Formulation and evaluation of an anti-aging topical emulsion utilizing pomegranate (punica granatum) seed oil: a comprehensive review

Introduction

Skin, the body's largest organ, serves as a dynamic biological barrier that protects against environmental insults while maintaining internal homeostasis (Proksch et al., 2008; Wang et al., 2020) [46,64] . Skin aging is a complex and multifactorial biological process characterized by progressive deterioration in physiological function and structural integrity, leading to reduced elasticity, increased fragility, dryness, and the formation of deep rhytides or wrinkles (Farage et al., 2008; Hussen et al., 2025) [14,24] . The pathophysiology of skin aging is broadly classified into intrinsic and extrinsic aging processes. Intrinsic aging, also referred to as chronological aging, is a genetically regulated and inevitable phenomenon associated with dermal fibroblast senescence, reduced collagen synthesis, and slower keratinocyte turnover (Makrantonaki and Zouboulis, 2007). In contrast, extrinsic aging is primarily driven by environmental factors such as ultraviolet (UV) radiation, atmospheric pollution, smoking, and lifestyle-related stressors (Kammeyer and Luiten, 2015; Suvedi et al., 2025) [30,59] . Although these mechanisms differ in origin, both pathways converge through excessive generation of reactive oxygen species (ROS), resulting in oxidative stress and chronic inflammation (Pillai et al., 2005; Wang et al., 2025) [45,65] . At the cellular level, elevated ROS production overwhelms the endogenous antioxidant defense system of the skin, triggering multiple pro-inflammatory signaling pathways that stimulate the expression of matrix metalloproteinases (MMPs), enzymes responsible for extracellular matrix (ECM) degradation (Fisher et al., 2002) [16] . Increased MMP activity particularly affects type I and type III collagen fibers, leading to collagen fragmentation, dermal matrix disorganization, and loss of skin resilience (Quan et al., 2009) [49] . As elastin fibers become fragmented and disordered, the skin progressively loses its tensile strength and elasticity, contributing to wrinkle formation and sagging (Baumann, 2007 [8] ; Hussen et al., 2025) [24] . Recent studies further emphasize that oxidative stress alters collagen homeostasis, enhances inflammatory cytokine release, and accelerates premature skin aging (Costa et al., 2022; Wang et al., 2025) [10,65] . In response to increasing concerns regarding premature skin aging, the dermatological and cosmetic industries have focused extensively on advanced anti-aging formulations. Although synthetic retinoids and peptides have traditionally dominated the anti-aging market, recent consumer preference has shifted toward plant-based and herbal cosmetics due to their improved biocompatibility, antioxidant potential, and lower incidence of adverse effects (Mukherjee et al., 2011) [42] . Natural phytochemicals including polyphenols, flavonoids, carotenoids, and essential fatty acids have demonstrated substantial protective effects against oxidative damage, inflammation, collagen degradation, and photodamage (Nowak-Perlak et al., 2025; Hussen et al., 2025) [24,43] . Recent clinical evidence also suggests that topical botanical formulations significantly improve skin hydration, elasticity, and overall skin appearance, Highlighting their growing relevance in modern cosmeceutical research (Burlando et al., 2024) [9] .

Pomegranate (punica granatum): an overview

Punica granatum L., commonly known as pomegranate, is a deciduous shrub or small tree that has been revered for millennia for its high nutritional and medicinal value (Jurenka, 2008) [29] . Native to the regions spanning from modern-day Iran to northern India, it is now widely cultivated in tropical and subtropical regions worldwide, including the Mediterranean, China, and the United States (Viuda-Martos et al., 2010; Mohammadi et al., 2023) [39,40,63] . Historically considered the "fruit of paradise," it is one of the oldest known fruits and serves as a vital natural resource for diverse therapeutic interventions (Lansky and Newman, 2007) [35] .

Botanical classification

Plant parts and their phytochemical profiles

Medicinal value is distributed across various compartments of the plant, with each part offering a unique array of bioactive metabolites (Viuda-Martos et al., 2010) [63] .

Seed and seed oil: seeds comprise roughly 10-20% of the total fruit weight. They are a dense source of total lipids, with pomegranate seed oil (PSO) containing between 12% and 20% of the seed weight (Lansky and Newman, 2007; Verardo et al., 2014) [35, 62] .

Peel (pericarp):

The inedible rind accounts for approximately 43-50% of the fruit's total weight. It is exceptionally rich in hydrolyzable tannins, specifically punicalagins and ellagic acid, which contribute to its potent antioxidant capacity (Elfalleh et al., 2012; Gullón et al., 2016) [13,20] .

Juice and arils:

The arils (edible portion) consist of juice (approx. 78%) and seeds (22%). Pomegranate juice is recognized for its high content of anthocyanins (giving it its red hue), vitamin C, and potassium (Jurenka, 2008; Mphahlele et al., 2014) [29,41] . [29,55,56] .

Gastrointestinal disorders: Traditionally, the bark, peel, and juice have been used to treat diarrhea, dysentery, and intestinal parasites.

In Ayurvedic medicine, the fruit is considered a "stomachic" and is used to manage acidity and abdominal distension (Lansky and Newman, 2007) [35] .

Oral health: In several cultures, powdered rinds are utilized in tooth powders and mouthwashes to treat gingivitis, dental plaque, and mouth ulcers due to their strong antibacterial properties (Ismail et al., 2012) [27] .

Wound and skin care: In the Iranian system of medicine, extracts are applied to cuts, wounds, and edemas. In TCM, it is valued for its astringent nature to address skin inflammations (Viuda-Martos et al., 2010) [63] .

Reproductive health: Traditional records suggest the use of seeds for managing menstrual pain and preventing miscarriage (Jurenka, 2008; Sharma et al., 2023) [29,55,56] .

Pomegranate seed oil and punicic acid (pa) Chemical composition of pso

A significant focus of recent research is the unique chemical composition of the seed's lipid fraction (Verardo et al., 2014) [62] . Punicic acid content: Pomegranate seed oil is characterized by an exceptionally high concentration of punicic acid (~64-85%), a rare omega-5 conjugated triene isomer of (alpha) linolenic acid (Melo et al., 2014; Almoraie et al., 2025) [5,38] .

Biological activity: PA is considered the "rising star" of pomegranate nutraceuticals due to its multifaceted biological effects (Almoraie et al., 2025) [5] .

Anticarcinogenic: It has been shown to induce apoptosis and inhibit the proliferation of breast, prostate, and colon cancer cells (Lansky and Newman, 2007; Rocha et al., 2012) [35] . [5,38] . Anti-inflammatory: It inhibits the production of pro-inflammatory cytokines like (TNF-alpha) and (IL-6), potentially serving as a therapeutic agent for inflammatory bowel diseases and cardiovascular protection (Juhaimi et al., 2017; Kobylinska et al., 2026) [4,28] . Neuroprotection: Emerging studies indicate that PA may reduce (beta) amyloid deposits and neuroinflammation, showing promise for Alzheimer's and Parkinson's disease research (Almoraie et al., 2025) [5] .

Punica granatum is a high-valu e medicinal plant where the seed oil, primarily through the action of punicic acid, provides significant anti-inflammatory, ant carcinogenic, and metabolic health benefits (Verardo et al., 2014; Kobylinska et al., 2026) [62] . Pomegranate Seed Oil (PSO) is a highly valued, nutrientdense oil extracted from the seeds of Punica granatum L., typically containing 74-85% conjugated linolenic acids (CLnA). It is increasingly used as a nutraceutical and in cosmetics due to its potent antioxidant, anti-inflammatory, and antimicrobial properties. The oil's therapeutic effects are derived from a synergistic interaction among its unique fatty acid profile, tocopherols, and polyphenols (Kobylinska et al., 2026; Verardo et al., 2014) [62] Phytochemical composition of pomegranate seed oil  Punicic acid (omega-5 fatty acid): As the primary bioactive component, punicic acid (often 70-80%+ of the oil) is a conjugated isomer of linolenic acid. It is a rare polyunsaturated fatty acid known for its unique ability to modulate lipid metabolism and inhibit tumor growth (Almoraie et al., 2025) [5]  Polyphenols: Although more concentrated in the peel and juice, PSO contains significant levels of phenolic compounds, specifically Gallic acid, catechin, vanillic acid, and ellagic acid. These act as secondary metabolites that contribute to the oil's overall stability and antioxidant capacity (Zielińska et al., 2022) [66,67]  Flavonoids: Pomegranate seeds contain various flavonoids (including catechin and quercetin), which are known for their strong scavenging ability against reactive oxygen species (ROS) (Afshari et al., 2016) [2]  Tocopherols (vitamin e): PSO is rich in tocopherols (360-392 mg/100g), with (gamma) tocopherol being the most abundant (accounting for up to 95% of total tocopherols). These compounds act as powerful antioxidants to protect the oil from degradation and provide vitamin E to the body ( [4,26,28,38] Biological and pharmacological activities  Antioxidant: The combination of punicic acid and tocopherols neutralizes free radicals and reduces oxidative stress, protecting cell membranes from lipid peroxidation (Almoraie et al., 2025) [5]  Anti-inflammatory: Punicic acid inhibits proinflammatory markers (such as TNF-(alpha), IL-6, and NF (kappa) B. This makes it effective in managing chronic inflammatory conditions like obesity-related inflammation, arthritis, and skin conditions (Juhaimi et al., 2017) [4,28]  Anti-microbial: PSO [5,22,62] . The high punicic acid content (above 70-80%) makes PSO a "superfood" for addressing metabolic syndrome, including the reduction of triglycerides and improvement of insulin sensitivity. (Almoraie et al., 2025; Melo et al., 2014) [5,38] . [24,42] Free Phenolics Ellagic Acid Inhibits copper-dependent tyrosinase activity and protects against UV-induced photodamage [24,42] .

Anti-inflammatory effects and epidermal thickening

Chronic, low-grade structural inflammation often termed "inflammaging" is a primary driver of dermal degradation (Frances chi et al., 2018; Wang et al., 2025) [65] . Punicic acid acts as a potent inhibitor of cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) pathways, reducing the conversion of arachidonic acid into pro-inflammatory mediators such as prostaglandin E2 (PGE2PGE_{2}PGE2) (Juhaimi et al., 2017; Almoraie et al., 2025) [4,5,28] . Concurrently, research shows that topical PSO selectively induces keratinocyte proliferation in the stratum basale, significantly increasing epidermal thickness and reinforcing the skin's physical barrier (Syed et al., 2006; Burlando et al., 2024) [9] . [1,30,65] . [9,42]  Serums: Concentrated anhydrous lipid delivery systems designed for rapid transepidermal penetration (Draelos, 2012; Kobylinska et al., 2026) [11] .  Lotions: Lower-viscosity fluids suited for broad body coverage (Baki and Alexander, 2015) [7] .  Emulsified creams: Biphasic systems that provide optimal skin delivery by sustaining active compounds on the skin surface while delivering immediate barrier hydration (Aulton, 2018; Burlando et al., 2024) [6,9] . [46,62] .  Barrier Repair: PSO accelerates healing in compromised or scaling skin barriers by promoting the cellular synthesis of essential ceramides and keratinocyte differentiation structures (Syed et al., 2006; Wang et al., 2025) [65] .  Dermal re-densification: The synergistic interaction of punicic acid, tocopherols, and phytoestrogens increases dermal fiber density, clinically reducing wrinkle depth and improving skin volume (Mukherjee et al., 2011; Hussen et al., 2025) [24,42] .

Photoprotection

Dermatological benefits

Formulation of an anti-aging cream Selection of emulsion system

An Oil-in-Water (O/W) emulsion system is generally preferred for anti-aging cosmeceutical creams. This structural design encloses the oil droplets within a continuous aqueous phase, ensuring a nongreasy texture, rapid skin absorption, and superior patient compliance compared to heavy, occlusive Water-in-Oil (W/O) bases (Aulton, 2018; Baki and Alexander, 2015; Burlando et al., 2024) [6,7,9] .

Functional ingredient selection

Developing a stable, dermatologically compatible O/W emulsion requires a precise balance of excipients (Lachman et al., 2013; Aulton, 2018) [6,34]  Oil phase (active & matrix): Punica granatum seed oil serves as the primary active botanical oil. It is blended with solid fatty acids, such as stearic acid (an emulsifying/structuring agent) and cetyl alcohol (a coemulsifier and consistency factor), to optimize the formulation's physical matrix (Rowe et al., 2009; Baki and Alexander, 2015) [7,52] .  Aqueous phase: Deionized, purified water serves as the continuous vehicle (Aulton, 2018) [6] .  Humectant: Glycerin or propylene glycol is added to the aqueous phase to draw moisture into the stratum corneum and prevent product desiccation (Draelos, 2012; Proksch et al., 2008) [11,46] .  Preservative system: Antimicrobial agents, such as methylparaben and propylparaben, are added to prevent microbial proliferation across both phases (Rowe et al., 2009; USP, 2023) [52] .  Stabilizers: Polymeric rheology modifiers, such as Carbopol 940, can be introduced to enhance long-term structural stability and prevent phase separation (Baki and Alexander, 2015; Aulton, 2018) [6,7] . [11,46] Carbopol 940 Stabilizer Baki and Alexander, 2015; Aulton, 2018 [6,7] Methyl paraben Preservative USP, 2023; Rowe et al., 2009 [52] Processing and preparation method The formulation is produced via an optimized hightemperature emulsification process (Aulton, 2018; Lachman et al., 2013) [6,34]  Phase separation and heating: The oil phase components (PSO, stearic acid, cetyl alcohol) are combined in a vessel and heated to 70-75ºC until completely liquefied. Concurrently, the aqueous phase components (water, glycerin, water-soluble preservatives) are combined and heated to the same temperature range (Baki and Alexander, 2015; Rowe et al., 2009) [7,52] .

 Phase blending: The heated aqueous phase is added slowly to the heated oil phase under continuous, highshear mechanical agitation. This high-energy mixing shears the internal lipid phase into sub-micron droplets (Aulton, 2018; Sinko, 2011) [6,57] .  Cooling and homogenization: Mechanical stirring is maintained as the system cools to room temperature (∼25ºC). Thermolabile additives, including natural fragrances or specialized antioxidants, are introduced during the cooling phase at approximately 40ºC to 45ºC maintain chemical stability (Lachman et al., 2013; Baki and Alexander, 2015) [7,34] .

Evaluation parameters of cream

To transition from laboratory scale to industrial processing, the formulated PSO anti-aging cream must satisfy rigorous pharmaceutical standards (ICH Q1A (R2), 2003; Aulton, 2018) [6] .

Physical evaluation  Color & Odor:

Visual and olfactory testing must confirm an appealing, uniform off-white to pale cream color with a characteristic mild, pleasant scent (Baki and Alexander, 2015; Lachman et al., 2013) [7,34] .  Homogeneity: Visual inspection and microscopic analysis must demonstrate consistent particle distribution without structural grittiness, lipid agglomeration, or phase separation (Aulton, 2018; Sinko, 2011) [6,57] .

PH determination

The pH of the topical cream must align with the acid mantle of human skin to minimize irritation and protect the skin barrier. Formulations should maintain a target pH range between 5.0 and 6.5, measured using a calibrated digital pH probe inserted directly into a 10% w/v aqueous dilution of the cream (Proksch et al., 2008; USP, 2023) [46] .

Viscosity and rheological profiles

Topical emulsions must exhibit non-Newtonian pseudo plastic (shear-thinning) flow behavior. Viscosity is quantified using a Brookfield viscometer at controlled temperatures (25ºC). High viscosity at rest prevents product sedimentation during storage, while decreased viscosity under shear force allows smooth topical application (Martin, 2011; Baki and Alexander, 2015) [7,37] .

Spreadability kinetics: Spreadability dictates user

Experience and ensures the uniform delivery of active ingredients across the skin surface. It is measured using two glass plates: a specified weight (e.g., 100g) is applied to the cream sample sandwiched between the plates, and the resulting spread diameter is recorded over a set timeframe, calculated using the formula (Garg et al., 2002; Aulton, 2018) [6,18]: [6,34] .

Dermal irritation and biocompatibility

Safety is validated via in vivo animal models (e.g., healthy Albino Wistar rats) or through human patch testing. The formulation is applied to a shaved skin site and monitored over 24 to 72 hours for signs of erythema, edema, or local hypersensitivity reactions, confirming its safety for longterm clinical use (Draize et al., 1944; OECD Guideline 404, 2021; Burlando et al., 2024) [9,12] . [34] Recent advances in nano-cosmeceuticals Conventional macro-emulsions often fail to cross the stratum corneum due to large droplet morphology and low active-ingredient bioavailability. Advanced nanotechnologybased delivery architectures overcome these physiological limitations (Puglia et al., 2018; Souto et al., 2020) [58] . [9,31,32] .

Nanoemulsions

Nanocapsules

Nano capsules represent vesicular reservoir systems containing a distinct polymeric shell (composed of biodegradable aliphatic polyesters such as poly-lactic-coglycolic acid -PLGA) wrapped around a core of liquid phototherapeutic oil. This encapsulation isolates unstable, highly volatile components from external atmospheric moisture and oxygen, providing sustained, controlled ingredient release (Fathi et al., 2018; Souto et al., 2020) [15] . [31,32] .

Synergistic model application

Hydrogel formulations

Hydrogels consist of three-dimensional, cross-linked hydrophilic polymer networks capable of swelling and holding large volumes of water. When nanocapsules or nanoemulsions are loaded into a secondary hydrogel base (forming a "nanogel" network), the formulation exhibits quasi-plastic rheological properties, maintaining a skincompatible pH and reducing trans-epidermal water loss (TEWL). In vivo histopathology confirms that these hydrogels decrease UV-induced epidermal hyperplasia and structural matrix damage, proving highly effective for target-specific photoaging treatments (Khurana et al., 2023; Wang et al., 2025) [31,32,65] . [62] .  Oxidation Vulnerability: Due to its molecular structure containing three conjugated double bonds, punicic acid is highly sensitive to autoxidation when exposed to atmospheric oxygen, ambient light, or high thermal ranges. Lipid peroxidation can lead to rancidity, the generation of irritating aldehydes, a dramatic loss of anti-aging efficacy, and formula discoloration (Melo et al., 2014; Almoraie et al., 2025) [5,38] [19] .  Standardization Deficits: Establishing uniform international quality control guidelines remains difficult. Regulatory challenges persist in standardizing the minimum therapeutic concentrations of punicic acid, limiting pesticide residues, and establishing standard biomarker thresholds across diverse international suppliers (Sagar et al., 2022; Burlando et al., 2024) [9] .

Challenges and limitations

Future perspectives

The future evolution of PSO-driven dermatological applications will focus on three key integration domains (Souto et al., 2020; Wang et al., 2025) [58,65]  Advanced nanotechnology-based delivery systems: Future formulations will increasingly utilize structured lipid nanocarriers (SLNs), nanostructured lipid carriers (NLCs), and ethosomes. These nanocarriers can carry both lipophilic molecules (like punicic acid) and hydrophilic botanical actives simultaneously, protecting active ingredients from chemical breakdown and allowing deeper dermal penetration (Gupta et al., 2019; Khurana et al., 2023) [21,31,32] .  Rigorous clinical evaluation protocols: Pre-clinical testing must transition toward extensive, multi-centered, double-blind, placebo-controlled human clinical trials. Studies should utilize advanced, non-invasive bioengineering techniques such as high-frequency ultrasound and optical coherence tomography to quantitatively validate long-term safety, cellular toxicity profiles, and in-depth wrinkle reduction metrics over extended application periods (Burlando et al., 2024; Hussen et al., 2025) [9,24] .  Integration with personalized skincare platforms:

The integration of digital diagnostic technology allows anti-aging products to be adapted to individual needs. Future cosmetic platforms can match specific consumer biomarkers such as genetic variations in collagen synthesis or sebum production with customized ratios of PSO nanocapsules, maximizing therapeutic efficacy while minimizing individual dermal reactivity (Wang et al., 2025) [65] .

Conclusion

Punica granatum seed oil stands as a premier botanical active for advanced anti-aging formulations. Its high content of punicic acid, combined with protective tocopherols and structural phytoestrogens, effectively targets the cellular mechanisms of skin aging by neutralizing free radicals, reducing chronic inflammation, and preserving dermal collagen integrity. When formulated into an optimized oilin-water emulsion or advanced nanostructured delivery systems, it provides stable physicochemical properties, excellent spreadability, and a safe biocompatibility profile. Integrating cold-pressed PSO into modern cosmetic systems offers a scientifically validated, sustainable pathway for the development of high-performance, natural anti-aging therapies.

Acknowledgement

AcknowledgementThe authors are sincerely grateful to the Principal and faculty members of Womens College of Pharmacy, Peth-Vadgaon, Kolhapur, for providing continuous academic guidance, facilities, and support during the preparation of this review article. The authors also acknowledge the valuable scientific literature and research contributions of various researchers and organizations that supported the development of this manuscript.

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