1 Introduction

Chronic wounds represent an important disease of great socioeconomic impact, often being subject to secondary infections that can be, in some cases, even life threatening [1]. In fact, burn wound infections are a major source of mortality in burn patients [1]. Burn injury disrupts both the normal skin barrier and many of the host defense mechanism that prevent infection. Consequently, the injured skin is susceptible to colonization with the subsequent development of burn wound sepsis. The control of both bacterial multiplication and invasion is of great importance to prevent microbial colonization and among topical anti-infective agents there are silver derivatives, such as silver sulfadiazine (AgSD) still largely used in burn and wound treatment for its broad activity spectrum [1] has to be mentioned. Traditionally, the injured area should be covered with an antimicrobial cream once or twice a day; patients frequently suffer from a considerable amount of discomfort during the application of such a topical drug in form of cream. The current carrier of AgSD are lipid soluble matrices as polypropylene glycol. This vector exhibits several disadvantages: it forms an adhesive pseudo-skin, which is difficult to distinguish from the burn real tissue; most importantly, the carrier is insoluble in water, thus difficult to remove from the burn wound. Traditional formulations of topical antibiotic for burning injury treatments present a series of other lacks: (i) the necessity of wearing sterile gloves for its application; (ii) the necessity of applying a layer of cream of at least 1.6 mm of thickness; (iii) the need to frequently expose to air the burned surface with an increased risk of contamination. To overcome these defects, spray formulations [2] or water soluble gel [3] were designed in the past. More recently, wound dressings or artificial skins containing antibiotics have been developed to inhibit wound infection. Fwu-Long Mi et al. proposed [4] a bilayer chitosan wound dressing that consists of an upper skin layer and a sponge-like sublayer. Chitosan membranes prepared by the combined wet/dry phase inversion process have the same thickness of skin layers, but different porous structures of sponge-like sublayers that have the ability to both control the release of antibiotics and prevent bacterial invasion [5]. An alternative and promising way can be represented by drug delivery systems (DDS). A DDS formulation assures therapeutic, social and economic advantages. In particular, with the number of administrations a DDS will also reduce the injury exposures to external agents, thus reducing the risk of infection. Moreover, fewer stresses of compromised tissue combined with the decrease of administration ensures better regeneration of the skin. A DDS for the release of AgSD must be able to retain high amount of drug and gradually release the active molecule for a prolonged time. Moreover, it might have an optimal texture that assure good comfort and spread ability. Given the potential advantages of this formulation, several papers have been recently published on this topic [5]. Polymeric matrices or composites made of clay and natural polymers have been used as DDS carriers. However, these papers are more focused on a pharmacokinetic studies [6–8]. To the best of our knowledge, a systematic study centered on the DDS formulation (for the preparation of a system with a good performance in terms of bioavailability but meeting the requirement of a topic DDS formulate) has not been reported yet. The final application needs materials with unique physical, chemical, biological, and biomechanical properties to provide effective therapy protocols. An ideal carrier might be biocompatible, comfortable for the patient, easy to administer and to remove. A very interesting approach to meet these requirements is the combination of a biopolymer with a second component to fabricate polymers blends and composites [9]. Polymers, like gelatine, poly(vinyl alcohol), poly(lactic acid) have been employed for preparing blends, while inorganic materials, hydroxyapatite, layered silicates, carbon nanotubes, and glass/ceramic particles, have been used to form polysaccarides composites. The addition of inorganic oxides [10–12] to natural polymer can be a successful alternative way to prepare efficient DDS carriers. The latter would have increased chemical and mechanical stability maintaining at the same time the excellent biological prerogatives and preventing the transport and accumulation of inorganic oxides in the body [13, 14]. Currently, bio-based materials are regarded as key formulation ingredients for the DDSs engineering, but only few examples are reported regarding the use of bio-hybrid containing inorganic oxides [15]. In this work, we have focused our efforts on a bioinorganic system made of chitosan and silica. Chitin, in particular Chitosan, are very appealing systems in terms of availability (to the extent of over 10 Gigatons annually), and of multidimensional potential applications: in food and nutrition, biotechnology, pharmaceuticals, agriculture, and environmental protection. Moreover, chitin and chitosan have long been known and used for the treatment of dermatitis, wounds and as adjuvant of tissue regeneration [15]. On the other hand, silica-based matrices show high biocompatibility–biodegradability [16] and resistance to microbial attack and they exhibit higher mechanical strength, enhanced thermal stability, and negligible swelling in organic solvents if compared to most organic polymers [17]. Moreover, physico-chemical and textural properties can be modulated ad hoc by the choice of a tailored synthetic approach [18]. The synergy between silica and chitosan is a potential way to obtain a high performant DDS carrier with improved physico-chemical features. Particular attention has been devoted to the optimization of an efficient and, above all, sustainable approach taking into great account the overall economy of the process. To this purpose, an effective “one-pot” sol–gel approach has been optimized by using precursors and reagents that are environmentally friendly, easily available and at low cost. Great attention has been devoted to the optimization of the process parameters, working in mild conditions (room temperature and atmospheric pressure) and avoiding the use of hazardous solvents, thus favoring the use of water as solvent. The final aim of the work is the formulation of an innovative gel for the controlled and prolonged release of AgSD by optimizing a sustainable and effective approach. First, the influence of silica alkoxides precursor on the DDS features has been verified. Four silica alkoxides, characterized by different functionalities of the organic chain, were investigated to assess how the different substituents groups can influence the final gel features and consequently the release. Then, in order to achieve the optimal formulation, different synthetic parameters (water/precursor ratio, catalysts, and drug amount) and different excipients were investigated too. The DDS performance was evaluated in vitro by a Franz diffusion cell; particular attention was addressed to the correlation among concentration, formulate dose and molecular penetration and adsorption.

2 Experimental section

2.1 Materials

Tetraethoxysilane (TEOS, 98%, Sigma Aldrich), methyltriethoxysilane (MTES, 99%, Sigma Aldrich), tetramethoxysilane (TMOS, 99%, Sigma Aldrich), aminopropyltriethoxysilane (APTES, 99%, Sigma Aldrich), Chitosan medium molecular weight (Sigma Aldrich), acetic Acid (Prolabo), HCl (37%, Sigma Aldrich), ammonia (33%, Sigma Aldrich), ethanol (VWR Chemicals), phosphate buffer solution (PBS, Sigma Aldrich, Tris Buffered Saline pH = 7.4), AgSD (98%, Sigma Aldrich), Ethylene Glycol (99.5%, Fluka).

2.2 Synthesis

A silica:chitosan = 80:20 weight ratio was selected [15]. A 100% silica, a 100% chitosan gel and a commercial sample were used as references. A solution of a proper amount of AgSD in phosphate buffer (1 mL) was prepared and stored protected from light. The amount of active principle was chosen in order to obtain a final formulation containing either 0.6 or 2.5 wt% of AgSD. This solution was added to a selected amount of silica alkoxide and PBS (SiO2: phosphate buffer = 1:10 molar ratio). Four different silica alkoxides were used: TEOS, MTES, TMOS, APTES. Both amount and nature of catalyst were optimized for each silica precursor. It was used hydrochloric acid (0.6 M) in the case of TEOS, and ammonia in the case of TMOS. In the case of MTES and APTES no catalyst was used. The obtained silica sols were sonicated for 30 min in order to foster homogeneity and hydrolysis. Meanwhile, chitosan (80 mg) was dissolved in a 2% (v/v) acetic acid solution (3 mL) and then mixed with the silica/drug sol. Such organic–inorganic hybrid sol was left to age at room temperature until the complete gelation (3 days for TEOS, 5 days for MTES, 8 h in the case of TMOS, and variable times, from a few hours to several days, for APTES). The gelation is considered complete when the drug release profile (collected by the standard drug delivery test, reported in the drug delivery test Section) is reproducible indipendently from the time of ageing. Finally, gels were coated with ethylene glycol (1 mL) in order to prevent drying and stored at 4 °C in darkened glass vials of 10 mL. Hybrid alkoxide—chitosan gels will be denoted as: TEOS + Ch, MTES + Ch, TMOS + Ch, APTES + Ch.

A 100% silica gel was used as reference. The sample was synthesized by using TEOS as precursor and following the procedure optimized in a previous work [19].

2.3 Drug delivery tests

2.3.1 Standard tests

In order to investigate stability, reproducibility and homogeneity of the formulates, a series of preliminary test was performed by using an in vitro standard test [20]. In a typical experiment, a proper amount of gel was soaked in 20 mL of a saline solution at pH 7.4 and maintained at 37 °C. Samples of 1 mL were removed from the solution at predetermined times and replaced by the same volume of fresh medium. The drug concentration in the liquid phase was evaluated by ultraviolet (UV) spectrometry at 272 nm (Perkin-Elmer λ40 instrument). Calibration curve of AgSD was determined by taking absorbance vs. ibuprofen concentration between 0 and 2000 ppm as reference parameters. The effective drug concentration in solution was calculated based on the following equation [21]:

$${C_{{\rm{eff}}}} = {C_{{\rm{app}}}} + \frac{v}{V}\mathop {\sum}\limits_t^{t - 1} {{C_{{\rm{app}}}}} ,$$

where Ceff is the corrected concentration at time t, Capp is the apparent concentration at time t, v is the volume of sample taken and V is the total volume of the dissolution medium.

In order to check the reliability of the collected data, a test was carried out in the conditions previously reported by taking a single sample from the dissolution medium at the end of the release experiment. We have obtained the same drug concentration value of that calculated on the basis of the formula for a drug release test studied with multiple sampling. In order to check for reproducibility, each release test was carried out in duplicate by collecting, each time, the data analysis simultaneously from two identical samples.

2.3.2 Franz diffusion cell

In order to simulate in vitro the drug diffusion from the formulate to the skin surface we have used a Franz Cell, as schematized in Fig. 1.

Fig. 1
figure 1

Schematization of Franz diffusion cell (color figure online)

Full size image

The cell consists of two parts: the sample holder, containing the suitable amount of sample (from 0.2 to 0.5 g), and the reservoir (25 mL) of the diffusion cell containing the receptor medium (physiological saline solution at pH 7.4). A synthetic membrane in polyvinylidene fluoride (PVDF) separates donor and receptor chambers. PVDF is an inert polymer which is thermally, chemically and mechanically resistant. Membranes are characterized by 125 μm of thickness, 70% of porosity and 0.45 μm of pore diameters. The membranes act as a diffusion medium and help to contain the test sample whilst ensuring its contact with the receptor medium. The physiological solution was stirred at 150 rpm. The receptor temperature was 37 °C. Samples of 1 mL were removed from the solution at predetermined times and replaced by the same volume of fresh medium. The drug concentration in the liquid phase was evaluated as previously reported for standard tests.

2.3.3 Characterization

FTIR spectra were obtained on a BRUKER IFS28 spectrophotometer equipped with both MCT and DTGS detectors. Spectra were collected in the 4000−400 cm−1 spectral range (4 cm−1 resolution and 128 scans). All materials were inspected in the form of dispersions in specpure KBr powder with a sample:KBr 1:20 weight ratio without any further pre-treatment.

3 Results and discussion

3.1 Optimization of DDS formulation

3.1.1 Influence of different silica precursors

A topical administration is the target for the DDS studied in the present work. Therefore, our formulated must retain a “texture” with three main characteristics: (i) easy applicability on the site of action; (ii) good control of the drug release; (iii) optimal drug adsorption on the site of action. The most appropriate technique for achieving such characteristics is the sol–gel method [22–26]. By this sustainable synthetic approach, we have prepared a series of hybrid organic–inorganic DDS made of silica and chitosan. In particular, we have investigated several parameters in order to ascertain their influence on the synthesized materials and to better optimize the final formulation. Firstly, the attention was focused on the silica precursors in order to assess how the alkoxides substituents groups can influence the physico-chemical, structural and morphological features of the DDS formulates. In a previous work [22, 23] we had investigated by a sol–gel approach silica-based DDS prepared by alkoxides containing both methyl and amino groups. We observed a close correlation between nature/amount of functional groups and the drug release behavior. In the present work the attention was focused on four silica alkoxides: TEOS, MTES, TMOS, and APTES. The goal was to assess how the different substituents groups can influence the final gel features and consequently the drug release process. As shown in Fig. 2, the various samples exhibit very different textures. TMOS + Ch gel is a solid and vitreous monolith. In this case, the precursor triggers a rapid gelation (8 h): moreover, gel drying is favored by the fast evaporation of methanol, derived from both hydrolysis and condensation reactions. APTES + Ch formulate is not completely homogeneous, very compact and not divisible. APTES is extremely reactive toward the hydrolysis reaction and renders the sol-gel process very fast, uncontrollable and consequently not reproducible. Therefore, neither TMOS + Ch nor APTES + Ch gels are appropriate for the final application that is for a topical administration. On the contrary, TEOS and MTES precursor represent the best compromise in terms of reactivity and nature of the “living” groups. In fact, samples synthesized from TEOS + Ch and MTES + Ch exhibit an optimal texture: they are homogeneous, malleable, and elastic. In particular, TEOS + Ch gel is thicker and therefore it would well remain on the site of action. Furthermore TEOS, between the used silica precursor, is the most safety. In the case of human exposure (inhalation, skin, eyes, ingestion) it causes small and not dangerous side effects that in the case of skin exposure are limited to slight and reversible dry skin and redness (https://pubchem.ncbi.nlm.nih.gov/compound/6517#section=Inhalation-Symptoms). Products obtained from TEOS are silica and ethanol. Silica is a biocompatible, biodegradable, and non-toxic compound that is extensively used in pharmaceutical and cosmetic formulation [27, 28]. Ethanol meet requirement of European Pharmacopeia; moreover, a recently study has demonstrated the safe of ethanol-based formulation destined to a topic administration [29]. For all these reasons, TEOS derived gel appears the most suitable formulate for a DDS to be administered by the dermal route. However, formulated’s texture is not the only requirement for a good DDS: a well-controlled and reproducible drug release is also necessary. In order to evaluate this aspect, drug delivery tests were performed on MTES + Ch and TEOS + Ch samples, according to the standard procedure reported in the experimental section. A series of preliminary tests were carried out at different aging times (1 day, 1 week, and 1 month after the gelation), to check the time necessary to achieve the complete gel cross-linking and therefore the gel stability. Regardless of the silica precursor (TEOS or MTES) the reticulation process was complete after 1 week from the gelation. In fact, release kinetics after 1 week and 1 month of gel aging are reproducible. We have also checked homogeneity and reproducibility of the synthetic procedure by tests on different portions of gel belonging to the same batch of preparation and on gel portions from different preparation batch. Fi after 1 week of ageing. In the first part, the curves are very similar: they are both characterized by an initial fast release rate. This is desirable in order to achieve, in an acceptable time, the minimal therapeutically concentration. Afterward the kinetics are clearly different: MTES + Ch sample completely releases AgSD before 24 h, while gel prepared from TEOS + Ch exhibits a gradual release that continues until 48 h. Moreover, the TEOS + Ch hybrid assures a net performance improvement if compared with a 100% chitosan and a 100% inorganic carrier, respectively (see Fig. 3b). The 100% chitosan carrier releases all drug in the first 6 h with a fast delivery rate. In this case, the matrix degradation and the lack of a real porous structure are determinant factors. On the contrary, a 100% silica DDS exhibits a more controlled initial release rate but it reaches a plateau after 5 h. In the case of the silica carrier a synergy of factors can explain the drug release: (i) diffusion through the carrier matrix; (ii) carrier matrix erosion. This last aspect is less marked than for chitosan. Furthermore, silica exhibits a porous structure that plays a shape control role on the drug delivery: the pore structure slows down the drug delivery and at the end of the release experiment part of the drug (30%) is hold back in the inorganic network. In any case, both the system are unsuitable as carriers for the formulation of a controlled DDS. On the contrary, the hybrid system exhibits a very controlled release, prolonged on the time and almost complete. The synergy between chitosan and silica assures then the optimal compromise in term of matrix degradation and drug diffusion control through the polymeric network. When chitosan is combined with silica, the inorganic oxide stabilizes the polymer and delays its degradation. At the same time, the drug delivery process is favored. Drug desorption is governed both from the diffusion through the chitosan-silica polymeric network and from the hydrophilic/hydrophobic balance of the matrix. Steric and electrostatic interactions of drug with the organic–inorganic carrier foster an optimal control of the release. Such more gradual and prolonged release is further improved by the increased affinity of the organic–inorganic matrix with the release medium with respect both a 100% silica and a 100% chitosan matrix. Moreover, the synergy of chitosan and silica assures the total desorption of the loaded drug. This is probably a consequence of the bond dissolution between the inorganic and organic moieties which is favored by the enzymatic action of lysozyme. The latter is a protein which is principally responsible for the in vivo degradation of chitosan by hydrolysis of the acetylated groups [30].

Fig. 2
figure 2

Images of silica–chitosan gels prepared by different silica precursors (color figure online)

Full size image
Fig. 3
figure 3

a Drug release profile for MTES + Ch and TEOS + Ch formulates after 1 week of ageing compared with an ideal profile [24]. b Drug release profile for 100% silica and 100% chitosan and for a TEOS + Ch derived sample (color figure online)

Full size image

3.2 FTIR characterization

FTIR spectroscopy was performed on TEOS + Ch sample in order to verify the nature of the interactions between silica and chitosan, and those between the matrix and the active principle. Figure 4 (section a) reports the FTIR spectra of (i) TEOS + Ch gel without drug (black curve), (ii) the same gel containing 0.6 wt% (red curve) and (iii) 2.5 wt % (blue curve) of AgSD, respectively. The spectrum of the hybrid matrix (TEOS + Ch) exhibits the vibrational bands of both silica and chitosan. In particular, in the region between 1100 and 400 cm−1 the typical signals of the silica structure relating to the antisymmetric and symmetric stretching vibrations of the Si–O–Si bonds can be observed. Such bands are clearly visible even in the samples containing AgSD. The typical bands of the ν stretching modes of the C–H groups of chitosan are evident at 2960 and 2830 cm−1. In addition, the spectral profile of the hybrid TEOS + Ch is characterized by the presence of a peak at 1400 cm−1, characteristic of the Si–C bond [31]. Since a silica gel synthesized only from TEOS doesn’t show absorption bands in the range between 1430 and 1390 cm−1, it’s possible to assert that the band at 1400 cm−1 is due to the formation of a bond between Si atoms of the inorganic matrix and carbon atoms of the natural polymer. However, it is extremely difficult to determine the type of interactions between the various components of the hybrid system. In order to put into evidence the presence of the drug, it is necessary to refer to differential spectra (i.e., spectra obtained by the subtraction of the spectral contribution due to the sole silica–chitosan matrix: see section b of Fig. 4).

Fig. 4
figure 4

a FTIR spectra of TEOS + Ch, TEOS + Ch with 0.6 wt%AgSD; TEOS + Ch with 2.5 wt%AgSD in the 400–1400 cm−1 region. b Differential spectra between TEOS + Ch with 0.6 wt% AgSD—TEOS + Ch and TEOS + Ch with 2.5 wt%AgSD—TEOS + Ch. c FTIR spectra in the 2000–1300 cm−1 region of a gel synthesized only with TEOS (color figure online)

Full size image

The main absorptions reminiscent of the presence of AgSD are then evident in the 1800–900 cm−1 range: (i) the two bands can be ascribed to either the bending mode of CH-containing species or the stretching mode of S=O groups, both typical of the AgSD drug; (ii) the doublet located at 1090–1040 cm−1 can be ascribed to the CN stretching mode again typical of the AgSD system.

3.3 Excipients

In order to further improve the DDS performance the formulation was optimized by the addition of excipients. The pharmaceutical industry is ever thirsty to satisfy patients therapeutically needs and apart from active ingredients, excipients play a major role in formulation development. The International Pharmaceutical Excipients Council defines an excipient as “any substance other than the active drug or prodrug that is included in the manufacturing process or is contained in a finished pharmaceutical dosage form” (http://www.ipec.org/). Today’s commercially available excipients provide a large selection of required functions: they process aids that increase lubricity, enhance flow ability, improve compressibility, and compatibility. In some cases they can impart a specific functional property to the final product (e.g., modifying drug release). The US Pharmacopeia–National Formulary (USP–NF) categorizes excipients as binders, disintegrants, diluents, lubricants, glidants, emulsifying–solubilizing agents, sweetening agents, coating agents, antimicrobial preservatives, and so forth. Some excipients are simply used to make the product taste and look better. This improves patient compliance, especially for children. In the case of a DDS for a topical administration, it is essential that the formulated keep unchanged the consistency of a spreadable gel. The addition of an opportune excipient is fundamental to guarantee this prerogative. During the gel ageing, solvent in the lattice of the polymeric gel gradually evaporates, and DDS took on the consistency of a dry and glassy solid. The addition of an excipient wants to prevent solvent evaporation, keeping the wet gel and maintaining the appropriate consistency. The effect of several excipients was evaluated on the best sample (TEOS + Ch). Alcohols (ethanol and 2-propanol) are not effective for this application: in fact, although more slowly, the gel became glassy 15 days after gelation. Ethylene glycol, chosen because already present in many pharmaceutical formulations [32], is resulted the best candidate. The high vapor pressure of ethylene glycol, produces a barrier between the gel and the outside, avoiding the solvent evaporation. With the addition of this excipient it was observed that the initial consistency of the formulates is unaltered for at least 4 months.

3.4 Influence of drug amount

Chitosan-silica hybrid gels are designed as a prolonged DDS. Therefore, they must contain a higher amount of AgSD than the traditional formulations. The next goal of the work was increasing the content of AgSD from 0.6 wt% (typical of traditional formulations) to 2.5 wt%. The amount of AgSD was selected tacking account the safety of use of the final DDS concerning the Ag release [33]. Of course, stability, consistency, high control on drug release of the previously optimized DDS must be preserved. The attention was focused on the most efficient hybrid gel that is on TEOS + Ch. As already highlighted, the sol–gel technique is extremely sensitive to many parameters and the minimum variation of a synthetic variable can alter the result. The synthetic procedure was improved by the modification of some parameters (molar ratio between silica and phosphate buffer, sonication time). The gel containing the 2.5 wt% of AgSD is homogeneous, spreadable and stable. Figure 5 shows the delivery profiles after one and 2 months of gel ageing. The release curves are identical: this means that the formulated is stable in time and this is an unavoidable condition for a potential application. Going into detail of the release kinetics, we can observe how the drug delivery is controlled and gradual over time. Contrary to what was observed for the formulation containing 0.6 wt% of AgSD, not all the drug is released in the case of 2.5 wt% AgSD. The formed hybrid network is, probably, characterized by a different texture compared with the previous gel and inhibits, in these experimental conditions, the total release of the active molecule.

Fig. 5
figure 5

Drug release profiles in tests with Franz diffusion cell. Different amounts of TEOS + Ch with 2.5 wt% AgSD (color figure online)

Full size image

3.5 Delivery tests by franz diffusion cell

The therapeutic efficacy of any drug depends on its bioavailability, which is the degree to which a drug becomes available to the target tissue after administration. In dermatology, the therapy effectiveness is based on the availability of the pharmacologically active element, in particular on its ability to penetrate the skin. The dermal adsorption is composed of three steps: penetration, permeation, and adsorption. This means that at first the molecules should be able to enter the skin; then, they should move from a layer to another; finally, they should be assimilated. In the pharmaceutical and cosmetic formulation the study of the skin penetration by molecules is a determinant step. Various studies have considered the impact of different physicochemical drug features and formulations, on the transition from the surface of the skin to the underlying tissues or the systemic circulation; however, the influence of drug concentration and of amount and thickness of applied formulate have been rarely faced [34, 35]. In this work, we have verified the correlation between AgSD concentration and its diffusion through a membrane. Such diffusion capacity has been evaluated by a Franz-cell-based test. The latter was conducted on TEOS + Ch containing 2.5 wt% of AgSD, which is the best formulate that we have synthesized. Different amounts of gel (0.5, 0.35, and 0.2 g) were spread on the membrane in order to obtain three layers with different thicknesses, as schematized in Fig. 5.

The same figure shows the corresponding profiles of release. We can observe, regardless of the thickness, a complete release of the drug after 48 h of experiment. The profiles are very similar and show that the release rate is inversely proportional to the thickness. To verify that the gels are effective as DDS for topical administration, we have performed delivery tests under the same experimental conditions even on a commercial sample of 1 wt% AgSD. The results are reported in Fig. 6.

Fig. 6
figure 6

Drug release for a commercial sample (left histograms) and for TEOS + Ch with 2.5 wt% AgSD formulate (right histograms) (color figure online)

Full size image

in which we show the amount of released drug vs. time. In the first hour, regardless of the thickness, all the samples release almost the same fraction of AgSD (from 1.8 to 2.0 mg); therefore, it is possible to assert that hybrid made of silica and chitosan reaches the therapeutic concentration in an acceptable time: the same of the commercial formulation. As regard as times between 2 and 48 h, the hybrid gel releases with a gradual and controlled trend the 100% of AgSD, this is true for all the amount of applied formulate. On the contrary, the commercial sample releases only 60% of AgSD. We can conclude that the optimized formulation is high performant as DDS and it could be effective in the treatment of acute skin infections.

4 Conclusions

A versatile and effective strategy for the formulation of a DDS for the controlled release of antibiotics for topical administration was developed. The DDS was formulated by a “one-pot” sol–gel approach by using chitosan and silica alkoxides as organic and inorganic precursor respectively. A sustainable approach was used. The composition of the hybrid gel was selected to achieve the optimal synergy between the chemical–physical features and the gel texture taking into great account the final application, which is a topical administration. Silver sulfadiazine (AgSD), an effective antimicrobial agent for preventing infections on burn wounds, was selected as model drug. Different silica alkoxides, characterized by different functionalities of the organic chain, were evaluated. Best results with TEOS + Ch formulated. The new DDS reaches the therapeutic concentration in the same time of a commercial sample and allows the complete release of even 2.5 wt% AgSD. The drug delivery is controlled and gradual over 48 h and the formulated is stable in time. Such innovative organic–inorganic hybrid is therefore an efficient DDS for acute skin infections treatment by controlled delivery.