High-energy cyclodextrin complexes

Abstract

Methods for enhancing the complexation efficiency of a drug with cyclodextrin and for enhancing the availability of a drug following administration of a cyclodextrin-drug complex.

What is claimed is:  
     
         1 . A method for enhancing the complexation efficiency of a benzodiazepine with a cyclodextrin, said method comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of at least 1% by weight of said benzodiazepine.  
     
     
         2 . A method according to  claim 1 , comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of at least 5% by weight of said benzodiazepine.  
     
     
         3 . A method according to  claim 1 , comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of 50% or more by weight of said benzodiazepine.  
     
     
         4 . A method according to  claim 1 , wherein the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam or loprazolam.  
     
     
         5 . A method according to  claim 4 , further comprising formulating the cyclodextrin-benzodiazepine complex thus obtained as a nasal spray, sublingual tablet or parenteral solution.  
     
     
         6 . A method according to  claim 1 , wherein the complexation is conducted at a pH level between about 3 and about 5.  
     
     
         7 . A method for enhancing the availability of a benzodiazepine following administration of a cyclodextrin-benzodiazepine complex to a warm-blooded animal in need of same, said method comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of at least 1% by weight of said benzodiazepine to enhance complexation efficiency, further comprising administering the cyclodextrin-benzodiazepine complex thus obtained to said animal.  
     
     
         8 . A method according to  claim 7 , comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in an aqueous medium at a pH below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of at least 5% by weight of said benzodiazepine to enhance complexation efficiency, further comprising administering the cyclodextrin-benzodiazepine complex thus obtained to said animal.  
     
     
         9 . A method according to  claim 7 , comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of 50% or more by weight of said benzodiazepine to enhance complexation efficiency, further comprising administering the cyclodextrin-benzodiazepine complex thus obtained to said animal.  
     
     
         10 . A method according to  claim 7 , wherein the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam or loprazolam.  
     
     
         11 . A method according to  claim 10 , further comprising formulating the cyclodextrin-benzodiazepine complex thus obtained as a nasal spray, sublingual tablet or parenteral solution.  
     
     
         12 . A method according to  claim 11 , further comprising administering the nasal spray, sublingual tablet or parenteral solution in an amount effective to produce a sedative, anti-anxiety, anticonvulsant or muscle relaxant effect.  
     
     
         13 . A method according to  claim 12 , further comprising administering the nasal spray, sublingual tablet or parenteral solution as a pre-anaesthetic medication, or to supplement anaesthesia, to induce and maintain anaesthesia or to induce a hypnotic effect.  
     
     
         14 . A method according to  claim 13 , wherein the benzodiazepine is alprazolam, clonazepam, lorazepam, midazolam or triazolam.  
     
     
         15 . A method according  claim 14 , wherein the complexation is conducted at a pH level between about 3 and about 5.  
     
     
         16 . A method according to  claim 7 , further comprising formulating the cyclodextrin-benzodiazepine complex thus obtained as an aqueous solution or a hydrogel.  
     
     
         17 . A method according to  claim 16 , further comprising administering the cyclodextrin-benzodiazepine complex as a nasal spray or nasal drops.  
     
     
         18 . A method according to  claim 16 , further comprising administering the cyclodextrin-benzodiazepine complex as a parenteral solution.  
     
     
         19 . A method according to  claim 16 , wherein said benzodiazepine is selected from the group consisting of midazolam, alprazolam, clonazepam, lorazepam and triazolam and wherein the cyclodextrin-drug complex is formulated as an aqueous solution.  
     
     
         20 . A method according to  claim 19 , further comprising formulating the aqueous solution to be at a pH level of below about 4.7 and administering it as a nasal spray.  
     
     
         21 . A method according to  claim 20 , wherein the pH level of the nasal spray is between about 3 and about 4.7.  
     
     
         22 . A method according to  claim 7 , further comprising formulating the cyclodextrin-benzodiazepine complex thus obtained for dermal administration.  
     
     
         23 . A method according to  claim 7 , further comprising formulating the cyclodextrin-benzodiazepine complex thus obtained as a solid.  
     
     
         24 . A method according to  claim 23 , wherein the solid cyclodextrin-benzodiazepine complex is formulated as a tablet for oral, buccal or sublingual administration.  
     
     
         25 . A method for enhancing the availability of a benzodiazepine following administration of a cyclodextrin-benzodiazepine complex to a warm-blooded animal in need of same, said method comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of at least 1% by weight of said benzodiazepine to enhance the complexation efficiency, removing the water from the aqueous complexation medium after formation of the cyclodextrin-benzodiazepine complex, and administering the cyclodextrin-benzodiazepine complex thus obtained to said animal.  
     
     
         26 . A method according to  claim 25 , comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of at least 5% by weight of said benzodiazepine to enhance the complexation efficiency, removing the water from the aqueous complexation medium after formation of the cyclodextrin-benzodiazepine complex, and administering the cyclodextrin-benzodiazepine complex thus obtained to said animal.  
     
     
         27 . A method according to  claim 25 , wherein the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam or loprazolam.  
     
     
         28 . A method according to  claim 25 , wherein the benzodiazepine is midazolam, alprazolam, clonazepam, lorazepam or triazolam.  
     
     
         29 . A method according to  claim 7 , further comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in the presence of from about 0.001 to about 5% (weight/volume) of a pharmacologically inactive, pharmaceutically acceptable water-soluble polymer at a temperature of from about 30° C. to about 150° C.  
     
     
         30 . A method according to  claim 29 , wherein the polymer is a cellulose derivative or a polyvinyl polymer.  
     
     
         31 . A method according to  claim 30 , wherein the polymer is methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl ethylcellulose, hydroxyethyl ethylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone.  
     
     
         32 . A method according to  claim 31 , wherein the cellulose derivative is hydroxypropyl methylcellulose.  
     
     
         33 . A method according to  claim 7 , further comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in the presence of at least one member selected from the group consisting of acetic acid and its pharmaceutically acceptable salts, the acetate-water ratio of the aqueous complexation medium being from about 1:1000 to about 2:1.  
     
     
         34 . A method according to  claim 33 , wherein the benzodiazepine is midazolam.  
     
     
         35 . A method according to  claim 7 , further comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in the presence of from about 0.001 to about 5% (weight/volume) of a pharmacologically inactive, pharmaceutically acceptable water-soluble polymer at a temperature of from about 30° C. to about 150° C., and further in the presence of at least one member selected from the group consisting of acetic acid and its pharmaceutically acceptable salts, the acetate-water ratio of the aqueous complexation medium being from about 1:1000 to about 2:1.  
     
     
         36 . A method according to  claim 35 , wherein the benzodiazepine is midazolam.  
     
     
         37 . An inclusion complex of a benzodiazepine with β-cyclodextrin sulfobutyl ether, at least 50% by weight of said benzodiazepine being in ring-opened form.  
     
     
         38 . An inclusion complex according to  claim 37 , wherein the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temezepam or loprazolam.  
     
     
         39 . An inclusion complex according to  claim 37 , wherein the benzodiazepine is midazolam.  
     
     
         40 . A pharmaceutical composition comprising an inclusion complex of a benzodiazepine with β-cyclodextrin sulfobutyl ether, at least 50% by weight of said benzodiazepine being in ring-opened form, said complex being in an amount effective to produce a sedative, anti-anxiety, anticonvulsant or muscle relaxant effect, and a pharmaceutically acceptable carrier therefor suitable for nasal, oral, sublingual, buccal, parenteral or dermal administration.  
     
     
         41 . A pharmaceutical composition according to  claim 40 , formulated as an aqueous solution.  
     
     
         42 . A pharmaceutical composition according to  claim 40 , in the form of a nasal spray or nasal drops.  
     
     
         43 . A pharmaceutical composition according to  claim 40 , wherein the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam or loprazolam.  
     
     
         44 . A pharmaceutical composition according to  claim 40 , wherein the benzodiazepine is midazolam.  
     
     
         45 . A method for enhancing the complexation efficiency of a benzodiazepine with a cyclodextrin, said method comprising complexing said benzodiazepine with a cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methylated α-cyclodextrin, methylated β-cyclodextrin, methylated γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, β-cyclodextrin sulfobutyl ether, hydroxyethyl-α-cyclodextrin, hydroxyethyl-γ-cyclodextrin, α-cyclodextrin carboxymethyl ether, β-cyclodextrin carboxymethyl ether and γ-cyclodextrin carboxymethyl ether, in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of at least 1% by weight of said benzodiazepine, further comprising detecting the presence of the ring-opened form of said benzodiazepine.  
     
     
         46 . A method for enhancing the complexation efficiency of a benzodiazepine with a cyclodextrin, said method comprising complexing said benzodiazepine with a cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methylated α-cyclodextrin, methylated β-cyclodextrin, methylated γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, β-cyclodextrin sulfobutyl ether, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, α-cyclodextrin carboxymethyl ether, β-cyclodextrin carboxymethyl ether and γ-cyclodextrin carboxymethyl ether, in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of about 50% or more by weight of said benzodiazepine.  
     
     
         47 . A method for enhancing the availability of a benzodiazepine following administration of a cyclodextrin-benzodiazepine complex to a warm-blooded animal in need of same, said method comprising complexing said benzodiazepine with a cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methylated α-cyclodextrin, methylated β-cyclodextrin, methylated γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, β-cyclodextrin sulfobutyl ether, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, α-cyclodextrin carboxymethyl ether, β-cyclodextrin carboxymethyl ether and γ-cyclodextrin carboxymethyl ether, in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of at least 1% by weight of said benzodiazepine to enhance the complexation efficiency, further comprising formulating the cyclodextrin-benzodiazepine complex thus obtained into a form suitable for administration to said animal, raising the pH level with base to above the pH level for the complexation, and administering said form.  
     
     
         48 . A method for enhancing the availability of a benzodiazepine following administration of a cyclodextrin-benzodiazepine complex to a warm-blooded animal in need of same, said method comprising complexing said benzodiazepine with a cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methylated α-cyclodextrin, methylated β-cyclodextrin, methylated γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, β-cyclodextrin sulfobutyl ether, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, α-cyclodextrin carboxymethyl ether, β-cyclodextrin carboxymethyl ether and γ-cyclodextrin carboxymethyl ether, in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of at least 1% by weight of said benzodiazepine to enhance the complexation efficiency, further comprising detecting the presence of the ring-opened form of said benzodiazepine, and administering the cyclodextrin-benzodiazepine complex thus obtained to said animal.  
     
     
         49 . A method for enhancing the availability of a benzodiazepine following administration of a cyclodextrin-benzodiazepine complex to a warm-blooded animal in need of same, said method comprising complexing said benzodiazepine with a cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methylated α-cyclodextrin, methylated β-cyclodextrin, methylated γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-γ-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, β-cyclodextrin sulfobutyl ether, hydroxyethyl-β-cyclodextrin, hydroxyethyl-y-cyclodextrin, α-cyclodextrin carboxymethyl ether, β-cyclodextrin carboxymethyl ether and y-cyclodextrin carboxymethyl ether, in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of about 50% or more by weight of said benzodiazepine to enhance the complexation efficiency, further comprising administering the cyclodextrin-benzodiazepine complex thus obtained to said animal.  
     
     
         50 . A method according to  claim 45 , wherein the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam or loprazolam.  
     
     
         51 . A method according to  claim 47 , wherein the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temezepam or loprazolam.  
     
     
         52 . A method according to  claim 45 , wherein the benzodiazepine is complexed with hydroxypropyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, β-cyclodextrin, γ-cyclodextrin or hydroxypropyl-γ-cyclodextrin.  
     
     
         53 . A method according to  claim 47 , wherein the benzodiazepine is complexed with hydroxypropyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, β-cyclodextrin, γ-cyclodextrin or hydroxypropyl-γ-cyclodextrin.  
     
     
         54 . A method according to  claim 45 , wherein the complexation is conducted at a pH level between about 3 and about 5.  
     
     
         55 . A method according to  claim 47 , wherein the complexation is conducted at a pH level between about 3 and about 5.  
     
     
         56 . A method according to  claim 47 , further comprising formulating the cyclodextrin-benzodiazepine complex thus obtained as an aqueous solution or a hydrogel.  
     
     
         57 . A method according to  claim 47 , wherein said benzodiazepine is selected from the group consisting of midazolam, alprazolam, clonazepam, lorazepam and triazolam and further comprising formulating the cyclodextrin-drug complex thus obtained as an aqueous solution.  
     
     
         58 . A method according to  claim 57 , further comprising formulating the aqueous solution to be at a pH level of below about 4.7 and administering it as a nasal spray.  
     
     
         59 . A method according to  claim 58 , wherein the pH level of the nasal spray is between about 3 and about 4.7.  
     
     
         60 . A method according to  claim 47 , further comprising complexing said benzodiazepine with said cyclodextrin in the presence of from about 0.001 to about 5% (weight/volume) of a pharmacologically inactive, pharmaceutically acceptable water-soluble polymer at a temperature of from about 30° C. to about 150° C.  
     
     
         61 . A method according to  claim 48 , further comprising complexing said benzodiazepine with said cyclodextrin in the presence of from about 0.001 to about 5% (weight/volume) of a pharmacologically inactive, pharmaceutically acceptable water-soluble polymer at a temperature of from about 30° C. to about 150° C.  
     
     
         62 . A method according to  claim 49 , further comprising complexing said benzodiazepine with said cyclodextrin in the presence of from about 0.001 to about 5% (weight/volume) of a pharmacologically inactive, pharmaceutically acceptable water-soluble polymer at a temperature of from about 30° C. to about 150° C.  
     
     
         63 . A method for enhancing the availability of a benzodiazepine following administration of a cyclodextrin-benzodiazepine complex to a warm-blooded animal in need of same, said method comprising complexing said benzodiazepine with β-cyclodextrin sulfobutyl ether in an aqueous medium at a pH level below about 5 and allowing the resultant complexation medium to equilibrate for sufficient time to effect chemically reversible ring-opening of 50% or more by weight of said benzodiazepine to enhance the complexation efficiency, removing the water from the aqueous complexation medium after formation of the cyclodextrin-benzodiazepine complex, and administering the cyclodextrin-benzodiazepine complex thus obtained to said animal.  
     
     
         64 . A method according to  claim 63 , wherein the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam or loprazolam.  
     
     
         65 . A method according to  claim 63 , wherein the benzodiazepine is midazolam, alprazolam, clonazepam, lorazepam or triazolam.