Eur Arch Otorhinolaryngol (2003) 260 : 131–134 DOI 10.1007/s00405-002-0534-2

RHINOLOGY

Werner Hosemann · Edith Schindler · Eckard Wiegrebe · Achim Göpferich

Innovative frontal sinus stent acting as a local drug-releasing system

Received: 6 March 2002 / Accepted: 9 August 2002 / Published online: 10 October 2002 © Springer-Verlag 2002

Abstract Contemporary endonasal sinus surgery has given rise to distinct extended procedures focusing on the frontal sinus. However, surgical results sometimes are flawed, with reactive scarring leading to a relapse of insufficiency of drainage and ventilation. Topical application of medicines may offer help, but the hidden operative field around the frontal sinus is not reached by the usual nasal drugs. The effectiveness of an intraoperative insertion of stents is still a subject of debate in the literature. In previous studies we have seen some positive results. Based on this fact we looked for additional modalities to boost the effectiveness of fronto-nasal stents. We present a new device acting both as a stent and also as a local drug-releasing system. The combination of two therapeutic modalities may improve our treatment results in endonasal frontal sinus surgery. The pharmaceutical basics of our device are presented, and the first clinical data are shown. The first clinical trial was completely successful. Modification of the polymer and also of the released pharmaceutical agents may provide future improvements and may allow additional applications of the system in other areas of our surgical specialty. Keywords Frontal sinus · Stent · Endoscopic sinus surgery · Releasing system · Chronic sinusitis

W. Hosemann (✉) Department of Otorhinolaryngology and Head and Neck Surgery, University of Greifswald, Walther Rathenau Str. 43–45, 17487 Greifswald, Germany e-mail: [email protected], Tel.: +49-3834-866200, Fax: +49-3834-866201 E. Schindler · A. Göpferich Department of Pharmaceutical Technology at the Institute of Pharmacy, University of Regensburg, Regensburg, Germany E. Wiegrebe Pharmaceutical Unit of the Medical School, University of Regensburg, Regensburg, Germany

Introduction Minimally invasive, optically guided endonasal surgery has gained wide acceptance for the treatment of chronic sinusitis if medical treatment has failed. Moreover, in the last years the range of indications for endonasal surgical interventions has been expanded, covering now most kinds of mucopyoceles, many benign tumors and other diseases [6]. Besides the introduction of new indications, endonasal surgery gave rise to a significant increase in its range of action due to advances in microanatomy, followed by the development of new surgical tools. One of the most recent areas of scientific development is represented by the endonasal surgery of the frontal sinus. A comprehensive system of distinct surgical procedures has been presented by Draf [2]. The frontal sinus attracts special attention not only in the operating theaters but also in the postoperative period. Usual wound healing takes months, and wound healing problems are frequently observed, especially in the area of the frontonasal transition zone, which is touched extensively during surgery [4]. One of the most troublesome side effects is reactive scarring in that area [5]. In general, complementary topical medical therapy is mandatory in sinus surgery to reduce scarring and provide sufficient neoostia. At present, corticosteroids have proven to be most effective. Unfortunately, the appropriate agents applied by nasal sprays and ointments do not reach the critical anatomical area around the frontal sinus outflow tract [10, 13]. Having this fact in mind, many rhinosurgeons have reconsidered the intraoperative insertion of stents for maintaining the widened frontal sinus access. Irrespective of individual positive experiences, stenting has not been shown to be effective in all cases. We have developed an innovative stenting system that preserves the merits of frontal sinus stents and provides in addition the sustained and precise local release of pharmaceutical active agents from the polymer. The following presentation focuses on the pharmaceutical aspects. Few preliminary clinical data are presented.

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Materials and methods Materials Dexamethasone was purchased in the medical grade from Merck, Darmstadt, Germany. Ethylvinyacetate (EVAC) was obtained from Elf-Atochem, Paris. Acetone, dichloromethane and ethanol were purchased from Merck in the analytical grade.

Fig. 1 Scheme of the rolled EVAC sheet acting as a frontal sinus stent. The inferior extension of the sheet permits fixation to the nasal septum applying a single mattress suture

Methods Polymer purifications EVAC was first purified by extraction with acetone. For a standard protocol, 50 g EVAC were weighed into an Erlenmeyer flask and extracted for 1 week with 250 ml acetone using a magnetic stirrer. After decanting the solvent, the polymer was washed three times with 80 ml acetone. The procedure was repeated twice using acetone and in a final purification step using ethanol. The final product was dried in a desiccator under vacuum for 24 h. Sterilization of dexamethasone, dichloromethane and EVAC Forty-five mg of dexamethasone were dissolved in 5 ml acetone, sealed in glass vials sterilized for 20 min in a water vapor-saturated atmosphere of 2 bar and 121°C for 20 min using a Vakulab 446 LS3000 sterilizer (Münchener Medizin Mechanik GmbH, Planegg/ Munich), and 500 ml dichloromethane were sterilized by filtration through a membrane filter with a pore size of 0.22 µm. EVAC was heat sterilized for 2 h at 160°C in a SL50 sterilizer (Willi Memmert KG, Schwabach, Germany). Manufacture of dexamethasone-loaded EVAC matrix films Dexamethasone-loaded matrices were obtained by solvent casting. All procedures were carried out under aseptic conditions in a laminar air-flow bench (BDK Luft-u.Reinraumtechnik GmbH, Sonnenbühl-Genkingen, Germany). In detail: 17.955 g sterile EVAC were dissolved in 98 ml sterile dichloromethane using a magnetic stirrer. After approximately 24 h, 1 ml of the sterile dexamethasone solution was added under gentle stirring. To avoid the formation of air bubbles, the solution was allowed to settle for 10 min and then cast into a round 15-cm diameter Teflon mold. To remove solvent residues, the films were dried for 5 days inside the laminar flow bench and finally cut into 2×2-cm pieces. In vitro release studies Dexamethasone release was monitored by HPLC analysis. For the investigation of in vitro release, cylindric 2.2-cm-diameter matrix discs were obtained by die-punching. Individual discs were incubated with 10 ml phosphate buffer, pH 7.4, supplemented with 0.02% sodium azide in 20 ml scintillation vials. The samples were kept for 28 days in a type 3047 shaking water bath (Kottermann, Hänigsen, Germany) at 37°C under gentle shaking. After at least every 3 days, the complete buffer was exchanged and kept frozen at –20°C until further analysis. For HPLC analysis, 50 µl of each sample was injected into a Shimadzu HPLC system equipped with a de-gasser (Knauer, Berlin), a LC-10AT pump, a FCV-10ATVP gradient mixer, a SIL-10ADVP autosampler, a CTO-6A column oven, a SPD-10AV UV detector and a SCL-10AVP controller (all from Shimadzu, Duisburg, Germany). A C18-reversed phase pre-column (Supelcosil LC318, 4.6 mm× 50 mm) in combination with C18-analytical column (Supelcosil LC318, 4.6 mm×250 mm, both from Supelco, Deisenhofen, Germany) served as a stationary phase. At 40° C, a gradient of 15– 30% solvent B in solvent A over 23 min was used as a mobile

Fig. 2 Release of dexamethasone out of three different EVAC matrices phase. Solvent A consisted of water and acetonitrile (90:10) and solvent B consisted of acetonitrile with 10% double-distilled water. Chromatograms were recorded at 254 and 274 nm, respectively. The ClassVP 5.0.1 software (Shimadzu, Duisburg) was used for data acquisition and analysis. Surgical procedure The frontal sinus was entered according to the rules of routine endoscopic endonasal sinus surgery [6]. Under constant endoscopic control, the exposed frontal sinus ostium was extensively enlarged by the sharp spoon and special punches [3]. Following this, the head of the middle turbinate was excised, and the medial frontal sinus floor was removed. In this way, a frontal sinus access “type 2”

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Fig. 3 Endoscopic photograph (30°) revealing inferior parts of a rolled EVAC sheet in the left nasal cavity of our first patient. The patient had been subjected unsuccessfully to repeated prior external frontal sinus surgery. Revision surgery consisted in an endoscopic endonasal ‘Draf II’ procedure followed by insertion of an EVAC sheet acting as a medicament releasing system. In spite of obvious crusting of the sheet, the patient has no complaints

Fig. 5 Endoscopic photograph (30°) revealing the frontal sinus access 2 weeks after stent removal (same patient as Fig. 3). The granulation polyp situated on the lateral wall of the frontal sinus access seemingly has its stalk in an area that was not completely covered by the rolled EVAC sheet. All other areas show obviously regenerated mucosa. The patient is free of complaints

rolled, and the roll was introduced transnasally into the frontal sinus neo-ostium (Fig. 1, Fig. 2, Fig. 3). The inferior portion of the sheet was fixed to the nasal septum by a mattress suture. The stent was easily removed in the office after 3–4 weeks (Fig. 4, Fig. 5). All patients did well after the stent removal (follow-up by endoscopy until definitive wound healing could be observed was about 3 months postoperatively).

Results

Fig. 4 Endoscopic photograph (30°) revealing the frontal sinus access immediately following stent removal 4 weeks after surgery (same patient as in Fig. 3)

according to Draf was created in the first patient (the second and third patients were subjected to a “type 3” procedure). A reduced external access was performed in the third patient in addition to the endonasal procedure. The sterile EVAC sheet of 2×3 cm was

Prior to the application of dexamethasone-loaded EVAC matrices in any surgical procedure, we investigated their in vitro release behavior. Figure 2 shows that the matrices deliver the drug for more than 2 weeks. The concave shape of the profiles is due to the release by diffusion [1]. Compared to the release in vitro, the release in vivo can be assumed to be prolonged, as in vivo only the surface of the matrix in contact with the tissue of the frontal sinus will release significant amounts of the drug. The inner wall of the hollow stent can be considered almost insulated after implantation into the frontal sinus. As the results of our in-vitro tests were promising and as the drug (dexamethasone) as well as the stent material (EVAC) are well-known medical products, we felt that preliminary studies in our patients applying a combination of a both of them were justified (approved by the Ethics Committee of the University of Regensburg and Greifswald, the latter dated 13 July 2001). We therefore inserted the device in three ‘Draf II/Draf III’ frontal sinus neo-ostia,

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which we created in patients suffering from desolate chronic frontal sinusitis. All patients had been subjected to repeated transfacial and also endonasal interventions before, which had failed. The clinical trial was completely successful – with some reservations due to the limited postoperative time period (Fig. 3, Fig. 4, Fig. 5).

Discussion Endonasal frontal sinus surgery for chronic sinusitis has been a subject of debate for more than a century [8]. This fact reflects difficulties in local microanatomy and possible side effects of surgery as well as frequent problems in postoperative healing. Surgeons facing scarring of the neoostium have introduced stents in order to promote healing of the neo-ostium while preserving drainage and ventilation of the sinus. A large range of stent materials and shapes are utilized [14]. Rolled silastic sheets similar to the present design of our releasing system have been introduced, e.g., by Neel et al. in 1987 [9]. According to the literature, stents are left in situ for weeks to months. However, there is an ongoing controversial discussion about their effectiveness. We have observed positive effects in our patients [15], but we got the definite impression that stenting should be complemented by specific, long-lasting topical medicamentous therapy. As routine topical therapy does not reach the critical areas of the frontal sinus access [10, 13], we had the idea of combining the stent with a local drug-releasing system. In general, anti-infective and anti-inflammatory releasing systems have been presented in the literature for different purposes [12]. However, the cumulative release of active agents covers a time period of up to a few days in the existing systems. The innovative stent presented here shows a combination of unique attributes especially designed for the needs of endonasal frontal sinus surgery: The pharmaceutical releasing system reveals a long-lasting release of agents that are correlated with the physiological data of intranasal would healing. In addition, the system claims the merits of stenting the frontonasal neo-ostium. In previous investigations, we have shown that wound healing in the paranasal sinuses following major surgery takes up to 3 months [4]. The recommended daily dosage of dexamethasone in commercial nasal sprays covering the whole inferior nasal lining is 60–120 µg [11]. This fact is addressed by our EVAC system, which releases about 60 µg dexamethasone per day around the frontal sinus access for 25 days at present. The very preliminary clinical data are promising. Confirmation by ongoing clinical investigations provided that there are different options for additional improvements: first, the design of the stent is to be optimized, and different standard sizes and fashions may have to be developed.

Second, a specially designed instrument may help to introduce the stent quickly and easily in a minimally invasive fashion under constant optical control. Third, and most important, the pharmaceutical agents released by the device will be modernized (replacing dexamethasone), and other varieties will be introduced: corticosteroids will be supplemented by growth factors or antiinflammatory drugs. The selection of agents is dominated by the special features of the polymeric device (restrictions in the molecular weight of the incorporated agents and pharmacodynamics of the following release). Modifications of the polymer itself may expand the time period of the drug release. We hope that the presented innovative releasing system will facilitate endonasal treatment of the frontal sinus significantly. The basic therapeutic principle of innovative releasing systems may also apply to other applications in our surgical speciality.

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