Vitamin B12 nasal spray and method of use

Abstract

The present invention relates generally to vitamin B 12 nasal spray compositions and methods of using the same in the treatment of vitamin B 12 deficiency and various disorders that are related to such deficiency. In particular embodiments, the present invention is directed to treatment methods comprising intranasal administration of a cobalamin composition according to a particular dosing and frequency schedule and to a preservative-free nasal spray composition comprising a cobalamin compound useful in the practice of such treatment methods.

1 . A method for maintaining vitamin B 12  blood serum levels in a mammal, the method comprising nasally administering to the mammal at least once every three days an aqueous composition comprising a cobalamin compound in an amount sufficient to deliver a dose of no more than about 150 μg of the cobalamin compound to the mammal.  
   
   
       2 . A method for maintaining normal hematologic status in a pernicious anemia patient following intramuscular vitamin B 12  injection therapy, said method comprising nasally administering to said patient at least once every three days an aqueous composition comprising a cobalamin compound in an amount sufficient to deliver a dose of no more than about 150 μg of the cobalamin compound to the patient.  
   
   
       3 . The method as set forth in  claim 1  or  claim 2  wherein the aqueous composition comprising a cobalamin compound is administered nasally at least once every two days.  
   
   
       4 . The method as set forth in any one of the preceding claims wherein the aqueous composition is isotonic.  
   
   
       5 . The method as set forth in any one of the preceding claims wherein the aqueous composition comprising a cobalamin compound is nasally administered at least once a day.  
   
   
       6 . The method as set forth in any one of the preceding claims wherein the aqueous composition comprising a cobalamin compound is nasally administered once a day.  
   
   
       7 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of no more than about 80 μg.  
   
   
       8 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 5 μg to about 80 μg.  
   
   
       9 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 10 μg to about 60 μg.  
   
   
       10 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 15 μg to about 50 μg.  
   
   
       11 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 20 μg to about 50 μg.  
   
   
       12 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 30 μg to about 50 μg.  
   
   
       13 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 40 μg to about 50 μg.  
   
   
       14 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 45 μg to about 50 μg.  
   
   
       15 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of about 50 μg.  
   
   
       16 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of no more than about 45 μg.  
   
   
       17 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of no more than about 40 μg.  
   
   
       18 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of no more than about 35 μg.  
   
   
       19 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 5 μg to about 45 μg.  
   
   
       20 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 10 μg to about 45 μg.  
   
   
       21 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 15 μg to about 45 μg.  
   
   
       22 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 20 μg to about 45 μg.  
   
   
       23 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 30 μg to about 45 μg.  
   
   
       24 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound of from about 40 μg to about 45 μg.  
   
   
       25 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound that is about 45 μg.  
   
   
       26 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound that is about 40 μg.  
   
   
       27 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound that is about 35 μg.  
   
   
       28 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound that is about 30 μg.  
   
   
       29 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound that is about 25 μg.  
   
   
       30 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound that is about 20 μg.  
   
   
       31 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound that is about 15 μg.  
   
   
       32 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound that is about 10 μg.  
   
   
       33 . The method as set forth in  claim 6  wherein the nasal administration of the aqueous composition comprises a dose of the cobalamin compound that is about 5 μg.  
   
   
       34 . The method as set forth in any one of the preceding claims wherein the total amount of cobalamin compound nasally administered to the mammal is less than about 1000 μg per week.  
   
   
       35 . The method as set forth in any one of the preceding claims wherein the total amount of cobalamin compound nasally administered to the mammal is from about 50 μg to about 500 μg per week.  
   
   
       36 . The method as set forth in any one of the preceding claims wherein the total amount of cobalamin compound nasally administered to the mammal is from about 100 μg to about 450 μg per week.  
   
   
       37 . The method as set forth in any one of the preceding claims wherein the total amount of cobalamin compound nasally administered to the mammal is from about 150 μg to about 400 μg per week.  
   
   
       38 . The method as set forth in any one of the preceding claims wherein the total amount of cobalamin compound nasally administered to the mammal is from about 200 μg to about 400 μg per week.  
   
   
       39 . The method as set forth in any one of the preceding claims wherein the total amount of cobalamin compound nasally administered to the mammal is from about 250 μg to about 350 μg per week.  
   
   
       40 . The method as set forth in any one of the preceding claims wherein the total amount of cobalamin compound nasally administered to the mammal is from about 300 μg to about 350 μg per week.  
   
   
       41 . The method as set forth in any one of the preceding claims wherein the dose of the cobalamin compound is administered to the mammal in a plurality of metered sprays of the aqueous composition.  
   
   
       42 . The method as set forth in any one of the preceding claims wherein the dose of the cobalamin compound is administered to the mammal in no more than two metered sprays of said aqueous isotonic composition.  
   
   
       43 . The method as set forth in any one of the preceding claims wherein the dose of the cobalamin compound is administered to the mammal in a single metered spray of the aqueous composition.  
   
   
       44 . The method as set forth in any one of the preceding claims wherein the mammal has an elevated blood metabolite serum level indicative of a vitamin B 12  deficiency.  
   
   
       45 . The method as set forth in any one of the preceding claims wherein the mammal has elevated homocysteine, cystathionine, methylmalonic acid or 2-methylcitric acid blood serum levels.  
   
   
       46 . A composition for nasal administration of a cobalamin compound, the composition comprising an aqueous solution containing a cobalamin compound and a pharmaceutically acceptable buffer, the composition having a pH of at least about 6.5.  
   
   
       47 . The composition as set forth in  claim 46  wherein the aqueous composition is isotonic.  
   
   
       48 . The composition as set for in  claim 46  or  47  wherein the composition further comprises a pharmaceutically acceptable additive selected from the group consisting of tolerance enhancers, absorption enhancers, preservatives, thickening agents, osmolarity adjusters, complexing agents, stabilizers, solubilizers, and any combination thereof.  
   
   
       49 . The composition as set forth in  claim 46  or  47  wherein the composition is free of preservatives.  
   
   
       50 . The composition as set forth in any one of  claims 46  to  48  wherein the composition comprises sodium chloride, 0.649% w/w (0.11M); sodium phosphate, monobasic, anhydrous, 0.19% w/w (0.016M); benzyl alcohol, NF, 0.366% w/w (0.034M); sodium hydroxide, NF, 0.04% w/w (0.010M); benzalkonium chloride, 50%, NF, 0.02% w/w; cyanocobalamin, USP, 0.025% w/w (0.00018M); in purified water, USP, 98.71% w/w.  
   
   
       51 . The composition as set forth in  claim 49  wherein the composition comprises sodium chloride, 0.649% w/w (0.11M); sodium phosphate, monobasic, anhydrous, 0.19% w/w (0.016M); sodium hydroxide, NF, 0.04% w/w (0.010M); cyanocobalamin, USP, 0.025% w/w (0.00018M); in purified water, USP, 99.096% w/w.  
   
   
       52 . A composition for nasal administration of a cobalamin compound, the composition comprising an aqueous solution containing a cobalamin compound and a pharmaceutically acceptable buffer and being free of preservatives.  
   
   
       53 . The composition as set forth in  claim 52  wherein the aqueous composition is isotonic.  
   
   
       54 . The composition as set for in  claim 52  or  53  wherein the composition further comprises a pharmaceutically acceptable additive selected from the group consisting of tolerance enhancers, absorption enhancers, preservatives, thickening agents, osmolarity adjusters, complexing agents, stabilizers, solubilizers, and any combination thereof.  
   
   
       55 . The composition as set forth in any one of  claims 52  to  54  wherein the composition comprises sodium chloride, 0.649% w/w (0.11M); sodium phosphate, monobasic, anhydrous, 0.19% w/w (0.016M); sodium hydroxide, NF, 0.04% w/w (0.010M); cyanocobalamin, USP, 0.025% w/w (0.00018M); in purified water, USP, 99.096% w/w.  
   
   
       56 . The method or composition as set forth in any one of the preceding claims wherein the cobalamin compound comprises cyanocobalamin.  
   
   
       57 . The method or composition as set forth in any one of the preceding claims wherein the cobalamin compound comprises hydroxocobalamin.  
   
   
       58 . The method or composition as set forth in any one of the preceding claims wherein the composition further comprises a pharmaceutically acceptable additive selected from the group consisting of tolerance enhancers, absorption enhancers, preservatives, thickening agents, osmolarity adjusters, complexing agents, stabilizers, solubilizers, and any combination thereof.  
   
   
       59 . The method or composition as set forth in any one of the preceding claims wherein the composition is stored in a container designed to inhibit or prevent degradation of, spoilage of, or bacterial growth in the composition.