclusion complexes ¹⁵, lyophilisation ¹⁶, co solvency ^17, etc. Despite the availability, these techniques are suffering from one or two drawbacks like reduced micromeritics or altered stability and still need further development to overcome them.

One of the novels and most promising techniques for promoting dissolution is the formation of liquisolid compacts among all. Liquisolid compacts promotes dissolution rate of water-insoluble drugs to a greater extent and also enhances the drug flow property ¹⁸. The liquisolid compaction technology is described by Spire as liquid medication may be transformed into a free-flowing, readily compressible, and apparently dry powder by simple physical blending with selected excipients named the carrier and coating material ¹⁹. When the drug is dissolved in the liquid vehicle and incorporated into a carrier material which has a porous surface and closely matted fibres in its interior as cellulose, where both absorption and adsorption mechanism takes place; i.e., initially the liquid is absorbed in the internal structure of carrier and after the saturation process, adsorption of the liquid on to the internal and external surfaces of the porous carrier particles takes place. And where the coating material posses high adsorptive property and large specific surface area that gives the desirable flow characteristic and also increases the wetting property. Thus, due to significantly increased wetting properties and surface area of drug available for dissolution ²⁰. So, liquisolid compacts of water-insoluble substances may be expected to enhancement of drug release and consequently, improved Oral bioavailability ²¹.

Eplerenone is a class II drug, aldosterone receptor antagonist approved by Food and drug administration on September 27, 2002 and October 7, 2003 with therapeutic applications as antihypertensive and can also be used as monotherapy for initial management of uncomplicated hypertension ^{22, 23}. In this study Eplerenone was taken as a model drug, dissolution enhancement was done by liquisolid compaction technology using combination of nonvolatile liquids and novel carriers to improve its oral bioavailability ²⁴.

MATERIALS AND METHODS:

Materials: Gift sample Eplerenone received from Dr Reddy’s Laboratories Ltd. Miyapur, Hyderabad, Telangana, India. The following materials were gifted by Abitec Corp, Mumbai, India and were used as received: Captex355 (Glyceryltricaprylate), Captex 200 (Propylene glycol dicaprylocaprate), Transcutol HP and Cremophor EL. Labrafil M 2125CS (Linoleyl macrogol-6 glycerides), Labrafil 1944CS, Lauroglycol 90 (Propylene glycol mono-laurate), PlurolOleique (Polyglyceryl-3 dioleate), Capmul MCM (Glycerylmonocaprylate), Capmul C8, Acconon C-80 (Polyoxyethylene 80 coconut glycerides) were received as gift sample from Gattefosse, India. Tween 80, PEG 400, and PG were purchased from SD Fine Chemicals, India. Fujicalin (Dibasic calcium phosphate anhydrous) and Neusilin (Magnesium aluminometasilicate) obtained as gift sample from Fuji Chemical Industry Co. Ltd., Japan.

Methods:

Saturation Solubility Studies: Eplerenone Saturation solubility studies done in different non-volatile solvents and followed by combination of solvents in which drug is shown to have maximum solubility was estimated by conducting saturation solubility studies. 10 mL Solvent was taken in a series of vials and an excess amount of drug added and subjected to continuous shaking using a rotary shaker for 48 h at room temperature. Then each solution was centrifuged, filtered through Whatman filter paper no. 42 and clear supernatants were analyzed for drug content and solubility using UV- spectrophotometer at 245 nm.

Selection of Coating, Carrier Materials & Preparation of Liquisolid Compacts: Novel carriers fujicalin (dibasic calcium phosphate anhydrous) and neusilin (magnesium alumina-metasilicate) were selected as carriers, Syloid FP 244 as coating material and carrier to coating ratio was varied from 5:1 to 10:1. From the saturation solubility studies it was observed that the drug is having maximum solubility in Transcutol HP: Capmul MCM and Cremophore: Capmul MCM when used in combination at the ratio of 1:1.

Hence, the solvent system has been used as non-volatile vehicle. The liquid medication was prepared at 25% w/w and 50% w/w drug concentration by adding the weighed quantity of drug to the required quantity of previously mixed liquid vehicle. The resultant liquid medication was incorporated into carrier and coating material by admixing in a mortar to get freely flowable non-adherent powder. The total quantity of each formulation was adjusted to 500 mg to get uniform weight for each formulation with Avicel pH 102. The liquid/powder admixtures were then evaluated for their micromeritics, uniformity of drug content and in-vitro dissolution.

In-vitro Drug Release Studies: Dissolution studies of all the prepared formulations were performed using USP Dissolution apparatus II using 1000 mL of 0.1 N HCl. The temperature and speed of rotation maintained were 37 ± 0.5 °C and 50 rpm, respectively. 5 mL samples were collected and the equal volume of fresh dissolution medium was replaced at predetermined time points and analyzed using UV-spectrophotometer at 245 nm.

In-vivo Evaluation for Pharmacokinetic Parameters: The study protocol (JIPS/IAEC/ 2018/01) was prepared and approved by the Institutional Ethics Committee of the institution (reg. no.:7970/PO/Re/S/76/ CPCSEA). The in-vivo pharmacokinetic study was conducted in white Wistar rats. Animals were fed with standard diet throughout the study as there was no impact of diet on drug absorption. 18 rats weighing 210-260 g were divided into 3 groups of six in each. Group 1 was administered with pure drug, group 2 was administered with marketed formulation (Eptus 25 mg) and group 3 was administered with optimum formulation at 2 mg/kg dose through oral route. Blood samples were collected from retro orbital vein at predetermined time points up to 8 h and were centrifuged at 5000 rpm for 5 min. Plasma was collected and stored at -20 °C until analyzed. The plasma samples were analyzed using RP-HPLC, and plasma drug concentrations were determined using standard calibration curve. All possible pharmacokinetic parameters (AUC, C_max, T_max, t_1/2) were calculated for each formulation and each subject. Relative bioavailability of optimized formulation was done comparatively with pure drug and marketed formulation.

RESULTS AND DISCUSSION:

Saturation Solubility Studies: Saturation solubility studies in different solvents were performed and the results obtained are represented as a bar graph in Fig. 1. Among all the solvents tested, Eplerenone was found to be higher in Cremophore EL (6.2 mg/ml), Transcutol HP (5.6 mg/ml), Capmul MCM (4.5 mg/ml) compared to other solvents.

Saturation solubility of the drug was also estimated in the combination of these solvent mixtures at the ratio of 1:1 to check the synergistic effect. It was found that the solubility of drug was increased to 7.5 mg/mL within the solvent blend of Cremophore EL: Capmul MCM and it was further increased to 8.2 mg/mL with the solvent blend of Transcutol HP: Capmul MCM.

Hence, the solvent blend consisting of Transcutol HP: Capmul MCM and Cremophore EL: Capmul MCM was selected as non-volatile liquid vehicle to improve the dissolution rate of drug.

FIG. 1: SATURATION SOLUBILITY OF EPLERENONE IN DIFFERENT SOLVENTS

Formulation of Liquisolid Compacts: Composition of various formulations of liquisolid compacts are represented in Table 1.

Micromeritics and Drug Content Uniformity of Liquisolid Formulations: Flow properties of all the formulations were evaluated and the results are shown in Table 2. Values of angle of repose (32.4 ± 0.4 - 40.1 ± 0.2), carr’s index (13.14 ± 0.2 - 18.66 ± 0.3) and Hausner's ratio (<1.24) in all the formulations corresponding to good flow. The flowability of Eplerenone liquisolid formulations was enhanced compared with pure drug.

TABLE 1: COMPOSITION OF LIQUISOLID COMPACTS OF EPLERENONE

TABLE 2: MICROMERITICS AND DRUG CONTENT UNIFORMITY OF LIQUISOLID FORMULATIONS

In-vitro Drug Release Profile of Liquisolid Formulations: In-vitro drug release of liquisolid formulation was estimated using USP Type II apparatus. The dissolution profile of formulations prepared with fujicalin is shown in Fig. 2 & 4, prepared with neusilin is shown in Fig. 3 & 5. Formulation  (F14) containing 25% of drug in liquid medication, neusilin as a carrier to coating ratio of 10:1 has shown fastest drug release (100% release in 15 min) when compared to other formulations, pure drug (25.6% release in 30 minutes) and marketed formulation (91.2% release in 30 min). The comparative dissolution profile of pure drug, marketed formulation and optimized formulation has shown in Fig. 6. The improved dissolution rate of optimized formulation might be achieved due to higher amount of liquid vehicle, hydrophilic properties attributed by carrier materials and higher surface area provided by Syloid244FP. Hence, F14 was selected as optimized formulation for evaluating its pharmacokinetic parameters.

TABLE 3: IN-VITRO DRUG RELEASE PROFILE OF PURE DRUG, LIQUISOLID FORMULATIONS, AND MARKETED FORMULATIONS

In-vivo Studies: In-vivo studies conducted in Wistar rats revealed that the bioavailability of optimized formulation is high compared to pure drug and marketed products. The plasma concentration-time profile is given in Table 4 and shown in Fig. 7. The pharmacokinetic parameters are calculated and listed in Table 5.

FIG. 6: COMPARATIVE DISSOLUTION PROFILE OF PURE DRUG MARKETED AND OPTIMIZED FORMULATIONS

TABLE 4: PLASMA CONCENTRATION VALUES OF PURE DRUG, OPTIMIZED FORMULATION AND MARKETED PRODUCT

TABLE 5: CALCULATED PHARMACOKINETIC PARAMETERS OF PURE DRUG, MARKETED AND OPTIMIZED FORMULATION

FIG. 7: COMPARATIVE PHARMACOKINETIC PROFILE OF PURE DRUG, MARKETED AND OPTIMIZED FORMULATION

CONCLUSION: From the results of in vivo pharmacokinetic evaluation conducted in rats, it was observed that the oral bioavailability of optimized formulation was found to be significantly higher than marketed and pure drug. Hence, it can be concluded that the liquisolid approach using a combination of solvents and novel carriers is promising technique to improve the bioavailability of poorly soluble drugs such as Eplerenone.

ACKNOWLEDGEMENT: Authors would like to thank Abitec corp, Gattefosse and fuji chemical industry for providing gift samples for successful completion of this research work.

CONFLICTS OF INTEREST: The authors do not have any conflict of interest.

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    How to cite this article:

    Naik GN and Sunder RS: Enhancement of solubility and dissolution profile of eplerenone by liquisolid compacts using novel excipients. Int J Pharm Sci & Res 2020; 11(6): 2892-98. doi: 10.13040/IJPSR.0975-8232.11(6).2892-98.

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