ENHANCEMENT OF DISSOLUTION RATE OF VORICONAZOLE BY SOLID DISPERSION IN PRIMOJEL AND POLOXAMER 188 ALONE AND IN COMBINATION

Abstract

This paper aims to prepare and evaluate solid dispersions of voriconazole in Primojel and Poloxamer 188 alone and in combination for enhancing the dissolution rate and dissolution efficiency of voriconazole. The individual and combined effects of the two carriers, Primojel and Poloxamer 188 in enhancing the dissolution rate and dissolution efficiency of voriconazole were evaluated in a 2^sup 2^ factorial study. Solid dispersions of voriconazole in combined carriers namely Primojel and Poloxamer 188 were prepared as per 2^sup 2^ factorial design. All the solid dispersions prepared were evaluated for drug content uniformity, dissolution rate and dissolution efficiency in comparison to voriconazole pure drug. Solid dispersions prepared employing Primojel and Poloxamer 188 alone as carriers gave rapid and higher dissolution of voriconazole. A 20% concentration of Primojel and 5% concentration of Poloxamer 188 were found to be optimum for enhancing the dissolution rate and dissolution efficiency of voriconazole. Poloxamer 188 gave higher enhancement in the dissolution rate of voriconazole than Primojel when used at the same concentration.

Headnote

ABSTRACT

Voriconazole, a widely prescribed antifungal drug belongs to class II under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. As such it needs enhancement in the dissolution rate and bioavailability to derive its maximum therapeutic efficacy. The objective of the present study is to prepare and evaluate solid dispersions of voriconazole in Primojel and Poloxamer 188 alone and in combination for enhancing the dissolution rate and dissolution efficiency of voriconazole. The individual and combined effects of the two carriers, Primojel and Poloxamer 188 in enhancing the dissolution rate and dissolution efficiency of voriconazole were evaluated in a 2^sup 2^ factorial study. Solid dispersions of voriconazole in Primojel alone were prepared using five ratios of drug: carrier namely 9:1, 8:2, 2:1, 1:1 and 1:3 by solvent evaporation method. Solid dispersions of voriconazole in Poloxamer 188 alone were prepared using three ratios of drug: carrier namely 19:1, 9:1 and 8: 2 by common solvent method. Solid dispersions of voriconazole in combined carriers namely Primojel and Poloxamer 188 were prepared as per 2^sup 2^ factorial design. All the solid dispersions prepared were evaluated for drug content uniformity, dissolution rate and dissolution efficiency in comparison to voriconazole pure drug. The dissolution rate (K^sub 1^) and dissolution efficiency (DE^sub 30^) of voriconazole could be significantly enhanced by solid dispersion in Primojel (a water dispersible super disintegrant) and Poloxamer 188 (a nonionic surfactant) alone and in combination. Solid dispersions prepared employing Primojel and Poloxamer 188 alone as carriers gave rapid and higher dissolution of voriconazole. A 20 % concentration of Primojel and 5 % concentration of Poloxamer 188 were found to be optimum for enhancing the dissolution rate and dissolution efficiency of voriconazole. Poloxamer 188 gave higher enhancement in the dissolution rate of voriconazole than Primojel when used at the same concentration. All solid dispersions prepared as per 2^sup 2^ factorial design gave rapid and higher dissolution of voriconazole when compared to voriconazole pure drug. ANOVA indicated that the individual and combined effects of Primojel (factor A) and Poloxamer 188 (factor B) in enhancing the dissolution rate (K^sub 1^) of voriconazole are highly significant (P < 0.01). A 11.35, 14.85 and 10.57 fold increase in the dissolution rate (K^sub 1^) and a 4.02, 3.87 and 3.71 fold increase in the dissolution efficiency (DE^sub 30^) was observed respectively with solid dispersions F^sub a^, F^sub b^ and F^sub ab^ when compared to F^sub 1^ (voriconazole pure drug). The order of increasing dissolution rate (K^sub 1^) of voriconazole observed with various solid dispersions was F^sub b^ > F^sub a^ > F^sub ab^ >F^sub 1^. Poloxamer 188 alone (F^sub b^) gave higher enhancement in the dissolution rate of voriconazole. Hence solid dispersion of voriconazole in Primojel or Poloxamer 188 alone is recommended to enhance the dissolution rate and dissolution efficiency of voriconazole, a BCS class II drug. There was no additional enhancement in the dissolution rate with combined carriers of Primojel and Poloxamer 188.

Keywords: Voriconazole; Solid dispersion; Dissolution Rate; Primojel; Poloxamer 188; Factorial study.

INTRODUCTION

About 95% of all new potential therapeutic drugs (APIs) exhibit low and variable oral bioavailability due to their poor aqueous solubility at physiological pH and consequent low dissolution rate. These drugs are classified as class II drugs under BCS with low solubility and high permeability characters and pose challenging problems in their pharmaceutical product development process.

Voriconazole, a widely prescribed antifungal drug belongs to class II under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. As such it needs enhancement in the dissolution rate and bioavailability to derive its maximum therapeutic efficacy.

Several techniques1 such as micronization, cyclodextrin complexation, use of surfactants and solubilizers, solid dispersion in water soluble and dispersible carriers, use of salts, prodrugs and polymorphs which exhibit high solubility, micro emulsions and self-emulsifying micro and nano disperse systems have been used to enhance the solubility, dissolution rate and bioavailability of poorly soluble drugs. Among the various approaches, solid dispersion2,3 in water soluble and water dispersible excipients is a simple, industrially useful approach for enhancing the solubility, dissolution rate and bioavailability of poorly soluble drugs. In solid dispersions the poorly soluble drug is dispersed in an inert water-soluble carrier such as urea, polyethylene glycol, poly vinyl pyrrolidone and surfactants at solid state. In the case of solvent deposited dispersions the drug is deposited in minuscular form on an inert water insoluble excipient such as silica gel, starch and modified starches at solid state.

Superdisintegrants are substances that rapidly swell in water and aqueous fluids to facilitate rapid disintegration of tablets and are widely used in tablet formulation in industry. Sodium starch glycolate (Primojel) is the sodium salt of a carboxy methyl ether of starch. Promojel is a water-insoluble tablet disintegrant and dissolution agent used at 2-5% concentration in tablets prepared by direct compression or wet- and dry-granulation methods. With the technique of co-evaporation, Primojel can be used to enhance the solubility and dissolution rate of poorly soluble drugs. In the present study Primojel was evaluated as a carrier in solid dispersions alone and in combination with a surfactant, Poloxamer 188. Surfactants are used as carriers in solid dispersions of poorly soluble drugs to enhance their solubility and dissolution rates. Poloxamer 188 is a polyethylene oxide-polypropylene oxide- polyethylene oxide triblock co-polymeric surfactant of non-ionic nature and is used as a solubilizing agent.4-6 Poloxamer 188 was also evaluated as carrier in solid dispersions for enhancing the dissolution rate of clonazepam7, rifampicin8, carvedilol9, finofibrate10, glipizide11, tenoxicam12 and glibenclamide13.

The objective of the present study is to prepare and evaluate solid dispersions of voriconazole in Primojel and Poloxamer 188 alone and in combination for enhancing the dissolution rate and dissolution efficiency of voriconazole. The individual and combined effects of the two carriers, Primojel and Poloxamer 188 in enhancing the dissolution rate and dissolution efficiency of voriconazole were evaluated in a 22 factorial study.

MATERIAL & METHODS

Materials

Voriconazole was a giftsample from M/s Hetero Drugs Ltd., Hyderabad. Poloxamer 188, Primojel and methanol (Qualigens) were procured from commercial sources. All other materials used were of Pharmacopoeial grade.

Estimation of Voriconazole

An UV Spectrophotometric method based on the measurement of absorbance at 255nm in 0.1N Hydrochloric acid was used for the estimation of voriconazole. The method was validated for linearity, accuracy, precision and interference. The method obeyed Beer's law in the concentration range of 1-10 ìg/ml. When a standard drug solution was repeatedly assayed (n=6), the relative error and coefficient of variance were found to be 1.2 % and 0.95 % respectively. No interference by the excipients used in the study was observed.

Preparation of Solid Dispersions in Primojel

Solid dispersions of voriconazole in Primojel using various ratios of drug:carrier were prepared by solvent evaporation method. The required quantity of voriconazole was dissolved in methanol (10ml) to get a clear solution in a dry mortar. Primojel was added to the drug solution in the mortar and mixed. The mixture was triturated continuously for 20mins to evaporate the solvent. Trituration was continued until a dry mass was obtained. The mass obtained was further dried at 50°C for 1h in hot air oven. The dried product was powdered and passed through mesh no 100 in each case.

Preparation of Solid Dispersions in Poloxamer 188

Solid dispersions of voriconazole in Poloxamer 188 using various ratios of drug:carrier were prepared by common solvent method. The required quantity of voriconazole and Poloxamer 188 were dissolved in methanol (10 ml) to get a clear solution in a dry mortar. The solution was triturated continuously for 20mins to evaporate the solvent. Trituration was continued until a dry mass was obtained. The mass obtained was further dried at 50°C for 1h in hot air oven. The dried product was powdered and passed through mesh no 100 in each case.

Preparation of Solid Dispersions in Combined Carriers

Solid dispersions of voriconazole in Primojel and Poloxamer 188 as per 22 factorial design were prepared by kneading method. The required quantities of drug and Poloxamer 188 were dissolved in the solvent methanol to get a clear solution in a dry mortar. Primojel was added to the drug- surfactant solution in the motor and mixed. The mixture was kneaded for 30min by continuous trituration. Small volume of the solvent was added to maintain the mixture as thick slurry during kneading process. Trituration was continued until a dry mass was obtained. The mass obtained was further dried at 50°C for 1 hour in a hot air oven. The dried product was powdered and passed through mesh no. 100 in each case.

Estimation of Drug Content of Solid Dispersions

From each batch four samples of solid dispersion equivalent to 20mg of the medicament was taken into a 100ml conical flask and extracted with 3 x 10 ml quantities of methanol. The methanolic extracts were filtered and collected into 50ml volumetric flask and the volume was made up to 50ml with methanol. The solution was subsequently diluted with 0.1N Hydrochloric acid and assayed for the voriconazole content at 255 nm.

Dissolution Rate Study

Dissolution rate of voriconazole from various solid dispersions prepared was studied in water (900ml) employing USP 8 station Dissolution Rate Test Apparatus (M/s Lab India Disso 8000) with a paddle stirrer at 50rpm. A temperature of 37±1°C was maintained throughout the study. Voriconazole or its solid dispersion equivalent to 50 mg of voriconazole was used in the test. Samples of dissolution fluid (5 ml) were withdrawn through a filter (0.45 ìm) at different intervals of time, suitably diluted and assayed for voriconazole at 255nm. The dissolution fluid withdrawn at each sampling time was replaced with fresh dissolution fluid and suitable correction is made in calculating the amount of drug dissolved. All dissolution rate experiments were conducted in triplicate (n=3).

RESULTS AND DISCUSSION

The objective of the present study is to prepare and evaluate solid dispersions of voriconazole in Primojel and Poloxamer 188 alone and in combination for enhancing the dissolution rate and dissolution efficiency of voriconazole, a BCS class II drug. Solid dispersions of voriconazole in Primojel alone were prepared using five ratios of drug: carrier namely 9:1, 8:2, 2:1, 1:1 and 1:3 by solvent evaporation method. These solid dispersions contain respectively 10, 20, 33, 50 and 75 % carrier (Primojel).Solid dispersions of voriconazole in Poloxamer 188 alone were prepared using three ratios of drug: carrier namely 19:1, 9:1 and 8:2 by common solvent method. These solid dispersions contain respectively 5, 10 and 20% carrier (Poloxamer 188).

Solid dispersions of voriconazole in combined carriers namely Primojel and Poloxamer 188 were prepared as per 22 factorial design by kneading method with a view to evaluate the individual main effects and combined (interaction) effects of Primojel (factor A) and Poloxamer 188 (factor B) on the dissolution rate and dissolution efficiency (DE30) of voriconazole. For this purpose two levels of Primojel (0 and 1:1 ratio of drug : carrier) and two levels of Poloxamer 188 (0 and 5%) were selected and the corresponding four treatments involved in the 22 factorial study were voriconazole pure drug (F1); voriconazole - Primojel (1:1) solid dispersion (Fa); voriconazole - Poloxamer 188 (5%) solid dispersion (Fb) and voriconazole - Primojel (1:1) - Poloxamer 188 (5%) solid dispersion (Fab). The above mentioned solid dispersions were prepared by kneading method.

All the solid dispersions prepared were found to be fine and free flowing powders. Low CV (< 1.0%) in the percent drug content indicated uniformity of drug content in each batch of solid dispersions prepared. The dissolution of voriconazole as such and from various solid dispersions was studied in water. The dissolution profiles of various solid dispersions prepared are shown in Figures 1, 2 and 3. The dissolution parameters of voriconazole and its solid dispersions prepared are given in Tables 1 and 2.

All solid dispersions prepared gave rapid and higher dissolution of voriconazole when compared to voriconazole pure drug. The dissolution data were analyzed as per zero order and first order kinetics in each case. The correlation coefficient (r) values were higher in the first order model than in zero order model indicating that the dissolution of voriconazole as such and from its solid dispersions followed first order kinetics. The correlation coefficient (r) values in the first order model were found to be in the range 0.920 - 0.985. The corresponding dissolution rate (K1) values of various products were estimated. Dissolution Efficiency (DE30) values were calculated as described by Khan.14 The dissolution parameters of various solid dispersions are summarized in Tables 1 and 2.

All the dissolution parameters namely PD15, DE30 and K1 (Table 1) indicated rapid dissolution of voriconazole from the solid dispersions prepared employing Primojel and Poloxamer 188 alone as carriers. With Primojel, the dissolution rate and dissolution efficiency of voriconazole were increased as the percent of carrier in the solid dispersion was increased upto 20%. There was no further increase in the dissolution rate and DE 30 values when the percent of carrier was increased above 20%. Hence 20% concentration of carrier (Primojel) is considered optimum for enhancing the dissolution rate and dissolution efficiency of voriconazole.

In the case Poloxamer 188, solid dispersions prepared at 5% carrier concentration gave higher enhancement in the dissolution rate and dissolution efficiency of voriconazole. At higher carrier concentrations (10 and 20%) the dissolution rate was decreased due to formation of aggregates of particles. Poloxamer 188 gave higher enhancement in the dissolution rate of voriconazole than Primojel when used at the same concentration. Poloxamer 188 gave 31.23 fold increase in the dissolution rate (K1) of voriconazole at 10% carrier concentration. Whereas Primojel gave only 4.75 fold increase in the dissolution rate (K1) of voriconazole at 10% carrier concentration.

In the case of combined carriers all solid dispersions prepared as per 22 factorial design gave rapid and higher dissolution of voriconazole when compared to voriconazole pure drug. The dissolution rates (K1) were subjected to Analysis of Variance (ANOVA) to find out the significance of the individual and combined (interaction) effects of Primojel (factor A) and Poloxamer 188 (factor B) in enhancing the dissolution rate and dissolution efficiency of voriconazole. ANOVA indicated that the individual and combined effects of Primojel (factor A) and Poloxamer 188 (factor B) in enhancing the dissolution rate (K1) of voriconazole are highly significant (P < 0.01).

A 11.35, 14.85 and 10.57 fold increase in the dissolution rate (K1) and a 4.02, 3.87 and 3.71 fold increase in the dissolution efficiency (DE30) was observed respectively with solid dispersions Fa, Fb and Fab when compared to F1 (voriconazole pure drug). The order of increasing dissolution rate (K1) observed with various solid dispersions was Fb > Fa > Fab >F1. Poloxamer 188 alone (Fb) and Primojel alone (Fa) gave higher enhancement in the dissolution rate of voriconazole. There was no additional enhancement in the dissolution rate with combined carriers of Primojel and Poloxamer 188. Hence solid dispersion of voriconazole in Primojel or Poloxamer 188 alone is recommended to enhance the dissolution rate and dissolution efficiency of voriconazole, a BCS class II drug.

CONCLUSION

The dissolution rate (K1) and dissolution efficiency (DE30) of voriconazole could be significantly enhanced by solid dispersion in Primojel (a water dispersible super disintegrant) and Poloxamer 188 (a nonionic surfactant) alone and in combination. Solid dispersions prepared employing Primojel and Poloxamer 188 alone as carriers gave rapid and higher dissolution of voriconazole. A 20 % concentration of Primojel and 5 % concentration of Poloxamer 188 were found to be optimum for enhancing the dissolution rate and dissolution efficiency of voriconazole. Poloxamer 188 gave higher enhancement in the dissolution rate of voriconazole than Primojel when used at the same concentration. All solid dispersions prepared as per 22 factorial design gave rapid and higher dissolution of voriconazole when compared to voriconazole pure drug. ANOVA indicated that the individual and combined effects of Primojel (factor A) and Poloxamer 188 (factor B) in enhancing the dissolution rate (K1) of voriconazole are highly significant (P < 0.01). A 11.35, 14.85 and 10.57 fold increase in the dissolution rate (K1) and a 4.02, 3.87 and 3.71 fold increase in the dissolution efficiency (DE30) was observed respectively with solid dispersions F a , F b and F a b when compared to F1 (voriconazole pure drug). The order of increasing dissolution rate (K1) of voriconazole observed with various solid dispersions was Fb > Fa > Fab >F1. Poloxamer 188 alone (Fb) gave higher enhancement in the dissolution rate of voriconazole. Hence solid dispersion of voriconazole in Primojel or Poloxamer 188 alone is recommended to enhance the dissolution rate and dissolution efficiency of voriconazole, a BCS class II drug. There was no additional enhancement in the dissolution rate with combined carriers of Primojel and Poloxamer 188.

References

REFERENCES

1. Chowdary K P R and Madhavi B L R; Novel Drug Delivery Technologies for Insoluble Drugs. Indian Drugs. 2005; 42(9):557-562.

2. Chiou W L and Riegelman S; Pharmaceutical Application of Solid Dispersion System. J Pharm Sci. 1971; 60(9):1281-1302.

3. Dhirendra K, Lewis S, Udupa N and Atin K; Solid Dispersions: A Review. Pak J Pharm Sci. 2009; 22(2):234-246.

4. Dumortier G, Grossiord J L, Agnely F and Chaumeil J C; A review of Poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2007; 23:2709-2728.

5. Giri T K, Badwaik H, Alexander A and Tripathi D K; Solubility enhancement of ibuprofen in the presence of hydrophilic polymer and surfactant. Int J Appl Biol Pharm Tech. 2010; 1(2):793-800.

6. Aejaz A, Jafar M, Dehghan M H G and Adil Shareef S; Meloxicam-PVP-SLS ternary dispersion systems: In-vitro and In-vivo Evaluation. Int J Pharm and Pharm Sci. 2010; 2(1):182-190.

7. Monzurul A R, Saiful I Md, Golam K, Sams M A S, Ruknuzzaman R Md, Hafizur R Md and Jalil R; Effects of Poloxamer and HPMC on the Dissolution of Clonazepam - Polyethylene Glycol Solid Dispersions and Tablets. Ind J Pharm Edu Res. 2011; 45(2):139-144.

8. Yadav B V, Yadav A V; Pharmaceutical Application of Supercritical Fluid Technique: An overview. J Pharm Res. 2009; 29(2):31-44.

9. Vinayak D K, Surendra G G and Sagar D K; Dissolution enhancement of Carvedilol by using surfactant as a coating material. Asian J Pharm and Clin Res. 2009; 2(3):39-43.

10. Patel T, Patel L D, Timir P, Sunil M, Tushar P and Tejas P; Enhancement of dissolution of Fenofibrate by Solid dispersion Technique. Int J Res Pharm Sci. 2010; 1(2):127-132.

11. Choudhary D, Kumar S and Gupta G D; Enhancement of solubility and dissolution of glipizide by solid dispersion (kneading) technique. Asian J Pharm. 2009; 3(3):245-251.

12. Saritha A and Nalini S; Preparation, physico chemical characterization of solid dispersions of tenoxicam with poloxamer. J Pharm Sci Tech. 2010; 2(9):308-311.

13. Tejas B P, Patel L D, Timir B P, Sunil H M and Tushar R P; Formulation and characterization of solid dispersions containing Glibenclamide. Int J Pharm Pharm Sci. 2010; 2(3):138-141.

14. Khan K A; The concept of dissolution efficiency. J Pharm Pharmacol. 1975; 27:48-49.