Pharmaceutical formulations of nitrite and uses thereof

Abstract

The present invention relates to pharmaceutical compositions of nitrites such as inorganic nitrites, or any pharmaceutically acceptable salts, solvates, or prodrugs thereof, and the medical use of these compositions. The pharmaceutical compositions, which can be formulated for oral administration, can provide immediate release or extended release of the nitrite ion (NO2−). The pharmaceutical compositions of the invention are useful, for example, for treating or reducing pain, improving symptoms of a microvascular disease, and improving nerve conduction velocity.

1 - 53 . (canceled) 
     
     
         54 . A method of treating or reducing pain in a patient, the method comprising:
 (i) administering between 5 mg to 50 mg of a therapeutic to the patient two times per day for a first treatment period of 6 weeks to 14 weeks; and then   (ii) administering 60 mg to 100 mg of the therapeutic to the patient two times per day for a second treatment period of 6 weeks to 14 weeks;   wherein the therapeutic is an inorganic nitrite or a pharmaceutically acceptable salt thereof.   
     
     
         55 . The method of  claim 54 , wherein the patient has a microvascular disease. 
     
     
         56 . The method of  claim 54 , further comprising determining whether the patient exhibits a reduction in pain. 
     
     
         57 . The method of  claim 56 , wherein the reduction in pain is determined as a decrease in pain intensity, frequency, duration, and/or improvements in quality of life. 
     
     
         58 . The method of  claim 56 , further comprising performing a Brief Pain Inventory, a Neuropathic Pain Symptom Inventory, and/or a McGill Pain Questionnaire to determine if the patient exhibits a reduction in pain. 
     
     
         59 . The method of  claim 54 , wherein step (i) of the method results in a reduction in pain. 
     
     
         60 . The method of claim  39 , wherein step (ii) is performed after the patient exhibits a reduction in pain. 
     
     
         61 . The method of  claim 54 , wherein the first treatment period is at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, or at least 13 weeks. 
     
     
         62 . The method of  claim 54 , wherein
 the first treatment period is at least 10 weeks;   the second treatment period is one of at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, and at least 13 weeks;   the therapeutic is NaNO 2 , and is formulated for one of topical, enteral, parenteral administration, as a solid dosage form for oral administration, as a tablet or capsule formulated for sustained release of the inorganic nitrite;   the therapeutic is formulated with one or more pharmaceutically acceptable excipients;   the therapeutic is present in an amount of 40 mg in step (i) of the method;   the therapeutic is present in an amount of 80 mg in step (ii) of the method;   the patient has type 1 diabetes or type 2 diabetes;   the patient is a mammal; and   the patient is a human.   
     
     
         63 . A method of treating or reducing pain in a patient, the method comprising:
 (i) administering a first amount of a therapeutic to the patient two times per day for a first treatment period; and then   (ii) administering a second amount of the therapeutic to the patient two times per day for a second treatment period;   wherein the therapeutic is inorganic nitrite or a pharmaceutically acceptable salt thereof; and   the first amount is less than the second amount.   
     
     
         64 . The method of  claim 63 , wherein the second amount is at least twice the first amount. 
     
     
         65 . The method of  claim 63 , wherein the first period is equal to the second period. 
     
     
         66 . The method of  claim 63 , wherein the first period is less than the second period. 
     
     
         67 . The method of  claim 63 , wherein the second period is one of at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, and at least 14 weeks. 
     
     
         68 . The method of  claim 63 , wherein the inorganic nitrite is administered in a extended release formulation. 
     
     
         69 . The method of  claim 63 , wherein the inorganic nitrite is one of ammonium nitrite (NH4NO2), barium nitrite (Ba(NO2)2; calcium nitrite (Ca(NO2)2; cesium nitrite (CsNO2), cobalt(II) nitrite (Co(NO2)2), cobalt(III) potassium nitrite (CoK3(NO2)6; lithium nitrite (LiNO2); magnesium nitrite (MgNO2); potassium nitrite (KNO2), rubidium nitrite (RbNO2), silver (I) nitrite (AgNO2), sodium nitrite (NaNO2), strontium nitrite (Sr(NO2)2), and zinc nitrite (Zn(NO2)2). 
     
     
         70 . The method of  claim 63 , wherein the first amount is between 30 mg and 50 mg and the second amount is between 70 mg and 85 mg. 
     
     
         71 . A method of treating or reducing pain in a patient, the method comprising:
 (i) administering between 30 mg and 50 mg of a therapeutic to the patient two times per day for a first treatment period; and then   (ii) administering between 70 mg and 85 mg of the therapeutic to the patient two times per day for a second treatment period;   wherein the therapeutic is NaNO2 or a pharmaceutically acceptable salt thereof;   the first period is less than the second period;   the second period is one of at least 7 weeks; and   the therapeutic is administered via for oral administration, as a tablet or capsule formulated for sustained release, and is formulated with one or more pharmaceutically acceptable excipients.