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Inclusion of SLNs in the Manufacture of Imiquimod Topical Cream
Nagamani Kumari Gokaraju, Market Research Associate, Vasudha Pharma Chem Ltd With the recent advances in the field of nanotechnology, the development of Solid Lipid Nanoparticles (SLNs) shows several potential applications in drug delivery and drug research. The use of SLNs also holds a great promise for attaining sustained and site specific delivery along with bioavailability enhancement. This article gives an overview of how the inclusion of SLNs may alter the formulation of this topical cream resulting in a more impressive formulation method.

Imiquimod, a heterocyclic amine in the form of a topical cream, acts as a immune response modifier. It helps to kill abnormal cells or stop their growth. In the case of genital warts, imiquimod is used to control the warts once they start to grow, but it will not stop new ones from growing. In order to formulate imiquimod into a topical cream, several solubility experiments were conducted to identify a solvent that dissolves imiquimod to achieve a 5 per cent formulation concentration. Studies were carried out to select surfactants, preservatives and viscosity-enhancing excipients to formulate an oil-in-water cream which indicated that fatty acids were the preferred solvents for topical imiquimod formulations, and Isostearic Acid (ISA) being the selected solvent among them.

With the recent advances in the field of nanotechnology, the development of solid lipid nanoparticles, otherwise known as SLNs show several potential applications in drug delivery and drug research. The ability to incorporate drugs into nanocarriers opens a new window in order to develop and formulate new therapeutics.

The use of SLNs also holds great promise for attaining sustained and site specific delivery along with bioavailability enhancement. This article gives all the information that one should know about imiquimod topical cream that is currently in use and an overview of how the inclusion of SLNs may alter the formulation of this topical cream resulting in a more impressive formulation method.

Imiquimod
Imiquimod is a novel compound in the class of compounds known as 'immune response modifiers'. It is a heterocyclic amine (biochemically, a non-nucleoside, imidiozoquinolone). Its molecular formula is C14H16N4 and its molecular weight is 240.3. Imiquimod is a relatively stable drug and is not hygroscopic in nature1.

Physical and Chemical Properties of Imiquimod Imiquimod is an off-white, crystalline and odourless solid and is practically insoluble in water and other organic solvents in its free base form. It is found more soluble as a salt form. It is commercially available as a 5 per cent topical cream. This molecule does not possess any asymmetric carbon atoms and does not exhibit stereoisomerism2.

Uses of Imiquimod
Imiquimod is a patient-applied cream used to treat certain skin growths or tumours, including skin cancers, pre-cancerous skin growths, actinic keratoses and superficial basal cell carcinoma on the neck, arms and legs. It is also commonly used to treat genital warts called as 'condyloma acuminate' and common warts that are usually difficult to treat3. Imiquimod causes the subclinical lesions to become visible. This unmasking effect is beneficial in treating the otherwise missed lesions clinically.

Side Effects of Imiquimod
Nonspecific inflammation and dermatitis can occur during the use of imiquimod for genital warts. The other side effects include back pain, changes in skin colour, diarrhea, headache, itching, burning, mild pain, or tenderness at the application site, redness, dryness, flaking, swelling and small sores at the application site, thick or hardened skin at the application site and tiredness4.

Mechanism of Action
Imiquimod is an immune response modifier. The exact mechanism of how the active ingredient imiquimod or its analogs activate the immune system is not fully known. Its activity is believed to be principally due to induction of interferon alpha (IFN-a) and other pro-inflammatory cytokines. These cytokines are believed to be activated by the immune cells through the toll-like receptor 7 (TLR7)5.

It is also evident that imiquimod activates several other cells such as Langerhans cells, macrophages and B-lymphocytes6.

Few studies show that imiquimod has anti-proliferative effects in vitro, where it exerts its effect by increasing the levels of opioid growth factor receptor (OGFr)7.

Imiquimod in Market
Imiquimod is available in the form of a topical cream. There are two creams in the market, that contain imiquimod, with different concentrations of the drug (5 per cent and 3.75 per cent). The more-concentrated cream (5 per cent) is used for cancer, genital warts and actinic keratoses. The less-concentrated drug (3.75 per cent) is used only for actinic keratoses. The two creams are used at different time intervals, but all the other information is very much similar for both.

Solid Lipid Nanoparticles (SLNs)
Representing an alternative carrier system to traditional colloidal carriers like, emulsions, liposomes and polymeric micro particles and nanoparticles, the solid lipid nanoparticles (SLNs) were introduced in the year 19918. A solid lipid nanoparticle (SLN) is typically spherical in shape, with an average diameter between 10 to 1000 nanometers. SLNs are aqueous colloidal dispersions, the matrix of which comprises of solid biodegradable lipids. They are manufactured by techniques like high pressure homogenisation, solvent diffusion method etc9. SLNs combine advantages of the traditional systems but overcome some of their major disadvantages. They exhibit major advantages such as improved bioavailability, use of cost effective excipients, improved drug incorporation and wide application spectrum8.

Advantages of SLNs
• Modulated or Sustained release of active drug over a long period can be achieved.
• Incorporated drug can be protected against chemical degradation.
• Possible sterilisation can be done by autoclaving or gamma irradiation.
• SLNs can be lyophilised as well as spray dried.
• Toxic metabolites are not produced.
• Organic solvents can be avoided.
• Relatively cheaper and stable.
• Industrial scale production by hot dispersion technique can be easily employed.
• Incorporation of drug can reduce distinct side effects of drug.
• Surface modification can be easily accomplished and hence used for site-specific drug delivery systems10,11.

However, there are certain limitations associated with SLN, like limited drug loading capacity and drug expulsion during storage, which can be minimised by the next generation of solid lipids, known as Nanostructured Lipid Carriers (NLC), which are lipid particles with a controlled nanostructure that improves drug loading and firmly incorporates the drug during storage11.
Preparation of Semisolid Drug Carriers for Topical Application Based on SLNs
Sustained drug release becomes important in dermal application concerning drugs that are irritating at high concentrations. Furthermore, it provides the possibility to supply an active ingredient over a prolonged period of time and can reduce systemic absorption.

Therefore, the liquid SLN dispersion usually has to be incorporated in convenient topical dosage forms like hydrogels or creams to obtain a topical application form having the desired semisolid consistency. This multistep production process however has a lot of disadvantages, which are listed below:

• The production process is time-consuming because SLN dispersion and dermal drug carrier have to be produced separately.
• Moreover, applying the hot homogenisation process for the preparation of SLN dispersions requires cooling down of the hot O:W nanoemulsion prior to adding it to the topical dosage form11.
• Conventional SLN dispersions contain about 10 per cent lipid and 8090 per cent water. Therefore, their loading into a topical dosage form is limited. Hence drug loading is also limited.
• Incompatibilities with ingredients from the hydrogel or cream may occur (e.g., gelling agent or surfactants).
• Aggregation of the nanoparticles is possible especially when using polar gelling agents like charged polysaccharides10.
• Also, the use of neutralising agents like sodium hydroxide for the preparation of polyacrylic acid gels can affect particle size.
• Electrolytes like sodium ions can reduce the zeta potential of the particles leading to aggregation of the particles, which is a well known fact also for lipid nanoemulsions12.
• Finally, the total amount of excipients is very high.

Avoiding these disadvantages the development of a new one-step production process delivering a semisolid topical formulation including SLN was noted13.

In SLNs for topical application, loading capacity of a drug depends on the solubility of a drug in a lipid melt, produced by high-pressure homogenisation by using an APV Lab 40 homogeniser. Most of the lipids used in SLNs have approved Generally Recognised As Safe (GRAS) status. Possessing a lot more advantages over the traditional manufacturing methods this one-step production process opens an opportunity for the researchers and scientists in their respective fields to explore new therapeutic targets using various active pharmaceutical ingredients.

Conclusion
Carrier systems like SLNs were developed with a perspective to meet industrial needs like scale up, qualification and validation, simple technology, low cost, etc. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could be used for further levels of drug targeting.
This review mainly focuses on the advantages and limitations of the solid lipid nanoparticles over other colloidal carriers and different traditional techniques available for the formulation of SLNs and their applications in therapeutics. Due to their unique size-dependent properties, lipid nanoparticles offer the possibility to develop new therapeutics. Owing to their properties and advantages, SLNs may find extensive application not only in oral and parenteral administration of pharmaceutical actives but also in topical drug delivery,

Acknowledgements
The author is greatly thankful to the Chairman and Managing staff of VASUDHA PHARMA CHEM LIMITED for providing required facilities and for rendering their co-operation and support.