Optimization and development of orodispersible films for ledipasvir and sofosbuvir through solid dispersion using Box-Behnken design

Uday Kumar Thummala^1,2*, Eswar Guptha Maddi³, Prameela Rani Avula⁴

¹Associate Professor, Aditya College of Pharmacy, Surampalem, Kakinada, Andhra Pradesh, India.

²Research Scholar, School of Pharmacy, JNT University Kakinada, Kakinada, Andhra Pradesh, India.

³Sir CR Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India.

⁴University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Guntur, Andhra Pradesh, India.

*Corresponding Author E-mail: udaykumar.chowdary16@gmail.com, meguptas@gmail.com, drapr64@gmail.com

ABSTRACT:

The fixed dose combination of ledipasvir (LDV) and sofosbuvir (SBV) is approved by USFDA in 2014 for the treatment of Hepatitis C virus infection and is available in the form of tablets. In the present work, the principal aim is to explore orodispersible films type dosage form to impart its characteristic advantages to these poorly soluble drugs so as to improve their bioavailability and ease of administration. Solid dispersions with low viscosity grade methyl cellulose A 15-LV (MC A 15-LV) at different ratios with LDV and SBV were prepared and evaluated to check their ability in improving the solubility of the drugs. The best drug to polymer ratio was selected to develop the films, using other excipients including plasticizer and superdisintegrant. Solvent casting method was used to develop the films. Three formulation parameters were selected as independent factors viz. thickness of the film (50-150 µm), concentration of superdisintegrant (sodium starch glycolate 6-10%) and concentration of plasticizer (polyethylene glycol 400, 10-20%). Disintegration time (DT), time for 90% dissolution (T90%) of LDV and time for 90% dissolution of SBV were taken as the response variables. The experiment was designed using Box-Behnken design. Among the polymers, MC A 15-LV produced maximum solubility at 1:2 ratio. The films obtained were found to have good tensile strength and % elongation with disintegration times in the range of 43-162 sec. The T90% values for LDV and SDV were found to be in the range of 8.4-21.2 min and 7.2-18.4 respectively. All the three formulation factors were found to have significant effect on the three responses. The optimum formulation was identified at 100 µm thickness, 10% superdisintegrant and 20% plasticizer which showed DT of 89 sec with T90% values of 8.4 min and 7.2 min for LDV and SBV respectively. The rapid disintegration and dissolution of the films signified that the set objective was achieved.

KEYWORDS: Ledipasvir and Sofosbuvir, Orodispersible films, Bioavailability enhancement, Box-Behnken design, Optimization

INTRODUCTION:

A fixed dose combination of ledipasvir (LDV) and sofosbuvir (SBV) in the tablet dosage form was approved by USFDA in 2014 for the treatment of chronic hepatitis C virus (HCV) infection in adults and pediatric patients of older than 3 years. The doses of ledipasvir and sofosbuvir are 90 mg and 400 mg respectively^1,2. The total dose of 490 mg along with excipients made the final weight of the tablet near to 1 g, made it difficult to swallow. Hence, development of rapidly oral dispersing/dissolving formulations is much needed to reduce the swallowing difficulties of the available commercial tablets. Further, ledipasvir is practically insoluble and sofosbuvir is slightly soluble in water over the pH range of 2.4 – 7.0³ and hence having dissolution limited bioavailability. These conditions necessitate development of fast dissolving or orodispersible films (ODFs) as the best suitable formulations to retain the advantages of solid dosage forms yet providing ease of administration with improved bioavailability for this poorly soluble fixed dose combination of LDV and SBV.

ODFs are the current interest of the formulation development research owing to their elegant appearance, ease of administration, rapid dissolution, rapid absorption and even easy to manufacture and scale-up when compared to the oral tablets^4-6. Their rapid disintegration and dissolution in the oral cavity itself improve the bioavailability of poorly soluble drugs. Further, absorption from the oral cavity can avoid first-pass metabolism. Several research results have been published to support these claims of ODFs and some recent ones including the work published by Khan Q et al. 2020⁷ about the enhancement of bioavailability of poorly soluble cefixime trihydrate using orodispersible films through solid dispersions; Ahmad A et al. 2020⁸ developed orodispersible films by solvent casting method for a poorly soluble drug eletriptan hydrobromide and reported that the dissolution of the drug was significantly enhanced. Raza SN et al. 2019⁹ reported that the dissolution rate of losartan potassium was greatly improved by formulating into mouth dissolving films. These literature reports greatly suggested that the development of ODF s for LDV and SBV can possible enhance their dissolution limited bioavailability.

Extensive literature on formulation development of LDV and SBV revealed that only one paper was published on development of only single drug LDV fast dissolving tablets by Guntaka PCR, Lankalapalli S 2018¹⁰. This suggested that there is a great scope to develop fast dissolving/oral dispersing dosage forms for the fixed dose combination of LDV and SBV. Hence, in this research work it was aimed to develop orodispersible films (ODFs) for the fixed dose combination of LDV and SBV to improve bioavailability as well as patient convenience.

A novel approach was adopted in this work i.e. selection of optimized film former through solid dispersions with the drugs followed by development of the films. Methyl cellulose (MC) is one of the most suitable film former and also similarly more suitable carrier to improve solubility/dissolution¹¹ of poorly soluble drugs by various solid dispersion techniques¹². Hence, in this study solid dispersions of LDV+SBV with MC were prepared and evaluated to identify the optimum ratio of drug to polymer. Later, this optimized ratio was used to develop the ODFs to achieve rapid disintegration as well as dissolution thus high bioavailability and patient convenience upon administration are accomplished. Design of experiments (DoE) was employed to optimize the ODFs. Box-Behnken design under response surface methodology was employed using StatEase Design Expert software. Three formulation variables viz. thickness of the film (viscosity of the polymer solution), super disintegrant concentration and plasticizer concentration were taken as independent factors; disintegration time, time for dissolution of 90% of LDV and SBV were taken as response variables for the optimization.

MATERIALS AND METHODS:

Materials:

Ledipasvir and Sofosbuvir were received as gift samples from Hetero Drugs Pvt. Ltd, Visakhapatnam; HPMC, MC, PVP, PEG 400 were purchased from Sigma Chemicals Co.; sodium starch glycolate, cross carmellose sodium, glycerol, isopropyl alcohol (IPA), Tween 80 were procured from SD Fine Chemicals, Mumbai; All other chemicals used were of analytical grade.

Analytical method:

Quantification of LDV and SBV in the formulation mixtures is necessary in order to evaluate the solid dispersions and dissolution studies of the films. A method for the simultaneous estimation of LDV and SBV using UV-Visible spectrophotometer developed, validated, and the results published separately¹³, was used in the present work.

Solid dispersions with methyl cellulose:

Solid dispersions were prepared for LDV and SBV with MC A 15-LV (low viscosity grade with viscosity of 15 cps for 2% w/v aqueous solution at 20^oC) at three different drug mixture to the carrier ratios of 1:1, 1:2 and 1:3, using solvent evaporation method. 1g of the drug mixture and the corresponding amount of the carrier were dissolved in 20 mL of IPA on a vertex mixture until the complete dissolution of the solids. Then the solution was subjected to removal of IPA under vacuum. The obtained dry powdered solid dispersions (SDs) were passed through sieve #44. The solid dispersions were subjected to solubility study by shake-flask method in comparison with pure drug. The optimized solid dispersion powder was subjected to differential scanning calorimetry (DSC) and powdered X-ray diffraction (PXRD)¹⁴ techniques to investigate the physical state of the drug mixture in the SDs and also to infer the possible mechanism of solubility enhancement.

Viscosity studies:

Different amounts of MC with 15% PEG 400 were dissolved separately in the solvent mixture of water and IPA at 4:6. These solutions were subjected to dynamic viscosity studies at 20^oC using Brookfield cup and bob viscometer. Further selected solutions were casted as films to check the thickness of the obtained films.

Preparation of Orodispersible Films:

Design of experiment:

Box-Behnken design under response surface methodology using StatEase Design Expert software was selected to study the influence of selected formulation variables on the quality characteristics of the films. From the extensive literature study three formulation variables with three levels each were selected as independent factors viz. thickness of the film (A, 50-150 µm), concentration of sodium starch glycolate (B, 6-10%) and concentration of PEG 400 (C, 10-20%). Disintegration time (R1), time for 90% dissolution (T90%) of LDV (R2) and time for 90% dissolution of SBV (R3) were taken as the response variables. Combinations of the possible 13 runs according to the design (shown in Table 1) were taken as 13 formulations for preparation of the ODFs.

Table 1: Combination of factors and their levels according to Box-Behnken design with actual composition

S. No.	Formulation code	Combination of the factors and their levels according to the Box-Behnken design			Composition
		Thickness (A)	Disintegrant concentration (% w/w)	Plasticizer concentration (% w/w)	LDV (mg)	SBV (mg)	MC (mg)	SSG (mg)	PEG 400 (mg)	Tween 80 (µL)	Final volume (mL)
1	F1	50.00	6.00	15.00	90	400	980	88.2	147	40	20
2	F2	50.00	8.00	10.00	90	400	980	117.6	98	40	20
3	F3	50.00	8.00	20.00	90	400	980	117.6	196	40	20
4	F4	50.00	10.00	15.00	90	400	980	147	147	40	20
5	F5	100.00	6.00	10.00	90	400	980	88.2	98	30	15
6	F6	100.00	6.00	20.00	90	400	980	88.2	196	30	15
7	F7	100.00	8.00	15.00	90	400	980	117.6	147	30	15
8	F8	100.00	10.00	10.00	90	400	980	147	98	30	15
9	F9	100.00	10.00	20.00	90	400	980	147	196	30	15
10	F10	150.00	6.00	15.00	90	400	980	88.2	147	20	10
11	F11	150.00	8.00	10.00	90	400	980	117.6	98	20	10
12	F12	150.00	8.00	20.00	90	400	980	117.6	196	20	10
13	F13	150.00	10.00	15.00	90	400	980	147	147	20	10

Method of preparation of ODFs:

Solvent casting method¹⁵ was used to prepare the ODFs so as to contain the drug mixture to MC at the optimized ratio of 1:2. According to the formula shown in the Table 1, desired amount MC was taken and dissolved in mixture of water and IPA (ratio of 4:6) containing 0.2% tween 80 using vertex mixture. Then the drug mixture was added into the polymer solution and dissolved. Then specified amounts of SSG and PEG 400 were added and mixed to obtain homogenous solution, and finally the volume was adjusted to 20/15/10 mL in order to obtain the films with desired thickness of 50, 100 and 150 µm upon evaporation. These solutions were poured into glass petri plates and subjected to evaporation of the solvent under ambient conditions. After complete evaporation of the solvents (nearly after 48 hours), the films were removed, cut with dimensions of 25 cm² and stored carefully for further analysis.

Characterization of the ODFs:

a) Physical characterization studies¹⁵:

The thickness of the films was measured using micrometer screw-gauge at five different locations and reported as their mean value. Folding endurance was determined by counting the number of times of folding the film at same place until breaking. Tensile strength and percentage elongation were determined using texture analyzer. Tensile strength is the highest stress applied to a point at which the film specimen breaks and can be calculated by dividing the maximum load by the original cross sectional area of the specimen and it was expressed in force per unit area (MPa). The percentage elongation was determined by measuring the distance between the tensile grips before (D₁) and after (D₂) fracture of the film.

                 D₂-D₁

E (%) = --------------- x 100

                    D₂

b) Drug content:

One complete film as casted was into a beaker containing 100 mL of the dissolution medium and was subjected to stirring for 2 h ensuring complete solubilization of both the drugs. Then the solution was filtered, diluted suitably and quantified using UV-Visible spectrophotometer.

c) Disintegration time:

It was determined using petri dish method¹⁵. 6 mL of phosphate buffer pH 6.8 was added into petri dish and the cut films were placed into it. The time taken for complete dispersion of the film was noted as the disintegration time.

d) Dissolution:

The dissolution study was carried out using USP apparatus 2 (Paddle type). The dissolution was carried out in 900 ml of 1.5% polysorbate 80 in 10 mM potassium phosphate buffer with 0.0075 mg/mL butylated hydroxytoluene, pH 6.0 at 37± 0.5°C. Six randomly selected films were used for the test. The samples were collected at various time intervals and replaced with the same buffer. The collected samples were quantified for both the drugs using UV-Visible spectrophotometer.

RESULTS AND DISCUSSION:

Studies on solid dispersions:

SDs with drug to polymer ratio of 1:1, 1:2 and 1:3 were prepared and subjected to solubility study in water for 24 h. The results were shown in the Table 2. The results suggested that the solubility of both the drugs was significantly improved upon solid dispersions with MC. Further, the solubility was found to be improved significantly upon increasing the amount of MC because of improved hydrophilicity^11,15. But, the increase in solubility from the ratios of 1:2 to 1:3 was not significant and hence the optimum ratio considered to be 1:2. The increase in solubility might be attributed to the conversion of the drugs from crystalline to amorphous form which was elucidated from the results of DSC and PXRD studies, whose images were shown in Fig 1. From the DSC studies, the thermogram of the mixture of pure drugs had two sharp endotherms at 114.1^oC and 187.4^oC corresponding to the melting points of LDV and SBV respectively. But in the thermogram of the SD, these endotherms were not observed which indicated the conversion of the drugs into amorphous form¹⁴. This was further evidenced by the results of PXRD studies, in which the sharp peaks present in the spectrum of the mixture of pure drugs were greatly reduced in their intensity in the spectrum of their SD. This might be attributed to the conversion of crystalline nature of the drugs into amorphous form because of the SD¹⁴.

Table 2: Results of solubility studies of pure drugs and SDs

S. No.	Drug name	Solubility in water (mg/mL)
		Pure drug	SD 1:1	SD 1:2	SD 1:3
1	LDV	0.008	0.103	0.386	0.398
2	SBV	0.936	8.472	14.362	14.658

Fig 1: (i) DSC thermograms of (a) Mixture of pure LDV and SBV; (b) Pure MC; and (c) SD of LDV and SBV with MC. (ii) PXRD spectra of (a) Mixture of pure LDV and SBV; (b) SD of LDV and SBV with MC

Viscosity studies:

The thickness of the films depends on the viscosity of the polymer solution to be casted. These were performed to fix the volume of solvent for the taken amount of polymer so as to obtain the films with desired thickness. 980 mg of MC with 15% of PEG400 was added into different volumes of the solvent mixture (water and IPA at 4:6 ratio). These solutions were checked for their dynamic viscosity at 20^oC and the same solutions were casted into films. The solutions with 20 mL, 15 mL and 10 mL which produced films of thickness of 50 µm, 100 µm and 150 µm were selected for the development of ODFs. The results of the viscosity studies for the selected volumes were shown in Table 3.

Table 3: Results of various characterization studies of ODFs F1 – F13

S. No.	Formulation	Viscosity (cP)	Thickness (µm)	Tensile strength (MPa)	% Elongation	Folding endurance	DT (sec.)	LDV-Assay (%)	SBV-Assay (%)	LPV-T90% (min.)	SBV-T90% (min.)
1	F1	1620	52	7.2	22.4	274	89	102.1	101.6	14.7	12.4
2	F2	1763	54	6.3	19.7	226	76	98.5	99.2	13.4	10.9
3	F3	1584	50	8.1	25.1	363	97	97.8	97.4	9.7	8.1
4	F4	1672	53	7.1	21.3	258	43	99.4	98.5	10.5	9.2
5	F5	3842	102	8.1	24.5	351	124	100.7	100.8	16.2	13.6
6	F6	3560	98	10.4	29.1	474	156	101.6	101.4	11.5	9.7
7	F7	3758	99	8.9	26.2	425	117	96.4	97.6	12.6	10.3
8	F8	4125	105	7.9	24.8	329	71	97.2	98.2	10.8	8.9
9	F9	3827	101	10.1	28.6	452	89	100.4	99.7	8.4	7.2
10	F10	5250	148	10.9	29.4	469	162	97.9	97.5	17.8	15.5
11	F11	5534	153	9.8	28.2	413	114	101.8	101.9	21.2	18.4
12	F12	5348	150	12.1	32.5	511	151	98.6	97.4	15.9	13.8
13	F13	5470	153	10.7	29.6	447	92	97.7	98.2	13.5	11.2

Characterization studies of ODFs

a) Physical characterization studies

The films were observed visually and found to be smooth, clear, uniform and transparent (shown in Fig 2). The results of thickness were shown in Table 3. Upon decreasing the volume of the solvent mixture from 20 mL (for F1-F4) to 15 mL (for F5-F9) to 10 mL (for F10-F13), the thickness of the films was increased which was attributed to increased viscosity of the polymer solution. Folding endurance, tensile strength and % elongation indicate the flexibility/elasticity of the film which resist breakage of the film during handling/packing. Results of these parameters were also shown in Table 2. Tensile strength values were found to be high and in the range of 6.3 – 10.9 MPa. These values were found to be increased upon increase in the concentration of plasticizer as shown in Fig 3. This might be attributed to the molecular entanglement of the plasticizer with the film forming polymer thus reducing the brittleness of the film. Further higher the concentration of the plasticizer, more increased molecular entanglement with the polymer might result the films with more elasticity¹⁶. The results of the % elongation and folding endurance were in agreement with the tensile strength as their values were found to be increased upon increase in the plasticizer concentration¹⁶.

Fig 2: ODFs of LDV and SBV of different thickness (a) 50 µm; (b) 100 µm; and (b) 150 µm

Fig 3: Effect of plasticizer concentration and thickness on tensile strength of the ODFs

b) Drug content:

The drug content values of all the formulations of ODFs for LDV and SBV were found to be in the range of 97.2 – 102.1 and 97.4 – 101.9 respectively. These values indicated that the drugs were homogenously dissolved and uniformly dispersed in the polymer upon film formation which inferred that the selection of the solvent mixture was appropriate for the drugs and the polymer selected.

c) Disintegration time:

This is one of the major quality characteristics of ODFs and so taken as one of the three responses in this study. The results were shown in the Table 3. DT values of all the formulations were obtained below three minutes and in the range of 43 – 156 sec. The effects of all the three formulation factors on DT were shown in the Fig 4 (a) and 4 (b). Upon increasing the thickness (A) of the films, the disintegration time was found to be increased. This could be attributed to the increased path length for the diffusion of water to reach the disintegrant particles to be swollen followed by disintegration that might take more time. These results were correlated with those reported by Zhang L et. al. 2018¹⁷. Upon increasing the concentration of disintegrant (B), the DT was found to be decreased. This could be because of rapid and high degree of swelling followed by immediate disintegration of the ODFs at high disintegration concentration. These results were correlated with those reported by Swamy SK et. al. 2016¹⁸. Upon increasing the concentration of plasticizer (C), the DT was found to be increased. This could be because of reduced swelling nature of the films at higher plasticizer concentration which resulted in slow disintegration and hence high DT values^16,19. The effect of all the three factors on DT was significant at p < 0.05 by ANOVA²⁰ and the results were shown in Table 4.

d) Dissolution studies:

The ODFs were developed for the combination of LDV and SBV. The dissolution profiles for both the drugs from all the formulations were illustrated in Fig 5. The time for 90% dissolution of LDV and SBV were taken as two other responses for the selected experimental design and their results were shown in Table 3. The influence of all the three formulation factors on LDV-T90% and SBV-T90% were illustrated in Fig 4 (c) & 4 (d); and in Fig 4 (e) and 4 (f) respectively. Upon increasing the film thickness (A), the T-90% was found to be increased. This could be attributed to the more complex gel matrix in the ODFs made with more viscous polymer solution. Further, higher diffusion path length for the solvent penetration and drug dissolution from the films with more thickness might increase the time for drug dissolution. These results were correlated with those reported by Zhang L et. al. 2018¹⁷.

Fig 4: Effect of the three formulation factors (A, B and C) on the three responses (R1, R2 and R3).

Images (a) & (b) indicate the effect of A, B and C on R1; Images (c) and (d) indicate the effect of A, B and C on R2; and Images (e) & (f) indicate the effect of A, B and C on R3.

Upon increasing the concentration of the disintegrant, the T90% was found to be decreased. This could be attributed to the rapid disintegration at higher disintegrant concentrations that could make the drugs to dissolve rapidly¹⁷. Upon increasing the concentration plasticizer, the T90% was decreased. This could be because of increased hydrophilicity of the film as well as increased free space between the polymer chains at higher plasticizer concentration²¹. The results obtained were correlated with those reported by Aguirre et. al. 2013²². The effects of all the three factors on LDV-T90% and on SBV-T90% were significant at p < 0.05 by ANOVA and the results were shown in Table 4.

Table 4: ANOVA test results of the three response variables

S. No.	Response	Source	SS^a	Df^b	MSS^c	F value	p-Value	Inference^d
1	R1 – DT	Model	13604.50	3	4534.83	34.19	< 0.0001	Significant
		A-Thickness	5724.50	1	5724.50	43.16	0.0001	Significant
		B-SDisintegrant	5832.00	1	5832.00	43.97	< 0.0001	Significant
		C-Plasticizer	2048.00	1	2048.00	15.44	0.0035	Significant
		Residual	1193.81	9	132.65
		Cor Total	14798.31	12
2	R2 – LDV-T90%	Model	119.03	3	39.68	10.27	0.0029	Significant
		A-Thickness	50.50	1	50.50	13.07	0.0056	Significant
		B-SDisintegrant	36.13	1	36.13	9.35	0.0136	Significant
		C-Plasticizer	32.40	1	32.40	8.39	0.0177	Significant
		Residual	34.76	9	3.86
		Cor Total	153.79	12
3	R3 – SBV-T90%	Model	90.00	3	30.00	8.61	0.0052	Significant
		A-Thickness	41.86	1	41.86	12.02	0.0071	Significant
		B-SDisintegrant	27.01	1	27.01	7.76	0.0212	Significant
		C-Plasticizer	21.13	1	21.13	6.07	0.0360	Significant
		Residual	31.35	9	3.48
		Cor Total	121.34	12

Note: ^a-Sum of Squares; ^b-Degrees of Freedom; ^c-Mean Sum of Squares; ^d-p-Value less than 0.05 indicates model terms are significant

Fig 5: Dissolution profiles of the ODFs. Plots (a) – (c) indicate dissolution profiles for LDV; and

Plots (d) – (f) indicate dissolution profiles for SBV from the ODFs

CONCLUSION:

The selected Box-Behnken design for the development of ODFs was found to be significant and all the three formulation factors at the selected levels were proved to have significant influence on all the three responses upon statistical analysis using Design Expert software. The results of these response variables and those of physical characterization studies indicated that the developed ODFs were effective formulation for LDV and SBV. Among the 13 formulations, the formulation F9 was found to be optimized as it exhibited 90% dissolution of LDV and SBV in 8.4 and 7.2 min. respectively with DT below 80 sec. Hence, the set objective of rapid disintegrating and dissolving ODFs was achieved successfully by adopting statistical experimental design.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation

ACKNOWLEDGEMENT:

The authors are acknowledged to the authorities of Aditya College of Pharmacy, Kakinada and Jawaharlal Nehru Technology University Kakinada for providing necessary facilities to carry out the research work.

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Received on 25.05.2021            Modified on 18.06.2021

Accepted on 03.07.2021       ©A&V Publications All right reserved

Res.  J. Pharma. Dosage Forms and Tech.2021; 13(3):201-208.

DOI: 10.52711/0975-4377.2021.00036