Formulation, optimization, and evaluation of non-propellent foam-based formulation for burn wounds treatment

Burn injuries worldwide pose significant health risks due to frequent microbial infections, which worsen complications and increase mortality rates. The conventional antimicrobial formulations are available in the form of ointments and creams. These formulations are very greasy and stick to the clothes. The applications of these formulations by finger or applicator produce pain in the affected area and incur the possibility of microbial infection. To overcome these hurdles, authors developed a novel non-propellent foam (NPF) based formulation containing chlorhexidine for effective topical delivery. Initially, NPF containing Labrasol® (26.7%), sodium lauryl sulfate (1.2%), hydroxy propyl methyl cellulose (0.56%), butylated hydroxytoluene (0.1%), ethanol (1%), and distilled water was prepared and assessed for its consistency, and ability to form foam. The NPF was statistically optimized using the Box-Behnken design to determine the effect of polymer and surfactants on the critical foam properties. The optimized formulation showed a collapse time of 45 s with a unique nature of collapsing upon slight touch which is highly beneficial for burn patients with microbial infection. The diffusion study showed that more than 90% of the drug was released within 6 h. The skin permeation study showed that 23% of the total drug permeated through the skin after 6 h with 7.64 µg/cm²/h permeation flux. The developed formulation showed good antibacterial activity. The minimum inhibitory concentration of prepared NPF was found to be 2.5 µg/mL, 2.5 µg/mL, and 5.0 µg/mL against E. coli (MTCC-1687), P. aeruginosa (MTCC-1688), and S aureus (MTCC-737) respectively. The developed NPF formulation showed quick collapse time, excellent spreadability, good anti-bacterial activity, and a non-sticky nature representing a promising avenue for burn wound treatment without using any applicator.

Introduction

Burn injuries represent a critical medical condition characterized by tissue damage resulting from exposure to thermal, chemical, electrical, or radiation sources ¹. They are not only a common cause of morbidity and mortality but also present significant challenges in clinical management and patient rehabilitation ². Burns can vary widely in severity, from superficial first-degree burns, which affect only the outer layer of the skin and cause redness and pain, to devastating third-degree burns that penetrate all skin layers and potentially impact underlying tissues such as muscles, bones, and nerves. The depth and extent of a burn injury determine its classification and guide treatment protocols. Effective management of burns requires prompt and appropriate first aid, pain relief, infection prevention, and strategies to promote healing and minimize scarring 3, 4, 5, 6.

Topical dosage forms, such as creams, gels, lotions, solutions, and ointments, are widely utilized in the treatment of burn injuries due to their ability to deliver the drug directly to the affected area ^7,8. Foam-based systems have garnered attention in dermatology among these formulations for several reasons. They offer a higher cosmetic appeal, being non-greasy and leaving minimal residue, which enhances patient comfort and compliance ⁹. Foam formulations are also easy to apply, spreading uniformly over the skin and ensuring even coverage, particularly beneficial for treating burns that may cover large or irregularly shaped areas ^9,10. The success of foam-based therapies in dermatology is exemplified by products like hexachlorophene (0.23%), betamethasone valerate (0.12%), allantoin (0.5%), and clobetasol propionate (0.05%) foams, which have received approval from the US Food and Drug Administration (FDA) for the treatment of skin conditions ¹¹. However, traditional propellant foams, which use propellants like alcohol, can be irritating and potentially damaging to burn-injured skin tissues due to their drying effects and potential for further irritation ¹².

In response to these concerns, non-propellant foams (NPF) have been developed, notably by Gattefosse in France, which do not rely on propellants or alcohol-based vehicles. These NPF formulations, using model drugs like lidocaine and betamethasone, aim to provide effective topical treatment for burns without the drawbacks associated with propellant-based foams. By eliminating irritants and focusing on gentle, effective delivery systems, NPFs represent a promising advancement in topical therapies for burn injuries, ensuring both efficacy and safety in clinical applications ¹³.

In burn injuries, the immune response is compromised, increasing the vulnerability of the wound to infections caused primarily by gram-positive bacteria ¹⁴. These microbes often originate from contaminated hands, surfaces, or airborne sources, as well as from the patient’s skin flora ¹⁵. Infections in burn wounds, predominantly caused by organisms like Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Pseudomonas aeruginosa (P. aeruginosa), can lead to significant discomfort, pain, and hindered wound healing ¹⁶. To mitigate the risk of opportunistic infections, topical antimicrobial agents are crucially recommended either directly applied to the wound or incorporated into dressings ^17,18.

Chlorhexidine (CHX) is an antiseptic and disinfectant widely used in healthcare and personal hygiene settings ¹⁹. Chlorhexidine was developed by Imperial Chemical Industries in England during the 1940s. It is effective against a broad spectrum of bacteria, fungi, and viruses. Chlorhexidine is commonly employed for various purposes, including skin disinfection before surgery, wound care, and oral hygiene ²⁰ . Chlorhexidine is often used as a preoperative skin antiseptic to reduce the risk of surgical site infections ²¹. CHX ruptures the cell membrane and can kill microorganisms. It is valued for its persistent antimicrobial effect and relatively low toxicity ^22,23.

In the present study, NPF was developed as a delivery system for CHX using varying the concentrations of surfactants, polymers, and solubilizers with response surface methodology i:e Box-Behnken design. The physicochemical properties of the foam, such as density, collapse time, pH, bubble size, viscosity, in vitro release study, and antimicrobial efficacy were evaluated. The NPF offers a very diverse and unique platform for the targeted applications. The results obtained with the current experimental approach using Box-Behnken provided a variation of results revealing the significant impact of the excipients on the formulations and results such as foam collapse time, foam density, and drug release.

These assessments revealed that the prepared NPF formulation is superior in healing burn wounds due to its non-greasy nature, minimal pain application, efficient drug release and skin permeation, and robust antibacterial activity. These qualities make it a promising alternative to traditional topical applications, addressing many of the limitations associated with conventional treatments.

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Materials

Chlorhexidine, glacial acetic acid (GAA), and sodium tripolyphosphate (STPP) were acquired from Sigma-Aldrich Chemicals Pvt Ltd., Bangalore, India. Acetonitrile (HPLC grade), methanol (AR & HPLC grade), NaOH, NaCl, NaH2PO4, and Na2HPO4 were obtained from MOLYCHEM in Mumbai, India. Hydroxy propyl methyl cellulose-E15 (HPMC-E15), butylated hydroxytoluene (BHT), and sodium lauryl sulfate (SLS) were obtained from Loba Chemie, India. Labrasol was gifted from Gattefosse, India.

Mohit Kumar, Shruti Chopra, Syed Mahmood, Mohamad Aamir Mirza, Amit Bhatia, Formulation, optimization, and evaluation of non-propellent foam-based formulation for burn wounds treatment, Journal of Pharmaceutical Sciences,
2024, ISSN 0022-3549,https://doi.org/10.1016/j.xphs.2024.07.004.

Read also our introduction article on Topical Excipients here: