Formulation and evaluation of vilazodone sublingual tablets by using lyophilization technique

 

K. C Panda ^1*, A. V Reddy², N. Panda², MD Shamim², M. Habibuddin³, K.N Jayaveera⁴

¹Research scholar, JNTUA, Ananthapuramu, Andhra Pradesh

²Anwarul Uloom College of Pharmacy, New Mallepally, Hyderabad, Telangana.

³Adept Pharma and Bioscience Excellence, Balanagar, RR Dist., Telangana.

⁴VEMU Institute of Technology, P. Kothakota, Chittoor, Andhra Pradesh

 

ABSTRACT:

Vilazodone is approved for treatment of acute episodes of major depression (Major Depressive Disorder (MDD). It is a BCS Class – II drug, offer challenges in developing a drug product with adequate bioavailability. The aim of present investigation was to formulate and evaluate vilazodone sublingual tablets using poloxamer 407 as a carrier by lyophilized solid dispersion technique.The lyophilized solid dispersion of vilazodone prepared by poloxamer 407 (1:5) showed more than 85% drug release within 5 min, so it was used for the development of sublingual tablets by direct compression technique. The physicochemical, solid-state properties, dissolution behaviour of lyophilized solid dispersion as well as sublingual tablets were evaluated. Finally, the bioavailability studies of the prepared tablets were performed by sublingual administration to rabbits. The sublingual tablets showed a higher in vitrodis solution rate and bioavailability compared with the commercial tablets. It is evident from the results herein that the developed sublingual tablets provide a promising drug delivery system in drug development, owing to their excellent performance of a rapid onset of action and improved bioavailability.

 

 

 

INTRODUCTION:

Drug delivery through the sublingual route had emerged from the desire to provide immediate onset of pharmacological effect. Dysphasia (difficulty in swallowing) is a common problem of all age groups, especially geriatrics, paediatric, and patients who are mentally retarded, uncooperative, nauseated or on reduced liquid intake/diets have difficulties in swallowing these dosage forms. Sublingual means under the tongue. Drugs that are given sublingually reach directly in to the systemic circulation through the ventral surface of the tongue and floor of the mouth. The drug is rapidly absorbed into the reticulated vein that lies underneath the oral mucosa^[1-2]. Vilazodone is approved for treatment of acute episodes of major depression (Major Depressive Disorder (MDD).

 

It acts as a serotonin reuptake inhibitor and 5HT1A receptor partial agonist ^[3-5]. It increases serotonin levels in the brain by inhibiting the reuptake of serotonin while acting as a partial agonist on serotonin-1A receptors.

 

It has therefore been coined by scientists as a selective partial agonist and reuptake inhibitor (SPARI). Because of its partial agonist activity for serotonin-1A, vilazodone helps to reduce anxiety. It is extensively metabolized by liver, through CYP and non- CYP pathways (major: CYP3A4, minor: CYP2C19 and CYP2D6)^[6-9].

 

It is a BCS Class - II drug, offer challenges in developing a drug product with adequate bioavailability ^[10]. The aim of present investigation was to formulate and evaluate vilazodone sublingual tablets using poloxamer 407 as a carrier by lyophilized solid dispersion technique to bypass first pass metabolism, owing to their excellent performance of a rapid onset of action and improved bioavailability.

MATERIAL AND METHODS:

Materials:

Vilazodone was gifted by Dr. Reddy's Laboratories Ltd., Hyderabad, poloxamer 407 purchased from S.D. Fine Chemicals Ltd. All other chemicals used were of analytical grade and procured from commercial sources.

 

Phase solubility analysis:

The effect of concentrations of Poloxamer 407 on the equilibration solubility of vilazodone in water and pH 6.8 phosphate buffer medium at room temperature was carried out by adding an excess quantity of drug (20 mg) into a screw-capped glass vial containing 20 ml of solvent with various concentrations of the carrier. The suspension were shaken for 24hrs on a rotary bath shaker and filtered through Whatman no.1 filter paper. The filtrate so obtained was diluted and analyzed spectrophotometrically at 240 nm^[14]. For determination of spontaneity of the process, the values of Gibbs free energy (ΔGtr) were calculated for each carrier.

 

Preparation of physical mixtures and solid dispersions:

Physical mixtures were prepared by mixing of vilazodone and poloxamer 407 in mortar and pestle according to 1:1, 1:3, 1:5 ratios by geometrical dilution method and coded as VZD-PXM 407 Pm1:1, VZD-PXM 407 Pm1:3, VZD-PXM 407 Pm1:5 respectively. The geometric mix blends passed through sieve no#60 and kept in the desiccator ^[12-13].

 

Vilazodone and the hydrophilic polymer PXM 407were weighed according to 1:1, 1:3, 1:5 ratios and coded as VZD-PXM 407 Lyo1:1, VZD- PXM 407 Lyo 1:3 VZD-PXM 407 Lyo1:5 respectively. Specified quantity of drug was weighed and dispersed into 100 ml poloxamer solution. The dispersion being stirred with the help of magnetic stirrer, to this 25% liquid ammonia added drop wise and stirred until a clear solution was obtained. Then the samples were transferred into glass vials and incorporated to the ports of lypholizer with closed mode of valves and frozen at a temperature of -40°C for 3 hours. Then the valves of lypholizer were opened slowly and the samples were sublimed under a pressure of 0.09 mbar and with a condenser temperature of -40°C for 12 hours followed by a secondary drying at 25°C for 2 hours using Yorco Freeze Dryer-Lypholizer. The frozen dried mass was passed through sieve no. #60 to get fine powders and kept in desiccators^[15-18].

 

Analysis of drug content in solid dispersions:

The drug content of vilazodone in each physical mixtures and solid dispersions were determined using UV-spectroscopy. Accurately weighed quantity of solid dispersion or physical mixture equivalent to 10 mg of vilazodone was transferred to 100 ml of volumetric flask and volume was made up to 100 ml with methanol and 1 ml of this solution was taken and it was diluted to 10 ml with methanol and absorbance was noted at 240 nm, concentration of vilazodone was determined using calibration curve of vilazodone in methanol.

 

Percentage yield value:

The Percentage yield value of solid dispersions and physical mixtures were measured by the following formula.

Percent yield value= (Practical yield value / Theoretical yield value) X 100

 

Characterization of solid dispersion:

Fourier transform infrared spectroscopy (FT-IR):

The FT-IR spectra were obtained using FT-IR spectrometer (Shimadzu).The samples were previously ground and mixed thoroughly with potassium bromide, an infrared transparent matrix in 1:5 (sample: KBr) ratio, respectively. The KBr discs were prepared by compressing the powders at a pressure of 5 tons for 5 min in a hydraulic press. Forty five scans were obtained at a resolution of 4 cm^-1 from 4500 to 400 cm^-1.

 

Differential Scanning Calorimetry:

The DSC measurements were performed on a Pyris Diamond TG/DTA differential scanning calorimeter with thermal analyzer. All accurately weighed samples (about 5 mg) were placed in sealed aluminium pans. An empty aluminium pan was used as reference. 

 

X-ray diffraction:

The X-ray powder diffraction patterns were obtained by using Philips Holland PW 1710 with Cu Ka (l = 1.54056A^o) radiation and a crystal monochromator, voltage: 45 mv and current: 20 amps. The diffraction patterns were run at 2⁰/min in terms of 2q angle.

 

In-vitro Dissolution rate studies:

The in vitro dissolution studies of physical mixtures and solid dispersions of vilazodone were carried out on USP type II dissolution apparatus and the results were compared with those for pure vilazodone. The dissolu­tion vessels contained 900 mL of phosphate buffer pH 6.8 maintained at 37°C ± 0.5°C and paddle speed set at 50 rpm. Solid dispersions equivalent to 20 mg of vilazodone were added to the dissolution medium in a powder form. Then, 5 mL samples were withdrawn at 5, 10, 20, 30, 45 and 60 min from the dissolution medium. The with­drawn sample was replenished with 5 mL of fresh media. The withdrawn samples were analyzed for vilazodone content by measuring the absorbance at 240 nm using UV-visible spectrophotometer (Shimadzu). Dissolution studies for each formulation were performed in triplicates.

 

Preparation of sublingual tablets:

The lyophilized solid dispersion VZD-PXM 407 Lyo1:5 showed the maximum solubility and dissolution rate was selected for preparation of sublingual tablets given in table 1.All the ingredients were mixed geometrically and subjected for direct compression using 8mm embossed flat punch. The sublingual tablets of vilazodone were prepared by direct compression using Polyplasdone XL 10 (VF₉ – VF₁₂) and Ac-Di-Sol (VF₁₃ – VF₁₆) as superdisintegrants with two control formulations (VC3–VC4).

 

Table 1: Formulation table of vilazodone sublingual tablets

Drug and Excipients(mg)	Formulation Batches
	VF9	VF10	VF11	VF12	VF13	VF14	VF15	VF16	VC3	VC4
Vilazodone Equivalent To 10 mg(Lyo Polo 407 1:5)	60	60	60	60	60	60	60	60	---	---
Vilazodone	---	---	---	---	---	---	---	---	10	10
Poloxamer 407	---	---	---	---	---	---	---	---	50	50
Avicel PH 112	47	32	22	13	29	22	15	8	13	8
Pearlitol SD 200	32	45	51	58	50	55	58	63	58	63
PVP K 30	5	5	7	7	5	5	7	7	7	7
Polyplasdone XL 10	2	4	6	8	---	---	---	---	8	---
Ac-Di-Sol	---	---	---	---	2	4	6	8	---	8
Aspartame	1	1	1	1	1	1	1`	1	1`	1
Magnesium  Stearate	2	2	2	2	2	2	2	2	2	2
Talc	1	1	1	1	1	1	1`	1	1`	1
Total tablet weight	150mg

 

Characterization of the prepared sublingual tablets:

Formulated vilazodone sublingual tablets were subjected to different physical characterization studies. Weight variation test was done by weighing 20 tablets individually, calculating the average weight and comparing the individual tablet weight to the average weight. The tablet hardness was determined using Monsanto tablet hardness tester and friability was determined Roche friabilator. The disintegration time was measured by using tablet disintegrator (Electrolab, India). Wetting time and dispersion were determined by well reported method. The uniformity of the drug content in tablets was evaluated by determining the contents of 3 tablets individually and analysed spectrophotometrically. Moisture uptake studies were carried out by taking ten tablets from each formulation were kept in a desiccator over calcium chloride at 37°C for 24 h. Then the tablets were weighed and exposed to 75% relative humidity (using saturated sodium chloride solution) at room temperature for 4 weeks. Tablets prepared by without lyophilization technique chosen as control formulations were kept to assess the moisture uptake due to other excipients. Tablets were weighed and the percentage increase in weight was recorded^[19-20].

 

In vitro Release Studies of vilazodone sublingual tablets:

The release rate of sublingual tablets containing control formulations (VC₃and VC₄ ) prepared by without lyophilization technique, lyophilized solid dispersion of vilazodone (VF₁₂), and marketed formulation(containing equivalent of 10 mg of vilazodone) was determined using USP type II apparatus (Paddle method). The dissolution test was performed using 900 mL of phosphate buffer pH 6.8 maintained at 37°C ± 0.5°C and paddle speed set at 50 rpm. Then, 5 mL samples were withdrawn at 5, 10, 20, 30, 45 and 60 min from the dissolution medium. The with­drawn sample was replenished with 5 mL of fresh media. The withdrawn samples were filtered and analyzed for vilazodone content by measuring the absorbance at 240 nm using UV-visible spectrophotometer (Shimadzu). Dissolution studies for each formulation were performed in triplicates. In order to evaluate the similarity between the best formulation and marketed formulation(MKF), the in vitro dissolution profiles of both were compared^[21-22].The similarity factor is stated as logarithmic conversion of the sum squared error of differences between the test formulations and reference formulation which is calculated by the using following equation:

 

 

Difference factor (f₁) measures the percent error between the drug release profiles of two formulations, usually one is test and other is standard over predetermined time points. The formula used to calculate the difference factors is presented as following equations.

 

 

In Vivo Bioavailability Studies:

Six healthy male New Zealand white rabbits were housed under standard conditions and allowed free access to food and water. All rabbits were dosed following an overnight fasting; Food was returned 2 h after dosing. Rabbits were used as animal model for in vivo study and permission for laboratory animal was approved by IAEC (IAUCP/IAEC/2016/11/PN-02).  The study was conducted by using parallel design. Six rabbits were randomly divided into two groups. One group received the marketed formulation viibryd10 (containing 10 mg vilazodone), whereas the other group received optimized sublingual tablets (VF₁₂). During the drug administration, an operator placed each rabbit in a body restraint device, which exposed the animal’s head, and lifted apart the gums with a wooden tongue depressor. Subsequently, sublingual tablets were placed under the rabbit’s tongue, wetting with 3 mL of water. At the same time, wooden rod was placed to prevent chewing or swallowing the tablet. Rabbit blood samples were obtained from the ear marginal vein before administration and at predetermined time intervals after administration (0.5, 1, 2, 3, 4, 8, 16 and 24 h) then stored in heparinised tubes. Plasma samples and deproteinizing solution were mixed in a ratio of 4:1 and added to a 2 ml polypropylene micro centrifuge tube. After capping, the tube contents were vortex mixed for 30 seconds, and the suspension is centrifuged at 4000 rpm for 10 minutes and then stored at -70°C for further analysis. Plasma was partitioned using micropipette for quantitative estimation of drug.). The supernatant liquid was collected and diluted with the mobile phase; was analyzed by RP HPLC method. For the HPLC instrument BDSC18 column (250×4.6 mm, 5µ) was used for the analysis. The mobile phase combination used for the assessment of vilazodone in the rabbit plasma was combination of Acetronitrile: Phosphate buffer (12.5 mM potassium dihydrogen orthophosphate) pH 3 in the ratio of 18:82. The flow rate was regulated with 1 ml/min. The detection was carried out at 240 nm with UV spectroscopic detector.

 

The pharmacokinetic parameters such as maximum plasma concentration (C_max), time for peak plasma concentration (t_max), plasma half-life (t_½), area under curve [AUC_(0-t)] and mean residence time (MRT)were calculated using by Kinetica 5.0 software^[23].

 

Accelerated stability studies:

The stability studies were carried outfor optimized vilazodone sublingual tablets (VF₁₂) according to ICH guidelines for three months at accelerated temperature 40 ± 2°C/75 ± 5% RH. The tablets were withdrawn at an interval of 30 days, 60 days and 90 days for evaluation in vitro drug release characteristics.

RESULTS AND DISCUSSION:

Phase solubility study:

Using the highest carrier concentration, the solubility increased approximately 6.28 fold in distilled water and 6.29 fold in pH 6.8 phosphate buffer as compared to pure drug. The solubility found in this study for vilazodone at 25ºC was 0.132 mg/mL in distilled water and 0.141 mg/mL in pH 6.8 phosphate buffer. The values of Gibbs free energy (ΔGtr_o) associated with the aqueous solubility of vilazodone in presence of carrier were all negative at various concentrations, indicating the spontaneous nature of drug solubilisation. The values decreased with increasing carrier concentration, demonstrating that the reaction became more favourable as the concentration of carrier increased.

 

Percent Yield and Drug Content:

The percent yield of various vilazodone physical mixtures and solid dispersions was within the range of 90.56 % to 99.02 %. The percentage drug content in physical mixtures and solid dispersions was within the range of99.89±0.21 % to 99.45±0.65 % and 97.95±0.24 % to 98.96±0.45 respectively. This indicated that drug was uniformly distributed in all of these prepared physical mixtures and solid dispersions the percent yield more in case of  physical mixtures than solid dispersions.

 

Solid state characterization study:

FTIR Spectroscopy Analysis:

FTIR spectra of pure vilazodone, poloxamer 407 and physical mixture are shown in Figure 1. The characteristic peaks of pure vilazodone were found at 3437cm-1 (NH stretching), 3216 cm-1 (Aromatic C-H stretching ), 2939 cm-1 (Aliphatic C-H stretching), 2217 cm-1 (C≡N stretching), 1669 cm-1 (C=O stretching), 1575&1443 cm-1 (C=C ring stretching). The intensity peaks of vilazodone were found to be present in the spectra of physical mixture with poloxamer 407. This finding reveals the lack of interac­tion between the drug and the carrier in the sample.

 

 

 

 

Fig. 1 (A) FTIT spectra of vilazodone, (B) Poloxamer 407, (C) VZD-PXM 407 physical mixture

DSC Analysis:

The DSC thermogram of pure vilazodone showed a sharp endothermic peak at 202.1°C, corresponding to its melting point. The DSC curve of physical mixture of VZD with poloxamer 407 showed the endothermic peaks at 202.1°C and 65.7°C which are the corresponding melting point of drug and polymer respectively.  The DSC curve of lyophilized solid dispersion showed reduction in melting point of drug to 173.5°C with widening of peak. This reduction in melting point and broadening of peak was an indication of conversion of crystalline fraction of drug into amorphous one. The DSC thermograms are shown in Figure 2.

 

 

Fig. 2 (A) DSC thermogram of vilazodone, (B) VZD-PXM 407 physical mixture, (C) VZD-PXM 407 lyophilized SD

 

X-ray diffraction:

X-ray diffraction spectra of pure vilazodone, physical mixture and solid dispersion are illustrated in Figure 3. The presence of sharp distinct peaks in vilazodone spectra indicated its high crystallinity. The diffraction spectrum showed that the drug in crystalline form as demonstrated by numerous distinct peaks at 2θof 8.41, 9.007, 12.09, 16.803, 18.899, 20.99, 21.879, 24.54, 25.69, 26.14, 28.16 and 29.52. The spectrum physical mixture prepared with poloxamer 407 showed numerous distinct peaks but lyophilized solid dispersion prepared with poloxamer 407 showed a reduction in the total number of peaks and base broadening of appeared peak along with a reduction in peak intensity providing convincing evidence for the formation of amorphous form in solid dispersion. The result indicated that the drug in solid dispersion was in amorphous form. Hence, VZD-PXM 407 Lyo1:5 showed the maximum solubility and dissolution rate was selected for preparation of sublingual tablets.

 

 

Fig. 3 (A) XRD Patterns of vilazodone, (B) VZD-PXM 407 physical mixture, (C) VZD-PXM 407 lyophilized SD

 

In-vitro Dissolution rate studies:

The in vitro dissolution profiles of the drug, various solid dispersions using poloxamer 407 and their respective physical mixtures in phosphate buffer (pH = 6.8) are shown in figures 4(A) and 4(B). All of the physical mixture and solid dispersion samples showed improved dissolution of vilazodone. Again, all of the solid dispersion samples showed more improved vilazodone dissolution than their respective physical mixture samples. This observation indicated that the increased dissolution of vilazodone from lyophilized solid dispersion due to presence of drug in amorphous state as compared to the physical mixtures and pure drug, where drug is present in crystalline state.  The pure drug showed up to 50% dissolution over 60 min, but its solid dispersions prepared by lyophilization technique with poloxamer 407 (VZD-PXM 407 Lyo1:5) showed the maximum solubility and dissolution rate at94.89% within 10 min. Hence, VZD-PXM 407 Lyo1:5 was selected for preparation of sublingual tablets.

 

 

Fig. 4: In-vitro drug release profiles of vilazodone from (A) Physical mixtures, (B) Solid dispersion

 

Characterization of the prepared sublingual tablets:

Solid dispersions prepared by lyophilization technique with poloxamer 407 (VZD-PXM 407 Lyo1:5) showed the maximum solubility and dissolution rate. So it was selected for preparation of sublingual tablets. The sublingual tablets of vilazodone were prepared by direct compression using Polyplasdone XL 10 (VF₉ – VF₁₂) and Ac-Di-Sol (VF₁₃ – VF₁₆) as superdisintegrants with two control formulations (VC3–VC4). Avicel PH 112 was used as directly compressible diluent as less compression force is required to produce tablets of a given hardness. It has very low moisture content (1.5%); so used in preparation of moisture sensitive lyophilized sublingual tablets. Pearlitol SD 200was also used directly compressible diluents as it imparts multidimensional benefits as it has excellent aqueous solubility, nonhygroscopicity and wetting properties facilitating tablet breakdown as well as negative heats of solution. The slight bitter taste of the drug has been masked by using 0.66 % w/w of aspartame. The average weight of the prepared tablets was in range of 147 to 151 and hardness of prepared tablets was in between 3.0 to 3.5 kg/cm². The friability of all the formulations was less than 1% indicating the ability of tablet to withstand abrasion in handling packaging and shipment. The drug content of the prepared formulations was found to be between 96.89% and 98.83% which was found within pharmacopoeia limits. The formulationVF₁₂prepared by lyophilization technique containing Polyplasdone XL 10 (5.33%) as superdisintegrant showed least wetting time, disintegration time and in-vitro dispersion time compared to other formulations due to its smaller, porous and granular particles which exhibit high capillary activity and pronounced hydration capacity, with little tendency to form gels. All sublingual tablets showed good stability when exposed to 75% relative humidity and final % increase in weight ranged from 1.3% to 2.4% due to use of nonhygroscopic excipients for formulation of sublingual tablets. The results of prepared sublingual tablets were presented in table 2.

 

Table 2: Evaluation of post compression parameters of Vilazodone sublingual tablets from formulation VF₉ – VF₁₆

Formula-tion code	Weight variation (mg)	Hardness kg/cm2	Friability (%)	Wetting time (Sec)	Disintegration Time (Sec)	Invitro dispersion time(Sec)	Drug content (%)	% Increase in weight (after 4 weeks)
VF9	149±0.34	3.00±0.25	0.75±0.03	22.43±0.56	17.12±0.12	31.88±0.14	98.34±0.81	1.7±0.03
VF10	149±1.05	3.00±0.25	0.73±0.02	16.77±0.13	14.07±0.11	29.69±0.13	96.89±0.83	2.1±0.08
VF11	148±1.04	3.50±0.25	0.41±0.02	14.88±0.09	12.05±0.18	25.51±0.15	97.86±0.39	1.9±0.05
VF12	151±1.67	3.50±0.15	0.38±0.01	13.86±0.14	10.11±0.12	22.62±0.15	98.25±0.72	1.6±0.11
VF13	151±0.95	3.00±0.15	0.70±0.03	35.65±0.87	29.06±0.13	39.08±0.14	97.45±0.32	2.4±0.09
VF14	151±0.96	3.00±0.25	0.66±0.02	27.65±0.65	24.08±0.21	30.17±0.15	98.83±0.88	2.2±0.05
VF15	148±0.85	3.25±0.15	0.63±0.02	22.99±0.54	19.10±0.14	27.45±0.16	97.76±0.39	2.0±0.08
VF16	147±0.68	3.50±0.25	0.57±0.01	19.64±0.23	16.10±0.23	21.72±0.19	98.15±0.72	1.9±0.03
VC3	151±0.95	3.5±0.25	0.26±0.01	57.99±0.23	39.11±0.12	69.45±0.16	97.99±0.74	1.3±0.06
VC4	151±0.78	3.0±0.25	0.23±0.03	58.92±0.96	37.08±0.34	65.72±0.19	98.64±0.81	1.5±0.15

All values are expressed as mean± SD; (n=3)

 

In vitro release studies of vilazodone sublingual tablets:

The dissolution profiles of vilazodone sublingual tablets prepared by lyophilized solid dispersion technique (VF₉-VF₁₆) compared with the marketed formulation viibryd10 (MKF) and control formulations (VC3–VC4) given in Fig 5. The extent of dissolution of vilazodone from the marketed formulation was 90.15% in 20 min. The control formulationsVC3and VC4 prepared without lyophilization technique showed 73.92% and 71.55% in 60 min respectively. Hence, the lyophilized solid dispersion VZD-PXM 407 Lyo1:5 showed the maximum solubility and dissolution rate was selected for preparation of sublingual tablets. All formulae showed acceptable dissolution rate. The formulationVF₁₂ prepared by lyophilization technique containing Polyplasdone XL 10 (5.33%), Pearlitol SD 200(38.66%) and Avicel PH 112 (8.66%) w/w showed the highest percentage of drug release 93.98% within 5 minutes; this may be due to faster uptake of water owing to the porous structure formed. It could be attributed to the formation of porous structure in lyophilized tablets in addition to incorporation of water soluble excipients. The tablets prepared by lyophilization technique containing Polyplasdone XL 10 as superdisintegrant showed more percentage of drug release than the sublingual tablets containing Ac-Di-Sol. The in vitro dissolution results of all the batches of prepared sublingual tablets were compared with dissolution results of marketed formulations by calculating the similarity factors (f₂) and difference factors (f₁). Control formulations VC3 and VC4 showed dissimilarity in the dissolution profile whereas all formulations such VF₉ to VF₁₆ showed similarity in the dissolution profile. Among all the formulations, VF₁₃ showed highest f₂ value (61.31) and lowest f₁ value (1.31).

 

 

Fig. 5 (A): Comparative in-vitro drug release profiles of vilazodone sublingual tablets (VF₉ – VF₁₂), control formulation (VC₃) and marketed formulation

Fig. 5 (B) Comparative in-vitro drug release profiles of vilazodone sublingual tablets (VF₁₃ – VF₁₆), control formulation (VC₄) and marketed formulation

 

In Vivo Bioavailability Studies:

The in vivo pharmacokinetic parameters for the optimized sublingual tablets (VF₁₂) along with marketed formulation were performed in male New Zealand white rabbits. The in vivo data for both the formulations were compared and represented in table 3. The plasma levels of vilazodone after sublingual administration of VF₁₂ were clearly faster and higher than those of the commercial tablets. In particular, the t_max after the administration of marketed formulation was observed at 4.08h; However, sublingual tablets (VF₁₂) resulted in the rapid appearance of vilazodone in plasma, attaining the T_max after 2.1h. In addition, the peak plasma concentration (C_max) for viibryd10 and test (VF₁₂) were found 118.43±0.25and 120.66±0.12ng/ml respectively.The differences between the two formulations for T_max were statistically significantly different having P value 0.0003 (P< 0.05) but in case of Cmax there was no significant different found, having P value 0.5559 (P < 0.05). These results indicated that the onset of action of vilazodone from optimized sublingual tablets (VF₁₂) is reaching much earlier than the marketed formulation.

Table 3: Pharmacokinetic parameters of optimized and marketed formulations

Pharmacokinetic parameters	Marketed formulation	Optimised formulation (VF12)
Cmax (ng/ml)	118.43±0.25	120.56±0.12
tmax (hour)	4.08 ±0.10	2.10 ±0.11
AUC0-t (ng-hour/ml)	2176.45	2206.23
AUC0-∞ (ng-hour/ml)	2235.83	2386.12
MRT (hour)	14.47	15.21

 

Accelerated stability studies:

The stability studies were carried out for optimized vilazodone sublingual tablets (VF₁₂)according to ICH guidelines for three months at accelerated temperature 40 ± 2°C/ 75 ± 5% RH. The stability studies indicated that there was no significant change observed for in vitro dissolution studies after three months. Vilazodone sublingual tablets (VF₁₂) were found to be stable for the period of three months at 40°C ±2°C/75% RH ± 5%.

 

 

 

CONCLUSION:

Solid dispersions prepared by lyophilization technique with poloxamer 407 (VZD-PXM 407 Lyo1:5) showed the maximum solubility and dissolution rate. So it was selected for preparation of sublingual tablets. The formulationVF₁₂ prepared by lyophilization technique containing Polyplasdone XL 10 as superdisintegrant showed least wetting time, disintegration time, in-vitro dispersion time and rapid drug dissolution, improving the solubility and dissolution rate of vilazodone compared to other formulations. The in vivo studies optimized sublingual tablets (VF₁₂) in rabbits suggested a faster absorption rate and a higher absorption extent in comparison with the commercial tablets. Hence, this dosage form could be a useful alternative to the commercial tablet with regards to its improved patient compliance, rapid onset of action, and increase in bioavailability.

 

ACKNOWLEDGMENTS:

The authors are thankful to the principal and management of Anwarul Uloom College of Pharmacy, New Mallepally, Hyderabad, Telangana, India for proving research facilities.

 

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Received on 08.11.2017             Modified on 24.11.2017

Accepted on 19.12.2017           © RJPT All right reserved