Aqueous composition of ceftizoxime stabilized with sulfobutyl ether-Β-cyclodextrin for topical application

Abstract

The invention relates to a novel topical pharmaceutical composition comprising ceftizoxime, a third-generation cephalosporin antibiotic, complexed with sulfobutyl ether-β-cyclodextrin (SBE-β-CD) to enhance solubility and stability in aqueous environments. The sterile, sprayable formulation is intended for direct topical use or dilution for the treatment and prevention of bacterial skin and wound infections. To overcome ceftizoxime's aqueous instability, the invention employs inclusion complexation with 2–10% w / v SBE-β-CD, prepared by shaking at 30°C for 72 hours followed by sterile filtration. Differential Scanning Calorimetry (DSC) confirms molecular encapsulation through suppression of the ceftizoxime melting peak, indicating loss of crystallinity. Antibacterial efficacy is demonstrated against Staphylococcus aureus and Escherichia coli using zone of inhibition assays. UV–Vis spectrophotometry at 258 nm confirms high linearity (R² = 0.998) for quantitative analysis. The formulation offers a stable, scalable, and patient-friendly alternative for localized antibiotic therapy and surgical prophylaxis with reduced systemic exposure.

Description

Aqueous composition of ceftizoxime stabilized with sulfobutyl ether-β-cyclodextrin for topical application

[0001] The present invention relates to the field of pharmaceutical formulations and drug delivery systems, and more particularly to topical compositions of antibiotics for the treatment and prevention of bacterial skin and wound infections.

[0002] Topical drug delivery offers several therapeutic advantages in managing localized infections, such as achieving high local concentrations of the active ingredient, minimizing systemic side effects, and avoiding first-pass metabolism. Despite these benefits, many conventional treatment regimens still rely on oral or parenteral administration of antibiotics, which may lead to suboptimal concentrations at the infection site, greater systemic exposure, and the potential for increased antimicrobial resistance.

[0003] Ceftizoxime is a third-generation cephalosporin with broad-spectrum activity against both gram-positive and gram-negative bacteria. It is typically administered parenterally due to its chemical and physical instability in aqueous solution, which limits its use in topical or liquid pharmaceutical formulations.

[0004] The invention is related to a novel aqueous topical pharmaceutical composition designed to treat and prevent bacterial skin and wound infections. It combines Ceftizoxime, a broad-spectrum third-generation cephalosporin antibiotic, with sulfobutyl ether-β-cyclodextrin (SBE-β-CD), which enhances the stability and solubility of the drug in aqueous environments.

[0005] Because Ceftizoxime is chemically unstable in the liquid form, which limits its topical use, systemic antibiotics often cause side effects and fail to deliver localized infections. This invention handles these challenges by providing a stable, localized delivery method.

[0006] The present invention addresses the above-mentioned needs by providing a novel pharmaceutical formulation comprising ceftizoxime complexed with sulfobutyl ether-β-cyclodextrin (SBE-β-CD), developed as a topical sprayable aqueous form for use in treating bacterial skin and wound infections.

[0007] The formulation enhances the solubility and stability of ceftizoxime in aqueous environments, providing localized drug delivery with minimal systemic exposure. This not only addresses ceftizoxime’s inherent instability in aqueous media but also maximizes its therapeutic effect at the site of infection.

[0008] The composition consists of ceftizoxime, SBE-β-CD (used in concentrations ranging from 2% to 10% w / v), and distilled water. The mixture is processed under controlled temperature and agitation conditions, filtered, and stored in sterile containers, forming a practical and stable formulation suitable for topical administration.The invention overcomes limitations in prior formulations and presents a more patient-friendly and clinically efficient alternative to current treatments.

[0009] Enhanced Aqueous Stability: Ceftizoxime, known for its poor stability in aqueous environments, is stabilized through complexation with sulfobutyl ether-β-cyclodextrin (SBE-β-CD), enabling a practical and shelf-stable liquid formulation.

[0010] Improved Solubility and Bioavailability: The SBE-β-CD complex significantly enhances the water solubility of ceftizoxime, ensuring consistent drug delivery and therapeutic action upon topical application.

[0011] Targeted Local Therapy: By enabling direct application to skin and wound surfaces, the invention achieves high local drug concentrations with minimal systemic absorption, reducing the risk of systemic side effects and resistance development.

[0012] Broad-Spectrum Antibacterial Activity: The encapsulated formulation demonstrates superior efficacy against both Staphylococcus aureus and Escherichia coli, as confirmed by antimicrobial testing.

[0013] Patient Convenience and Safety: The sterile, ready-to-use spray format is easy to administer, non-invasive, and suitable for use in outpatient, surgical, or emergency settings.

[0014] Scalability and Manufacturing Feasibility: The formulation process is reproducible under mild conditions using conventional pharmaceutical equipment, making it viable for commercial-scale production.

[0015] is a schematic illustration showing the application of a pharmaceutical composition comprising ceftizoxime complexed with sulfobutyl ether-β-cyclodextrin in the form of a topical spray, administered directly to a wound site on human skin. The illustration includes a labeled spray bottle, a hand activating the spray nozzle, and a visible wound area receiving the spray. Two petri dishes labeled “E. coli” and “S. aureus” are depicted in the foreground, representing test organisms used for antimicrobial evaluation.

[0016] Antimicrobial Activity of Pure and Encapsulated Ceftizoxime.

[0017] This figure shows a bar chart comparing the antimicrobial activity (zone of inhibition in mm) of two formulations against Escherichia coli and Staphylococcus aureus:

[0018] Sample 1 (Pure Ceftizoxime).

[0019] Sample 2 (Encapsulated Ceftizoxime–SBE-β-CD).

[0020] Calibration Curve of Ceftizoxime Using UV-Visible Spectrophotometry.

[0021] This figure presents a calibration curve plotting the absorbance against concentration of ceftizoxime solutions measured at 258 nm using UV-Visible spectrophotometry. The tested concentration range was 10–50 µg / ml.

[0022] A linear regression was obtained, described by the equation:

[0023] y = 0.0148x + 0.008

[0024] where y is the absorbance and x is the concentration.

[0025] The coefficient of determination (R² = 0.998) indicates high linearity and reliability of the method for quantitative analysis.

[0026] presents Differential Scanning Calorimetry (DSC) thermograms of four different samples:

[0027] pure ceftizoxime (solid line).

[0028] sulfobutyl ether-β-cyclodextrin (SBE-β-CD) (dashed line).

[0029] physical mixture of ceftizoxime and SBE-β-CD (dash-dot line).

[0030] the ceftizoxime–SBE-β-CD inclusion complex (dotted line).

[0031] The thermogram of pure ceftizoxime exhibits a sharp endothermic peak near 226°C, while SBE-β-CD displays a broad endothermic peak around 100°C, attributed to moisture loss.

[0032] The physical mixture retains both characteristic peaks, indicating no interaction. The inclusion complex shows a significant reduction or disappearance of the ceftizoxime melting peak, confirming successful molecular encapsulation and structural transformation.

[0033] Formulation Composition:

[0034] The invention comprises a topical spray formulation containing:

[0035] Ceftizoxime as the active pharmaceutical ingredient.

[0036] Sulfobutyl ether-β-cyclodextrin (SBE-β-CD 2.14%) is the encapsulating and solubilizing agent.

[0037] Distilled water as the aqueous vehicle.

[0038] Optional excipients such as pH-adjusting agents for formulation stability.

[0039] Formulation Preparation:

[0040] Ceftizoxime is encapsulated with SBE-β-CD using the following method:

[0041] Prepare aqueous solutions of (SBE-β-CD 2.14%) at concentrations ranging from 2% to 10%.

[0042] Add ceftizoxime to the solution and shake on a temperature-controlled orbital shaker at 30°C and 120 rpm for 72 hours.

[0043] Filter the final solution through a 0.2 µm syringe filter to obtain a sterile, clear topical spray.

[0044] The experimental conditions for complex preparation are summarized in Table 1.

[0045] Analytical Confirmation:

[0046] The encapsulation efficiency and drug loading were quantified using UV–Vis spectrophotometry:

[0047] Absorbance was measured at 258 nm, confirming the λmax of ceftizoxime.

[0048] A calibration curve was prepared over a 10–50 mg / L range, yielding a regression equation of y = 0.00148x + 0.008 with R² = 0.998, indicating excellent linearity.

[0049] The absorbance data used for calibration are provided in Table 2, and the calibration curve is illustrated in.

[0050] Antimicrobial Test:

[0051] To assess the antibacterial efficacy of the encapsulated formulation, an antimicrobial susceptibility test was performed:

[0052] Test organisms: Staphylococcus aureus and Escherichia coli.

[0053] Method: Standard agar diffusion method.

[0054] Procedure: Sterile discs soaked in the encapsulated ceftizoxime solution were placed on agar plates inoculated with the test bacteria and incubated at 37°C for 24 hours.

[0055] Results: Zones of inhibition were recorded and compared to those produced by pure ceftizoxime solution—the encapsulated formulation produced clear and measurable zones of inhibition against both organisms. As shown in.

[0056] Thermal Characterization of the Inclusion Complex by DSC:

[0057] As illustrated in, Differential Scanning Calorimetry (DSC) was used to evaluate the thermal behavior of pure ceftizoxime, SBE-β-cyclodextrin (SBE-β-CD), their physical mixture, and the ceftizoxime–SBE-β-CD inclusion complex.

[0058] The thermogram of pure ceftizoxime shows a sharp endothermic peak at approximately 226°C, which corresponds to its melting point and confirms its crystalline nature. The SBE-β-CD thermogram reveals a broad endothermic peak centered near 100°C, which is attributed to the loss of bound moisture commonly associated with cyclodextrins.

[0059] The physical mixture of ceftizoxime and SBE-β-CD exhibits both peaks without significant shift or alteration, indicating the absence of molecular interaction or complexation under physical mixing conditions.

[0060] In contrast, the DSC curve of the inclusion complex displays a marked suppression or complete disappearance of the ceftizoxime melting peak, suggesting a loss of crystallinity. This thermal behavior strongly supports the formation of a molecular inclusion complex in which ceftizoxime is encapsulated within the hydrophobic cavity of SBE-β-CD.

[0061] The thermal shift and disappearance of the melting peak confirm that ceftizoxime is no longer present in its free crystalline form, but rather in an amorphous or molecularly dispersed state. This encapsulation is a key aspect of the invention as it enhances the thermal stability, solubility, and suitability of ceftizoxime for use in aqueous topical spray formulations.

[0062] Intended Use:

[0063] The resulting formulation is designed for topical use in treating or preventing bacterial infections of the skin and soft tissues. It may be used pre-operatively or for managing superficial wounds, with improved drug delivery and reduced systemic exposure.

[0064] Table 1: Experimental Conditions for Ceftizoxime–SBE-β-CD Complex Preparation:S.noConcentration of ceftizoxime (mg)Amount of SBE-β-CD(2.14%)TemperatureRunning period (on orbital shaker) hourAmount of water (ml)15230c°72825430c°72635630c°72445830c°722551030c°720

[0065] Table 2:UV–Vis Absorbance Data for Ceftizoxime Calibration Curve:S. No.Concentration (µg / mL)Absorbance1100.152200.323300.444400.605500.75

[0066] The present invention is industrially applicable in the pharmaceutical industry. The topical ceftizoxime formulation described herein can be manufactured using conventional pharmaceutical production techniques and equipment. It is suitable for large-scale production and clinical use in the treatment and prevention of bacterial skin and wound infections. The composition can be packaged in sterile containers and delivered as a ready-to-use or reconstitutable spray product, enabling practical application in hospitals, clinics, and outpatient settings.

[0067]

[0068] Reference signDescriptionSample 1Pure ceftizoximeSample 2Encapsulated ceftizoxime–SBE-β-CD compleax258 nmWavelength for UV–Vis spectrophotometryR²Correlation coefficient of calibration curve (linearity)SBE-β-CDSulfobutyl ether-β-cyclodextrinE. coliEscherichia coli (Gram-negative test organism)S. aureusStaphylococcus aureus (Gram-positive test organism)mmMillimeters, used to measure zone of inhibitionUV–VisUltraviolet–Visible spectrophotometryµg / mLMicrograms per milliliter, used for ceftizoxime concentrationDSCDifferential Scanning CalorimetryEndothermicDirection of heat absorption shown downward on the thermograma.u.Degrees Celsius, used for temperature scale on the X-axis

[0069] US20030078215A1 – Method of increasing the efficacy of antibiotics by complexing with cyclodextrins.

[0070] US20140220112A1 – Solubilized β-lactam compositions and methods for making and using the same.

[0071] WO2009058327A1 – Cyclodextrin derivatives as potentiators of antibiotic activity.

[0072] Boczar, M. et al., 2022 – Complexation of cefixime with SBE-β-cyclodextrin. Pharmaceutics, 14(7), 1389.

[0073] Patent US20030078215A1: Describes the use of methyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin to enhance the bioactivity of biologically active agents. However, it does not disclose the use of sulfobutyl ether-β-cyclodextrin (SBE-β-CD), which possesses distinct chemical properties that improve aqueous solubility and formulation stability. Moreover, the document does not mention ceftizoxime or any topical formulation. Accordingly, there remains a clear and unmet need for a stable, practical, and topically applicable formulation of ceftizoxime that:

[0074] Overcomes its aqueous instability, Enhances localized antibacterial activity and

[0075] Minimizes systemic exposure associated with injectable therapies.

[0076] The present invention addresses this need by providing a novel ceftizoxime–SBE-β-CD complex, formulated as a topical spray, manufactured under controlled conditions, and validated through analytical and microbiological testing.

[0077] Patent US20140220112A1: Discloses solubilized β-lactam compositions but focus on injectable or oral dosage forms. It does not teach or suggest the use of ceftizoxime, SBE-β-CD, or any topical spray formulation

[0078] Patent WO2009058327A1: Relates to the use of cyclodextrin derivatives as antibiotic potentiators. However, it does not mention ceftizoxime or its complexation with SBE-β-CD and does not disclose or suggest a topical formulation for wound or skin infection management

[0079] Boczar et al., 2022 (Pharmaceutics, 14(7), 1389): Reports the complexation of SBE-β-CD with cefixime, a different cephalosporin antibiotic. However, ceftizoxime has unique chemical degradation and solubility challenges in aqueous systems, which are not addressed. The article does not disclose the complexation of SBE-β-CD with ceftizoxime, nor any use in topical delivery systems.

Claims

A pharmaceutical composition in a pharmaceutically acceptable aqueous dosage form suitable for topical administration, comprising:ceftizoxime as an active pharmaceutical ingredient;sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as an encapsulating and solubilizing agent;and distilled water as a vehicle.wherein the ceftizoxime is present in a complexed form with SBE-β-CD.The composition according to Claim 1, wherein the concentration of SBE-β-CD is between 2% and 10% w / v of the total aqueous solution.The composition according to Claim 1, wherein the presence and amount of ceftizoxime is determined by UV–Vis spectrophotometry at a wavelength of 258 nm.The composition of claim 1, wherein the inclusion complex formation is confirmed by Differential Scanning Calorimetry (DSC), showing suppression or disappearance of the ceftizoxime melting peak.The composition according to Claim 1, wherein the formulation exhibits antimicrobial activity against Staphylococcus aureus and Escherichia coli, as demonstrated by a zone of inhibition assay.The composition according to Claim 1, for use in the prevention or treatment of bacterial skin and wound infections, including pre-operative prophylactic topical application.

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