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 . The dispenser of claim 2 wherein respective successive spray doses establish in a said patient a C max of desmopressin having a coefficient of variation within 25% of the coefficient of variation of said subcutaneous dose.
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 . The dispenser of claim 4 wherein respective successive spray doses establish in a said patient by intranasal delivery a C max of desmopressin in successively administered doses that vary by no more than 50%.
6 . The dispenser of claim 1 wherein respective successive spray doses establish in a said patient a C max of desmopressin within one of the following blood concentration ranges (in pg/ml of blood): 1-3, 2-5, 3-6, 4-7, 5-8, 6-9, 7-10.
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 . The dispenser of claim 7 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.
9 . The dispenser of claim 1 further comprising means for blocking dispensing of a second said desmopressin dose from said reservoir for a predetermined time interval after dispensing a said dose.
10 . The dispenser of claim 1 formulated to induce antidiuresis in a target patient population for less than about six hours.
11 . The dispenser of claim 10 formulated to induce antidiuresis in a target patient population for between about 2 and 4 hours.
12 . The dispenser of claim 1 formulated to induce antidiuresis in a target patient population for between about 4 and 7 hours.
13 . The dispenser of claim 1 formulated for a target population selected from children, children weighing less than 35 kg, children weighing between 35 and 50 kg, adult females, adult males, females weighing between 50 and 75 kg, males weighing between 70 and 85 kg, and males weighing more than 85 kg.
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 . The dispenser of claim 1 wherein said composition is characterized by a desmopressin bioavailability greater than 10%.
17 . The dispenser of claim 16 wherein said composition characterized by a desmopressin bioavailability greater than 15%.
18 . The dispenser of claim 17 wherein said composition characterized by a desmopressin bioavailability greater than 20%.
19 . The dispenser of claim 1 being free of preservatives.
20 . The dispenser of claim 1 wherein said pump prevents backfill of bacterially contaminated ambient air after a dispensing of said composition.
21 . The dispenser of claim 1 wherein said dispenser establishes in a said patient by drug transport across intranasal mucosal membranes delivery of blood concentrations of desmopressin substantially directly proportional to the mass of desmopressin dispensed into the nostril(s) of a said patient.
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 . The dispenser of claim 23 wherein respective successive spray doses establish in a said patient a C max of desmopressin having a coefficient of variation within 25% of the coefficient of variation of said subcutaneous dose.
25 . The dispenser of claim 22 wherein respective successive spray doses establish in a said patient by intranasal delivery a C max of desmopressin in successively administered doses that vary by no more than 50%.
26 . The dispenser of claim 22 wherein respective successive spray doses establish in a said patient a C max of desmopressin within one of the following blood concentration ranges (in pg/ml of blood): 1-3, 2-5, 3-6, 4-7, 5-8, 6-9, 7-10.
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 . The dispenser of claim 22 further comprising means for blocking dispensing of a second said desmopressin dose from said reservoir for a predetermined time interval after dispensing a said dose.
29 . The dispenser of claim 22 formulated to induce antidiuresis in a target patient population for less than about six hours.
30 . The dispenser of claim 29 formulated to induce antidiuresis in a target patient population for between about 2 and 4 hours.
31 . The dispenser of claim 22 formulated to induce antidiuresis in a target patient population for between about 4 and 7 hours.
32 . The dispenser of claim 22 formulated for a target population selected from children, children weighing less than 35 kg as the target population, children weighing between 35 and 50 kg, adult females, adult males, females weighing between 50 and 75 kg, males weighing between 70 and 85 kg, and males weighing more than 85 kg.
33 . The dispenser of claim 22 comprising a multiplicity of droplets with an average volume distribution in the range of 20 μm for D10 to about 300 μm for D90.
34 . The dispenser of claim 22 wherein said permeation enhancer is selected from the group consisting of macrocyclic esters, diesters, amides, diamides, amidines, diamidines, thioester, dithioester, thioamides, ketones or lactones.
35 . The dispenser of claim 22 wherein said composition is characterized by a desmopressin bioavailability greater than 10%.
36 . The dispenser of claim 35 wherein said composition characterized by a desmopressin bioavailability greater than 15%.
37 . The dispenser of claim 22 wherein said composition characterized by a desmopressin bioavailability greater than 20%.
38 . The dispenser of claim 22 being free of preservatives.
39 . The dispenser of claim 22 wherein said pump prevents backfill of bacterially contaminated ambient air after a dispensing of said composition.
40 .- 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 . The method of claim 47 wherein the administration produces a desmopressin concentration no greater than 15+/−3 pg/ml in the bloodstream of the patient.
49 . The method of claim 48 wherein the administration produces a desmopressin concentration no greater than 10+/−3 pg/ml in the bloodstream of the patient.
50 . The method of claim 49 wherein the administration produces a desmopressin concentration no greater than 7+/−3 pg/ml in the bloodstream of the patient.
51 . The method of claim 47 wherein the administration induces antidiuresis for less than about six hours.
52 . The method of claim 51 wherein the administration induces antidiuresis for between about 2 and 4 hours.
53 . The method of claim 47 wherein the administration induces antidiuresis for between about 4 and 7 hours.