Resumen
Inhalation antifungal formulations based on collapsed microparticles containing carbohydrates and amino acids. Commercial formulations with antifungal agents for the treatment and prophylaxis of lung infections caused by fungi or intracellular pathogens (such as leishmaniasis or tuberculosis) are usually based on lipid excipients and, in most cases, their use is intended for intravenous administration. or by means of aerosols. However, a formulation that allows administration using dry powder inhalers would be more desirable. The present invention describes new pharmaceutical formulations of antifungals in the form of collapsed microparticles that do not contain lipid excipients but rather mono and oligosaccharides, in addition to amino acids so that they can be administered using dry powder inhalers or by aerosols. (Machine-translation by Google Translate, not legally binding)
Reivindicaciones
1. Amphotericin B formulation based on collapsed microparticles to be administered by inhalation in the form of dry powder, or aerosols after reconstitution in water, comprising amino acids, oligosaccharides, and monosaccharides as excipients, characterized by not containing lipid excipients and the microparticles having a geometric and aerodynamic size suitable for the pulmonary route (1 - 5 µm) with an antifungal drug load of more than 25% by weight of the dry powder of the total content of the formulation and where the drug can be in amorphous or semi-crystalline form (up to 50%). 2. Formulation according to claim 1, wherein the oligosaccharides and monosaccharides are γ-cyclodextrin and mannose, and the amino acid is leucine. 3. Formulation, according to claim 2, wherein the ratio AmB: mannose is 1:1 and leucine represents 10 - 13 wt.% of the total formulation. 4. Formulation, according to claim 3, wherein the ratio AmB: γ-cyclodextrin:mannose is 1:1:1. 5. Formulation, according to claim 3, further comprising other antifungal and/or bronchodilator drugs. 6. Formulation according to claim 5, wherein the added antifungal is itraconazole. 7. Formulation, according to claim 6, wherein the itraconazole is in a proportion of up to 40% within the microparticles. 8. Formulation, according to claim 5, wherein the bronchodilator is salbutamol. 9. Method for the preparation of the claimed formulation comprising the following steps: (a) Preparation of an aqueous solution of γ-cyclodextrin and adjusted pH between 12 and 14. b) Amphotericin B addition (in an amount between 5 - 40% of the total weight of the formulation) to the solution of step (a) in a weight ratio AmB: γ-cyclodextrin between 1:1 under constant stirring until complete dispersion. c) Adjustment of the pH of the mixture of step (b) to a value between 6 and 8, follow by sonication if necessary to obtain a homogeneous mixture. d) Addition of a monosaccharide to the aqueous suspension in a relation weight AmB: monosaccharide of 1:1. e) Addition of an amino acid to the previous suspension in proportions between 10 and 13% by total weight formulation. f) Atomization of the aqueous suspension by spray drying for the preparation of the dry powder formulation. g) Collection of the atomized powder from the collection vessel. 10. Method according to claim 9, wherein the antifungal is amphotericin B (AmB) the monosaccharide is mannose, and the amino acid is leucine. 11. Method, according to claim 9, wherein the atomization stage is carried out employing an air or nitrogen inlet flow rate between 600 and 800 Uh, the aqueous suspension is pumped at a rate between 2 and 6 ml/min, the evaporation temperature is maintained above 110°C, and the suction force above 80%. 12. Method according to claim 11, wherein the air or nitrogen flow rate is maintained at 742 L/h, the suspension is pumped at 2.5 ml/min, the evaporation temperature is maintained at 150°C, and the suction force is above 90%. 13. Use of the claimed formulation for the manufacture of an antifungal drug for inhalation administration. 14. Use according to claim 13, wherein the administration is by a dry powder inhaler (DPI). 15. Use according to claim 14, wherein the administration is by using aerosols, after reconstitution of the powder in water.
