Pharmaceutical containers with low adsorption/absorption of active ingredients, and a method of testing materials for adsorption/absorption of active ingredients

Abstract

The present invention relates to a container comprising, one or more polyolefins exhibiting less than 20% sorption of one or more active ingredients as determined by a suitably acceptable method; and a composition comprising one or more active ingredients. The invention also provides a method of determining whether a package material will provide a desired stability of an active ingredient of a pharmaceutical composition; a method of maintaining the concentration of an active ingredient of a pharmaceutical composition upon storage in a container; and a method of manufacturing a storage container utilizing a pharmaceutically acceptable material comprising one or more active ingredients in a therapeutically effective concentration.

1 . A container comprising, 
 a) one or more polyolefins exhibiting less than 20% sorption of one or more active ingredients as determined by a suitably acceptable method; and    b) a composition comprising said one or more active ingredients.    
   
   
       2 . The container according to  claim 1 , wherein the suitably acceptable method comprises the steps of: 
 a) providing a sample of said container having a surface area of S;    b) immersing said sample in a volume V of said composition, such that the surface area to volume ratio S/V is in the range of from about 1 to about 100 cm −1 ; and    c) subjecting said sample immersed in said composition to a temperature T that is above room temperature for a period of time P that is less than two weeks.    
   
   
       3 . The container according to  claim 2 , wherein said P is 10 days.  
   
   
       4 . The container according to  claim 2 , wherein said T is 56° C.  
   
   
       5 . The container according to  claim 1 , wherein said one or more polyolefins comprise either ethylene monomers, propylene monomers, or both.  
   
   
       6 . The container according to  claim 5 , wherein said one or more polyolefins are selected from the group consisting of low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene (PP), and blends thereof.  
   
   
       7 . The container according to  claim 6 , wherein said one or more polyolefins are selected from the group consisting of homopolymers of low-density polyethylene (LDPE), homopolymers of high-density polyethylene (HDPE), and homopolymers of polypropylene(PP).  
   
   
       8 . The container according to  claim 5 , wherein said one or more polyolefins are selected from the group consisting of DuPont™ 20 LDPE, Chevron 5502 HDPE, Atofina 3020 PP, polypropylene homopolymers, low ethylene content (<8%) polypropylenes, and polymers (HDPE, PP) with low content of additives (<5%) and with low flexural modulus (<200 kpsi).  
   
   
       9 . The container according to  claim 1 , wherein said one or more polyolefins exhibit less than 10% sorption of one or more said active ingredient(s).  
   
   
       10 . The container according to  claim 9 , wherein said one or more polyolefins exhibit less than 5% sorption of said active ingredient(s).  
   
   
       11 . The container according to  claim 1 , wherein said composition is an ophthalmic composition.  
   
   
       12 . The container according to  claim 11 , wherein said ophthalmic composition is for treatment of glaucoma.  
   
   
       13 . The container according to  claim 1 , wherein said one or more active ingredient(s) is selected from the group consisting of prostaglandin, analogues, and derivatives thereof.  
   
   
       14 . The container according to  claim 13 , wherein said one or more active ingredient(s) comprises one or more physiologically acceptable derivatives of prostaglandin F (PGF), in which the omega chain has the formula:  
     
       
         
         
             
             
         
       
       the bond between C 13  and C 14  is optionally a single bond or double bond;  
       D is a chain with 2-3 carbon atoms, optionally comprising at least one heteroatom selected from the group consisting of O, S, and N, and optionally substituted by one or more substituents selected from the group consisting of H, C 1 -C 5  alkyl, halo, keto and hydroxy;  
       R is a 
 (i) phenyl group optionally substituted by one or more substituents selected from the group consisting of C 1 -C 5  alkyl, C 1 -C 4  alkoxy, trifluoromethyl, C 1 -C 3  aliphatic acylamino, nitro, halo, and phenyl; or  
 (ii) an aromatic heterocyclic group having 5-6 ring atoms, selected from the group consisting of thiozol, imidazole, pyrrolidine, thiophene and oxazole, optionally substituted by one or more substituents selected from the group consisting of C 1 -C 5  alkyl, C 1 -C 4  alkoxy, trifluoromethyl, C 1 -C 3  aliphatic acylamino, nitro, halo, and phenyl; or  
 (iii) C 3 -C 7  cycloalkyl or C 3 -C 7  cycloalkylene optionally substituted by C 1 -C 5  alkyl.  
 
     
   
   
       15 . The container according to  claim 14 , wherein said one or more physiologically acceptable derivatives of PGF are selected from the group consisting of 17-phenyl-18,19,20-trinor derivatives, 13,14-dihydro-17-phenyl-18,19,20-trinor derivatives, 16-phenoxy-17,18,19,20-tetranor derivatives, and 16-phenyl-17,18,19,20-tetranor derivatives.  
   
   
       16 . The container according to  claim 15 , wherein said active ingredient is latanoprost.  
   
   
       17 . The container according to  claim 13 , wherein the concentration of said active ingredient in said composition is in the range of from 0.001% to 5% (w/v).  
   
   
       18 . A medicinal product comprising a container according to  claim 1 , wherein said container contains a pharmaceutical composition according to  claim 1 .  
   
   
       19 . A method of determining whether a package material will provide a desired stability of an active ingredient of a pharmaceutical composition, said pharmaceutical composition comprising said active ingredient in a therapeutically effective concentration and optionally a pharmaceutically acceptable excipient, dissolved and/or dispersed in an aqueous medium, comprising the steps of: 
 (i) providing a sample having a surface area S of said package material;    (ii) immersing said sample of step (i) in a volume V of said composition, such that the surface area to volume ratio S/V is in the range of from about 1 to about 100 cm −1 ;    (iii) subjecting said sample immersed in said composition of step (ii) to a temperature T that is above room temperature, for a period of time P that is less than two weeks;    (iv) following said period of time P of step (iii), calculating the concentration of said active ingredient; and    (v) calculating the stability provided by the sample by comparing the concentration determined in step (iv) with the initial concentration of said active ingredient.    
   
   
       20 . The method according to  claim 19 , wherein said one or more active ingredient(s) are selected from prostaglandins, analogues and derivatives thereof.  
   
   
       21 . The method according to  claim 20 , said active ingredient(s) being selected from the group consisting of physiologically acceptable derivatives of PGF, in which the omega chain has the formula:  
     
       
         
         
             
             
         
       
     
     the bond between C 13  and C 14  is optionally a single bond or double bond; 
 D is a chain with 2-3 carbon atoms, optionally comprising at least one heteroatom selected from the group consisting of O, S, and N, and optionally substituted by one or more substituents selected from the group consisting of H, C 1 -C 5  alkyl, halo, keto and hydroxy;  
 R is a 
 (i) phenyl group optionally substituted by one or more substituents selected from the group consisting of C 1 -C 5  alkyl, C 1 -C 4  alkoxy, trifluoromethyl, C 1 -C 3  aliphatic acylamino, nitro, halo, and phenyl; or  
 (ii) an aromatic heterocyclic group having 5-6 ring atoms, selected from the group consisting of thiozol, imidazole, pyrrolidine, thiophene and oxazole, optionally substituted by one or more substituents selected from the group consisting of C 1 -C 5  alkyl, C 1 -C 4  alkoxy, trifluoromethyl, C 1 -C 3  aliphatic acylamino, nitro, halo, and phenyl; or  
 (iii) C 3 -C 7  cycloalkyl or C 3 -C 7  cycloalkylene optionally substituted by C 1 -C 5  alkyl.  
 
 
   
   
       22 . The method according to  claim 21 , wherein said physiologically acceptable derivatives of PGF are selected from the group consisting of 17-phenyl-18,19,20-trinor derivatives, 13,14-dihydro-17-phenyl-18,19,20-trinor derivatives, 16-phenoxy-17,18,19,20-tetranor derivatives, and 16-phenyl-17,18,19,20-tetranor derivatives.  
   
   
       23 . The method according to  claim 22 , wherein said one or more active ingredient is latanoprost.  
   
   
       24 . The method according to  claim 20 , wherein the initial concentration of said one or more active ingredient in said composition is in the range of from 0.001% to 5% (w/v).  
   
   
       25 . The method according to  claim 19 , wherein said surface area to volume ratio S/V is in the range of from about 10 to about 40 cm −1 .  
   
   
       26 . The method according to  claim 25 , wherein said surface area to volume ratio S/V is about 20 cm −1 .  
   
   
       27 . The method according to  claim 19 , wherein said temperature T is in the range of from 25° C. to 80° C.  
   
   
       28 . The method according to  claim 27 , wherein said temperature T is in the range of from 50° C. to 60° C.  
   
   
       29 . The method according to  claim 28 , wherein said period of time P is in the range of from 1 to 10 days.  
   
   
       30 . The method according to  claim 29 , wherein said material comprises one or more polyolefins.  
   
   
       31 . The method according to  claim 30 , wherein said one or more polyolefins comprise either ethylene monomers, propylene monomers, or both.  
   
   
       32 . The method according to  claim 19 , wherein said sample of said material is provided in the shape of discs and/or pellets and/or beads.  
   
   
       33 . A method of maintaining the concentration of an active ingredient of a pharmaceutical composition upon storage in a container, comprising the steps of: 
 (i) providing said pharmaceutical composition, comprising said active ingredient in a therapeutically effective concentration and optionally a pharmaceutically acceptable excipient, dissolved and/or dispersed in an aqueous medium;    (ii) providing said container, which is comprised, at least partially, of a pharmaceutically acceptable material comprising one or more polyolefins, said material exhibiting less than 20% sorption of said active ingredient as measured by immersing a sample of said material having a surface area S in a volume V of said composition, the surface area to volume ratio S/V being about 20 cm −1 , at a temperature of 56° C. for 10 days; and    (iii) storing said pharmaceutical composition in said container.    
   
   
       34 . A method of manufacturing a storage container utilizing a pharmaceutically acceptable material comprising one or more active ingredients in a therapeutically effective concentration and optionally a pharmaceutically acceptable excipient, dissolved and/or dispersed in an aqueous medium, wherein said material 
 (i) comprises one or more polyolefins; and    (ii) exhibits less than 20% sorption of said active ingredient(s) as measured by immersing a sample of such material having a surface area S in a volume V of said composition, the surface area to volume ratio S/V being about 20 cm −1 , at a temperature of 56° C. for 10 days.