INTRODUCTION:

Elvitegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) used for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults. Because integrase is necessary for viral replication, inhibition prevents the integration of HIV-1 DNA into the host genome and thereby blocks the formation of the HIV-1 provirus and resulting propagation of the viral infection. Although available as a single dose tablet, elvitegravir must be used in combination with an HIV protease inhibitor coadministered with ritonavir and another antiretroviral drug ^(1-6).

Drug delivery systems (DDS) are a strategic tool for expanding markets/indications, extending product life cycles and generating opportunities. Oral administration is the most popular route for systemic effects due to its ease of ingestion, pain, avoidance, versatility and most importantly, patient compliance. Also solid oral delivery systems do not require sterile conditions and are therefore, less expensive to manufacture. The development of enhanced oral protein delivery technology by immediate release tablets which may release the drugs at an enhanced rate are very promising for the delivery of poorly soluble drugs high molecular weight protein and peptide. The oral route remains the perfect route for the administration of therapeutic agents because the low cost of therapy, manufacturing and ease of administration lead to high levels of patient compliance. Many patients require quick onset of action in particular therapeutic condition and consequently immediate release of medicament is required. It is estimated that 50% of the population is affected by this problem, which results in a high incidence of ineffective therapy ^(7-11).

SOLID DISPERSIONS:

The formulation of hydrophobic drugs as solid dispersions is a significant area of research aimed at improving the dissolution and bioavailability of hydrophobic drugs. Solid dispersions consisting of two components in the solid state are referred to as binary systems. The two components are a water-soluble carrier and a hydrophobic drug dispersed in the carrier substance. Chiou and Riegelman² defined the term solid dispersion as ‘the dispersion of one or more active ingredients in an inert carrier matrix at solid-state prepared by the melting (fusion), solvent or melting- solvent method’ While Corrigan suggested the definition as ‘product formed by converting a fluid drug-carrier combination to the solid state’ ^(12-15)

PRE-FORMULATION STUDIES:

Pre-formulation study is the process of optimizing the delivery of drug through determination of physicochemical properties of the new compound that could affect drug performance and development of an efficacious, stable and safe dosage form. It is the first step in rational development of drug dosage forms of a drug substance. It provides the information required to define the nature of the drug and a framework for the drug combination with pharmaceutical excipients in dosage form. Hence, pre-formulation studies were performed on the obtained sample of drug for identification and compatibility studies.

Wavelength Estimation of Elvitegravir:

Development of calibration curve for Elvitegravir

Elvitegravir was weighed accurately 100 mg using digital analytical balance and transferred to 100 ml volumetric flask, dissolved in methanol and the final volume was made up to 100 ml with 6.8pH Phosphate buffer to get a stock solution A. From the stock solution A, 10 ml was pipette out in 50 ml volumetric flask and the final volume was made upto 50ml with 6.8pH Phosphate buffer to get a stock solution B. From the stock solution B, further dilution was made with 6.8pH Phosphate buffer in 10 ml volumetric flasks to get the solutions in the range of 2-10 µg/ml concentration and absorbance was recorded at 313nm against suitable blank using UV- Visible spectrophotometer (1601, Shimadzu, Kyoto, Japan).

Solid Dispersion of with Polyethylene Glycol 6000,

Urea and Mannitol

Methods of Preparation of Solid Dispersion²³

Solid dispersions were prepared by different methods like solvent evaporation and fusion method.

Solvent evaporation method:

Elvitegravir and each of water soluble carrier PEG 6000, Urea and Mannitol were weighed accurately in various ratios (1:1, 1:2 and 1:3) and transferred to beaker containing sufficient quantity of acetone to dissolve. The solvent was evaporated at room temperature. The resulting solid dispersion was stored for 24 hrs in a desiccator to congeal. Finally, dispersion were passed through sieve no.85 and stored in desiccator till further use.

Fusion Method:

Each of water soluble carrier PEG 6000, Urea and Mannitol were weighed accurately in various ratios (1:1, 1:2 and 1:3) and melted in a porcelain dish at 80-85ºC and to this calculated amount of Elvitegravir was added with thorough mixing for 1-2 minutes followed by quick cooling. The dried mass was then pulverized by passing through sieve no.85 and stored in a dessicator until used for further studies. Solid dispersions were prepared using compositions as given in Table

Table 3: Composition of Elvitegravir solid dispersions by Fusion method

Solid dispersion composition	Method	Drug-Polymer ratio	Formulation Code
Elvitegravir: Urea	Fusion method	1:1	FSDUN1
		1:2	FSDUN2
		1:3	FSDUN3
Elvitegravir: PEG 6000	Fusion method	1:1	FSDPN1
		1:2	FSDPN2
		1:3	FSDPN3
Elvitegravir: Mannitol	Fusion method	1:1	FSDMN1
		1:2	FSDMN2
		1:3	FSDMN3

Table 4 Composition of Elvitegravir solid dispersions by Solvent evaporation method

Solid dispersion composition	Method	Drug-Polymer ratio	Formulation Code
Elvitegravir: Urea	Solvent evaporation method	1:1	SSDUN1
		1:2	SSDUN2
		1:3	SSDUN3
Elvitegravir: Mannitol	Solvent evaporation method	1:1	SSDMN1
		1:2	SSDMN2
		1:3	SSDMN3

Characterization of Solid Dispersions:

Drug content

An accurately weighed quantity of solid dispersion equivalent to 20mg of Elvitegravir was taken into a 100ml volumetric flask, dissolved in acetone and suitably diluted with 6.8pH Phosphate buffer. The content of Elvitegravir was determined spectrophotometrically at 313 nm against suitable blank using UV-visible spectrophotometer (1601, Shimadzu, Kyoto, Japan).

In vitro Dissolution Studies:

The quantity of solid dispersion equivalent to 20mg of Elvitegravir was filled in colourless hard gelatin capsule by hand filling method. The dissolution study of capsules was conducted using dissolution testing USP apparatus 1 (basket method) in 900 ml of 6.8pH Phosphate buffer at 37±0.5ºC and at a speed of 50 rpm. Aliquot of 5ml was withdrawn at predetermined time interval and equivalent amount of fresh medium was replaced to maintain a constant volume after each sampling and analyzed spectrophotometrically at 312 nm against suitable blank using UV-visible spectrophotometer (1601, Shimadzu, Kyoto, Japan).

Preparation of sustained release tablets of solid dispersion by direct compression method

Solid dispersion of PEG-6000 (1:3 ratio) equivalent to 150mg of drug prepared by fusion method were taken and mixed with directly compressible diluent, super disintegrants and other excipients in a plastic container. Table gives composition of the tablet formulation. Powder blend were directly compressed using 8mm, round-shaped flat punch in a multi station tablet compression machine (Cadmach, Ahmedabad, India).

Table 5: Formulation Table

Ingredients (mg)	E1	E2	E3	E4	E5	E6
Elvitegravir SD	150	150	150	150	150	150
Guar gum	20	40	-	-	-	-
HPMC K4M	-	-	20	40	-	-
EC	-	-	-	-	20	40
MCC	QS	QS	QS	QS	QS	QS
Magnesium Stearate	10	10	10	10	10	10
Talc	10	10	10	10	10	10
Total weight	400	400	400	400	400	400

Evaluation Parameters for Fast Dissolving Tablets of Solid Dispersion of Elvitegravir²⁵

Active Pharmaceutical Ingredient (API) Characterization:-

Organoleptic evaluation:

These are preliminary characteristics of any substance which is useful in identification of specific material. Following physical properties of API were studied.

a) Color

b) Odour

c) Taste

Table no. 6 Organoleptic Evaluation

PARAMETER	DESCRIPTION
Organoleptic Evaluation	white-to-pale yellows
Solubility Analysis	Practically insoluble in water and freely soluble at pH 1

RESULTS AND DISCUSSION

PREFORMULATION STUDIES

Description

These test results were illustrated below:

Table no 7: Table showing the description of Elvitegravir (API)

Test	Description
Colour	A cream to pale brown powder
Odour	Free of odour

RESULT:

The results were found as per specifications.

Solubility

These tests results were illustrated below:

Table no 8: Table showing the Solubility of Elvitegravir (API) in various solvents.

Solvents	Solubility
Water	soluble
Methanol	Soluble
Dimethyl sulphoxide	Freely Soluble

Melting Point

These tests results were illustrated below:

Table no 9: Table showing the melting point of API’s

Material	Melting Point
ELVITEGRAVIR	180-192⁰c

Standard calibration curve

In the pre-formulation study, it was found that the λmax of Elvitegravir by spectrophotometric method in 6.8pH Phosphate buffer was found to be 313nm.

Table 10: Calibration Curve of Elvitegravir in 6.8pH Phosphate buffer

S.no	Concentration (µg/ml)	Absorbance
1	0	0
2	2	0.200
3	4	0.418
4	6	0.608
5	8	0.803
6	10	0.994

Fig 1: Standard Graph of Elvitegravir in 6.8pH Phosphate buffer

Fig no- 2 UV Spectrum for Elvitegravir at 313nm

drug and excipient compatibility FTIR studies

Fig No 3: FTIR Spectra of Elvitegravir

Fig No 4: FTIR Spectra of Elvitegravir optimized

DISCUSSION:

Calibration Curve of Elvitegravir

The calibration curve of Elvitegravir was obtained in the range of 2-10µg at the wavelength of 313nm. It has shown good linearity with a regression coefficient of 0.999 (r² value).

Solid Dispersions of Elvitegravir with PEG 6000, Urea and Mannitol:

In vitro dissolution studies of Elvitegravir and its solid dispersions

In vitro dissolution test results indicate complete dissolution of drug from all its solid dispersion within 20min figure. Among the different methods of preparation of solid dispersion, fusion method was found to be most effective. The formulation FSDPN3 showed highest drug release within 20min.

Evaluation Parameters for Sustained Release Tablets of Elvitegravir:

Precompression Parameters

The values for angle of repose were found in the range of 27.21°-31.43°. Bulk densities and tapped densities of various formulations were found to be in the range of 0.41±0.006 to 0.72±0.007 (g/cc) and 0.48±0.01 to 0.87±0.02 (g/cc) respectively. From the result it was concluded that the powder blends had good to fair flow properties and these can be used for tablet manufacture.

Post compression Parameters:

Hardness test

Hardness of the three tablets of each batch was checked by using Monsanto hardness tester and the data’s were shown in Table. The results showed that the hardness of the tablets was in range of 3.0to 3.6 Kg/cm².

Weight variation test:

Tablets of each batch were subjected to weight variation test, difference in weight and percent deviation was calculated for each tablet and was shown in the Table The average weight of the tablet is approximately 400 mg; so the permissible limit is ±7.5%. The results of the test showed that, the tablet weights were within pharmacopeial limit.

Friability:

Tablets of each batch were evaluated for percentage friability and the data’s were shown in the Table. The average friability of all the formulations lies in the range of 0.32 % to 0.42% which was less than 1% as per official requirement of IP indicating a good mechanical resistance of tablets.

In vitro dissolution studies:

Finally, the tablets were evaluated for in vitro dissolution studies in simulated gastric fluid and the results were shown in the Table. Formulations E1 showed 94.8% of drug release with 20mg of Guar gum, E2 showed 97% of drug release with 40mg of Guar gum, E3 which contain 20mg 0f HPMC K4M showed 78.6% of drug release within 15 min, E4 showed 88.3% of drug release with 40mg of HPMC K4M, E5 showed 98.3% of drug release with 20mg of EC and finally E6 showed 90.2% of drug release with 40mg of EC. This result exhibit a direct relationship between concentration of polymers and drug release. Among the various formulations tablets of batch E2 prepared with 40mg Guar gum showed complete release of drug within 12 hrs.

SUMMARY:

The calibration curve of Elvitegravir was obtained in the range of 2-10µg at the wavelength of 313 nm. It has shown good linearity with a regression coefficient of 0.999 (r² value). In vitro dissolution test results indicate complete dissolution of drug from all its solid dispersion within 20min figure. Among the different techniques of preparation of solid dispersion, using fusion techniques was found to be most effective. The formulation FSDPN3 showed highest drug release within20min. The values for angle of repose were found in the range of 27.21°-31.43°. B.D and T.D of various formulations were found to be in the range of 0.41±0.006 to 0.721±0.007 (g/cc) and 0.483±0.01 to 0.873±0.02 (g/cc) respectively. Tablets of each batch were evaluated for in vitro disintegration time and the data’s were shown. Finally, the tablets were evaluated for in vitro dissolution studies in simulated gastric fluid and the results were shown in the Table. Formulations E1 showed 94.8% of drug release with 20mg of Guar gum, E2 showed 97% of drug release with 40mg of Guar gum, E3 which contain 20mg 0f HPMC K4M showed 78.6% of drug release within 15 min, E4 showed 88.3% of drug release with 40mg of HPMC K4M, E5 showed 98.3% of drug release with 20mg of EC and finally E6 showed 90.2% of drug release with 40mg of EC. This result exhibit a direct relationship between concentration of polymers and drug release. Among the various formulations tablets of batch E2 prepared with 40mg Guar gum showed complete release of drug within 12 hrs.

CONCLUSION:

Among the various solid dispersions prepared, the formulation i.e., the solid dispersion of Elvitegravir with PEG 6000 prepared by fusion method shows faster dissolution rate it was decided to use formulations FSDPN3 to formulate sustained release tablets using polymers like Guar gum, HPMCK4M, E.C by direct compression Method. The powder blend was subject to various physical characteristics tests such as bulk density, tapped density, Hausners ratio, compressibility index. The powder was compressed and the core tablets were evaluated for weight variation, hardness, thickness, disintegration time and the results were within specification. In the formulation the best results showed was with Guar gum10% in formulation with MCC.

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Received on 06.01.2019 Modified on 26.09.2019

Research J. Pharm. and Tech. 2020; 13(12):5909-5913.

DOI: 10.5958/0974-360X.2020.01031.8