Nanocrystal cellulose as drug excipient in transdermal patch for wound healing : an overview

Wound must be carefully treated to avoid serious infection that needs costly treatment. Method to enhance the recovery of the wound is crucial to have effective wound treatment. One of the technologies in wound treatment is transdermal patch that has the benefits of being non-invasive, easy to handle and permits constant drug dosage. In order to obtain a good controlled drug release, drug excipient needs to be investigated. Recently, natural Nanocrystal Cellulose (NCC) which can be synthesized from animal, algae, microorganism or plant has been actively used in drug delivery system as excipient. The application of NCC is advantageous due to its large surface area, biodegradable, non-toxic and abundance source.


Introduction
Wound is a common infection that happens to human body and animal.It can occur due to mechanical, chemical or thermal injury [1].The injury ranges from a simple skin damages or it can be dangerous damages which involves deep cut.Serious injury can penetrates deep into subcutaneous tissue and harm other structures such as tendons, muscles, vessels, nerves, parenchymal organs and bones [1].Wound injury to critical patients such as diabetic patients, really need a good care and rapid healing rate to aid in their recovery.There are two basic principles in wound management which are; removing the impediments, and provide and maintain clean and conducive environment to heal the wound [2].The wound has to be kept clean and the wound surface has to be insulated and protected [2].
One of the drug delivery system (DDS) for wound healing that has been used for long period of time is transdermal patch.In December 1979, the United States Food and Drug Administration has approved the first prescription patch which is scopolamine for motion sickness.The drug delivery technology for dermatology disorder has evolved from ointment and cream to the transdermal patch because of its advantages such as; it allows constant dosing which prevent the fluctuation of drug level and it is also non-invasive.Besides, it is a better alternative to be used instead of the drug delivery through the stomach which sometimes becomes problematic when there is a difficulty for the drug to be absorbed through the gastrointestinal track.The steps for transdermal permeation of drug begins with the sorption by stratum corneum, followed by the penetration of drug through viable epidermis and continued with the uptake of the drug in the dermal capillary layer.
There are four types of transdermal drug delivery system which are membrane permeation controlled, matrix diffusion-controlled, adhesive dispersion-controlled and microreservoir/microsealed dissolution controlled system.The transdermal patch is not only used for wound healing but also has been used in other treatments as shown in table 1 -Electrospinning technique -The resulted nanomembrane of the drug and excipient were stable -The vitamin B12 was nearly 100% -The curcumin release was up to 70% The Diclofenac release was 80% [5] Schizophrenia Blonanserin (antipsychotic) -Investigation on effect of permeation enhancer, fisopropyl myristate -The release rate of blonanserin increased with an increasing concentration of fisopropyl myristate [6] Pain killer Methadone -Film casting method -The problem of drug release onto skin has been solved by blending the methadone with the enhancer (Dimethylsulfoxide) -The permeation of the methadone was increase up to 70 % [7] Pain killer Fentanyl -Fentanyl containing geopolymer granules results in a better resistance to tampering [8] -Eserine and pralidoxime chloride -The patch resulted in a complete drug release after 72 hours -The transdermal patches were stable for 6 months at 40 0  From table 1, transdermal patch shows great potential to be studied as drug delivery technique and can be applied for wound healing treatment.The drug release of the antibacterial drug in the patch can be sustained and controlled.Usually, the transdermal patch consists of outer liner and matrix membrane formed by active material and excipient.Besides the active material, it is also important to study the drug excipient because it has its own role in delivering the drug into targeted cell, tissue or organ.

Drug Excipient
Typically, the highest content in a drug tablet, capsule, patch or liquid is not the active pharmaceutical ingredient (API) but the excipient.Excipient is an inactive material that is purposely included in formulation of drug.Usually it has been properly tested for safety and it is considered essential to include the excipient in drug formulation to improve the manufacturability and stabilization of the API.There are many type of drug excipients such as binder (povidones, polysaccharide), filler or diluent (calcium phosphate, lactose), disintegrant (sodium starch glycolate, crospovidones), lubricant (magnesium stearate, glycerides), glidant or anticaking agent (talc, colloidal silicon dioxide), colorant (titanium dioxide; food, drug and cosmetic (FD&C) colours), capsule shell (gelatin, hypromellose), coating agent (hypromellose, shellac), flavour and fragrance (peppermint, berry), release modifier (ethylcellulose, guar gum), pH modifier (citric acid and its salts, salts of phosphoric acid), wetting or solubilizing agent (sodium lauryl sulfate, polysorbates), antimicrobial preservative (glycerin, benzyl alcohol), chelating or complexing agent (ethylenediaminetetraacetic acid salts, cyclodextrins), antioxidant (ascorbic acid, butylated hydroxyanisole) and sweetening agent (sucrose, saccharin) [11].Among the type of drug excipient that has been introduced before, polysaccharide was actively studied as an excipient in transdermal patch [12][13][14][15][16]).Starch, glycogen and dextrans are some of the example of polysaccharide used as an excipient and all of them are converted into energy in liver and muscles for a later use.Nowadays, there are numerous researches regarding cellulose (natural polysaccharide) as drug excipient which is discussed in next section.

Nanocrystal cellulose (NCC)
Nowadays, natural polysaccharide has become popular to be studied as an excipient in drug delivery system because of its properties such as highly safe, non-toxic, has abundant resources in nature, low cost in its processing, biodegradable, biocompatible, high water solubility and bioactivity [17 -20].There are many natural sources that supply polysaccharide i.e animal (chitosan, Chondroitin sulphate), plant (guar gam, pectin, cellulose, mannan), algae (alginate) and microorganism (dextran, pullulan) [21][22][23].Besides, large number of reactive functional groups havehydroxyl, amino and carboxylic acid groups on their backbone which make the polysaccharide structure to be easily derived.This characteristic contribute to their structural and functional diversity [24].From multi-functional group, it can be biochemically or chemically modified into many types of polysaccharide derivatives such as cellulose [25].
Rod-shaped cellulose with typical 10-100 nm in length and 1-100 nm in diameter is called nanocrystal cellulose (NCC) and it has potential to be investigated as drug excipient [26,27].There are many studies that have been done in drug delivery field using NCC as shown in table 2. NCC derived from plant has been actively studied in polymer reinforcement as a potentially new material [28].Commonly, the plant fibre contains of cellulose (40-50%), hemicelluloses (20-30%) and lignin (10-18%).The advantages of NCC are due to its large surface area and excellent colloidal stability [29].Most of the results from previous researches showed that NCC give positive effects on the quality of the drug release.The drug release has been significantly affected by pH of solution and formulation ratio.Since it shows the potential in controlling the drug release, it will result in constant drug permeation into the targeted area.Hence, this shows that NCC is a promising drug carrier to be further studied.

Conclusion
In this overview, transdermal patch shows a great potential to be further studied as drug delivery system to deliver the active ingredient onto the targeted treatment area especially skin because it can give constant drug release and fulfill the patient compliance since it is a non-invasive treatment.It is easy for the patient to use the patch to treat the targeted area such as wound.Besides, other ingredient in the patch that gives important effect on drug release and permeation is the excipient.The excipient shows positive result on controlling the drug release.Nanocrystal cellulose (NCC), a type of polysaccharide extracted from natural source such as plant has been actively studied to be used as excipient and from the results, it shows that NCC has great potential to be used in improving the control of the drug release for transdermal patch application.

Table 1 .
. Literature review on transdermal patch.

Table 2 .
Literature review on nanocrystal cellulose as drug excipient.