Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-12-16
2002-11-12
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S103000, C536S124000, C525S054240
Reexamination Certificate
active
06479467
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a new composition of matter which comprises epoxybutene (EpB) derivatives of cyclodextrins (HBenCD) or mixed ethers of cyclodextrins where at least one of the ether substituents is EpB (HBenRCD where R is an ether substituent other than EpB). This invention also relates to two novel processes for the preparation of cyclodextrin ethers. This invention further relates to inclusion complexes formed between HBenCD or HBenRCD and guest molecules. Such inclusion complexes are useful in pharmaceutical, cosmetic and food applications. Furthermore, this invention relates to the incorporation of HBenCD or HBenRCD or their inclusion complexes in thermoplastic materials, textiles or membranes.
BACKGROUND OF THE INVENTION
Cyclodextrins (CD) are cyclic oligomers of glucose which typically contain 6, 7, or 8 glucose monomers joined by &agr;-1,4 linkages. These oligomers are commonly called &agr;-CD, &bgr;-CD, and &ggr;-CD, respectively. Higher oligomers containing up to 12 glucose monomers are known, but their preparation is more difficult.
Those skilled in the art of modifying cyclodextrins will understand that there are a number of ways to indicate the extent to which a cyclodextrin molecule has been modified. Each glucose unit of the cyclodextrin has three hydroxyls available at the 2, 3, and 6 positions. Hence, &agr;-cyclodextrin has 18 hydroxyls or 18 substitution sites available and can have a maximum degree of substitution (DS) of 18. Similarly, &bgr;- and &ggr;-cyclodextrin have a maximum DS of 21 and 24, respectively.
It should be noted that at less than full substitution, there will be a distribution of substituted CD molecules in the reaction product. At a low DS, some of the CD molecules potentially will have no substituents. The reported DS will reflect the average value of this distribution.
Topologically, CD can be represented as a toroid in which the primary hydroxyls are located on the smaller circumference, and the secondary hydroxyls are located on the larger circumference. Because of this arrangement, the interior of the torus is hydrophobic while the exterior is sufficiently hydrophilic to allow the CD to be dissolved in water. This difference between the interior and exterior faces allows the CD to act as a host molecule and to form inclusion complexes with guest molecules, provided the guest molecule is of the proper size to fit in the cavity. The CD inclusion complex can then be dissolved in water thereby providing for the introduction of insoluble or sparingly soluble guest molecule into an aqueous environment. This property makes CD particularly useful in the pharmaceutical, cosmetic and food industries. Reviews of CD complexes can be found in
Chem. Rev.,
1997, 97, 1325-1357 and in
Supramolecular Chemistry,
1995, 6, 217-223.
The production of CD involves first treating starch with an &agr;-amylase to partially lower the molecular weight of the starch followed by treatment with an enzyme known as cyclodextrin glucosyl transferase which forms the cyclic structure. By conducting the reaction in the presence of selected organic compounds, e.g., toluene, crystalline CD complexes can be formed which facilitate isolation of CD with predetermined ring size. This process has been extensively reviewed by Szejtli et al.,
Compr. Supramol. Chem.,
1996, 3, 41-56. This process yields the native CD discussed above. Table 1 provides a summary of selected physical properties of cyclodextrins.
TABLE 1
Physical Properties of &agr;-, &bgr;-, and &ggr;-CD.
Property
&agr;-CD
&bgr;-CD
&ggr;-CD
No. of Glucose Units
6
7
8
MW (anhydrous)
972
1135
1297
Solubility (water, g/100 ml, 25° C.)
14.5
1.9
23.2
Optical Rotation &agr;
D
(H
2
O)
150.5
162.0
177.4
Approximate Cavity Diameter (Angstroms)
5.2
6.6
8.4
As seen in Table 1, there is an unexpected drop in solubility in water for &bgr;-CD relative to the &agr;- and &ggr;-CD. This is most unfortunate as &bgr;-CD has a highly desirable cavity size and is the most abundant CD available. Many investigators have found that this difficulty can be somewhat overcome by preparing derivatives with low DS (typically lower than 7).
Although many CD derivatives are known, ethers prepared by displacement of halides (U.S. Pat. No. 4,638,058) or by opening of epoxides (U.S. Pat. No. 4,727,064) are preferred. In special cases, the ether may be polyhydroxylated (EP 486445 A2). Preferred methods of ether formation via epoxide opening are disclosed in U.S. Pat. Nos. 3,459,731 and 4,727,064. The preferred epoxides are ethylene oxide (EO) and propylene oxide (PO). It is important to note that opening of the epoxide generates a new primary hydroxyl (from EO) or secondary hydroxyl (from PO). These newly formed hydroxyls can, in turn, react with epoxide, as well, to form oligomeric side chains. Such derivatives are characterized by molar substitution (MS), which is the total number of epoxide groups attached to the cyclodextrin. Because of chain extension, MS can exceed the DS. Other than the hydroxyls formed by opening of the epoxide, these side chains do not contain functionality suitable for further reactions. Investigators have sought to overcome this limitation by incorporation of anionic or cationic groups as part of the starting epoxide (U.S. Pat. No. 3,453,257).
In addition to their utility in the pharmaceutical, cosmetic, and food industries, CD has begun to find utility in the plastic and textile industries. For example, U.S. Pat. No. 5,603,974 discloses a barrier film composition comprised of a thermoplastic and a substituted CD. It was necessary that the CD be substituted in order to obtain sufficient compatibility with the thermoplastic. The invention further required that the substituted CD be “substantially free of an inclusion complex” meaning that a large fraction of the dispersed CD derivative in the film did not contain a guest molecule. This film acts as a barrier to permeants such as water, aliphatic and aromatic hydrocarbons, carboxylic acids, aldehydes, and the like.
Similarly, WO97/30122 discloses a thermoplastic/CD composition for rigid polymer beverage bottles. The preferred thermoplastic is polyethylene terephthalate (PET), and the preferred CD derivatives are acetylated and trimethylsilylated CD. Like U.S. Pat. No. 5,603,974, this invention requires that a guest molecule not be hosted by the CD prior to compounding.
In EP 186,146, the formation of CD complexes with perfumes, insecticides, or fungicides and their incorporation into polyethylene are disclosed. JP 88-265,926 discloses transparent plastics containing slow-release inclusion complexes prepared by mixing polyesters with maltosyl CD complexes of perfumes, insecticides, and the like. The maltosyl CD complexes were reported to give greater transparency than the corresponding complexes prepared from &agr;-, &bgr;-, or &ggr;-CD.
JP 01-149,884 discloses sustained-release insecticides, air fresheners, deodorants, etc. in the form of sheet, tape or fiber. Mixing the appropriate CD complex with a plastic material and a water-absorbing polymer forms these sustained-release materials. JP 02-240,166 discloses the preparation and application of complexes of CD and deodorants in the manufacture of plastic products like trash bags.
3,4-Epoxy-1-butene (EpB) is formed by the monoepoxidation of butadiene (U.S. Pat. No. 4,897,498). Ring opening of this epoxide with a lower aliphatic alcohol under acidic conditions leads to the formation of 2-alkoxy-3-butene-1-ols. Under basic conditions, formation of 1-alkoxy-3-butene-2-ols is favored. These butenols can be further reacted with acrylic or methacrylic acids to form acrylic esters, which may be used in subsequent polymerization reactions (U.S. Pat. No. 2,504,082).
Also, the reaction of 3,4-epoxy-1-butene with an oxygen nucleophile in the presence of a Pd(0) complex catalyst leads to the formation of 1,4-dioxy-2-butenes (U.S. Pat. No. 5,189,199). Furthermore, polymerization of 3,4-epoxy-1-butene in the presence of tetrahydrofuran, an acid catalyst, and a nucleophilic initiator provides for the forma
Buchanan Charles M.
Dixon, Jr. Daniel W.
Lambert Juanelle L.
Offerman Ricky J.
Wood Matthew D.
Blake Michael J.
Eastman Chemical Company
Graves, Jr. Bernard J.
Maier Leigh C.
Wilson James O.
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