INTRANASAL DESMOPRESSIN ADMINISTRATION
Disclosed is a family of intranasal spray dispensers for administering uniform low doses of desmopressin so as to achieve safe antidiuresis in human patients. The dispensers of the invention may be used in the treatment of nocturia, primary nocturnal enuresis, incontinence, urinary frequency, diabetes insipidus, or any disease or syndrome where desmopressin therapy is useful or where safe temporary suppression of urine production may lead to beneficial health effects or increased convenience in voiding control.
1 . A safety dispenser for inducing in members of a patient population an antidiuretic effect while reducing the risk that a member of the population may develop hyponatremia, the dispenser comprising:
a reservoir having disposed therein a composition comprising a desmopressin preparation and a nasal membrane permeation enhancer in an amount sufficient to constitute multiple drug doses, said composition characterized by a desmopressin bioavailability greater than 5%;
an outlet in communication with said reservoir;
a manually actuatable pump for serially dispensing from said reservoir through said outlet, and to an intranasal surface of a patient, measured doses of said composition in the form of a spray,
respective doses of spray being restricted within the range of 0.5 ng desmopressin per kilogram of the patient's body weight and 75 ng desmopressin per kilogram of the patient's body weight so as to achieve a target C max in members of said patient population less than 18 pg/ml of blood,
respective successive spray doses of the same volume being sufficient to establish in a said patient by drug transport across intranasal mucosal membranes delivery of a maximum blood concentration (C max ) of desmopressin having a coefficient of variation similar to the coefficient of variation of C max produced by a subcutaneous dose of desmopressin designed to achieve the same target C max .
2 . The dispenser of claim 1 , wherein respective successive spray doses establish in a said patient a C max of desmopressin having a coefficient of variation within 50% of the coefficient of variation of said subcutaneous dose.
3 . (canceled)
4 . The dispenser of claim 1 , wherein respective successive spray doses establish in a said patient a C max of desmopressin in successively administered doses that vary by no more than 100%.
5 - 6 . (canceled)
7 . The dispenser of claim 1 , wherein respective doses of spray are restricted to achieve a target C max in members of said patient population less than about 15 pg/ml of blood.
8 - 11 . (canceled)
12 . The dispenser of claim 1 , formulated to induce antidiuresis in a target patient population for between about 4 and 7 hours.
13 . (canceled)
14 . The dispenser of claim 1 , comprising a multiplicity of droplets with an average volume distribution in the range of 20 μm for D10 to about 300 μm for D90.
15 . The dispenser of claim 1 , wherein said permeation enhancer is selected from the group consisting of macrocyclic esters, diesters, amides, diamides, amidines, diamidines, thioester, dithioester, thioamides, ketones or lactones.
16 - 21 . (canceled)
22 . A safety dispenser for inducing in members of a patient population an antidiuretic effect while reducing the risk that a member of the population may develop hyponatremia, the dispenser comprising:
a reservoir having disposed therein a composition comprising a desmopressin preparation and a nasal membrane permeation enhancer in an amount sufficient to constitute multiple drug doses, said composition characterized by a desmopressin bioavailability greater than 5%;
an outlet in communication with said reservoir;
a manually actuatable pump for serially dispensing from said reservoir through said outlet, and to an intranasal surface of a patient, measured doses of said composition in the form of a spray,
respective doses of spray being restricted within the range of 0.5 ng desmopressin per kilogram of the patient's body weight and 75 ng desmopressin per kilogram of the patient's body weight so as to achieve a target C max in members of said patient population less than about 15+/−3 pg/ml of blood,
said dispenser being sufficient to establish in a said patient by drug transport across intranasal mucosal membranes delivery of blood concentrations of desmopressin in the range below about 15+/−3 pg/ml substantially directly proportional to the mass of desmopressin dispensed into the nostril(s) of a said patient.
23 . The dispenser of claim 22 , wherein respective successive spray doses establish in a said patient by drug transport across intranasal mucosal membranes delivery of a maximum blood concentration (C max ) of desmopressin having a coefficient of variation within 50% of the coefficient of variation of C max produced by a subcutaneous dose of desmopressin designed to achieve the same target C max .
24 - 26 . (canceled)
27 . The dispenser of claim 22 , wherein respective doses of spray are restricted to achieve a target C max in members of said patient population less than about 10 pg/ml of blood.
28 - 30 . (canceled)
31 . The dispenser of claim 22 , formulated to induce antidiuresis in a target patient population for between about 4 and 7 hours.
32 - 46 . (canceled)
47 . A method of inducing an antidiuretic effect in a patient, the method comprising intranasally administering to the patient desmopressin from a dispenser according to claim 1 .
48 - 53 . (canceled)
54 . A method for treating nocturia in an adult patient in need thereof comprising administering to a nostril of said patient a single spray of a preservative-free nasal spray comprising an oil-in-water emulsion comprising desmopressin and a permeation enhancer, the single spray having a volume of 100 μL and a desmopressin content of 500-800 ng or 1.0-1.6 μg.
55 . The method of claim 54 , wherein the desmopressin content of the single spray is 0.75 μg desmopressin or 1.5 μg desmopressin.
56 . The method of claim 54 , wherein the oil-in-water emulsion is a cottonseed oil-in-water emulsion.
57 . The method of claim 54 , wherein the permeation enhancer is cyclopentadecanolide.
58 . The method of claim 55 , wherein the oil-in-water emulsion is a cottonseed oil-in-water emulsion having a pH of 5.5 and further comprises sorbitan monolaurate; polysorbate 20; citric acid, anhydrous; sodium citrate dihydrate, and water, wherein the permeation enhancer is cyclopentadecanolide.
59 . A composition comprising a preservative-free oil-in-water emulsion comprising desmopressin acetate and cyclopentadecanolide.
60 . The composition of claim 59 , further comprising cottonseed oil; sorbitan monolaurate; polysorbate 20; citric acid, anhydrous; sodium citrate dihydrate; and water; wherein the composition has a pH of 5.5.
61 . A nasal spray safety dispenser comprising a reservoir having disposed therein the composition of claim 60 .