Journal of Scientific & Industrial Research Vol. 60, April 200 1 , pp 3 1 1 -3 I 8

Applications of Organogels in Pharmaceuticals

B Anand , S S Pisal, A R Paradkar * and K R Mahadik Department of Pharmaceutics, B V's Poona College of Pharmacy, Erandavane,

Pune 4 1 1 038, India

Organogels are emerging as novel drug carrier systems for drug molecules with diverse physico-chemical properties and macromolecules like proteins and peptides. These are basically gels in which the continous or macroscopic phase is composed of biocompatible organic solvents (isopropyl myristate, i sopropyl palmitate, etc.). B iocompatible solvents meaning are those that are non-toxic and safe to the mucosal membranes. The present review describes reflects the structure, mechanism of formation and gelation process of organogels. Most of the organogels in pharmaceuticals are lecithin, gelatin or sorbitan ester based systems. These exhibit pharmaceutically useful properties like thermoreversibility, ability to i ncorporate all types of drug mol­ecules, improved and controlled drug release, increased resistance to microbial contamination and reduced risk of irritation. The concept of drug delivery through organogel-based systems has been studied extensively for various routes of drug administra­tion, viz. transdermal, rectal, ophthalmic and carriers for vaccines. Of all these, lot of work has been done on their use for transdermal route of administration using various systems. The drug release from most of the organogel systems is controlled by simple diffusion process. However, not much work has been done on the usefulness of these systems for the other routes of administration and their potential for these remains to be uncovered.

Introduction Gels are the intennediate state of matter containing

both solid and liquid components. The three dimensional network of interconnected gelator molecules immobi­lizes the liquid continuous phase. A high degree of phy si­cal or chemical crosslinking may be involved. The in­creased viscosity caused by the interlacing and conse­quential internal friction is responsible for the semisolid state. Gels may be classified as hydrogels and organogels. Hydrogels consist of an aqueous external phase, while organogels consist of a liquid organic solvent as a con­tinuous medium. The formation and applicability of hydrogels has been studied extensively. These gels have a variety of applications in administration of medica­tions orally, topically, intranasally, vaginally and rectally. Hydrogels include ingredients that are dispersible as col­loids or are soluble in water, e.g. methyl cellulose, hy­droxy ethyl cellulose and sodium carboxy methyl cellu­lose which are some of the commercially available cel­lulose products. Hydrogels as a drug delivery systems frequently require the use of penetration enhancers and the various other fonnulation adjuvants whose long-tenn safety must be evaluated l .4•

Interest in the physical organogel field has increased

* Author for correspondence

tremendously in the late nineties. The discovery of a number of biocompatible substances capable of gelling various organic solvents has opened a new area in devel­opment of novel drug delivery systems. Organogels can be simply prepared by decreasing the interaction of gelator molecules and the organic solvent.

The salient features of these organogels include _,.x:

• Use of b iocompatible materials suitable for long-tenn use

• High capacity to incorporate polar and non-po­lar guest molecules

• Thennoreversibility ( concentration and tem­perature dependent )

• High degree of stability to moisture and tem­perature

• Ability to act as templates • Many of these gels are transparent systems (

e'.g. lecithin based and AOT (also known as Aerosol- OT which is sodium bis(2-ethylhexyl) sulphosuccinate) phenol organogels) or opaque ( e.g. sorbitan mono-oleate based organogels)

• Capabil ity to controlling the release rates of drugs .

3 1 2 J SCI IND RES VOL 60 APRIL 200 1

Various Organogel-based Systems

Depending upon the type of gelator molecule used a number of organogel systems have been developed; some of these are :

( 1 ) ALS-based Organogels - These refer to gelator molecules consisting of three components- an aro­matic rpoiety which is l inked to a steroidal molecule (ALS) with linker atoms . Example of these gelators include cholesteryl 4-(2-anthry loxy) butanoate (CAB) which has the ability to gel reversibly with a variety of organic solvents. Various modifications in the basic structure of these gelators and the effect of these on gelation have been discussed by Yih­chyuan Lin et aP

(2) AOT - Phenol-based Organogels - Hydrogen-bond­ing interactions between suitable phenols and the head group of the twin-tailed anionic surfactant so­dium bis (2-ethylhexyl )sulphosuccinate (AOT), form the basis for a novel class of organogels. The gels are special in the sense that very small quanti­ties of these low mol . wt. solutes are sufficient to cause gelation . These gels are very sensitive to mois­ture and hence have potential application as mois­ture sensors 10, 1 1 .

(3) Lecithin-based Organogels - This class of gels are biocompatible. The various solvents used in these gels include isopropyl palmitate , cyclooctane , me­dicinal vaseline oi l , etc. These are microemulsion­based gels and a polar agent is added to effect the gelation. These are thermodynamically stable sys­tems meaning there is no seperation of the phases and hence can be stored for a long periods in a closed vessel6, 1 2 .

(4) AOT - Gelatin-based OrganogeLs - These are microemulsion-based gels in which gelatin is solu­bilized in the water microphase of the microemulsion system AOTI waterl isooctane. The gel consists of more than 80 per cent organic solvent. The gel, which is formed, is proposed to consist of an extensive, rigid, interconnected network of gelatin I water rods stabil ized by a monolayer of surfactant, in coexist­ence w i th a populat ion of convent ional wlo microemulsion droplets. Gel formation doesn' t oc­cur only with in the water pool of reverse micelles; the whole micellar solution becomes a gel 1 3· 1 4 . These

have been mainly used for enzyme immobiliza­tion J5 • 1 6 .

(5) Non - ionic Surfactant-based Gels - S orbitan monostearate, a hydrophobic non-ionic surfactant, has been used to gel a variety of solvents. Gelation is achieved by dissolving the surfactant in hot or­ganic solvent and cool ing. The addition of a small amount of another surfactant in these gels has been found to result in stabilization of the gels , maybe due to the formation of a mixed surfactant film at the interface. The solvent plays an important role in these systems and it should provide the right solu­bi litylinsolubility balance towards the gelator 1 7 .

(6) Miscellaneous Systems: Callixerine-based Gelling Agents - Cal ix (n) arenes having long chains ( long aliphatic chains at para positions) act as excellent ge lators of organ ic so l vents . These exh ib i t thermoreversibility and the three dimensional struc­ture is formed mainly by hydrogen bonding between C=O and OH groupslX . Carbohydrate amphiphiles l ike derivatives of gluconamide are also able to yield organogels of very high viscosity to form gels, which are highly stable. The gel formation is entropy driven and the gels formed are thermodynamically stable 1 9

Gel Formation and Effect of Adjuvants

The formation of gel requires the gelator particles to separate into the finely dispersed colloidal particles that join together to form a continuous coherent frame­work throughout the fluid volume. Hence, the develop­ment of a three-dimensional network by the gelator to capture small domains of isotropic fluid is critical in gel formation and this framework should be immobile. The gelation temperature is dependent on the concentrations of fluid and gelator and all physical organogels have a relatively broad gel temperature range. This is due to the fact that gel-sol change involves the rupture of junc­tions between aggregates. The temperature increase rup­tures these junctions and there is a corresponding in­crease in the solubility of surfactant molecules in the given organic solvent. This explains the general gela­tion process as applied to organogels. The effect of vari­ous adjuvants in the organogel formulation is summa­rized below:

• The Microemulsion-based Gels (MBGs) - In these gels, the process of gel formation occurs

•

•

ANAND el at. : APPLICATIONS OF ORGANOGELS IN PHARMACEUTICSLS 3 1 3

A

'* Addition of water

guest molecules a hydrophilic " hydrophobic fP'O amphlphUic

� ;>

Figure I - Schematic representation of (A) formation of lecithin gels and (8) location of solubil ized 'guest molecules' within lecithin gelsZ7

after the formation of emulsion. Here, water can be replaced by other polar substances l ike glyc­erin, polyethylene glycol, etc. In all these cases, the quantity of water plays an important role. This is represented by the molar ratio of water to gelator (Wo), e.g. in the case of lecithin-based systems, gelation starts at Wo values more than one. The organogels are stable only in a narrow range of Wo values . When th i s value i s exceeded,gel i s destroyed. A visual clouding of the gels precedes their destruction6. 16. Concentration of Gel at or- In the case of leci­thin-based organogels, v iscosity of the gels in­creases w ith increase in lecithin concentration . W h i l e i n the case of su rfac tan t based organogels, when surfactant concentration is insufficient, there is preferential ordered floc­culation of surfactant aggregates to form a three­dimensional network within the solvent. This network is able to gel only a l imited part of the solvent and a fibrous gel mesh is observed within the excess solvent ( solvent not gelled ) 17. This may lead to an increased viscosity of the system leading to slower release of drug from the system. Effect of Other Adjuvants - In the case of sur­factant-based gels (e.g. sorbitan monostearate­based gels), addition of another type of surfac­tant results in increased stabil ity due to the for­mation of a mixed surfactant film at the inter­face 1 7. In the case of lecithin-based organogels, the presence of other phospholipids l ike phos­phatidylethanolamine, lyso-phosphatidylcho­l ine in a significant amount leads to the decom­position of micel les into smaller aggregates. This is due to the formation of cylindrical mi-

celles because of the change in the hydrogen bonds between phosphate groups of phosphati­dyl choline molecules 20.

Mechanism of Gel Formation

The first perquisite for gel formation is the balance of intermolecular interaction amongst the gelator molecules (e.g. H-bonding, van der Waals interactions, etc .) and between gelator and solvent molecules. The latter helps in the formation of a continuous three-dimensional net­work IX.

The simplest mechanism of gel formation involves the shifting the balance of intermolecular and intramo­lecular interactions of the gelator molecules and organic solvent. This should result in a comparative increase in the intermolecular attraction amongst the gelator mol­ecules and a comparative decrease in the interaction be­tween the gelator molecules and solvent (e.g. by decreas­ing temperature) . Thi s leads to the

formation of a molecular dispersion which further re­sults in the formation of a three- dimensional network in which the solvent molecules are trapped.

During the preparation of all microemulsion-based organogels (MBGs), the amount of water added also plays an important role in formation, otherwise l ique­faction of gel occurs. The water molecule appears to be bound to the polar surfactant head and influences the micelle formation6. The water molecules are supposed to be located within the surfactant aggregates and due to the hydrogen bonding with surfactant heads, may fur­ther stabi l ize the gel 22. The water that is added leads to the branch ing of the l inear miceller aggregates of the gelator in the case of lecithin-based gels (as shown in Figure 1 ) . It is these giant micelles which are responsible for the h igh viscoelasticity of the gels. Thus, the amount of water is a very important factor which is borne out

3 1 4 J SCI IND RES VOL 60 APRIL 200 I

Figure 2 - Structure of gelatin -based MBG 11

clearly in the case of AOT-based microemulsion-based organogels (MBGs). In this case, the gel is highly mois­ture sensitive and l iquefies if exposed to excessive mois­tureill.

Structure As like conventional gels, organogels possess a three­

dimensional network of particles or solvated macromol­ecules of the dispersed phase, with a high degree of physi­cal (weak in termolecular) attract ion or chemical crosslinking. The molecular interaction involved in these cases is usually the dipole - dipole type of weak van der waal forces 9. In many cases, such as microemulsion­based organogels (MBGs), H-bonding appears to be the major interaction responsible for the three-dimensional network The schematic representative structure of gela­tin containing microemulsion based organogel is shown in Figure 2 23.

In case of ALS- based organogels, the gelator net­work consists of domain of fibrous bundles that immo­bil ize the fluid component by surface tension. Each fi­bre is several gelator molecules long in its smallest di­mension, which leads to the conclusion that each fibre consists of several molecular threads of the gelator mol­ecules.

In the case of sorbitan- based organogels, the three­dimensional network has been found to be rod like tubu­lar surfactant aggregates. These were formed through the intermediate formation of torroidal vesicles. The fur­ther molecular orientation of tubular network is thought to be l ike multiple inverted bilayers. The aqueous phase

is found to be located within the surfactant bilayer (as shown in Figures 3 and 4)23.

Drug Release from Organogels

The exact mechanism of drug release varies with the organogel system used. However, in the C(lse of a major­ity of organogel systems, drug release occurs by simple diffusion. This d iffusion is controlled by the presence of three-dimensional network of gelator molecules. The extent of cross-linking determines the rate of drug re­lease. More the crosslinking (higher concentration of gelator), slower is the rate of drug release.

However, in the case ofEudragit-L based organogels, which have been proposed for use as rectal delivery of drugs, the release of drugs occurs by surface erosion of the gel . In the case of Eudragit S based organogels, how­ever, the drug release is via s imple diffusion process24. In the case of transdemml and ophthalmic delivery of drugs through organogels, attempts have been made to enhance the permeation of drug rather than controll ing the release of drug which occurs by diffusion . When organogels are used as carrier for delivery of vaccines, the percolation of interstitial fluid into the three-dimen­sional network of the gel leads to its breakdown into smaller fragments. This leads to the release of anti­gen 23.

Applications Of Organogels

Organogels as Matrix for Transdermal Transport of Drugs Drugs administered by conventional means often have

undesirable side effects and are many a times ineffec­tive. Transdermal delivery of drugs have been recognized as a superior mode of drug delivery because it avoids l SI pass metabolism, increased drug efficacy , etc . , as men­tioned by Yien 25. But as the skin is an exceptional ly effective barrier to most chemicals, very few drugs can penetrate it in a manner sufficient to deliver a therapeu­tic dose. Therefore, systems that make the skin local ly more permeable and thereby enable transdermal trans­port of drugs are of great interest. In this context, con­ventional transdermal delivery systems have made the use of penetration enhancers, whose long-term use has been associated with sensitization and irritation. Because of this, their long-term use is avoided 26.

Lecithin-based organogels have been proposed as a matrix for transdermal delivery of drugs . The lecithin-

ANAND et at. : APPLICATIONS OF ORGANOGELS IN PHARMACEUTICSLS 3 1 5

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 11 1 1 1 1 1 H 1 1 1 1 1 1 1 1 1 ,-------------, 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Legend:

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 hydrophilic bead group I hydrophobic tail

of sorbitan monostearatelpolysorbate 20 surfactant molecule 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I I I I I I I 1 I 1 I I I I I l i l 1 1 i Bilayer organisation of surfactant

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 aqueous CF solution •

molecules in the anhydrous organogel IJ�!MtUHoU k�l

a��!Ju! I I phase in the wlo gel

Figure 3 - Schematic diagram showing location of aqueous phase within bilayers bound by surfactant headgroups 27

based organogels are particularly of interest because of the fol lowing reasons:

• Its ability to solubilize guest molecules having dif­ferent physico-chemical properties 27.

• Its low acute and cumulative skin irritation poten­tial.

• Lecithin acts as a biocompatible penetration en­hancer, i .e. it enhances the transport of various drugs.

• The technological process doesn't require any com­plicated devices.

• Lecithin is a commercially available product.

The mechanism, which is offered for the enhanced penetration is that lecithin disorganizes the structure of the skin slightly and thus increases the penetration of various drugs. This may be due to the interaction be­tween the skin lipids and the phospholipids in the gels . This observation has been confirmed in the case of stud­ies regarding the effect of phospholipids on invivo and invitro percutaneous absorption of methyl nicotinate 2M.

Formulation Aspects The drug containing gels are prepared by dissolving

the drug in the solvent containing lecithin and water is added to induce gelation. The amount of solubilized drug has an effect on the viscosity of gels . The Wo values of the lecithin-based gels have been found to be between 1 -3.

Potential Drug Candidates Many drugs have been studied for formulation in

transdermal delivery systems. These include NSAIDS l ike indomethacin and dic10fenac 29 . Also, studies on sco-

': >

Figure 4 - Diagrammatic representation of a surfactant tubule and the aggregates (magnified cross-section view) 17

polamine, a drug for motion sickness and broxaterol , a new drug for asthma, indicate a higher transdermal trans­port rate as compared to that of commercial patches. In addition to the above drugs, preliminary investigations indicate that various other drugs l ike nifedepine, vita­min A palmitate, isosorbide dinitrate, c1onidine, estra­diol, aminoacids and peptides can also be transported via transdermal route using lecithin-based organogels 27.

Transdermal medication for a large number of pa­tients is presently considered as in the case of Phlogel®( a unique topical base in the form of p luronic-lecithin organogels) . The total replacement of p luronics with premixed lecithin organogels has made the gel less sen­sitizing to the skin . Improved penetration of Ibuprofen has benn observed with these lecithin-based organogels . The new gel system is temperature stable, having long shelf-life and with increased efficiency of compound­mg.

3 1 6 J SCI IND RES VOL 60 APRIL 200 1

Organogels as Iontophoretic Transdermal Drug Deliv­ery Systems

Iontophoresis has been used extensively in recent years as a means of enhancing the rate of drug delivery. This is particularly effective for the transdermal deliv­ery of large hydrophilic species such as peptides, pro­teins, etc. that exhibit poor penetration under passive conditions 30. But, drug dellivery via iontophoresis poses problems in case during use of solutions. This limitation can be offset by the use of drug loaded gels. Formula­tion of a drug as a gel rather than a solution faci litates drug handling. Hydrogels have till date been been of­fered as one of the options as a drug reservoir for ionto­phoresisJo. However, a major drawback of such aqueous systems during clinical use has been the potential risk of microbial contamination and hydrogels are no excep­tion to this problem3 1 . This can lead to breakdown of gel structure, pH changes and redox reactions.

Organogels offer a convenient means of avoiding the above problems of microbial contamination . This can be attributed to the existence of organic solvent as the continuous phase which itself inhibits any chances of microbial contamination. Also in the case of MBGs, the aqueous domains are dispersed as droplets having di­mensions smaller than the size of bacteria and as a re­sults it is very difficult to support microbial growth in an MBG matrix 32 . Unlike most of the organogels, MBGs exhibit the property of e lectrical conduction because of which these can be used for transdermal iontophoretic transport of drugs. Kantaria et al,32 have developed gela­tin MBGs using Tween-85 and isopropyl myri state . These organogels have high viscosity comparable to those attainable using hydrogel systems . This system shows a macroscopic hydrophobic continuous phase, i e. an interconnected gelatin network that is hydrated and stabilized from direct contact with oil by surfactant. This structure coexists with conventional wlo microemulsion droplets. Sodium salicylate was used as the model drug. Iontophoresis has been found to increase significantly the release rate as compared to passive diffusion. Fluxes have been found to be proportional to drug loading and charge density. These systems are practical ly more con­venient and simple for clinical usages.

Orgalloge!.,· as Ophthalmic Drug Delivery Systems Most ocular treatments call for the topical adminis­

tration of drugs in the tissues around the ocular cavity. Various types of dosage forms have been developed for ocular drug delivery of drugs, which include drops, SllS-

pensions, ointments and ocusserts and more recently eyelid skin delivery systems ".

Eye drops are the most widely used and most popular but suffers from the drawback that a majority of the medication is immediately diluted by tears and is rap­idly drained out by the constant tear flow. Therefore, only a fraction of the administered drug is absorbed to target tissue and thus, repeated administration of eye drops becomes essential, leading to poor patient com­pliance and also undesirable side effects .

Suspensions have the disadvantage that the rate of drug release is dependent on the rate of dissolution of drug particles which vary due to constant change in com­position and outflow of lachrymal fluid.

In order to increase the therapeutic efficacy, one of the methods suggested is to increase the viscosity so as to prolong the contact period. But, the addition of vis­cosity builders like CMC did not improve the situation much and in the case of water insoluble ointments, im­mediate vision was affected.

Lecithin-based organogels offer a potential ophthalmic drug delivery system, which may overcome the above mentioned difficulties. These gels present a unique fea­ture of being able to incorporate lipophi llic, hydrophi lic as well as amphoteric bioactive compounds. They are transparent and hence even their long-term presence in the ophthalmic cavity does not affect vision. The drug is released at a steady rate because of the three-dimensional network of the gel . Also, because of its high viscosity and organic solvent as a continuous phase, they are dif­ficult to wash off. The macroviscosity is high due to the formation of giant micel les containing water which have long tails .

Three formulations of organogels have been prepared by Fresta et al .34 using lecithin as gelator and organic solvents used are paraffin , i sopropyl palmitate and cyclooctane. Cyclooctane gels have been found to be toxic and paraffin-based gels, the safest, whereas iso­propyl palmitate gels cause mild morphological changes. Stabi lity of these gels has been confirmed by UV and Ff-IR spectroscopy.

Hence, lecithin-based organogels hold good potential as ophthalmic drug deli very systems owing to their very low toxic potential, coupled with its unique abi l ity to incorporate lipophillic as wel l as hydrophilic compounds.

Organogels as Rectal Drug Delivery Systems Organogels containing Eudragit L and S have been

designed for rectal delivery of drugs . The drugs used are

ANAND et al.: APPLICATIONS OF ORGANOGELS IN PHARMACEUTICSLS 3 1 7

Salicylates, Procaine and Ketoprofen 35. Further, invitro evaluation of the drug (using rotation disc method- JP XI) has shown that after a initial burst of drug release, the drug follows apparent first order kinetics. The burst effect has suggested to be due to rapid release of drug existing on the gel surface at the moment of insertion into the dissolution media. The drug release has found to be dependent on the concentration of Eudragit L or S. While in the case of Eudragit L, the release mechanism has been found to be a erosion dependent process, in the case of Eudragit S, the release has found to confirm to the diffusional model 24.

In-vivo evaluation of these systems using rabbits has shown sustained plasma drug levels. Further on the ad­dition of 1 0% l inoleic acid or oleic acid as absorption enhancer, bioavailabil i ty has been found to be increase to 1 .55- 1 .75 -fold and 1 .46- 1 .85- fold3s. Thus, Eudragit L based organogels containing linoleic acid or oleic acid hold potential for use as rectal sustained release prepa­rations.

Organogels as Delivery Systems for Vaccines The microemulsion-based organogels can be used as

a vehicle for delivery of hydrophilic vaccines 23 . Accord­ing to Florence et ai . , these systems offer various advan­tages l ike the slow release of antigen from the organogel system produces a depot effect. This has been proved by measuring the clearance rate of radio labeled bovine se­rum albumin administered in wlo gel to mice. The clear­ance rates when compared to those from wlo emulsion and aqueous solution prove that maximum depot effect is obtained from wlo gels. But, this depot effect is com­promised by the access of water to the system by perco­lation. The percolation of interstitial fluid into the three­dimensional network of gel leads to its breakdown into smaller fragments and thus leads to the release of the antigen. This is bas ically useful where a short depot ef­fect is effective, e.g. immunoadjuvants, where a short depot action is thought to be effective in enhancing the immune response to antigens.

Further, organogel have been formulated to contain niosomes. The vaccine has been found to be trapped in these niosomes which themselves are located within the surfactant network in the organic medium. A depot ef­fect has been observed after i .m. administration of these gels . The gels could be prepared by the addition of a hot (600 C) aqueous niosome suspension containing the an­tigen ( bovine serum albumin) to the organic solution of the gelator; a vesicle in water in oil (v/w/o) emulsion is

formed. This on further cool ing gives an opaque and thermoreversible geP7. Thus, organogel-based formula­tions hold a good potential as carriers for vaccines .

Acknowledgement

One of the authors (SSP) is thankfu l to A.I .C.T.E. for providing financial assistance for the project.

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