PHARMACEUTICAL GELS: IN SUMMARIZED FORM

About Author:
Piyush Tripathi
Kota College of Pharmacy,
Kota (RAJ)
piyushtripathi1992@rediffmail.com

Definition:
A gel is a solid or semisolid system of at least two constituents, consisting of a condensed mass enclosing and interpenetrated by a liquid⁴.

Advantages^5,6,7:

Gels are used to achieve optimal cutaneous and percutaneous drug delivery.
They can avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH.
Gels are having property to avoid enzymatic activity and drug interaction with food and drinks.
They can substitute for oral administration of medication when the route is unsuitable.
They can avoid the first pass effect, that is, the initial pass of drug substance through the human body.
They avoid systemic and portal circulation following gastrointestinal absorption.
Gels are not deactivated by liver enzymes because the liver is bypassed.
They are non-invasive and have patient compliance.
They are applied over skin for slow and prolonged absorption.
Gels have also been applied in pharmacy to some viscous suspension for oral use for example Aluminium hydroxide gel.
They have localized effect with minimum side effects.

REFERENCE ID: PHARMATUTOR-ART-1871

Disadvantages^6,8,9:

Gels have possibility of allergenic reactions.
Enzyme in epidermis may denature the drugs of gels.
Drugs of larger particle size do not absorb through the skin.
They have poor permeability of some drugs through the skin.
Selection of area to be examined carefully during application of gels.
Gels which are used for the introduction into body cavity or the eyes should be sterilized.
They may causes application side reactions.
They may cause skin allergy during application.

DELIVERY THROUGH SKIN
Delivery of drugs to the skin is an effective and targeted therapy for local dermatological disorders. Topical gel formulations provide a suitable delivery system for drugs because they are less greasy and can be easily removed from the skin¹⁰.

Fig: Longitudinal section showing layers of skin

Advantages of This Route⁶^,16:

It provides a largest surface area.
It avoids first-pass effects, gastrointestinal irritation.
It avoid metabolic degradation associated with oral administration.

Mechanism of Drug Absorption¹⁹:
The principal mechanisms of drug absorption are:
1.Passive diffusion
2.Pore transport
3.Facilitated diffusion
4.Active transport
5.Ionic or electrochemical diffusion
6.Ion-pair transport
7.Endocytosis

Physiological Factors Affecting Skin Penetration^13,21:
1. Skin integrity
2. Skin hydration
3. Skin temperature
4. Regional variation
5. Traumatic/pathologic injury to skin
6. Cutaneous drug metabolism

Formulation Factors Affecting Skin Penetration^13,21,22:

1. Penetration enhancer.
2. Occlusivity
3. Drug concentration
4. pH
5. Solubility
6. Surfactant

CLASSIFICATION

Classification of Gels is Following:
A. Controlled release gels
B. Organogels
C. Extended release gels
D. Amphiphilic gels
E. Hydrophilic gels
F. Non aqueous gels
G. Bioadhesive gels
H. Thermosensitive sol-gel reversible hydrogels
I. Complexation gels
J. Hydrogel

A. Controlled Release Gels :
Drug delivery to nasal or ocular mucosa for either local or systemic action suffers from many obstacles. Gel formulations with suitable rheological and mucoadhesive properties increase the contact time at the site of absorption. However, drug release from the gel must be sustained if benefits are to be gained from the prolonged contact time.

These gels were formed in simulated tear fluid at concentrations of polymer as low as 0.1%, and it was shown that sodium was the most important gel-promoting ion in vivo. Rheology, although it may be a questionable technique for evaluating mucoadhesive properties of polymers, showed that interactions between mucin and polymers were most likely to be seen with weak gels.

B. Organogels :
Sorbitan monostearate, a hydrophobic nonionic surfactant, and numbers of organic solvents such as hexadecane, isopropyl myristate, and a range of vegetable oils are present. Gelation is achieved by dissolving/dispersing the organogelator in hot solvent to produce an organic solution/dispersion, which, on cooling sets to the gel state.

Such organogels are affected by the presence of additives such as the hydrophilic surfactant, polysorbate 20, which improves gel stability and alters the gel microstructure from a network of individual tubules to star-shaped "clusters" of tubules in the liquid continuous phase. Another solid monoester in the sorbitan ester family, sorbitan monopalmitate, also gels organic solvents to give opaque, thermoreversible semisolids. Like sorbitan monostearate gels, the microstructure of the palmitate gels comprises an interconnected network of rod like tubules.

C. Extended Release Gels:
It is a controlled release technology consists of an agglomerated, hydrophilic complex that, when compressed, forms a controlled-release matrix. It consisting of xanthan and locust bean gums (two polysaccharides) combined with dextrose surrounds a drug core. In the presence of water, interactions between the matrix components form a tight gel while the inner core remains unwetted.

The drug is encapsulated in the pores of the gel, and as the matrix travels through the patient’s digestive system, the tablet swells and begins to erode. This erosion allows the drug to “back-diffuse” out through the gel-matrix at a controlled rate until the matrix erodes and a majority of the drug is released. The fundamental component controlling the rate of release lies in the properties of the gel matrix.

D. Amphiphilic Gels :
Amphiphilic gels can prepared by mixing the solid gelator like sorbitan monostearate or sorbitan monopalmitate and the liquid phase like liquid sorbitan esters or polysorbate and heating them at 60°C to form a clear isotropic sol phase, and cooling the sol phase to form an opaque semisolid at room temperature.

Amphiphilic gel microstructures consisted mainly of clusters of tubules of gelator molecules that had aggregated upon cooling of the sol phase, forming a 3D network throughout the continuous phase. The gels demonstrated thermoreversibility. Gelation temperature and viscosity increased with increasing gelator concentration, indicating a more robust gel network. At temperatures near the skin surface temperature, the gels softened considerably, this would allow topical application.

E. Hydrophilic Gels :
Hydrophilic gels are composed of the internal phase made of a polymer producing a coherent three-dimensional net-like structure, which fixes the liquid vehicle as the external phase. Intermolecular forces bind the molecules of the solvent to a polymeric net, thus decreasing the mobility of these molecules and producing a structured system with increased viscosity.

F. Non Aqueous Gels :
Ethylcellulose was successfully formulated as a nonaqueous gel with propylene glycol dicaprylate/dicaprate. The novel nonaqueous gel exhibited rheological profiles corresponding to a physically cross-linked three dimensional gel network, with suitable mechanical characteristics for use as a vehicle for topical drug delivery. Molecular conformation of the solvent was found to influence the molecular interactions associated with formation of ethylcellulose gel networks.

The gel matrices exhibited prominent viscoelastic behavior, yield stress and thixotropy. Rheological and mechanical properties showed significant upward trends with increased polymeric chain length and polymer concentrations. Good linear correlations were obtained between rheological and mechanical properties. The solvent molecular conformation was found to play a role in affecting the formation of gel networks via intermolecular hydrogen bonding between ethylcellulose polymer chains.

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G. Bioadhesive Gels:
Bioadhesive gels were formulated for nasal delivery of insulin. A nasal perfusion test was carried out to study the toxicity of four absorption enhancers like saponin, sodium deoxycholate, ethylenediamine tetra-acetic acid (EDTA) and lecithin.

The gels contained 4000 Iu/dl insulin, 2% or 4% of low and medium molecular weight of chitosan, and lecithin or EDTA. Drug release was studied by a membraneless diffusion method and bioadhesion by a modified tensiometry test. The optimized gel was administered nasally in diabetic rats. The serum insulin levels were analyzed by an insulin enzyme immunoassay kit and serum glucose by glucose oxidase method kits.

H. Thermosensitive Sol-Gel Reversible Hydrogels :
They are polymeric solutions which undergo reversible sol to gel transformation under the influence of environmental conditions like temperature and pH which results in insitu hydrogel formation.

I. Complexation Gels :
The goal of oral insulin delivery devices is to protect the sensitive drug from proteolytic degradation in the stomach and upper portion of the small intestine.

The insulin remained in the gel and was protected from proteolytic degradation. In the basic and neutral environments of the intestine, the complexes dissociated which resulted in rapid gel swelling and insulin release. Within 2 hr of administration of the insulin-containing polymers, strong dose-dependent hypoglycemic effects were observed in both healthy and diabetic rats. These effects lasted for up to 8 hr following administration²³.

J. Hydrogels:
Hydrogels are gel systems in which water immobilised by insoluble polymer. The elements of hydrogels are water and a polymeric substance that is hydrophilic, but not water soluble. When exposed to water, the dry polymer swells and absorbs liquid. The polymer strands are cross-linked either chemically or by physical forces. For convenience, hydrogels may be defined by the type of polymer employed and/or the cross-linking mechanism²⁴.

PROPERTIES OF GELS

Various Properties of Gels are Following:
A. Physical properties
B. Physiological properties
C. Application properties
D. Hydrophilic properties
E. Rheological properties

A. Physical Properties^21,26,27:

Smooth texture
Elegant in appearance
Non dehydrating
Transparent and transluscent
Non greasy
Semi solid in nature

B. Physiological Properties²¹ :

Non irritating
Do not alter membrane / skin functioning
Miscible with skin secretion
Have low sensitization index

C. Application Properties²¹ :

Easily applicable with efficient drug release.
High aqueous washability.

D. Hydrophilic Properties :
The water absorbing capacity of oleaginous and water-in-oil bases may be expressed in terms of the water number, defined in 1935 by Casparis and Meyeras the maximum quantity of water that is held (partly emulsified) by 100g of a base at 20^o C.

The test consists of adding increments of water to the melted base and triturating until the mixture has cooled. When no more water is absorbed, the product is placed in a refrigerator for several hours, removed, and allowed to come to room temperature. The material is then rubbed on slab until water no larger exudes, and finally, the amount of water remaining in the base is determined⁴.

E. Rheological Properties :
Gels exhibit different rheological properties. Do not flow at low shear stresses but undergo reversible deformation like elastic solids.

When a characteristic shear stress, called the yield value or yield stress, is exceeded, they flow like liquids. Yield stresses usually are caused by structural networks extending throughout an entire system. To break such a network requires stress produce no flow but only elastic deformation. When the yield stress is exceeded, the network is partly ruptured and flow occurs²⁸.

COMMON INGREDIENTS

Ingredients Used in Preparation of Gels are:
A. Antimicrobial preservatives
B. Antioxidant
C. Chelating agents
D. Humectants
E. Fragrances
F. Ideal emulsifier
G. Types of gelling agents
H. Permeation enhancer
I. Co solvent
J. Polymers
K. Colour
L. Adhesives
M. Adsorbents
N. Air displacement agents
O. Alkalizing agents
P. Anticaking agents
Q. Antifoaming agents
R. Antifungal preservative
S. Antistatic agents
T. Bases
U. Binders
V. Buffering agents
W. Flocculating agents
X. Lubricating agents

EVALUATION

Types of Evaluations are Following:
A. pH
B.Drug content
C.Viscosity
D.Spreadability
E.Extrudability study
F.Skin irritation studies
G.Invitro release
H.Invivo study
I.Stability

A. Measurement of pH :
The pH of various gel formulations was determined by using digital pH meter. One gram of gel was dissolved in 100 ml distilled water and stored for two hours. The measurement of pH of each formulation was done in triplicate and average values are calculated.

B. Drug Content :
1 g of the prepared gel was mixed with 100ml of suitable solvent. Aliquots of different concentration were prepared by suitable dilutions after filtering the stock solution and absorbance was measured. Drug content was calculated using the equation, which was obtained by linear regression analysis of calibration curve.

C. Viscosity Study :
The measurement of viscosity of the prepared gel was done with a Brookfield Viscometer. The gels were rotated at 0.3, 0.6 and 1.5 rotations per minute. At each speed, the corresponding dial reading was noted.

D. Spreabability :
One of the crieteria for a gel to meet the ideal quantities is that it should possess good spreadability. It is the term expressed to denote the extent of area to which gel readily spreads on application to skin or affected part. The therapeutic efficacy of a formulation also depends upon its spreading value.

Spreadability is expressed in terms of time in seconds taken by two slides to slip off from gel and placed in between the slides under the direction of certain load. Lesser the time taken for separation of two slides, better the spreadability.

E. Extrudability Study :
The formulations were filled in the collapsible tubes after the gels were set in the container. The extrudability of the formulation was determined in terms of weight in grams required to extrude a 0.5 cm. ribbon of gel in 10 second.

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F. Skin Irritation Study :
Guinea pigs (400-500 g) of either sex were used for testing of skin irritation. The animals were maintained on standard animal feed and had free access to water. The animals were kept under standard conditions. Hair was shaved from back of guinea pigs and area of 4 cm.²was marked on both the sides, one side served as control while the other side was test. Gel was applied (500 mg / guinea pig) twice a day for 7 days and the site was observed for any sensitivity and the reaction if any, was graded as 0, 1, 2, 3 for no reaction, slight patchy erythema, slight but cofluent or moderate but patchy erythema and severe erythema with or without edema, respectively³⁹.

G. In VitroRelease Studies:
The principal in vitro technique for studying skin penetration involves use of some variety of a diffusion cell like Franz cell and Flow through cell in which animal or human skin is fastened to a holder and the passage of compounds from the epidermal surface to a fluid bath is measured.

Hairless rats were sacrificed by an overdose of halothane anesthesia. The skin from the dorsal surface was excised, and the adherent fat and subcutaneous tissue were removed. The skin was mounted on Franz diffusion cells with the epidermis facing the donor compartment. The skin permeation studies were performed by the procedure as described under “release studies”.

H. In VivoStudies :
Inhibition of carrageenan – induced rat paw odema – Three groups of 6 male wistar albino rats were used one for marketed sample (reference). Other for test formulation and one group for control. The volume of unilateral hind paw test animal were measured. On each paw, 100 mg of preparation was carefully rubbed twice at 1 and 2 h. before carrageenan administration. They were placed in cages with copography meshes. 0.1 ml of 1 % w/v carrageenan was injected subcutaneously into the paw and volume of hind paw measured at hourly interval for 5 hr using a mercury plethysmometer. Percentage of inhibition was calculated.

I. Stability :
The stability studies were carried out for all the gel formulation by freeze - thaw cycling. In this syneresis was observed by subjecting the product to a temperature of 4° C for 1 month, then at 25°C for 1 month , then at 40°C for 1 month. After this gel is exposed to ambient room temperature and liquid exudates separating is noted³⁹.

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