Cyclodextrin complexes of benzodiazepines

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C514S219000, C514S220000, C536S046000, C536S103000, C540S569000

Reexamination Certificate

active

06699849

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
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.
2. Background Art
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 (&agr;-1,4)-linked &agr;-D-glucopyranose units, with a somewhat lipophilic central cavity and a hydrophilic outer surface. The most common naturally occurring cyclodextrins are &agr;-cyclodextrin, &bgr;-cyclodextrin and &ggr;-cyclodextrin consisting of 6, 7 and 8 glucopyranose units, respectively. Of these three derivatives, &bgr;-cyclodextrin appears to be the most useful pharmaceutical complexing agent due to its cavity size, availability, low cost and other properties.
The natural cyclodextrins, in particular &bgr;-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 &bgr;-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 &bgr;-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.
Cyclodextrin derivatives of current pharmaceutical interest include the hydroxypropyl derivatives of &agr;-, &bgr;- and &ggr;-cyclodextrin, sulfoalkylether cyclodextrins such as sulfobutylether &bgr;-cyclodextrin, alkylated cyclodextrins such as the randomly methylated &bgr;-cyclodextrin, and various branched cyclodextrins such as glucosyl- and maltosyl-&bgr;-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)).
Preparation of Cyclodextrin Inclusion Complexes
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)).
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 &bgr;-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° 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° C.
Methods for Enhancing Cyclodextrin Complexation
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)).
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
0
) times the stability constant of the drug-cyclodextrin complex (K
C
). In aqueous cyclodextrin solutions saturated with drug, the concentration of free drug ([D]) is approximately equal to S
0
. Thus, increased complexation efficiency can be obtained by either increasing S
0
or by increasing K
C
or by increasing both simultaneously. Addition of organic solvents, such as ethanol,

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Cyclodextrin complexes of benzodiazepines does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Cyclodextrin complexes of benzodiazepines, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclodextrin complexes of benzodiazepines will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-3246759

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.