The United States of America As Represented by the Department of Health

Other

The United States of America As Represented by the Secretary of

Leland Stanford Junior University

University of Florida Research Foundation, Incorporated

Children's Medical Center Corporation

Josef Pitha

Bengt Lindberg

Kaneto Uekama

Tetsumi Irie

Thomas Wimmer

Stephen J Peroutka

C Trinadha Rao

Mitchell Harman

Thomas O Carpenter

Juan J Torres-Labandeira

Stephen P Baker

John W Kusiak

Certain mixtures of cyclodextrin derivatives, which were synthesized in mildly basic conditions, can be separated into mixtures that crystallize easily and mixtures of similar composition, which remain amorphous. Thus, it is possible to obtain the particular advantages of crystalline and/or amorphous state components from one reaction product. Both crystalline and amorphous components of the product have good ability to form inclusion complexes.

Crystalline mixtures of partial methyl ethers of beta-cyclodextrin and related compounds

A method is disclosed for the potentiation of formation of inclusion complexes of electroneutral and anionic compounds. Included are compositions containing complexes of two different cyclodextrin species. New complexes containing as guest molecules active agents which have been first converted to salts are also disclosed.

Potentiation of inclusion complex formation of cyclodextrin derivatives

The preparation of compositions containing cyclodextrin moieties which are modified by fusing 1,4 dioxane rights to glucopyranosyl residues is described. These compositions are suited as carrier for pharmaceuticals, agricultural chemicals and

Dioxane-substituted cyclodextrin macromolecules and inclusion complexes

By controlling basicity of the reaction, is possible to alkylate preferentially the secondary hydroxyls of cyclodextrins. These hydroxyls surround the principal, wide, entry into the cyclodextrin cavity and, thus, their substitution by suitably chosen substituents can improve the formation of inclusion complexes. By methods of the invention, cyclodextrin derivatives substituted with fused 1,4-dioxane ring(s) can be obtained. If a reagent with one alkylating moiety is used, a mixture of ethers of cyclodextrin is formed. Using methods of this invention, up to 96% of the substitution can be directed to the secondary hydroxyls.

Alkylations of cyclodextrins leading to derivatives which have a

By controlling basicity of the reaction, it is possible to alkylate preferentially the secondary hydroxyls of cyclodextrins. These hydroxyls surround the principal, wide, entry into the cyclodextrin cavity and, thus, their substitution by suitably chosen substituents can improve the formation of inclusion complexes. By methods of the invention, cyclodextrin derivatives substituted with fused 1,4-dioxane ring(s) can be obtained. If a reagent with one alkylating moiety is used, a mixture of ethers of cyclodextrin is formed. Using methods of this invention, up to 96% of the substitution can be directed to the secondary hydroxyls.

Selective alkylations of cyclodextrins leading to derivatives which have

The invention relates to cyclodextrin glycosides and processes for their preparation. The cyclodextrin glycosides according to the invention are cyclodextrins substituted by 2-acetamido-2-deoxyaldoses. These cyclodextrin glycosides are prepared by a process which is characterized in that cyclodextrins are reacted with 2-acetamido-2-deoxyaldoses in an anhydrous acid medium and the reaction products are then treated with a mild base. The cyclodextrin glycosides can be used for solubilization of substances which are sparingly soluble or insoluble in water.

Cyclodextrin glycosides and processes for their preparation

Compounds that selectively bind 5-HT.sub.1A receptors in preference to other 5-HT receptors are provided along with methods for their use. Such compounds have the formula ##STR1## wherein A is an aromatic group selected to provide, with the glycidyl residue that forms the next portion of the molecule, a 5-HT-like portion of the molecule that represents the primary binding site of the molecule with a 5-HT receptor: X represents a quarternary carbon and its attached alkyl groups: Y represents a hydrocarbon linking group: Z represents hydrogen or an organic group containing up to 12 carbon and/or heteroatoms in its skeletal structure: and R.sup.1 and R.sup.2 independently represent hydrogen or an alkyl group. The aromatic group is most preferably indole or an indole derivative.

Method for relieving anxiety using

A process for producing monosubstituted alpha-, beta-, and gamma-cyclodextrins includes the step of condensing an excess of a cyclodextrin with an epoxide under alkaline conditions. A process for increasing the solubility of cyclodextrins includes the step of reacting a cyclodextrin with an amine under heterogenous catalytic conditions, or subjecting the cyclodextrin to sulfatation. Compositions useful in these processes include one containing at least one cyclodextrin, ammonia and Raney nickel, and a second composition containing at least one cyclodextrin, chlorosulfonic acid and pyridine.

Preparation of specifically substituted cyclodextrins

The dissolution of lipophilic compounds in aqueous solutions of hydroxypropylcyclodextrins can be accelerated by the addition of co-solubilizers, such as ethanol or ammonia, which again can be removed, together with water, by evaporation or by freeze-drying leaving lipophile: hydroxypropylcyclodextrin complexes as a residue. The co-solubilizer method was used successfully with steroid drugs (5-androstene-3.beta.,17.beta.-diol, 4-androstene-3,17-dione, dehydroepiandrosterone, dexamethasone, 5-.alpha.-dihydro-testosterone, 6-methylprednisolone, and testosterone), peptides (gramicidin S) and a macrocyclic antibiotic (amphotericin B). The complexes prepared in this manner were amorphous and possessed satisfactory stability.

Preparation of lipophile:hydroxypropylcyclodextrin complexes by a method

Alkylating analogs of prazosin were synthesized and found to compete with nanomolar potency at .sup.3 H-prazosin binding sites of rat tissues. The compounds were found to be irreversible ligands at .sup.3 H-prazosin binding sites, and denoted a subtype of alpha.sub.1 -adrenoceptors.

Prazosin analog with increased selectivity and duration of action

A method for obtaining a desired pattern of substitution of hydroxyalkyl groups on cyclodextrins which comprises controlling the basicity of a reaction mixture comprising epoxide and cyclodextrins and a suitable solvent. Through the proper control of basicity with, e.g., sodium hydroxide, hydroxyalkyl substitution may be directed either toward the narrow or wide opening of the cavity of cyclodextrins.

Regioselective substitutions in cyclodextrins

Beta-agonist carbostyril derivatives having the formula ##STR1## wherein X may be the ortho, meta or para position and is selected from the group consisting of halogen, amino and substituted and unsubstituted lower alkanoylamino having from 1 to 6 carbon atoms and pharmaceutically acceptable salts and complexes thereof.

Beta-agonist carbostyril derivatives, assay method and pharmacological

Crystalline complexes of steroid hormones with gamma-cyclodextrin are prepared by mixing the components together. Tablets can be formed from the complexes, which can be administered by contact with the mucosa to provide effective transfer of the hormones into the systemic circulation, gradually eliminating the hormones therefrom.

Administration of steroid hormones

Levels of cholesterol, vitamin A, triglycerides, and other lipophiles in the human circulation can be manipulated by intravenous infusion of cyclodextrin-type compounds. The cyclodextrin-type compound should be highly soluble in water, amorphous and of only moderate molecular weight in order to be easily excreted; one preferred cyclodextrin, 2-hydroxypropyl-.beta.-cyclodextrin with an average molecular weight of 1460, is administered at doses of 0.5 g/kg x day. The serum levels of the lipophiles indicate that the infusion may serve to mobilize the lipophile from tissues, induce its excretion, and furthermore affect its homeostasis.

Method of enhancing lipophile transport using cyclodextrin derivatives

The invention comprises pharmaceutical preparations consisting generally of a drug with a substantially low water solubility and an amorphous, water-soluble cyclodextrin-based mixtures. In these preparations a stable amorphous state can be achieved. This improves the dissolution properties of the drug and hence its absorption by the body. The required cyclodextrin-based mixtures were prepared from .alpha.-, .beta.-, or .gamma.-cyclodextrin which were rendered amorphous through non-selective alkylation. The alkylation agents suitable for that purposes are exemplified by propylene oxide, glycidol, iodoacetamide, chloroacetate, or 2-diethylaminoethylchloride; their reactions with cyclodextrins were performed in a manner to yield mixtures containing many components, a circumstance which effectively prevents crystallization processes within the above pharmaceutical preparation.

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Baltimore, MD, United States of America

Josef Pitha