Transdermal drug delivery devices with amine-resistant silicone adhesives

Abstract

This invention relates to an improved transdermal drug delivery device for the controlled transdermal delivery of amino-functional drugs. The improvement resides in providing the device with a silicone pressure-sensitive adhesive layer which has been chemically treated to reduce the silicon-bonded hydroxyl content of the pressure-sensitive adhesive composition to render the adhesive layer resistant to loss of tack and preserve the instant adherence of the device to the skin of a wearer during storage and while the device is being worn. Preferably, the composition used comprises a silicon-bonded hydroxyl radical containing resinous copolymer of R 3 SiO 1/2 units and SiO 4/2 units and a polydiorganosiloxane which have been chemically treated with R 3 SiO 1/2 units where R is preferably a hydrocarbon radical such as a methyl group to reduce the silicon-bonded hydroxyl content of the adhesive and thereby its sensitivity to amino-functional drugs.

That which is claimed is: 
     
       1. In a transdermal drug delivery device for the controlled transdermal delivery of a drug comprising a container having a controlled drug delivery means associated therewith, said container being adapted to hold said drug delivery means in close proximity to the skin of a wearer, said device having a biocompatible silicone pressure-sensitive adhesive layer thereon for maintaining contact between said container and the skin of a wearer, the improvement which comprises the combination of an amino-functional drug to be delivered from said drug delivery means and a biocompatible silicone pressure-sensitive adhesive layer which has been deposited from a silicone pressure-sensitive adhesive composition containing silicon-bonded hydroxyl radicals which comprises a combination of (A) from 40 to 70 inclusive parts by weight of at least one benzene-soluble resionous copolymer containing silicon-bonded hydroxyl radicals and consisting essentially of triorganosiloxy units of the formula R 3  SiO 1/2  and tetrafunctional siloxy units of the formula SiO 4/2  in a ratio of about 0.6 to 0.9 triorganosiloxy units for each tetrafunctional siloxy unit present in the copolymer and (B) from 30 to 60 parts by weight of at least one polydiorganosiloxane consisting essentially of ARSiO units terminated with endblocking TRASiO 1/2  units, each said polydiorganosiloxane having a viscosity of from 100 centipoise to 30,000,000 centipoise at 25° C. where each T is R-- or X--, which composition has been chemically treated with at least one chemical treating agent that is reactive to silicon-bonded hydroxyl groups to reduce the silicon-bonded hydroxyl content of the composition to a sufficient degree to thereby render said adhesive layer more resistant to the loss of tack and instant adherence to the skin caused by said amino-functional drug, wherein each R is a monovalent organic radical selected from the group consisting of hydrocarbon radicals of from 1 to 6 inclusive carbon atoms, each X radical is selected from the group consisting of HO--, H-- and R'O-- radicals, each R' is an alkyl radical of from 1 to 4 inclusive carbon atoms, and each A radical is selected from the group consisting of R-- and halohydrocarbon radicals of from 1 to 6 inclusive carbon atoms. 
     
     
       2. The device as claimed in claim 1 wherein .[.prior to said chemical treatment, the silicone components of the adhesive composition are composed of (A) from 40 to 70 inclusive parts by weight of at least one benzene soluble resin copolymer containing silicon-bonded hydroxyl radicals and consisting essentially of triorganosiloxy units of the formula R 3  SiO 1/2  and tetrafunctional siloxy units of the formula SiO 4/2  in a mole ratio of 0.6 to 0.9 R 3  SiO 1/2  units for every SiO 4/2  unit present and   (B) from 30 to 60 parts by weight of at least one polydiorganosiloxane consisting essentially of ARSiO units terminated with endblocking TRASiO 1/2  units, each said polydiorganosiloxane having a viscosity of from 100 centipoise to 30,000,000 centipoise at 25° C. where each T is R-- or X--,.]. said chemical treatment is accomplished by a method which comprises condensing .[.at least.]. said (A).[., optionally in the presence of.]. and (B), with   (C) a sufficient amount of .Iadd.the chemical treatment agent comprising .Iaddend.at least one organosilicon endblocking agent capable of generating an endblocking triorganosilyl unit selected from the group consisting of ZR 2  Si-- units, CH 3  Z'-- units, RZ"-- units, and Z'"R 2  Si-- units to provide a 1:0.8 to 1:3 mole ratio of total silicon-bonded hydroxyl radicals present in said (A) and.[., when present,.]. any silicon-bonded hydroxyl and X radicals present in said   (B) to total endblocking triorganosilyl units provided by all .Iadd.organosilicon .Iaddend.endblocking agent present, said .Iadd.organosilicon endblocking .Iaddend.agent being selected from the group consisting of ZR 2  SiY, (ZR 2  Si) q  D, CH 3  Z'Y, (CH 3  Z') 2  O, RZ"Y' and (RZ") 2  O and Z"'R 2  SiY' .Iadd.wherein said condensing is carried out .Iaddend.at least until a substantial amount of the endblocking triorganosilyl units have reacted with the silicon-bonded hydroxyl radicals of said (A), and .[.when present,.]. with the silicon-bonded hydroxyl radicals and X radicals of said (B), wherein each R is a monovalent organic radical selected from the group consisting of hydrocarbon radicals of from 1 to 6 inclusive carbons atoms, each X radical is selected from the group consisting of HO--, .[.H'.]. .Iadd.H-- .Iaddend.and R'O-- radicals, each R' is an alkyl radical of from 1 to 4 inclusive carbons atoms, each Y radical is a monovalent hydrolyzable organic radical or HO--, each Y' is HO-- or a monovalent hydrolyzable organic radical free of nitrogen, each A radical is selected from the group consisting of R-- and halohydrocarbon radicals of from 1 to 6 inclusive carbon atoms, each Z radical is A-- or QR"--, each R" is a divalent alkylene radical of from 1 to 6 inclusive carbon atoms, each Q is an organofunctional monovalent radical selected from the group consisting of RCOE'--, RE'OC--, NC--, R'E'--, HO--, G 2  N--, HO(R"O) n  --and G 2  NCH 2  CH 2  NG--, where E' is --O--, --NG-- or --S--, n has a value of from 1 to 6, Z' is ##STR7## Z" is ##STR8## Z'" is selected from the group consisting of HSR"--, HSCH 2  CH 2  NGR"-- and HOCH 2  CH 2  SR"-- radicals, each G is R-- or H--, D is a divalent or trivalent radical capable of being hydrolyzed to release said endblocking silyl unit, q has a value of 2 when D is a divalent radical and q has a value of 3 when D is a trivalent radical, any (B) not having been present when the chemical treatment was made being combined with the endblocked material to complete formation of the silicone portion of said pressure-sensitive adhesive composition.     
     
     
       3. The device of claim 2 wherein the silicone-pressure sensitive adhesive composition is made by the method comprising the steps of (I) mixing said (A), (B), (C) (D) optionally, an additional catalytic amount of a mild silanol condensation catalyst in the event that none is provided by said (C) .Iadd.to produce a mixture of (A), (B), (C) and (D) having a viscosity .Iaddend.and   (E) when necessary, an effective amount of an organic solvent which is inert with respect to (A), (B), (C) and (D) to reduce the viscosity of a mixture of (A), (B), (C) and (D) and     (II) condensing the mixture of (A), (B), (C) and (D) at least until a substantial amount of the endblocking triorganosilyl units have reacted with the silicon-bonded hydroxyl radicals and X radical of said (A) and (B).   
     
     
       4. The device as claimed in claim 3 wherein R is a methyl radical, each said polydiorganosiloxane (B) is composed of ARSiO units selected from the group consisting of (C 6  H 5 ) 2  SiO, R'"RSiO units and combinations of both where each R'" is selected from the group consisting of methyl, vinyl and 3,3,3-trifluoropropyl radicals and no more than 50 mole percent of the ARSiO units present in said (B) are (C 6  H 5 ) 2  SiO units, the endblocking agent of (C) is selected from the group consisting of ZRR""SiY, (ZRR""Si) 2  NH, and mixtures thereof where each Z is R'" and Y is NH 2  -- or R'O--, and each R"" is a methyl or a phenyl radical, there being present 50 to 65 parts by weight of (A) and 35 to 50 parts by weight of said (B) and .[.the pKa of the most basis amino-functional radical of.]. said amino-functional drug .[.is.]. .Iadd.contains an amino-functional radical having a pKa of .Iaddend. at least equal to 8.5. 
     
     
       5. The device as claimed in claim 4 wherein R"" is methyl radical, all of said ARSiO units in said (B) are R 2  SiO units and said (C) is (R 3  Si) 2  NH. 
     
     
       6. The device as claimed in claim 3 wherein said method by which the adhesive composition is made is one wherein Step (I) comprises the steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), and (D) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       7. The device as claimed in claim 4 wherein said method by which the adhesive composition is made is one wherein Step (I) comprised the Steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), any (D) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       8. The device as claimed in claim 5 wherein said method by which the adhesive composition is made is one wherein Step (I) comprises the Steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), any (D) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       9. The device as claimed in claim 2 whereto the pressure sensitive adhesive composition comprises a blend of the chemically treated silicone pressure-sensitive adhesive composition with less than about 30 weight percent based on nonvolatile solids content of a chemically-treated modifier comprising from 1 to 100 parts by weight of a silicone resin copolymer consisting essentially of R 3  SiO.sub. 1/2 units and SiO 4/2  units in a mole ratio of from 0.6 to 0.9 R 3  SiO.sub. 1/2 units for each SiO 4/2  unit present and from 0 to 99 parts by weight of at least one polydiorganosiloxane consisting essentially of ARSiO units terminated with endblocking TRASiO.sub. 1/2 units, each said polydiorganosiloxane having a viscosity of from 100 centipoise to 30,000,000 centipoise at 25° C. wherein the chemical treatment has been made with said endblocking agent (C). 
     
     
       10. The device as claimed in claim 3 wherein said (C) is selected from the group consisting of ZR 2  SiNH 2 , (ZR 2  Si) 2  NH and mixtures thereof and Q is an organofunctional monovalent radical selected from the group consisting of RCOE'--, RE'OC--, NC--, GE', HO(R"O) n  --, where E' is --O--, --NH-- or --S--, and said silicone pressure-sensitive adhesive composition is made by a method comprising the steps of (I) mixing (A), (B), (C), (E), (D) and   (F) from 0.1 to 10 moles of water per mole of ═NH provided by said (C),   (G) optionally, from 0.001 to 10 parts by weight per 100 parts by weight of (A) and (B) of at least one ammonia scavenger compound selected from the group consisting of HOC m  H 2m+1 , HOC x  H 2x  (OC x  H 2x ) y  (O) v  H, C w  H 2w+1  (OC x  H 2x- ) y  OC w  H 2w+1 , C w  H 2w+1 , C(O)OC n  H 2n+1 , H 2  C(O)OC n  H 2n+1 , and     (II) condensing (A), (B) and (C) at a temperature of from 80° C. to 160° C. and at the same time at least periodically removing any condensation by-products from the mixture at least until a substantial amount of the endblocking triorganosilyl units have reacted with the silicon-bonded hydroxyl radicals and X radicals of said (A) and (B), and   (III) stripping substantially any remaining condensation by-products, (F) and any (G) from the mixture after the condensation reaction of step II is substantially complete, wherein m has a value of from 2 to 4, n has a value of from 1 to 6, v is 0 or 1, w has a value of from 1 to 3, x has a value of from 2 to 6 and y has a value of from 0 to 3, there being at least 0.5 moles of water present when (G) is not present.     
     
     
       11. The device as claimed in claim 10 wherein R is a methyl radical, each said polydiorganosiloxane (B) is composed of ARSiO units selected from the group consisting of (C 6  H 5 ) 2  SiO R'"RSiO units and combinations of both where each R'" is selected from the group consisting of methyl, vinyl and 3,3,3-trifluoropropyl radicals and no more than 50 mole percent of the ARSiO units present in said (B) are (C 6  H 5 ) 2  SiO units, the endblocking agent of (C) is selected from the group consisting of ZRR""SiNH 2 , (ZRR""Si) 2  NH, and mixtures thereof where each Z is R'" and each R"" is a methyl or a phenyl radical, there being present 50 to 65 parts by weight of (A) and 35 to 50 parts by weight of said (B) and .[.the pKa of the most basis amino-functional radical of.]. said amino-functional drug .[.is.]. .Iadd.contains an amino-functional radical having a pKa of .Iaddend.at least 8.5. 
     
     
       12. The device as claimed in claim 11 wherein R"" is a methyl radical, all of said ARSiO units in said (B) are R 2  SiO units and said (C) is (R 3  Si) 2  NH. 
     
     
       13. The device as claimed in claim 10 wherein aid method by which the adhesive composition is made is one wherein Step (I) comprises the steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), (F), (G) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       14. The device as claimed in claim 11 wherein said method by which the adhesive composition is made is one wherein Step (I) comprised the Steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), (F), (G) and any further amount of (E) which is necessary prior to proceeding with Step (II), aid polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       15. The device as claimed in claim 12 wherein said method by which the adhesive composition is made is one wherein Step (F) comprises the Steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), (F), (G) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       16. The device as claimed in claim 10 wherein Step (I) comprises the steps of (Ia) mixing (A), (B) and any (E) together, (Ib) adding said (C) to the mixture formed in step (Ia) to form a reaction mixture and (Ic) adding said (F) and (G) to the reaction mixture at a preselected point during said Step (II) prior to commencing Step (III). 
     
     
       17. The device as claimed in claim 10 wherein the pressure sensitive adhesive composition comprises a blend of the chemically-treated silicone pressure-sensitive adhesive composition with less than about 30 weight percent based on nonvolatile solids content of a chemically-treated modifier comprising from 1 to 100 parts by weight of a silicone resin copolymer consisting essentially of R 3  SiO.sub. 1/2 units and SiO 4/2  units in a mole ratio of from 0.6 to 0.9 R 3  SiO.sub. 1/2 units for each SiO 4/2  unit present and from 0 to 99 parts by weight of at least one polydiorganosiloxane consisting essentially of ARSiO units terminated with endblocking TRASiO.sub. 1/2 units, each said polydiorganosiloxane having a viscosity of from 100 centipoise to 30,000,000 centipoise at 25° C. wherein the chemical treatment has been made with said endblocking agent (C). 
     
     
       18. The device as claimed in claim 4 wherein there is present from 58 to 65 parts by weight of said (A) and from 35 to 42 parts by weight of said (B). 
     
     
       19. The device as claimed in claim 7 wherein there is present from 58 to 65 parts by weight of said (A) and from 35 to 42 parts by weight of said (B). 
     
     
       20. The device as claimed in claim 3 wherein a catalytic amount of said (D) is present. 
     
     
       21. The device as claimed in claim 5 wherein a catalytic amount of said (D) is present. 
     
     
       22. The device as claimed in claim 10 wherein a catalytic amount of said (D) is present. 
     
     
       23. The device as claimed in claim 12 wherein a catalytic amount of said (D) is present. 
     
     
       24. The device as claimed in claim 2 wherein said (C) is selected from the group consisting of ZRR""SiNH 2 , (ZRR""Si) 2  NH, and mixtures thereof where each R"" is a methyl or a phenyl radical and Q is an organofunctional monovalent radical selected from the group consisting of RCOE'--, RE'OC--, NC--, GE', HO(R"O) N  --, where E' is --O--, --NH-- or --S--, and said silicone pressure-sensitive adhesive composition is made by a method comprising the steps of (I) mixing (A), (B), (C),(E), (D) and (F) from 0.1 to 10 moles of water per mole of ═NH provided by said (C),   (II) condensing (A), (B) and (C) at a temperature of from 80° C. to 160° C. and at the same time at least periodically removing any condensation by-products from the mixture at least until a substantial amount of the endblocking triorganosilyl units have reacted with the silicon-bonded hydroxyl radicals and x radicals of said (A) and (B),   (III) mixing, from 0.001 to 10 parts by weight per 100 parts by weight of (A) and (B) of at least one ammonia scavenger compound selected from the group consisting of HOC m  H 2m+1 , HOC x  H 2x  (OC x  H 2x ) y  (O) v  H, C w  H 2w+1  (OC x  H 2x ) y  OC w  H 2w+1 , C w  H 2w+1  C(O)OC n  H 2n+1 , H 2  C(O)OC nH   2n+1 , with the product of Step (II),   (IV) maintaining the mixture of Step Ill at reflux temperature for a period of time sufficient to improve the removal of residual ammonia present in the mixture of Step III by a stripping step, and   (V) stripping substantially any remaining condensation by-products, (F) and (G) from the mixture of Step IV, wherein m has a value of from 2 to 4, n has a value of from 1 to 6, v is 0 or 1, w has a value of from 1 to 3.   
     
     
       25. The device as claimed in claim 24 wherein R"" is a methyl radical, all of said ARSiO units in said (B) are R 2  SiO unit and said (C) is (R 3  Si) 2  NH. 
     
     
       26. The device as claimed in claim 24 wherein said method by which the adhesive composition is made is one wherein Step (I) comprises the steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), (F), and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       27. A method of preserving the instant adherence to the skin of a wearer of a transdermal drug delivery device for the controlled transdermal delivery of an amino-functional drug wherein said device is maintained in contact with the skin by a skin-contacting silicone pressure-sensitive adhesive layer, said method comprising providing said device with a silicone pressure-sensitive adhesive layer which has been deposited from a silicone pressure-sensitive adhesive composition which consists essentially of a silicone pressure-sensitive adhesive composition containing silicon-bonded hydroxyl radicals which comprises a combination of (A) from 40 to 70 inclusive parts by weight of at least one benzene-soluble resinous copolymer containing silicon-bonded hydroxyl radicals and consisting essentially of triorganosiloxy units of the formula R 3  SiO.sub. 1/2 and tetrafunctional siloxy units of the formula SiO 4/2  in a ratio of about 0.6 to 0.9 triorganosiloxy units for each tetrafunctional siloxy unit present in the copolymer and (B) from 30 to 60 parts by weight of at least one polydiorganosiloxane consisting essentially of ARSiO units terminated with endblocking TRASiO.sub. 1/2 units, each polydiorganosiloxane having a viscosity of from 100 centipoise to 30,000,000 centipose at 25° C. where each T is R-- or X--, which composition has been chemically treated with at least one chemical treating agent that is reactive to silicon-bonded hydroxyl groups to reduce the silicon-bonded hydroxyl content of the composition to a sufficient degree to thereby render said adhesive layer more resistant to the loss of tack and instant adherence to the skin caused by said amino-functional drug, wherein R is n monovalent organic radical selected from the group consisting of hydrocarbon radicals of from 1 to 6 inclusive atoms, each X radical is selected from the group consisting of HO--, H-- and R'O--radicals, each R' is an alkyl radical of from 1 to 4 inclusive carbon atoms, and each A radical is selected from the group consisting of R-- and halohydrocarbon radicals of from 1 to 6 inclusive carbon atoms. 
     
     
       28. The method as claimed in claim 27 wherein .[.prior to said chemical treatment, the silicone components of said adhesive composition are composed of (A) from 40 to 70 inclusive parts by weight of at least one benzene soluble resin copolymer containing silicon-bonded hydroxyl radicals and consisting essentially of triorganosiloxy units of the formula R 3  SiO.sub. 1/2 and tetrafunctional siloxy units of the formula SiO 4/2  in a mole ratio of 0.6 to 0.9 R 3  SiO.sub. 1/2 units for every SiO 4/2  unit present and   (B) from 30 to 60 parts by weight of at least one polydiorganosiloxane consisting essentially of ARSiO units terminated with endblocking TRASiO.sub. 1/2 units, each said polydiorganosiloxane having a viscosity of from 100 centipoise to 30,000,000 centipoise at 25° C. where each T is R-- or X--,.]. said chemical treatment is accomplished by a method which comprises condensing .[.at least.]. said (A).[., optionally in the presence of.]. .Iadd.and .Iaddend.(B), with   (C) a sufficient amount of .Iadd.the chemical treatment agent comprising .Iaddend.at least one organosilicon endblocking agent capable of generating an endblocking triorganosilyl unit selected from the group consisting of ZR 2  Si-- units, CH 3  Z'-- units, RZ" --units, and Z'"R 2  Si-- units to provide a 1:0.8 to 1:3 mole ratio of total silicon-bonded hydroxyl radicals present in said (A) and.[., when present,.]. any silicon-bonded hydroxyl and X radicals present in said   (B) to total endblocking triorganosilyl units provided by all .Iadd.organosilicon .Iaddend.endblocking agent present, said .Iadd.organosilicon endblocking .Iaddend.agent being selected from the group consisting of ZR 2  SiY, (ZR 2  Si) q  D, CH 3  Z'Y, (CH 3  Z') 2  O, RZ"Y' and (RZ") 2  O and Z'"R 2  SiY' at least until a substantial amount of the endblocking triorganosilyl units have reacted with the silicon-bonded hydroxyl radicals of said (A), and .[.when present,.]. with the silicon-bonded hydroxyl radicals and X radicals of said (B), wherein each R is a monovalent organic radical selected from the group consisting of hydrocarbon radicals of from 1 to 6 inclusive carbons atoms, each X radical is selected from the group consisting of HO--, H-- and R'O-- radicals, each R' is an alkyl radical of from 1 to 4 inclusive carbons atoms, each Y radical is a monovalent hydrolyzable organic radical or HO--, each Y' is HO--or a monovalent hydrolyzable organic radical free of nitrogen, each A radical is selected from the group consisting of R-- and halohydrocarbon radicals of from 1 to 6 inclusive carbon atoms, each Z radical is A-- or QR"--, each R" is a divalent alkylene radical of from 1 to 6 inclusive carbon atoms, each Q is an organofunctional monovalent radical selected from the group consisting of RCOE'--, RE'OC--, NC--, R'E'--, HO--, G 2  N--, HO(R"O) n  --and G 2  NCH 2  CH 2  NG--, where E' is --O--, --NG-- or --S--, n has a value of from 1 to 6, Z' is ##STR9## Z' is ##STR10## Z'" is selected from the group consisting of HSR"--, HSCH 2  CH 2  NGR"-- and HOCH 2  CH 2  SR"-- radicals, each G is R-- or H--, D is a divalent or trivalent radical capable of being hydrolyzed to release said endblocking silyl unit, q has a value of 2 when D is a divalent radical and q has a value of 3 when D is a trivalent radical, any (B) not having been present when the chemical treatment was made being combined with the endblocked material to complete formation of the silicone portion of said pressure-sensitive adhesive composition.     
     
     
       29. The method as claimed in claim 28 wherein the silicone-pressure sensitive adhesive composition is made by the method comprising the steps of (I) mixing said (A), (B), (C) (D) optionally, an additional catalytic amount of a mild silanol condensation catalyst in the event that none is provided by said (C) .Iadd.to produce a mixture of (A), (B), (C) and (D) having a viscosity .Iaddend.and   (E) when necessary, an effective amount of an organic solvent which is inert with respect to (A), (B), (C) and (D) to reduce the viscosity of a mixture of (A), (B), (C) and (D) and     (II) condensing the mixture of (A), (B), (C) and (D) at least until a substantial amount of the endblocking triorganosilyl units have reacted with the silicon-bonded hydroxyl radicals and X radical of said (A) and (B).   
     
     
       30. The method as claimed in claim 29 wherein R is a methyl radical, each said polydiorganosiloxane (B) is composed of ARSiO units selected from the group consisting of (C 6  H 5 ) 2  SiO, R'"RSiO units and combinations of both where each R'" is selected from the group consisting of methyl, vinyl and 3,3,3-trifluoropropyl radicals and no more than 50 mole percent of the ARSiO units present in said (B) are (C 6  H 5 ) 2  SiO units, the endblocking agent of (C) is selected from the group consisting of ZRR""SiY, (ZRR""Si) 2  NH, and mixtures thereof where each Z is R'" and Y is NH 2  -- or R'O--, and each R"" is a methyl or a phenyl radical, there being present 50 to 65 parts by weight of (A) and 35 to 50 parts by weight of said (B) and .[.the pKa of the most basis amino-functional radical of.]. said amino-functional drug .[.is.]. .Iadd.contains an amino-functional radical having a pKa of .Iaddend.at least equal to 8.5. 
     
     
       31. The method as claimed in claim 30 wherein R"" is a methyl radical, all of said ARSiO units in said (B) are R 2  SiO units and said (C) is (R 3  Si) 2  NH. 
     
     
       32. The method as claimed in claim 29 wherein said method by which the adhesive composition is made is one wherein Step (I) comprises the steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), and (D) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       33. The method as claimed in claim 30 wherein said method by which the adhesive composition is made is one whereto Step (I) comprises the Steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), any (D) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       34. The method as claimed in claim 31 wherein said method by which the adhesive composition is made is one whereto Step (I) comprises the Steps of (1a) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), any (D) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       35. The method as claimed in claim 28 wherein the pressure sensitive adhesive composition comprises a blend of the chemically treated silicone pressure-sensitive adhesive composition with less than about 30 weight percent based on nonvolatile solids content of a chemically-treated modifier comprising from 1 to 100 parts by weight of a silicone resin copolymer consisting essentially of R 3  SiO.sub. 1/2 units and SiO 4/2  units in a mole ratio of from 0.6 to 0.9 R 3  SiO.sub. 1/2 units for each SiO 4/2  unit present and from 0 to 99 parts by weight of at least one polydiorganosiloxane consisting essentially of ARSiO units terminated with endblocking TRASiO.sub. 1/2 units, each said polydiorganosiloxane having a viscosity of from 100 centipoise to 30,000,000 centipoise at 25° C. wherein the chemical treatment has been made with said endblocking agent (C). 
     
     
       36. The method as claimed in claim 29 wherein said (C) is selected from the group consisting of ZR 2  SiNH 2 , (ZR 2  Si) 2  NH and mixtures thereof and Q is an organofunctional monovalent radical selected from the group consisting of RCOE'--, RE'OC--, NC--, GE', HO(R"O) n  --, where E' is --0--, --NH-- or --S--, and said silicone pressure-sensitive adhesive composition is made by a method comprising the steps of (I) mixing (A), (B), (C), (E), (D) and   (F) from 0.1 to 10 moles of water per mole of ═NH provided by said (C),   (G) optionally, from 0.001 to 10 parts by weight per 100 parts by weight of (A) and (B) of at least one ammonia scavenger compound selected from the group consisting of HOC m  H 2m+1 , HOC x  H 2x  (OC x  H 2x ) y  (O) v  H, C w  H 2w+1  (OC x  H 2x ) y  OC w  H 2w+1 , C w  H 2w+1  C(O)OC n  H 2n+1 , H 2  C(O)OC n  H 2n+1 , and     (II) condensing (A), (B) and (C) at a temperature of from 80° C. to 160° C. and at the same time at least periodically removing any condensation by-products from the mixture at least until a substantial amount of the endblocking triorganosilyl units have reacted with the silicon-bonded hydroxyl radicals and X radicals of said (A) and (B), and   (III) stripping substantially any remaining condensation by-products, (F) and any (G) from the mixture after the condensation reaction of step II is substantially complete, wherein m has a value of from 2 to 4, n has a value of from 1 to 6, v is 0 or 1, w has a value of from 1 to 3, x has a value of from 2 to 6 and y has a value of from 0 to 3, there being at least 0.5 moles of water present when (G) is not present.     
     
     
       37. The method as claimed in claim 36 wherein R is a methyl radical, each said polydiorganosiloxane (B) is composed of ARSiO units selected from the group consisting of (C 6  H 5 ) 2  SiO, R'"RSiO units and combinations of both where each R'" is selected from the group consisting of methyl, vinyl and 3,3,3-trifluoropropyl radicals and no more than 50 mole percent of the ARSiO units present in said (B) are (C 6  H 5 ) 2  SiO units, the endblocking agent of (C) is selected from the group consisting of ZRR"41 SiNH 2 , (ZRR""Si) 2  NH, and mixtures thereof where each Z is R'" and each R"" is a methyl or a phenyl radical, there being present 50 to 65 parts by weight of (A) and 35 to 50 parts by weight of said (B) and .[.the pKa of the most basis amino-functional radical of.]. said amino-functional drug .[.is.]. .Iadd.contains an amino-functional radical having a pKa of .Iaddend.at least 8.5. 
     
     
       38. The method as claimed in claim 37 wherein R"" is a methyl radical, all of said ARSiO units in said (B) are R 2  SiO units and said (C) is (R 3  Si) 2  NH. 
     
     
       39. The method as claimed in claim 36 wherein said method by which the adhesive composition is made is one wherein Step (I) comprises the steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), (F), (G) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       40. The method as claimed in claim 37 wherein said method by which the adhesive composition is made is one wherein Step (I) comprised the Steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), (F), (G) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       41. The method as claimed in claim 38 wherein said method by which the adhesive composition is made is one wherein Step (I) comprises the Steps of (1a) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), CF), (G) and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C. 
     
     
       42. The method as claimed in claim 36 wherein Step (I) comprises the steps of (1a) mixing (A), (B) and any (E) together, (1b) adding said (C) to the mixture formed in step (1a) to form a reaction mixture and (1c) adding said (F) and (G) to the reaction mixture at a preselected point during said Step (II) prior to commencing Step (III). 
     
     
       43. The method as claimed in claim 36 wherein the pressure sensitive adhesive composition comprises a blend of the chemically-treated silicone pressure-sensitive adhesive composition with less than about 30 weight percent based on nonvolatile solids content of a chemically-treated modifier comprising from 1 to 100 parts by weight of a silicone resin copolymer consisting essentially of R 3  SiO.sub. 1/2 units and SiO 4/2  units in a mole ratio of from 0.6 to 0.9 R 3  SiO.sub. 1/2 units for each SiO 4/2  unit present and from 0 to 99 parts by weight of at least one polydiorganosiloxane consisting essentially of ARSiO units terminated with endblocking TRASiO.sub. 1/2 units, each said polydiorganosiloxane having a viscosity of from 100 centipoise to 30,000,000 centipoise at 25° C. wherein the chemical treatment has been made with said endblocking agent (C). 
     
     
       44. The method as claimed in claim 30 wherein there is present from 58 to 65 parts by weight of said (A) and from 35 to 42 parts by weight of said (B). 
     
     
       45. The method as claimed in claim 33 whereto there is present from 58 to 65 parts by weight of said (A) and from 35 to 42 parts by weight of said (B). 
     
     
       46. The method as claimed in claim 29 wherein a catalytic amount of said (D) is present. 
     
     
       47. The method as claimed in claim 31 wherein a catalytic amount of said (D) is present. 
     
     
       48. The method as claimed in claim 36 wherein a catalytic amount of said (D) is present. 
     
     
       49. The method as claimed in claim 38 wherein a catalytic amount of said (D) is present. 
     
     
       50. The method as claimed in claim 36 wherein said (C) is selected from the group consisting of ZRR""SiNH 2 , (ZRR""Si) 2  NH, and mixtures thereof where each R"" is a methyl or a phenyl radical and Q is an organofunctional monovalent radical selected from the group consisting of RCOE'--, RE'OC--, NC--, GE', HO(R"O) n  --, where E' is --0--, --NH-- or --S--, and said silicone pressure-sensitive adhesive composition is made by a method comprising the steps of (I) mixing (A), (B), (C), (E), (D) and (F) from 0.1 to 10 moles of water per mole of ═NH provided by said (C),   (II) condensing (A), (B) and (C) at a temperature of from 80° C. to 160° C. and at the same time at least periodically removing any condensation by-products from the mixture at least until a substantial amount of the endblocking triorganosilyl units have reacted with the silicon-bonded hydroxyl radicals and X radicals of said (A) and (B),   (III) mixing, from 0.001 to 10 parts by weight per 100 parts by weight of (A) and (B) of at least one ammonia scavenger compound selected from the group consisting of HOC m  H 2m+1 , HOC x  H 2x  (OC x  H 2x ) y  (O) v  H, C w  H 2w+1  (OC 2x ) y  OC w  H 2w+1 , C w  H 2w+1  C(O)OC n  H 2n+1 , H 2  C(O)OC n  H 2n+1 , with the product of step (II),   (IV) maintaining the mixture of step III at reflux temperature for a period of time sufficient to improve the removal of residual ammonia present in the mixture of step III by a stripping step, and stripping substantially any remaining condensation by-products, (F) and (G) from the mixture of Step IV. wherein m has a value of from 2 to 4, n has a value of from 1 to 6, v is 0 or 1, w has a value of from 1 to 3.     
     
     
       51. The method as claimed in claim 50 wherein R"" is a methyl radical, all of said ARSiO units in said (B) are R 2  SiO units and said (C) is (R 3  Si) 2  NH. 
     
     
       52. The method as claimed in claim 50 wherein said method by which the adhesive composition is made is one wherein Step (I) comprises the steps of (Ia) mixing (A), (B) and any (E) together in the presence of a silanol condensation catalyst, (Ib) condensing said (A) and (B) to form a condensed product and (Ic) mixing the product of Step (Ib) with (C), (F), and any further amount of (E) which is necessary prior to proceeding with Step (II), said polydiorganosiloxane of (B) having a viscosity of from 100 to 100,000 centipoise at 25° C.