Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges

*Kapil Gore, Sankha Bhattacharya and Bhupendra Prajapati*

## **Abstract**

Nanosponges are a class of nanoparticles characterized by their sponge-like surface that ensures high loading capacity. Cancer causes high mortality and requires precise treatment without harming the body. Hence, nanoparticles are required to target medications to tumor. Nanosponges may be synthesized from various polymers and metals, giving them distinct properties. The majority of polymer synthesis entails crosslinking, while metal synthesis entails the isolation of metal nanoparticles accompanied by their assembly into sponges. Nanosponges must be functionalized to precisely attack tumors. There are several patents on nanosponges synthesis and their use. Future trends in the usage of nanosponges include simultaneous distribution of several molecules and expanding the spectrum of use from medicinal delivery to substance encapsulation for a multitude of applications. As their usage in the pharmaceutical industry grows, more emphasis should be put on toxicity-related aspects induced by the near association of cell membrane and nanosponge resulting in intracellular dissolution or reactive oxygen species (ROS) generation, which in turn damages various cellular components. Many techniques have been created to reduce toxicity, including functionalization with various materials such as antioxidants, polymers and altering nanosponges composition. As the application of nanosponges increases in many industries, the phenomenon related to toxicity must be further explored through research.

**Keywords:** nanosponges, nanoparticles, silver nanosponges, cyclodextrin nanosponges, cancer therapy, β-hydroxypropyl beta-cyclodextrin

## **1. Introduction**

Cancer is a collection of diseases triggered due to uncontrolled cell division [1]. Cancer cells are able to migrate from their original site to any other site through the vasculature is what that makes them harmful [2]. Cancer occupies the second position in list of deaths worldwide by causing 9.6 million deaths in 2018. Cancer causes a tremendous economic burden on the patient and ultimately on the nation [3]. Traditional treatments for cancer include surgery, chemotherapy and

radiation therapy [4]. The traditional therapies are now more advanced as the time has progressed. Yet, they have many drawbacks which make them ineffective for destruction of tumor [5]. Surgical treatments suffer from disadvantages such as early diagnosis, presence of micro metastases, disruptions of tumors and side effects of anesthesia [6]. Radiotherapy involves treatment with ionizing radiations with a drawback of non-discriminate action against healthy cells at the sites where cells have a rapid growth rate such as hair follicles. It causes side effects like hair loss, anemia, sores in mouth and throat, neuropathy, skin dryness, and change in skin color [7]. To prevent these side effects, nanoparticles are used that can penetrate inside the tumor due to their nanosize. It reduces not only the amount of drug used but also the associated side effects due to action at places where it is not needed [8]. Many nano-formulations such as nanosponges and nanoparticles have been invented for their delivery to cancer [9]. In this chapter, we have discussed about nanosponges, their classification, advantages, disadvantages, and how they are better than other nanocarriers. We have also enlisted the barriers affecting delivery to cancer and how nanosponges can be used to overcome them along with some applications of nanosponges along with functionalization of nanosponges to ease delivery to cancer. We have also discussed about toxicity of nanosponges and the probable mechanisms to reduce that toxicity.

## **2. Nanoparticles in treatment of cancer**

Nanoparticles are nanosized particles containing polymers or lipids which contain drugs adsorbed or encapsulated in them [10]. One advantage of nanotechnology in cancer treatment is modifications of delivery system to achieve targeting [11]. Nanoparticle-mediated delivery of any cytotoxic agent allows control on the biodistribution of drug, hence controlling the toxicity [12]. Nanoparticles allow drugs with lower molecular weight to stay in the circulation for a prolonged period [13]. Nanoparticles being 1000 times smaller than a cancer cell can easily cross the vasculature and reach the interstitium. Due to their small size, and a relatively large surface area allows loading with large number of molecules [14]. Nanoparticles also help to remove difficulties due to innate properties of active pharmaceutical ingredient (API) such as poor solubility can be overcome by using water-soluble polymers to trap the drug within [15]. Many chemotherapeutic agents which have low molecular weight face issue of hepatic clearance, but conversion into nanoparticles prevents quick clearance [16]. Nanoparticles reduce the exposure of drugs to the environment inside the body and prevent the degradation of the drugs and the side effects due to exposure of healthy cells to cytotoxic drugs [17]. Nanoparticles are being explored to give multiple actions at the same time. The researchers Xie et al. [18] inserted curcumin into nanoparticles made from bamboo charcoal. The nanoparticles were functionalized using D-α-tocopherol polyethylene glycol 1000 succinate. Due to a nano-formulation, the system gave better internalization, and this composite dosage form showed inhibition of P-gp which increased the efficacy of treatment. At the same time, the presence of antioxidants such as tocopherol and curcumin helped to remove any reactive radicals and showed radioprotective action [18]. Ma et al. [19] synthesized nanoparticles of poly-(acrylic acid) with CoSe using the aqueous precipitation method. These particles had photothermal transfer efficiency greater than 40% and negligible cytotoxicity. These nanoparticles were loaded with doxorubicin (DOX) which was shown to release in the acidic tumor conditions in cancer.

*Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges DOI: http://dx.doi.org/10.5772/intechopen.105817*

These particles gave a synergistic cytotoxic action due to chemotoxicity as well as phototoxicity [19].

Hu et al. [20] synthesized gold nanoparticles by rapidly reducing gold chloride trihydrate. To that solution, thio-PEG and thio-glucose were added which showed covalent bonding on gold nanoparticles. Glucose was attached to take advantage of excess glucose consumption of cancer cells as compared to normal body cells. The cells were allowed to take in the Glu-GNPs which were found to be effective than only irradiation or only gold nanoparticles [20].

#### **3. Barriers to drug delivery in solid tumors**

Tumors are a major presentation in cancer which exhibit presence of abnormal cellular and extracellular elements which can create obstacles in drug delivery to cancer cells situated deep within the tumors. Below given are barriers to drug delivery in tumors and ways to overcome those barriers-.

#### **3.1 Biological barriers**

Biological barriers include physiological components which prevent the reach of drug to tumors. To reach the desired site, the drug should circulate in the blood. Blood contains many proteins that form a structure around the drug particle called 'protein corona'. This phenomenon is called opsonization, and such opsonized particle is destroyed by phagocytes and macrophages. The physical characters of nanoparticle are determinants of extent of opsonization [21]. To prevent opsonization, the circulatory time is controlled using polymers such as PEG [22]. Yapa et al. targeted leucocytes and neural stem cells to facilitate entry into tumors as well as targeting metastases. The nanosponges were formulated using cholesterol and a CASPASE-6 sequence ((cholesterol-(K/D)nDEVDGC)3 trimaleimide) attached to a triangular maleimide linker which were then used to join lysine or aspartic acid. These function as apoptotic bodies and destroy the tumors [23]. If the nanoparticle avoids being opsonized, it still has to face many challenges to reach to its target sites, one being endothelium of blood vessels which is selectively permeable and on the top of that, being 'coated' by a negatively charged glycocalyx, it further restricts the reaction of particles with endothelial membrane [24]. Haemodynamic involves movement of nanoparticles through the blood vessels. As erythrocytes flow in the centre of the vessel, the other contents of blood are forced to move along the walls of the vessel. Understanding this phenomenon in context of nanoparticles will be helpful in design of better nanoparticles [25]. Particles larger than 5–6 nm are not able to squeeze through the continuous endothelium of a 'healthy' capillary. But in case of tumors, endothelial lining is more permeable and does not remain continuous. So, nanoparticles larger than 6 nm can cross these gaps to enter into the tumor microenvironment [26]. Because of inadequate lymphatic drainage, those particles do not get removed from the body. There is also a disparity in the sizes of the pores, which can be found in primary tumors, metastasized tumors, and even the same primary tumor, which is another drawback of this the enhanced permeability and retention effect (EPR) effect [27].

#### **3.2 Tumor microenvironment**

After the nanoparticle crosses successfully the endothelium and enters the tumor, it still has to cross the tortuous tumor microenvironment to reach to the tumor cells. The microenvironment consists of the tumor extracellular matrix that contains a network of collagen, elastin incorporating proteoglycans and hyaluronic acid. It maintains the tumor structure and provides nutrients and oxygen to cells. If the matrix is highly developed, it may cause the drug to get released far away from the target site [28]. Incorporating collagenase in the nanoparticles may help circumvent the collagen barrier and allow reach of nanoparticles [29]. The tumor growth cannot be infinite and is arrested because of presence of an extracellular matrix. The extracellular matrix also prevents efficient metastasis of the tumor cells. Tumor cells release various enzymes to degrade this matrix which are called matrix metalloproteinases [30]. These can be used in diagnosis of cancer as a marker. In this enzyme family, types 2 and 9 are more important in formation of tumors. Using drugs which inhibit metalloproteinases can be a best possible approach to counter this resistance [31]. Wang et al. synthesized nanosponges loaded with matrix metalloproteinase-14 inhibitor naphthofluorescein, which targets collagen in cardiovascular disease [32]. Flow of interstitial fluid in the tumor affects drug distribution as the drug exits vasculature from interstitium and finally reaches to cells. The movement occurs either by a concentration or a pressure gradient. As the blood vessel network is not uniform within a tumor, so the blood flow becomes uneven. Also, the drainage of interstitial fluid is poor due to poorly formed lymphatic network. It increases the interstitial fluid pressure. Due to high heterogeneity in tumor structure, the fluid pressure can be different for two tumors in the same organism [33]. As cancer cells prefer a type of fermentation over aerobic respiration, the amount of oxygen decreases and the number of acids increases near the centre. These conditions make the tumor resistant to certain treatments as radiation [34]. Hypoxia causes increased production of chemokines which promote angiogenesis and avoids detection from immune cells [35]. Also, the acidic pH may aid in targeting by using acid-sensitive polymers to release medication at the centre of tumor [36]. Caldera et al. synthesized nanosponges from cyclic nigerosyl-1-6 nigerose using pyromellitic dianhydride as a crosslinker. The nanosponges were prepared using high-pressure homogenization and showed swelling at lower pH which caused DOX release [37].

## **3.3 Cellular barriers**

Cellular barriers include various cellular components which prevent the reach of the drug to intracellular environment. Many drugs show their effects inside the cell. Hence, even if the drug reaches near cancer cells inside the tumor, it has to cross the cell membrane to enter inside the cell to exert its actions. The carrier should interact with cell membrane to achieve the release [38]. Physical characteristics of carrier such as size, surface charge and hydrophobicity affect the interaction with cell membrane. Charged particles show more interaction with cell membrane. Neutral particles may crowd near cell membrane preventing any further entry into the cell [39]. Particles smaller than 200 nm get internalized by clathrin-mediated endocytosis, and those which are larger undergo clavioline-mediated endocytosis. This process is an energy-dependent process. Cancer cell membranes express many ligands which can be targeted [40]. Singh et al. [41] prepared cyclodextrin nanosponges and attached cholesterol as a functionalization moiety. Cholesterol being a major component of cell membrane facilitates easy interactions with cell membrane and hence easy penetration in cells.

## **3.4 Organellar and vesicular barriers**

Once inside the cell, the carrier should travel to the designated target site so as to release the drug. This travel is mediated by endosomes, which is energy-dependent. Endocytosis occurs by various pathways physiologically, and the pathways may be different for different types of nanoparticles. Generally, all these pathways end up in taking contents to lysosomes where they are destroyed. Use of fusogenic lipids is advised to prevent this fate [42]. Yan et al. synthesized nanosponges and coated them with fusogenic lipids which enhanced internalization and a better delivery inside the cells [43].

## **3.5 Drug efflux transporters**

Till the medications reach the target site, only a small fraction of original dose remains which shows its effect. Hence, many tumors contain efflux pumps which remove the drugs out of tumor cells [44]. P-glycoprotein is one such receptor to throw the drugs out of cells. Various small molecules which are P-glycoprotein inhibitors can be used to avoid the efflux [45]. Arima et al. [46] prepared nanosponges of dimethylβ-cyclodextrin and loaded them with an immunosuppressant tacrolimus. These complexes were tested on rats where they showed increased bioavailability and dissolution rate. Pre-treatment of apical membrane with dimethyl-β-cyclodextrin showed dislodging of receptors from the membrane and successfully inhibited P-glycoprotein showing increased absorption of drugs [46].

## **4. Definition of nanosponges**

Nanosponges are sponges of very small size with diameter less than 1 μm. These are three-dimensional networks made of polymers which act as frames to hold the drug molecules inside them. These sponges circulate the body and can release the drug at a specific site [47].

## **4.1 Advantages of nanosponge**

Nanosponges offer advantages over other nanoparticles such as a targeted release of active constituents inside the body which is caused due to functionalization on the surface. Nanosponges allow flexibility of formulation due to various polymers used as well as stability due to the drug entering the pores of sponge. These are non-toxic, nonallergenic and non-mutagenic due to biocompatible ingredients used. As these sponges are made of biodegradable molecules, they are able to provide extended release due to slow degradation of drug. Nanosponges are stable over wide temperature range and show excellent stability over the pH range. As nanosponges have diameter less than a bacterium, the formulation is self-sterile as bacteria are unable to enter the formulation. They exhibit excellent thermal, physical and chemical stability [48].

## **4.2 Disadvantages of nanosponge**

Nanosponges can be used for only small molecules as large molecules may not enter the nanosized pores of nanosponge. The drug loading is also affected by the degree of crystallization. Dose dumping may be observed due to sudden degradation of carrier [49].

#### **Figure 1.**

*(A) Classification of nanosponge—this figure shows classification of nanosponges based on the materials used for synthesis. (B) Beta-cyclodextrin nanosponge—beta-cyclodextrin nanosponges are prepared by crosslinking betacyclodextrin molecules using crosslinkers. (C) Metal nanosponge—these are made by irregular arrangements of metal nanoparticles in irregular ways to create pores and channels on the surface. (D) Polystyrene nanosponge the polystyrene is chloromethylated and reacted with tin chloride to give a hyper-condensed polymeric nanosponge.*

## **5. Classification of nanosponges**

The classification of nanosponges based on the material used is illustrated in **Figure 1A** [50].

*Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges DOI: http://dx.doi.org/10.5772/intechopen.105817*


#### **Table 1.**

*Different types of beta-cyclodextrin-based nanosponges.*

#### **5.1 Cyclodextrin-based nanosponges**

Cyclodextrins have been majorly used for the preparation of nanosponges. These are cyclic oligosaccharides. These are cone-shaped molecules made of glucopyranose units. These units are arranged around a hydrophobic hollow core which is used to trap any molecules.

Selection of crosslinkers is important to alter the properties of the final product. Crosslinkers such as epichlorohydrin give cyclodextrin nanosponges with hydrophilic pores whereas crosslinkers such as diphenyl carbonate and diisocyanates give hydrophobic nanosponges [51]. Various types of cyclodextrin-based nanosponges are enlisted in **Table 1** and **Figure 1B** [52].

#### **5.2 Metal and metal oxide nanosponges**

Metal and metal oxide nanosponges have desirable characters such as a wide surface area, small particle size and better stability. Metal oxides are being shown interest due to their ability of interaction with other species such as atoms, ions and molecules. They are able to form a porous interconnected network and show properties different than bulk. These also show magnetism and semiconductor properties. Metallic nanosponges can be made from one, two or multiple metals simultaneously. The nanosponges made from two or more metals are desirable over those made from single metal as they are more porous and based on porosity, and they can be classified as micro, meso and microporous based on the size of sponge where microporous are smaller than 2 nm, macroporous being larger than 50 nm and mesoporous lying in between them (**Figure 1C**) [53].

#### **5.3 Polystyrene nanosponges**

Davankov et al. [54] prepared nanosponges of linear polystyrene by causing intramolecular hyper-crosslinking. The polymer was initially chloromethylated using dichloro monoethyl ether, and this solution was added to the solution of zinc chloride in the same ether which acted as a catalyst. This mixture was heated at 40°C for 3 h. The precipitated polymer was washed and dried. This polymer is dissolved

in 2 L ethylene dichloride distilled over phosphorous pentoxide. Tin chloride solution was added which changed the colors gradually from pink to brown. Acetone was added to dissolve colored complex. The solution was allowed to cool and was washed with water. The organic layer was separated and concentrated to 20% of starting volume. The nanosponges were isolated using methanol. They were dried and stored (**Figure 1D**) [54].

## **6. Mechanism and preparation of polymeric nanosponges**

For the formation of nanosponges made out of polymer, reaction conditions such as heat and solvents promote uncoiling of long polymer chains and reveal the groups for reaction with crosslinkers. Crosslinkers such as diphenyl carbonate release the phenyl group upon reaction which remains in reaction mixture, and the carbonyl group acts as crosslinkers during the formation of nanosponges. The extensive crosslinking causes winding and coiling of long polymer chains and forms pores and cavities leading to the formation of nanosponges. The prepared formulation is later purified using organic solvents such as ethanol to remove those impurities.

## **6.1 Melt method**

Cyclodextrins are made to react with crosslinkers like diphenyl carbonate, dimethyl carbonate and diisocyanates. All the dry ingredients are homogenously mixed and put into a flask and heated at 100°C. A magnetic stirrer is used to achieve uniform mixing of contents. The heating is kept up for a total of 5 h so that the reaction can take place. After allowing the mixture to cool down, the obtained solid is broken up into smaller pieces using mortar. It is then purified using the Soxhlet extraction method after being washed to remove any unreacted reactants [55]. Sadjadi et al. synthesized beta-cyclodextrin nanosponges using the melt method. A calculated amount of diphenyl carbonate was melted at 90°C in a beaker. Preheated beta-cyclodextrin was added to it. The mixture was stirred for half a day at temperature exceeding 100°C to allow reaction to get completed. The solidified product was cooled and pulverized. The product was washed using water and organic solvent and later purified using Soxhlet extraction [56].

## **6.2 Solvent diffusion method**

## *6.2.1 Emulsion solvent diffusion method*

Ethyl cellulose and polyvinyl alcohol are used to prepare nanosponges. Cellulose and drug are dissolved in organic solvent such as dichloromethane. Then this dispersed phase is added to continuous phase which is aqueous poly (vinyl) alcohol (PVA) solution. This mixture is stirred at high speed for a specific amount of time, and the product is filtered and dried [57]. Solunke et al. [58] prepared gliclazide nanosponges using emulsion solvent diffusion method. Gliclazide and Eudragit were added to organic phase, and aqueous phase was a PVA solution. Organic phase was added to aqueous phase, it was stirred, and nanosponges were collected and washed [58].

*Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges DOI: http://dx.doi.org/10.5772/intechopen.105817*

#### *6.2.2 Quasi-emulsion solvent diffusion*

This process involves polymers such as Eudragit. The polymer is dissolved into a solvent and the drug is added to same solution. This inner phase is added to PVA solution and stirred. The product is filtered out and dried [59]. Salunke et al. [60] prepared budesonide-loaded nanosponges by quasi-emulsion solvent diffusion method. Weighed amounts of Polymethyl-methacrylate (PMMA) and Eudragit S-100 were dissolved in organic solvent containing dichloromethane and methanol in equal proportions. Dibutyl phthalate was added to enhance polymer plasticity. The organic phase was added to aqueous PVA solution and was stirred for 2 h. The prepared nanosponges were recovered by filtration and were washed and dried [60].

## **6.3 Solvent method**

The polymer is mixed with an aprotic solvent such as dimethyl sulfoxide. Carbonyl crosslinkers are added to this solution. The reaction is allowed to take place at a range of temperature which may not increase the boiling point of solvent. The solution is cooled at room temperature, and a large amount of water is added to it. The product is recovered by filtration [61]. Rao et al. [62] synthesized nanosponges by the solvent method by dissolving anhydrous β-cyclodextrin and diphenyl carbonate and heating that solution at 90–100°C under stirring. The prepared product was washed with water and later with organic solvents to remove any unreacted constituents. The product was dried to use later [62].

## **6.4 Ultrasound assisted synthesis**

This method involves energy from ultrasound to carry on the reaction. The reactants are placed in the flask and heated with help of ultrasound. The mixture is allowed to react. Later the product is cooled down and broken with mortar. The product is washed with water and purified by Soxhlet apparatus [63]. Jasim et al. [63] prepared cyclodextrin nanosponges using ultrasound-assisted method. Weighed quantities of β-CD and diphenyl carbonate. The mixture was heated on an oil bath and was sonicated using a probe sonicator at 50% amplitude for 4 h. The product was broken down and washed to give final product [63].

## **7. Mechanism and methods of metal and metal oxide nanosponge formation**

Metal nanosponges are prepared by reducing a metal salt using a suitable reagent. Surfactants or capping agents are used to control the growth rate and structure of nanosponges. Ghosh and Jagirdar [64] prepared silver nanosponges in their research activity. Silver nitrate was used as a substrate for synthesis on nanosponge. The salt was reduced to silver cations using boranes. This reaction was carried out at a temperature above 300 K. The reduced metal salt releases free metal atoms. These join together to form nanoparticles. These nanoparticles join together to form nanosponges due to their irregular joining which produce pores or gaps in the structure. This process works like bottom-up approach of synthesis of nanoparticles as they are built from the atoms themselves [64]. Different mechanisms are used to prepare metal oxide nanosponges such as precipitation and removal from alloy. Dealloying involves removal of a more reactive metal from an alloy. Chemical dealloying is the most common method involving use of acids to react with more reactive metal to remove it from the alloy. Alloy nature and leaching conditions affect this process. Another method utilizes the mechanism of precipitation of metal separated from its salt. This separation is brought about by using reducing agents such as NaBH4. Later, it is heated at very high temperature to deposit the metal oxide which gives out hydrogen bubbles which are responsible for generation of channels and pores which are required for drug loading. A disadvantage is the variable pore size due to uncontrolled particle size which gets sedimented. Electrochemical deposition utilizes the mechanism of movement of ions towards the oppositely charged electrodes. The ions that migrate form a thin film on the surface of metallic/metal electrode. The changes in pH, temperature and current density can be carried out to vary the properties of the sponge prepared. Another method based on hydrolysis of metal precursors and their conversion to metal species is the sol-gel method. It involves electrolysis of metal compounds in 'sol' phase in a solvent. After passing the electric current, the metal particles deposit on the electrode with internal pores and cavities in form of gel. The coagulation of prepared particles can be avoided by altering pH of medium. Drying is performed by evaporation or supercritical methods which evaporate the solvent and forms pores [53].

## **8. Advantages of nanosponges over other nanocarriers**

Nanoparticles after reaching the site of action release their loaded drug all at once creating a 'burst'. Hence, effective dosage cannot be determined properly, whereas nanoparticles being made of biodegradable polymers release their drugs in a slow, controlled manner after the sponges encounter a tumor [48]. Nanosponges are soluble in aqueous as well as organic solvents. These are non-toxic carriers which are heatstable [65]. Nanosponges are water-soluble which allow the researchers to use them for dissolution of insoluble drugs after loading them into the sponge [66]. Loading and functionalization of nanosponges is pretty easy as compared to other nanoparticles. The functional groups protruding out of nanosponge surface can be used for postmodification strategies such as functionalization [67]. Many nanoparticles have complex chemistry; hence, they cannot be scaled up easily for large-scale production. On the other hand, nanosponges made of only polymers and crosslinkers are easy to scale up for commercial production [68]. As compared to other nanoparticles, where reconstruction of nanoparticles is difficult if they lose their structure, nanosponges can be easily remade by methods such as washing with eco-compatible solvents, mild heating or changing pH or ionic strength [69]. Where many types of nanoparticles are used to contain solid medications, nanosponges can be used to encapsulate not only solids but also liquids and gaseous drugs [70]. Nanosponges can be used to load both hydrophilic and hydrophobic drugs owing to the hydrophobic core and external hydrophilic branching. Hence, these nanostructures can be flexibly loaded with hydrophilic or hydrophobic molecules [71]. **Figure 2** highlights major researches on nanosponges from 2005 to 2022.

## **9. Methods of preparation of nanosponges**

Nanosponges can be prepared with a variety of methods and then can be loaded to give a varying amount of drug loading. Kumar et al. [72] prepared cyclodextrin

*Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges DOI: http://dx.doi.org/10.5772/intechopen.105817*

**Figure 2.** *Nanosponges major research timeline.*

nanosponges loaded with babchi oil using tiring at high speed. Similar approaches are described in **Table 2.**

## **10. Optimization of nanosponges**

Optimization involves obtaining a best combination of starting materials to get a formula which gives the desired results. Due to a simple composition, nanosponges can be optimized without much hassle, which is evident from the examples given in **Table 3**.

## **11. Morphological characterization**

Morphological characterization involves various instrumental methods to analyze the morphology of prepared nanostructure. Transmission electron microscopy (TEM) involves scanning a sample with a beam of focused electrons which is transmitted through the sample to understand composition of particle. Argenziano et al. [86] prepared β-cyclodextrin nanosponges loaded with paclitaxel. Pyromellitic anhydride was used as a crosslinking agent. Methods such as high-pressure homogenization were used to reduce the particle size. The analysis was performed on Philips CM 10 device. The sample was prepared on formvar-coated copper. The coated samples were air-dried. The results showed that spherical particles were formed. The size was in nano-range due to application of high-pressure homogenization in the synthesis of nanosponges [86]. Scanning electron microscopy involves scanning a sample using an electron beam focused on sample which is then converted into signals. Mady and Mohamed Ibrahim (2018) prepared nanosponges using β-cyclodextrin and diphenyl carbonate crosslinker in DMF as solvent. The mixture was sonicated and refluxed using water and ethanol to remove impurities. Scanning electron microscopy was carried out using model LEO-435 VP, Cambridge (UK). It was used at 15 KV accelerating



*Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges DOI: http://dx.doi.org/10.5772/intechopen.105817*

#### **Table 2.**

*Methods of preparation of nanosponges.*

voltage, and different resolutions were used to obtain images. The images showed a perfect spherical shape of loaded nanosponges. Some drug particles were present on the surface as well as numerous porous channels were present on the surface. As compared to blank nanosponges, drug-loaded nanosponges were more porous [87]. Atomic force microscopy involves interactions of probe with sample through up-down and side-to-side movement along area of sample which is checked using a laser beam. Choudhary et al. [88] synthesized two peptides. And these linked peptides were attached to a trimaleimide frame. It gave two structures with positive and negative charge. Then using those differently charged structures, two variants were formed having 15 and 20 subunits, respectively. These two types of structures were mixed under conditions mimicking human body which resulted in the formation of nanosponges. 0.05 M stock solution of NS was prepared in PBS, and a drop was added on a freshly prepared mica sheet. The buffer was removed using nitrogen stream for 2 min. Bruker Innova AFM system was used to take the pictures using a TESPA-HAR probe in tapping mode. Spring constant was kept 50 N/m and operated at a frequency of 350 KHz. Images were taken at a scan rate of 1 Hz. The structures with 15 subunits showed formation of bundles made from three to five subunits. The structure with 20 subunits formed excellent nanosponges in the range of 80–115 nm [88].


#### **Table 3.**

*Optimization of nanosponges.*

Photon correlation spectroscopy involves measuring Brownian motion of particles as a function of time which is recorded by scattering of laser where scattering is directly proportional to particle size. Yakavets et al. [89] synthesized nanosponges from ethyl cellulose, PVA and pleuronic F68 by emulsion solvent diffusion technique. The particle size was measured using a Nano ZS-90 (Malvern instruments Ltd., UK) at an angle of 25°. The sample was diluted 10 times and analyzed. The composition F2 showed minimum particle size at 83 nm [89]. Wang and Schaaf [90] synthesized size-controlled Au-Ag nanosponges. Their structural characterization was carried out using SEM and TEM. Advanced techniques, such as focused ion beam, were used to reveal the hybrid composition of nanosponges. 3D structural properties were analyzed using techniques such as synchrotron X-ray nanometography. Atom probe tomography can be used where the obtained images are aligned again and again to allow reconstruction of particle image and thus to obtain the parameters. Nanosponges have peculiar optical properties due to their complex structure. Properties such as optical scattering and photoluminescence can be measured using

*Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges DOI: http://dx.doi.org/10.5772/intechopen.105817*

dark field florescence confocal microscopy [90]. The analytical techniques may vary with use of the final product. Maity et al. [91] synthesized nanosponges of acidic aminosilicates for the purpose of catalysis. Those were analyzed using morphological characterization techniques such as SEM and TEM which confirmed the formation of nanosponges as well as their porous structure. X-ray diffraction studies were carried out to understand the percentage of aluminium precursors. 1-D and 2-D NMR studies were carried out to understand the locations of catalytically active sites of nanosponges. A temperature-programmed desorption study using ammonia was carried out to understand the distribution of acidic sites in nanosponges and to identify their correlation with NMR data [91].

#### **12. Encapsulation efficiency**

Encapsulation efficiency indicates the amount of drug which gets successfully entrapped in a nanoparticle. Rezaei et al. (2019) prepared cyclodextrin nanosponges loaded with ferulic acid where three ratios of β-CD: crosslinker taken namely 1:2, 1:4 and 1:8 were synthesized. To determine the encapsulation efficiency, drug-loaded and blank nanosponges were suspended in ethanol and sonicated at room temperature separately. The sonicated dispersions were filtered using a filter paper with pore size of 0.45 μm. Ferulic acid content was determined using UV-visible spectrophotometry at 319 nm. The analysis showed that nanosponge prepared with 1:4 ratio of β-CD to crosslinker showed maximum encapsulation as lower ratio resulted in an insufficient amount of crosslinking and a ratio of 1:8 showed hyper-crosslinking, hence reducing the amount of encapsulated ferulic acid [92]. Dhakar et al. [93] prepared cyclodextrin nanosponges loaded with resveratrol and oxyresveratrol. The prepared nanosponges were added to water to give a solution of 10 mg/ml, and drugs were added in different ratios of drug: nanosponge, i.e. 1:2, 1:4 and 1:6. The mixtures were stirred for a day in dark after sonicating them for some time. The supernatant was collected after centrifugation of formulation, and it was lyophilized to give a dry powder. The powder was subjected to High-performance liquid chromatography(HPLC) analysis to understand loading of the drugs. The powder was taken in vials containing ethanol and sonicated for an hour. It was analyzed using High-performance liquid chromatography(HPLC). The drug loading was maximum in the ratio of drug to nanosponge which is 1:4, since saturation solubility was achieved. The encapsulation efficiency of the nanosponges was found to be 77% for resveratrol and 80% for oxyresveratrol. In addition, the encapsulation demonstrated an increase in the solubility of previously insoluble compounds. Diphenyl carbonate and beta-cyclodextrin were used to make nanosponges in various molar ratios, including 1:2, 1:4, 1:6, 1:8, and 1:10. Through the process of freeze-drying, which involved adding specific amounts of blank nanoparticles and babchi oil to water, stirring, and sonicating for a day, they were loaded with the babchi oil. The mixture was centrifuged to remove the oil which did not enter the inclusion complex. The supernatant was removed and freeze-dried. A specific amount of NS were added to dimethyl sulfoxide and sonicated to separate drugs from complex. The samples were analyzed using UV spectrophotometer at 265 nm. The encapsulation efficiency was observed in the range 62–93%. The maximum efficiency was present in formulation with the molar ratio of cyclodextrin to carrier 1:4. In formulations with higher number of crosslinking agents, hyper-crosslinking resulted in less loading [72]. Appleton et al. [94] prepared β-cyclodextrin nanosponges by reacting polymer, triethanolamine

and pyromellitic dianhydride in DMSO at 90° in an RBF. The prepared product was solidified, washed and ground. The coarse product was ground and purified with acetone using Soxhlet extraction. Insulin was loaded in blank carriers by mixing an acidic solution of drug in a solution of nano-formulation where the ratio between insulin and nanosponges was 1:5. The mixture was stirred, and the sediment was lyophilized. Such prepared nanosponges were added to a mobile phase in a proper concentration and sonicated. The solvent was analyzed using UV spectrophotometry. The encapsulation efficiency was 91% [94]. The product was washed using water and ethanol and later purified using Soxhlet extraction. For loading, solvents such as ethanol, methanol, acetone and only essential oil were tested for four different time intervals from 1 to 4 days. A weighed quantity of nanosponges were placed in a microtube, and coriander essential oil dissolved in a solvent was added. The mixture was stirred at room temperature to facilitate loading. Then the sample was centrifuged to separate the loaded nanosponges and was freeze-dried. After freezedrying, the samples were dispersed in acetone and stirred for a day which were later centrifuged to separate the acetone supernatant. The obtained supernatants were analyzed using Gas chromatography–mass spectrometry (GC-MS). Five major constituents such as pinene, cynene, camphor, linalool and geranyl acetate were used to detect quantitatively [95].

## **13. Nanosponges for delivery of anticancer drug**

Anticancer drugs are notoriously famous for their side effects which can be decreased by the use of nano-formulations which reduce the dose required and hence the side effects. Wang et al. synthesized nanosponges from DNAzymecontaining ZnO to release therapeutically active ROS [96]. **Table 4** indicates such similar results and show enhanced action of dosage forms over administration of single API.

## **14. Functionalization of nanosponges**

Functionalization involves attachment of various functional group or functional molecules on nanoparticle surface. Such a process imparts targeting properties to the nanoparticle. Femminò et al. functionalized cyclodextrin nanosponges using oxygen to relieve hypoxic conditions in ailments such as tumors [103]. Some examples of functionalization of nanosponges using chemical as well as biological functional ingredients are shown in **Table 5.**

## **15. Future trends**

Nanosponges have been limited for catalytic action or use as a carrier. Mostly simple nanosponges or those with basic functionalization are synthesized and used for delivery of single therapeutic agents, but the future trends are nanosponges that have been designed for storage of phase change materials. 3-D carbon-based materials such as nanosponges are preferred for loading of phase change materials which can be applied in locations such as operation tables, storage of medical and pharmaceutical products. Nanosponges can show advantages for application of both solid- and liquid-phase change


#### *Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges DOI: http://dx.doi.org/10.5772/intechopen.105817*


**Table 4.**

*Nanosponges for delivery of anticancer drugs.*


*Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges DOI: http://dx.doi.org/10.5772/intechopen.105817*

#### **Table 5.**

*Functionalization of nanosponges.*

materials. Carbon nanosponges have high loading and can be filled with a high number of materials. And nanosponges do not behave to changes in temperature [108–110]. Korea Ceramic Technology Institute developed a thermosponge for the treatment of cancer. It is a thermoresponsive nanosponge used for delivery of both hydrophilic and hydrophobic drugs. This nanosponge is made up of a core of poly-D, L-lactide which is loaded with a hydrophobic drug and the outer covering is made up of Pluronic-F127 which is loaded with a hydrophilic drug. The drugs can be released at the same time or the drug entrapped in the core may be released at a later time showing a prolonged release. The system is biodegradable and biocompatible, hence showing very less to no toxicity at all.

## **16. Conclusion**

In this review, nanosponges and their synthesis, characterization, optimization and applications regarding cancer have been discussed. According to the literature, nanosponges can be classified based on their starting materials which could be polymers, metals, metal oxides, etc. Polymer nanosponges can be manufactured by methods such as melt method, emulsion method, solvent method and ultrasoundassisted method. Metallic nanosponges are manufactured by methods such as dealloying and sol-gel methods. Factors related to drugs or process parameters influence formation of nanosponges. These process parameters were used by many researchers to optimize the formulation of nanosponges to give the optimum results related to loading efficiency, particle size and encapsulation efficiency. Polymer structure also affects the formation of nanosponges. Tumors are important manifestations of cancer and provide many challenges to deliver drugs inside the tumor where dividing cells are located. These challenges can be overcome by the process of functionalization with chemical moieties or biological entities such as cell membrane fragments. Such prepared nanosponges can be characterized with many methods such as SEM and TEM which are reported in literature. Toxicity of nanosponges may be a growing concern due to their ever-increasing role in multiple industries. According to the literature, nanosponges are safe for use as a carrier. But their nanosize may alter their properties, and hence reactivity causes toxicity due to processes such as physical interaction, ROS generation and intracellular dissolution. Many methods have been reported in literature such as using antioxidants and altering the material available to reduce this toxicity.

## **Declaration of interest statement**

Authors declare there are no conflicts of interest.

## **Abbreviations**


*Recent Pharmaceutical Developments in the Treatment of Cancer Using Nanosponges DOI: http://dx.doi.org/10.5772/intechopen.105817*

## **Author details**

Kapil Gore1 , Sankha Bhattacharya1 and Bhupendra Prajapati2 \*

1 Department of Pharmaceutics, School of Pharmacy and Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra, India

2 Shree S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Gujarat, India

\*Address all correspondence to: bhupendra.prajapati@ganpatuniversity.ac.in, bhupen27@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 5**

## Organogel: A Propitious Carman in Drug Delivery System

*Anjali Bedse, Deepa Singh, Shilpa Raut, Kajal Baviskar, Aarti Wable, Prajwal Pagare, Samruddha Wavikar and Samiksha Pagar*

## **Abstract**

A gel is a semi-solid formulation having an external solvent phase that is either apolar (organogels) or polar (hydrogels) that is immobilized inside the voids contained in a three-dimensional networked structure. Organogels are bi-continuous systems composed of apolar solvents and gelators. When used at a concentration of around 15%, the gelators form self-assembled fibrous structures that become entangled with one another, resulting in the formation of a three-dimensional networked structure. The resulting three-dimensional networked structure blocks the flow of the external apolar phase. Sterol, sorbitan monostearate, lecithin, and cholesteryl anthraquinone derivatives are examples of gelators. The unique characteristics such as thermo-reversibility, viscoelasticity, and versatility impart a longer shelf-life, prolonged drug release, and patient compliance. These characteristics can easily be adjusted by simple formulation modifications, resulting in highly-structured architectures. Organogels are more likely to be used in various types of delivery systems because of their ability to entrap both hydrophilic and hydrophobic molecules inside their structure. Their combination with other materials allows for tailoring their potential as dosage forms. Organogels have potential applicability in numerous ways; hence this article discusses the various aspects of it.

**Keywords:** organogels, organogelators, drug delivery, lecithin

## **1. Introduction**

Gels are defined as semisolid, cross-linked systems containing condensed solid particles interpenetrated by a liquid [1]. Gels can be referred to as hydrogels or organogels, which can be distinguished on the basis of polarity comprised by the gel, that is, if the liquid phase in the gel is water then it is referred to as a hydrogel, whereas if the liquid phase in the gel is an apolar solvent, then it is referred as an organogel. Organogels are the carriers used for delivering the medicament at its desired site [2]. Organogels are formed by gelators, which are foundational building blocks. Gelators are often certain low-molecular-mass substances (e.g., sorbitan derivatives, lecithin, fatty acid derivatives, bis-urea compounds) [3–5]. The gelators help in the formation of a 3D structure of a mesh network due to the entanglement of self-assembled fibrous structures, which are formed due to some physical or chemical interactions of gelators when used in the concentration of <15% (approx.) [6, 7]. Gelators are hence responsible for immobilizing the apolar solvent phase. The gels formed by the physical interactions are termed physical gels (held by physical forces such as Van der Waals and hydrogen bonds) whereas the gels formed by chemical bonding are termed chemical gels (held by covalent bonds) [7]. The gelators elevate the surface tension which predominantly prevents the flow of the solvent phase. Gelators immobilize organic solvents by the establishment of non-covalent intermolecular interactions forces (H-bonds, electrostatic interactions, metal coordination, p–p stacking, and London dispersion forces), resulting in the formation of various entangled structures like wrinkles, lamellar, and fibers [8–11]. The thermo-reversible property, non-irritating nature, and biocompatibility of the organogels have generated much interest in their potential application as a drug delivery system. Wide formulations can be developed for the administration of drugs via various routes using organogels as they can incorporate hydrophilic and hydrophobic bioactive agents within their gel structure. The rate-limiting step in the bioavailability of drugs from organogels is its characteristic features, that is, high permeability, and low aqueous solubility, which affect the rate of drug release from drug delivery systems. They have no confined application as they can be used for topical application or for the release of drugs into systemic circulation by cutaneous delivery and percutaneous absorption [7, 12].

## **2. Types of organogel**

## **2.1 Lecithin organogels (LOs)**

Since LOs have the desirable physicochemical characteristics ideal for topical formulations, these are employed most frequently for topical application. These are useful for the delivery of a wide variety of hydrophilic as well as lipophilic drugs through the skin. Lecithin is a constituent of natural origin which can be isolated from various animal and plant sources (except egg yolk) and hence biocompatible, safe and stable [7, 13, 14]. It is a potential vehicle for a number of bioactive agents. Lecithin is chemically a phosphatidylcholine, a constituent of the class phospholipids. It has been observed that lecithin is unable to form a gel if its phosphatidyl content is less than 95% [7, 15]. The concept of designing organogels with lecithin was first mentioned by Luisi and Scartazzini in the year 1988 [16]. Lecithin can only produce gelation if it is used in its pure form (e.g., the hydrogenated form of soya-lecithin failed to induce gelation). The unsaturated fatty acids present in naturally occurring lecithin are hence important [15].

## **2.2 Pluronic lecithin organogels (PLOs)**

High-purity lecithin is costly and difficult to procure in significant quantities. Due to the convenience of synthetic polymers such as pluronics, which serve as co-surfactant and stabilizers, they have been widely studied in combination with lecithin to formulate lecithin micro-emulsion-based organogels [17]. It was prepared in 1990 in the US by a compounding pharmacist to use as a topical carrier system [15]. The primary benefit of employing PLs in organogels is their capacity to self-assemble into micelles at approximate physiological temperatures [11]. Pluronic F-127 is a

*Organogel: A Propitious Carman in Drug Delivery System DOI: http://dx.doi.org/10.5772/intechopen.107951*

copolymer which causes gelation when used in a concentration of 15–30% w/v [18]. It is formed by adding the Pluronic F-127 to the LOs. It is majorly used for transdermal as well as topical drug delivery systems and also for oral and mucosal drug delivery systems to some extent [15]. It forms a non-transparent yellow gel [19]. After topical administration, PLOs rupture the lipid layer of the stratum corneum and deliver the drug into the systemic circulation with minimal irritation to the skin [7, 18]. Additionally, in order to have a synergistic effect, it has also been demonstrated to be a useful transporter for combinations of drugs [20]. It works best when combined with medications whose molecular weight is less than 500 Da [21].

#### **2.3 Limonene GP1/PG organogels**

Limonene is a terpenoid with magnificent penetration power and is used in transdermal drug delivery systems as it can enhance the bioavailability of drugs [22]. This organogel is prepared by mixing a suitable amount of GP1 (dibutyllauroylbutamide) amino acid type of organogelator with limonene and PG (propylene glycol), followed by its incubation at 120°C. After cooling down to an appropriate temperature, it forms a gel that appears white in color. It has been observed that the co-existence of limonene with GP1 and PG influences its rheological behavior to some extent, whereas their chemical characteristics are not significantly affected [7, 15, 19, 23]. The GP1/PG organogels tend to have increased gel moduli due to the incorporation of limonene, which gives an indication of increased gel physical stability [24]. Other terpenoids such as cineole and linalool, have also been successfully mixed with GP1 and PG to obtain an effective organogel with improved penetration power [18].

#### **2.4 Micro-emulsion-based organogels (MBG) stabilized by gelatin**

Micro-emulsions offer good bioavailability of drugs when introduced via topical or systemic routes of the drug delivery systems. Micro-emulsions are known to deliver a greater amount of drug than other gel systems [15]. The micro-emulsion system can undergo gelation when gelatin is dissolved in the water microphase, and the resultant gel will consist of more than 80% hydrocarbon solvent [25]. The basic mechanism involved in the formation of MBG is that a solution of gelatin in water is added to the parent micro-emulsion after it has been incubated at 50°C in the incubation chamber. In order to obtain an optically transparent single-phase gel, the resulting liquid is forcefully mixed and then allowed to cool to ambient temperature [26]. Gelatin is a protein that has the ability to form gels. It can undergo gelation when its concentrated solution is heated beyond 45°C and is then cooled down below 35°C and increases thermostability. When gelatin is added to w/o micro-emulsions, a transparent gel of the complete micellar solution is obtained [7, 15, 19, 27, 28].

#### **2.5 Sorbitan organogels derived from fatty acids**

Sorbitan monopalmitate (span 40) and Sorbitan monostearate (span 60) are the gelators of this class. They are non-ionic, hydrophobic in nature, and possess surfactant properties. They form a solid-fiber matrix when heated with the apolar solvent and then cooled down to a relatively lower temperature. A gel of toroidal reverse micelle is formed due to a drop in the temperature, which is followed by self-assembly leading to its transformation into rod-shaped tubules. The gel so obtained is white,

opaque, semisolid, and thermostable at room temperature. These organogels are used as vehicles for hydrophilic vaccines [29–31].

## **2.6 Polyethylene organogels**

Low molecular-weight polyethylene is solubilized in mineral oil at a high temperature of more than 130°C, yielding a colorless organogel. This causes intermolecular interaction within the polyethylene, which leads to the precipitation of its molecules, which forms a solid-fiber matrix to form a gel [16]. They are generally used as a base for ointment preparations [19]. A study conducted in the 1950s concluded that the patches of polyethylene organogel were found to be non-irritating along with low sensitizing properties [15].

## **2.7 Eudragit organogels**

Eudragit organogels are formed by the mixture of polyhydric alcohols (propylene glycol and glycerol), a high concentration (30–40%) of Eudragit (L or S), and liquid PEG. To prepare a formulated Eudragit organogel, the drug is first dissolved in the PEG, and this solution is then added to the Eudragit powder. This mixture is further triturated with the help of a mortar and pestle for approximately 1 minute. The concentration of Eudragit and the amount of drug are found to directly influence the consistency of the gel. The gel viscosity is enhanced with a high concentration of Eudragit, whereas it decreases with an increasing amount of the drug. In low concentrations of drugs, the gel has high rigidity as well as stability [7, 15].

## **2.8 Supramolecular organogels**

These organogels are made of gelators of low molecular mass. The molecules of different gelators of this class differ immensely in their structural characteristics. Hence, they have offered a scope of interest to develop different gels with technological application. For example, having sensitivity toward external stimuli like light. Remarkable thermoreversibility and mechanical capabilities are displayed by supramolecular organogel systems with controlled self-assembled structures. These organogels can offer controlled drug delivery. They can be used as carriers for multiple purposes [15, 32].

## **2.9 L-alanine-derived organogels**

LAM (N-lauroyl-L-alanine methylester) undergoes gelation with organic solvents such as triglycerides and soya-bean oil. It is not as extensively used as other organogels. At room temperature, it remains in a gel state [7, 15, 18]. In a biphasic mixture of water and apolar solvent, a fatty acid derivative of L-alanine aids the gelling of the solvent-specific portion of the mixture without gelling the aqueous portion [33]. This characteristic makes it considerably more appealing to use in organogel. It can be used as an implant for sustained release system. Currently, it is used as a vehicle for the drugs like leuprolide, rivastigmine [7, 18].

## **3. Importance of organogels**

For the conveyance of medications in the body/target site, numerous procedures and frameworks have been analyzed. Out of the effective applications accessible, organogels are getting greater fame on account of the simplicity of utilization, better

#### *Organogel: A Propitious Carman in Drug Delivery System DOI: http://dx.doi.org/10.5772/intechopen.107951*

ingestion through the skin layers, etc. Amongst the existing dosage forms, organogels are the easiest to prepare and have also been proven to be cost-effective [7, 34, 35]. They offer a better stability profile than that of other gels. The characteristic features of organogels not only make it easier for the manufacturer to process but also provide an easy handling and utilization method for the consumers, hence making it of commercial importance. The organogels can deliver the drugs more effectively than other dosage forms. This has been validated through a study which was conducted by I.M. Shaikh et al., where it was observed that the penetration efficiency of organogel (LO) was greater than that of hydrogels when applied over skin [35, 36]. As it offers a controlled drug delivery system, many chronic diseases could be cured if the organogels are loaded with appropriate drugs and then implanted at the target site. This characteristic also eliminates the obligation of frequent dosing. They have an extended application as they lend opportunities to incorporate various constituents having wide-ranging characteristics. Organogels can be used as an alternative to UV-treatment methods. Hence, it will eliminate the chances of cancer caused by exposure to UV rays [37, 38]. Organogel can reduce/control the dissemination rate of medication, hence making it liable for designing an appropriate formulation for an appropriate purpose to deliver the drug as required. As it comprises both hydrophilic and lipophilic parts, both lipophilic and hydrophilic bioactive agents could be consolidated within it [15, 38]. Therefore, wide-ranging drugs could be incorporated into them.

## **4. Advantages of organogels**

It is an easy formulation to prepare and has a longer life span. Bioactive agents of distinct characteristics can be incorporated [37, 38]. Their physical form remains unaffected by the factor of time owing to structural cohesion. It is cost-effective as it requires a lower number of components [37–39]. They have simple handling and usage requirements. It also provides improved patient compliance [34]. It has various applications for topical delivery systems. It has thermal stability [38]. A few chemical modifications can lead to the release of drugs in the desired manner and at the desired place [34]. It bypasses first-pass metabolism, ensuring that medicines have the highest possible bioavailability. They are relatively safe as bio-compatible constituents are used. Hence, it can be used to deliver various drugs. It is non-invasive and is better tolerated by the patients. It is a thermodynamically stable system. As it can be used for an extended period of time, the need for dosing is less frequent. It has both hydrophobic and hydrophilic units. Therefore, bioactive agents of either nature can be incorporated into it. There is no risk of microbial contamination as they are insensitive to moisture [34, 38].

## **5. Limitations**

It accounts for low thermostability. It has a greasy texture [2]. For the drugs that are intended to be penetrated through the skin, they must possess an appropriate partition coefficient. It holds good chances for the occurrence of swelling (uptake of liquid resulting in an increase in its volume) or syneresis (natural shrinkage if allowed to be at rest for a period of time) [15, 40]. Organogels intended for topical application might irritate the local skin. Topical organogels cannot comprise bioactive agents with

molecular weights of more than 500 Dalton, since skin can be permeated by drugs with molecular weights under 500 Dalton [18]. The purity of the constituents present is important, or else there might be no gel formation. Few organogelators are not available on a large scale, hence causing expense elevation for formulation, for example, lecithin organogelator. The purity of the constituents present is important, or else there might be no gel formation. Precise control of process variables (pH, temperature, etc.) is mandatory. Skin permeation enhancers and non-polar solvents are added in order to achieve deep penetration through skin, which may produce toxicity. Because of the gelator and the necessary solvent used, it is difficult to determine whether the gelation process will be successful [41].

## **6. Properties of organogel**

A few characteristic attributes that organogels possess include non-invasiveness, non-toxicity, etc. But its substantial physicochemical properties, which frame it as a significant and essential system, are as follows.

## **6.1 Viscoelasticity**

The term "viscoelasticity" is related to the materials that possess the two properties, that is, viscosity and elasticity. The viscoelastic property of organogels has also been authenticated by stress relaxation studies [6, 42]. They act as solids at lower shear stress (elasticity) and as a flowing fluid at escalated shear stress [15, 38]. At low shear rates, there is no pressure acting over them; hence they behave like solids with an intact structure, but at higher shear stress, as the pressure increases, the 3D-mesh network within the structure starts rupturing, permitting it to flow. It is observed that the organogels appear to follow the Maxwell model of viscoelasticity. It is observed that they retain plastic-flow behavior. "Organogels" are similar to other gel systems; the gelling agent creates an ongoing, three-dimensional network in the solvent, obstructing the flow of liquid. The rheological behavior of the gelator solution and its interaction with the solvent can greatly influence the flow property of the organogels [6, 15].

## **6.2 Thermostability**

The nature of the organogels makes them innately thermostable. The capability of the gelators to undergo self-assembly under suitable conditions to produce organogels may be responsible for the stability of the organogels. The overall free energy of the system decreases when the gelators undergo self-assembly, yielding a low-energy thermostable organogel. At elevated temperatures, the molecules within the organogels acquire some kinetic energy to reduce any loss in their structure, and low temperatures, they resume their original structure. This innate property of the organogel is responsible for its longer shelf-life, thereby making it ideal for the delivery of bioactive agents [15, 16, 19].

## **6.3 Thermoreversibility**

The matrix structure of the organogel is distorted when it is heated at a temperature that is extended from its critical temperature and hence it starts flowing. This

*Organogel: A Propitious Carman in Drug Delivery System DOI: http://dx.doi.org/10.5772/intechopen.107951*

added thermal energy causes interaction amongst the molecules of the organogel, causing disruption in the structure. But as the temperature decelerates, the interaction of the molecules also retards, which results in the reverting back of the organogel to its original configuration. This whole phenomenon is called thermoreversibility property of the organogels. For example, PLOs, when heated above 25°C (critical temperature), lost solid-matrix configuration, and after cooling, and returned to a stable configuration. The fluid matrix systems (Fluid matrix organogels) are thermoreversible [7, 16].

#### **6.4 Non-birefringence**

Birefringence is the optical property of a material that allows propagation of light when polarized light passes through it. The organogels are non-birefringent, that is, they do not allow the propagation of light when polarized light passes through their matrix. As a result, when organogels are observed under polarized light, these appear as dark matrix. This can be attributed to the isotropic property of the organogels [16, 19, 29, 43].

#### **6.5 Optical clarity**

The transparency or opacity of the organogels will depend on the chemical makeup they possess. For example, sorbitan monostearate organogels and PLOs are opaque, whereas the lecithin organogels are transparent in nature [30, 44].

#### **6.6 Chirality effect**

It has been observed that the stability and growth of the solid-fiber networks are both impacted by the presence of chirality in LMW (Low-Molecular Weight) gelators. Additionally, the thermoreversibility of the gels produced as a result of the selfassembled solid-fiber network is related to chirality. A competent solid-fiber gelator has been shown to be generally effective in possessing a chiral center, but fluid-fiber gels are unaffected by chirality. The gelators inclusive of chiral centers aid in the production of a tight molecular packing, hence impart kinetic and thermodynamic stability to organogels. The Crown ether phthalocyanine organogel is a good chiral organogel example [7, 45].

#### **6.7 Biocompatibility**

Previously, the organogels were formulated by using several non-biocompatible components, which resulted in non-biocompatible organogels. Currently, research on organogels involving different biocompatible constituents such as vegetable oil and cocoa butter has increased their potential for extended use in biomedical field [15, 19, 38, 40].

#### **7. Organogelators**

Organogelators are the gelling agents that have the capability to transform a preparation into a semisolid mass, that is, gel. They are used to impart the desired consistency in organogels. Hence, they are an integral component in the formulation of

organogels. The solubility of the organogelator in the solvent generates a few forces, which is the reason for the stability of the thermodynamic and kinetic characteristics of the gel [7]. Organogelators have the property of changing their physical state depending upon the temperature. They remain as a solid matrix at room temperature but transform into liquid at relatively lower temperatures. The structure of organogels mainly depends upon the constructing ability of the organogelator [9]. The degree of cooperative self-assembly in an organogel is also regulated by the gelator structure and solubility [46]. The most manageable type of organogelators are n-alkanes and are useful in gelling the other proportionally short-chained alkanes [2]. It precipitates out as fibers form a 3D-structure. It is mainly responsible for the design/structure of organogels. They produce bond formation within the molecules of organogels, leading to their interaction and bonding amongst each other and an increase in the thickness of the preparation. Depending upon the type of bond they form, organogelators can be regarded as-hydrogen bond forming organogelators, viz., amino acids, amides, carbohydrates, etc., or as non-hydrogen bond forming organogelators, viz., anthraquinone, steroidal moieties, anthracene, etc. [9, 19, 38]. The ongoing research on organogelators has formed a branch for other novel types of gelators, including sugar-based organogelators and green organogelators, etc. [47, 48]. These new types of gelators each have their own concepts that should be studied comprehensively for a better understanding of the widespread availability of organogelators from a variety of sources.

## **7.1 Types of organogelators**

## *7.1.1 Aryl cyclohexanol derivatives*

These are 4-Tertiary Butyl-1-aryl cyclohexanols derivatives. Their characteristic features, which they impart in the gel, may differ depending upon the nature of the apolar solvent involved in the organogel. They possess low solubility in apolar solvents and hence they might appear as a turbid or transparent preparation, depending on the nature of apolar solvent involved. Their physical state is solid at room temperature. They can produce gelation only if the phenyl group in their structure lies in the axial configuration. The derivatives possessing phenyl groups in the equatorial configuration are unable to form the gel. They help in obtaining the organogels with the desired property of thermo-reversibility. A few common examples of this class are CCl4, benzene, cyclohexane, etc.

## *7.1.2 Polymer organogels*

These are long chain-containing gelling agents. These are the gelators that possess a high capability of inducing gelation. They have a molecular size of more than 2 kilo Dalton. They can impart gel formation even if used in very low concentrations. They can appear in different shapes (straight, branched, etc.). Their efficiency of imparting gelation can be modified if their chemical structure is somewhat altered. They can be further divided into physical or chemical organogelators. If they form chemical bonds within the network of organogel, then they are regarded as physical organogelators which result in a cross-linked network, and if they form non-covalent bonds, then they are regarded as chemical organogelators which result in an entangled chain-linked network. The transition temperature for the transformation of the gel state to a sol state is also very low. They have relatively higher gel-strength than other LMOGs. They mostly

include L-lysine derivatives and the other conventional examples are polyethylene, polycarbonate, polymethylmethacrylate, polyester, etc. [18, 19, 34, 38, 40].

#### *7.1.3 Gemini organogelator*

"Gemini" means "twins". This word has been derived from Latin language. The first Gemini organogelator of L-lysine was synthesized by Suzuki et al. [49]. It had two chains of L-lysine of different chain lengths, linked together by an amide bond. This chain length is inversely proportional to the gelation ability of the gelator. They possess good gelation properties. They have a high ability to immobilize various kinds of apolar solvents. A good example of this class is Bis (N-lauroyl-L-lysine ethyl ester) oxylamide which can immobilize solvents like ketones, alcohols, etc. [9, 18, 19, 38].

## *7.1.4 Boc-Ala(1)-Aib(2)-β-Ala(3)-OMe organogelators*

It is a synthetic tripeptide gelator of synthetic origin. It is capable of undergoing self-CB (1, 2-dichlorobenzene), 1-chlorobenzene, etc.

## *7.1.5 Low-molecular-weight organogelators (LMWOs)*

These are the gelling agents that possess a small molecular weight (≤3000 Dalton) [9, 50]. Assembly which is the contributor of its gel-formation ability. They form thermoreversible and transparent gels. The apolar solvents, to which they can immobilize include benzene. These are most widely used organogelators. They contain a high capability of immobilizing the aqueous phase, even if used in small concentrations (<2%). The length of the alkyl chain in LMWO directly influences its gelling ability [51]. They mostly form solid-fiber matrices or can form fluid-fiber matrices based on the intermolecular interaction they perform. A solid-fiber matrix can be obtained if the organogelator is cooled down beyond the solubility range of the gelator, which is then followed by a rapid, incomplete precipitation, in the organic solvent, which leads to physical intermolecular interactions. For forming a fluid matrix, a polar solvent should be added to the solution of surfactant, leading to the re-arrangement of molecules to form a clump, hence immobilizing the aqueous phase. This also results in a difference in the kinetic-stability between both the matrices, which can be used as a distinguishing factor. Solid-fiber matrix offers an enhanced mechanical property compared to that of fluid-fiber matrix. This is because a solid-fiber matrix contains a highly arranged molecular structure compared to a fluid-fiber matrix. LMOGs have been further categorized into steroidal organogelators, ALS organogelators, etc., depending on the chemical backbone they possess [7, 19, 34, 38, 52].

## **8. Mechanism of organogelation**

Organogelation is generally induced by the incorporation of a polar solvent into the organogel. If lecithin is present in it, then, it forms reverse spherical micelles at a ~ 0.01 mM concentration. This is induced by the addition of a small quantity of polar additives which bind to the hydrophilic head of the lecithin. This creates linear networks. If the amount of polar additive is further increased, then it leads to the formation of long tubular flexible micelles. After overlapping with each other sufficiently, they entangle themselves and build up a transient 3D network (**Figure 1**).

**Figure 1.** *Mechanism of Organogelation.*

In the case of PLOs, the mechanism of gelling and the structural network may be related to the synergistic contribution of both phospholipids and polymeric cosurfactant molecules in their respective hydrated states. In this case, solvent molecules and lecithin phosphate groups can be arranged in such a way that a hydrogen-bonded network will be formed [15, 34, 52].

## **9. Mechanism of gel permeation into skin**

Human skin is made up of different types of tissue layers. The outermost layer, Stratum corneum is the rate limiting barrier for the permeation of gel into the skin [35]. It has been observed that lipid based formulations enhance penetration through the skin; however, they modify the hydration state of the skin, causing dermatitis. Aqueous formulations maintain the skin intact and bioactive, but have less penetration [18]. In the case of Pluronic Lecithin organogels, penetration and permeation are enhanced due to lecithin, which alters the skin structure and transiently opens the skin pores. It is believed that this happens due to the interaction between the lecithin's phospholipid and skin lipids. Hence, there occurs the formation of a cylindrical network which results in an increase in the area of the lecithin polar region, and nonpolar solvent acts as a penetration enhancer and then penetration occurs by forming a thin film on the skin surface (**Figure 2**) [16, 18, 35].

## **10. Method for preparation of organogels**

At 60°C, the oil-surfactant mixture is heated to produce a transparent solution that, when cooled, transforms into organogels. Lecithin solutions are made by first dissolving lecithin in organic solvents using a magnetic stirrer, according to the phase diagrams that have been constructed. Organogels are created by adding water with the use of a micropipette syringe. Heat may be used occasionally to completely dissolve drugs. Lecithin and an organic solvent are combined to create the oil phase, which is then let to stand overnight to guarantee full breakdown. When preparing the aqueous (polar) phase, pluronic is added to ice-cold water and stirred to ensure

**Figure 2.** *Pathways for permeation of organogel into skin.*

thorough dissolve. The produced PLO is blended with the Pluronic's aqueous phase using a high-shear mixing technique by a magnetic stirrer. Fatty-acid gelators can also be used to create organogels by first dissolving them at a higher temperature in a water-in-oil emulsion, then lowering the temperature. The solubility of the gelator decreases as a result of the drop in temperature, which leads to precipitation and selfassembly of the gelators into a network of tubules that become entangled to create a gelled structure [2, 19].

## **10.1 Fluid-filled fiber method**

It is a well-known technique for making organogels, where in reverse micelles are produced by dissolving surfactants and co-surfactants in an apolar solvent. Reverse micelles are then transformed to tubular reverse micelles after the addition of water. The elongated reverse micelle becomes entangled to create a 3-dimensional network, which immobilizes apolar solvent [53].

## **10.2 Solid fiber method**

In the Solid fiber method, an apolar solvent and solid organogelator are heated together at an apolar solution of the solid organogelator is produced. Then cool it at room temperature, the organogelator precipitates out as fibers that interact physically with one another to form a three-dimensional network structure that immobilizes apolar solvent [15, 38].


#### **Table 1.**

*Formulations of organogels used in drug delivery.*

## **10.3 Hydration method**

In this technique the inorganic chemical is directly hydrated to form the dispersed phase of the dispersion, which is then used to create gel. Other substances such as propylene glycol, propyl gallate, and hydroxypropyl cellulose may be employed in addition to water as a carrier to improve gel formation [53].

## **10.4 Novel methods**

Conventional methods of preparing organogels usually require longer heating times and neutralizing agents. Evren et al. prepared organogels employing a new technique, high-speed homogenization which was followed by microwave heating. Evren et al. prepared Triclosan organogel employing Carbopol 974 NF in PEG 400. Carbopol in varying concentrations (2–4%) was dispersed in PEG 400. The resulting dispersion was homogenized at 24,000 rpm.. The dispersion was heated using two methods. The first involved heating at 80°C, stirring mechanically at 200 rpm. In the second method, the dispersion was subjected to micro-irradiation (1200 W/1 h) for 2 min. The results demonstrated that microwave heating was suitable for preparing carbopol organogels. Owing to significant reduction in time and energy, the method holds good promise for industrial applicability [54] (**Table 1**).

## **11. Factors affecting organogels**

## **11.1 pH**

A pH change stimulates the reversible transition of an organogel from a gel state to a sol state [61]. Hence, pH can influence the physical state of gels.

## **11.2 Temperature**

Organogels are often less stable with increasing temperatures, causing disruption of the 3D mesh-network structure. Temperature also affects viscosity. As the temperature increases, the viscosity decreases [4]. Hence, the temperature range during their storage should be closely controlled [5, 18, 19].

## **11.3 Organogelator**

The type of organogelator used for the preparation has the capability to influence the mechanical and rheological properties of the organogel [40].

## **11.4 Adjuvants**


Terpenes operate as chemical penetration enhancers and also act as rheology modifiers, which may result in any alteration in the flow property and deformation characteristics of an organogel [63].

## **11.5 Moisture**

Organogels swell when exposed to moisture as they absorb water molecules from it This may aid in the instability of the organogels [38].

## **11.6 Purity**

The constituents used in an organogel should be in its pure form. Any impurity in the components may lead to instability in the network of the matrix, for example, lecithin is unable to induce gelation if not used in its pure form [2, 40].

## **12. Application of organogels**

## **12.1 Pharmaceutical industry**

a.Topical drug delivery system.

The skin, being the largest tissue in the body, provides good bioavailability of drugs, as the drugs meant to enter the systemic circulation via permeation through the skin bypass the first-pass metabolism. Pluronic lecithin organogels (PLOs) contain isopropyl myristate/isopropyl palmitate as an apolar organic solvent used as a vector for the release of NSAIDs (ketoprofen, flurbiprofen, diclofenac sodium), used as an analgesic. Reverse micellar MBGs possess soya-lecithin/iso-octane/water as a solvent phase for the delivery of propranolol. Organogels can be regarded as potential matrices for the controlled release of topical antimicrobials. Organogels loaded with Piroxicam are used for the treatment of rheumatoid arthritis. In-situ forming organogel of L-alanine injectable can be used for the release of labile macromolecular drugs. Various studies on formulation of transdermal organogels, such as development of PLO with mometasone furoate for psoriasis and fluconazole-loaded organogels based on olive oil for fungal infections, have exhibited positive results [9, 42, 64].

b.Oral and trans-mucosal drug delivery system.

The drugs can be delivered through oral cavity with the help of implantation of bio-adhesive organogels, that is, the drugs will be administered as implants. The drug can be dissolved within the organic solvent and then mixed with the muco-adhesive polymer. An organogel of 12-HSA-soyabean oil was used for the delivery of ibuprofen [15]. An in-vivo study conducted in rats depicted that the organogels can be employed as a vector for controlled release of lipophilic drugs [38]. Sorbitan monoleate based organogel, incorporated with cyclosporine A is given orally. An oral organogel can be prepared by incorporating an NSAID (ibuprofen) to achieve desired therapeutic results [65].

c.Parenteral drug delivery system.

Parenteral routes are the preferential choice for the administration of drugs, as it avoids first-pass metabolism, provides quicker onset of action, etc. An in-situ forming organogel prepared for sustain delivery of leuprolide (used in prostate cancer) from the L-alanine derivatives in safflower oil and was injected by SC route. It was observed that the gel degraded slowly for drug release over a span of 14–25 days [7, 15]. Sorbitan monostearate organogel preparation have been developed and given by SC and IM route for the release of propranolol/ cyclosporine A/ BSA and HA [7]. A study depicted that, safflower oil-based N-methyl pyrrolidone (NMP) injections were introduced into rats subcutaneously, which was welltolerated by the surrounding tissues over a period of 8 weeks [66]. The injection of an in-situ organogel forming implant based on SAM (N-stearoyl-L-alanine methyl ester) demonstrated significant promise for safe and suitable delivery method for therapeutic medications that require regulated release [67]. A successful evaluation was conducted for the purpose of using parenteral organogel in schizophrenia therapy [68]. The micro-emulsion based organogels and niosomes containing organogels have been formulated for delivery of vaccines. After administration of these gels via intramuscular route, a depot effect was observed (**Table 2**) [15].

d.Ophthalmic drug delivery system.

Ophthalmic solutions are generally used for administering drugs in the eye, but due to its consistency, frequent dosing is required as the drug may not be properly


#### **Table 2.**

*Evaluation of organogels.*

absorbed in the target site. Hence thicker preparations like gels are desired to increase the contact time to facilitate the maximum absorption of drugs from the formulation. Methazolamide is incorporated into carbomer and poloxamer gels for the treatment

of glaucoma which was ineffective when formulated as ophthalmic solution [38]. Organogelators are employed with drugs such as Eudragit L and S for ophthalmic preparation for sustained delivery [50].

## **12.2 Food industry**

Organogels are primarily employed in the food industry owing to their ability to reduce oil mobility in food items, particularly those containing multiple ingredients. Organogels can be used as replacer for Trans and saturated fat in processed foods to install a specific texture. Wax-based organogels provide good oxidative stability, and also influence the firmness and spreadability and thus can be used in spreadable food product [18, 64, 70].

## **12.3 Cosmetics industry**

Low molecular weight organogelators (LMOGs) such as DBS and 12-HSA are used for preparation of lipsticks [71]. 12-HSA organogelator is used in sunscreens to block UVB rays [41]. It is possible to improve the properties of organogels developed for cosmetic applications by using organic solvents like Amazonian oils, which already possess moisturizing and nourishing effects [72]. Various dermatological cosmetics such as lip-gels, skin, and hair protectants can be prepared in the form of organogels [18, 38]. Other cosmetic preparations such as shampoo, dentifrices, and perfumes are prepared in the form of organogels [15].

## **13. Conclusion**

Organogels are a visco-elastic substance primarily made by gelling the organic solvent with a bioactive agent. It has captivated a section of curiosity to explore all the aspects of their application, as these can potentially eliminate or replace many components, techniques as well as limitations being faced normally for different types of formulations, due to unique properties. The organogels have a huge area for application, although possess few drawbacks and limitations. Though these can be administered to the body via various drug delivery routes, the major site is topical route considering ease of application and many more reasons. A stable organogel designed with all the bio-compatible components might attract the commercial market in future as they can potentially become the preferential choice of formulators and consumers.

## **Acronyms and abbreviations**


*Organogel: A Propitious Carman in Drug Delivery System DOI: http://dx.doi.org/10.5772/intechopen.107951*


## **Author details**

Anjali Bedse\*, Deepa Singh, Shilpa Raut, Kajal Baviskar, Aarti Wable, Prajwal Pagare, Samruddha Wavikar and Samiksha Pagar Department of Pharmaceutics, K K Wagh College of Pharmacy, Dr Babasaheb Ambedkar Technological University, Raigad, Maharashtra, India

\*Address all correspondence to: bedseanjali1980@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 6**

## Transdermal Delivery of Drugs for Acute and Chronic Pain

*Carlos Miguel López-Mendoza, Ana Jared Tenorio-Salazar and Luz Eugenia Alcántara-Quintana*

#### **Abstract**

Pain is universal, it contributes substantially to morbidity, mortality, and disability, and is a serious health problem. Acute pain usually lasts less than 7 days, but often lasts up to 30 days, and may recur periodically. Chronic pain, defined as lasting more than 3 months, affects approximately 50 million people and generates costs of \$635 billion. The problems related to inadequate pain management are frequent and important, so much so that emphasis has been given to the effective delivery of drugs through the skin. This organ has been studied extensively over the last decade because it is easily accessible and would help to solve the problem. It is evident that there is a need to improve transdermal drug delivery (TDD) as it offers multiple advantages, they are noninvasive, can be self-administered, and provide prolonged release. This chapter recapitulates the history of transdermal drug delivery and focuses on addressing the inadequate management of acute and chronic pain.

**Keywords:** transdermal drug delivery; chronic pain, acute pain, skin

## **1. Introduction**

The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory emotional experience associated with actual or potential tissue damage." It is the most frequent symptom in the medical office, associated with innumerable diseases. Pain negatively affects the patient's quality of life because it is usually poorly tolerated and interferes with daily activities. The presence of pain indicates that something is not working well, the perception is subjective and with a great emotional component. The etiology of pain is not always an easy task and requires an accurate assessment to determine its origin [1, 2]. It is important to recognize that not all pain is the same, so we must distinguish and classify each type of pain. Pain is mainly classified according to its duration as chronic pain, whose commonly accepted definition is "that pain that persists beyond the normal healing time," persists to the original cause, and has more than 3 months of duration. On the other hand, we have acute pain, which is of recent onset and lasts less than 3 months. It is important to distinguish between these two types of pain because their pathophysiology is different, therefore, the treatment is different (**Figure 1**) [1, 3]. Common routes of drug

#### **Figure 1.**

*Conventional and nonconventional pain treatment. The upper part of the figure shows the conventional treatment. The ascending pathway transmits pain and sensory information from the periphery to the brain. Painful stimuli activate primary afferent nociceptors of the mechanosensitive Aδ and C fibers, which send signals to second-order neurons in the spinal cord. This information is transmitted through the spinothalamic tract to tertiary neurons in the thalamus, and pain is perceived in the somatosensory cortex. The descending pathway inhibits pain via noradrenergic/serotonergic neurons and Aβ fibers. Conventional pain treatments and their sites of action (numbers) are shown. The lower part shows the nonconventional treatment, which consists of the application of transdermal patches to control pain. Abbreviation: NSAIDs: Nonsteroidal anti-inflammatory drugs; α2-agonists: α2-adrenergic receptor agonists; TCAs: Tricyclic antidepressants; SSRIs: Selective serotonin reuptake inhibitor.*

administration are the oral and parenteral routes. However, their use is limited due to rapid degradation in the stomach. This is just one example as the conventional routes of drug administration could be overcome by using new technologies.

## **2. History (pain management)**

In the 1970s, the first transdermal patches began to be developed, the first one approved being scopolamine, a treatment for motion sickness, which released the drug for 72 hours. Subsequently, nitroglycerin, clonidine, fentanyl, buprenorphine, lidocaine, nicotine, and hormone replacement therapy patches were approved for population management [4, 5].

## **3. Classification of drugs for acute and chronic pain**

Pain is almost universal, and contributes substantially to morbidity, mortality, disability, and health system burden. Acute pain usually lasts less than 7 days, but often lasts up to 30 days, and may recur periodically. Although acute pain usually


#### **Table 1.**

*Pain control options.*

resolves quickly, in some cases it may persist until it becomes chronic. Chronic pain, defined as pain lasting more than 3 months, is a serious public health problem in the United States, affecting approximately 50 million people and generating costs of \$635 billion. Chronic pain substantially affects physical and mental functioning, reducing productivity and quality of life [6–10].

The American Geriatrics Society Panel on Chronic Pain identified four basic pathophysiologic pain mechanisms that have important implications for choosing pain management strategies [11]. In choosing pain management strategies, it is necessary to adhere to various scales and in this regard, there are several pain measurement scales that help to classify and quantify the magnitude of pain complaints. The results of these scales are also useful for documenting and communicating pain experiences. And in correlation to these scales, the classification of drugs used to treat pain has been made (**Table 1**).

## **4. Limitations and adverse effects of conventional treatments**

The problems related to inadequate pain management are frequent and important. Uncontrolled severe pain can have serious adverse effects on the physical, psychological, emotional, social, and spiritual condition of patients, which has repercussions on daily life activities and leads to economic, labor, and social losses that affect a significant proportion of the population. The functional disability caused by pain is a cause of suffering in patients, their families, and other people close to them. Currently, there are four general categories of analgesic agents frequently used for the most common types of pain: paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. And one more category such as gamma-aminobutyric acid analogs, gabapentin analogs, and anticonvulsants. However, all of them have adverse effects, Paracetamol has been shown to cause liver damage [10, 11]. NSAIDs are associated with varying degrees of gastrointestinal (GI), cardiovascular, and renal adverse effects. Opioids can cause respiratory depression and cognitive and motor impairment; they can also cause dependence and addiction [12, 13].

## **5. Transdermal drug delivery systems**

The effective delivery of drugs through the skin has been studied during the last decade since the skin is easily accessible. Most compounds are administered with a hypodermic needle, the main limitation of this is pain, needle phobia, and transmission of infectious diseases, so alternatives that circumvent these aspects are sought [14]. However, needles are required to penetrate the skin barrier. The main barrier to delivering a therapeutic agent is the outermost layer of the skin, the stratum corneum (SC). Because of the above, skin permeabilization methods have been developed that offer great advantages over other drug delivery systems [14]. It is evident that there is a need to improve transdermal drug delivery (TDD) as it offers multiple advantages since they are noninvasive and can be self-administered; in addition, it provides prolonged release, i.e., for long periods, and is generally inexpensive when it becomes commercially available. TDD is a painless systemic delivery method, drugs are administered through healthy and intact skin, the drug initially penetrates through the stratum corneum, then passes through the deeper epidermis and dermis without accumulation in the dermal area. When the drug reaches the dermal layer, it becomes available for systemic absorption through dermal microcirculation [14, 15].

First-generation transdermal delivery systems have continued to evolve to reach the clinical setting. They are used in the administration of small, lipophilic, and lowdose drugs. Second-generation delivery systems where we see a different design using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products. Third-generation delivery systems target the stratum corneum using tools such as microneedles, thermal ablation, microdermabrasion, electroporation, and cavitational ultrasound. Currently, TDDS with microneedle and thermal ablation technology has been developed and is progressing through clinical trials for the delivery of macromolecules, such as insulin and parathyroid hormone [16, 17].

## **6. Formulation**

The basic components of a TDDS include polymer matrix, membrane, drug, penetration enhancers, pressure-sensitive adhesives (PSA), backing laminates, and release coating, the characteristics and examples are enounced in **Table 2**. In **Figure 2** we can observe the composition of each layer that compose different types of TDDS.

## **7. When to use them or not to use them?**

#### **7.1 Transdermal patches are used when**

• The patient has intolerant side effects and is unable to take oral medication (dysphagia) and is requesting an alternative method of drug delivery.

## *DOI: http://dx.doi.org/10.5772/intechopen.106449 Transdermal Delivery of Drugs for Acute and Chronic Pain*

#### **Figure 2.**

*Types of TDDS. This figure describes the different types of TDDS. Starting from left to right we have single-layer drug-in-adhesive and multi-layer drug-in-adhesive, which are similar in that they contain the drug in the adhesive layer and a solid-state, except for the multilayer, which has a membrane. Finally, we have the microneedle patches, which have penetration to the dermis, with biodegradable needles, from which the solid drug will be released. All these TDDS are intended for the active ingredient to travel to the capillaries between the dermis and the hypodermis.*


## **7.2 Transdermal patches are not used when**


## **8. Advantages, disadvantages, and limitations**

In **Table 3** we can observe the advantages and disadvantages of being treated with TDDS.

## **9. Permeation mechanisms**

## **9.1 Passive (patches)**

Patches belong to the first generation of transdermal delivery systems. Significant advances in patch technology have led to their everyday commercial use. Patches are



*DOI: http://dx.doi.org/10.5772/intechopen.106449 Transdermal Delivery of Drugs for Acute and Chronic Pain*

> **Table 2.**

*Characteristics of the TDDS components [18–22].*


#### **Table 3.**

*Advantages, disadvantages, and limitations of the TDDS [24–27].*

passive permeation systems; drugs diffuse through a membrane from a region of high concentration to areas of low concentration. The rate of diffusion is proportional to the gradient but also depends on the properties of the administered molecule such as solubility, size, degree of ionization, and the adsorption surface. The drug is stored in the polymer and has contact on one side with the impermeable backing and on the other with the adhesive. Some designs employ the drug dissolved in a liquid or gel reservoir, which can simplify formulations [14, 17].

#### **9.2 Active (microneedles)**

A simple way to selectively permeabilize the stratum corneum is to pierce it with very short needles. Micro-needle (MN) matrices are minimally invasive drug delivery systems that have the advantage of avoiding the use of hypodermic needles, thus improving patient compliance combines bine the ease of use of a transdermal patch with the effectiveness of hypodermic needle and syringe administration [27, 28].

MN are multiple microscopic projections assembled on a support base or patch; the support must be flexible with characteristics dictated by the properties of the material from which they will be made. Generally ranging from 25 to 2000 μm in height, 50 to 250 μm in width and base, and 1 to 25 μm in tip diameter [27]. The needles must be of adequate length, width, and shape to avoid contact with nerves when inserted into the skin layers. MNs are made of a polymeric matrix, which eventually degrades, thus releasing the therapeutic molecules into the dermis layer in the skin, to reach the blood vessels.

MNs are designed to create transient aqueous conduits through the skin, thus improving the flow of molecules such as low molecular weight heparins, insulin, and vaccines, all without pain [29]. The advantages offered by MN technology are the fact that they do not cause bleeding, eliminate the variability of transdermal dosing of small molecules, minimal risk of introduction of pathogens through MN-induced holes, can be self-administered, and the ease of disposal of MN waste [27, 30].

## **10. Types of TDDS**

## See **Figure 2**.

## **10.1 Single-layer (Unilayer)**

It is fabricated with three layers, a temporary liner in the lower, an adhesive in the middle, and a backing on the top, and Is called a Single Layer because the adhesive layer accomplishes two functions: the adhesion in the skin and a container for the active molecule.

## **10.2 Multilayer**

It is like the single layer in that the adhesive layer is the same as the one containing the drug but differs in that it adds another layer of drug-adhesive, usually separated by a membrane. It also has a temporary liner and a permanent backing.

## **10.3 Reservoir**

Unlike the unilayer and multilayer, this system has a separate drug layer. This layer is a liquid compartment containing the drug in solution or suspension separated by an adhesive layer. This patch also has a backing and a temporary liner. Its release kinetics is of zero order.

#### **10.4 Matrix**

This system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer surrounds the drug layer partially enveloping it.

## **10.5 Vapor**

The adhesive layer of the patch contains oils or another vaporized solution for its release. They release essential oils for more than 6 h to be used in cases of decongestion, other patches improve the quality of sleep and reduce the number of cigarettes in a month [31, 32].

## **11. Properties affecting delivery**

## **11.1 Physicochemical properties of penetrating molecules**

## *11.1.1 Partition coefficient*

A lipid/water partition coefficient, if 1 or greater is required for optimal transdermal permeability.

## *11.1.2 pH conditions*

At moderate pH, the flux of ionizable drugs can be affected by changes in pH that alter the ratio of charged to uncharged species and their transdermal permeability.

## *11.1.3 Penetrating concentration*

At a concentration higher than the solubility, the excess solid drug acts as a reservoir and helps to maintain a constant drug constitution for prolonged periods of time [33, 34].

## **11.2 Physicochemical properties of the delivery system**

## *11.2.1 Release characteristics*

The release mechanisms depend on whether the drug molecules are dissolved or suspended in the systems. Also on the partition coefficient of the drug from the delivery system to the skin and the pH of the vehicle.

## *11.2.2 Composition of drug systems*

The composition of the system (bonded layers, thickness, polymers, and vehicles) not only affects the drug release rate but also the permeability of the stratum corneum due to hydration, making skin lipids or other effects that promote absorption [34].

## **12. Processing methods**

## **12.1 Patches**

Patch manufacturing methods vary according to the type and purpose of the drug to be administered. Transdermal patches are complex pharmaceutical forms, consisting first of an impermeable outer coating layer—whose function is to protect the formulation—a reservoir with the active ingredient and permeation potentiators, an adhesive film that allows its fixation to the skin, and on top of it a removable protective layer that must be removed before application [17, 35].

## **12.2 Microneedle arrays**

The original MN fabrication methods involved clean-room sculpting of siliconbased structures, these have moved to low-cost fabrication methods [36] to make microneedles from metals, silicones, and polymers commonly found in FDA-approved devices. Microneedles offer a high range of possibilities in terms of delivery substances; in several studies, they have been dip-coated with a variety of compounds, including small molecules, proteins, DNA, and virus particles [28, 30, 37].

The shape and geometry of MN are very relevant during design and manufacturing. The needles should be able to be inserted into the skin without damage or breakage and should have the ideal length, width, and shape to avoid contact with nerves [38].

In general, four TDD strategies using MNs. These are solid, coated, soluble, and hollow MNs. Solid MNs are usually fabricated from sheets of solid materials either stainless steel or biocompatible materials, then electropolished. MNs used in antigen delivery studies are prepared as single rows of 5 needles. The needle should have the geometry of a pointed tip on a long elongated shaft, 50 mm thick and 200 mm wide at the base [11].

A recent method in MN fabrication is the use of biocompatible polymers on flexible backings that can be water-soluble. The patches dissolve completely in the skin; because the backing is water-soluble, there is no need to remove the device, ensuring total dissolution and reducing biohazard waste. In addition, due to the flexible backing, the patch can adapt to the skin and localize the insertion forces, this increases the ability of each MN to perforate the SC [18].

High-precision three-dimensional (3D) printing is a novel method of constructing solid micromodels. However, this method is still in its early stages both in the research field and in the pharmaceutical industry [39]. Another recent fabrication method for dissolving needles is the droplet air blowing method. Stamped droplets of polymer can be stretched between two plates. By blowing air between the two plates. The advantages of this method are the mild temperature and pressure requirements and the short fabrication time [40, 41].

## **13. Application according to the duration of pain**

#### **13.1 Acute**

The treatment of acute pain should act on the cause, although pain is only a symptom, the sensation of pain should be treated as part of the treatment. In mild pain, the first option is paracetamol. When the pain is moderate, NSAIDs alone or associated with opioids are the best option, and if they are to be avoided, the association of paracetamol with minor opioids is an acceptable alternative. Analgesic escalation prolongs the patient's suffering. Therefore, according to the assessment of pain intensity, prompt action should be taken [42].

For the treatment of acute pain, there are several options available on the market patches, whose active components are ketoprofen, diclofenac, and capsaicin (mild pain); buprenorphine and fentanyl are normally used in cases of chronic pain, in people who are expected to need analgesics 24 hours a day for a long time and who cannot be treated with other drugs.

These options in patch presentation offer advantages such as the patient can apply the patch himself without the need of a professional, the dosage is sustained, does not cause pain, avoids the hepatic metabolism step, is comfortable to wear, and can continue with daily activities.

#### **13.2 Chronic**

Chronic pain is associated with malignant (cancer) or nonmalignant conditions. TDDS are effective for the treatment of this type of pain, as the amount of intravenous and oral treatments can become harmful in a short period of time, causing mostly gastrointestinal tract problems. As we have seen throughout this chapter, the advantages of TDDS are also applied to treatment over long periods, although it implies a risk-benefit because these transdermal treatments can also give rise to adverse effects, although of lesser impact.

The approved TDDS for clinical use are composed of opioids, such as buprenorphine (BuTRANS, Transtec) and fentanyl (Duragesic). In addition, these systems can be directed to the elderly patient (> 65 years), we must remember that in these patients the metabolism decreases and the ratio in the body of fat/muscle is altered, consequently the doses of drugs should be decreased, in contrast to those of a young adult, because in the treatment of chronic pain they may suffer from respiratory depression when opioids and non-opioids are delivered by other routes, being an advantage a TDDS of prolonged release. TDDS for chronic pain are contraindicated in the management of acute and postoperative pain [43].

#### *13.2.1 TDDS buprenorphine*

Buprenorphine is a semisynthetic opioid, lipophilic in nature, which is intended to provide analgesia. The effect of this drug is of long duration (6−8 h), due to the dissociation of buprenorphine from the mu receptor. On the other hand, the buprenorphine transdermal patch has a slow onset (12−24 h) and a long duration (3 days) [44].

Clinical trials revealed that in patients with moderate to severe chronic pain it is possible to make a treatment switch from weak opioids to transdermal buprenorphine without problems. For patients who respond favorably to this form of release, an example of this is by reporting uninterrupted sleep for more than 6 h compared to a placebo group (without the active ingredient). The mean duration of treatment has been up to 7.5 months of analgesia in 90% of patients. In addition, it has been observed that it can work for neuropathic and nociceptive pain. The safety profile (renal), analgesia over long periods, and is a noninvasive treatment make it an attractive choice for the treatment of chronic pain in elderly patients [44].

Long-term treatment of chronic pain with transdermal buprenorphine has been evaluated for its efficacy and tolerability in cancer and non-cancer patients with moderate to severe pain. Buprenorphine 35 μg/h patches and buprenorphine sublingual tablets (0.2 mg) were used as rescue medication. The duration of maximum participation in cancer patients was 3.4 years and in non-cancer patients 5.7 years. Treatment adherence was 78.7%, with most patients (65.9%) managing their pain with only the patch or taking no more than 1 sublingual tablet daily as adjuvant. Ninety percent of patients reported pain relief and the patch was well tolerated [45].

However, these treatments are not free of adverse effects, since the typical conditions of opioid use have been reported, such as nausea, dizziness, vomiting, constipation, and tiredness, in addition to local effects such as erythema, pruritus and exanthema [44, 45].

## *13.2.2 TDDS fentanyl*

In 1990, the FDA approved the first formulation of an opioid pain medication in a fentanyl-containing patch with a 72 h duration. Fentanyl TDDS is effective and tolerated, forming a depot in the most superficial layers of the skin before entering the microcirculation. Therapeutic concentrations are obtained 12−16 h after patch application and decrease slowly, with a half-life of 16−22 h after patch removal. However, transdermal fentanyl should be used prior to patient sensitization with oral or parenteral opioids to avoid exacerbation of pain or opioid-related adverse effects, which is a disadvantage compared to transdermal buprenorphine [46].

Fentanyl patches were studied in patients with moderate to severe nom-cancer related chronic pain. With starting doses of 12.5 g/h to be later increased by 12.5 g/h or 25 g/h if the average pain score was equal or more than 4 in the first 72 h, the patients' pain relief was notorious, from a scale of 7 out of 10 of pain assessment it was reduced to 2 out of 10, after 12 weeks. In the treatment of soft tissue cancer chronic pain, the relief of pain comes with a 25 g/h dose patch, within the first 72 h and the severity of pain after treatment decreased significantly [47].

*DOI: http://dx.doi.org/10.5772/intechopen.106449 Transdermal Delivery of Drugs for Acute and Chronic Pain*

We must remember that these TDDS have their benefit, but also their risk, since the use of this TDDS has reported adverse effects in up to 72% of cases, such as nausea, vomiting and drowsiness. In addition, another effect related to opioids and the transdermal form of the drug is hypoventilation, so its use should be considered in patients with preexisting conditions of lung damage, such as emphysema. Other serious effects of TDDS include cognitive and physical impairments such as confusion or abnormal coordination [48].

## **14. Conclusions and perspectives**

There are several patch options available on the market for the treatment of acute and chronic pain, TDDS are an attractive option because of its advantages over other systems (pills, tablets) and it promotes pharmaceutical adhesion because it is a noninvasive method of dosage and the self-administration. However, considerations must be made in diminishing the secondary and adverse effects of the current ones or to combine new nanosystems for the drug encapsulation for better control of the release. In future outlooks, new smart transdermal delivery systems are being developed that include external stimuli for the release of the drug.

## **Acknowledgements**

We would like to thank CIACYT for their support.

## **Conflict of interest**

The authors declare no conflict of interest.

#### **Notes/thanks/other declaration**

We have no further statement to make.

#### **Nomenclature**


*Advanced Drug Delivery Systems*

## **Author details**

Carlos Miguel López-Mendoza, Ana Jared Tenorio-Salazar and Luz Eugenia Alcántara-Quintana\* Cellular and Molecular Diagnostics Innovation Unit, Coordination for the Innovation and Application of Science and Technology, Lomas Segunda Sección, San Luis Potosí, SLP, Mexico

\*Address all correspondence to: lealcantara@conacyt.mx

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 7**
