Review Of SNEDDS on Antihypertensive Drug for Treatment of Hypertension

Hypertension (HTN) is a chronic disease characterized by persistent hypertensive (HT) levels of blood pressure (BP). As it is recognized as one of the major cardiovascular disease (CVD).This is not only a major risk factor, but also one of the biggest public health challenges in the world. Surprisingly, actually, more than 50 % of the individuals with hypertension are observed to have additional cardiovascular disease (CVD) risk factors, such as Obesity, overweight, diabetes mellitus, metabolic syndrome, hyperlipidemia etc. ( Sindhu R et al 2021). ¹

Mechanisms: ( Ibrarz N et al 2022)

• Renin-angiotensin-aldosterone system:

Renin- angiotensin aldosterone system is a cascade peptidergic systems in the management of renal, adrenal and cardiovascular homeostasis. Angiotensin peptide Renin cleaves angiotensinogen (produced by the liver and filtered) to Ang I Angiotensin I is also adhered in the circulatory system by enzymes( e.g., Angiotensin converting enzyme) to form different peptides that ultimately act in colorful organs. Among these fractionalization peptides, the function of angiotensin II has been illustrated the most. Angiotensin II binds to angiotensin II receptor in several organs and directly leads to vasoconstriction, water- sodium retention, and myocardial redoing. In addition, when angiotensin II acts on the order, it further stimulates aldosterone stashing and exacerbates water- sodium retention. RAAS inhibitors are one of the three cornerstones of existing antihypertension medications, and are also the drugs of first-line.

• Centrally acting sympatholytics
• ACE inhibitors
• angiotensin II receptor blockers
• diuretics
• calcium channel blockers and vasodilators

 Commonly used to manage hypertension.

 In addition, natural bioactive compounds from foods such as grains, vegetables, fruits, dairy products, meat, fish, soybean, tea, and mushrooms also show antihypertensive effects.

These foods contain important constituents like ACE inhibitory peptides, vitamins C and E, flavonoids, polyphenols, tannins, resveratrol, fiber, saponins, and minerals such as potassium and calcium. They help reduce blood pressure through mechanisms like ACE inhibition, antioxidant activity, vasodilation, and calcium channel blocking.

Bioactive compounds like flavonoids, terpenoids, phenolic acids, and glucosinolates are especially found in green-colored foods and contribute to various physiological functions. ²

Types and sources of bioactive compound :

1.Flavonoids :

Flavonoids are a major group of polyphenols known for their anti-inflammatory and cardiovascular protective effects. They are classified into flavonols, flavanones, flavan-3-ols, flavones, anthocyanins, and isoflavones. Studies have shown that flavonoids, such as those from Brazilian green propolis, exhibit significant antihypertensive activity.³

2. Tannins :

Tannins are water-soluble polyphenols with astringent properties that bind to proteins and other macromolecules. They act as plant defense compounds and are stored in vacuoles. Tannins from plants like Magnolia species have shown antihypertensive effects and can lower blood pressure in experimental models.

3. Carotenoids :

Carotenoids are lipid-soluble pigments (red, yellow, orange) found in chloroplasts. They include xanthophylls (oxygenated forms). They act as antioxidants, support enzyme activity, and help prevent cardiovascular diseases such as stroke and coronary heart disease. They also show anticancer potential.⁴

4. Plant Sterols (Phytosterols):

Plant sterols are plant-derived fatty compounds found in free and esterified forms. They help reduce cholesterol levels and lower the risk of coronary heart disease.

5. Polyphenols (Anthocyanins) :

Anthocyanins are water-soluble polyphenols present in fruits, flowers, leaves, and roots. They are responsible for red, blue, and purple colors in plants and possess antioxidant and health-protective properties.⁵

 Self-Nano Emulsifying Drug Delivery System (SNEDDS)

SNEDDS is an isotropic mixture of oils (natural or synthetic), surfactants, and co-surfactants that forms a fine oil-in-water nanoemulsion when exposed to aqueous media with mild agitation. The globule size is typically less than 100 nm.SNEDDS, along with SMEDDS and SEDDS, is widely used to improve the solubility and bioavailability of poorly water-soluble drugs. It works by dispersing medium-chain triglyceride oils into nano-sized droplets using non-ionic surfactants, enhancing drug absorption.

SNEDDS and Role of Surfactants are essential in oral SNEDDS as they enhance drug dissolution and absorption. SNEDDS is a thermodynamically stable, clear or translucent system composed of oils, surfactants, and co-surfactants that forms a stable oil-in-water (o/w) nanoemulsion under mild agitation in aqueous media, improving drug plasma concentration.

Suitable Drug Candidates for SNEDDS. SNEDDS is a novel approach to improve the oral bioavailability of poorly water-soluble drugs. According to the Biopharmaceutical Classification System (BCS), drugs are divided into four classes based on solubility and permeability. Class II and Class IV drugs have low solubility and benefit most from SNEDDS.SNEDDS enhances solubility, absorption, and bioavailability^.6

 

Fig. No 1: Biopharmaceutical Classification System.

Fig.No.2. High pressure Homogenizer

 

Fig.No.4. Phase Inversion

 

Fig No 5 : Pseudo ternary phase diagram

EVALUATION OF NANOEMULSION: (Alhasani K et al 2019)

1. Drug content:

UV visible spectroscopic method is suitable to measure the drug content of nanoemulsion formulation. The 2 ug/ml aliquot was prepared using nanoemulsion formulation with using diluting solvents. The sample were measured at 278.2nm by using UV VISIBLE spectroscopy. The average of triplicate result were taken into consideration.

2. pH :

Another important parameter of nanoemulsion is pH. The excipients used in the formulation decide the pH of the final Preparation and hence the route of administration. The Change in the pH may affect the zeta potential of the Formulation which in turn can affect the stability of Preparation. The pH of the formulations was measured using Digital pH meter. Results were taken in triplicate and the Average was taken in to consideration. ¹⁵

3.Viscosity:

To determine rheological Properties of formulations the viscosity was measured. Brookfield Rheometer viscometer at 30°C with a CPE 61 Spindle at 30 rpm was used to determine the viscosity. Results Were taken in triplicate and the average was taken into consideration.

4. Dilution tests:

In nanoemulsion if the continuous phase will added, it will not Crack or separate into phases. Maximum amount of water And oil were added to o/w and w/o formulations respectively And then observed visually for clarity and phase separation. Here 50 and 100 times aqueous dilution of the formulation Were visually observed and checked for phase separation and clarity. Results were taken in triplicate and the average was taken into consideration.

5. Globules size and zeta potential analysis:

The formulation of nanoemulsion was diluted 50 times and 100 Tomes with distilled water. The final resultant samples were Prepared by gentle agitation for 5 minutes using a magnetic Stirrer. In addition, globule size distribution (PSD) and zeta Potential of the final nanoemulsion were determined using Dynamic light scattering technique by Malvern zetasizer (NANOZS). Results were taken in triplicate and the average Was taken in to consideration. ¹⁶

6. Stability of Drug Nanoemulsion:

Drug nanoemulsion formulations samples was sealed in Ampoules and then kept in Stability chambers at different Temperature conditions i.e., room temperature (250?) and Accelerated temperature (40±20?) for 2 months. Duplicate Samples were withdrawn at 0,1 and 2 months to evaluate Their physical and chemical stabilities. By visual inspection the physical stability Was checked for physical changes (such as phase separation and drug precipitation), and a Globule size analyzer used to determine the mean Globule size and zeta potential after Dilution with water. Chemical stability was expressed as the content of Drug Determined by UV visible spectroscopic method at 257 nm.¹⁷

7. Thermodynamic stability tests:

Thermodynamic stability tests it includes the centrifugation studies, heating-cooling cycle and Freeze thawing cycle. It is performed to evaluate the phase separation and temperature effect Variation on SNEDDS formulation stability. In this the formulations are diluted with water to Check if they are stable as single phase system. For three times the formulation incubated at 4 Degree Celsius and 45 degree Celsius for 48 hrs . After that the formulation incubated for Three times between 20 to 25 degree Celsius for 48 hrs. It is performed to evaluated the Effect of temperature and phase separation on formulation. ¹⁸

CONCLUSION:

Self Nano-Emulsifying Drug Delivery Systems (SNEDDS) are a modern approach used to improve the delivery of drugs with poor water solubility. They consist of a uniform (isotropic) mixture of oils, surfactants, co-surfactants, and co-solvents. When introduced into an aqueous environment with mild agitation, SNEDDS rapidly form fine oil-in-water nanoemulsions.This system increases the surface area of the drug, leading to enhanced absorption and improved oral bioavailability, especially for lipophilic drugs. SNEDDS also allow easier oral administration and can be modified (e.g., with polymers) to prolong drug release.Overall, SNEDDS offer a promising and industrially viable strategy for delivering bioactive compounds, particularly in the management of hypertension, by overcoming challenges related to solubility, stability, and bioavailability

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