Semi-solid delivery vehicle and pharmaceutical compositions

Abstract

A semi-solid delivery vehicle contains a polyorthoester and an excipient, and a semi-solid pharmaceutical composition contains an active agent and the delivery vehicle. The pharmaceutical composition may be a topical, syringable, or injectable formulation; and is suitable for local delivery of the active agent. Methods of treatment are also disclosed.

1 . A pharmaceutical composition comprising: 
 (A) semi-solid delivery vehicle, comprising: 
 (i) a polyorthoester of formula I or formula II  
                     
 where:  
   R is a bond, —(CH 2 ) a —, or —(CH 2 ) b —O—(CH 2 ) c —; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;    R* is a C 1-4  alkyl;    n is an integer of at least 5; and    A is R 1 , R 2 , R 3 , or R 4 , where    R 1  is:                          where:    p is an integer of 1 to 20;    R 5  is hydrogen or C 1-4  alkyl; and    R 6  is:                          where:    s is an integer of 0 to 30;    t is an integer of 2 to 200; and    R 7  is hydrogen or C 1-4  alkyl;    R 2  is:                          R 3  is:                          where:    x is an integer of 0 to 30;    y is an integer of 2 to 200;    R 8  is hydrogen or C 1-4  alkyl;    R 9  and R 10  are independently C 1-12  alkylene;    R 11  is hydrogen or C 1-6  alkyl and R 12  is C 1-6  alkyl; or R 11  and R 12  together are C 3-10  alkylene; and    R 4  is the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups; 
 in which at least 0.01 mol percent of the A units are of the formula R 1 ; and 
 (ii) a pharmaceutically acceptable, polyorthoester-compatible liquid excipient selected from polyethylene glycol ether derivatives having a molecular weight between 200 and 4000, polyethylene glycol copolymers having a molecular weight between 400 and 4000, mono-, di-, or tri-glycerides of a C 2-19  aliphatic carboxylic acid or a mixture of such acids, alkoxylated tetrahydrofurfuryl alcohols and their C 1-4  alkyl ethers and C 2-19  aliphatic carboxylic acid esters, and biocompatible oils; and  
 
   (B) an antiemetic agent, and/or an anesthetic agent.    
     
     
         2 . The semi-solid delivery vehicle of  claim 1  where the concentration of the polyorthoester ranges from 1% to 99% by weight.  
     
     
         3 . The semi-solid delivery vehicle of  claim 1  where the polyorthoester has a molecular weight between 1,000 and 20,000.  
     
     
         4 . The semi-solid delivery vehicle of  claim 1  where the fraction of the A units that are of the formula R 1  is between 1 and 90 mol percent.  
     
     
         5 . The semi-solid delivery vehicle of  claim 1  where the polyorthoester is of formula I, where: 
 none of the units have A equal to R 2 ;    R 3 is:                          where:    x is an integer of 0 to 10;    y is an integer of 2 to 30; and    R 6 is:                          where:    s is an integer of 0 to 10;    t is an integer of 2 to 30; and    R 5 , R 7 , and R 8  are independently hydrogen or methyl.    
     
     
         6 . The semi-solid delivery vehicle of  claim 5  where: 
 R 3  and R 6  are both —(CH 2 —CH 2 —O) 2 —(CH 2 —CH 2 )—;    R 5  is methyl; and    p is 1 or 2.    
     
     
         7 . The semi-solid delivery vehicle of  claim 5  where: 
 R 3  and R 6  are both —(CH 2 —CH 2 —O) 9 —(CH 2 —CH 2 )—;    R 5  is methyl; and    p is 1or2.    
     
     
         8 . The pharmaceutical composition of  claim 1  where the anesthetic agent is selected from the group consisting of bupivacaine, lidocaine, mepivacaine, pyrrocaine and prilocaine.  
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the concentration of the anesthetic agent in the composition is about 1-5 wt. %.  
     
     
         10 . The pharmaceutical composition of  claim 1  where the antiemetic agent is granisetron.  
     
     
         11 . The pharmaceutical composition of  claim 1  where the fraction of the antiemetic agent is from 0.1% to 80% by weight of the composition.  
     
     
         12 . The pharmaceutical composition of  claim 11  where the fraction of the antiemetic agent is from 1% to 5% by weight of the composition.  
     
     
         13 . The pharmaceutical composition of  claim 10  where the composition is in topical, syringable, or injectable form.  
     
     
         14 . The pharmaceutical composition of  claim 1  where the antiemetic agent is selected from the group consisting of 5-HT 3  antagonists, a dopamine antagonists, an anticholinergic agents, a GABA B  receptor agonists, an NK 1  receptor antagonists, and a GABA A α 2  and/or α 3  receptor agonists.  
     
     
         15 . The pharmaceutical composition of  claim 14  where the antiemetic agent is a 5-HT 3  antagonist.  
     
     
         16 . The pharmaceutical composition of  claim 15  where the 5-HT 3  antagonist is selected from the group consisting of ondansetron, granisetron and tropisetron.  
     
     
         17 . The pharmaceutical composition of  claim 16  further comprising a second antiemetic agent to form a combination composition.  
     
     
         18 . The pharmaceutical composition of  claim 17  where the second antiemetic agent is selected from the group consisting of alpha-2 adrenoreceptor agonists, a dopamine antagonist, an anticholinergic agent, a GABA B  receptor agonist, an NK 1  receptor antagonist, and a GABA A α 2  and/or α 3  receptor agonist.  
     
     
         19 . The pharmaceutical composition of  claim 18  where the alpha-2 adrenoreceptor agonists is selected from the group consisting of clonidine, apraclonidine, para-aminoclonidine, brimonidine, naphazoline, oxymetazoline, tetrahydrozoline, tramazoline, detomidine, medetomidine, dexmedetomidine, B-HT 920, B-HIT 933, xylazine, rilmenidine, guanabenz, guanfacine, labetalol, phenylephrine, mephentermine, metaraminol, methoxamine and xylazine.  
     
     
         20 . A method for the treatment of emesis induced by a chemotherapeutic agent, by radiation-induced nausea and vomiting, and/or by post operative induced nausea and vomiting in a patient in need thereof which comprises administering to the patient the composition comprising the 5-HT 3  antagonist of  claim 15 .  
     
     
         21 . The method of  claim 20  wherein the 5-HT 3  antagonist is selected from the group consisting of ondansetron, granisetron and tropisetron.  
     
     
         22 . The method of  claim 20  wherein the patient is a human.  
     
     
         23 . The method of  claim 22  wherein the administration comprises the deposition of the composition comprising the 5-HT 3  antagonist into a surgical site.  
     
     
         24 . A method for the prevention of emesis induced by a chemotherapeutic agent in a patient in need thereof which comprises administering to the patient the composition comprising the 5-HT 3  antagonist of  claim 15 .  
     
     
         25 . The method of  claim 24  wherein the 5-HT 3  antagonist is selected from the group consisting of ondansetron, granisetron and tropisetron.  
     
     
         26 . The method of  claim 24  wherein the patient is a human.  
     
     
         27 . A method for ameliorating the symptoms attendant to emesis induced by a chemotherapeutic agent, by radiation-induced nausea and vomiting, and/or by post operative induced nausea and vomiting in a patient comprising administering to the patient in need thereof the composition comprising the 5-HT 3  antagonist of  claim 15 .  
     
     
         28 . The method of  claim 27  wherein the 5-HT 3  antagonist is selected from the group consisting of ondansetron, granisetron and tropisetron.  
     
     
         29 . The method of  claim 27  wherein the patient is a human.  
     
     
         30 . A method for the prevention of emesis induced by a chemotherapeutic agent, by radiation-induced nausea and vomiting, and/or by post operative induced nausea and vomiting in a patient in need thereof which comprises administering to the patient the composition comprising the 5-HT 3  antagonist of  claim 15 , and a second antiemetic agent.  
     
     
         31 . The method of  claim 30  wherein the second antiemetic agent is a compound selected from the group consisting of alpha-2 adrenoreceptor agonists, a dopamine antagonist, an anticholinergic agent, a GABA B  receptor agonist, an NK 1  receptor antagonist, and a GABA Aα2  and/or α 3  receptor agonist.  
     
     
         32 . A process for the preparation of the delivery vehicle of  claim 1 , comprising mixing the components (A) and (B) in the absence of a solvent, at a temperature between about 20 and 150° C.  
     
     
         33 . A process for the preparation of the pharmaceutical composition of  claim 1  where the antiemetic agent and/or anesthetic agent is in solid form, comprising: 
 (1) optionally milling the active agent to reduce the particle size of the active agent;    (2) mixing the active agent and the delivery vehicle; and    (3) optionally milling the composition to reduce the particle size of the active agent.    
     
     
         34 . A process for the preparation of the pharmaceutical composition of  claim 1  where the antiemetic agent and/or the anesthetic agent is in solid form, comprising: 
 (1) warming the polyorthoester to 70° C.;    (2) dissolving the active agent in the excipient at 120-150° C.; and    (3) mixing the 70° C. polyorthoester into the 120° C. solution of the active agent in the excipient with an agitator under the following conditions to obtain a homogeneous distribution of the components: 
 (a) under an inert atmosphere  
 (b) optionally warming the mixing vessel to 70° C.; or  
 (c) optionally allowing the temperature of the mixture to equilibrate under ambient conditions during the mixing process.