Solubility Enhancement of Itraconazole by Hypromellose Formulated by Solution-Suspension Layering Technique

 

Suresh Kolli^1*, K. Vijaya Sri², P. N. Murthy¹, V. R. Sirisha. K³

¹Department of Pharmaceutics, Royal College of Pharmacy and Health Sciences, Andhapasara Road,

Berhampur - 760 002, Orissa, India.

²Department of Pharmaceutics, Malla Reddy College of Pharmacy, Maisammaguda,

Secunderabad-500 014, India.

³Asst. General Manager, Ocean Pharma Coat, Jeedimetla, Hyderabad

 

ABSTRACT:

Itraconazole is an imidazole/triazole type, broad spectrum antifungal compound. It has low water solubility and low bioavailablity. In the present study, to enhance the solubility and dissolution rate of Itraconazole, immediate release pellets were formulated by solution-suspension layering using solubility enhancing polymer- hypromellose (HPMC). Drug coating was done with Itraconazole and Hypromellose (3 or 5 cps) in different ratios 1:1.25, 1:1.5, 1:1.6, 1:1.75. A successive seal coat was layered onto the drug pellets with Polyethylene glycol 20000. The prepared pellets were evaluated and compared with marketed formulation for drug content estimation and in-vitro drug release study. Dissolution studies revealed that formulations containing Itraconazole and Hypromellose, 3 cps (1:1.6), showed better drug release within 45 minutes. The study concluded that the affect of viscosity and concentration of solubility enhancer- Hypromellose on the drug release profile of poorly soluble and low bioavailable drug was ascertained.

 

 

 

INTRODUCTION:

Itraconazole is an imidazole/triazole type, broad spectrum antifungal compound. It is active against Aspergillosis, Candidiasis, Cryptococcosis, Blastomycosis, Sporotrichosis, Histoplasmosis and Onychomycosis. It inhibits the fungal-mediated synthesis of ergosterol, an essential component of the fungal cell membrane and results in increased cellular permeability causing leakage of cellular contents, endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis [1, 2].

 

 

The present study was aimed to formulate immediate release pellets in capsule of Itraconazole (100 mg). Pellets are various kinds of subunits with defined less-porous surface, spherical shape, low surface area to volume ratio; suitable for flexible and uniform drug-polymer coating. They offers numerous technological, physiological and therapeutic advantages like ease of dispersing  throughout  the  GIT,  maximize  the  drug absorption, less risk of dose dumping, reduced  peak  plasma  fluctuations and minimize  potential  side  effects  with  improved drug  bioavailability [3];  reduced inter and intra patient variability [4];  more suitable for  fabrication  of  formulations  with  acid sensitive  drugs [5]. 

 

Various techniques to prepare pellets include solution-suspension layering, powder layering, extrusion-spheronization etc. Solution-Suspension layering involves deposition of successive layers of solution and/or suspension of drug substance and binders on existing inert cores. Droplets  of  the  binding  liquid  spread  on  to  the surface  of  the  cores.  During drying, the liquid evaporates, the dissolved substances crystallize out and capillary forces formed draw the particles towards each other and towards the inert cores, forming solid bridges [6].

 

In formulation development, drug solubility is one of the challenging aspects as it affects the dissolution rate. The solubility and bioavailability can be increased by solubility enhancing methods. Itraconazole has low water solubility and low bioavailability. The solubility is enhanced by using hypromellose - a binder, coating agent and also a solubility enhancer. The formulation consists of (a) a central, rounded or spherical core inert pellets (sugar spheres) coated with (b) a coating film of a hydrophilic polymer (Hypromellose) and an antifungal agent (Itraconazole), and (c) a seal outer coating layer (d) finally filled into capsules. The coating of various layers was carried out in a Wurster bottom spray insert (Glatt GPCG 1.1).

 

The prepared capsule form is a molecular dispersion of Itraconazole in Hypromellose polymer. Hypromellose is a non-ionic and water soluble (hydrophilic) polymer, mixed cellulose ether, which is of great importance as a carrier in drug release systems. It can control the drug release rate due to its swelling and dissolution properties in aqueous solution, which are probably associated with the formation of soluble complexes between the water-soluble polymeric carrier and the poorly-water-soluble drug. The fast-dissolving polymer targets a supersaturated solution of Itraconazole from which enhanced absorption can be expected.

MATERIALS AND METHODS:

Materials

Itraconazole (Hetero Drugs Ltd.), Hypromellose, 3 and 5 cps (The Dow Chemicals), Polyethylene glycol 20000 (Clariant), Sugar spheres (Signet Chemicals), Dichloromethane (Runa chemicals), Ethanol (Runa chemicals). All other chemicals and reagents were of analytical grade.

 

Methods

Preparation of different coating solutions/ suspensions

(a) Drug coating solution: Dichloromethane and Ethanol were taken in a suitable beaker in required proportions and kept under continuous stirring. Then, hydrophilic polymer-Hypromellose (HPMC) was added slowly and stirred to get clear solution. To this, Itraconazole was added under stirring and stirred to get clear solution.

 

(b) Seal coating solution: This layer is applied onto the drug coated pellets to prevent sticking of the pellets which would have an undesirable effect of a concomitant decrease of the dissolution rate and bioavailability. Polyethylene glycol was added to the mixture of Dichloromethane and Ethanol; and stirred to get clear solution.

 

(c) Intermediate drying: In order to minimize residual solvent levels, the coated pellets were then subjected to drying for an hour at the end of every 25% drug coating and at the end of seal coating.

 

(d) Capsule filling: The prepared immediate release pellets were filled into hard-gelatin capsules of size ‘0’.

 

Formulation of Immediate Release Pellet in Capsules

Different formulations and coating parameters of Itraconazole immediate release pellet in capsules were tabulated in Table 1 and 2.

 

 

 

Table 1: Optimization of Drug coating and Seal coating

INGREDIENTS	mg/unit
	F1	F2	F3	F4	F5	F6	F7	F8
DRUG COATING
Drug : Polymer ratio	1 : 1.25	1 : 1.5	1 : 1.6	1 :1.75	1 : 1.25	1 : 1.5	1 : 1.6	1 :1.75
Sugar Spheres (#20/25)	225.80	200.80	190.80	175.80	225.80	200.80	190.80	175.80
Itraconazole	100.00	100.00	100.00	100.00	100.00	100.00	100.00	100.00
Hypromellose (HPMC), 3cps	-	-	-	-	125.00	150.00	160.00	175.00
Hypromellose (HPMC), 5cps	125.00	150.00	160.00	175.00	-	-	-	-
Dichloromethane	1553.00	1725.00	1794.00	1898.00	1215.00	1350.00	1404.00	1485.00
Ethanol	1035.00	1150.00	1196.00	1265.00	810.00	900.00	936.00	990.00
Total weight	450.80	450.80	450.80	450.80	450.80	450.80	450.80	450.80
SEAL COATING
Polyethylene glycol 20000	39.20	39.20	39.20	39.20	39.20	39.200	39.20	39.20
Dichloromethane	212.00	212.00	212.00	212.00	212.00	212.000	212.00	212.00
Ethanol	141.00	141.00	141.00	141.00	141.00	141.000	141.00	141.00
Total weight of pellets	490.00	490.00	490.00	490.00	490.00	490.000	490.00	490.00

 

Table 2: FBP Process Parameters

FBP Process Parameters	Operating Range
	Drug coating	Seal coating
Inlet temperature (°C)	50-60	50-60
Product temperature (°C)	45-55	45-55
Exhaust temperature (°C)	40-55	40-55
Air flow (CFM)	30-50	30-50
Atomization air pressure (Barr)	0.5-1.0	0.5-1.0
Spray rate (g/min)	3-10	3-10
Wurster height (mm)	20-40	20-40

 

 

EVALUATION PARAMETERS

The coated pellets filled in capsules were estimated for drug content and invitro drug release.

 

Estimation of Drug Content

The drug content was estimated by HPLC using column C₈ at a wavelength 260 nm, flow rate- 1.0 mL/min, run time - 20 minutes at ambient column temperature. The mobile phase was 550 mL of ammonium phosphate buffer and 450 mL of acetonitrile; pH was adjusted with diluted ortho phosphoric acid to 2.50+0.05. The diluent was 1000 mL of methanol and 5.0 mL of conc. HCl. The concentration of the standard solution was 0.5 mg/mL and diluted standard was 0.05 mg/mL of Itraconazole. Preparation of sample solution: 20 capsules content or its equivalent weight pellets were taken. Sample equivalent to 100 mg of Itraconazole was weighed and transferred into a 200 mL volumetric flask with the aid of diluent; sonicated for 15 minutes with occasional shaking to dissolve the solids. The solution was allowed to equilibrate to room temperature. A portion of the sample was centrifuged for about 15 minutes. 5 mL of the sample solution was transferred into a 50 mL volumetric flask; diluted to volume with diluent and mixed well. Blank (Diluent), five consecutive injections of diluted standard preparations were injected and determined the system suitability. Once the system suitability was attained, diluted sample preparations were injected. Drug content was estimated by the following formula.

 

% Drug Content

 = Au x C x P x 200ml x 50 ml x AFW x 100

    As                   Ws        5 ml                  100 (lable claim)

 

Where Au and As are Peak area of Itraconazole in diluted sample and diluted standard preparations respectively; C is Concentration of Itraconazole in diluted standard preparation in mg/mL; P is Purity of Itraconazole marketed standard in decimal form; Ws is Itraconazole sample weight in mg; AFW is Average filled weight in mg; 100 is Conversion factor for percent.

 

 

 

Invitro Dissolution

Invitro dissolution was carried out in 900 mL, SGF without enzyme at 37.0 + 0.5ºC, USP apparatus II (Paddle) at 100 rpm {with sinkers}. The drug release profile was estimated by UV Spectrophotometry at a wavelength 258 nm using 1 cm flow cell. The diluent was  100 mL of dissolution media and 400 mL of methanol. The concentration of standard solution was 0.2220 mg/mL and the diluted standard was 0.0222 mg/mL of Itraconazole. Preparation of sample solution: 10 mL of aliquot from each vessel was withdrawn from each vessel at specified time point, filtered through 0.45 µ nylon 66 membrane filter. 2 mL of aliquot solution was transferred into 10 mL volumetric flask; diluted to volume with methanol and mixed well. Absorbance of the diluted standard and sample preparation was determined at maximum absorbance at 258 nm. Sampling time intervals were 10, 20, 30, 45, 60, 75 and 90 minutes. % Drug dissolved was estimated by the following formula.

 

% Drug dissolved = Au x C x P x 900 ml x 10 ml x 100

                                 As                               2 ml        100 (lable claim)  

 

Where Au and As is Absorbance of Itraconazole in diluted sample and diluted standard preparations respectively; C is Concentration of Itraconazole in diluted standard preparation in mg/mL; 100 is Conversion factor for percent; Label claim in mg.

 

SIMILARITY AND DISSIMILARITY FACTORS

FDA guidance documents consider some approaches such as difference (f1) and similarity (f2) factors to analyze the dissolution data equivalence. The dissimilarity factor (f1) should be computed using the following equation:

 

Where Rt and Tt are the cumulative percentage of the drug dissolved at each of the selected n time points of the reference and test product, respectively.

 

The similarity factor (f2) is a logarithmic transformation of the sum-squared error of differences between the test T_j and reference products R_j over all time points, m.

 

Where w_j is an optional weight factor [7].

 

 

 

 

RESULTS AND DISCUSSION:

Drug Content:

The drug content for formulations F1 to F8 was 96- 99%.

 

Invitro dissolution

The drug release profiles were depicted in Figure 1. The trails F1 to F4 were formulated with Itraconazole: Hypromellose, 5 cps and F5 to F8 with Itraconazole: Hypromellose, 3 cps in the ratios 1: 1.25, 1: 1.5, 1: 1.6, 1:1.75 respectively. When compared to the marketed product, the drug release profile was found to be low in trails F1 to F4. These trials showed increasing trend in drug release with increased drug-polymer concentration. Hence, further trails were planned with low viscosity grade polymer i.e., hypromellose, 3 cps. Comparatively, the drug release profile was faster in trails F5 to F8 than trails with Itraconazole: Hypromellose, 5 cps (F1 to F4). The drug release profile of F7 was found to be comparable with the marketed product.

 

Based on the above results, it was concluded that ‘F7’ was finalized as optimized formulation for immediate release capsules of Itraconazole (100 mg dose) as the solubility was enhanced with Itraconazole: Hypromellose, 3 cps in the ratio 1: 1.6.

 

 

 

 

Figure 1: Graph showing comparative invitro dissolution profiles of different formulations with marketed product

 

Similarity and dissimilarity factors

For invitro dissolution curves to be considered f1 values should be in the range of 0-15 while values of f2 should lie within 50-100. The dissimilarity (f1) and similarity (f2) factors for optimized (F7) and marketed formulation were found to be 2 and 82, respectively.

 

CONCLUSION:

In line with the above results, it has been found that the incorporation of poorly soluble antifungal agent in a hydrophilic polymer and coating this mixture as a film over many small pellets yield a composition with enhanced solubility which is suitable and conveniently be manufactured for preparing immediate release pellet in capsules of Itraconazole (100 mg dose) for oral administration as the solubility was enhanced with                        Drug: Hypromellose, 3 cps (1:1.6).

 

 

 

 

REFERENCES:

1.          Takara K, Tanigawara Y, Komada F, Nishiguchi K, Sakaeda T, Okumura K. Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs. Biol Pharm Bull 1999; 22: 1355-1359

2.          Koks CH, Meenhorst PL, Bult A, Beijnen JH. Itraconazole Solution: Summary of Pharmacokinetic Features and Review of Activity in the Treatment of Fluconazole-Resistant Oral Candidosis in HIV-Infected Persons. Pharmacological Research. 2002, 46 (2), 195-201.

3.          Ghebre-Sellassie I and Knoch A. Pelletization techniques: Encyclopedia of Pharmaceutical Technology.  Informa Healthcare, 3rd ed: 2002.

4.          Bechgaard H and Neilson GH. Controlled release multiple units and single-unit doses. Drug Development and Industrial Pharmacy. 1978; 4: 53-67.

5.          Digenis GA. The invivo behavior of multiparticulate versus single unit dosage formulations. In: Ghebre-Sellassie I, editor. Multipaticulate Oral Drug Delivery, Marcel Dekker, New York. 1994; 333-355.

6.          Bauer KH, Lehmann K, Osterwald HP and Rothgang G. Equipment for sugar coating and film coating processes Coated pharmaceutical dosage forms. Medpharm Scientiphic Publishers, Stuttgart. 1998.

7.          Moore JW, Flanner HH. Mathematical comparison of dissolution profiles. Pharm. Tech. 1996; 20 (6): 64-74.

 

 

 

 

 

Accepted on 05.10.2018           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(11): 4850-4853.