BR-102024017926-A2 - Nanofibrous system containing amphotericin B for the topical treatment of cutaneous leishmaniasis.

Abstract

The present invention relates to nanofibers produced by the solution blow spinning (SBS) technique, consisting of poly(ethylene oxide), PEO, poly(lactic acid), PLA and amphotericin B, to their production process and to the use of the nanofibers in the manufacture of a drug for the treatment of ulcers caused by cutaneous leishmaniasis. The nanofibers are composed of PEO/PLA, biocompatible and biodegradable polymers, and a drug, corresponding to amphotericin B, an antifungal of the polyene class; other drugs may be incorporated into the polymeric nanofibers. The present invention also relates to antifungal compositions of said nanofibers with other excipients, if necessary. The nanofibers, compositions, topical drug delivery system or the manufactured drugs are administered to ulcers resulting from cutaneous leishmaniasis in humans and animals.

Inventors

• KALINE DO NASCIMENTO FERREIRA
• Eliton Souto De Medeiros
• FÁBIO ANDRÉ BRAYNER DOS SANTOS
• LUIZ CARLOS ALVES
• ANA PAULA SAMPAIO FEITOSA

Assignees

• UNIVERSIDADE FEDERAL DA PARAIBA

Dates

Publication Date

20260317

Application Date

20240830

Claims (10)

1. 1 Nanofibers characterized by having a nanometric fibrous network consisting of a combination of a hydrophobic/hydrophilic polymer capable of carrying amphotericin B, not limited to, but preferably composed of poly(ethylene oxide), PEO, poly(lactic acid), PLA and amphotericin B.
2. 2 Nanofibers, according to claim 1, characterized by having diameters smaller than 1 μm, preferably in the range of 100 to 800 nanometers.
3. 3 Nanofibers, according to claims 1 and 2, characterized by additionally containing other incorporated drugs.
4. 4 Nanofibers, according to claims 1 to 3, characterized by being administered topically to ulcerations resulting from cutaneous leishmaniasis in humans and animals.
5. 5. Nanofiber preparation process, according to claims 1 to 4, characterized by having the following steps: 1) Dissolve 1:1, 3:7, 7:3 parts of poly(ethylene oxide), PEO, poly(lactic acid), PLA in 1:9 parts of organic solvents, under magnetic stirring for 1 to 2 hours at room temperature; 2) To the solution described in step "a", add 0.010 to 0.030 grams of amphotericin B; 3) Maintain magnetic stirring for 30 minutes to 1 hour; 4) In the SBS apparatus, eject the solution obtained in step "c" with a controlled injection rate of 5.0 to 8.0 mL/hour, at a pressure of 5 to 15 psi; and a working distance of 10 to 20 cm; and a rotary collector preferably rotating between 200 and 600 rpm, as well as a static collector.
6. 6. Process for preparing nanofibers, according to claim 5, characterized by the organic solvents being chloroform and dimethyl sulfoxide.
7. 7. Antifungal pharmaceutical composition, according to claims 1 to 4, characterized by containing nanofibers composed of poly(ethylene oxide), PEO, poly(lactic acid), PLA and amphotericin B.
8. 8. Antifungal pharmaceutical composition, according to claim 7, characterized by being administered topically to ulcerations resulting from cutaneous leishmaniasis in humans and animals.
9. 9. Use of the antifungal pharmaceutical composition, according to claim 6, characterized by being for the preparation of a medicament for the treatment of infections, mainly ulcerations caused by cutaneous leishmaniasis in humans and animals.
10. 10. Use of nanofibers, according to claims 1 to 4, characterized by being for the preparation of a medicament mainly for the treatment of ulcerations resulting from cutaneous leishmaniasis in humans and animals, and by the medicament being administered topically.

Description

Field of invention [001] PEO/PLA and amphotericin B nanofibers constitute topical drug delivery systems with leishmanicidal activity, intended for the local treatment of cutaneous leishmaniasis. These systems enable the release of amphotericin B in therapeutic doses directly onto leishmanial ulcers, ensuring local therapy in order to reduce/eliminate the toxic effects promoted by the drug while treating the lesioned area. In addition, they provide the absence of systemic toxic effects by acting directly on the tissue to be treated. Thus, the nanofibers have biodegradable, biocompatible polymers in their composition, with the possibility of covering the area like a dressing, eliminating the occurrence of secondary infections that hinder the healing process. Therefore, it eliminates the need for outpatient hospitalizations, reducing the discomfort caused by conventional treatments, which compromise adherence and continuity of treatment. State of the art: [002] Leishmaniasis consists of a set of diseases that affect humans, caused by protozoa of the genus Leishmania, subgenera Viannia and Leishmania (C.G.X. FERREIRA, M.D. DE OLIVEIRA, F. SUGUIMOTO, R.F. SOUZA, A.M. MACHADO, A.R. DA S.R. MACHADO. Retrospective Evaluation of Confirmed Cases of American Cutaneous Leishmaniasis in Três Lagoas - MS from 2007 to 2019. Brazilian J. Dev., v.7, p. 13535-13550, 2021). Based on the symptoms presented by humans, the disease can be characterized into two major groups: dermotropic/mucotropic (cutaneous) leishmaniasis and viscerotropic leishmaniasis. [003] This disease is widespread throughout the world; currently, more than 1 billion people in more than 100 countries are at risk of infection (WHO. Global Health Observatory data repository: Number of cases of cutaneous leishmaniasis reported, 2017). Despite the worrying numbers, investments in promoting more effective treatments are low, and the largest number of cases are located in developing countries, thus classifying it as a neglected disease (M. GHORBANI, R. FARHOUDI. Leishmaniasis in humans: Drug or vaccine therapy? Drug Design, Development and Therapy. v. 12 p. 25-40, 2018). [004] Cutaneous leishmaniasis (CL) primarily affects the skin structure, and especially the mucous membranes of the upper airways, being clinically recognized in three forms: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and diffuse cutaneous leishmaniasis (DCL) (P. MINODIER, P. PAROLA. Cutaneous leishmaniasis treatment, Travel Medicine and Infectious Disease. V. 5, p. 150-158, 2007). [005] LC is identified as the most frequent form of this infection and occurs predominantly in Afghanistan, Algeria, Brazil, Colombia, Iran, Pakistan, Peru, Saudi Arabia and Syria (B.S. REITHINGER R, DUJARDIN JC, LOUZIR H, PIRMEZ C, ALEXANDER B, Cutaneous leishmaniasis, The Lancet Infectious Diseases. V. 7, p. 581- 596, 2007). In 2020, the Pan American Health Organization (PAHO) identified that the countries that reported the highest number of cases of CL were Brazil (16,432), Colombia (6,161), Peru (4,178), Nicaragua (3,443), and Bolivia (2,059), which together accounted for 81% of cases in the Region (PAHO, LEISHMANIASIS. Epidemiological Report of the Americas. Vol. 10, 2020). [006] Cutaneous leishmaniasis (CL) is characterized by the occurrence of ulcers in exposed areas of the skin, with a rounded shape, which can become large (diameter > 5 cm), but are rarely larger than 10 cm, having an erythematous, infiltrated base of firm consistency, well-defined and generally raised borders, which may eventually penetrate the subcutaneous tissues, except for the cartilage in the auricle (M.S. BAILEY, D.N.J. LOCKWOOD. Cutaneous leishmaniasis, Clinics in Dermatology. V. 25, p. 203-21, 2007). Involvement of the nasal mucosa, palate, pharynx, larynx and vocal cords may occur, but in a small percentage of affected patients. [007] Controlling leishmaniasis is challenging and may be related to three main risk factors: anthropogenic/environmental changes, host immune responses, and failure of treatment with conventional drugs (Jean-Claude Dujardin. Risk factors in the spread of leishmaniases: towards integrated monitoring? TRENDS in Parasitology. Vol. 22, p. 4-6, 2006). [008] For the treatment of cutaneous leishmaniasis, amphotericin B can be administered by intravenous infusion, as well as parenterally. Its low solubility is the main reason why gastrointestinal reabsorption is practically nil, providing minimal oral bioavailability; therefore, when administered parenterally, high doses of amphotericin B need to be used to achieve effective therapeutic levels (A. LEMKE, A.F. KIDERLEN, O. KAYSER. Amphotericin B. Applied Microbiology and Biotechnology. V. 68, p. 151-162, 2005). Similarly, intravenous administration also requires high doses of amphotericin B to achieve the expected result. [009] The recommended dose of amphotericin B deoxylate is usually 0.5 to 1.0 mg/kg/day, with a total dose of 25 to 40 mg/kg, a