Orodispersible films of Ledipasvir and Sofosbuvir Combination: Formulation optimization and development using Design of Experiments
Uday Kumar Thummala1,2*, 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:
Ledipasvir (LDV) and sofosbuvir (SBV) are poorly soluble drugs and hence dissolution limited bioavailability is a major concern. Further, the high total dose of this combination (LDV-90mg and SBV-400mg) may cause swallowing difficulties if formulated into tablets. Considering these challenges, it was aimed in the current research work to develop orodispersible films (ODFs) for this combination to enhance dissolution thereby bioavailability and also patient convenience. ODFs, because of their ready dispersibility in the oral cavity dissolution would be rapid and also high doses of drugs can be incorporated avoiding swallowing difficulties. HPMC E15 was taken as the film former. Thickness of the films (50µm – 150µm), concentration of superdisintegrant (sodium starch glycolate 6-12% w/w) and concentration of plasticizer (polyethylene glycol 400, 10-20% w/w) were taken as three formulation factors each at three levels. Using Design Expert software, Box-Behnken design under response surface methodology was selected as the experimental design. Disintegration time (DT), time for 90% dissolution of LDV (LDV-T90%) and time for 90% dissolution of SBV (SBV-T90%) of the ODFs were taken as response. The films were developed using solvent casting method. The obtained films were subjected for various quality characteristic studies like differential scanning calorimetry, X-ray diffraction, tensile strength, % elongation, folding endurance, disintegration time, drug content uniformity and dissolution studies. All the formulations were found to have favorable tensile strength, % elongation and folding endurance. The DT values were found to be in the range of 37 – 139 sec.; the values of LDV-T90% and SBV-T90% were found to be in the range of 7.1 – 20.7 min. and 6.8 – 15.6 min. respectively. The results of these three responses were subjected to ANOVA studies and found that all the three formulation factors were having significant effect. The results of optimization by desirability functions approach indicated the ODFs with thickness 50µm, disintegrant at 12% w/w and plasticizer at 17.46%w/w as the optimized formulation. The ODFs prepared at this combination showed DT of 45 sec, LDV-T90% of 7.51 min. and SBV-T90% of 6.23 min. these results indicated that ODFs for LDV and SBV were successfully optimized and developed.
KEYWORDS: Ledipasvir and Sofosbuvir, Orodispersible films, Dissolution enhancement, Box-Behnken design, Optimization.
INTRODUCTION:
Hepatitis C viral (HCV) infection is a severe liver infection and needs to be treated to avoid long term damage to the liver. Several antiviral drugs are used in this treatment. The recently approved combination for this purpose is ledipasvir (LDV) of 90mg and sofosbuvir (SBV) of 400mg and especially in untreated patients of genotype 1a of HCV1,2. LDV is practically insoluble in water with 0.004mg/mL and SBV is slightly soluble with 0.824mg/mL3. It is evident from their doses and poor solubilities that the dose-to-solubility (DS) ratios of LDV and SBV are extremely higher than 250mL and hence this leads to dissolution limited bioavailability4,5. DS indicates the solubility of a drug with respect to its dose. A drug with DS value more than 250mL requires more than 250mL to dissolve the maximum its maximum dose. This indicates the drug is less soluble according and may fall into BCS class II or class IV which has dissolution limited bioavailability. Based on this condition, it is necessary to develop a dosage form which enhances dissolution rate of LDV and SBV and thereby bioavailability.
Orodispersible films (ODFs) gaining significant interest recently owing to their wide range of advantages over tablets and suspensions like high patient acceptability, ease of administration, considerable high stability over suspensions, flexible to incorporate high doses of drugs, rapid disintegration and high dissolution rate over tablets6,7. Several research reports have been published on the usage of ODFs for dissolution thereby bioavailability enhancement of poorly soluble drugs and some of them were by Khan Q et al. 20208, Ahmad A et al. 20209 and Varsha A et al. 202110. Further, the wide literature search regarding formulation development of LDV and SBV combination exposed that only one research report was published on development of LDV fast dissolving tablets by Guntaka PCR, Lankalapalli S 201811. From this extensive literature study, it is evident that there is significant opportunity and scope to develop fast dissolving/oral dispersing films for the fixed dose combination of LDV and SBV. Henceforward, it was aimed in this research work to optimize and develop (ODFs) for the combination of LDV and SBV to improve dissolution thereby bioavailability.
The experiment was designed based on the principles of Design of Experiments (DoE)12,13. Box-Behnken design under response surface methodology was adopted in this experiment with the aid of Design Expert software. Using preliminary studies, HPMC E15 (low viscosity grade) at 3:1 level to the drugs mixture was selected as the film former owing to its high dissolution enhancing characteristics. Three different formulation variables were taken independent factors viz. thickness of the films, concentration of superdisintegrant (sodium starch glycolate, SSG) and concentration of plasticizer (polyethylene glycol 400, PEG400). Disintegration time (DT), time for 90% dissolution of LDV (LDV-T90%) and time for 90% dissolution of SBV (SBV-T90%) of the ODFs were taken as response variables which critically establish the desired quality of the ODFs. The developed films were characterized for the responses and the results were analyzed statistically. Later optimization was performed to identify the suitable combination of the factors and their level, using desirability functions approach14 by considering minimum DT, minimum LDV-T90% and minimum SBV-T90% as the desirability.
MATERIALS AND METHODS:
Materials:
LDV and SBV were procured from Hetero Drugs Pvt. Ltd, Visakhapatnam; HPMC E15 and PEG 400 were acquired from Sigma Chemicals Co.; sodium starch glycolate, isopropyl alcohol (IPA) and Tween 80 were purchased from SD Fine Chemicals, Mumbai; All other chemicals of analytical grade were used.
Analytical method:
Simultaneous estimation of LDV and SBV is required to evaluate the ODFs for drug content and dissolution studies. A method for the simultaneous estimation of LDV and SBV using UV-Visible spectrophotometer developed, validated, and the results published separately15, was used in the present work.
Viscosity studies:
Various quantities of HPMC E15 with 15% PEG 400 were dissolved independently in the mixture of water and IPA at a ratio of 4:6. The obtained polymer solutions were studied for their dynamic viscosity at 20oC using Brookfield cup and bob viscometer that was operated at the least flow rate. Then these polymer solutions were casted as films, and their thickness was measured so as to identify the viscosity ranges of the polymer solutions to obtain films with desired thickness.
Development of orodispersible films of LDV and SBV
Design of experiment:
Three formulation parameters were selected as the independent factors which were A: thickness of the film (50-150 µm), B: concentration of superdisintegrant (SSG, 6-12 %w/w) and C: concentration of plasticizer (PEG 400, 10-20%). Three critical quality attributes of the ODFs were taken as the responses which were R1: DT, R2: LDV-T90% and R3: SBV-T90%. Box-Behnken design under response surface methodology16,17 was selected as the experimental design and executed using StatEase Design Expert software. This design produced 13 different runs as the combinations of the factors with their levels (shown in table 1). ODFs were prepared at all these combinations as 13 different formulations.
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) |
HPMC (mg) |
SSG (mg) |
PEG 400 (mg) |
Tween 80 (µL) |
Final volume (mL) |
||
|
1 |
F1 |
50.00 |
6.00 |
15.00 |
90 |
400 |
1470 |
117.6 |
220.5 |
60 |
30 |
|
2 |
F2 |
50.00 |
9.00 |
10.00 |
90 |
400 |
1470 |
176.4 |
147 |
60 |
30 |
|
3 |
F3 |
50.00 |
9.00 |
20.00 |
90 |
400 |
1470 |
176.4 |
294 |
60 |
30 |
|
4 |
F4 |
50.00 |
12.00 |
15.00 |
90 |
400 |
1470 |
235.2 |
220.5 |
60 |
30 |
|
5 |
F5 |
100.00 |
6.00 |
10.00 |
90 |
400 |
1470 |
117.6 |
147 |
46 |
23 |
|
6 |
F6 |
100.00 |
6.00 |
20.00 |
90 |
400 |
1470 |
117.6 |
294 |
46 |
23 |
|
7 |
F7 |
100.00 |
9.00 |
15.00 |
90 |
400 |
1470 |
176.4 |
220.5 |
46 |
23 |
|
8 |
F8 |
100.00 |
12.00 |
10.00 |
90 |
400 |
1470 |
235.2 |
147 |
46 |
23 |
|
9 |
F9 |
100.00 |
12.00 |
20.00 |
90 |
400 |
1470 |
235.2 |
294 |
46 |
23 |
|
10 |
F10 |
150.00 |
6.00 |
15.00 |
90 |
400 |
1470 |
117.6 |
220.5 |
30 |
15 |
|
11 |
F11 |
150.00 |
9.00 |
10.00 |
90 |
400 |
1470 |
176.4 |
147 |
30 |
15 |
|
12 |
F12 |
150.00 |
9.00 |
20.00 |
90 |
400 |
1470 |
176.4 |
294 |
30 |
15 |
|
13 |
F13 |
150.00 |
12.00 |
15.00 |
90 |
400 |
1470 |
235.2 |
220.5 |
30 |
15 |
Preparation of ODFs:
The ODFs were prepared using the solvent casting method18 with HPMC E15 as the film former and water-IPA (at 4:6 ratio) mixture as the solvent. Desired quantity of the HPMC E15 as per the formulae shown in the table 1, was taken, added into the solvent mixture containing 0.2% v/v tween 80 and subjected to vertex mixing. To the obtained polymer solution, LDV and SBV were added and mixed. Then, desired amounts of SSG and PEG 400 were added, mixed to obtain homogenous dispersion and adjusted to the final volume of 30/23/15mL so as to obtain the ODFs with thickness of 50, 100 and 150µm respectively after evaporation. Finally, 30mL each of these mixtures were transferred into glass petri plates and allowed to evaporation of the solvent under ambient conditions. After nearly 48 hours, the solvent was evaporated and the films were separated from the petri plates, and stored carefully for further characterization studies.
Characterization of the ODFs:
a) Differential scanning calorimetry (DSC) and X-ray diffraction studies (X-RD):
One of the casted films was subjected to both DSC and X-RD studies in comparison with pure drug substances. These were performed to designate the state of the drugs in combination with the HPMC E15 in the ODFs so as to elucidate possible mechanism for change in the dissolution rate of the drugs upon ODFs development.
b) Physical characterization studies18,19:
The thickness of the ODFs was measured at five different locations using micrometer screw-gauge and the obtained values were reported as their mean value. Folding endurance was determined by counting the number of times folding was done on the films at the same place until breaking. Tensile strength and % elongation were estimated using texture analyzer. The tensile strength was obtained by dividing the maximum load at which the film breaks by the initial cross sectional area of the film and hence it was expressed as the force per unit area (MPa). The distance between the tensile grips before (D1) and after (D2) fracture of the film was used to calculate the percentage elongation by multiplying the ratio of D2 – D1 to the D2. All the estimations were performed in triplicate.
c) Drug content:
One ODF as casted was transferred into a beaker having 100mL of the dissolution medium and was stirring for 2 h confirming complete solubilization of both the drugs. Then the dispersion was filtered to remove any insoluble matter. The obtained filtrate was suitably diluted and analyzed for the content of LDV and SBV using UV-Visible spectrophotometer. The test was performed in triplicate.
d) Disintegration time:
Petri dish method18 was used to determine disintegration time. 6mL of phosphate buffer pH 6.8 was transferred into the petri dish and the cut films of 25 cm2 were positioned in it. The ODFs were observed for complete dispersion and the time was noted when it happened. This time was taken as disintegration time. The test was performed in triplicate.
e) Dissolution study:
The dissolution test was conducted using paddle apparatus (USP type II). The USFDA suggested dissolution medium i.e. 1.5% polysorbate 80 in 10mM potassium phosphate buffer with 0.0075mg/mL butylated hydroxytoluene, pH 6.0 of 900mL was taken. Six randomly selected films were used for the test. The samples were collected for every five minutes and replaced with the same buffer. The collected samples were analyzed for both the LDV and SBV spectrophotometrically.
RESULTS AND DISCUSSION:
Viscosity studies:
Viscosity of the polymer solution is the critical factor that defines the thickness of the films casted. As the thickness was selected as one of the independent factors in this study, the volume of the final casting solution for a given amount of polymer to obtain the desired viscosity and hence thickness was needed to be determined. Hence, these studies were performed to fix the volumes of solvent for 1470mg (three times to that of the drugs’ total dose) of HPMC E15 so as to obtain films with thickness of 50, 100 and 150µm. Into different volumes of the solvent mixture, 1470mg of the polymer with 15% of the plasticizer was added, dissolved, checked for their viscosities and casted into films. The obtained films were tested for thickness. Finally, the volumes 30mL, 23mL and 15mL were selected which produced films with thickness around 50, 100 and 150 µm. The results were shown in Table 2.
Characterization studies of ODFs:
a) DSC and X-RD studies:
The thermograms of DSC studies and spectra of X-RD were shown in Fig 1. The DSC thermogram of pure drugs showed two distinct endotherms at 114.1oC and 187.4oC matching to the melting points of LDV and SBV respectively. But, the DSC thermogram of the ODFs did not exhibit any endotherms which might be attributed to the conversion of crystalline drugs into amorphous forms17. This elucidation was confirmed by the X-RD studies also. The spectrum of pure drug powders exhibited sharp peaks which were significantly reduced in the spectrum of ODFs. This indicated reduction in drugs’ crystallinity and conversion into amorphous nature. These results indicated that possible improvement in the dissolution rates of both the LDV and SBV upon developing into ODFs20.
b) Physical characterization studies:
The developed ODFs were visually observed to smooth, uniform and almost transparent. The results of various physical characterization studies were shown in Table 2. The thickness values were found to be close to 50 µm for the ODFs of F1-F4; 100 µm for the ODFs of F5-F9; and 150 µm for the ODFs of F10-F14. This could be attributed to the considered final volume of the mixture and hence the viscosity values of the polymer dispersions. Folding endurance values of all the formulations were found to be more than 267. Tensile strength and % elongation were found to be in the range of 6.9 – 11.3 MPa and 21.6 – 34.6% respectively. These high values indicated that all the films were flexible and having good elasticity so that they could prevent cracking/breaking upon handling. Further, the tensile strength values were observed to be increased with increased concentration of plasticizer. This could be because of the entanglement of the plasticizer molecules with those of the film forming polymer that could reduce brittleness of the obtained film. So, increased entanglement at higher concentration of the plasticizer resulted in increased tensile strength and elasticity of the ODFs21,22. The folding endurance and % elongation values were correlated proportionally with tensile strength and increased upon increase in the plasticizer concentration21,22.
Fig 1: (i) DSC thermograms of (a) Mixture of pure LDV and SBV; (b) Pure MC; and (c) SD of LDV and SBV with HPMC.
(ii) PXRD spectra of (a) Mixture of pure LDV and SBV; (b) SD of LDV and SBV with HPMC
Table 2: 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 (%) |
LDV-T90% (min.) |
SBV-T90% (min.) |
|
1 |
F1 |
1758 |
54 |
8.1 |
24.1 |
312 |
73 |
97.6 |
98.9 |
12.8 |
10.2 |
|
2 |
F2 |
1695 |
51 |
6.9 |
21.6 |
267 |
82 |
101.3 |
100.2 |
12.4 |
9.0 |
|
3 |
F3 |
1660 |
49 |
8.5 |
24.7 |
389 |
89 |
99.2 |
97.8 |
8.6 |
7.7 |
|
4 |
F4 |
1726 |
52 |
7.8 |
22.4 |
328 |
37 |
100.5 |
98.2 |
9.4 |
7.2 |
|
5 |
F5 |
3951 |
100 |
7.9 |
23.9 |
341 |
108 |
101.4 |
100.7 |
15.3 |
11.9 |
|
6 |
F6 |
3896 |
98 |
9.6 |
28.8 |
426 |
139 |
98.9 |
99.6 |
13.9 |
10.1 |
|
7 |
F7 |
4170 |
92 |
9.3 |
27.3 |
381 |
126 |
98.3 |
102.1 |
11.9 |
9.4 |
|
8 |
F8 |
4116 |
101 |
7.7 |
24.1 |
345 |
66 |
100.6 |
101.5 |
10.1 |
7.9 |
|
9 |
F9 |
4296 |
104 |
10.5 |
29.2 |
403 |
81 |
99.5 |
102.4 |
7.1 |
6.8 |
|
10 |
F10 |
5864 |
155 |
9.8 |
31.9 |
422 |
146 |
97.9 |
98.3 |
15.6 |
14.1 |
|
11 |
F11 |
5538 |
149 |
9.3 |
29.5 |
374 |
124 |
102.3 |
99.1 |
20.7 |
15.6 |
|
12 |
F12 |
5618 |
151 |
11.3 |
34.6 |
450 |
137 |
98.4 |
100.4 |
16.4 |
12.3 |
|
13 |
F13 |
5685 |
154 |
11.1 |
32.1 |
416 |
78 |
99.1 |
98.6 |
13.9 |
10.4 |
Fig 2: Effect of the formulation factors (A and B) on the three responses (R1, R2 and R3).
Images (a), (b) &(c) indicate the effect of A and B on R1, R2 and R3 as contour plots; Images (d), (e) & (f) indicate the effect of A and B on R1, R2 and R3 as 3D-surface plots.
c) Drug content:
The contents of LDV and SBV in all the formulations of ODFs were observed in the range of 97.6 – 101.4% and 97.8 – 102.1% respectively. These acceptable values designated homogenous dispersion of LDV and SBV in the polymer dispersion which further inferred that the selected solvent mixture and polymer combination were suitable for these drugs to be developed into ODFs.
d) Disintegration time:
DT was one of the three selected responses as it is the critical quality characteristic of the ODFs. The DT values of all the formulations were shown in Table 2 and were observe to be in the range of 37 – 139 sec. It was observed that DT was increased upon increasing the level of factor A (thickness of the ODFs). At higher thickness of the ODFs, the path length for diffusion of water to reach all the disintegrant particles is increased and hence it would take more time for disintegration of the films. The obtained results were correlated with those reported by Zhang L et al. 201823. The DT was found to be decreased upon increasing the level of factor B. this might be attributed to the higher degree of the swelling of more disintegrant at its increased concentration that made rapid disintegration of the ODFs. The obtained results were correlated with those reported by Swamy SK et al. 201624. The DT was found to be increased with increased level of the factor C. at higher concentration of plasticizer, the swelling nature of the polymer is reduced and this might result in increased time for disintegration of the ODFs22,25. Among all the three factors, the effect of A and B were found to be statistically significant at p < 0.05 by ANOVA (shown in Table 3). The effect of the factors A and B as contour and 3D-surface plots were shown in Fig 2.
e) Dissolution studies:
The dissolution profiles for both LDV and SBV were shown in Fig 3. The T90% values for both LDV and SBV which were the R2 and R3, were presented in Table 2. The effect of all the three formulation factors on R3 was same as those on R2. Upon increasing the level of the factor A, the dissolution rate was decreased and hence the T90% was increased. This might be because of the increased complexity of the polymer gel matrix of the ODFs prepared from higher viscous polymer solution. Besides, the higher diffusion path length at higher thickness of the films might also delay the drug diffusion followed by dissolution. The obtained results were correlated with those reported by Zhang L et al. 201823. Upon increasing the level of the factor B, the dissolution rate was found to be increased and hence the T90% was decreased. The rapid disintegration at higher concentration of the disintegrant could lead to rapid dissolution and hence less T90%23. The T90% was found to be decreased and dissolution was rapid upon increasing the level of the factor C. As the plasticizer concentration increases, the free space between the polymer chains also increases which improves easy diffusion of the drug present in it26. This might cause rapid dissolution and decreased T90% at higher concentration of the plasticizer PEG 400. Among all the three factors, the effect of A and B on R2 and R3 were found to be statistically significant at p < 0.05 by ANOVA (shown in Table 3). The effect of the factors A and B as contour and 3D-surface plots were shown in Fig 2.
Table 3: ANOVA test results of the three response variables for response surface linear model
|
S. No. |
Response |
Source |
SSa |
Dfb |
MSSc |
F value |
p-Value |
Inferenced |
|
1 |
R1 – DT |
Model |
10948.50 |
3 |
3649.50 |
13.13 |
0.0012 |
Significant |
|
A-Thickness |
5202.00 |
1 |
5202.00 |
18.71 |
0.0019 |
Significant |
||
|
B-Disintegrant |
5202.00 |
1 |
5202.00 |
18.71 |
0.0019 |
Significant |
||
|
C-Plasticizer |
544.50 |
1 |
544.50 |
1.96 |
0.1952 |
Not Significant |
||
|
Residual |
2502.42 |
9 |
278.05 |
|
|
|
||
|
Cor Total |
13450.92 |
12 |
|
|
|
|
||
|
2 |
R2 – LDV-T90% |
Model |
124.53 |
3 |
41.51 |
10.07 |
0.0031 |
Significant |
|
A-Thickness |
68.44 |
1 |
68.44 |
16.61 |
0.0028 |
Significant |
||
|
B-SDisintegrant |
36.55 |
1 |
36.55 |
8.87 |
0.0155 |
Significant |
||
|
C-Plasticizer |
19.53 |
1 |
19.53 |
4.74 |
0.0574 |
Not Significant |
||
|
Residual |
37.08 |
9 |
4.12 |
|
|
|
||
|
Cor Total |
161.61 |
12 |
|
|
|
|
||
|
3 |
R3 – SBV-T90% |
Model |
73.39 |
3 |
24.46 |
17.60 |
0.0004 |
Significant |
|
A-Thickness |
41.86 |
1 |
41.86 |
30.12 |
0.0004 |
Significant |
||
|
B-SDisintegrant |
24.50 |
1 |
24.50 |
17.63 |
0.0023 |
Significant |
||
|
C-Plasticizer |
7.03 |
1 |
7.03 |
5.06 |
0.0511 |
Not Significant |
||
|
Residual |
12.51 |
9 |
1.39 |
|
|
|
||
|
Cor Total |
85.90 |
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
f) Design validation and optimization
Box-Behnken (BB) design was selected so as to reduce the number of trials and make the design more economical. Because a full factorial design for three factors each at three levels give 27 runs, whereas BB design gives only 13 runs for the same case. The ANOVA studies on the three responses indicated that the selected model along with the factors A and B were found to be significant. Besides, the differences between predicted and adjusted R2 values in case of all the three responses were below 0.2 (shown in Table 4) that indicated the suitability of the selected linear model to navigate the design space. So, the optimization to identify the ODFs formulation having desired responses was performed by desirability functions approach using the Design Expert software. To improve the dissolution efficiency and hence bioavailability, all the three responses DT, LDV-T90% and SBV-T90% would be as minimum as possible. Hence, this was taken as the desirability to proceed for the optimization. Then, among the different suggestions (combination of all the three formulation factors with levels) indicated by the model, the one suggestion having the factor A at 50µm; the factor B at 12% w/w; and the factor C at 17.46% w/w (shown as overlay plot in Fig 4) had the maximum desirability of 0.952. So, ODFs were prepared at this optimized combination of the three factors, the obtained results of the responses were correlated with those suggested by the model (shown in Table 5). As the observed values were close and in the 95% confidence intervals (CI) range of the predicted formulation, it was established that ODFs for LDV and SBV were effectively formulated with rapid disintegration and dissolution.
Table 4: Predicted and observed R2 values for all the three responses
|
Response |
Predicted R2-Value |
Adjusted R2-Value |
|
R1 – DT |
0.6457 |
0.7519 |
|
R2 – LDV-T90% |
0.5003 |
0.6941 |
|
R3 – SBV-T90% |
0.6863 |
0.8059 |
Table 5: Comparison of the predicted and observed values of the responses for the optimized formulation
|
Factors combination |
Responses |
Predicted values |
95% CI low |
95% CI high |
Observed values |
|
A: Thickness 50 µm |
R1: DT (sec.) |
51.9794 |
29.44 |
74.52 |
45 |
|
B: Disintegrant conc. (12% w/w) |
R2: LDV-T90% (min.) |
7.10008 |
4.36 |
9.84 |
7.51 |
|
C: Plasticizer conc. (17.46% w/w) |
R3: SBV-T90% (min.) |
5.70159 |
4.11 |
7.30 |
6.23 |
Fig 3: 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
Fig 4: Overlay plot indicating the optimized combination of the three factors and predicted response values
CONCLUSION:
ODFs for the combination of LDV and SBV were aimed to be developed in order to increase the dissolution and hence the bioavailability of LDV and SBV. Three different formulation factors selected and the experiment was designed using Box-Behnken design employing Design Expert software. The results of the physical characterization studies including the response variables of the ODFs indicated that the films were efficient. Upon optimization by desirability functions approach, the suggested optimized formulation of the ODFs with thickness at 50 µm; SSG at 12% and PEG 400 at 17.46% was developed and characterized. The obtained response values of 45 sec. of DT; 7.51 min. of LDV-T90% and 6.23 min. of SBV-T90% of this optimized formulation confirmed effective formulation of ODFs for LDV and SBV towards improved dissolution and hence successfully achieved the objective of the study.
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 26.07.2021 Modified on 10.10.2021
Accepted on 06.01.2022 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Res. 2022; 12(1):11-18.
DOI: 10.52711/2231-5691.2022.00003