Advances in Nanotechnology Based Topical Drug Delivery Systems for Arthritis Management

Abstract

A targeted drug delivery system has been developed as a result of current advances in nanotechnology. However, a specialized medication delivery method is needed to successfully target a molecule to a specified spot. Additionally, the NS has been utilized to increase the solubility and rate of dissolution of medications that are poorly soluble. By enhancing their stability and half-life, nanosponges with controlled release characteristics can reduce medication toxicity. They are a three-dimensional, biodegradable network that releases the medication as it gradually breaks down in the body. The NS particles travel throughout the body until they reach a particular target place, adhere to surfaces, and start releasing the medication in a predictable and regulated way.Nanotechnology and nanomedicines represent a broad research domain that provides solutions to numerous unresolved issues related to drug delivery and therapeutics, and it is a rapidly growing field of science. Among the various nanoparticle-based dosage forms, nanosponges (NS) are at the forefront due to their ability to solubilize poorly water-soluble drugs and extend the release of medications. Nanosponges are extremely small, nanoscopic, sponge-like structures that contain multiple cavities filled with therapeutic agents. Arthritis, an autoimmune condition, leads to inflammation in the affected areas of the body. The use of nanosponge gel holds significant promise for the treatment of Arthritis, as it facilitates controlled and prolonged drug release while ensuring good stability.

Keywords

Meloxicam, Topical Nanosponges formulations, Arthritis management, Drug delivery, Inflammation, Drug encapsulation, Controlled drug release

Introduction

Topical drug delivery systems have emerged as a promising alternative for treating arthritis, enabling direct administration of medication to the site of inflammation. This localized approach results in a higher concentration of the drug at the affected joints while minimizing systemic absorption, thus reducing gastrointestinal and systemic side effects. Commonly utilized topical formulations, such as creams, ointments, and gels, are favored in arthritis management due to their ease of application and patient acceptability. However, traditional topical formulations frequently encounter challenges such as inadequate penetration through the stratum corneum, rapid drug release, a short duration of action, and the necessity for frequent reapplication. Recent advancements in nanotechnology have facilitated the creation of innovative drug delivery systems that can address the limitations of conventional topical formulations. Among these advanced systems, nanosponges have attracted considerable attention as effective carriers for delivering poorly water-soluble drugs. Nanosponges are nanosized, highly porous, three-dimensional polymeric networks created by cross-linking appropriate polymers. Their distinctive sponge-like structure offers a large surface area and internal cavities that can efficiently encapsulate drug molecules.

A gel formulation based on nanosponges functions as a reservoir system, enabling the controlled release of the drug over an extended duration. This prolonged release mechanism aids in sustaining therapeutic drug concentrations at the inflammation site, thereby decreasing the frequency of dosing and enhancing patient adherence to the treatment regimen. Arthritis is a chronic inflammatory condition marked by pain, swelling, stiffness, and diminished joint mobility. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly employed in the treatment of arthritis due to their anti-inflammatory and pain-relieving effects. Nevertheless, oral administration can lead to gastrointestinal side effects, liver toxicity, and poor patient compliance during prolonged treatment. Topical drug delivery systems present numerous benefits, including the avoidance of first-pass metabolism, minimized systemic side effects, and targeted drug action. Nanosponges represent innovative nanocarrier systems made up of cross-linked polymeric networks that can encapsulate both hydrophilic and lipophilic medications. These nanosponges facilitate controlled drug release, enhance drug stability, and improve skin permeation. They are designed to address local irritation or infection in the mouth or pharynx and may also be utilized for systemic drug absorption.

TYPES OF ARTHRITIS

Osteoarthritis - Osteoarthritis represents the most prevalent form of arthritis, resulting from the gradual deterioration of cartilage found in the joints. It primarily impacts older adults and frequently involves the knees, hips, and hands. As the cartilage deteriorates, bones begin to grind against one another, resulting in pain, stiffness, and limited joint mobility. This condition is non-inflammatory and advances slowly over time.

Rheumatoid Arthritis - Rheumatoid arthritis is a persistent autoimmune condition wherein the body’s immune system targets the synovial lining of the joints. This results in inflammation, swelling, pain, and stiffness, particularly noticeable in the morning. It typically affects joints symmetrically, such as both hands or both knees. If left untreated, it may lead to joint deformities and functional impairment.

Psoriatic Arthritis - Psoriatic arthritis manifests in individuals with psoriasis, a skin condition. It leads to joint pain, stiffness, and swelling, accompanied by skin symptoms such as red, scaly patches. This type of arthritis can impact any joint and may also induce changes in nails, including pitting or thickening.

Septic Arthritis - Septic arthritis arises from an infection in the joint, most often caused by bacteria. It results in intense pain, swelling, redness, and fever. The knee is the joint most frequently affected. This condition is considered a medical emergency and necessitates prompt treatment with antibiotics to avert joint damage.

Gout - Gout is a form of arthritis triggered by the build up of uric acid crystals in the joints due to elevated levels of uric acid in the bloodstream. It is marked by sudden and intense episodes of pain, redness, and swelling, often impacting the big toe. Dietary choices, alcohol consumption, and metabolic disorders are common contributing factors.

NANOSPONGES GEL

Nanosponges gel serves as a topical drug delivery system that incorporates tiny porous nanoparticles, known as nanosponges, into a gel base. These nanosponges are capable of encapsulating drug molecules within their structure and gradually releasing them upon application to the skin. This method of controlled release contributes to a sustained therapeutic effect while enhancing the stability and absorption of the drug. Furthermore, nanosponges gel minimizes side effects and skin irritation in comparison to traditional formulations. It is frequently utilized in dermatological treatments, pain management, and anti-inflammatory applications. The release of the drug from meloxicam nanosponge gel is characterized as a controlled, sustained, and diffusion-dominant process, influenced by the structural properties of the nanosponges and the physicochemical characteristics of the gel matrix. In contrast to conventional topical formulations that deliver drugs rapidly, nanosponge-based systems function as reservoir delivery systems, providing extended therapeutic action.

The mechanisms of drug release include:

•Diffusion from the polymeric matrix

•Swelling of the carrier system

•Controlled release from the reservoir

•Skin-controlled permeation

METHODS OF PREPARATION

Emulsion–Solvent Diffusion Method

The emulsion–solvent diffusion technique is the most widely utilized method for creating polymeric nanosponges. In this process, the drug and a polymer such as ethyl cellulose or Eudragit RS100 are dissolved in an organic solvent like ethanol or acetone to create the organic phase. This organic phase is then introduced dropwise into an aqueous phase that contains a stabilizer, such as polyvinyl alcohol, while continuously stirring. As a result of the diffusion and evaporation of the organic solvent, a porous nanosponge structure is generated. The resulting nanosponges are collected, washed, and dried. This method is straightforward, reproducible, and does not necessitate toxic cross-linking agents, rendering it highly appropriate for topical drug delivery systems.

Emulsion solvent evaporation method

Combine the polymer with an appropriate polar aprotic solvent, such as dimethyl formamide or dimethyl sulfoxide. Next, introduce this mixture to an excess amount of the cross-linker, ideally maintaining a cross linker polymer molar ratio between 4 and 16. Conduct the reaction at a temperature ranging from 10° C to the reflux temperature of the solvent, for a duration of 1 to 48 hours. Upon completion of the reaction, allow the solution to cool to room temperature, then add the product to a large excess of distilled water and recover the product through vacuum filtration, followed by purification using a Soxhlet apparatus with ethanol. Finally, dry the product under vacuum and grind it in a mechanical mill to achieve a homogeneous powder.

Solvent Method (Cross-linking Method)

The solvent method entails the creation of nanosponges through the chemical cross-linking of polymers, such as β-cyclodextrin, utilizing cross-linking agents like diphenyl carbonate or citric acid. In this approach, the polymer and cross-linker are combined and heated at a regulated temperature to establish a three-dimensional network structure. Subsequently, the drug is integrated into this network, leading to the development of nanosponges. This technique offers a robust and stable structure with a high drug entrapment efficiency; however, it necessitates meticulous handling of cross-linking agents and precise reaction conditions.

Ultrasound-Assisted Method

The ultrasound-assisted method employs ultrasonic energy to create nanosponges without the use of organic solvents. In this process, the drug and polymer are blended and subjected to ultrasonication, which produces high-energy waves that disintegrate particles and promote the formation of nanosponge structures. This method is rapid and environmentally sustainable; nevertheless, it requires specialized equipment and is less frequently utilized in standard laboratory environments.

Ionic Gelation Method

The ionic gelation method relies on the interaction between oppositely charged ions. In this technique, a polymer such as chitosan is cross-linked using agents like sodium tripolyphosphate. When the polymer solution is combined with the cross-linking agent, ionic interactions result in the creation of nanosponge-like structures. This method is straightforward, safe, and does not necessitate organic solvents, rendering it appropriate for environmentally friendly formulations.

Melt Method

The crosslinker and β-cyclodextrins are combined through the melting technique. The other components are finely homogenized and introduced into a 250 ml jar that has been preheated to 100°C. The reaction proceeds for 5 hours under magnetic stirring. After cooling, the resulting mixture is disaggregated and thoroughly washed multiple times with appropriate solvents such as ethanol, in order to remove any excipients and unreacted by-products.

ADVANTAGES

Reduced Gastrointestinal Side Effects

Topical delivery circumvents oral administration and first-pass metabolism, thereby significantly minimizing gastrointestinal irritation and bleeding typically associated with NSAIDs.

Localized Drug Delivery

The nanosponge gel administers the drug directly to the inflamed joint site, resulting in a higher local drug concentration and enhanced therapeutic efficacy in arthritis.

Controlled and Sustained Drug Release

Nanosponges function as reservoir systems, offering controlled and prolonged release of the drug, which aids in maintaining therapeutic drug levels over an extended duration.

Enhanced Skin Penetration and Retention

Owing to their nanoscale and porous structure, nanosponges facilitate improved drug permeation through the skin and enhance drug retention within the skin layers.

Improved Patient Compliance

Gel formulations are non-greasy, easy to apply, washable, and cosmetically acceptable, thereby improving patient comfort and adherence.

FORMULATION METHOD OF NANOSPONGES GEL 

Step 1: Preparation of Organic Phase

Carefully weigh meloxicam and Eudragit RS-100, then dissolve them in ethanol to achieve a clear solution. 

Step 2: Preparation of Aqueous Phase

Dissolve PVA in distilled water with gentle heating to create a PVA solution. 

Step 3: Phase Dispersion

Gradually add the organic phase into the aqueous PVA solution while stirring continuously with a mechanical stirrer. 

Step 4: Solvent Diffusion & Evaporation

Maintain stirring at room temperature. The organic solvent will diffuse and evaporate, resulting in the formation of porous nanosponges. 

Step 5: Collection of Nanosponges

Isolate the formed nanosponges through centrifugation. Rinse the nanosponges with distilled water to eliminate residual PVA and dry them in a hot air oven. Store in a desiccator until needed. 

Step 6: Preparation of Gel Base

Disperse Carbopol 934 in distilled water and allow it to hydrate for 24 hours. Gradually incorporate the meloxicam nanosponges into the hydrated gel base while stirring gently, then add propylene glycol and mix thoroughly. 

Step 7: pH Adjustment

Introduce triethanolamine dropwise until a clear gel is achieved and adjust the pH to 5.5–7.0. Complete the final weight with distilled water and stir gently to obtain a smooth, homogeneous gel.

PHYSIOCHEMICAL EVALUATION

The synthesized nanosponges will undergo assessment for physicochemical characteristics, which include- 

Physical Appearance

pH

Viscosity

Spreadability

Solubility

Melting point

Partition coefficient

Drug–excipient compatibility studies utilizing

FTIR

UV Spectroscopy

CONCLUSION

Nanosponges have surfaced as a promising and innovative drug delivery system within the realm of pharmaceutics, providing considerable benefits over traditional formulations. Their distinctive porous architecture facilitates effective drug encapsulation, regulated release, and enhanced stability for both synthetic and herbal medications. This renders them particularly advantageous for improving the therapeutic efficacy of drugs utilized in managing chronic ailments such as arthritis. Various techniques, including emulsion–solvent diffusion, solvent method, ultrasound-assisted method, and microwave-assisted approaches, have been investigated for the fabrication of nanosponges. Among these, the emulsion–solvent diffusion technique is predominantly favored due to its ease of use, reproducibility, and compatibility with laboratory-scale production. The choice of suitable polymers and excipients is vital in influencing the performance and efficacy of the nanosponge formulation.

The integration of nanosponges into topical gel systems further optimizes drug delivery by enhancing skin penetration, ensuring sustained drug release, and minimizing systemic side effects. Assessment criteria such as particle size, entrapment efficiency, drug release, pH, viscosity, and stability studies are crucial for guaranteeing the quality and effectiveness of the formulation. In summary, nanosponge-based gel formulations signify a novel and efficient strategy for the topical management of arthritis. They provide enhanced drug delivery, improved patient adherence, and superior therapeutic results. Future investigations may concentrate on refining formulation parameters and examining new polymers to further progress this drug delivery system. 

REFERENCES

1. Choy EHS and Panayi GS: Cytokine Pathways and Joint Inflammation in Rheumatoid Arthritis. New Engl J Med2001; 344: 907-16.
2. Patel Ek and Oswal RJ: Nanosponge And Micro Sponges:A Novel Drug Delivery System. IJRPC 2012;2(2): 237-44.
3. Swaminathan S, Darandale S and Vavia PR: Nanosponge-Aided Drug Delivery. A Closer Look. Pharm Formul Qual2012; 2(7): 12-15.
4. Shinde G, Rajesh Ks, Bhatt D, Bangale G, Umalkar D andVirag G: Current status of colloidal system (nano range).Int J Drug Formul Res 2011; 2(6): 39-54.
5. Salunkhe A, Kadam S, Magar S and Dangare K:Nanosponges: A modern formulation approach in drug delivery system. World J Pharm Sci 2018; 7(2):575-92.
6. Van der Ende AE, Kraviz EJ and Harth E: Approach to Formation of multifunctional polyester particles in controlled nanoscopic dimensions. J Am Chem Soc 2008; 130: 8706-13.
7. Swaminathan S, Vavia PR, Trotta F and Torne S:Formulation of betacyclodextrin based nanosponges of Itraconazole. J Incl Phenom Macrocyl Chem 2017; 57: 89-94
8. Indian Pharmacopoeia 2018. 2nd ed; 2: 29.

 

9. Verma N and Deshwal S: Design and in-vitro evaluation of transdermal Patches containing Ketoprofen. World J Pharm Res 2014; 3(3): 3930- 44.
10. Available from: https://en.wikipedia.org/wiki/Nonsteroidal anti-inflammatory drug [Last accessed on July 2021 25th].
11. Kumar AS, Sheri PS and Kuriachan MA: Formulation and Evaluation of Antifungal Nanosponge Loaded Hydrogel for Topical Delivery. Int J Pharm Res 2018; 13 (1):

362-79.

12. Abbas N, Parveen K, Hussain A, Latif S, Zaman SU, Shah PA and Ahsan M: Nanosponge-based hydrogel preparation
13. Raj PP, Gopal RK, Sanniyasi E. Investigating the anti-inflammatory and anti-arthritis effects of fucoidan from a brown seaweed. Current Research in Biotechnology. 2024;7. doi: 10.1016/j.crbiot.2024.100220.
14. Rodrigues K, Nadaf S, Rarokar N, Gurav N, Jagtap P, Mali P. QBD approach for the development of hesperetin loaded colloidal nanosponges for sustained delivery: in vitro, ex-vivo, and in vivoassessment. OpenNano. 2022;7:2022.100045. doi: 10.1016/j.onano.2022.100045.
15. Yang M, Feng X, Ding J, Chang F, Chen X. Nanotherapeutics relieve rheumatoid arthritis. J Control Release. 2017;252:108-24. doi: 10.1016/j.jconrel.2017.02.032, PMID 28257989.
16. Luthuli S, Wu S, Cheng Y, Zheng X, Wu M, Tong H. Therapeutic effects of fucoidan: a review on recent studies. Mar Drugs. 2019;17(9):487. doi: 10.3390/md17090487, PMID 31438588.
17. Jayawardena TU, Nagahawatta DP, Fernando IP, Kim YT, Kim JS, Kim WS. A review on fucoidan structure, extraction techniques, and its role as an immunomodulatory agent. Mar Drugs. 2022;20(12):755. doi: 10.3390/md20120755, PMID 36547902.
18. Ahmed MM, Fatima F, Anwer MK, Ansari MJ, Das SS, Alshahrani SM. Development and characterization of ethyl cellulose nanosponges for sustained release of brigatinib for the treatment of non-small cell lung cancer. J Polym Eng. 2020;40(10):823-32. doi: 10.1515/polyeng-2019-0365.
19. GS, Chandra GK, KE, Mahapatra DR, AS, ZG. Nanoparticles and bacterial interaction of host-pathogens and the detection enhancement of biomolecules by fluorescence Raman spectroscopic investigation. Eng Sci. 2022;20:341-51. doi: 10.30919/es8d767.
20. Salunke A, Upmanyu N. Formulation, development and valuation of budesonide oral nano-sponges using DOE approach: in vivo evidences. Adv Pharm Bull. 2021;11(2):286-94. doi: 10.34172/apb.2021.041, PMID 33880350.