Transoral dosage forms comprising sufentanil and naloxone

Abstract

The invention pertains to methods that include administering to a subject a transoral dosage form comprising a pharmaceutical carrier and sufentanil, and maintaining a mean pH ranging from about 3.5 to about 5.5 during a dosing period after administration of the transoral dosage form as determined using an in vitro donor media test. Related dosage forms are also disclosed. Also disclosed are transoral dosage forms and related methods, wherein a transoral dosage form may comprise: (1) about 5 to about 1000 micrograms of sufentanil; (2) about 50 micrograms to about 100 milligrams of naloxone; and (3) acidifying material in an amount sufficient to provide a mean pH ranging from about 3.5 to about 5.5 during a dosing period after administration of the transoral dosage form as determined using an in vitro donor media test; wherein the dosing period begins no earlier than about 1 minute after administration of the transoral dosage form, and ends no later than about 120 minutes after administration of the transoral dosage form.

1 . A method comprising:
 administering to a subject a transoral dosage form comprising a pharmaceutical carrier and sufentanil, and   maintaining a mean pH ranging from about 3.5 to about 5.5 during a dosing period after administration of the transoral dosage form as determined using an in vitro donor media test;   wherein the dosing period begins no earlier than about 1 minute after administration of the transoral dosage form, and ends no later than about 120 minutes after administration of the transoral dosage form.   
   
   
       2 . The method of  claim 1 , wherein the dosing period begins no earlier than about 2 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       3 . The method of  claim 2 , wherein the dosing period begins no earlier than about 2 minutes after administration of the transoral dosage form, and ends no later than about 30 minutes after administration of the transoral dosage form. 
   
   
       4 . The method of  claim 1 , wherein the dosing period begins no earlier than about 3 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       5 . The method of  claim 4 , wherein the dosing period begins no earlier than about 4 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       6 . The method of  claim 5 , wherein the dosing period begins no earlier than about 5 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       7 . The method of  claim 1 , wherein the transoral dosage form comprises a transoral dosage form having a fixed drug releasing area. 
   
   
       8 . The method of  claim 1 , wherein the transoral dosage form comprises a transoral dosage form having a variable drug releasing area. 
   
   
       9 . The method of  claim 1 , wherein the transoral dosage form comprises a gel dosage form. 
   
   
       10 . The method of  claim 1 , wherein the sufentanil comprises a pharmaceutically acceptable salt of sufentanil free base. 
   
   
       11 . The method of  claim 10 , wherein the pharmaceutically acceptable salt comprises sufentanil citrate. 
   
   
       12 . The method of  claim 1 , wherein the mean pH is maintained in a range from about 4.5 to about 5.5. 
   
   
       13 . The method of  claim 1 , wherein the transoral dosage form comprises an acidifying agent that operates to maintain the mean pH in a range from about 3.5 to about 5.5 during the dosing period, as determined using an in vitro donor media test. 
   
   
       14 . The method of  claim 13 , wherein the acidifying agent comprises a buffer. 
   
   
       15 . The method of  claim 1 , wherein the pharmaceutical carrier comprises one or more permeation enhancers. 
   
   
       16 . A transoral dosage form comprising:
 about 5 to about 1000 micrograms of sufentanil; and   acidifying material in an amount sufficient to provide a mean pH ranging from about 3.5 to about 5.5 during a dosing period after administration of the transoral dosage form as determined using an in vitro donor media test;   wherein the dosing period begins no earlier than about 1 minute after administration of the transoral dosage form, and ends no later than about 120 minutes after administration of the transoral dosage form.   
   
   
       17 . The transoral dosage form of  claim 16 , comprising sufentanil citrate. 
   
   
       18 . The transoral dosage form of  claim 16 , wherein the acidifying material comprises an acid or a buffer. 
   
   
       19 . The transoral dosage form of  claim 16 , wherein the buffer comprises one or more of ascorbic acid, acetic acid, citric acid, D-gluconic acid, dimethylglutaric acid, DL-lactic acid, L-malic acid, fumaric acid, galactaric acid, L-lactic acid, L-tartaric acid, or succinic acid, in each case an acid being paired with the acid's corresponding conjugate base. 
   
   
       20 . The transoral dosage form of  claim 19 , wherein the dosing period begins no earlier than about 2 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       21 . The transoral dosage form of  claim 20 , wherein the dosing period begins no earlier than about 2 minutes after administration of the transoral dosage form, and ends no later than about 30 minutes after administration of the transoral dosage form. 
   
   
       22 . The transoral dosage form of  claim 16 , wherein the dosing period begins no earlier than about 3 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       23 . The transoral dosage form of  claim 22 , wherein the dosing period begins no earlier than about 4 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       24 . The transoral dosage form of  claim 23 , wherein the dosing period begins no earlier than about 5 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       25 . The transoral dosage form of  claim 16 , wherein the transoral dosage form comprises a transoral dosage form having a fixed drug releasing area. 
   
   
       26 . The transoral dosage form of  claim 16 , wherein the transoral dosage form comprises a transoral dosage form having a variable drug releasing area. 
   
   
       27 . The transoral dosage form of  claim 16 , wherein the transoral dosage form comprises a gel dosage form. 
   
   
       28 . The transoral dosage form of  claim 16 , wherein the acidifying material is present in an amount sufficient to provide a mean pH ranging from about 4.5 to about 5.5 during a dosing period, as determined using an in vitro donor media test. 
   
   
       29 . The transoral dosage form of  claim 16 , further comprising a pharmaceutical carrier. 
   
   
       30 . The transoral dosage form of  claim 29 , wherein the pharmaceutical carrier comprises one or more permeation enhancers. 
   
   
       31 . The transoral dosage form of  claim 16 , wherein the sufentanil comprises a pharmaceutically acceptable salt of sufentanil free base. 
   
   
       32 . The transoral dosage form of  claim 31 , wherein the pharmaceutically acceptable salt comprises sufentanil citrate. 
   
   
       33 . A method comprising:
 administering to a subject a transoral dosage form comprising
 (1) sufentanil; 
 (2) naloxone; and 
 (3) a pharmaceutical carrier, and 
   maintaining a mean pH ranging from about 3.5 to about 5.5 during a dosing period after administration of the transoral dosage form as determined using an in vitro donor media test;   wherein the dosing period begins no earlier than about 1 minute after administration of the transoral dosage form, and ends no later than about 120 minutes after administration of the transoral dosage form.   
   
   
       34 . The method of  claim 33 , wherein the dosing period begins no earlier than about 2 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       35 . The method of  claim 34 , wherein the dosing period begins no earlier than about 2 minutes after administration of the transoral dosage form, and ends no later than about 30 minutes after administration of the transoral dosage form. 
   
   
       36 . The method of  claim 33 , wherein the dosing period begins no earlier than about 3 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       37 . The method of  claim 36 , wherein the dosing period begins no earlier than about 4 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       38 . The method of  claim 37 , wherein the dosing period begins no earlier than about 5 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       39 . The method of  claim 33 , wherein the transoral dosage form comprises a transoral dosage form having a fixed drug releasing area. 
   
   
       40 . The method of  claim 33 , wherein the transoral dosage form comprises a transoral dosage form having a variable drug releasing area. 
   
   
       41 . The method of  claim 33 , wherein the transoral dosage form comprises a gel dosage form. 
   
   
       42 . The method of  claim 33 , wherein the sufentanil comprises a pharmaceutically acceptable salt of sufentanil free base. 
   
   
       43 . The method of  claim 42 , wherein the pharmaceutically acceptable salt comprises sufentanil citrate. 
   
   
       44 . The method of  claim 33 , wherein the mean pH is maintained in a range from about 4.5 to about 5.5. 
   
   
       45 . The method of  claim 33 , wherein the transoral dosage form comprises an acidifying agent that operates to maintain the mean pH in a range from about 3.5 to about 5.5 during the dosing period, as determined using an in vitro donor media test. 
   
   
       46 . The method of  claim 45 , wherein the acidifying agent comprises a buffer. 
   
   
       47 . The method of  claim 33 , wherein the pharmaceutical carrier comprises one or more permeation enhancers. 
   
   
       48 . The method of  claim 33 , wherein the naloxone comprises a pharmaceutically acceptable salt of naloxone free base. 
   
   
       49 . The method of  claim 48 , wherein the pharmaceutically acceptable salt comprises naloxone hydrochloride. 
   
   
       50 . A transoral dosage form comprising:
 (1) about 5 to about 1000 micrograms of sufentanil;   (2) about 50 micrograms to about 100 milligrams of naloxone; and   (3) acidifying material in an amount sufficient to provide a mean pH ranging from about 3.5 to about 5.5 during a dosing period after administration of the transoral dosage form as determined using an in vitro donor media test;   wherein the dosing period begins no earlier than about 1 minute after administration of the transoral dosage form, and ends no later than about 120 minutes after administration of the transoral dosage form.   
   
   
       51 . The transoral dosage form of  claim 50  comprising sufentanil citrate. 
   
   
       52 . The transoral dosage form of  claim 50 , wherein the acidifying material comprises an acid or a buffer. 
   
   
       53 . The transoral dosage form of  claim 50 , wherein the buffer comprises one or more of ascorbic acid, acetic acid, citric acid, D-gluconic acid, dimethylglutaric acid, DL-lactic acid, L-malic acid, fumaric acid, galactaric acid, L-lactic acid, L-tartaric acid, or succinic acid, in each case an acid being paired with the acid's corresponding conjugate base. 
   
   
       54 . The transoral dosage form of  claim 50 , wherein the dosing period begins no earlier than about 2 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       55 . The transoral dosage form of  claim 54 , wherein the dosing period begins no earlier than about 2 minutes after administration of the transoral dosage form, and ends no later than about 30 minutes after administration of the transoral dosage form. 
   
   
       56 . The transoral dosage form of  claim 50 , wherein the dosing period begins no earlier than about 3 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       57 . The transoral dosage form of  claim 56 , wherein the dosing period begins no earlier than about 4 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       58 . The transoral dosage form of  claim 57 , wherein the dosing period begins no earlier than about 5 minutes after administration of the transoral dosage form, and ends no later than about 60 minutes after administration of the transoral dosage form. 
   
   
       59 . The transoral dosage form of  claim 50 , wherein the transoral dosage form comprises a transoral dosage form having a fixed drug releasing area. 
   
   
       60 . The transoral dosage form of  claim 50 , wherein the transoral dosage form comprises a transoral dosage form having a variable drug releasing area. 
   
   
       61 . The transoral dosage form of  claim 50 , wherein the transoral dosage form comprises a gel dosage form. 
   
   
       62 . The transoral dosage form of  claim 50 , wherein the acidifying material is present in an amount sufficient to provide a mean pH ranging from about 4.5 to about 5.5 during a dosing period, as determined using an in vitro donor media test. 
   
   
       63 . The transoral dosage form of  claim 50 , further comprising a pharmaceutical carrier. 
   
   
       64 . The transoral dosage form of  claim 63 , wherein the pharmaceutical carrier comprises one or more permeation enhancers. 
   
   
       65 . The transoral dosage form of  claim 50 , wherein the sufentanil comprises a pharmaceutically acceptable salt of sufentanil free base. 
   
   
       66 . The transoral dosage form of  claim 65 , wherein the pharmaceutically acceptable salt comprises sufentanil citrate. 
   
   
       67 . The transoral dosage form of  claim 50 , wherein the naloxone comprises a pharmaceutically acceptable salt of naloxone free base. 
   
   
       68 . The transoral dosage form of  claim 67 , wherein the pharmaceutically acceptable salt comprises naloxone hydrochloride.