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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 15  |  Issue : 3  |  Page : 113-121

Bigels: A newer system – An opportunity for topical application


Pharmacy, Sigma Institute of Pharmacy, Vadodara, Gujarat, India

Date of Submission15-Apr-2022
Date of Decision07-Jun-2022
Date of Acceptance09-Jun-2022
Date of Web Publication21-Sep-2022

Correspondence Address:
Jigar Vyas
Sigma Institute of Pharmacy, Ajwa-Nimeta Road, Vadodara - 390 019, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/hmj.hmj_33_22

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  Abstract 


Introduction: A gel is a solid or semisolid system composed of at least two parts, namely a condensed mass containing and interpenetrating a liquid. Hydrogel, emulgel and organogel are novel gel systems that are widely known but have some drawbacks. For example, hydrogel delivers hydrophilic but not poorly water-soluble drugs and has a lower ability to penetrate the stratum corneum, organogel has a greasy nature that causes stickiness and difficulty in removal and emulgel has different mechanical phases that cause instability. This impediment can be solved by using a unique and innovative formulation termed bigels. Method: The aqueous phase is typically made by a hydrophilic polymer, while the organic phase is comprised of gelled vegetable oil due to the presence of an organogelator. For the bigel manufacturing process, the percentage of the respective gelling agent in each phase, the organogel/hydrogel ratio, as well as the mixing temperature and speed, should be considered. The presence of desirable characteristics in both hydrogels and organogels increases patient compliance as well as the loading capacity of both lipophilic and hydrophilic drugs. Result: The substantial focus of this descriptive review is to look at the possible correlations (i.e. cross-linked polymer structures) among various parts of hybrid systems (i.e. bigels or multi-component organogels). Bigels are systems formed by combining a hydrogel with an organogel. Discussion: So far, researchers have mostly investigated bigel systems for regulated drug administration in topical applications. These bigels are investigated in research, yet to find popularity in the market.

Keywords: Bigel, hydrogel, hydrophilic, hydrophobic, organogel


How to cite this article:
Raytthatha N, Vyas J, Shah I, Upadhyay U. Bigels: A newer system – An opportunity for topical application. Hamdan Med J 2022;15:113-21

How to cite this URL:
Raytthatha N, Vyas J, Shah I, Upadhyay U. Bigels: A newer system – An opportunity for topical application. Hamdan Med J [serial online] 2022 [cited 2022 Oct 7];15:113-21. Available from: http://www.hamdanjournal.org/text.asp?2022/15/3/113/356432




  Introduction Top


Gels are semisolid compounds composed of two components: a liquid component (which can be polar or apolar) that acts as a solvent and a solid component (usually referred to as a gelator) that acts as a gelling agent.[1] The gelator is usually utilised at concentrations <15% w/v and raises surface tension, inhibiting solvent flow. To achieve semisolid properties, a gelling agent entangles the solvent phase by generating a three-dimensional (3D) network structure.[2] Gels are classed as hydrogels, organogels or emulgels based on their novel approach.[2]

Hydrogels are 3D networks of physically or chemically attached polymeric matrices that trap liquid (water) via intermolecular space. Hydrogels are hydrophilic gels using water as the dispersion medium.[3] Hydrogels have several benefits as pharmaceutical forms for topical use, including ease of manufacture, non-oily appearance, excellent spreadability, the ability to promote skin barrier moisture, cooling effect and quick removal following application since they can be easily washed. All of this contributes to a significant level of patient compliance. All examples are listed in [Table 1]. However, they may transport hydrophilic but not hydrophobic drugs and have a reduced capacity to permeate the epidermal barrier. Organogels are also convenient to manufacture, and their lipophilic nature enables them to dissolve hydrophobic drugs and enhance their penetration through the skin barrier. The major downside of organogels is their oily composition, which makes removal from the skin following application difficult due to adhering and to greasy remains, resulting in decreased patient accordance.[3],[4],[5]
Table 1: Hydrogel, organogel and emulgel examples and their study outcomes

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Emulsion gels, also known as emulgels developed to address the shortcomings of hydrogels with respect to drug release. These are biphasic systems with a gelled continuous component that generally consist of a water-soluble component and a lipid-soluble component that act as an emulsion. Emulgels combine the features of emulsions with gels. They can be emulsion hydrogels or emulsion organogels.[6] Emulgels have minimal structural stability due to the varying structural properties of its two phases, resulting in formations that are structured in both phases.

The discrepancy in the mechanical properties of the two components in emulgels adds to the challenge of poorer stability in this kind of system over a long period prompting researchers to seek alternate systems with superior qualities. This barrier can be overcome by structuring a novel and intriguing formulation known as bigels.


  Bigels Top


Bigels are homogeneous semisolid dispersion complexes, wherein 2 gel components are blended with significant shear speed and appear optically as a single-phase gel. Each bigel's two gels are prepared separately using a different gelator. The principal resemblance amongst bigels and other multicomponent systems such as emulgel and emulsions is that bigels are structured or gelled as both phases.[14] Bigels have intriguing characteristics in both of their phases (lipid and aqueous phase), such as cooling and hydrating effect, administration of hydrophobic and hydrophilic drugs, and enhanced spreadability, enhanced therapeutic absorption through the skin, and water washability after application. Because of all these bigel properties, they are an excellent choice for a variety of applications, involving medicinal and dermatological systems.[15]

Types of bigel

Types of bigel include four types as shown in [Figure 1] with diagrammatic presentation in [Figure 2]
Figure 1: Types of bigels

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Figure 2: Diagrammatic presentation of types of bigel

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Organogel in hydrogel

These bigels are characterised as systems that have organogel as a dispersion medium and hydrogel as a continuous phase. Behera developed bigels by combining Span sunflower oil organogel with water-soluble synthetic polymer aqueous gels (plural/singular) (e.g. polyvinyl alcohol and polyvinyl pyrrolidone).[16] Singh et al. reported the development of oil-in-water (o/w) emulsion bigels by combining Carbopol 934 hydrogel with Sorbitan monostearate sesame oil oleogel.[17]

Hydrogel in organogel

These bigels are developed by distributing the hydrogel throughout the organo-gel system. Patel et al. developed bigels by combining a water soluble-fumed silica and sunflower oil-organo-gel with a weak water gel-based on polysaccharides (1% wt locust bean gum: carrageenan, 1:1 ratio). The bigel's morphology was confirmed using confocal microscopy (CM).[17]

Bicontinuous bigel

With the addition of surfactant having required hydrophilic-lipophilic balance value in the range of 6.5–7.5, where no phase is in dominance rather both phases are in a continuous phase. Singh et al. developed bicontinuous bigels with guar gum hydrogel and sesame oil-based organogel.[18]

Complex bigel

Organogel is modified to contain water to form oil in water or water in oil type of emulsion system when this system is mixed with hydrogel it forms complex bigel. This system behaves like multiple-phase emulsion. Lupi et al. described how to create a sophisticated matrix-in-matrix system. Microscopy verified the structural arrangement.[19]

Factors determining the type of bigels

Amount of phase added

The type of bigel depends on the amount of organogel and hydrogel in bigel if both phases are in equal proportion then the type of bigel will depend on surfactant.

Type and amount of surfactant added

This factor is one of the most important factors in determining the type of bigel form. The hydrophobic surfactant will form organogel as the external phase and the hydrophilic surfactant will form hydrogel as an external phase. Apart from this the surfactant's amount also plays a key role in making this system stable.

Rate of mixing and mixing time

The rate and duration of mixing will have a prominent effect in the preparation of stable bigel. A high or low rate of mixing may either lead to separation or non-formation of bigel phases.

Presence of electrolytes

If electrolytes are present in the bigel system, then it may lead to instability or phase inversion. The monovalent electrolyte may promote hydrogel (aqueous) as an external phase whereas multivalent may promote organogel (oil) as an external phase.

Formulation of bigels

The formulation includes hydrogel-forming polymers and organogel-forming oils.

Hydrogel forming polymers

Many hydrophilic polymers have been used in the manufacturing of hydrogels for the development of pharmaceutical bigels. The most commonly described in this literature include synthetic polymers (Carbopol), semisynthetic polymers (Hydroxy propyl methyl cellulose [HPMC]), and naturally obtained polymers (Alginates, Guar gum, Gelatin and Xanthan gum). Other polymers selected as hydrogelators in bigel include gum acacia, chitosan, sodium carboxymethylcellulose (Na. CMC), Poloxamer 407, Poly Vinyl Alcohol and sodium polyacrylate.

Carbopol

Carbopol resins contain hydrophilic compounds that are water-insoluble. When these polymers are dispersed in water, they swell and produce a colloidal, mucilage-like dispersal. They are dry powders having high bulk densities and acidic watery action structures (pH around 3.0). At higher pH levels, they thicken (at pH 5-6). They will also expand to 1000 times their remarkable volume in a fluid of that pH. They are pH-sensitive and exhibit mucoadhesion properties due to their capacity to form hydrogen bonds with mucin.[17] This is one of the most often used polymers in the preparation of bigels. In order for the gel to sufficiently develop, this polymer often requires the incorporation of triethanolamine as a neutralising agent. This polymer has predominantly been used in bigels for topical administration[20] and additionally for vaginal[18] and buccal[21] administrations. [Table 2] data obtained from Samala and Sridevi (2016).[22]
Table 2: Carbopol grades with viscosity and its properties

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Hydroxy propyl methyl cellulose

HPMC has good film-forming capabilities and is odourless, stable, flavourless, clear, oil-resistant, safe and edible.[23] The FDA, the EU and the Joint Expert Committee of Food Additives have all given HPMC GRAS (Generally recognised as safe) certification.[24]This polymer is classified into classes depending on the level of substitutions and molar mass, which are the criteria that influence the gelling ability. This bioadhesive polymer is used as a hydrogel formulating polymer in bigels for vaginal drug delivery of tenofovir[25] as well as topical drug delivery of imiquimod,[26] diltiazem hydrochloride[27] and flurbiprofen.[28]

Alginates

Alginate (mainly sodium alginates) is obtained naturally from seaweed, is an anionic polymer that has been widely researched and utilised for numerous biomedical applications because of its biocompatibility, low toxicity, low cost and moderate gelation caused by the addition of divalent cations like Ca2+. By cross-linking with di- or trivalent ions, alginates may create homogeneous, clear, water-insoluble and thermally irreversible gels at room temperature.[29] Alginate is a polymer that produces gels with pH-dependent swelling. It also exhibits mucoadhesive characteristics. Alginate hydrogels have also been used in the development of bigels for antioxidants,[30] and antifungal[31] pharmaceuticals, as well as oral delivery of metronidazole.[32]

Guar gum

It is non-ionic and hydro-colloidal in water. It is unaffected by ionic strengths or pH, but can degrades at high pH and temperatures (e.g. pH 3 at 50°C).[33] It is stable as in solution form throughout a pH range of 5-7. It is employed in bigels for topical administration of antimicrobial drugs[34] and vaginal drug delivery of tenofovir.[35]

Gelatin

Gelatin is translucent, colourless and flavourless, slightly yellow in colour substance derived from collagen. Gelatin is miscible in solvents such as hot water, glycerol and acetic acid, but not in solvents such as alcohol.[36] To produce a gel, it absorbs approximately in a solvent such as water, it swells to ten times its weight. The gelatin used for bigels that been extensively researched, with the antibacterial antibiotic ciprofloxacin serving as a model active component.[37]

Xanthan gum

It is a hydrophilic polymer that hydrates quickly and dissolves readily at ambient temperature. Constant stirring and mixing shorten the overall hydration period of xanthan. Long-chain xanthan polymer is faster to distribute yet takes longer to hydrate. The behaviour of xanthan solutions is unaffected by a broad pH range (3–10). It is said to be stable than other thickeners and to be unaffected to enzymes including amylases, proteolytic enzymes and cellulases.[38] Xanthan gum hydrogel is used for topical delivery of liranaftate,[39] vaginal delivery of ciclopirox olamine.[40]

Organogel phase forming oils

Vegetable oils are the most common organic gel base used in the production of bigels. According to Andonova et al., various fixed oils such as sunflower oil, sesame oil, pomegranate seed oil, olive oil and almond oil and fish oil have been used widely as available in the literature for preparing bigels. Amongst these, sesame oil, fish oil and olive oil are the most prevalent.

Olive fruit oil

The fruit of the olive grove is employed to extract olive oil (Olea europaea). Lupi et al. developed methoxyl pectin hydrogel and olive oil, glyceryl stearate organo-gel bigels for cosmetic purposes.[4] This bigel formulation preserves the advantages of oil-in-water (o/w) systems while maintaining physical integrity and stability. Oleic acid, the best fatty acid in olive oil, is utilised as an excipient in topical treatments to increase drug penetration via the skin. Another important component of this oil is oleocantal, which has analgesic and anti-inflammatory properties. It acquires anti-ageing, anti-fungal and anti-neoplastic characteristics and has been extensively researched for use in cosmetic and topical therapeutic bigels. It is also utilised as an organo-gel base in bigels for gastro-intestinal drug administration.[41]

Fish oil

Fish oil is increasingly being used in supplements, fortified foods and drug delivery, as opposed to industrial and feed uses. The majority of the long-chain omega-3 fatty acids are found in this oil including anchovy, sardines, cod liver oil and others. Anchovy and sardine oils are said to offer the greatest concentrations of EPA 18% and DHA 12%.[42] Fish oils, particularly liver oils, contain Vitamins A and D. Because of its anti-inflammatory properties and propensity to enhance dermis penetration, it is excellent for use in bigels for topical and transdermal formulations.[43]

Sesame seed oil

Sesame oil is a high-quality vegetable oil obtained from the seeds of the sesamum indicum plant.[44] Sesame seed oil frequently employed in pharmaceutical systems due to its antioxidants, anti-inflammatory, antiviral, antibacterial and antifungal characteristics. It includes emollients such as palmitic, linoleic, oleic and stearic acids, that assist to hydrate the skin and keep it smooth and supple. It also includes antioxidant Vitamins A, D, C, E and K. Black sesame oil is practically unique in that it includes nutrients that permeate all layers of the skin.[19] Bigels utilising sesame oil as the organogel base have indeed been developed for medication delivery via topical and vaginal routes.[45]

Sunflower seed oil

It is a non-volatile oil derived from seeds of helianthus annuus. Sunflower seed oil is triglycerides composed mostly of palmitic, stearic, oleic and linoleic acids. It is widely employed in the development of antimicrobial drug bigels and has advantages when delivered orally and topically.[46]

Pomegranate seed oil

Pomegranate is obtained from seeds of Punicagranatum L. and is widely grown in tropical and subtropical nations, including Iran, India and the United States. Pomegranate seeds have a high percentage of oil (60%–80%) that is high in 9-cis, 11-trans and 13-cis octadecatrienoic acid, also known as punicic acid. In addition, it is high in polyphenol, namely gallic acid and ellagic acid, phytosterols and tocopherols, primarily tocopherol.[47]

Almond oil

In terms of chemical characteristics, almond oil is a one-of-a-kind not toxic, not irritating, not sensitising and not comedogenic, water-insoluble, freely emulsifiable ester with the following unforeseen properties and attributes: enhanced solubiliser of lipid-soluble cosmetic raw resources, particularly sunscreen substances and significantly favourable spreading coefficient, anti-tack agent, particularly in antiperspirant formulations wetting agent and auxiliary gelling agents for water-insoluble powdered products sustainable to hydrolysis within a pH range of about 2–12. It is known to have several diverse qualities, including anti-inflammatory, immunity boosting and antihepatotoxicity benefits.[48] This organogel is explored for biomedical use such as cardiovascular disease prevention.[49] Andonova et al. developed bigels with almond oil as an organogel base.[50]

Preparation of bigels

Individually, the aqueous (hydrogel) and oleaginous (organogel) components are generated by stirring the components at a specific rate and temperature, and then, these phases are mixed to form the bigel. Refer [Figure 3] for preparation of bigels.
Figure 3: Preparation of bigels

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Formulating hydrogel phase

These are water dispersion systems developed by combining a hydrophilic polymer (gelling agent) in water (aqueous phase). The processing variables (for instance, rate and temp) is adjusted based on the gelation characteristics of the system.[28] The hydrogel can be formulated by chemical bonds or by hydrogen (physical gels) bonds. A chemically cross-linked gel is a cross-linked structure while physical gels are held by molecular interactions and/or secondary forces such as hydrophobic interactions. Physical interactions between distinct polymer chains inhibit disintegration in physically cross-linked gels.[51]

Formulating organogel phase

Organogels are formulated initially by accurately weighing the organogelators, which are then dissolved in a specific oil phase at a predetermined homogenisation condition and a temperature higher than the melting point of the organogelators. When the temp is lowered down to room temperature, gel formation occurs (25°C). The oil phase can be an organic solvent (e.g. benzene, hexane)/vegetable oils like castor oil[52] groundnut oil,[53] olive oil[54] and sesame oil.[55]

Preparation of bigel

Bigels are made by blending hydrogel and organogel at high shearing rates while keeping the characteristics of both components. By applying a certain shearing speed and temperature to the homogeneous mixture, a smooth gel is formed. When cooled down, the mixture either gels or separates into phases. The combination of both phases influences the development of a stable bigel. The tube inversion test is used to confirm gel formation.[19]

Evaluation of bigels

Physicochemical characteristics

The spreadability, viscosity colour, odour and appearance of the bigels were examined at various time intervals.

  • Viscosity: The rheological properties of bigel as a function of time were studied using a Brookfield viscometer.
  • Spreadability: The spreadability of the bigels was determined by placing 0.5 g of bigel inside a 1 cm diameter circle pre-marked on a glass plate. A comparable glass plate was placed on top of this glass plate. For 300 s, 1 kg mass was held on the upper glass plate. The augmented diameter formed by the bigel spreading was measured.[56] Spreadability was measured using the formula;




where,

S-Spreadability, g. cm/s

M-Weight put on the upper glass slide

D-diameter of spreading (cm)

T-Time for spreading gel in section (Approximately 300 s)

Stability studies

The bigel's stability is assessed using a long-term stability study and accelerated stability study.

Long-term stability study

  • Because the bigels are a mixture of 2 semisolid phases, their thermodynamic stability improves many times. The formulations are tested for pH, colour, homogeneity, uniformity, phase separation and physical appearance. During the long-term stability research, any other symptoms of instability are examined after each cycle of freeze-thaw thermos cycling and at preset intervals (0, 3, 6, 12, 18 and 24 months or up to 36 months depending on the active component contained in the bigel).[57]


Accelerated-stability studies

The stability studies were carried out for 3 months in compliance with ICH guidelines. The stability studies' purpose is to provide information on how the application programming interface varies over time as a consequence of environmental conditions such as humidity, temperature and light. The experiment was carried out at 25°C ± 2°C (60% RH) and 45°C ± 2°C.(75% RH) All of the prepared combinations were crimped into a collapsible metal tube. After that, the packed bigels are stored under the various temperature and environmental factors, following the experiment, the bigels were tested for percentage drug content, percentage drug release, viscosity and pH.[58]

Thermal properties

The drop-ball method with the EI melting point apparatus-931 was used to determine the thermal characteristics of the formed bigels. The temperature profiles of the bigels were examined using a differential scanning calorimeter (DSC). Bigels were accurately weighed and wrapped in pierced metal pans. The experiment was conducted in a nitrogen conditions at with a circulation rate of 40 ml/min, scanned at a rate of 5.0°C/min within a temp range of 25–150°C yielded the heating and cooling DSC characteristics.[1]

Microscopy

Various microscopy methods such as CM, cryo-scanning electron microscopy, transmission electron microscopy and phase-contrast microscopy are used to investigate the relative distribution of aqueous and organic phases within bigels.[20]

Electrical conductivity

To comprehend the conductivity profiles of the bigels, their electrical properties are measured. A computer controlled impedance analyser may be utilised to measure the electrical characteristics of the bigels. At room temperature, the information is obtained in a specified frequency range (e.g. 0.1 Hze1 MHz). The formulations' conductivity aids in determining their transport behaviour when subjected to current. It also aids in comprehending the bigel system's microstructural layout. Because of the protons available in the water phase, bigels with a larger proportion of hydrogel have better conductivity. Water in oil bigels exhibits insulative behaviour, whereas Oil in water bigels exhibit conductive behaviour, i.e., almost zero electrical conductivity.[20]

Fourier transform infrared spectroscopy

Fourier transform infrared spectroscopy (FTIR) is a spectroscopic method frequently used to determine molecular interactions between hydrogels and organogels. The FTIR spectrum of bigels has been shown to be affected by the polymer composition of the hydrogel as well as the fraction of bigels. This spectroscopic method has also been employed to study drug-bigel interactions or compliance.[7]

In vitro drug release

In vitro release studies are carried out on Franz's diffusion cell. The volume needed for dissolving, the pH of the dissolution fluid, the temperature and the stirring speed are all chosen accordingly. The analysis is conducted over a set period of time. The drug sample is collected at various time intervals, filtered through with a 0.45 mm millipore filter and analysed using a Ultraviolet-visible spectrophotometer or high-performance liquid chromatography. To match the drug release kinetics, many mathematical models for Bigels (zero-order, first-order, Higuchi and Korsmeyer-Peppas models) are utilised. Many variables influence drug release, comprising (but not limited to) initial water content, drug's content, electrostatic forces between drugs, lipid bilayers and swelling capacity.[59][60][61][62][63][64]

Application of bigel

Numerous bigel systems have been researched in recent years for a variety of purposes as listed in [Table 3]. These systems are often utilised as carriers for the regulated release of active ingredients in topical and transdermal applications. Various drugs can be effectively and efficiently delivered through bigels including antimicrobials, such as metronidazole, ciprofloxacin and moxifloxacin, antiretrovirals such as tenofovir and a combination of tenofovir and maraviroc, antifungals, such as ciclopirox olamine and terbinafine hydrochloride, drugs for acne treatment, such as isotretinoin, immune response modifiers, such as imiquimod, pain reliever drugs, such as paracetamol, anti-inflammatory drugs, such as ketoprofen, ibuprofen and diclofenac diethylamine calcium channel blockers, such as diltiazem hydrochloride and antioxidants, such as coenzyme naphthoquinones, Vitamin E and thymoquinone.
Table 3: Examples of bigels with their applications

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  Conclusion Top


These bigels are investigated in academic research, but commercial and marketable products have yet to be developed. Although the majority of drug-loaded bigels formulated are designed for topical drug delivery, various methods of delivery have previously been proposed. Buccal and vaginal bigels have emerged as viable alternatives, expanding the potential uses of these dosage forms as drug delivery systems.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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