Formulation And Evaluation of SNEDDS-Based Moisturising Cream Loaded with Serum Pearls

Abstract

The Self-Nanoemulsifying Drug Delivery Systems have emerged over the last few years as a modern and effective strategy to improve the apparent solubility, dissolution rate, and bioavailability of poorly water-soluble drugs. SNEDDS consists of isotropic, anhydrous mixtures of oils, surfactants, and co-surfactants that are characterised by a spontaneous formation of fine oil-in-water nano-emulsions after their mild agitation in aqueous media. The resultant nanosized droplets (<200 nm) bring about an increase in surface area for rapid absorption, thus improving therapeutic performance. The review comprehensively discusses the fundamentals on SNEDDS, including formulation components, the mechanism of spontaneous emulsification, preparation methods, characterisation techniques, and evaluation of thermodynamic stability. Besides that, pharmaceutical and cosmetic applications, including the enhancement of bioavailability, mucus permeation, biomolecule delivery, topical and transdermal systems, and incorporation into hydrogel and serum pearls, are highlighted. Despite these advantages, challenges relating to surfactant concentration, cost of formulation, and in vitro-in vivo correlation persist. Overall, SNEDDS is a promising, versatile platform for both drug delivery and cosmeceutical development.

Keywords

Introduction

Skin is the largest organ of the body, behaving like a critical barrier against environmental aggressors, microbial invasion, and excess water loss. Adequate hydration of the skin is important in preserving its integrity, elasticity, and health. Conventional moisturizing creams are topical formulations aimed at improving hydration of the skin by preserving or restoring the status of the skin's lipid barrier and reducing trans epidermal water loss¹.Moisturising creams are semisolid emulsions and can be water-in-oil (W/O) or oil-in-water (O/W) formulations. These formulations of creams make them offer greater residence time of the substance at the application site compared to other semisolid formulations. This is because of the nature of the emulsion properties and the oil part of the cream acting as an emollient that forms a barrier against the evaporation of water from the skin. This assists the skin to appear less greasy and feel smooth. Moreover, the creams are nongreasy and penetrable and therefore less irritating and easily washable. Poor penetration through the skin by the lipophilic active ingredients, instability, and consequently diminished bioavailability are common drawbacks of conventional moisturizing creams that might seriously impede their therapeutic and cosmetic efficacies².During recent years, the progress of nanotechnology has facilitated the development of new drug and cosmetic delivery systems that are intended to surmount these disadvantages. Among the well-promising approaches, one is called the Self Nanoemulsifying Drug Delivery System (SNEDDS). SNEDDS are isotropic mixtures of oils, surfactants, and co-surfactants that form fine oil-in-water nano emulsions spontaneously upon contacting aqueous media under gentle agitation. These systems develop nano-sized droplets, normally less than 100 nm, which enhance the solubility, stability, and delivery of lipophilic compounds enormously³.

Advantages of incorporating SNEDDS in moisturising creams.

 The use of SNEDDS in the preparation of moisturising creams has many advantages over traditional creams. Moisturising creams composed of SNEDDS can be used to enhance the distribution and diffusion of lipophilic moisturising agents and biologically active substances within the layers of the skin. The nanosized particles in these substances have high surface areas, which can easily interact with the stratum corneum of the skin. In addition, SNEDDS has been known to have improved properties such as thermodynamic stability.In addition, the SNEDDS-based moisturising creams have the advantage of being able to offer a controlled and sustained release of the active components, thus extending the duration of the skin hydrating and protection effects. The technology is well-suited for the delivery of the biologically active components, such as antioxidants, vitamins, plant extracts, and lipids, that contribute to skin hydration⁴.

• Why Use SNEDDS in a Moisturising Cream?

1. Improved Delivery of Active Ingredients

When mixed with lipophilic actives such as vitamins, antioxidants, ceramides, or natural oils, SNEDDS can result in enhanced solubility for these actives that can penetrate the skin layers more effectively than creams⁵.

2. Nano-Scale Emulsion for Better Penetration

The droplet size of nanometres created upon application has an enhanced surface area that helps in better interaction of the skin, thus facilitating the better entry of beneficial ingredients within the epidermis and dermis⁵.

3. Stability & Sensory Feel Enhancers

SNEDDS formulations usually result in a thermodynamically stable system and may produce a smooth, non-greasy, and spreadable texture that could be lighter than a cream formulation rich in oil⁶.

4. Potential for Controlled Release

The structure of the nano emulsion may be useful for time-controlled release mechanisms, which can increase the functional effect of active substances on skin hydration and barrier repair mechanisms⁶.

MECHANISM OF ACTION

• • Spontaneous nano emulsion

On application, the water present on the skin surfaces initiates the self-emulsification process of the SNEDDS formulation. In turn, there is the formation of oil droplets of nanometric size.

• • Increased solubilization and dispersion of actives

The nano-droplets enhance the surface area, which is beneficial for the dissolution of the drug or active. The solubility and distribution of the lipophilic actives, which always have difficulty being delivered via conventional cream, are improved.

• • Enhanced interaction with skin lipids

The nano-emulsion particles are engaged with the lipid matrix within the stratum corneum layer. This makes it possible to increase penetration and accumulation of actives in lower skin layers. This also assists with hydration, repair, and sustained release⁵.

Components of SNEDDS for Topical Drug Delivery

Topical Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) are the lipid nano systems that create nano-emulsion on their own on interacting with semisolid bases (creams and gels) or upon application on the skin, which are developed for the improved solubility, penetration, and retention of drugs on the skin. The typical formula for topical SNEDDS consists of the following components: oil phase, surfactant, co-surfactant/co-solvent, and optionally, penetration enhancers/excipients for the skin, which are selected based on⁵_.

1. Oil Phase (Lipid Component)

Role:

• Makes lipophilic drug soluble.
• Participates in formation of the internal phase (oil) in the nano-emulsion.
• Can serve as a skin penetration enhancer by interacting with lipids in the stratum corneum.

Examples

1. Labrafil® M 1944 CS - A combination of mono, di, and triglycerides. It is used as the oil phase in the SNEDDS drug astaxanthin.
2. Essential lipids or terpenes (Limonene, geraniol, etc.) – useful for increasing the permeability of the skin, if added to the oil phase.

Topical Delivery Mechanism: Lipophilic oils assist in distributing the drug into the lipophilic layers of the stratum corneum, thus enhancing the driving force to distribute the drug further into the inner layers of the epidermis⁵.

2.Surfactants

Role:

• Stabilize the nano-emulsion droplets
• Used as wetting and spreading agent
• Reduce the interfacial tension

Examples

1. Kolliphor® EL (polyoxyl-35 hydrogenated castor oil) - non-ionic surfactant; of high HLB value; used in
2. Tween 80, Span series, Cremophor® EL – often used due to low irritation and emulsifying properties. The above is well accepted in topical dosage forms (such as creams or gels in the nano-emulsion system).

3. Non-ionic surfactants of high hydrophilic-lipophilic balance (HLB) values can be considered to be much better in topical dosage forms to reduce irritation to the skin. They produce stable fine nanodroplets⁵.

 3. Co-Surfactants

Role:

• Help surfactants further decrease the interfacial tension.
• Flexible adsorbed interfacial films to help in nano-emulsion formations.
• As penetration enhancers, they disrupt the skin's lipid components, the stratum corneum

Examples

1. Transcutol P (diethylene glycol monoethyl ether), used as a co-surfactant and a penetration enhancer through the skin because of its capacity to solubilize water and oil phases⁵.
2. Additionally, PEG 200/400 and alcohols of low molecular weight are used as solubilizers and to enhance percutaneous penetration in topical gels⁷.

4. Penetration Enhancers and Functional Additives

• Additional ingredients may be added to topical products to assist in penetration beyond a basic nano-emulsion:

Examples & Mechanisms

1. Terpenes (D-Limonene, Geraniol, Farnesol): These can alter the interlamellar packing pattern in the SC lipid layer and aid in the diffusion of drug substances

2. These terpenes may be present as components of the oil phase or as additives to the formulation⁵_.

5. Vehicle / Semisolid Base (Cream, Gel)

• Although not a part of the SNEDDS formula, the actual dosage form becomes important for the intended drug delivery route:
• Usually, SNEDDS carriers mix in creams or gels (Carbopol, Pemulen TR-1, etc.), to favour their administration in an appropriate dosage.
• The base may be provided with emollients and/or polymer to modify viscosity and spreadability in a manner that promotes compliance⁵_.

Topical Applications of SNEDDS

1.Increased Penetration into Human Skin for Lipophilic Ingredients

• Astaxanthin SNEDDS for Topical Skin delivery

• The SNEDDS containing astaxanthin was found to significantly facilitate penetration through the stratum corneum, and into the layers of epidermis, dermis, and follicle compared to oil solution and commercial serum.
• Furthermore, terpenes, such as D-limonene, were also effective⁵.

2.Curcumin SNEDDS for Topical Dosage Forms: Creams and Gels

• Topical Curcumin SNEDDS for Skin Delivery

• Curcumin was found to have poor penetration through the skin due to hydrophobicity. Formulation of curcumin with SNEDDS and its incorporation into creams and gels increased the efficacy of the drug by enhancing the drug’s release and permeation, and the anti-inflammatory.

• The gel, which contained SNEDDS, was seen to have faster penetration than conventional products in Franz diffusion studies⁸.

3. Topical Cream of 5-Fluorouracil for Skin Cancer Therapy (SNEDDS)

• 5-FU SNEDDS Cream for Actinic Keratosis

• An isopropyl myristate, Tween 80, and Transcutol P combination was incorporated into a cream.
• Exhibited enhanced spreadability, release of the drug (~88.7%), and cytotoxic activity against carcinoma cells compared to the conventional formulation⁹.

4. Transdermal Curcumin SNEDDS for Anti-inflammatory

• Curcumin SNEDDS for Transdermal Delivery

• SNEDDS with incorporated curcuminoids and lipid carriers were found to exhibit adequate skin penetration with considerable in vivo anti-inflammatory activities with reductions of about ~80% for paw edema in animal studies¹⁰.

5. Azelaic Acid SNEDDS Hydrogel for Atopic Dermatitis

• Azelaic Acid SNEDDS Hydrogel

• It was also observed that in the preparation of hydrogel with azelaic acid-loaded SNEDDS, skin permeation was enhanced compared to marketed formulation and offered no irritation to the skin in animal tests¹¹.

 6. Ocular Topical SNEDDS – Non-Invasive

• Triamcinolone SNEDDS for Ocular Topical Delivery

• A SNEDDS of triamcinolone acetonide applied topically to the eyes showed enhanced permeability into the posterior tissues of the eye (retina and sclera) as well as safety¹².

Advantages of SNEDDS for topical delivery

1. Increased Skin Permeation

Topical SNEDDS form nano-sized oil-in-water droplets of large interfacial surface area, which enhances permeation through the stratum corneum due to an improvement in drug diffusivity and interaction with skin lipids.^10,11

2. Enhanced Solubility of Poorly Water-Soluble Drugs

SNEDDS can keep the lipophilic drugs in a solubilized state in the oil phase, thereby increasing the thermodynamic activity and enhancing drug partitioning into the skin. ^5,9

3. Increased Local Drug Retention with Reduced Systemic Exposure

Topical SNEDDS Favor drug deposition within skin layers, leading to higher local drug concentration while minimizing systemic absorption and associated adverse effects.^8,10

 4. Protection of Drugs from Chemical and Environmental Degradation

Encapsulation of the drug is achieved, where the drug will be protected from degradants like oxidation, exposure to direct or indirect light, as well as environmental conditions on the skin surface.^5,8

5. Versatile Incorporation into Patient-Friendly Topical Dosage Forms

The incorporation of SNEDDS into gels, creams, ointments, and nanoemulgels can be done effectively to enhance spreadability, aesthetic properties, and patient compliance.^9,11

6. Use of Skin-Compatible and Less Irritating Excipients

Non-ionic surfactants and other biocompatible oils that make up topical SNEDDS have also cut down irritation to the skin compared to the use of other topical enhancers.^5,8

7. Enhanced Therapeutic Efficacy in Dermatological Disorders

Topical SNEDDS formulations have also demonstrated superior therapeutic results in skin disorders like inflammation, hyperpigmentation, actinic keratosis, and dermatitis due to their penetration and controlled drug release properties.^9,10,11

Disadvantages of SNEDDS for topical delivery

1. Risk of Skin Irritation

The high concentrations of surfactants and co-surfactants, which are often essential for nano emulsification, have been shown to have the potential for disrupting skin barrier integrity. ^5,11

2. Limited Suitability for Hydrophilic Drugs

SNEDDS are mostly applicable for lipophilic drugs, while the incorporation of a hydrophilic drug might show difficulty in maintaining solubilization in the oil phase, which may be a drawback in formulation. ⁵

3. Stability Issues

Concerns regarding topical SNEDDS involve various physical issues during storage or after the product is entrapped in semisolids.^8,9

4. Excessive or Uncontrolled Skin Penetration

Increased permeability can sometimes result in unwanted systemic absorption, thus enhancing the chances of systemic side effects. ^10,11

5. Scale-Up and Regulatory Challenges

The optimization of excipients and the lack of standardized regulations for topical SNEDDS may pose challenges in their manufacture and approval.⁸

METHODOLOGY

1)Preparation of the SNEDDS Preconcentrate

 Measure the proportion of the various required ingredients in a pre-optimized ratio. For example, an optimized ratio may be MCT Oil – 30% w/w, Tween 80 – 60% w/w, Propylene Glycol – 9.5% w/w, Vitamin E – 0.5% w/w. In most cases, this falls into the Type IIIA classification All the constituents are mixed within the confines of a glass vial or beaker. A magnetic stirrer-hot plate apparatus can then be procured, upon which the mixing solution can be placed. It can then be subjected to mild heat. Sticking to values within the range of 40 °C ± 2, the elements can be stirred at around 500 revolutions per minute. The isotropic solution would most likely be achieved within 10-20 minutes. The solution is cooled to a room temperature of 25°C and put in a container to rest.¹³

2)Preparation of hydrogel base.

 Carbopol 940 is accurately weighted to achieve a final concentration of 0.75% (w/v) within the target range. It is slowly sprinkled into a portion of distilled water containing glycerin, for example, 5-10% w/v as a humectant, and the chosen preservative under high mechanical stirring (~800-1000 rpm). This slow addition is important to avoid the formation of lumps or so-called fish-eyes, which are hardly soluble later on. This is mixed for 20-30 minutes to ensure adequate wetting of the polymer particles. This has been left standing as such to allow swelling for 1-2 hours or overnight at 4°C to allow full hydration and give a clear viscous dispersion at low pH (~2.5-3.5). The hydrated Carbopol dispersion is returned to stirring. Triethanolamine (TEA) is added dropwise-e.g., approximately 0.5-0.8% w/v, depending on Carbopol grade and concentration-to neutralize the carboxylic acid groups on the polymer backbone. The pH is continuously monitored using a calibrated pH meter until a stable value within the target range of 6.0-6.5 is achieved. This neutralization causes electrostatic repulsion and uncoiling of the polymer chains, resulting in a dramatic increase in viscosity and the formation of a clear, smooth, and elegant hydrogel.¹⁰

3)Preparation of Serum Pearls by gelation.

 In a separate beaker, weigh out and dissolve 2.0 g of sodium alginate in ~80 mL of water. Continuous stirring until homogeneous (10-15 min). Measure 10 mL of distilled water and place it in a beaker. Add slowly with gentle stirring until complete dissolution occurs (~5 min) – 1.0 g of niacinamide. Mix the prepared niacinamide aqueous solution into the alginate solution contained in the mixing tank under constant Stirring.Add 0.5 g mica powder to the 2.0g of glycerine stirring until well distributed (avoiding clumps) In a small vial, combine 0.5 g of essential oil of orange and 0.5 mL of Tween-80. Slowly add this oil to Tween 80 mixture into the alginate solution while stirring modestly to prepare a uniform oil-in-water system.¹⁴ Making CaCl? Gelling Bath: 3.0g of CaCl? in 100ml of Distilled Water. The Ca²? ions act as crosslinkers between the alginates, forming gel beads. Load solution of alginate oil mixture in a syringe with a 0.8–1. Extrude droplets into the gently stirred CaCl? solution from 5-10 cm height. Let the beads cure for ~20-30 min. Dissolve 0.25 g chitosan in 100 mL 1% acetic acid solution by stirring until dissolved. Add the newly formed alginate particles to this solution of chitosan. Stir gently for 10–20 min to permit ionic complexing of chitosan on the beads. Gently rinse the beads with distilled water. Air dry or gently pat the beads dry. Store the beads in airtight amber-coloured container.¹⁵

4)Final composite formulation.

It is essential to ensure that the alginate pearls are removed from their aqueous storage solution and blotted using a lint-free material or, better still, filter papers. This prevents the dilution of the hydrogel base, which may be reflected in a change of its pH. A known quantity of serum pearls (for instance, 3.5% w/w of the final product, in the 2–5% range) is gradually added to the SNEDDS hydrogel base. For incorporation, a low-shear mixing process is used, which involves an overhead stirrer with a wide, flat paddle or spatula blade. The mixing is carried out at slow speed (between 50–150 rpm) for 5 to 10 minutes. Under this process, macroscopic uniform distribution of pearls is attained

Evaluation of Cream:

1) physical properties:  

The cream was observed for the colour, odour, appearance and homogeneity.

2) Washability: 

The cream was applied on the hand and observed under the running water.

 3) pH:

The pH meter was calibrated with the help of standard buffer solution. Weigh 0.5 gm of cream dissolved it in 50.0ml of distilled water and its p H was measured with the help of digital pH meter.

 4) Viscosity: 

Viscosity of the cream was determined with the help of Brookfield viscometer at 100 rpm with the spindle no. 7.

5) Spread ability test:

The cream sample was applied between the two glass slides and was   compressed between the two-glass slide to uniform thickness by placing 100 gm of weight for 5 minutes then weight was added to the weighing pan.

The time in which the upper glass slide moved

s=weight tight to upper slide 

l =length moved on the glass slide 

t =time take  

6) Irritancy test: 

 Mark an area (1sq.cm) on the left-hand dorsal surface. The cream was applied to the specified area and time was noted. Irritancy, erythema, oedema, was checked if any for regular intervals up to 24 hrs. and reported¹⁶

7) In vitro diffusion study   

In vitro diffusion studies using a dialysis method were carried out for all the formulations prepared. Phosphate buffer pH 6.8 was used as the dialysis fluid. The thread was attached to one end of the pre-treated cellulose dialysis tubing of 7 cm length, and then 1 ml of self-nano-emulsifying formulation and 0.5 ml of dialysis fluid were introduced into it. Further, the other end of the tube was tied with a thread and allowed to freely rotate in 200 ml of dialysis fluid and stirred at 100 rpm with a magnetic bead on a 37°C magnetic plate. Samples of 1 ml at different time intervals were withdrawn and further diluted. Each time, the quantity of samples was replaced with fresh dialysis fluid. These samples were analysed quantitatively for drug diffused through the membrane at different time intervals using a UV-visible spectrophotometer.¹⁷

Evaluation of SNEDDS

1. Emulsification Time Method

• The emulsification time can be measured by the following visual assessment technique in a specific environment:

A known volume of the SNEDDS preconcentrate (usually a volume of around 0.5 to 1 mL) is slowly added to a volume of distilled water or a phosphate buffer (pH from 5.5 to 7.4) ranging from 100 to 500 mL at aThe medium is gently agitated using a magnetic stirrer or a paddle stirrer set to 50-100 rpm.The time for complete emulsification is measured by the help of a stop-watch.The achievement of complete emulsification is observed when the system shows the presence of a clear or even slightly bluish colour of the formed nano emulsion with no phase separation, the absence of oil globules.

Interpretation

• Emulsification time < 1 min suggests efficient SNEDDS self-nano emulsification, desirable for topical SNEDDS formulations.

• Rapid emulsification facilitates enhanced drug release, skin spreading, and skin penetration, especially in a semisolid dosage form after the SNEDDS contains a vehicle.¹⁸

2. pH Measurement 

The pH of each SNEDDS formulation was measured using a calibrated digital pH meter (pH-700). A total of 5 mL of SNEDDS was placed in a container and the electrode was immersed into the sample. The pH value displayed by the instrument was recorded.¹⁸

3. Viscosity Measurement      

Viscosity was measured using a Brookfield cone and plate viscometer to determine the effect of surfactants and preparation techniques on the viscosity of SNEDDS. The sample cup plate was filled with 0.5–2.0 mL of SNEDDS.¹⁹

4. Scanning electron microscopy     

The sample was analysed in scanning electron microscope after preparing the sample by lightly sprinkling on a double adhesive tape stuck to an aluminium stub. The stubs were then coated with platinum. The stub containing the coated sample was placed in scanning electron microscope (JEOL JSM 6380LA, Japan). The samples were then randomly scanned and photomicrographs were taken at the acceleration voltage of 20 kV. From the resulting image, average particle size was determined.

5. Drug entrapment efficiency (%)          

100 mg of beads were taken and crushed using pestle and mortar. The crushed powders of drug-containing beads were placed in a very 250 ml volumetric flask and volume was made up to 250 ml by phosphate buffer, pH 7.4, and kept for 24 h with infrequently shaking at 37 ± 0.50 C. After the specified time mixture was stirred at 500 rpm for 20 min using a magnetic stirrer (Remi Motors, India). The polymer debris fashioned after the disintegration of the bead was removed by filtering through Whatman® filter paper (No. 40). The drug content within the filtrate was determined using a UV–vis spectrophotometer (Shimadzu, Japan) at 233 nm against an acceptable blank. The DEE (%) of these prepared beads was calculated by the subsequent formula.²⁰

 DEE (%) =actual drug content in beads/Theoretical drug content in beads×100.

 6.Stability studies   

Stability testing plays a crucial role in the drug development process. The purpose of stability testing is to provide evidence on how the quality of drug product varies with time under the influence of a variety environmental factors, such as temperature, humidity and light to recommend shelf life for drugproduct and recommended storage conditions. Stability studies were carried out on the optimised formulation according to ICH guidelines. The optimised formulation was packed in a tightly closed containers and was stored in ICH certified stability chamber maintained at 40 ± 2oC and 75% ± 5% RH for one month. The formulation was evaluated before and after at periodic intervals for change in appearance, drug content and in vitro drug release.²¹

CONCLUSION

SNEDDS-based moisturizing creams provide a new and effective way to deliver cosmetics and skincare products. The formulation successfully combines a SNEDDS base with alginate pearls. This combination leads to better skin penetration, protects sensitive active ingredients, and allows for controlled release. The SNEDDS system also enhances the stability and availability of lipophilic Vitamin E. At the same time, alginate pearls support the sustained delivery of niacinamide and orange essential oil, which together improve hydration, brightness, and antioxidant effects.In addition to its functional benefits, the formulation has excellent aesthetic quality, appeals to consumers, and remains stable on the shelf. These qualities make it suitable for commercial cosmetic use. The results further highlight the growing use of SNEDDS beyond oral drug delivery into topical and cosmetic products, offering flexibility, better performance, and protection for bioactive compounds.Despite challenges such as surfactant load, cost, and safety issues, ongoing optimization and assessment can help overcome these obstacles. Overall, this work emphasizes the significant potential of SNEDDS as a flexible and innovative delivery system. It makes a meaningful contribution to the progress of cosmetic nanotechnology and next-generation skincare formulations.

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