Development and Evaluation of Ketorolac-Loaded Patches for Transdermal Treatment of Acute Inflammation

Acute inflammation is a defensive biological reaction of bodily tissues to detrimental stimuli, including damage, infection, or irritation. It is marked by erythema, edema, hyperthermia, dolor, and functional impairment, predominantly driven by the release of inflammatory mediators such as prostaglandins, cytokines, and histamines. Nonsteroidal anti-inflammatory medicines (NSAIDs) are extensively utilized for managing inflammation and related pain by inhibiting cyclooxygenase (COX) enzymes and diminishing prostaglandin synthesis. [1] Ketorolac is a powerful nonsteroidal anti-inflammatory drug (NSAID) recognized for its significant analgesic and anti-inflammatory effects. It is frequently employed for the short-term management of moderate to severe pain. [2] Conventional administration modalities, including oral and injectable forms, are linked to numerous restrictions, such as gastrointestinal irritation, ulceration, renal toxicity, and significant first-pass metabolism, which might diminish bioavailability and patient adherence. [3] Transdermal drug delivery systems (TDDS) have developed as a viable alternative to address these limitations. Transdermal patches administer pharmaceuticals through the skin into systemic circulation, circumventing the gastrointestinal tract and hepatic first-pass metabolism. This method provides multiple benefits, such as prolonged medication release, increased bioavailability, decreased dose frequency, and greater patient adherence. [5] Moreover, transdermal devices can sustain consistent plasma medication concentrations, reducing volatility and related adverse effects. [6] Notwithstanding these benefits, the stratum corneum, the skin's outermost layer, serves as a significant barrier to drug absorption. [7] Consequently, the development of an efficient transdermal patch necessitates meticulous selection of polymers, plasticizers, and permeation enhancers to promote drug dispersion through the skin. Diverse methodologies, including chemical enhancers, microneedles, and innovative carrier systems, have been investigated to boost transdermal medication delivery. [8] This study seeks to formulate and assess ketorolac-encapsulated transdermal patches for the management of acute inflammation. The formulation aims to achieve regulated and prolonged medication release while maintaining sufficient mechanical strength and skin permeability. The assessment encompasses physicochemical characterization, in vitro drug release, ex vivo permeation tests, and stability testing to ascertain the appropriateness of the proposed system as an alternative to traditional dosage forms. [9]                

Figure 1: Diagrammatic Representation of Transdermal Drug Delivery System for Acute Inflammation

Drug Profile

Ketorolac Tromethamine is a potent nonsteroidal anti-inflammatory drug (NSAID) widely used for the short-term management of moderate to severe pain and inflammation. Chemically, it is the tromethamine salt of ketorolac, which enhances its aqueous solubility and bioavailability. The drug exerts its pharmacological action by inhibiting cyclooxygenase (COX-1 and COX-2) enzymes, thereby reducing the synthesis of prostaglandins responsible for pain, inflammation, and fever. Ketorolac is highly soluble in water and alcohol, with a biological half-life of approximately 4–6 hours. Although it shows good bioavailability when administered orally or parenterally, its use is often associated with adverse effects such as gastrointestinal irritation, ulceration, and renal toxicity due to systemic exposure and first-pass metabolism. These limitations make it a suitable candidate for transdermal drug delivery systems, which can provide controlled and sustained drug release, bypass hepatic first-pass metabolism, reduce gastrointestinal side effects, and improve patient compliance. [10]

MATERIAL AND METHODS

Preparation of Ketorolac Transdermal Patch [13,16]

Polymer Selection (PVA + PVP)
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Dissolution in Solvent (Ethanol/Water)
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Addition of Plasticizers (Propylene Glycol, Glycerol)
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Drug Addition (Ketorolac Tromethamine)
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Addition of Permeation Enhancer (DMSO)
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Stirring & Homogenization
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Removal of Air Bubbles (Degassing)
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Casting in Petri Dish
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Drying (24 hrs)
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Film Formation
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Cutting into Patches
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Storage in Desiccator

Table: Formulation of Ketorolac Transdermal Patches

Evaluation of Transdermal Patches

A) Organoleptic Evaluation

The prepared patches were evaluated visually using naked-eye examination for their physical appearance. The patches were found to be circular in shape, transparent, smooth in texture, and flexible without any visible imperfections. [17]

B) Thickness of Patch

The thickness of the patches was measured at three different points using a digital vernier caliper, and the average value was calculated. The thickness of the formulated patches was found to be approximately 0.5 mm, indicating uniformity. [18]

C) Surface pH

The patch was allowed to swell in 1 mL of distilled water for 2 hours at room temperature. The pH was measured using pH paper (or digital pH meter). The pH of the patch was found to be in the range of 5–6.5, which is compatible with skin pH.[19]

D) Percentage Moisture Content

The patches were weighed initially and then dried in a desiccator for 24 hours. The final weight was recorded, and moisture content was calculated using the formula:

Moisture Content (%) = (Initialweight-Finalweight)/Initialweight

The percentage moisture content was found to be 7.14%, indicating good stability. [20]

E) Thumb Tack Test

This test was performed to evaluate the adhesive property of the patch. The thumb was pressed lightly on the patch surface, and the time required for detachment was observed. The patch showed good tackiness, taking approximately 2–2.5 seconds to release. [21]

F) Skin Irritability Test

The skin irritation test was performed to assess the safety of the patch. The patch was applied on the shaved skin area and secured with surgical tape for 24 hours. No signs of redness, swelling, or irritation were observed, indicating that the formulation is safe and non-irritant. [22]

RESULT AND DISCUSSION

The developed Ketorolac transdermal patches were successfully prepared and evaluated for various physicochemical parameters. The patches were found to be circular in shape with a uniform surface and appearance ranging from off-white to pale yellow. All formulations showed good flexibility with no signs of cracking or breaking upon folding, indicating adequate mechanical strength. The thickness and weight variation of the patches were within acceptable limits, confirming uniform distribution of the formulation components. The surface pH of the patches was found to be in the range of 5.8–6.2, which is compatible with skin pH and suggests minimal chances of skin irritation. The moisture content and moisture uptake values were also within acceptable ranges, indicating good stability and resistance to environmental conditions. The thumb tack test confirmed that the patches possessed adequate adhesiveness, ensuring proper contact with the skin surface. Furthermore, the skin irritability test revealed no signs of erythema or edema, indicating that the formulation is safe and non-irritant for topical application. The mechanism of action of ketorolac involves inhibition of cyclooxygenase enzymes (COX-1 and COX-2), which are responsible for the synthesis of prostaglandins that mediate pain and inflammation. By reducing prostaglandin production, ketorolac exhibits significant anti-inflammatory and analgesic effects. Overall, the formulated transdermal patches demonstrated satisfactory physicochemical properties, good stability, and safety profile. These findings suggest that ketorolac transdermal patches can serve as an effective alternative to conventional dosage forms for the treatment of acute inflammation, providing localized action with reduced systemic side effects.

Table: Evaluation Results of Transdermal Patches