Paula Machado

Nystatin and lidocaine pastilles for the local treatment of oral mucositis

Abstract Oral mucositis (OM) is a common adverse reaction to radiotherapy and chemotherapy in oncology. Its treatment requires oral formulations that enhance therapy compliance, improve administration and ensure drug effectiveness. Solid dosage forms that act by slow dissolution, such as pastilles, are an effective alternative to mouthwashes, for their versatility, ease of administration and extended residence time in the oral cavity. The present work describes the development and stability studies of an innovative formulation of nystatin and lidocaine pastilles for the treatment of oral mucositis. Full pharmaceutical quality testing was carried out, including disintegration and dissolution testing, texture profile analysis, grittiness and an antifungal activity testing. A soft pastille formulation containing 0.25% lidocaine and 78,000 IU nystatin was obtained, presenting suitable pharmaceutical characteristics, as a disintegration time of 17 ± 2 min, dissolution rate and microbiological and physicochemical for 30 days when stored at 2–8 °C under light protection. Palatability was also evaluated, being well accepted by a panel of 38 healthy volunteers. This formulation allows an accurate drug dosing by the prescriber, while enabling the patients to control the retention time of the drugs in the oral cavity and consequently manage their pain treatment.

Betamethasone dipropionate compounding for cutaneous T-cell lymphoma management

Background Primary cutaneous lymphomas (extranodular non-Hodgkin lymphomas) are rare (incidence 1:100 000). Mycosis fungoides is the most common cutaneous T-cell lymphoma (CTCL) subtype. Treatment options are based on the diagnosis and the stage of the disease. Skin-directed therapies are useful for the initial stages and include topical treatments such as corticosteroids. Betamethasone dipropionate (BD) is a synthetic glucocorticoid with high anti-inflammatory activity, potency and immunosuppressant effects. It is used for topical treatment of CTCL within the following dosage 0.025–0.1% (w/w). In the Portuguese market only one topical cream contains BD at 0.05% (w/w). Objectives To develop a new and stable emulsion containing 0.1% of BD. Methods To accomplish this aim, development, stability, in vitro release and clinical studies of a new topical water-in-oil emulsion containing BD 0.1% w/w were assessed for the topical treatment of CTCL. Results The three batches prepared were physically, chemically and microbiologically stable over a period of 90 days. 40% of BD was released over 6 hours and evaluation of skin lesions showed a favourable clinical effect (less itching, less infiltration, fewer patches and a reduced area of plaque). Conclusions The clinical results show the effective cutaneous improvement of skin barrier conditions during the study.

TCH-049 Topical Morphine Gels For Painful Wounds

Background The use of morphine applied topically to painful wounds has potential advantages such as a lower dose than with systemic administration and fewer side effects. Gels are known to be suitable for treating wounds. Purpose To develop two physicochemically and microbiologically stable gels: a more viscous formulation (F1) and a fluid formulation for spraying (F2), both containing morphine hydrochloride (MH). The effect of viscosity on drug release from both gels was also investigated. Materials and Methods Sodium carboxymethylcellulose-based aqueous gels were prepared and sterilised by autoclaving. The 0.125% w/w (F1) and 1.0% w/w (F2) gels containing MH were compounded using an injectable solution of MH and preservatives (parabens). Preparation and primary packaging were performed inside a horizontal laminar flow hood. Primary packaging consisted of single dose syringes for F1 and 10 mL amber glass bottles with pump sprays for F2. Stability studies were performed using 3 batches of each final formulation. Samples were stored at 5 ± 3°C, at 22 ± 3°C (light exposed and protected) and 40 ± 2°C/75 ± 5% RH for 98 days (samples collected at 6 time points). Organoleptic characteristics, pH, viscosity, MH and preservative content were assessed. Sterility tests, microbiological control and preservative efficacy were studied according to Ph. Eur. The MH release profile was evaluated using Franz cells. Results Formulations were odourless, yellowish, translucent and homogeneous. The pH was 6.35 (F1) and 5.70 (F2), viscosity was 52.933 mPa.s at 6.12 s-1 (F1) and 16.7 mPa.s at 12.24 s-1 (F2). Methylparaben, propylparaben and MH contents were between 90–110%. Preservatives were effective and preparations remained sterile and stable for 60 days. MH release was slow and inversely proportional to viscosity. Conclusions The MH gels presented suitable physicochemical and pharmaceutical characteristics for topical application to painful wounds. The slow release profile may reduce the number of applications. No conflict of interest.

TCH-010 Development of a Topical Lidocaine Sterile Formulation 20% (W/V)

Background The topical use of concentrated solutions of lidocaine (4 to 20%), which are usually unavailable, has been reported for microvascular surgery. Vasospasm is known to have an adverse effect on the survival of free tissue transfers. Prolonged vasoconstriction decreases blood flow to the flap and promotes thrombosis at the anastomotic site. The wide availability and rapid effect of topically applied lidocaine is used by many surgeons to prevent and correct vasospasm. Purpose To compound a sterile 20% (w/v) lidocaine solution physicochemically and microbiologically stable for topical application during surgery. Materials and Methods Three batches of a 20% (w/v) sterile lidocaine solution were prepared using two sterilisation steps: autoclaving followed by filtration (0.22 µm) inside a horizontal laminar flow hood. Packaging in 10 ml dropping containers prevents intravenous administration and ensures a maximum safe dose (2 g). For physicochemical and microbiological stability studies, samples were stored in the dark at 5 ± 3°C and 22 ± 3°C, for 15 days. Sterility tests and bacterial endotoxins assays were performed (Ph. Eur.). Samples were collected and characterised on days 0 (T0), 7 (T7) and 15 (T15). Colour, odour, appearance, pH, osmolarity, density and lidocaine hydrochloride content were analysed. Results Throughout the study, the 20% (w/v) lidocaine hydrochloride solutions remained clear, colourless, limpid and odourless. The pH of the solutions stored at 5 ± 3°C was 3.6 ± 0.04 (T0), 3.8 ± 0.08 (T7), 3.9 ± 0.02 (T15), and 3.6 ± 0.04 (T0), 3.9 ± 0.02 (T7), 4.0 ± 0.03 (T15) for the solutions maintained at 22 ± 3ºC. The HPLC analyses showed that the lidocaine hydrochloride content was maintained (90–110%) after 15 days in all conditions tested. Density and osmolality remained constant, i.e. 1.0049 ± 0.0036 g/cm3 and 1175.3 ± 20.2 mOsm/kg, respectively (n = 3). The three batches proved to be sterile and endotoxins-free during the study. Conclusions The lidocaine hydrochloride solution proved to be physicochemically and microbiologically stable for 15 days stored in the dark. No conflict of interest.

TCH-007 Development of a Betamethasone (Dipropionate) Topical Emulsion 0.1% (W/W) (1Mg/G) For Cutaneous T-Cell Lymphoma

Background Cutaneous lymphomas are a heterogeneous group of lymphomas characterised by T and B clonal lymphoproliferative infiltrates that appear and remain confined to the skin without evidence of involvement of other organs/systems in the six months following diagnosis. Some subtypes of cutaneous T epidermotropic lymphomas respond favourably to topical treatment with steroids. Betamethasone dipropionate is a synthetic high-potency glucocorticoid with anti-inflammatory and immunosuppressive action used as the main topical treatment in the early stages of LNH-T–Mycosis Fungoides, or as an adjuvant treatment in advanced stages of the disease. In the Portuguese pharmaceutical market only a 0.05% (w/w) (0.5 mg/g) cream is available although for this therapeutic indication strengths in a range of 0.025%–0.1% (w/w) are required. This was already an off-label clinical use and a higher concentration was required due to insufficient response to the concentration available. Purpose To prepare and characterise a topical 0.1% (w/w) (1 mg/g) betamethasone (dipropionate) cream and evaluate the overall response in cutaneous T-cell lymphomas. Materials and Methods Several batches of a compounded W/O emulsion containing betamethasone 0.1% (w/w) (1 mg/g) were prepared and analysed for macroscopic characteristics, pH, rheological properties and microbiological quality (total germs, fungal, yeasts and E. coli). Patients were evaluated monthly and the overall response was recorded (CR-cutaneous lesion totally disappeared; PR-partial remission – objective response >50%<100%; Stabilized disease if cutaneous lesions were similar; No response if cutaneous lesions worsened). Results We obtained a white, homogeneous, opaque and odourless cream with a pseudoplastic behaviour. The pH of the formulations at 22 ± 3ºC was 5 (±0.5). Microbiological control for non-sterile products revealed no growth of micro-organisms. By the end of the first month one patient (11.1%) showed partial remission, the others (88.9%) had their cutaneous disease lesions stabilised. Conclusions The topical emulsion developed has pH values and rheological characteristics suitable for drug stability and topical skin application. Clinical data is still insufficient for any conclusions. No conflict of interest.