INTRODUCTION:

Out of different types dosage form which are administered to body, oral route is the most preferred choice of drug administration. Dosage form in tablets and capsules, though widely used, but sometimes this form has certain limitations when it is administered to children who faces lot of difficulty in swallowing, so we may choose semisolid products over solid forms for administration of drugs. Similarly, topical semisolid formulations are important class of drug delivery systems and their use in therapy is becoming more widespread. However, dermal application of drugs is not easy because of the impermeable nature of the skin. So the main challenge is to permeation the drug through the skin by translocation of the drug molecule across the stratum corneum layer of skin, the outermost layer.

The semisolid preparations more particularly Gel-based semisolid products which having both solid and liquid components in its structures¹ also known as organogels or oleogels are formulated as a way of structuring of liquid oils in various fields including pharmaceutical or cosmetics industry, for drug delivery that can make it easier to consume a variety of medicines^2.

Oleogels are semisolid non-crystalline, thermo-reversible viscoelastic systems which consist of a lipophilic liquid phase (mineral or vegetable oils, isopropyl myristate) gelled with suitable gelling agent referred as organogelators which can improve drug penetration through the stratum corneum because of their lipophilic nature^3-5 ^.

Based on polarity of liquid components, gel-based pharmaceutical products are classified as hydrogels, emulgels, and organogels or oleogels. In Hydrogels system water is the dispersion medium which then gelled with a hydrophilic gelling agent, but oleogels or organogels have non-polar dispersion medium like fixed oil, and mineral oil, organic solvents, etc which are gelled with an agent named as organogelators.

In oleogels, the polar phase gets trapped inside the three-dimensional networked structure present in oleogels systems. Due to their resistant to moisture and absence of stabilizers or preservatives in this system, they are preferred choice for drug delivery systems over conventional gels. Due to good organoleptic properties, satisfactory extrudability and spread ability, high flexibility, high thermal stability, they are more preferred for topical application to spread evenly as a film over the surface of the skin for drug release^6-11. So due to easy method of preparation and inherent long-term stability, use of oleogels based drug delivery products is increasing in pharmaceutical fields.

Components of an Oleogel System:

Generally an oleogels system has two important parts. One component is organic solvent and the other component is called oleogelators, which immobilises the organic solvent. Oleogels are oil-structured a three-dimensional (3D) network of crystalline particles systems developed by either by heat, shear or by cooling of the hydrophobic system. These systems are self-assembled fibres, or polymers which encapsulate the liquid oil^12,13. Oleogels have more advantages in comparison to conventional semi-solids and improves consumer satisfaction^14,15. Studies have been undergoing to use oleogels for the oral delivery of lipophilic compounds, which may be due to their stability at high temperatures for prolonged durations^16-19. This system mainly contain two important components which are discussed below.

i) Oils:

The gel property and up take of droplets of lipid molecules in the gastro-intestinal phase in an oleogels system is due to the presence of oil phase. Mainly, the chemical structure of oil i.e. number of unsaturated fatty acids and chain length of fatty acids predict the gelation reaction of oleogels. Gels with higher firmness are observed due to long carbon chains. In addition to that, sometimes increased hydrophobicity of oil is also due to the higher degree of unsaturation in the oil phase, which forms a more crooked spatial arrangement. The increased hydrophobicity property enhances the solubilisation of non-polar structurants by producing stronger gels which is due to the formation of large number of junctions in this type of system^20-22.

ii) Oleogelators: They are of two types

Low molecular weight oleogelators:

This type of oleogelators have self-assembling properties having a stable crystal network. The main driving force for this is the physical interactions is either Vander Waals or hydrophobic and hydrogen bonding forces. The important examples of low molecular weight oleogelators are class of waxes and phytosterols like mono-acylglycerol, 𝛽-Sitosterol/ 𝛾-oryzanol , fatty acids and fatty alcohols^23,24 lecithin/ tocopherol²⁵, lecithin/ phytosterols²⁶ and waxes/ monoacylglycerols, whose properties are discussed below

1. Waxes and shellac:

These Low molecular weight oleogelators form a 3D network by entangling oil within their pores and by adsorbing oil onto the surface of the network^27,28 . This type of oleogel is formulated by heating of wax in liquid oil above its melting point followed by subsequent cooling to 27°C under shear or quiescent conditions. The gelation property depends on the oil quality and also has an effect on the behaviour of gelation. Due to easy availabilty this type of oleogelators is more used in foods based producs. Their thermo-reversible nature ocuurs by fabricating water in oil type structured emulsion^29,30. Rice bran waxes, candelilla wax, carnauba wax and sunflower waxes are examples of waxes which are used in edible oleogels of this category³¹.

2. Phytosterols based oleogels:

Phytosterols based oleogels are 𝛽- Sitosterol and 𝛾-oryzanol . The phytosterols 𝛽- Sitosterol contain a steroid skeleton, to which hydroxyl group is attached to the 3rd carbon of A ring. Similarly an aliphatic side chain is attached to the 17th carbon of D ring³². 𝛾-oryzanol contain mixture of ferulic acid esters of phytosterols like campesteryl ferulate, 24-methylenecycloartanyl ferulate , cycloartanyl ferulate and triterpene alcohols³³ . The ratio of 𝛽-Sitosterol and 𝛾-oryzanol along with vegetable oils determines the oil absorbing capacity of prepared oleogels³⁴. Some literature review suggests addition of mono glyceride which acts as an emulsifier predicts the crystallisation behaviour of the phytosterol based oleogel³⁵.

High molecular weight oleogelators:

These oleogels are made up of with high molecular weight structurants like proteins and polysaccharides and can encapsulate oil by forming a 3D network via hydrogen bonding. The viscoelastic properties of this type of oleogelators mainly influenced by polymers molecular weight, conformation and concentration. Different examples of this category are,

1. Polysaccharide based oleogels:

Polysaccharides based oleogels are largely used in pharmaceutical field. The important class of polysaccharide based oleogels is Ethyl cellulose, due to its hydrophobic property it forms gel in liquid oils^36,37. By heating Ethyl cellulose above its glass transition temperature i.e. at 130°C followed by subsequent cooling, it form a rigid three-dimensional entangled network that helps in entrapment of oil³⁸. There are number of factors affects mechanical properties of Ethyl Cellulose oleogels like molecular weight, the influence of polymer concentration, cooling rate of gel, surfactant type and polymer to surfactant ratio etc. So the addition of surfactants results in increase in molecular weight of polymer which enhances gel hardness and gel point temperature forming more elastic gels^39,40.

2. Protein based oleogels:

The hydrophilic nature of Proteins makes it unsuitable to formulate oleogels. But scientists by using solvent exchange method and emulsion template method are able to produce Protein based oleogels. In the solvent exchange procedure solvents like acetone or tetrahydrofuran (THF) is used. Similarly for formulating oleogels in emulsion template method a novel technique called high internal phase pickering emulsions (HIPE’s) is used. In this technique by using protein as an emulsifier an emulsion is first prepared followed by stripping off water phase. Here the proteins like b-lactoglubulin ,soy protein and gelatine used to formulate oleogels^41,42,43 .

Modified Oleogels:

Oleogels, due to their better stability and suitable property to use in various pharmaceutical products, scientists are trying to modify their properties by preparing ideal oleogels to use in various range of food products. By using novel techniques called High- intensity ultrasound technique which helps in determining Crystallisation behaviour of an oleogelators that helps in resulting better oleogels property in terms of rheological, textural, and thermal properties⁴⁴.

Formulation of Oleogels:

Oleogels can be formulated via following gelation mechanisms.

1. Fatty acid crystallisation

2. Polymeric networks

3. Self-assembled fibrillar networks

Fatty acid crystallisation:

In fatty acid crystallisation method for oleogel formulations, long hydrocarbon chain oleogelators like natural waxes, fatty acids, fatty alcohols, phytosterols, sorbitan esters monoacylglycerols, diacylglycerols, and phosphor lipids are used. These hydrocarbon chains oleogelators by reaching at a concentration of particular range starts to develop crystallite conformations which retain oil and promote solid structuring upon cooling. The waxes due to their low polarity, longer chain length and high melting point induces oleogelation at a low concentration that leads to formation of needle shaped crystals network into which oil gets entrapped leading to oleogelation^45. However, sunflower wax, bees wax and mineral wax⁴⁶developed plate like crystal structure instead of needle like structure⁴⁷.

Polymeric networks:

Oleogels are formulated using polymer networks. In this method of formulation of oleogels, food grade polymers like hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, chitosan and chitin, zein, 𝛽-lactoglobulins, gelatine, ethylene-vinyl acetate copolymer etc., used as oleogelators to engulf oil phase to form oleogels.

Self-assembled fibrillar networks:

In this method for oleogels formulation fibrillar network is induc by edself assembled fibrillar networks oleogelation in non-polar solvents via non-covalent interactions like H- bonding, 𝜋-𝜋 stacking, electrostatic and vander waals interactions forming a three-dimensional network which then entraps the oil⁴⁸. During this method of formulation of oleogels, different environmental factors like storage temperature and cooling rate determines the shape,hardness and compactness of oleogels formed⁴⁹.

Pharmaceutical Applications of Oleogels:

Oleogels have wide range of application in various fields as shown in Figure 1.

Bioactive delivery:

The oleogels system not only helps in controlling drug release but, they have also targeted drug release of lipid soluble nutraceutical like carotene, lycopene, co-enzyme Q10, docosahexaenoic acid, eicosapentaenoic acid, tannins, etc. by imparting different health benefits in humans like by decreasing platelet aggregation, blood viscosity, and fibrinogen, antioxidant properties, and by lowering the incidences of chronic disease like Cardio Vascular Diseases and cancers⁵⁰. By encapsulating this bioactive lipid soluble compound in oleogels, it increases their solubility in the gut and helps in controlling release of drugs. Along with the above lipids compounds, various carbohydrates like (modified and hydrolysed starches), cellulose derivatives, proteins (whey proteins, caseinates, and gelatine), gums (exudates, extracts, etc.) are also used in oleogels.

Topical Applications:

In order to reduce the side effects associated with the oral route of drug delivery, topical formulations are the preferred mode of drug delivery which enhances permeability of drug⁵¹. So oleogels formulations help in penetration of drugs like nitroglycerine, scopolamine, nicotine, clonidine, fentanyl, estradiol, testosterone, lidocaine, and oxybutinin, and hence have been investigated successfully as dermal pharmaceuticals⁵². Scientists are formulating aceclofenac topical transdermal drug delivery oleogels system by avoiding severe gastric irritation caused due to oral administration of aceclofenac^53,54.

Oleogels in cosmetics:

Today’s cosmetics formulations are mainly emulsion-based products containing water and oil. Due to the presence of oils, oleogels cosmetic pharmaceutical formulations make dry and cracked foot skin soft and smooth. The oleogels formulations are also recommended for the supportive care of diabetic skin, perianal skin disorders, and also used as sun protection products protecting skin from harmful rays of sunlight ^55,56.

Nutraceutical applications:

A nutraceutical is a pharmaceutical alternative which has physiological benefits. Nowadays, scientists are modifying the physical properties of oils to resemble those of fats and by incorporating specific molecules (polymers, amphiphiles, and waxes) into the oils to form oleogels. For example, Ethylcellulose is showing great potential to bind oil at levels of 10% and under, forming oleogels of widely varying properties used as bases for topical application.

Figure 1. Dıfferent Roles of Oleogel System

CONCLUSIONS:

Since from last decades the field of oleogels has grown extensively either in food products or use in pharmaceuticals fields and applicability in drug delivery system. Over recent years, number of oleogels formulations is available in the market as solid, liquid, and semisolid dosage forms. Different topical formulations like Ointments or creams or gels shows various problems related to physical and microbial stability. So the current literature reviews suggests that oleogel is a promising base for various drugs to design topical formulations showing its resistance to microbiological activity and also have better physical and chemical stability as compared to conventional topical bases formulations. Role of oleogels in various pharmaceutical fields like topical formulations, bioactive delivery, bakery products, indicates its applicability in larger commercial scale suggests, it is one of the best drug delivery system in future.

ACKNOWLEDGEMENTS:

The authors are also thankful to the Principal and Management of Royal College of Pharmacy and Health Sciences, Berhampur for providing us with the facility for writing this paper.

CONFLICT OF INTEREST:

No conflict of interest was declared by the authors.

REFERENCES:

1. Loos MD, Feringa BL,VanEsch JH. Design and application of self-assembled low molecular weight hydrogels. Eur J Org Chem. 2005; 17: 3615-31.

2. Biswas RG, Mishra S, Sufian A. Gel Based Formulations in Oral Controlled Release Drug Delivery. Research Journal of Pharmacy and Technology. 2022; 15(5): 2357-3. doi: 10.52711/0974-360X.2022.00392

3. Rehman K, Zulfakar MH. Recent advances in gel technologies for topical and transdermal drug delivery.Drug Dev. Ind. Pharm. 2014; 40(4): 433-440.

4. Murdan S. Organogels in drug delivery. Expert Opin Drug Deliv. 2005; 2: 489- 505.

5. VanEsch JH., Feringa BL. New functional materials based on self assembling organogels: From serendipity towards design. Angew Chem Int Ed Engl. 2000; 39: 2263-6.

6. Murdan S, VanDer BB, Gregoriadi G., Florence AT.. Water-insorbitan monostearate organogels. J Pharm Sci .1999; 88:615-9.

7. Jose J, Gopalan K. Organogels: A Versatile Drug Delivery Tool in Pharmaceuticals. Research J. Pharm. and Tech. 2018; 11(3): 1242-1246. doi: 10.5958/0974-360X.2018.00231.7

8. Vintiloiu A, Leroux JC. Organogels and their use in drug delivery-A review. J Control Release. 2008 ;125:179-92.

9. Hughes NE. Potential food applications of edible oil organogels. Trends Food Sci Tech. 2009; 20: 470-80.

10. Nigar KM, Sangramsinh LG., Veerendra CY. Organogel: factors and its importance. Int J Bio Chem Sci. 2014; 4: 758-73.

11. Rehman K, Zulfakar MH. Recent advances in gel technologies for topical and transdermal drug delivery. Drug Dev Indian Pharm. 2014; 40: 433–40.

12. Marangoni AG. Organogels: An alternative edible oil-structuring method. J. Am. Oil Chem. Soc.2012; 89: 749–780 .

13. Stortz TA, Marangoni AG. Heat resistant chocolate. Trends Food Sci. Technol. 2011; 22: 201–214.

14. Patel AR, Cludts N, BinSintang MD., Lesaffer AK. Dewettinck K. Edible oleogels based on water soluble food polymers: Preparation, characterization and potential application. Food Funct. 2014; 5: 2833–2841 .

15. Colla K, Costanzo A, Gamlath S. Fat replacers in baked food products. Foods. 2018; 7(12): 192.

16. Iwanaga K, Sumizawa T, Miyazaki M, Kakemi M. Characterization of organogel as a novel oral controlled release formulation for lipophilic compounds. Int. J. Pharm. 2010; 388, 123–128 .

17. Lupi FR.,Gabriele D, Baldino N, Mijovic P,Parisi OI,Puoci F.Olive oil/policosanol organogels for nutraceutical and drug delivery purposes. Food Funct. 2013; 4: 1512–1520.

18. O’Sullivan CM., Davidovich-Pinhas M, Wright AJ., Barbut S., Marangoni AG. Ethylcellulose oleogels for lipophilic bioactive delivery—Effect of oleogelation on in vitro bioaccessibility and stability of beta-carotene. Food Funct. 2017; 8: 1438–1451.

19. O’Sullivan CM., Barbut S, Marangoni AG. Edible oleogels for the oral delivery of lipid soluble molecules: Composition and structural design considerations. Trends Food Sci. Technol. 2016; 57: 59–73.

20. Valoppi F, Calligaris S, Barba L, Š egatin N, Poklar Ulrih N, Nicoli MC. Influence of oil type on formation, structure, thermal, and physical properties of monoglyceride based organogel. European Journal of Lipid Science and Technology. 2017; 119 (2): 1–10.

21. Shaziya Manzoor S ,Masoodi FA , Naqash F, Rashid R. Oleogels: Promising alternatives to solid fats for food applications. Food Hydrocolloids for Health. 2022; 2: 100058

22. Zetzl AK, Gravelle AJ, Kurylowicz M, Dutcher J, Barbut S,Marangoni AG. Microstructure of ethylcellulose oleogels and its relationship to mechanical properties. Food Structure. 2014; 2 (1–2): 27–40

23. Gandolfo FG, Bot A,Flöter E. Structuring of edible oils by long-chain fa, fatty alcohols, and their mixtures. JAOCS, Journal of the American Oil Chemists’ Society. 2004; 81 (1): 1–6.

24. Schaink HM, van Malssen KF, Morgado-Alves S, Kalnin D, van der Linden E Crystal network for edible oil organogels: Possibilities and limitations of the fatty acid and fatty alcohol systems. Food Research International. 2007; 40 (9): 1185–1193.

25. Nikiforidis CV,Scholten E. Self-assemblies of lecithin and 𝛼-tocopherol as gelators of lipid material. RSC Advances. 2014; 4 (5): 2466–2473.

26. Okuro P K,Malfatti-gasperini AA., Vicente AA., Cunha RL. Lecithin and phytosterols-based mixtures as hybrid structuring agents in different organic phases. Food Research International. 2018; 111: 168–177.

27. da Silva TLT, Arellano DB, Martini S. Physical properties of Candelilla wax, monoacylglycerols, and fully hydrogenated oil oleogels. JAOCS, Journal of the American Oil Chemists’ Society. 2018; 95 (7): 797–811.

28. Toro-Vazquez JF, Morales-Rueda JA., Dibildox-Alvarado E.,Charó-Alonso,M, Alonzo-Macias M, González-Chávez M M. Thermal and textural properties of organogels developed by candelilla wax in safflower oil. Journal of the American Oil Chemists’ Society. 2007; 84 (11): 989–1000.

29. Blake AI, Co ED, Marangoni A G. Structure and physical properties of plant wax crystal networks and their relationship to oil binding capacity. Journal of the American Oil Chemists’ Society. 2014; 91 (6): 885–903.

30. Patel AR, Schatteman D, De Vos WH., Lesaffer A., Dewettinck K. Preparation and rheological characterization of shellac oleogels and oleogel- based emulsions. Journal of Colloid and Interface Science. 2013; 411 : 114–121.

31. Hwang HS,Singh M, Bakota E L,Winkler-Moser JK,Kim S,Liu S X. Margarine from organogels of plant wax and soybean oil. Journal of the American Oil Chemists’ Society. 2013; 90(11): 1705–1712.

32. Bot A,Gilbert E ,Bouwman W G,Sawalha H, Den Adel R, Garamus VM et al. Elucidation of density profile of self-assembled sitosterol oryzanol tubules with small-angle neutron scattering. Faraday Discussions. 2012; 158 : 223–238.

33. Bitencourt RG, Filho WAR, Paula JT, Garmus TT, Cabral F A. Solubility of 𝛾-oryzanol in supercritical carbon dioxide and extraction from rice bran. Journal of Supercritical Fluids. 2016; 107, 196–200.

34. Alhasawi FM.,Rogers MA.Ternary phase diagram of 𝛽-Sitosterol- 𝛾-oryzanol- canola oil. Journal of the American Oil Chemists’ Society. 2013; 90 (10): 1533–1540.

35. Doan CD,Tavernier I,Sintang MDB,Danthine S,Van de Walle D,Rimaux T and Dewettinck K. Crystallization and Gelation Behavior of Low-and High Melting Waxes in Rice Bran Oil: a Case-Study on Berry Wax and Sunflower Wax. Food Biophysics. 2017; 12(1): 97-108.

36. Davidovich P, Gravelle A J,Barbut S, Marangoni A G.Temperature effects on the gelation of ethylcellulose oleogels. Food Hydrocolloids. 2015; 46 : 76–83.

37. Zetzl AK, Marangoni A G,Barbut S. Mechanical properties of ethylcellulose oleogels and their potential for saturated fat reduction in frankfurters. Food and Function. 2012; 3 (3): 327–337.

38. Gravelle AJ,Barbut S,Quinton M, Marangoni A G. Towards the development of a predictive model of the formulation-dependent mechanical behaviour of edible oil-based ethylcellulose oleogels. Journal of Food Engineering. 2014; 143 : 114–122.

39. Winter H H,Chambon F. Analysis of linear viscoelasticity of a crosslinking polymer at the gel point. Journal of Rheology. 1986; 30(2): 367–382.

40. Gravelle AJ,Davidovich-Pinhas M,Zetzl A K,Barbut S,Marangoni AG. Influence of solvent quality on the mechanical strength of ethylcellulose oleogels. Carbohydrate Polymers. 2016; 135: 169–179.

41. Mezzenga R. Protein-template oil gels and powders. Edible oleogels. Elsevier Inc. 2018.

42. Tavernier I,Patel AR,Meeren P,Van Der, Dewettinck K. AC SC. Food Hydrocolloids . 2016.

43. Patel AR,Rajarethinem P S,Cludts N,Lewille B,De Vos W H,Lesaffer A et al. Biopolymer-based structuring of liquid oil into soft solids and oleogels using water-continuous emulsions as templates. Langmuir : The ACS Journal of Surfaces and Colloids. 2015; 31(7), 2065–2073.

44. Giacomozzi AS,Carrín M E, Palla CA. Muffins elaborated with optimized monoglycerides oleogels: from solid fat replacer obtention to product quality evaluation. Journal of Food Science. 2018; 83(6): 1505–1515.

45. Mukkamala R, Weiss RG. Physical gelation of organic fluids by anthraquinone-steroid-based molecules. Structural features influencing the proper- ties of gels. Langmuir : The ACS Journal of Surfaces and Colloids.1996; 12 (6):1474–1482.

46. Miyazaki Y,Marangoni AG. Structural-mechanical model of wax crystal networks-a meso scale cellular solid approach. Materials Research Express. 2014; 1 (2).

47. Martins A J, Cerqueira MA,Fasolin LH,Cunha RL,Vicente AA. Beeswax organogels: Influence of gelator concentration and oil type in the gelation process. Food Research International. 2016; 84: 170–179.

48. Okesola BO,Vieira VMP,Cornwell DJ,Whitelaw N K,Smith DK. 1,3:2,4-dibenzylidene-d-sorbitol (DBS) and its derivatives-efficient, versatile and industrially-relevant low-molecular-weight gelators with over 100 years of history and a bright future. Soft Matter. 2015; 11(24): 4768–4787.

49. Lam R, Quaroni L, Pedersen T,Rogers M A. A molecular insight into the nature of crystallographic mismatches in self-assembled fibrillar networks under non- isothermal crystallization conditions. Soft Matter. 2010; 6(2): 404–408.

50. Osullivan CM, Davidovich-Pinhas M,Wright AJ,Barbut S,Marangoni AG. Ethylcellulose oleogels for lipophilic bioactive delivery- effect of oleogelation on: In vitro bio accessibility and stability of beta-carotene. Food and Function. 2017; 8(4): 1438–1451.

51. Prausnitz MR,Mitragotri S and Langer R.Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov. 2004; 3: 115-24.

52. Kumar ,Katare OP.Lecithin organogels as a potential phosphor lipid structured system for topical drug delivery: A review. AAPS Pharm Sci Tech. 2005; 6: E298-310.

53. Tessari L,Ceciliani L,Belluati A,Letizia G,Martorana U,Pagliara, L. Aceclofenac cream versus piroxicam cream in the treatment of patients with minor traumas and phlogistic affections of soft tissues: A double blind study. Curr Ther Res. 1995; 56:702-12.

54. Priya P. Munshi, D.S. Mohale, R. Akkalwar, A.V. Chandewar. Formulation and Evaluation of Diclofenac gel. Research J. Pharm. and Tech. 2011; 4(9): 1394-1399.

55. Sanchez R,Stringari GB,Franco JM,Valencia C,Gallegos C. Therma l and mechanical characterization of cellulosic derivatives-based oleogels potentially applicable as bio-lubricating greases: Influence of ethyl cellulose molecular weight. Carbohydr Polym. 2011; 83: 151-8.

56. Sanchez R, Franco JM, Delgado MA, Valencia C, Gallegos C. Rheological and mechanical properties of oleogels based on castor oil and cellulosic derivatives potentially applicable as bio-lubricating greases: Influence of cellulosic derivatives concentration ratio. Ind Eng Chem. 2011; 17: 705-11.

Received on 11.08.2022 Modified on 17.12.2022

Research J. Pharm. and Tech 2023; 16(12):6095-6099.

DOI: 10.52711/0974-360X.2023.00989