JP2007502790A5

JP2007502790A5 -

Info

Publication number: JP2007502790A5
Application number: JP2006523577A
Authority: JP
Filing date: 2004-08-12
Publication date: 2007-09-27

Claims

CGRP antagonist 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazoline-3-] as active substance in the form of spherical nanostructured microparticles Yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine

Or an inhalation powder for pulmonary or nasal administration by inhalation comprising a physiologically acceptable salt thereof and one or more excipients,
(a) the particles have a specific surface area of 1m ^² / g~20m ² / g,
(b) the characteristic Q _(5.8) is 50% to 100%, and
(c) Inhalable powder, characterized in that parameter X ₅₀ is in the range from 1 μm to 10 μm.

1m particle ²² / g-10m ²² The inhalable powder according to claim 1, having a specific surface area of / g.

Parameter X ₅₀₅₀ The inhalable powder according to claim 1, wherein is in the range from 1 μm to 6 μm.

The physiologically acceptable salt is 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] ] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride, sulfate, phosphate, hydrobromide, carbonate, methanesulfonate, p-toluenesulfonic acid Salt, nitrate, citrate, malate, tartrate, lactate, succinate, gluconate, acetate, formate, propionate, caproate, oxalate, maleate, fumaric acid Inhalable powder according to claim 1, characterized in that it is selected from the group consisting of salts, mandelate and hydroxysuccinate.

The physiologically acceptable salt is 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] Inhalation according to claim 1, characterized in that it is selected from the group consisting of] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride, sulfate and hydrobromide Powder.

The physiologically acceptable salt is 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] Inhalable powder according to claim 1, characterized in that it is] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride.

One or more excipients are selected from inert polysaccharides, polylactides / polyglycolides, disaccharides, monosaccharides, polyalcohols, amino acids, chitosan and mixtures of these excipients, active substance: excipient mass Inhalable powder according to claim 1, characterized in that the ratio is from 1:10 to 100: 1.

One or more excipients are maltodextrin, starch, cellulose, dextran, resomer (registered trademark), trehalose, lactose, maltose, saccharose, fructose, glucose, mannitol, sorbitol, arginine hydrochloride, chitosan and these excipients Inhalable powder according to claim 1, characterized in that it is selected from a mixture and the mass ratio of active substance: excipient is from 1:10 to 100: 1.

The one or more excipients are selected from trehalose, lactose, polylactide / polyglycolide, saccharose, maltodextrin, dextran and mannitol, and the mass ratio of active substance: excipient is 1:10 to 100: 1 The inhalable powder according to claim 1, wherein

Inhalable powder according to any one of claims 7 to 9, wherein the mass ratio of active substance: excipient is from 1: 3 to 20: 1.

One or more excipients are magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, calcium behenate, calcium arachidate, hydrogenated castor oil, hydrogenated cottonseed oil, fatty acid ester, sodium stearyl fumarate, sodium dodecyl sulfate, dodecyl Inhalation according to claim 1, characterized in that it is selected from magnesium sulfate, phospholipids and mixtures of these excipients, the active substance: excipient mass ratio being between 50: 1 and 5000: 1. Powder.

The inhalable powder according to claim 11, wherein the mass ratio of active substance: excipient is from 100: 1 to 1000: 1.

CGRP antagonist 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl as active substance ] Preparation of microparticles in the form of embedded particles comprising -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) or a physiologically acceptable salt thereof and one or more excipients A method,
(a) preparing a solution of the active substance having a concentration of the active substance of 1% to 20% by weight by dissolving the active substance in water, an organic solvent or an organic solvent-aqueous solvent mixture;
(b) adding one or more excipients in an active substance: excipient ratio from 1:10 to 100: 1;
(c) spray the resulting solution in the usual way,
(i) 50% to 100% characteristic Q _(5.8) and
(ii) Parameter X _{50 in} the range from 1 μm to 20 μm
Obtaining a spray mist having a droplet size having
(d) The following parameters
(i) Dry gas inlet temperature from 100 ° C to 350 ° C, and
(ii) drying the resulting spray mist using a drying gas while applying a drying gas outlet temperature from 40 ° C to 120 ° C; and
(e) A method for preparing fine particles, comprising a step of separating dried solid particles from a flow of dry gas by a usual method.

(a) preparing a solution of the active substance having a concentration of the active substance of 1% to 20% by weight by dissolving the active substance in water, an organic solvent or an organic solvent-aqueous solvent mixture;
(b) adding one or more excipients in an active substance: excipient ratio from 1:10 to 100: 1;
(c) spray the resulting solution in the usual way,
(i) 50% to 100% characteristic Q _(5.8) and
(ii) Parameter X _{50 in} the range from 1 μm to 20 μm
Obtaining a spray mist having a droplet size having
(d) The following parameters
(i) Dry gas inlet temperature from 100 ° C to 350 ° C,
(ii) Dry gas outlet temperature from 40 ° C to 120 ° C,
(iii) spray gas flow volume from 1 Nm ³ / hour to 15 Nm ³ / hour and
(iv) drying the resulting spray mist using a drying gas while applying a flow volume of drying gas from 15 Nm ³ / hour to 1500 Nm ³ / hour; and
14. The method of claim 13, comprising the step of (e) separating the dried solid particles from the drying gas stream in a conventional manner.

The method according to claim 13 or 14, wherein the concentration of the active substance is 2% by mass to 10% by mass.

The method according to claim 13 or 14, wherein the concentration of the active substance is 3% by mass to 8% by mass.

15. A method according to claim 13 or 14, wherein the active substance: excipient ratio is from 1: 3 to 20: 1.

Parameter X ₅₀₅₀ 15. The method according to claim 13 or 14, wherein is in the range from 1 [mu] m to 8 [mu] m.

Parameter X ₅₀₅₀ 15. The method according to claim 13 or 14, wherein is in the range from 1 [mu] m to 3 [mu] m.

The process according to claim 13 or 14, wherein the drying gas inlet temperature is preferably from 120 to 250 ° C.

15. Process according to claim 13 or 14, wherein the inlet temperature of the drying gas is preferably from 130C to 200C.

Dry gas flow volume is 15Nm ^3Three 150Nm / hour ^3Three 15. The method of claim 14, wherein the method is up to / hour.

14. Process according to claim 13 , characterized in that water or an alcohol-water mixture or a water-dichloromethane mixture is used as solvent.

14. Process according to claim 13, characterized in that an ethanol-water mixture is used as solvent.

Use of embedded particles obtained according to one of claims 13 or 14 for the preparation of a powder inhalant.