Acylated cyclodextrin derivatives

Details Acylated cyclodextrin derivatives Acylated cyclodextrin derivatives

1999-04-08

2001-03-20

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S778000, C514S784000, C514S785000, C525S054200, C530S300000, C530S307000, C530S311000, C530S813000, C530S815000, C530S817000, C536S046000, C536S048000, C536S103000, C536S119000

Reexamination Certificate

active

06204256

ABSTRACT:

BACKGROUND OF THE INVENTION
In 1904, Schardinger first characterized cyclodextrins as cyclic oligosaccharides. The &agr;, &bgr;, and &ggr;-cyclodextrins, which consist of six, seven, and eight glucose units, respectively, are the most common natural cyclodextrins.
Cyclodextrins have been used as inclusion complexes by complexing with a guest compound or molecule as a host compound or molecule. Such inclusion complexes have been used to mask the bitter taste or unpleasant odor of a guest compound, to solubilize a hardly soluble guest compound, to enlarge the stability of a guest compound against heat, light, or air, to stabilize emulsions, or as a sustained release preparation using a hydrophobic alkylated cyclodextrin. See U.S. Pat. No. 4,869,904. However, no one has attempted to make carboxyacylated cyclodextrins, or used such cyclodextrin derivatives to form ionic sustained release compositions.
SUMMARY OF THE INVENTION
In one aspect, the present invention features a cyclodextrin derivative, wherein at least 60 (e.g., between 75 and 100) percent of the free hydroxy groups of the cyclodextrin are acylated with acyl groups where at least one of the acyl groups comprises a free carboxylic group. What is meant by cyclodextrin is a cyclic oligosaccharide. Examples of cyclodextrins include &agr;-cyclodextrin, &bgr;-cyclodextrin, or &ggr;-cyclodextrin.
In one embodiment the acyl groups are selected from COE
1
, where E
1
is selected from the group consisting of C
2-32
carboxy alkyl, C
3-33
carboxy alkenyl, C
7-37
carboxyaryl, C
8-38
carboxyaryl alkyl, and C
9-39
carboxyaryl alkenyl, and COE
2
, where E
2
is selected from the group consisting of C
1-30
alkyl, C
2-30
alkenyl, C
6-36
aryl, C
7-37
arylalkyl, and C
8-38
arylalkenyl, wherein at least one of the acyl group is COE
1
.
In a further embodiment, between 10 and 80 (e.g., between 30 and 80) percent of the free hydroxy groups of the cyclodextrin are acylated with COE
1
and between 10 and 80 (e.g., between 15 and 60) percent of the cyclodextrin are acylated with COE
2
. In still a further embodiment, E
1
is C
2-10
carboxy alkyl (e.g., COE
1
is CO(CH
2
)
n
COOH (where n=2-3)) and E
2
is C
1-10
alkyl (e.g., COE
2
is CO(CH
2
)
n
CH
3
(where n=0-5)).
In another aspect, the invention features a copolymer comprising the cyclodextrin derivative described above, wherein the cyclodextrin derivative comprises at least one free hydroxy group which is acylated with a polyester comprising hydroxy acid monomers. In one embodiment, the copolymer has an average molecular weight of between 500-40,000 daltons (e.g., 500-10,000). In a further embodiment, the polyester comprises hydroxy acid monomers selected from the group consisting of lactic acid, glycolic acid, hydroxy caprolic acid, or any optically active isomer thereof. Such polyesters can be manufactured by reacting said cyclodextrin derivative with lactide, glycolide, caprolactone, p-dioxanone, trimethyl carbonate, or any optically active isomer thereof.
In still another aspect, the invention features a composition comprising the cyclodextrin derivative described above and a drug, the drug comprising at least one effective ionogenic amine, wherein at least 50 percent, by weight, of the drug present in the composition is ionically bonded to the cyclodextrin derivative. In one embodiment, the composition comprises between 1 and 30 (e.g., between 10 and 20) percent, by weight, of the drug. In a further embodiment, the drug is a polypeptide. In still a further embodiment, the polypeptide comprises between 4 and 200 amino acids (e.g., between 4 and 50 amino acids). Examples of the polypeptide include somatostatin, bombesin, calcitonin, amylin, parathyroid hormone, parathyroid hormone related protein, gastrin releasing peptide, luteinizing hormone releasing hormone, growth hormone, growth hormone releasing factor, interferons, erythropoietin, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, pituitary adenylate cyclase activating polypeptide, vasoactive intestinal peptide, thyrotropin releasing hormone, corticotropin releasing hormone, Acetyl-Ser-Asp-Lys-Pro, arginine vasopressin, angiotensin, and any fragments, agonists, or antagonists thereof.
In yet another aspect, the invention features a composition comprising the copolymer described above and a drug, the drug comprising at least one effective ionogenic amine, wherein at least 50 percent, by weight, of the polypeptide present in the composition is ionically bonded to the cyclodextrin derivative. In one embodiment, the composition comprises between 1 and 30 (e.g., between 10 and 20) percent, by weight, of the drug. In a further embodiment, the drug is a polypeptide.
As used herein, “lower alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, sec-butyl, and the like. “Lower alkenyl” groups include those branched and straight chain aliphatic hydrocarbon groups having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, and the like. All alkyl, alkenyl, and alkynyl groups are noncyclic.
As used herein, “aryl” is intended to include any stable monocyclic, bicyclic, or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthreynl, and the like. The term “carboxy” is meant to include the recited chemical group (e.g., alkyl, alkenyl, aryl, arylalkyl, arylalkenyl) substituted with 1 to 3 carboxy groups.
Other features and advantages of the present invention will be apparent from the detailed description of the invention, and from the claims.
DESCRIPTION OF THE INVENTION
It is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference.


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