INTRODUCTION:

NSAIDs (nonsteroidal anti-inflammatory drugs) are one of the most commonly given medications in modern medicine. Since the discovery of the soothing effects of willow bark more than 3,500 years ago, NSAIDs have been very efficient in the reduction of pain, fever, and inflammation, and millions of patients throughout the world have benefited from their use¹.

Oxicam belong to a long-acting class of non-steroidal anti-inflammatory drugs (NSAIDs) which display potent anti-inflammatory and analgesic activity and is effective in the treatment of rheumatoid arthritis, osteoarthritis, and degenerative joint diseases. These drugs are also found to be very good antioxidants. The oxicam group's representative medications include tenoxicam which appears to be the equivalent of aspirin, indomethacin, or naproxen in the long-term treatment of rheumatoid arthritis and osteoarthritis when taken at prescribed doses².

Tenoxicam is an anti-inflammatory pain reliever that is also known as NSAIDs (non-steroidal anti-inflammatory medications) or simply anti-inflammatories^3-4. Tenoxicam is used to treat painful conditions such as sprains, strains, and other muscles or joints, as well as to relieve pain and reduce inflammation in rheumatic conditions. It operates by inhibiting the action of cyclooxygenase (COX) enzymes in our bodies. These enzymes aid in the production of prostaglandins, which are a type of molecule found in the body. Some are created at the site of injury or damage, causing inflammation and pain. Fewer prostaglandins are formed when COX enzymes are inhibited, which reduces pain and inflammation. Rheumatoid arthritis is a chronic, progressive inflammatory disease that affects a variety of tissues and organs, but primarily affects on the joints^4-5. Non-steroidal anti-inflammatory medicines (NSAIDs) are the most commonly utilized class of drug for its treatment, despite the fact that other types of drugs are also used.

Tenoxicam is an oxicam-class NSAIDs that is particularly powerful and beneficial for chronic rheumatoid arthritis treatment. However, like other NSAIDs, this medication might cause GI adverse effects to include nausea, dyspepsia, epigastric discomfort, indigestion, diarrhea, vomiting, and flatulence. The most prevalent symptoms were nausea and epigastric discomfort, which were observed in 7–17% of patients treated. As a result, the negative effects of oral tenoxicam strongly indicate the necessity for a tenoxicam in to the transdermal formulation. This form of treatment may be free of GI adverse effects and related to other topical NSAIDs advantages (e.g. site-specific delivery)^5-6.Moreover, compared to other NSAIDs, tenoxicam has a low penetration rate when used topically. The use of penetration enhancers to reversibly overcome the stratum corneum barrier is the most popular and effective method, and has been successfully applied in recent years.

The use of ultra-deformable vesicles to solve the problem of tenoxicam transcutaneous transport in order to lessen side effects and give more focused delivery for chronic rheumatoid arthritis treatment. Finally, the study's goals include turning the ultra-deformable vesicular system's colloidal suspension into a more patient-acceptable and physiologically viable formulation by inserting it into the carbopol hydrogel system⁶.

New nanotechnology-based medicines and a better knowledge of rheumatoid arthritis and osteoarthritis have gotten us closer to finding a safe and effective treatment for the disease. Microemulsion, nanogel, niosomes, liposomal hydrogel, deformable liposomes, and solid lipid nanoparticles (SLNs) have all been tested as new topical carriers for improving tenoxicam (TNX) skin penetration⁷. However, they have some drawbacks such as ineffective drug encapsulation, drug ejection during storage, and high water content in the formulation. Nanogel has primarily been studied in topical applications, where they overcome many of the disadvantages of other nanocarriers. It's a next-generation nanogel formulation made up of a solid lipid matrix that encases changeable spatially incompatible liquid lipid Nano-compartments and is stabilized by surfactants. Nanogel has an irregular crystal structure that inhibits encapsulated drugs from being expelled, therefore boosting the drug loading⁸.

MATERIAL AND METHODS:

Materials:

Pure tenoxicam (TNX) drug was gift sample from Ramdev Chemicals, Pvt. Ltd. Boisar. Noveon Polycarbophil AA- 1(NP AA-1) gift sample from Lubizol PVT.LTD Mumbai, Methyl paraben, Propyl paraben, propylene glycol, Tween 80 and Euckolyptus oil were purchased from Unique Biological, Kolhapur and DMSO was purchased from Fine Chemical Ltd., Mumbai.

Nanogel Synthesis:

The tenoxicam nanogel was formed using a modified emulsification-diffusion process. Briefly, the 30mg of tenoxicam were weighed and dissolved in 20mL of DMSO containing the polymer noveon Polycarbophil AA-1 (NP AA-1) with steady stirring at 5,000-10,000 rpm using T-10 basic Ultra Turrex. The organic phase containing drug-polymer combination was introduced to the 10mL of aqueous phase containing Tween 80 and polyethylene glycol and euckolyptus oil. The organic phase was added at a rate of 0.5ml/min using a syringe with a needle inserted directly into the aqueous stabilizer solution. The dispersion was then sonicated for 5- 10 minutes after being agitated for 6 minutes at 10,000-25,000rpm. After that, double distilled water was gently added to the dispersion, followed by 1 hour of stirring to induce organic solvent diffusion into the continuous phase, resulting in the creation of nanogel the pH was adjusted with triethanolamine and used for further study ⁹.

Characterization of TNX nanogel:

The various physico-chemical parameters studied to characterize the topical TNX nanogel are as following:

Homogeneity:

The homogeneity study of topical TNX nanogel was examined by using visual inspection of prepared nanogel. All developed topical nanogel were filled into flint color vial containers and subjected for visual inspection to check the prepared topical nanogel was homogenous and presence of aggregates or not.

Spreadability:

The spreadability of topical TNX nanogel was performed by using two slides (5cm²). The 0.5g of topical TNX nanogel of each batch were placed between two slides and left for 1 min. Diameter of spread circle of topical nanogel measured and compared with each other.

Grittiness:

The formulation was evaluated microscopically for the presence of particles if any.

FT-IR spectral analysis:

The FT-IR spectra of pure TNX and TNX nanogel formulation were compared to see if there was any probable interaction between the medicine and the excipients. For a formulation, the nanogel excipients must be compatible with the medicine¹⁷.

Determination of pH:

The pH of all prepared batch TNX nanogels was determined by using by using a calibrated pH (METTLER TOLEDO, India Ltd). The pH meter was calibrated before each use with standard 4, 7 and 9.2 pH buffer solutions, for pH determination bathe wise 1.0g of nanogel was taken and dissolved in 20mL of distilled water by stirring on magnetic stirrer for 10 min at room temperature and pH was measured. The readings were taken in triplicate¹⁰.

Drug content and entrapment efficiency:

1 gm of TNX nanogel was dissolved in 10mL of DMSO, using a microcentrifuge, the formulation centrifuged for 15minutes at 5,000rpm (Remi-900). 1mL of supernatant was extracted and diluted with DMSO to a concentration (10mL). The UV-spectrophotometer (Shimadzu UV-1900, Japan) was used to compare the diluted supernatant solution to blank/control DMSO at 365nm. The EE and drug content were calculated¹¹.

Viscosity study:

The viscosity of prepared TNX nanogel was determined by using a viscometer, (Brookfield, DV1MHA) by using small sample adapter having spindle number C75-1 at 30/min rpm. The TNX nanogel (50g) at room temperature (25°±3C) was subjected to torque ranging from 10 to 100%. Viscosity was calculated in Pascal (Pa.s), viscosity for each formulation was taken in triplicate¹².

Particle size distribution and zeta potential:

The mean particle size distribution of the prepared TNX nanogel was measured by Photon Correlation Spectroscopy (Nano ZS, Malvern, UK) at room temperature (298°K). For study 1ml of LSLNs suspension was diluted ten times (10ml) with distilled water and average particle size, size distribution as polydispersity index (PDI) and zeta potential was measured¹⁹.

Particle size:

Photon correlation spectroscopy (PCS), which uses a Zetasizer to evaluate fluctuations in light scattering owing to Brownian motion of the droplets, was used to quantify the particle size of the generated TNX nanogel (Ver. 6.20 Malvern Instruments Ltd.). In a volumetric flask, the formulation (0.1mL) was distributed in 50mL of DMSO, fully mixed with vigorous shaking, and light scattering was observed at 25±0.5°C at a 90° angle. Malvern Zetasizer determined the droplet size distribution of the improved TNX nanogel (Ver. 6.20 Malvern Instruments Ltd.). At 25±0.5°C, all measurements were made in triplicate.

Transmission electron microscopy (TEM):

A TEM microscope (FEI Tecnai T-20ST) was used to examine the morphology of the prepared TNX nanogel formulations: a drop of the dispersion was diluted 10-fold in deionized water, then a drop of the diluted dispersion was applied to a carbon-coated 300 mesh copper grid and left for 1 minute to allow some of the nanogel to adhere to the carbon substrate. By absorbing the drop with the corner of a sheet of filter paper, the leftover dispersion was eliminated. After rinsing the grid twice with deionized water for 3–5 seconds, a drop of 2 % aqueous uranyl acetate solution was applied for 1 second¹⁶.

In-vitro permeation study:

The in-vitro release study was performed using a Franz diffusion cell and an artificial cellophane membrane (molecular weight cutoff 1000 Da). The cell is divided into two compartments: the donar and receptor compartments. The top of the donar chamber was open and exposed to the atmosphere. The temperature was kept constant at 37±0.5°C, and the receptor compartment had a sampling port. Phosphate buffer pH 7.5 was used as the diffusion medium. The drug-containing nanogel was kept in the donar compartment with backing membrane support and was separated from the receptor compartment by a cellophane membrane. The cellophane membrane had previously been immersed in phosphate buffer pH 7.5 for 24 h. A clamp was used to hold the donar and receptor chambers together. To avoid the formation of a concentrated drug solution layer behind the cellophane membrane, the receptor compartment was kept at 37±0.5°C and swirled with a magnetic stirrer with 30mL phosphate buffer pH 7.5. At predetermined intervals, 1mL samples were collected and replaced with fresh medium. A UV-spectrophotometer set to 365nm was used to determine the drug concentration¹⁸.

Stability study:

The stability study of prepared TNX nanogel was carried out at 25°C with 60% RH and 40°C with 75% RH for 90 days, sampling was done at 0, 30, 60 and 90 days for any change in clarity, homogeneity, pH change, viscosity and spreadability.

RESULTS:

Evaluation of topical TNX nanogel:

The prepared TNX nanogel formulation was characterized for various evaluation parameters, the results are shown in the Table 2. The TNX nanogel was discovered to be transparent yellow, smooth, with small particles and good spreadability. Furthermore, Fig. 1 shows a standard calibration curve of tenoxicam in the DMSO that was used to estimate the drug content and entrapment efficiency (EE) in TNX nanogel. The following calculation was used to compute the drug content and EE using the straight line equation of the standard curve with observed absorbance:

Total amount of Nanogel × Amount of drug in 0.1gms

Durg content (%) = --------------------------------------------- × 100 (1)

Amount of nanodel in gms

W intial drug – W free drug

Emtrament Efficiency (%) = ------------------------------------ × 100 (2)

W initial drug

The FT-IR spectral analysis of TNX nanogel and pure tenoxicam revealed no interactions between a drug and prepared TNX nanogel formulation (Fig 2 & 3). However, the excipients used in the formulation were found to be compatible with tenoxicam. According to an in-vitro diffusion investigation of TNX nanogel and marketed formulation (®Omni gel) over an artificial cellophane membrane, the results were found to be 89.80% and 97.30% respectively after 8 hours. This means prepared TNX nanogel showed highest permeation than marketed formulation (Fig. 7) with the use of penetration enhancers which helps to the diffusion of TNX nanogel can be boosted even further.

Table 1: Nanogel composition for 30 gm of TNX nanogel

Sr. No	Drug/Excipients	Quantity
1	Tenoxicam (mg)	30
2	Noveon polycarbophil AA-1 (mg)	500
3	Propyl Paraben (mg)	0.5
4	Methyl Paraben (mg)	0.7
5	Polyethylene glycol (mL)	2
6	Tween 80 (mL)	1.5
7	Euckolyptus oil (mL)	1
8	DMSO (mL)	20
9.	Triethanolamine (mL)	qs
Total Weight (gm)		30

Table 2: Evaluation parameters for TNX nanogel.

Sr. No	Evaluation parameters	Results
1	Gel appearance	Transparent yellow
2	Homogeneity	Good
3	Grittiness	Absent
4	Viscosity	0.3678 Pa.s
5	pH	6.2±0.5
6	Spread ability	8.37±07g.cm/sec
7	Drug content	97.50 %
8	Entrapment efficiency	92.30 %
9	% Drug release	97.40 %
10	Particle size	125.30 nm
11	Zeta potential	-8.4 mV

Fig 1: Standard calibration curve of TNX in DMSO

Fig 2: FT-IR spectra of pure TNX drug

Fig 3: FT-IR spectra of TNX Nanogel

Fig 4: Particle size distribution of TNX nanogel

Fig 5: Zeta potential of TNX nanogel

Fig. 6: Transmission electron microscopy (TEM)

Fig 7: In-vitro diffusion study of TNX nanogel with marketed formulation

DISCUSSION:

A tenoxicam nanogel is the semi-solid system form of drug delivery and constitutes a well reputation among various pharmaceutical dosage forms. Now a day’s nanogel is becoming popular due to their safe and effective use and higher penetration rate. So, the study was designed to formulate topical tenoxicam nanogel.

CONCLUSION:

The novel nanogel form represents an effective and better carrier for topical formulations. The prepared TNX nanogel formulation showed better penetration in the skin than the marketed formulation may be due to the enhanced contact between the drug and the skin resulting from more surface area and hydration. The formulation showed stability over the study period and showed a substantial increase in efficacy. The prepared formulation proves to be the better alternative for the oral administration of tenoxicam (NSAID) and eliminates the limitations of the drug-like gastric disturbances, low bioavailability; short half-life, and first-pass effect. The production of the formulation is also proved to be better and cost-effective in comparison with oral dosage forms.

It can be concluded that tenoxicam nanogel is an ideal and effective formulation. It can be used safely for the treatment of rheumatoid arthritis and inflammatory conditions. This study also supports the activities of this tenoxicam nanogel for the treatment of pain, inflammation, and pyrexia. Furthermore, determination of the exact mechanism of action and lead active constituent for the anti-inflammatory activity of TNX nanogel will be the new target of study.

ACKNOWLEDGEMENT:

We convey our sincere appreciation to the Principal, Tatyasaheb Kore Pharmacy College, Warananagar for the provision of laboratory equipment.

CONFLICTS OF INTEREST:

The author states that no conflict of interest exists.

ABBREVIATIONS USED:

TNX: Tenoxicam; nm: Nanometer; TEM: Transmission electron microscopy; gm: Gram; ml: Milliliter; kg: Kilogram; cm: Centimeter; rpm: Revolutions per minute; μm: Micrometer; mm: Milimeter; sec.: Second; μg/mL: Microgram per mililiter; g.cm/s: Gram centimeter per second; EE: Entrapment efficiency

REFERENCES:

1. Meek I.L.; Van de Laar A.F.J.M.; Vonkeman.H.E: Non-Steroidal Anti-Inflammatory Drugs: An Overview of Cardiovascular Risks, Pharmaceuticals (Basel). 2010 Jul; 3(7): 2146–2162.

2. Demiralay E.C.; Yılmaz H: Potentiometric pKa Determination of Piroxicam and Tenoxicam in Acetonitrile-Water Binary Mixtures; SDU Journal of Science (E-Journal), 2012, 7 (1):34-44.

3. Mundada M.S.; Wankhede S: Formulation and Evaluation of Topical gel Lornoxicam using a range of penetration Enhancer; Ind J. Pharm. Edu Res;Apr-Jun,2013/Vol.47/Issue 2; 168-171.

4. Reddy D.; Trost L.W.; Lee T.; Baluch A.R.; Kaye A.D: Rheumatoid Arthritis: Current Pharmacologic Treatment and Anesthetic Considerations.

5. Ammara H.O.; Ghorabb M.; El-Nahhasc S.E.; Higazya I.M: Proniosomes as a carrier system for transdermal delivery of tenoxicam, Int Jou. of Pharm. 405 (2011) 142–152.

6. Negi L. M.; Chauhan M: Nano-appended transdermal gel of Tenoxicam via ultradeformable drug carrier system. Journal of Experimental Nanoscience. Volume (8)2013:657-669.

7. Devi V.K.; Jain N.; Valli K.S: Importance of novel drug delivery systems in herbal medicines; Pharmacogn. Rev. 2010 Jan-Jun; 4(7): 27–31.

8. Martin G.P; Stuart A. Jones S.A; Akomeah F.K: Dermal and Transdermal Drug Delivery Systems: Current and Future Prospects; Taylor & Francis; Drug Delivery, 13:175–187, 2006; ISSN: 1071-7544 print / 1521-0464.

9. Phatak A.A; Chaudhari P.D: Development and evaluation of Nanogel carrier for transdermal delivery of Aceclofenac; Asian J.pharm.Tech.2012; Vol.2: Issue 4; 125132.

10. Dhawal D: Nanogel as novel and versatile Pharmaceuticals; Int.J pharm Sci, Vol 4, Issue 3, 2012; 67-74.

11. Divya L; Ravichandiran S: Nanogels - as a drug delivery carrier. Indo American Journal of Pharm Research.2013:3(9)7356-7370.

12. Jithan A.V; M. Swati: Development of Topical Diclofenac sodium Liposomal Gel for Better Anti-inflammatory activity; Int.J.Pharm.Sci. Nanotech, Vol 3; Issue 2, July-Sept 2010; 986-993.

13. Alexander V.K; Serguei.V.Vinogradov: Nanogels as pharmaceutical carriers: finite networks of infinite capabilities, Angew.Chem.Int. Ed, 2009, 48:5418–5429.

14. Chauhan M; Negi L. M: Nano-appended transdermal gel of Tenoxicam via ultradeformable drug carrier system; journal of experimental nanoscience; volume (8)2013:657-669.

15. Avasatthi V; Chander P. D; Bansode P: A novel nanogel formulation of Tenoxicam for topical treatment of psoriasis: optimization, in vitro and in vivo evaluation. Pharmaceutical Development and Technology, 2015; 1-9.

16. Gupta G; Gaud R. S: Anti-inflammatory nanogel. Indian Journal of Pharmaceutical Sciences.2006, 68(3)356-359.

17. Reuben T. Chacco, Jiaming Zhuang; Thayumanavan S: Polymer nanogels: A versatile nanoscopic drug delivery platform. Advanced Drug Delivery Review, 2012, 64:836-851.

18. Koen R; Joseph De and Stefaan De Smedt: Advanced nanogel engineering for drug delivery. Soft Matter. 2009:707-715.

19. Amal J. Sivaram, P.Rajitha, S.Maya, R.Jayakumar and M.Sabitha: Nanogels for Delivery, Imaging and Therapy, 2015, 7(4):509-533.

20. Eckmann D; Composto R; A. Muzykantov V: Nanogel carrier design for targeted drug delivery, Journal of Materials Chemistry B, 2014, 2:1-13.

21. Gupta R; Gupta G.D: Formulation Development and Evaluation of Anti-inflammatory Potential of Cordia obliqua Topical Gel on Animal Model; Pharmacogn J. 2017; 9(6) Suppl: s93-s98.

22. Chippada S.C; Sharan Suresh Volluri S.S; Bammidi S.R: In vitro anti inflammatory activity of methanolic extract of centella asiatica by HRBC membrane stabilization; Rasayan.j.Chem; Vol.4, No.2 (2011), 457-460; ISSN: 0974-1496.

23. Pant K; Kshitij A; Prem S: To study in vitro anti-inflammatory activity of Anthracephalus cadamba leaves extract; DHR Int. Jour.Pharm. Sci. (DHR-IJPS) ISSN: 2278-8328, Vol. 3(1), 2012.

24. Aiyalu R; Govindarjan A; Ramasamy A: Formulation and evaluation of topical herbal gel for the treatment of arthritis in animal model; Brazilian Journal of Pharm. Sci. vol. 52, n. 3, jul./sep., 2016.

25. Yvonne M. C. B; Arlene F. C; Rhoda B. M; Chad R. L. R; Riel A.T: Anti-inflammatory Property of the Formulated Topical Gel from the Crude Leaf Extracts of Sampaguita (Jasminum sambac L. Family: Oleaceae); Int. Jou. Chem. Eng. & Appl; Vol. 7, No. 3, June 2016.

26. Mundada M.S; Wankhede S: Formulation and Evaluation of Topical gel Lornoxicam using a range of penetration Enhancer; Ind J. Pharm. Edu Res; Apr-Jun,2013/Vol.47/Issue 2; 168-171.

27. Khan AW, Kotta S, Ansari SH, Sharma RK, Kumar A, Ali J. Formulation develop¬ment, optimization and evaluation of Aloe Vera gel for wound healing. Pharmacognosy Mag. 2013; 9 (1):S6-S10.

Received on 11.10.2021 Modified on 27.01.2022

Asian J. Pharm. Tech. 2022; 12(4):299-304.

DOI: 10.52711/2231-5713.2022.00048