Proniosome Gel : Potential Carrier System in Topical/Transdermal Delivery for Drugs and Cosmetics/Cosmeceuticals

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Abstract

Proniosomal gel is nonionic surfactant based vesicle system which exists in different liquid crystalline phases. Mixing of the surfactant in an alcohol and limited hydration with aqueous phase leads to the formation of proniosomal gel. Due to the limited amount of water present, these systems behave as viscous phases. The various phases of liquid crystalline structures can be utilized as such for topical/transdermal applications or can be used after further hydration to form niosomes. An introduction to the skin structure along with the conversion of proniosomal gel to niosomes is also explained. A review of literature is presented here and a sincere attempt has been made to highlight the properties and characteristics of proniosomes in drugs and cosmetic/cosmeceuticals applications. Interaction studies between proniosome components and skin is also discussed along with the formulation aspects of proniosome gel formulation. Many research papers reports the delivery of therapeutic agents through topical/dermal route, but cosmetic applications were not much explored. Our aim is to introduce and explore proniosome gel as a carrier system for various applications of drugs and cosmeceuticals.

Keywords: Niosomes, Proniosomes, Cosmeceuticals, Topical, Transdermal

Introduction:

The traditional colloidal systems like micro-spheres and emulsions appeared in 1950's, out of which emulsions has primarily used by the cosmetic industry in the topical/dermal delivery of cosmetic agents. In 1960's liposomes were discovered, and the introduction of liposomes in cosmetic market was in 1986 by company Dior [1]. And from a long time liposomes were considered as the main innovative contributors in the dermal area for both pharmaceutical and cosmetic products. Due to some drawbacks like high cost, variable purity of natural phospholipids and unstable nature, surfactant based vesicles 'Niosomes' came into existence.

Niosomes are microscopic lamellar structures, which are formed on the admixture of non-ionic surfactants with or without incorporation of cholesterol or other lipids [2]. Niosomes are widely studied as an alternative to liposomes. These vesicles appear to be similar to liposomes in terms of their physical properties. From a technical point of view, niosomes are promising drug carriers as they possess greater stability and lack of many disadvantages associate with liposomes. These vesicular delivery systems have attracted considerable attention in topical/transdermal drug delivery for many reasons. These penetration enhancers are biodegradable, non-toxic, amphiphilic in nature, and effective in the modulation of drug release properties. Their effectiveness is strongly dependent on their physiological properties, such as composition, size, charge, lamellarity and application conditions [3]. L'Oreal had brought the first cosmetic product called 'Niosomes' containing niosome vesicles into the market [4]. The product also had its successors like 'Niosome Plus' anti-ageing cream by Lancome, which reached the market in the early 1990's.

But the advancements in the delivery systems are necessary to produce the better characteristics and simplification of the formulation process. The advancement in the niosomes leads to the evolution of proniosomal delivery systems. Proniosomes are non-ionic based surfactant vesicles, which may be hydrated immediately before use to yield aqueous niosome dispersions [5, 6, 7]. Proniosomes are nowadays used to enhance drug delivery in addition to conventional niosomes. They are converted into niosomes respectively upon simple hydration or by the hydration of skin itself after application. Proniosomes exists in two forms, i.e. semisolid liquid crystal gel and dry granular powder, depending on their method of preparation [8]. Out of these two forms, the proniosome gel is mainly used for topical/transdermal applications.

The active ingredients present in the formulation of drugs and cosmetics/cosmeceuticals permeate through the intercellular lipid matrix, i.e. intercellular and transcellular. However, vesicular delivery systems use three pathways for permeation of drugs in the tissues and they are, a) hair follicle associated with sebaceous glands, b) through sweat glands and c) across the continuous stratum corneum (SC) layer [33, 34].

Introduction to the skin

A brief introduction of skin's structure and function is required for better understanding of features of drug and cosmetic preparations for topical / transdermal delivery. The skin is the largest human organ covering an area of about 2 sq. m. in an average human adult and consists of three functional layers: epidermis, dermis and subcutaneous as described in fig.1. It is also composed of blood vessels, nerve endings, appendages, fat and connective tissue. One major task of the skin is to protect the organism against the loss of endogenous substances and mechanical, chemical, microbial and physical influences. The outermost layer of the skin, the epidermis, provides the protective properties. Out of the five layers of the epidermis, it is mainly the uppermost stratum corneum (SC), which is responsible for the permeation barrier properties of the skin. The SC consists of the keratin-filled dead cells, the corneocyte, which are entirely surrounded by crystalline lamellar lipid region. The cell boundary, the cornified envelope, is a very densely cross-linked protein structure, which reduces absorption of drugs into the cells. The dermis contains a variable amount of fat, collagen and elastin fibres which provide strength and flexibility. Subcutaneous fat is the innermost layer of the skin structure, varies its thickness in different regions of the body. For these reasons most of the active substances applied onto the skin diffuse along the lipid lamellae in the intercellular region. It is now widely reported that skin is not only a protective membrane but is increasingly becoming popular as a portal for the administration of many drugs [9, 10, 11].

Proniosome Gel: An overview

Proniosomes are vesicular systems, in which the vesicles are made up of non-ionic based surfactants, cholesterol and other additives. Semisolid liquid crystal gel (proniosomes) prepared by dissolving the surfactant in a minimal amount of an acceptable solvent, namely ethanol and then hydration with least amount of water to form a gel. These structures are liquid crystalline compact niosomes hybrids that can be converted into niosomes immediately upon hydration [19, 20] or used as such in the topical/transdermal applications. Use of proniosome gel in topical/dermal delivery does not require hydration prior to application, but they can be applied as such or loaded on a base material of emulsion, gel, ointment, etc. prior to application. The base material helps in the application of the formulation to the skin and dilution of the active material. Proniosomes are nowadays used to enhance drug delivery in addition to conventional niosomes. They are becoming popular due to their semisolid/ liquid crystalline compact nature when compared to niosome dispersion.

Proniosomal gels are generally present in transparent, translucent or white semisolid gel texture, which makes them physically stable during storage and transport. Due to the limited solvent system present, the proniosomes formed were the mixture of many phases of liquid crystal, viz. lamellar, hexagonal and cubic phase liquid crystals as given in fig. 2. Dissolution of most surfactants in water, leads to the formation of lyotropic liquid crystals rather than micellar solution [39]. Lamellar phase shows sheets of surfactants arranged in bilayer form, whereas in hexagonal phase cylindrical units are packed in hexagonal fashion. Cubic phase consists of curved bio-continuous lipid bilayer extending in three dimensions, separating two congruent networks of water channels [40]. These liquid crystals present an attractive appearance because of their, transparency and high viscosity, although in the beginning of its formation, a short range of less viscous compositions (so called liquid/gel compositions) appear in some cases [41]. Addition of water leads to interaction between water and polar groups of the surfactant results in swelling of bilayers.

When the concentration of solvent is increased above a limited value, the bilayers tend to form random spherical structures, i.e., multilamellar, multivesicular structures. When shaken with water i.e. the aqueous phase of water, complete hydration takes place leading to the formation of niosomes. The beauty of these proniosomes lies in their ability to rearrange as stable noisomal suspensions, on hydration with water [6].

Interaction Between skin and vesicles

There is a direct contact of proniosome formulation with skin after applies, so it is better to discuss the potential interactions between skin and vesicles formed in proniosome/niosome formulations. As we know that proniosomes or proniosomes derived niosomes are composed of non-ionic surfactants, and the vesicles are composed of these non-ionic surfactant only. So it is advisable to study the interactions between non-ionic surfactants and the skin. The non ionic surfactants are amphipathic molecules consisting of a hydrophobic (alkylated phenol derivatives, fatty acids, long chain linear alcohols, etc.) and a hydrophilic part (usually ethylene oxide chains of variable length). Nonionic surfactants are used widely in pharmaceuticals to increase their stability, solubility and permeation [12]. There is a strong indication that the degree of interaction between vesicles and skin mainly depends on physicochemical properties of the surfactant molecules of which the niosomes or proniosomes are composed. Skin consists of a range of bioactive material like membrane phospholipids, proteins, amino acids, peptides, etc.

Vesicles prepared from cholesterol and polyoxyethylene alkyl ether surfactants were studied with isolated human stratum corneum incubated for 48 hours and for vesicle skin interactions. Fusion of liquid as well as gel state vesicles on the superficial layer of stratum corneum takes place, but liquid state vesicles induced perturbations in liquid organization, so water pool formation within the stratum corneum was observed [13]. Stacks of lamellae and irregular structures were formed on the skin with fusion and adsorption of vesicles onto the stratum corneum surface. These structures and interactions strongly depend on vesicle composition and physiological properties [14]. After a 12-hour pretreatment, permeation across span 60-treated skin was significantly higher than that across non-treated skin. Surfactant treated formulations were found to be superior to phospholipid treated and non-treated formulations in facilitating the permeation of enoxacin, as well as drug deposition into the skin. On the basis of results, two types of interaction were observed between vesicles and skin surface. First, interaction was the skin-formulation interface involving adsorption and fusion of vesicles of niosome or proniosomes on the stratum corneum surface, resulting in new structure formation. Secondly, vesicle-skin interactions found in the deeper layers of the stratum corneum, involve alteration of the bilayer ultra-structure [3, 15]. A fluorescence depolarization study indicated that alkanoyl-N-methylglucamide surfactants decrease the fluidity of dipalmitoyl phosphatidylcholine membranes [16]. Non-ionic surfactants decreased the phase transition temperature of negatively charged dilauroylphosphatidic acid membrane. The interaction between surfactant molecules incorporated in the lipid membrane was also observed [17].

Surfactants are known to increase the permeability of vesicles and phospholipid membranes, causing low molecular mass compounds to leak. The interaction between biological membranes and non-ionic surfactant tested for phospholipid composition and rate of biosynthesis of major phospholipid components indicate no significant change in the phospholipid composition, where as biosynthesis and turnover rates of phospholipids were increased two to four times. The available data suggests that the tested surfactant damaged the epidermis membranes [18]. Surfactant cause modification in physicochemical characteristics of natural membranes and can disrupt artificial membranes but also. Nonionic surfactants have the ability to increase the permeability of sarcoplasmic reticulum. This phenomenon has been frequently exploited to extract and solubilize sparingly soluble proteins such as membrane proteins [12].

Cosmetics and cosmeceuticals

The natural function of the skin is to protect the body for unwanted influences from environment. Being a vital organ, the skin must be nourished as the other organs of the body. Such nourishment is usually - in addition to the supply by the body - supported by the use of well-known cosmetic formulations. However, one must take into account that the skin's functions can be disturbed by some systemic diseases, by vitamin deficiencies and by disturbances of endocrine glands. In these cases, active ingredients with a particular pharmacological activity are required. Thus, the distinction between cosmetics and topical pharmaceuticals is sometimes hard to establish because of several borderlines. In general, cosmetic formulations have usually aesthetic and personal hygiene functions. In the majority of the cases, cosmetics are concerned with the biological variations of normal skin [32]. Nowadays consumers are replacing cosmetics frequently with cosmeceuticals. Cosmeceuticals are skin care medicines which combine cosmetics and medicines. Many times consumer claims that their cosmetics are not effective, this is true because the availability of the cosmetic agent is must at the site of action. The skin is a complex organ and allows entry of only selective components. So the formulation of a cosmetic/cosmeceutical is very important in terms of delivering the active agent at the site of action. The new drug delivery systems are required to deliver the actives into the skin. Applying a cosmetic/cosmeceuticals in a certain way may change its activity. For example, increased time of application usually leads to higher activity. Occlusion (covering the product with something, as plastic or a medical membrane/hydrogel) usually increases activity. Proniosome gel can be used as-an effective delivery systems for cosmetics and cosmeceuticals due to their unique properties [3].

Preparation of proniosome gel [6, 20, 21]

Preparation of proniosome gel was adopted by the method given by Perrett S, et. al. for pro liposome preparation which was then modified and used for preparation of proniosomal gel. Later on, some of modifications were also observed in favor to improve the preparation process and the proniosome characteristics. Proniosomal gel preparation is based on the fact that when surfactant and other components are dissolved using an organic solvent with the aid of heat, and limited concentration of hydrating medium is added. Limited hydration medium enables formation of gel instead of dispersion. Proniosome gel preparation involves mixing of surfactant, cholesterol, phosphatidyl choline and the drug with a suitable alcohol. After mixing all the ingredients, it is covered with a lid to prevent the loss of solvent and warm on a water bath at 60deg - 70degC until the surfactant dissolves completely, see fig. 3. To it is added an aqueous phase, which may be purified water, dilute glycerol solution or an isotonic buffer solution like, phosphate buffer or saline solution. It is warmed again form a clear solution, which on storage for overnight under dark converts to proniosomal gel. The ratio of surfactant, alcohol and the aqueous phase plays an important role in gel formation. Surfactant: alcohol: aqueous phase in 5: 5: 4 ratios were selected in levonorgesrel proniosome formation. Micelle formation was not possible, due to the lesser amount of solvent (polar organic solvent) present. But self-assembly of the surfactant into w/o micro-emulsion sol phase initiates with the addition of small amount of water [22, 23].

Vesicle formation in proniosomes

The ability of nonionic surfactant to form bilayer vesicles instead of micelles is not only depends on the hydrophilic-lipophilic balance (HLB) values of the surfactant and the chemical structure of the components, but also on the critical packing parameter (CPP) [2]. In proniosomes the vesicle-forming tendency is similar to niosomes. The relationship between the structure of the surfactant including size of hydrophilic head group, and length of hydrophobic alkyl chain in the ability to form vesicles is described as

CPP = y/ lca0

where y = hydrophobic group volume, lc = the critical hydrophobic group length and a0 = the area of the hydrophilic head group. A CPP of between 0.5 and 1 indicates that the surfactant is likely to form vesicles. A CPP of below 0.5 (indicating a large contribution from the hydrophilic head group area) is said to give spherical micelles and a CPP of above 1 (indicating a large contribution from the hydrophobic group volume) should produce inverted micelles, the latter presumably only in an oil phase, or precipitation would occur [2, 23, 24].

Addition of cholesterol suppresses the tendency of the surfactants to form aggregates and also provides greater stability to the bilayer membranes by increasing the gel liquid transition temperature of the vesicle and also attributes to the higher HLB and smaller critical packaging parameters. Cholesterol addition also enables more hydrophobic surfactants to form vesicles. Apart form this addition of cholesterol also influences membrane permeability, encapsulation efficiency and bilayer rigidity [26].

Stabilization and permeability can also be enhanced by the addition of lecithin and by the addition of charged molecules like, diacetyl phosphate (DCP) and stearyl amine (SA) to the bilayer.

Conversion of proniosome gel into niosomes [6, 8, 35]

Proniosome gel is an intermediate state of formation of niosome. Minimum quantity of continuous phase, leads to the formation of liquid crystalline compact mass of proniosomes. Proniosome gel thus obtained has some advantages over conventional niosomes due to their compact gel nature, which helps in degradation, transportation and stability. The conversion of proniosome gel into niosomes can be achieved in two ways.

*Hydration by skin: The hydration is achieved by skin itself i.e. the water in the skin is used to hydrate the proniosome formulation and conversion to niosomes.

*Hydration by solvents: Aqueous systems i.e. purified water, saline solution and buffers are used to convert proniosomes to niosomes with or without agitation and sonication.

The proniosome gel system is directly being formulated in the patch for used in dermal and transdermal applications without the requirement of polymeric matrix for dispersion. The formulation takes water from the skin and converts into niosomes. The addition of aqueous phase from outside also leads to the formation of niosomes. After the addition of aqueous phase, agitation and sonication leads to formation of niosomes with small size vesicles. The addition of water into compact mass of proniosome leads to the swelling of bilayers as well as vesicles due to the interaction of water with polar groups of the surfactant. Due to the inclusion of water in the bilayers, the stacked structures tend to separate. Above a limiting concentration of solvent bilayers tends to form spherical structure which gives rise to unilamellar to multilamellar vesicular structures. Addition of shaking step in hydration process leads to complete hydration and formation of niosomes.

Mechanisms for permeation of vesicles through skin

Proniosome gel is a liquid crystalline compact mass, which upon hydration leads to unilamellar to multivesicular, multilamellar and spherical shaped niosomes. The drug is entrapped into the vesicles (derived niosomes self-assembly of non-ionic surfactant). Stratum corneum is considered to be a particularly impermeable barrier, so there is need to elucidate the mechanism through which the drug into vesicles is delivered to the deeper layers.

Proniosomes contain both non-ionic surfactant and phospholipids, both can act as penetration enhancer and useful in increasing permeation powers of many drugs [27, 28]. A single mechanism is not sufficient to describe the permeation of drug containing vesicles into the skin. Many hypotheses exist relating to the permeation of vesicles through skin for drug release in deeper layers. The ability of vesicles (present in many delivery systems) to modulate drug transfer across skin can be explained by several mechanisms [2, 6, 20, 29].

  1. Adsorption and fusion of vesicles onto the surface of skin leading to a high thermodynamic activity gradient of drug at the interface, which is the driving force for permeation of lipophilic drugs.
  2. The penetration enhancers effect of vesicles to reduce stratum corneum barrier properties.
  3. The bilayers present in niosomes acts as rate-limiting membrane barrier for drugs.

Modification in the structure of stratum corneum is also one of the possible mechanisms for the permeation of the vesicle-encapsulated drug. Intracellular lipid barrier in the stratum corneum was found dramatically looser and more permeable after treating with liposomes and niosomes [30, 31]. Proniosome gel of Levonorgestrel formed from Span 80 showed highest flux due to their high permeability [6].

Topical Delivery Of Drugs And Cosmeceuticals

For applying therapeutic and cosmetic agents onto or through skin requires a non toxic, dermatologically acceptable carrier, which not only control the release of the agent for prolong action but also enhances the penetration to the skin layer [44]. Proniosome gel is promising delivery systems for delivering the actives through skin via different formulations of drugs and cosmetics. The delivery system not only enhances the delivery of active agent through skin but also controls the rate of release. A wide variety of active agents of different therapeutic functions were formulated into proniosomal gel delivery system. Proniosomal gel carrier system entraps not only hydrophilic but hydrophobic agents also. There is great scope for cosmetic agents to be incorporate in the proniosomal gel delivery system.

Nowadays a large number of cosmetic preparations available in the market are utilizing niosomes and liposomes as a carrier for delivery of actives. Liposomes were prepared using unacceptable organic solvents, whose traces in the final preparation can cause harm to the skin. It is proved that proniosomes are as effective as niosomes and liposomes, but their preparation, handling, storage and transportation make them superior over others.

The therapeutic agents which can be utilized for incorporation into proniosomal carrier systems include, moisturizing, nutritional, anti wrinkle, anti ageing, cleansing, sunscreen particles, etc. The different liquid crystalline phases prepared by using various surfactants [43], which appear in proniosome gel also, are used for various cosmetic applications.

Advantages of Proniosome GEL [4, 6, 8]

Liposomes and niosomes are well known drug/cosmetic delivery systems. But these delivery systems have been reported to have many disadvantages in terms of preparation, storage, sterilization, etc. The disadvantages of liposomes and niosomes are given below, which can be overcome by proniosomes.

  • Liposomes and niosomes are dispersed aqueous systems and have a problem of degradation by hydrolysis or oxidation.
  • Liposomes and niosomes require special storage and handling.
  • Sedimentation, aggregation or fusion on storage is usually seen.
  • In liposomes, purity of natural phospholipids is also variable.
  • Difficulty in sterilization, transportation, distribution, storage uniformity of dose and scale up.
  • Use of unacceptable solvents the preparation.
  • Incomplete hydration of the lipid/surfactant film on the walls during hydration process.

Applications

Proniosome gel system is a step forward to niosomes, which can be utilized for various applications in delivery of actives at desired site. Proniosomes are easily hydrated using aqueous phase or by skin itself if used topically. Their incorporation into base gel/cream/ointment along with other ingredients leads to form a cosmetic preparation. These cosmetic formulations can be used for topical/transdermal applications for various functions. Proniosome gel formulation shows advantages in controlled drug delivery [8], improved bioavailability, reduced side effects and entrapment of both hydrophilic and hydrophobic drugs [46]. Proniosome gel has an affinity towards biological membranes which helps in enhancing the permeation of actives through skin. A brief compilation related to wide range of actives including therapeutic agents and cosmetic agents are given in table 1, which have been reported to be utilized for various applications.

Future trends

Studies on proniosome gel formulation indicate that it has become a useful dosage form for drug permeation into the skin, especially due to their simple, scaling-up production procedure and ability to modulate drug delivery across the skin. There is a strong need for exploring the proniosomal delivery systems for cosmetics, herbal actives and nutraceuticals. Use of proniosome in the cosmetic formulation will lead to prolong action, better absorption along with many advantages. To get the desired characteristics of a particular proniosome gel formulation, it is important to select the surfactant of suitable HLB in the formulation of proniosome gel. Hence, a more extensive study should be undertaken to find out the optimal proniosome formulation for drug/cosmetic permeation into the skin.

Descriptive diagram of skin indicating various layers with characteristics

Fig. 1. Descriptive diagram of skin indicating various layers with characteristics

Descriptive diagram of skin indicating various layers with characteristics

Fig 2. Schematic representation of various liquid crystalline phases

Descriptive diagram of skin indicating various layers with characteristics

Fig. 3. Diagrammatic representation for preparation of proniosome gel

Table 1. Examples of some therapeutic and cosmetic agents used in carrier systems.

Name of therapeutic agent

Therapeutic category

Route of delivery

Delivery system

Reference

Levonorgestrel

Contraceptive agent

Transdermal

Proniosome gel

[6]

Flurbiprofen

NSAID

Transdermal

Proniosome gel

[8]

Captopril

Antihypertensive

Transdermal

Proniosome gel

[19]

Estradiol

Female hormone

Transdermal

Proniosome gel

[20]

Ketorolac tromethamine

NSAID

Transdermal

Proniosome gel

[35]

Frusemide

Diuretic

Transdermal

Proniosome gel

[36]

Losartan potasium

Antihypertensive

Transdermal

Proniosome gel

[37]

Chlorpheniramine Maleate

Anti-histamine

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Transdermal

Proniosome gel

[38]

Pseudo-ceramide

Anti-wrinkle

Topical

Liquid crystal

[42]

Benzophenone -4 / octyl methoxycinnamate

Sunscreen agent

Percutaneous

Liquid crystal

[43]

Vitamin A

Antioxidant

Topical/ Transdermal

Liquid crystal

[44]

Cosmetic composition

Skin cleansing agent

Topical

Liquid crystal

[45]

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About Authors :

N K Yadav, Sanju Nanda, and K Saroha

N. K. Yadav

N. K. Yadav

Working as a Research Scientist in Jubilant Organosys Ltd., R&D Center, Noida, UP, INDIA, Having 4.5 years of industrial experience in product development. Area of interest is formulation development, novel drug delivery systems related to topical and Transdermal purposes.

Kamal Saroha

Kamal Saroha

Working as a Lecturer in Institute of Pharmaceutical Sciences, Kurukshetra University, Haryana, INDIA. She is having more than five years of experience of teaching graduates and 2 years for postgraduates. Her area of interest is novel drug delivery systems.

Sanju Nanda

Sanju Nanda

Dr. Sanju Nanda has done her B.Pharm and M.Pharm from Dr. Hari Singh Gour Vishwavidyala, Sagar M.P.), obtained her Ph.D from Indian Institute of Technology (IITD), Delhi and pursuing LLB(Hons) from MD University,Rohtak. She has more than 15 years of teaching experience and is presently working as a Lecturer (Senior Scale) at the Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana).She is also guiding many M.Pharm and Ph.D students and her areas of interest are Cosmetics, Drug Regulatory Affairs, New Drug Delivery Systems and Consumer Awareness. She is the co-author of the book "Cosmetic Technology" and has contributed a Monograph for the Consumer Education Series entitled "Cosmetics and Consumers".

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