U.S. patent application number 10/750940 was filed with the patent office on 2004-09-23 for high-energy cyclodextrin complexes.
Invention is credited to Loftsson, Thorsteinn, Masson, Mar, Stefansson, Einar.
Application Number | 20040186075 10/750940 |
Document ID | / |
Family ID | 31720016 |
Filed Date | 2004-09-23 |
United States Patent
Application |
20040186075 |
Kind Code |
A1 |
Loftsson, Thorsteinn ; et
al. |
September 23, 2004 |
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.
Inventors: |
Loftsson, Thorsteinn;
(Reykjavik, IS) ; Masson, Mar; (Reykjavik, IS)
; Stefansson, Einar; (Reykjavik, IS) |
Correspondence
Address: |
BURNS DOANE SWECKER & MATHIS L L P
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Family ID: |
31720016 |
Appl. No.: |
10/750940 |
Filed: |
January 5, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10750940 |
Jan 5, 2004 |
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09250185 |
Feb 16, 1999 |
|
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6699849 |
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60075544 |
Feb 23, 1998 |
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Current U.S.
Class: |
514/58 ;
536/46 |
Current CPC
Class: |
C08B 37/0015 20130101;
B82Y 5/00 20130101; A61K 47/6951 20170801 |
Class at
Publication: |
514/058 ;
536/046 |
International
Class: |
A61K 031/724; C08B
037/16 |
Claims
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 .beta.-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 .beta.-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 .beta.-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 .beta.-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 .beta.-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 .beta.-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 .beta.-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 .beta.-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 .beta.-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.degree. C.
to about 150.degree. 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 .beta.-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 .beta.-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.degree. C.
to about 150.degree. 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
.beta.-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 .beta.-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 .alpha.-cyclodextrin, .beta.-cyclodextrin,
.gamma.-cyclodextrin, methylated .alpha.-cyclodextrin, methylated
.beta.-cyclodextrin, methylated .gamma.-cyclodextrin,
hydroxypropyl-.alpha.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin, maltosyl-.alpha.-cyclodextrin,
maltosyl-.beta.-cyclodextrin, maltosyl-.gamma.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether,
hydroxyethyl-.alpha.-cyclodextrin,
hydroxyethyl-.gamma.-cyclodextrin, .alpha.-cyclodextrin
carboxymethyl ether, .beta.-cyclodextrin carboxymethyl ether and
.gamma.-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 .alpha.-cyclodextrin, .beta.-cyclodextrin,
.gamma.-cyclodextrin, methylated .alpha.-cyclodextrin, methylated
.beta.-cyclodextrin, methylated .gamma.-cyclodextrin,
hydroxypropyl-.alpha.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin, maltosyl-.alpha.-cyclodextrin,
maltosyl-.beta.-cyclodextrin, maltosyl-.gamma.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether,
hydroxyethyl-.beta.-cyclodextrin,
hydroxyethyl-.gamma.-cyclodextrin, .alpha.-cyclodextrin
carboxymethyl ether, .beta.-cyclodextrin carboxymethyl ether and
.gamma.-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 .alpha.-cyclodextrin, .beta.-cyclodextrin,
.gamma.-cyclodextrin, methylated .alpha.-cyclodextrin, methylated
.beta.-cyclodextrin, methylated .gamma.-cyclodextrin,
hydroxypropyl-.alpha.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin, maltosyl-.alpha.-cyclodextrin,
maltosyl-.beta.-cyclodextrin, maltosyl-.gamma.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether,
hydroxyethyl-.beta.-cyclodextrin,
hydroxyethyl-.gamma.-cyclodextrin, .alpha.-cyclodextrin
carboxymethyl ether, .beta.-cyclodextrin carboxymethyl ether and
.gamma.-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 .alpha.-cyclodextrin, .beta.-cyclodextrin,
.gamma.-cyclodextrin, methylated .alpha.-cyclodextrin, methylated
.beta.-cyclodextrin, methylated .gamma.-cyclodextrin,
hydroxypropyl-.alpha.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin, maltosyl-.alpha.-cyclodextrin,
maltosyl-.beta.-cyclodextrin, maltosyl-.gamma.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether,
hydroxyethyl-.beta.-cyclodextrin,
hydroxyethyl-.gamma.-cyclodextrin, .alpha.-cyclodextrin
carboxymethyl ether, .beta.-cyclodextrin carboxymethyl ether and
.gamma.-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 .alpha.-cyclodextrin, .beta.-cyclodextrin,
.gamma.-cyclodextrin, methylated .alpha.-cyclodextrin, methylated
.beta.-cyclodextrin, methylated .gamma.-cyclodextrin,
hydroxypropyl-.alpha.-cyclodextrin,
hydroxypropyl-.alpha.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin, maltosyl-.alpha.-cyclodextrin,
maltosyl-.beta.-cyclodextrin, maltosyl-.gamma.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether,
hydroxyethyl-.beta.-cyclodextrin, hydroxyethyl-y-cyclodextrin,
.alpha.-cyclodextrin carboxymethyl ether, .beta.-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-.beta.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether, .beta.-cyclodextrin,
.gamma.-cyclodextrin or hydroxypropyl-.gamma.-cyclodextrin.
53. A method according to claim 47, wherein the benzodiazepine is
complexed with hydroxypropyl-.beta.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether, .beta.-cyclodextrin,
.gamma.-cyclodextrin or hydroxypropyl-.gamma.-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.degree. C. to about 150.degree. 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.degree. C. to about 150.degree. 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.degree. C. to about 150.degree. 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 .beta.-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.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of copending U.S. patent
application Ser. No. 09/250,185, filed Feb. 16, 1999, now allowed,
which claims the priority of U.S. Provisional Patent Application
No. 60/075,544, filed Feb. 23, 1998, both of which are incorporated
by reference herein in their entireties and relied upon.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to methods for enhancing the
complexation of a heterocyclic drug with cyclodextrin and to
methods for enhancing the availability of a heterocyclic drug
following administration of a cyclodextrin-drug complex.
[0004] 2. Background Art
[0005] Cyclodextrins are a group of structurally related
saccharides which are formed by enzymatic cyclization of starch by
a group of amylases termed glycosyltransferases. Cyclodextrins are
cyclic oligosaccharides, consisting of (.alpha.-1,4)-linked
.alpha.-D-glucopyranose units, with a somewhat lipophilic central
cavity and a hydrophilic outer surface. The most common naturally
occurring cyclodextrins are .alpha.-cyclodextrin,
.beta.-cyclodextrin and .gamma.-cyclodextrin consisting of 6, 7 and
8 glucopyranose units, respectively. Of these three derivatives,
.beta.-cyclodextrin appears to be the most useful pharmaceutical
complexing agent due to its cavity size, availability, low cost and
other properties.
[0006] The natural cyclodextrins, in particular
.beta.-cyclodextrin, have limited aqueous solubility and their
complex formation with lipophilic drugs often results in
precipitation of solid drug-cyclodextrin complexes. Thus, the
solubility of .beta.-cyclodextrin in water is only about 18.5 mg/ml
at room temperature. This low aqueous solubility is, at least
partly, associated with strong intramolecular hydrogen bonding in
the cyclodextrin crystal lattice. Substitution of any of the
hydrogen bond-forming hydroxyl groups, even by hydrophobic moieties
such as methoxy groups, will increase the aqueous solubility of
.beta.-cyclodextrin. In addition, since these manipulations
frequently produce large numbers of isomeric products, chemical
modification can transform the crystalline cyclodextrins into
amorphous mixtures increasing their aqueous solubility.
[0007] Cyclodextrin derivatives of current pharmaceutical interest
include the hydroxypropyl derivatives of .alpha.-, .beta.- and
.gamma.-cyclodextrin, sulfoalkylether cyclodextrins such as
sulfobutylether .beta.-cyclodextrin, alkylated cyclodextrins such
as the randomly methylated .beta.-cyclodextrin, and various
branched cyclodextrins such as glucosyl- and
maltosyl-.beta.-cyclodextrin (T. Loftsson and M. E. Brewster,
"Cyclodextrins as pharmaceutical excipients", Pharm. Technol. Eur.,
9(5), 26-34 (1997); T. Loftsson and M. E. Brewster, "Pharmaceutical
applications of cyclodextrins. I. Drug solubilization and
stabilization", J. Pharm. Sci. 85(10), 1017-1025 (1996); R. A.
Rajewski and V. J. Stella, "Pharmaceutical applications of
cyclodextrins. 2. In vivo drug delivery", J. Pharm. Sci. 85(11),
1142-1169 (1996); T. Irie and K. Uekama, "Pharmaceutical
applications of cyclodextrins. 3. Toxicological issues and safety
evaluation", J. Pharm. Sci., 86(2), 147-162 (1997); V. J. Stella
and R. A. Rajewski, "Cyclodextrins: their future in drug
formulation and delivery", Pharm. Res., 14(5), 556-567 (1997); T.
Loftsson, "Increasing the cyclodextrin complexation of drugs and
drug bioavailability through addition of water-soluble polymers",
Pharmazie, 53, 733-740 (1998)).
[0008] Preparation of Cyclodextrin Inclusion Complexes
[0009] In aqueous solutions, cyclodextrins form complexes with many
drugs through a process in which the water molecules located in the
central cavity are replaced by either the whole drug molecule, or
more frequently, by some lipophilic portion of the drug structure.
Once included in the cyclodextrin cavity, the drug molecules may be
dissociated through complex dilution, by replacement of the
included drug by some other suitable molecule (such as dietary
lipids or bile salts in the GI tract) or, if the complex is located
in close approximation to a lipophilic biological membrane (such as
the mucosal membrane of the GI tract), the drug may be transferred
to the matrix for which it has the highest affinity. Importantly,
since no covalent bonds are formed or broken during the
drug-cyclodextrin complex formation, the complexes are in dynamic
equilibrium with free drug and cyclodextrin molecules (R. A.
Rajewski and V. J. Stella, "Pharmaceutical applications of
cyclodextrins. 2. In vivo drug delivery", J. Pharm. Sci. 85(11),
1142-1169 (1996)).
[0010] Various methods have been applied to the preparation of
drug-cyclodextrin complexes (T. Loftsson and M. E. Brewster,
"Pharmaceutical applications of cyclodextrins. I. Drug
solubilization and stabilization", J. Pharm. Sci. 85(10), 1017-1025
(1996); T. Loftsson and M. E. Brewster, "Cyclodextrins as
pharmaceutical excipients", Pharm. Technol. Eur., 9(5), 26-34
(1997)). In solution, the complexes are usually prepared by
addition of an excess amount of the drug to an aqueous cyclodextrin
solution. The suspension formed is equilibrated (for periods of up
to one week at the desired temperature) and then filtered or
centrifuged to form a clear drug-cyclodextrin complex solution.
Since the rate determining step in complex formation is often the
phase to phase transition of the drug molecule, it is sometimes
possible to shorten this process by formation of supersaturated
solutions through sonication followed by precipitation. For
preparation of the solid complexes, the water is removed from the
aqueous drug-cyclodextrin solutions by evaporation or sublimation,
e.g. spray-drying or freeze-drying. Other methods can also be
applied to prepare solid drug-cyclodextrin complexes including
kneading methods, co-precipitation, neutralization and grinding
techniques. In the kneading method, the drug is added to an aqueous
slurry of a poorly water-soluble cyclodextrin such as
.beta.-cyclodextrin. The mixture is thoroughly mixed, often at
elevated temperatures, to yield a paste which is then dried. This
technique can frequently be modified so that it can be accomplished
in a single step with the aid of commercially available mixers
which can be operated at temperatures over 100.degree. C. and under
vacuum. The kneading method is a cost-effective means for preparing
solid cyclodextrin complexes of poorly water-soluble drugs.
Co-precipitation of a cyclodextrin complex through addition of
organic solvent is also possible. Unfortunately, the organic
solvents used as precipitants can interfere with complexation which
makes this approach less attractive than the kneading method.
However, we have discovered that some organic solvents under some
specific conditions, e.g. 10% (v/v) aqueous acetic acid solution,
can enhance the complexation. Solid complexes of ionizable drugs
can sometimes be prepared by the neutralization method wherein the
drug is dissolved in an acidic (for basic drugs) or basic (for
acidic drugs) aqueous cyclodextrin solution. The solubility of the
drug is then lowered through appropriate pH adjustments (i.e.
formation of the unionized drug) to force the complex out of
solution. Finally, solid drug-cyclodextrin complexes can be formed
by the grinding of a physical mixture of the drug and cyclodextrin
and then heating the mixture in a sealed container to 60 to
90.degree. C.
[0011] Methods for Enhancing Cyclodextrin Complexation
[0012] For a variety of reasons including cost, production
capabilities and toxicology, the amounts of cyclodextrin which can
be used in most drug formulations is limited (T. Loftsson and M. E.
Brewster, "Cyclodextrins as pharmaceutical excipients", Pharm.
Technol. Eur., 9(5), 26-34 (1997); T. Loftsson, "Increasing the
cyclodextrin complexation of drugs and drug bioavailability through
addition of water-soluble polymers", Pharmazie, 53, 733-740
(1998)).
[0013] If one drug molecule (D) forms a complex with one
cyclodextrin molecule (CD), then the complexation efficiency
([D-CD]/[CD]) will be equal to the intrinsic solubility of the drug
(S.sub.0) times the stability constant of the drug-cyclodextrin
complex (K.sub.C). In aqueous cyclodextrin solutions saturated with
drug, the concentration of free drug ([D]) is approximately equal
to S.sub.0. Thus, increased complexation efficiency can be obtained
by either increasing S.sub.0 or by increasing K.sub.C or by
increasing both simultaneously. Addition of organic solvents, such
as ethanol, to the aqueous complexation media can result in
enhanced complexation efficiency through increase in S.sub.0. Drug
ionization can increase the complexation efficiency through
increase in S.sub.0. Addition of certain low molecular weight
acids, such as acetic, citric, malic, or tartaric acid, to aqueous
complexation media can enhance cyclodextrin solubilization of basic
drugs through increase in S.sub.0 (i.e. salt formation, pH changes
and lowering melting point) and/or increase in the apparent
K.sub.C. Water-soluble polymers can increase the complexation
efficiency through increase in the apparent K.sub.C. Furthermore,
it is often possible to enhance cyclodextrin complexation even
further by using several different methods simultaneously to
enhance the cyclodextrin complexation. Pharmaceutical applications
of these and other methods have been reviewed (See T. Loftsson,
"Increasing the cyclodextrin complexation of drugs and drug
bioavailability through addition of water-soluble polymers",
Pharmazie, 53, 733-740 (1988); T. Loftsson and M. E. Brewster,
"Cyclodextrins as pharmaceutical excipients", Pharm. Technol. Eur.,
9(5), 26-34 (1997); T. Loftsson and M. E. Brewster, "Pharmaceutical
applications of cyclodextrins. I. Drug solubilization and
stabilization", J. Pharm. Sci. 85(10), 1017-1025 (1996)).
[0014] Permeability of Drugs Through Biological Membranes
[0015] The cyclodextrin molecules are relatively large (molecular
weight ranging from almost 1000 to over 1500), with a hydrated
outer surface, and under normal conditions, cyclodextrin molecules
will only permeate biological membranes with considerable
difficulty (R. A. Rajewski and V. J. Stella, "Pharmaceutical
applications of cyclodextrins. 2. In vivo drug delivery", J. Pharm.
Sci. 85(11), 1142-1168 (1996); T. Irie and K. Uekama,
"Pharmaceutical applications of cyclodextrins. 3. Toxicological
issues and safety evaluation", J. Pharm. Sci. 86(2), 147-162
(1997); K. -H. Fromming and J. Szejtli, Cyclodextrins in pharmacy,
Kluwer Academic Publishers, Dordrecht, The Netherlands, 1994; T.
Loftsson and J. H. lafsson, "Cyclodextrins: new drug delivery
systems in dermatology", Int. J. Dermatol., 37, 241-246 (1998); T.
Loftsson and E. Stefnsson, "Effect of cyclodextrins on topical drug
delivery to the eye", Drug Dev. Ind. Pharm. 23(5), 473-481 (1997)).
It is generally recognized that cyclodextrins act as true carriers
by keeping the hydrophobic drug molecules in solution and deliver
them to the surface of the biological membrane, e.g. skin, mucosa
or the eye cornea, where they partition into the membrane. The
relatively lipophilic membrane has low affinity for the hydrophilic
cyclodextrin molecules and therefore they remain in the aqueous
membrane exterior, e.g. the aqueous vehicle system, salvia or the
tear fluid. Conventional penetration enhancers, such as alcohols
and fatty acids, disrupt the lipid layers of the biological
barrier. Cyclodextrins, on the other hand, act as penetration
enhancers by increasing drug availability at the surface of the
biological barrier. Furthermore, addition of water-soluble polymer,
such as polyvinylpyrrolidone, apparently increase even further the
availability of the drug molecules at the surface of the biological
membrane resulting in enhanced drug bioavailability (T. Loftsson,
"Increasing the cyclodextrin complexation of drugs and drug
bioavailability through addition of water-soluble polymers",
Pharmazie, 53, 733-740 (1998); T. Loftsson, M. Masson and E.
Stefnsson, "Cyclodextrins as Permeation enhancers", Proceedings of
the 17.sup.th Pharmaceutical Technology Conference and Exhibition,
Volume 2, Dublin, 24-26 March, 1998, pp. 313-324).
OBJECTS AND SUMMARY OF THE INVENTION
[0016] Enhancing Complexation Efficiency
[0017] It is possible to enhance the cyclodextrin (CD) complexation
efficacy, or efficiency, of drugs (D), and other "guest" molecules,
by either increasing the apparent stability constant (K.sub.C) of
the drug-cyclodextrin complex (D-CD) or increasing the apparent
intrinsic solubility (S.sub.0) of the drug. For example, K.sub.C
can be increased by addition of water-soluble polymers to the
aqueous complexation media and S.sub.0 can be increased by
ionization of the drug molecule, as described previously. However,
increased complexation efficiency by itself does not necessarily
result in increased drug availability in the aqueous complexation
media or increased drug availability from solid drug-cyclodextrin
complexes. On the other hand, if the drug-cyclodextrin complexes
are prepared under conditions which ensure enhanced complexation
and if the complexation efficiency decreases upon administration,
then enhanced drug availability will be observed. Thus, the present
invention involves: i) enhancement of the complexation efficiency
and ii) reduction of the complexation efficiency after
administration. For example, it is possible to enhance the
complexation efficiency of many ionizable drugs by preparing the
complexes at a pH where the drug is ionized but obtain decreased
efficiency upon administration due to pH changes and consequent
decreased ionization. One example of such a drug is phenyloin (pKa
8.1). Its solubility in water at room temperature (25.degree. C.)
is only 18 .mu.g/ml at pH 5 and 32 .mu.g/ml at pH 8 (P. A.
Schwartz, C. T. Rhodes and J. W. Cooper, "Solubility and ionisation
characters of phenyloin", J. Pharm. Sci., 66, 994-997 (1977)).
Addition of 25% (w/v) 2-hydroxypropyl-.beta.-cyclodextri- n to the
aqueous solutions increases the solubility of phenyloin to 5.0
mg/ml at pH 5 and 6.4 mg/ml at pH 8, which is 280- and 200-fold
solubility enhancement, respectively. Although the apparent
stability constant (K.sub.C) of the phenyloin-cyclodextrin complex
is much larger for the drug in the unionized form than for the
anionic form, it is possible to obtain much higher total solubility
by increasing the apparent intrinsic solubility (S.sub.0) of the
drug (T. Loftsson and N. Bodor, "Effects of
2-hydroxypropyl-.beta.-cyclodextrin on the aqueous solubility of
drugs and transdermal delivery of 17.beta.-estradiol", Acta Pharm.
Nord., 1, 185-194 (1989)). However, if the pH 8.0 solution was
placed in an environment which would decrease the pH from 8 to 5
(e.g. topical application to the skin), then a supersaturated
solution would be formed which would result in enhanced drug
availability (e.g. it would result in enhanced transdermal drug
delivery). Other means to enhance S.sub.0 include reversible
derivation (e.g. prodrug formation) of the guest molecule and
addition of certain low molecular weight acids. The value of
K.sub.C can, for example, be increased by addition of certain low
molecular weight acids, by addition of water-soluble polymers to
the aqueous complexation media or by using mixed solvent systems
such as aqueous 10% (v/v) acetic acid. For example, addition of the
polymers and heating in an autoclave (to 120-140.degree. C. for
20-40 minutes) does not only increase the complexation but it has
also been shown to enhance transdermal and transcorneal drug
delivery (T. Loftsson and A. M. Sigurdardottir, "Cyclodextrins as
skin penetration enhancers", in J. Szejtli and L. Szente (Eds.)
Proceedings of the Eighth International Symposium on Cyclodextrins,
Kluwer Academic Publishers, 1996, pp. 403-406; T. Loftsson and E.
Stefansson, "Effect of cyclodextrins on topical drug delivery to
the eye", Drug Devel. Ind. Pharm., 23(5), 473-481 (1997)). As shown
in TABLE 1 below, it is not enough to add the polymers to the
complexation medium. Addition of polymers to the unheated vehicles
did not enhance the transdermal delivery of enalaprilat. However,
heating the vehicles after addition of the polymers resulted in
significant enhancement. The effect of the polymers on the
transdermal delivery of enalaprilat can, at least partly, be
explained by decreased complexation efficiency (i.e. decrease in
K.sub.C) at the skin surface.
1TABLE 1 The effect of heating on transdermal delivery of
enalaprilat from 10% (w/v) HP.beta.CD solutions at pH 5.0
containing 2.5% enalaprilat in a suspension. The concentration of
dissolved enalaprilat was between 2.0 and 2.3% (w/v). Donor phase
Flux (mg h.sup.-1 cm.sup.-2) (w/v per cent) Un-heated Heated Ratio
HP.beta.CD 18 .+-. 2 -- -- HP.beta.CD, 0.25% PVP 16 .+-. 6 23 .+-.
7 1.4 HP.beta.CD, 0.10% HPMC 14 .+-. 3 37 .+-. 12 2.6
[0018] In one aspect of the present invention there is provided a
method for enhancing the complexation efficacy, i.e. efficiency, of
a drug with cyclodextrin, said drug having a structure comprising
at least one heterocyclic ring having a total of from 4 to 7 ring
atoms, of which from 1 to 3 are hetero ring atoms, each of said
hetero ring atoms being selected from nitrogen, oxygen and sulfur,
said ring being a cyclic imine, enamine, lactone, lactam,
thiolactam, anhydride, imide, hemiacetal or hemiketal, said method
comprising subjecting said drug to chemically reversible
ring-opening so that at least a portion (at least 0.1% by weight)
thereof is in ring-opened form, and complexing said drug with
cyclodextrin.
[0019] In a related aspect of the invention, there is provided a
method for enhancing the complexation efficiency of a drug with
cyclodextrin, said drug having a structure comprising at least one
heterocyclic ring having a total of from 4 to 7 ring atoms, of
which from 1 to 3 are hetero ring atoms, each of said hetero ring
atoms being selected from nitrogen, oxygen and sulfur, said ring
being a cyclic imine, enamine, lactone, lactam, thiolactam,
anhydride, imide, hemiacetal or hemiketal, said method comprising
complexing said drug with cyclodextrin in an aqueous medium under
conditions which effect chemically reversible ring-opening of at
least a portion (at least 0.1% by weight) of said drug.
[0020] In another aspect of the invention, there is provided a
method for enhancing the availability of a drug following
administration of a cyclodextrin-drug complex to a warm-blooded
animal in need of same, said drug having a structure comprising at
least one heterocyclic ring having a total of from 4 to 7 ring
atoms of which from 1 to 3 are hetero ring atoms, each of said
hetero ring atoms being selected from nitrogen, oxygen and sulfur,
said ring being a cyclic imine, enamine, lactone, lactam,
thiolactam, anhydride, imine, hemiacetal or hemiketal, said method
comprising complexing said drug with cyclodextrin in an aqueous
medium under conditions which effect chemically reversible
ring-opening of at least a portion (at least 0.1% by weight) of
said drug to enhance the complexation efficiency, followed by
administering the cyclodextrin-drug complex thus obtained to said
animal under conditions which reduce the complexation
efficiency.
[0021] In still another aspect, the present invention provides a
method for enhancing the availability of a basic drug (i.e. a
proton acceptor) following administration of a cyclodextrin-drug
complex to a warm-blooded animal in need of same, said basic drug
having a structure comprising at least one heterocyclic ring having
a total of from 4 to 7 ring atoms, of which from 1 to 3 are hetero
ring atoms, each of said hetero ring atoms being selected from
nitrogen, oxygen and sulfur, said ring being a cyclic imine,
enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal
or hemiketal, said method comprising subjecting said basic drug to
complexation in an aqueous medium at a pH level below the pKa+2
value of said basic drug to enhance the complexation efficiency,
followed by administering the cyclodextrin-drug complex thus
obtained to said animal under conditions which reduce the
complexation efficiency.
[0022] In yet another aspect, the present invention provides a
method for enhancing the availability of an acidic drug following
administration of a cyclodextrin-drug complex to a warm-blooded
animal in need of same, said acidic drug having a structure
comprising at least one heterocyclic ring having a total of 4 to 7
ring atoms, of which from 1 to 3 are hetero ring atoms, each of
said hetero ring atoms being selected from nitrogen, oxygen and
sulfur, said ring being a cyclic imine, enamine, lactone, lactam,
thiolactam, anhydride, imide, hemiacetal or hemiketal, said method
comprising subjecting said acidic drug to complexation in an
aqueous medium at a pH level above the pKa-2 value of said acidic
drug to enhance the complexation efficiency, followed by
administering the cyclodextrin-drug complex thus obtained to said
animal under conditions which reduce the complexation
efficiency.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a graph illustrating the effect of pH on the
phase-solubility of phenyloin (pKa 8.1) in aqueous
hydroxypropyl-.alpha.-cyclodextrin (HP.beta.CD) solutions at
25.degree. C. at pH 10.19 (.diamond-solid.); pH 7.55 (.box-solid.)
and pH 2.74 (.circle-solid.);
[0024] FIG. 2 is a graph illustrating the effect of pH on the
solubility of alprazolam (pKa 2.4) in aqueous 10% (w/v) HP.beta.CD
solutions at room temperature;
[0025] FIG. 3 is a graph illustrating the effect of pH (i.e. the
diazepine ring-opening) on the solubility of midazolam (pKa 6.2) in
pure aqueous buffer solutions (.circle-solid.), aqueous buffer
solutions containing 10% (w/v) HP.beta.CD (.box-solid.) and aqueous
buffer solutions containing both 10% (w/v) HP.beta.CD and 0.10%
(w/v) hydroxypropyl methylcellulose (HPMC) (.diamond-solid.) at
room temperature;
[0026] FIG. 4 is a graph illustrating the effects of cyclodextrins,
pH and 10% (v/v) acetic acid on the solubility of midazolam in
aqueous solutions: pure aqueous buffer solution (.tangle-solidup.);
aqueous 10% (v/v) acetic acid solution (.circle-solid.); 10% w/v
HP.beta.CD solution containing 0.10% (w/v) HPMC in aqueous 10%
(v/v) acetic acid solution (.box-solid.); 10% (w/v) aqueous
sulfobutyl ether-.beta.-cyclodextrin (SBE.beta.CD) solution in
aqueous 10% (v/v) acetic acid solution (.diamond-solid.); and
[0027] FIG. 5 is a graph plotting the concentration in ng/ml of
midazolam in serum after intravenous administration of 2 mg of a
commercial intravenous formulation of midazolam (.largecircle.) and
nasal administration of 4.8 mg of a nasal formulation of midazolam
prepared in accord with the present invention (.DELTA.), against
time in minutes, where each point represents the mean value and
error bars represent standard deviation.
DETAILED DESCRIPTION OF THE INVENTION
[0028] The expression "cyclodextrin" as used herein means .alpha.-,
.beta.- or .gamma.-cyclodextrin or a derivative thereof. The
following table (TABLE 2) lists .alpha.-cyclodextrin derivatives,
.beta.-cyclodextrin derivatives and .gamma.-cyclodextrin
derivatives for use in the present invention.
2TABLE 2 Some of the currently available cyclodextrins obtained by
substitution of the OH-groups located on the edge of the
cyclodextrin ring. Since both the number of substituents and their
location will affect the physicochemical properties of the
cyclodextrin molecules, such as their aqueous solubility and
complexing abilities, each derivative listed should be regarded as
a group of closely related cyclodextrin derivatives.
.alpha.-Cyclodextrin .beta.-Cyclodextrin .gamma.-Cyclodextrin Type
derivatives derivatives derivatives Alkylated: Methyl Methyl Methyl
Ethyl Butyl Butyl Butyl Pentyl Hydroxylalkylated: 2-Hydroxypropyl
Hydroxyethyl Hydroxyethyl 2-Hydroxypropyl 2-Hydroxypropyl
2-Hydroxybutyl Esterified: Acetyl Acetyl Acetyl Propionyl Butyryl
Succinyl Succinyl Succinyl Benzoyl Palmityl Toluenesulfonyl
Esterified and alkylated: Acetyl methyl Acetyl butyl Branched:
Glucosyl Glucosyl Glucosyl Maltosyl Maltosyl Maltosyl Ionic:
Carboxymethyl ether Carboxymethyl ether Carboxymethyl ether
Carboxymethyl ethyl Phosphate ester Phosphate ester Phosphate ester
3-Trimethylammonium- 2-hydroxypropyl ether Sulfobutyl ether
Polymerized: Simple polymers Simple polymers Simple polymers
Carboxymethyl Carboxymethyl Carboxymethyl
[0029] Particularly preferred cyclodextrins for use herein are
hydroxypropyl-.alpha.-cyclodextrin, .beta.-cyclodextrin sulfobutyl
ether, the branched .beta.-cyclodextrins (especially
glucosyl-.beta.-cyclodextri- n and maltosyl-.beta.-cyclodextrin),
.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin and
.gamma.-cyclodextrin.
[0030] In preferred aspects of the present invention, the drug for
use herein is one having a structure comprising at least one
heterocyclic ring. The heterocyclic ring generally has a total of 4
to 7 ring atoms, of which from 1 to 3 are hetero ring atoms. While
each hetero ring atom can be nitrogen, oxygen or sulfur,
heterocycles having at least one nitrogen or oxygen ring atom are
preferred. Preferably, the drug has at least one heterocyclic ring
which is a cyclic imine, enamine, lactone, lactam, thiolactam,
anhydride, imide, hemiacetal or hemiketal.
[0031] Especially desirable drugs for use in accord with the
present invention are benzodiazepines. Benzodiazepines contain a
benzene ring fused with a diazepine ring which is a 7-membered ring
with nitrogen atoms in positions 1 and 4. By way of example, the
chemical name of alprazolam is
8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodi-
azepine, the chemical name of midazolam is
8-chloro-6-(2-fluorophenyl)-1-m-
ethyl-4H-imidazo[1,5-a][1,4]benzodiazepine and that of triazolam is
8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazep-
ine. Thus, all of these compounds have the 1,4-benzodiazepine
structure with a double bond between nitrogen atom number 4 and
carbon atom number 5 (which gives the molecule a cyclic imine
structure). The benzodiazepines are cyclic imines. They are all
basic, i.e. they are proton acceptors. Preferred benzodiazepines
for use herein are alprazolam, brotizolam, chlordiazepoxide,
clobazam, clonazepam, clorazepam, demoxazepam, flumazenil,
flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam,
nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam,
triazolam, temazepam and lorazolam. Especially preferred are
midazolam, alprazolam, clonazepam, lorazepam and triazolam.
[0032] Another group of preferred drugs for use herein consists of
the barbituric acid derivatives. The barbituric acids contain a
2,4,6-trihydroxypyrimidine (also called
2,4,6-trioxohexahydropyrimidine) ring in their structure, a
6-member ring with nitrogen in positions 1 and 3. Thus, the
chemical name of barbital is 5,5-diethyl-2,4,6(1H,3H,5H)-pyr-
imidinetrione and that of phenobarbital is
5-ethyl-5-phenyl-2,4,6(1H,3H,5H- )-pyrimidinetrione. The barbituric
acids can be characterized as cyclic amides or lactams (cyclic
amides are called lactams) or imides (which are nitrogen analogues
of cyclic anhydrides). Barbituric acids are weak acids. Preferred
barbituric acid derivatives are barbital, butobarbital,
amobarbital, phenobarbital, aprobarbital, secobarbital,
crotylbarbital, cyclobarbital, phenobarbital, hexobarbital,
methylphenobarbital, thiopental, isopropylbromallylbarbituric acid,
cyclohexenylallylthiobarbi- turic acid and their salts. Thiopental
is 5-ethyldihydro-5-(1-methylbutyl)- -2-thioxo-4,6(1H,
5H)-pyrimidinedione, i.e. one .dbd.O moiety in the barbituric acid
structure has been replaced by .dbd.S.
[0033] Yet another group of preferred drugs for use in the present
invention consists of the hydantoins. Hydantoins are, like
barbituric acids, cyclic urea derivatives. The ring-opened acyl
derivatives of hydantoins and barbituric acids are sometimes called
ureides. Both hydantoins and barbituric acids can form urea upon
hydrolysis. Hydantoins contain a 2,4-imidazolidinedione ring in
their structure, a 5-membered ring with nitrogen in positions 1 and
3. The chemical name of, for example, phenyloin, is
5,5-diphenyl-2,4-imidazolidinedione. Hydantoins are closely related
to barbituric acids and are acids like them.
[0034] Still another group of preferred drugs for use in the
present invention consists of pyrazole derivatives. The expression
"pyrazole derivatives" as used herein includes drugs containing a
pyrazole ring, 3-pyrazoline ring or pyrazolidine ring in their
structure, all of which are 5-membered rings with nitrogens in
positions 1 and 2. These compounds are either basic or acidic.
Preferred pyrazole derivatives for use herein include phenazone,
phenylphenazone, metamidazole, phenylbutazone, oxyphenbutazone and
sulfinpyrazone.
[0035] Yet another group of drugs preferred for use herein consists
of imidazole derivatives. The expression "imidazole derivatives" as
used herein includes drugs containing an imidazole, imidazoline or
imidazolidine ring in their structure. These are 5-membered rings
with nitrogen atoms in positions 1 and 3. These compounds are
either basic or acidic. Preferred compounds of this type include
histamine, miconazole, pilocarpine, naphazoline and clonidine.
[0036] Another group of preferred drugs for use in this invention
are pyrimidine derivatives. These drugs contain a 6-membered ring
with nitrogen atoms in positions 1 and 3. These derivatives are
usually basic. Preferred pyrimidine derivatives include thiamine,
trimethoprim, orotic acid, methylthiouracyl and prothiouracyl.
[0037] Still another group of preferred drugs for use herein are
purine derivatives, which contain purine, that is,
imidazo(4,5-d)pyrimidine, in their structures. These drugs are
frequently basic but some of them are acidic. Preferred purine
derivatives include caffeine, theophylline, etophylline,
proxyphylline and theobromine.
[0038] Cyclic drugs having heterocyclic rings characterized as
enamines, lactones, lactams, thiolactams, anhydrides, imides,
imines, hemiacetals and hemiketals are thus appropriate for use in
preferred embodiments of the invention, in which ring opening of
the heterocyclic ring takes place.
[0039] In various aspects of the present invention, the drug is
subjected to chemically reversible ring-opening so that at least a
portion thereof is in ring-opened form. The portion in ring-opened
form is at least 0.1% by weight, preferably at least 1 or 2% by
weight, more preferably at least 5% by weight of said drug. In
aqueous formulations, the amount of drug in ring-opened form is
frequently from about 5 to about 10% by weight and usually no more
than about 50%. In solid formulations, the portion of drug in
ring-opened form can generally be much higher, frequently about 50%
or more, and sometimes even about 90 to 95%.
[0040] When the method of the invention comprises complexing the
drug with cyclodextrin in an aqueous medium under conditions which
effect chemically reversible ring-opening of at least a portion (at
least 0.1% by weight) of the drug, the complexation is
advantageously conducted at a pH level which affords ring-opening
of at least 5% by weight of said drug. Preferably the complexation
is conducted at a pH level of below about 5.
[0041] In one preferred embodiment, the drug is a basic drug,
especially a benzodiazepine, and the complexation is conducted at a
pH level of below about 5. It is also preferred that the
cyclodextrin is hydroxypropyl-.beta.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether, a branched
.beta.-cyclodextrin (especially glucosyl .beta.-cyclodextrin or
maltosyl-.beta.-cyclodextrin), .beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin or .gamma.-cyclodextrin. It is
also preferred that 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; and that
the cyclodextrin-drug complex thus obtained be formulated as a
nasal spray, sublingual tablet or parenteral solution, especially
when formulated suitable for use in producing a sedative,
anti-anxiety, anticonvulsant or muscle relaxant effect, most
especially as a pre-anaesthetic medication, or to supplement
anaesthesia, to induce and/or maintain anaesthesia or to induce a
hypnotic effect. In especially preferred embodiments, the
benzodiazepine is midazolam, alprazolam, clonazepam, lorazepam or
triazolam; the cyclodextrin is hydroxypropyl-.alpha.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether, a branched
.beta.-cyclodextrin (especially glucosyl .beta.-cyclodextrin or
maltosyl .beta.-cyclodextrin), .beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin or .gamma.-cyclodextrin; and the
complexation is conducted at a pH level below about 5, preferably
between about 3 and about 5.
[0042] In another embodiment of the present method utilizing
chemically reversible ring-opening described above, the drug is an
acidic drug.
[0043] In yet another embodiment of the present method utilizing
chemically reversible ring-opening described above, the drug is a
barbituric acid derivative, a hydantoin, a pyrazole derivative, an
imidazole derivative, a pyrimidine derivative or a purine
derivative. When the drug is a barbituric acid derivative, it is
preferably barbital, butobarbital, amobarbital, phenobarbital,
aprobarbital, secobarbital, crotylbarbital, cyclobarbital,
phenobarbital, hexobarbital, methylphenobarbital, thiopental,
isopropylbromallylbarbituric acid, or
cyclohexenylallylthiobarituric acid, or a salt thereof. When the
drug is a hydantoin, it is preferably phenyloin. When the drug is a
pyrazole derivative, it is preferably phenazone, propylphenazone,
metamidazole, phenylbutazone, oxyphenbutazone or sulfinpyrazone.
When the drug is an imidazole derivative, it is preferably
histamine, miconazole, pilocarpine, naphazoline or clonidine. When
the drug is a pyrimidine derivative, it is preferably thiamine,
trimethoprim, orotic acid, methylthiouracyl or prothiouracyl. When
the drug is a purine derivative, it is preferably caffeine,
theophylline, etophylline, proxyphylline or theobromine.
[0044] When the present invention comprises complexing the drug
with cyclodextrin in an aqueous medium under conditions which
effect chemically reversible ring-opening of at least a portion (at
least 0.1% by weight) of the drug to enhance the complexation
efficacy, followed by administering the cyclodextrin-drug complex
thus obtained to said animal under conditions which reduce the
complexation efficacy, the complexation is generally conducted at a
pH level which affords ring-opening of at least 5% by weight of the
drug. Preferably, the complexation is conducted at a pH level of
below about 5, especially between about 3 and about 5. The
cyclodextrin is preferably hydroxypropyl-.alpha.-cyclodextrin,
.beta.-cyclodextrin sulfobutyl ether, a branched
.beta.-cyclodextrin (especially glucosyl-.beta.-cyclodextrin or
maltosyl-.beta.-cyclodextrin)- , .beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin or .gamma.-cyclodextrin. The
drug is preferably a benzodiazepine, especially midazolam,
alprazolam, clonazepam, lorazepam or triazolam. The
cyclodextrin-drug complex is preferably administered in the form of
an aqueous solution or a hydrogel, particularly as a nasal spray or
nasal drops, or as a parenteral solution. As a nasal spray of a
benzodiazepine, the aqueous solution is advantageously brought to a
pH level of below about 6, preferably below about 4.7, most
especially to a pH between about 3 and about 4.7. When administered
as a solid, the cyclodextrin-drug complex is preferably formulated
as a tablet for oral, buccal or sublingual administration. The
water may be removed from the aqueous complexation medium after
formation of the cyclodextrin-drug complex.
[0045] When the present invention comprises subjecting a basic drug
to complexation in an aqueous medium at a pH level below the pKa+2
value of said basic drug to enhance the complexation efficiency,
followed by administering the cyclodextrin-drug complex thus
obtained to an animal under conditions which reduce the
complexation efficiency, the basic drug is preferably a
benzodiazepine. Benzodiazepines of particular interest are
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam,
midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam and
loprazolam. Particularly preferred benzodiazepines are alprazolam,
midazolam, clonazepam, lorazepam and triazolam. The
cyclodextrin-benzodiazepine complex obtained in the complexation
step is preferably formulated as a nasal spray, sublingual tablet
or parenteral solution, which is preferably administered in an
effective sedative, anti-anxiety, anticonvulsant or muscle relaxant
amount, particularly as a pre-anaesthetic medication, or to
supplement anaesthesia, to induce and/or maintain anaesthesia or to
induce a hypnotic effect. In this general aspect of the invention,
the pH level of the aqueous complexation medium is advantageously
selected so that it also affords ring-opening of at least 5% by
weight of the drug. For the benzodiazepines, the complexation is
preferably conducted at a pH level of below about 5, most
preferably between about 3 and about 5. Also in this general aspect
of the invention, in one preferred embodiment, the complexation is
carried out 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.degree. C. to about 150.degree. C. Preferably, the polymer is a
cellulose derivative or a polyvinyl polymer; more preferably, the
polymer is methylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, hydroxyethyl
methylcellulose, hydroxypropyl ethylcellulose, hydroxyethyl
ethylcellulose, sodium carboxymethylcellulose or
polyvinylpyrrolidone. An especially preferred cellulose derivative
is hydroxypropyl methylcellulose. A method for enhancing
drug-cyclodextrin complexation utilizing a pharmacologically
inactive water-soluble polymer is described in Loftsson U.S. Pat.
No. 5,324,718 and No. 5,472,954, both of which are incorporated by
reference herein in their entireties and relied upon. In another
preferred embodiment of this general aspect of the invention, the
complexation is also carried out in the presence of acetic acid
and/or one or more pharmaceutically acceptable salts of acetic
acid, the acetate=water ratio of the aqueous complexation medium
being from about 1:1000 to about 2:1, preferably from about 1:100
to about 1:1, more preferably from about 1:20 to about 1:4.
Preferably, the drug is midazolam and the cyclodextrin is
hydroxypropyl-.beta.-cyclodextrin, .beta.-cyclodextrin sulfobutyl
ether, a branched .beta.-cyclodextrin (especially
glucosyl-.beta.-cyclodextrin or maltosyl-.beta.-cyclodextrin)- ,
.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin or
.gamma.-cyclodextrin.
[0046] When the present invention comprises subjecting an acidic
drug to complexation in an aqueous medium at a pH level above the
pKa-2 value of said acidic drug to enhance the complexation
efficiency, followed by administering the cyclodextrin-drug complex
thus obtained to an animal under conditions which reduce the
complexation efficiency, preferably the pH level of the aqueous
complexation medium is selected such that it also affords
ring-opening of at least 5% by weight of said drug.
[0047] In order to further illustrate the present invention and the
advantages thereof, the following specific examples are given, it
being understood that same are intended only as illustrative and in
no way limitative of the invention.
EXAMPLE 1
[0048] Phenyloin (5,5-diphenylhydantoin) is a water-insoluble weak
acid (pKa 8.1) which forms a somewhat water-soluble anion in
alkaline solution. Solubility (S) of phenyloin at three different
pH levels was determined in aqueous solutions containing various
amounts of 2-hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD) of
molar substitution (MS)=0.9, i.e. (a) pH 2.74.+-.0.18 (SD), (b) pH
7.55.+-.0.12, and (c) pH 10.19.+-.0.14. Excess amount of the drug
was added to the aqueous HP.beta.CD solution and the suspension
formed sonicated for one hour at room temperature (23.degree. C.).
After equilibration at 25.degree. C. in a water-bath for three
days, the suspension was filtered through a 0.45 .mu.m membrane
filter, diluted with aqueous methanolic solution and the amount of
dissolved phenyloin determined by a high pressure liquid
chromatographic method (HPLC). FIG. 1 illustrates the effect of pH
on the phase-solubility of phenyloin (pKa 8.1) in aqueous
HP.beta.CD solutions at 25.degree. C. The results set forth in FIG.
1 show significant enhancement in the HP.beta.CD solubilization
(i.e. the efficiency of the complexation) of the drug at pH 10.19
(.diamond-solid.) where the drug is mainly in the ionized form.
Formation of phenyloin-HP.beta.CD complexes at pH 10.19 can result
in enhanced bioavailability of phenyloin. For example, topical
application of such a solution to the skin will result in lowering
of pH, which will decrease the efficiency of the complexation,
which again will result in enhanced permeability of phenyloin into
and through the skin. Also, formation of phenyloin-HP.beta.CD
complexes at pH of about 10 (e.g. in aqueous ammonia solutions) and
lyophilization of the complex will result in phenyloin-HP.beta.CD
complex powder which can, for example, be formulated into tablets.
The bioavailability of phenyloin from such tablets will be enhanced
compared to the phenyloin availability from tablets containing
phenyloin-HP.beta.CD complex prepared at lower pH, e.g. at pH 2.7
(.circle-solid.) or 7.6 (.box-solid.).
EXAMPLE 2
[0049] Alprazolam is a water-insoluble weak base (pKa 2.41) which
forms a somewhat water-soluble cation in acidic solution.
Solubility (S) of alprazolam at several different pH levels was
determined in aqueous solutions containing 10% (w/v)
2-hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD) of molar
substitution (MS)=0.3. Excess amount of the drug was added to the
aqueous HP.beta.CD solution and the suspension formed heated in a
sealed container in an autoclave (120-140.degree. C. for 20-40
minutes). After equilibration at room temperature (22-23.degree.
C.) for seven days, the suspension was filtered through a 0.45
.mu.m membrane filter, diluted with aqueous methanolic solution and
the amount of dissolved alprazolam determined by a high pressure
liquid chromatographic method (HPLC). FIG. 2 illustrates the effect
of pH on the solubility of alprazolam (pKa 2.4) in aqueous 10%
(w/v) HP.beta.CD solutions at room temperature. The results set
forth in FIG. 2 show significant enhancement in the HP.beta.CD
solubilization (i.e. the efficiency of the complexation) of the
drug at a pH at which the drug is mainly in the ionized form. The
sharp increase in the solubility can, however, only partly be
explained by the ionization of the alprazolam molecule.
EXAMPLE 3
[0050] Several drugs which have a nitrogen-containing heterocycle
in their structure are known to undergo reversible ring-opening
which frequently is pH dependent. For example, barbituric acids
undergo reversible ring cleavage (H. J. Roth, K. Eger and R.
Troschutz, Pharmaceutical Chemistry. Volume 2. Drug Analysis. Ellis
Horwood, 1991, pp. 308-309): 1
[0051] Another example of such reversible ring-opening is the
opening of cyclic imines through formation of an aldehyde or ketone
and a primary amine:
[0052] Another example of such reversible ring-opening is the
opening of cyclic imines through formation of an aldehyde or ketone
and a primary amine: 2
[0053] An example of such structure is the 1H-1,4-diazepine ring
which, for example, is an essential structure of the benzodiazepine
derivatives. These structural changes are pH-dependent and
reversible, and it is known that the open form frequently co-exists
with the closed one in several commercial products. One example is
the iv solution of midazolam (Dormicum.TM. from F. Hoffmann-LaRoche
& Ltd, Switzerland) where the drug is partly in the open form
(M. Gerecke, "Chemical structure and properties of midazolam
compared with other benzodiazepines", Br. J. Clin. Pharmac.,
11S-16S (1983)). However, the open form of midazolam is rapidly
converted to the closed one upon iv administration.
[0054] We have determined the effect of pH and cyclodextrins, i.e.
HP.beta.CD MS 0.3, sulfobutylether .beta.-cyclodextrin
(SBE.beta.CD) with degree of substitution (DS) 6.4,
.alpha.-cyclodextrin (.alpha.CD) and .gamma.-cyclodextrin
(.gamma.CD) on the ring-opening of several benzodiazepines. The
cyclodextrin concentration was 10% (w/v) and the benzodiazepine
concentration was 1.times.10.sup.4 M. The concentration of the
closed form was determined immediately after dissolving the
benzodiazepine in the aqueous cyclodextrin solution and again 24
hours later (i.e. after equilibration at 23.degree. C.).
Preliminary experiments had shown that equilibrium between the
closed and the open form was attained within 3 hours at 23.degree.
C.
[0055] It is clear from the results displayed in TABLE 3 below that
a large fraction of the benzodiazepines (over 50% at pH below 2)
are in the open form at low pH and that the fraction of open form
frequently increases upon addition of cyclodextrin to the aqueous
solution. For example, at pH 3 about 60% of alprazolam in aqueous
HP.beta.CD solution is in the open form. This will increase the
apparent intrinsic solubility (S.sub.0). This increase in S.sub.0
will result in enhanced complexation efficiency. The observed
increase in the complexation efficiency will result in enhanced
cyclodextrin solubilization of the benzodiazepines in aqueous
solutions.
3TABLE 3 The effect of pH and cyclodextrins on the fraction of the
open form of several benzodiazepines at room temperature (approx.
23.degree. C.). Benzodiazepine Cyclodextrin pH Fraction open
Alprazolam (pKa 2.4) None 2 0.82 3 0.56 4 0.33 HP.beta.CD 2 0.89 3
0.60 4 0.23 SBE.beta.CD 2 0.96 3 0.84 4 0.33 .alpha.CD 2 0.94 3
0.79 4 0.25 .gamma.CD 2 0.81 3 0.41 4 0.42 Diazepam (pKa 3.3) None
2 0.30 3 0.23 4 0.15 HP.beta.CD 2 0.65 3 0.29 4 0.15 SBE.beta.CD 2
0.63 3 0.56 4 0.22 .alpha.CD 2 0.67 3 0.51 4 0.13 .gamma.CD 2 0.41
3 0.17 4 0.13 Midazolam (pKa 6.2) None 2 0.74 3 0.28 4 0.18
HP.beta.CD 2 0.56 3 0.18 4 0.23 SBE.beta.CD 2 0.81 3 0.39 4 0.11
.alpha.CD 2 0.79 3 0.32 4 0.10 .gamma.CD 2 0.61 3 0.21 4 0.17
Triazolam None 2 0.53 (pKa between 2 and 3) 3 0.08 4 0.00
HP.beta.CD 2 0.51 3 0.09 4 0.00 SBE.beta.CD 2 0.71 3 0.25 4 0.00
.alpha.CD 2 0.75 3 0.23 4 0.00 .gamma.CD 2 0.33 3 0.01 4 0.00
EXAMPLE 4
[0056] Midazolam is a water-insoluble weak base (pKa 6.2) which
forms a somewhat water-soluble cation in acidic solution.
Solubility (S) of midazolam at several different pH levels was
determined in: a) pure aqueous buffer solutions (i.e. without
HP.beta.CD and HPMC); b) aqueous buffer solutions containing 10%
(w/v) 2-hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD) of molar
substitution (MS) 0.3; and c) aqueous solutions containing 10%
(w/v) 2-hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD) of molar
substitution (MS)=0.3 and 0.10% (w/v) hydroxypropyl methylcellulose
(HPMC) 4000. Excess amount of the drug was added to the aqueous
solution and the suspension formed was heated in a sealed container
in an autoclave (120-140.degree. C. for 20-40 minutes). After
equilibration at room temperature (22-23.degree. C.) for seven
days, the suspension was filtered through a 0.45 .mu.m membrane
filter, diluted with aqueous methanolic solution and the amount of
dissolved midazolam determined by a high pressure liquid
chromatographic method (HPLC). FIG. 3 illustrates the effect of pH
(i.e. the ring-opening) on the solubility of midazolam (pKa 6.2) in
pure aqueous buffer solutions (.circle-solid.), aqueous buffer
solutions containing 10% (w/v) HP.beta.CD (.box-solid.), and
aqueous buffer solutions containing both 10% (w/v) HP.beta.CD and
0.10% (w/v) HPMC (.diamond-solid.) at room temperature. The results
set forth in FIG. 3 show significant enhancement in the HP.beta.CD
solubilization (i.e. the efficiency of the complexation) of the
drug at pH levels where the drug exists partly in the open form.
Addition of HPMC significantly improves the efficiency.
EXAMPLE 5
[0057] Solubility (S) of midazolam at several different pH levels
was determined in: a) pure aqueous buffer solutions (i.e. without
cyclodextrin, polymer or acetic acid); b) aqueous buffer solutions
containing 10% (v/v) acetic acid as a co-solvent; c) aqueous buffer
solutions containing 10% (w/v) sulfobutylether .beta.-cyclodextrin
(SBE.beta.CD) and 10% (v/v) acetic acid as a co-solvent; and d)
aqueous buffer solutions containing 10% (w/v)
2-hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD), 0.10% (w/v)
hydroxypropyl methylcellulose (HPMC) and 10% (v/v) acetic acid as a
co-solvent. Excess amount of the drug was added to the aqueous
HP.beta.CD solution and the suspension formed was heated in a
sealed container in an autoclave (120-140.degree. C. for 20-40
minutes). After equilibration at room temperature (22-23.degree.
C.) for seven days, the suspension was filtered through a 0.45
.mu.m membrane filter, diluted with aqueous methanolic solution and
the amount of dissolved midazolam determined by a high pressure
liquid chromatographic method (HPLC). FIG. 4 illustrates the
effects of cyclodextrins, pH and 10% (v/v) acetic acid on the
solubility of midazolam in aqueous solutions: pure aqueous buffer
solution (.tangle-solidup.); aqueous 10% (v/v) acetate solution
(.circle-solid.); 10% (w/v) HP.beta.CD solution containing 0.10%
(w/v) HPMC in aqueous 10% (v/v) acetic acid solution
(.circle-solid.); 10% (w/v) aqueous SBE.beta.CD solution in aqueous
10% (v/v) acetate (.diamond-solid.). The results set forth in FIG.
4 show that addition of 10% (v/v) acetic acid significantly
improves the complexation. Addition of the acetic acid increases
the value of S.sub.0 without having any significant effect on the
value of K.sub.C, which significantly improves the complexation
efficiency and, consequently, enhances the cyclodextrin
solubilization of the drug. Midazolam carries a positive charge at
acidic pH and, thus, the negatively charged SBE.beta.CD forms a
more stable complex than the uncharged HP.beta.CD with midazolam at
these conditions. Addition of 10% (v/v) acetic acid as a co-solvent
resulted in a small decrease in the fraction of the open ring form
of the drug.
EXAMPLE 6
[0058] Female hairless mice were sacrificed by cervical dislocation
and their full-thickness skins removed. The outer surface of the
skin was rinsed with 35% (v/v) methanol in water and subsequently
with distilled water to remove any contamination. The skin was
placed in Franz diffusion cells. The receptor phase consisted of
phosphate buffer saline pH 7.4. The skin diffusion cells were
stirred with a magnetic bar and kept at 37.degree. C. by
circulating water through an external jacket. The donor phase (2.0
ml) consisted of a solution of the drug in aqueous 7% (w/v)
SBE.beta.CD solution pH 3.3, or aqueous cyclodextrin solution where
the pH had been raised from 3.3 to 4.1 (by addition of NaOH) before
it was applied to the skin. The alprazolam concentration in the
donor phase was 1.85 mg/ml at pH 3.3. Samples (200 .mu.l) of
receptor phase were removed from the cells at various time
intervals up to 48 hours and replaced with a fresh buffer solution.
The samples were kept frozen until analyzed by HPLC. The flux was
calculated from the linear part of each permeability profile and
the permeability coefficient obtained by dividing the flux with the
concentration of dissolved drug in the donor phase. The results set
forth in TABLE 4 show clearly that raising the pH from 3.3 to 4.1
increases the flux though biological membranes such as hairless
mouse skin.
4TABLE 4 The flux of alprazolam through hairless mouse skin. The
donor phase consisted of aqueous pH 3.3 buffer solution containing
7% (w/v) SBE.beta.CD saturated with the drug. In one case the pH of
the donor phase was kept constant at pH 3.3, but in the other case
the pH was raised to 4.1 (by addition of NaOH) before it was
applied to the skin. The alprazolam concentration in the donor
phase was 1.85 mg/ml at pH 3.3. Donor phase Flux (mg/cm.sup.2/h)
Ratio Without increasing the pH 3.91 .times. 10.sup.-4 1.0
Increasing the pH from 3.3 to 4.1 4.56 .times. 10.sup.-4 1.2
EXAMPLE 7
[0059] The effect of cyclodextrins and organic solvents on the rate
of diazepine ring-closure of several selected benzodiazepines was
investigated. Stock solutions containing 1.0.times.10.sup.-3 M of
the benzodiazepine in 0.10 M aqueous hydrochloric acid solution (pH
approx. 1.1) were prepared and stored at 37.0.degree. C. The
benzodiazepines were in the ring-open form in these stock
solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was
prepared. The observed first-order rate constant for the closing
(i.e. formation) of the benzodiazepine ring was determined in the
following reaction media: a) pure aqueous tris buffer solution; b)
aqueous tris buffer solution containing 10% (w/v) cyclodextrin; c)
tris buffer solution containing 10% (w/v) cyclodextrin and 10%
(v/v) ethanol (EtOH); d) tris buffer solution containing 10% (w/v)
cyclodextrin and 50% (v/v) EtOH; e) tris buffer solution containing
10% (w/v) cyclodextrin and 10% (v/v) dimethylsulfoxide (DMSO); and
f) tris buffer solution containing 10% (w/v) cyclodextrin and 50%
(w/v) DMSO. The stock solution (30 .mu.l) was added to 1.50 ml of
the reaction media which had previously been equilibrated to
37.0.degree. C. and the first-order rate constant for the
appearance of the closed form determined from the appearance of the
closed form as observed on HPLC. TABLES 5, 6 and 7 show the effects
of cyclodextrins, EtOH and DMSO on the observed first-order rate
constant for the regeneration of alprazolam, triazolam and
midazolam, respectively. In pure aqueous buffer solutions, addition
of EtOH and DMSO decreases somewhat the rate of ring closure, at
least in the case of alprazolam and midazolam. Addition of
cyclodextrin or the organic solvents have insignificant effect on
the pH under these conditions. The dielectric constant of the
reaction medium will, however, decrease upon addition of the
organic solvents. It is possible that this decrease in the
dielectric constant will reduce the ability of the reaction media
to stabilize the transition state which could explain the decrease
in the observed rate constant. Addition of cyclodextrin decreased
significantly, in all cases, the rate of ring closure. The
cyclodextrins formed stable complexes with the ring-open form of
the drug and, thus, the rate decreased upon addition of
cyclodextrin. Addition of EtOH or DMSO to the
cyclodextrin-containing reaction media resulted in increase in the
rate, compared to reaction media containing only cyclodextrin,
which could be due to decreased complexation of the diazepine
ring-open form. EtOH and DMSO will compete with the diazepine
ring-open form for a space in the cyclodextrin cavity resulting in
decreased complexation.
5TABLE 5 The effect of cyclodextrins, ethanol (EtOH) and
dimethylsulfoxide (DMSO) on the first-order rate constant for the
formation of the diazepine ring, i.e. regeneration of alprazolam,
at pH 7.5 and 37.degree. C. The observed first-order rate constant
.times. 10.sup.2 (min.sup.-1) Pure 10% 50% 10% 50% Cyclodextrin
water EtOH EtOH DMSO DMSO No CD 14.2 11.5 7.24 9.68 10.7 10%
RM.beta.CD 2.97 4.90 6.70 3.97 7.92 10% HP.beta.CD 3.30 5.23 7.07
4.44 8.57 10% SBE.beta.CD 3.11 5.18 5.82 4.77 9.36
[0060]
6TABLE 6 The effect of cyclodextrins, ethanol (EtOH) and
dimethylsulfoxide (DMSO) on the first-order rate constant for the
formation of the diazepine ring, i.e. regeneration of triazolam, at
pH 7.5 and 37.degree. C. The observed first-order rate constant
.times. 10.sup.-2 (min.sup.-1) Pure 10% 50% 10% 50% Cyclodextrin
water EtOH EtOH DMSO DMSO No CD 1.32 1.31 1.84 1.28 1.37 10%
RM.beta.CD 0.64 0.92 1.00 0.78 1.12 10% HP.beta.CD 0.66 0.92 1.02
0.79 1.14 10% SBE.beta.CD 0.58 0.82 0.97 0.73 1.13
[0061]
7TABLE 7 The effect of cyclodextrins, ethanol (EtOH) and
dimethylsulfoxide (DMSO) on the first-order rate constant for the
formation of the diazepine ring, i.e. regeneration of midazolam, at
pH 7.5 and 37.degree. C. The observed first-order rate constant
.times. 10.sup.-2 (min.sup.-1) Pure 10% 50% 10% 50% Cyclodextrin
water EtOH EtOH DMSO DMSO No CD 17.9 12.6 8.41 13.8 10.9 10%
RM.beta.CD 3.05 4.24 6.99 4.94 8.48 10% HP.beta.CD 2.77 3.86 6.53
3.36 8.40 10% SBE.beta.CD 1.30 3.30 6.50 2.24 8.55
EXAMPLE 8
[0062] The bioavailability of midazolam in a nasal spray according
to the invention was evaluated. The composition of the midazolam
nasal spray was as follows: midazolam 1.70% (w/v), sulfobutylether
.beta.-cyclodextrin sodium salt (Captisol.RTM.) 14.00% (w/v),
benzalkonium chloride 0.02% (w/v), sodium edetate (EDTA
tetrasodium) 0.10% (w/v), hydroxypropyl methylcellulose 0.10%
(w/v), phosphoric acid 0.50% (v/v), sodium hydroxide quantum satis
ad pH 4.35 in purified water. The intravenous (iv) dose was fixed
at 2 mg (Dormicum.TM. 5 mg/ml iv solution from F. Hoffmann-La Roche
& Ltd., Switzerland) but the intranasal (in) dose was 0.06
mg/kg or 4.84 mg (285 .mu.l nasal spray) on the average. This was a
cross-over study where each individual received both the iv and in
formulation (via nasal spray) with a one week resting period
between administrations. Serum samples were collected at various
time points after administration of the drug and the midazolam
concentration determined with an HPLC method. FIG. 5 illustrates
the concentration profile of midazolam in serum after
administration of 2 mg of midazolam intravenously (.largecircle.)
or 4.8 mg of midazolam intranasally (.DELTA.). Each point
represents the mean value; error bars represent standard deviation.
The bioavailability of midazolam after intranasal administration
was determined to be 61% and the mean C.sub.p.sup.max was
determined to be 52 ng/ml at 12 min after intranasal administration
of the drug. Sedation was not observed after the iv administration
but sedation was observed in all three individuals within 10 min
after intranasal administration of the drug. This sedation lasted
for about one and one-half hours. Insignificant irritation was
observed in the three individuals tested after intranasal
administration of the drug.
[0063] While the invention has been described in terms of various
preferred embodiments, the person skilled in the art will
appreciate that various modifications, substitutions, omissions and
changes can be made without departing from the spirit thereof.
Accordingly, it is intended that the scope of the present invention
be limited solely by the scope of the following claims, including
equivalents thereof.
* * * * *