Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-08-08
2003-06-10
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S488000, C514S524000
Reexamination Certificate
active
06576261
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the solubilization and stabilization of compounds using cyclodextrins.
BACKGROUND OF THE INVENTION
Cyclodextrins are a group of compounds consisting of, or derived from, the three parent cyclodextrins—alpha-, beta- and gamma-cyclodextrins. Cyclodextrins have numerous uses based on their ability to solubilize and complex chemicals.
Alpha-, beta- and gamma-cyclodextrins cyclodextrins are simple oligosaccharides consisting of six, seven or eight glucose residues, respectively, connected to macrocyles by alpha (1 to 4) glycosidic bonds. Each of the glucose residues of a cyclodextrin contains one primary (O6) and two secondary hydroxyls (O2 and O3) which can be substituted, for example, methylated. Many cyclodextrin preparations in practical use are mixtures of chemically individual derivatives in which only a part of hydroxyl groups were substituted and which differ in number and position of these substituents.
This invention uses many different cyclodextrin derivatives including several mixtures of partially methylated cyclodextrins. One composition is a commercial preparation (Wacker Chemie, Beta W7M1.8) in which the methyl substituents are about equally distributed between the primary and secondary hydroxyls of glucose residues; it is abbreviated here as RAMEB. A second class has methyls predominantly substituting for hydrogen at the secondary hydroxyls. These are prepared as described in U.S. Pat. No. 5,681,828 and are referred to as Pitha's methyl derivatives. A third type of methylated cyclodextrins is formed by those cyclodextrin derivatives or their mixtures that have more than half of their secondary hydroxyl groups (i.e., O2 and O3) methylated. For brevity, these are called “highly methylated cyclodextrins.” Other mixtures of cyclodextrin derivatives used in this work are partial 2-hydroxypropyl ethers, abbreviated as HPACD, HPBCD or HPGCD for derivatives of alpha-, beta- and gamma-cyclodextrins, respectively.
In addition to the mixtures described in the preceding paragraph, the invention also uses five chemically individual cyclodextrin derivatives: (1) fully methylated alpha-, beta- and gamma-cyclodextrins, abbreviated as TRIMEA, TRIMEB and TRIMEG, respectively, (2) dimethyl derivative of beta-cyclodextrin, DIMEB, in which all glucose residues carry methyl groups on O2 and O6, and (3) maltosyl derivative of beta-cyclodextrin, G2, in which beta-cyclodextrin carries maltosyl residue on O6. The compounds under (1) are of the group of highly methylated cyclodextrins and, like the highly methylated mixtures, have unique properties. Compounds under (2) and (3) do not belong to this group.
Cyclodextrins solubilize insoluble compounds into polar media by forming what is known as an inclusion complex between the cyclodextrin and the insoluble compound; cyclodextrin solubilization power is directly proportional to the stability of the complex. Inclusion complexes are non-covalent associations of molecules in which a molecule of one compound, called the host, has a cavity in which a molecule of another compound, called a guest is included. Derivatives of cyclodextrins are used as the hosts and the insoluble compound is the guest.
Although cyclodextrins and derivatives solubilize many compounds, they are not useful in all cases. For numerous compounds of general interest, cyclodextrins do not have sufficient solubilizing power to make their use practicable. Overcoming this defect requires using large amounts of host compound. However, this is not only uneconomical (making cyclodextrins too expensive for many applications), but also dangerous. Cyclodextrins in very large amounts can boost the effects of various toxicants potentially present outside and in the body itself (Horsky, J. & Pitha, J., J. Incl. Phen. & Mol. Rec. Chem., 18, 291-300, 1994).
Previous art relevant to the current invention discusses three areas of interest: a) highly methylated cyclodextrins, b) doubling cavity size by association of two cyclodextrin moieties and c) forming salts of guest compounds and choosing counterions when forming complexes between cyclodextrin hosts and ionic guests.
Previous art concerning modification of cyclodextrin hosts has been marginally concerned with highly methylated cyclodextrins. The reason for this lack of interest is that the most accessible compound of this group, TRIMEB, was found to be a weak host for several guests (J. Szejtli, Ccylodextrin Technology, Kluwer Academic Publishers, Dordrecht, 1988, p.56). TRIMEA, since it is a derivative of the smallest parent cyclodextrin, was assumed to have a too small cavity. See, for example, A. R. Hedges, Chem. Rev., 98, 2035-2044, 1998; K. Uekama et al., Chem. Rev., 98, 2045-2076, 1998; U.S. Pat. No. 4,687,738; Japanese Patent JP 10319587A; J. Szejtli, Cyclodextrin Technology, Kluwer Academic Publishers, Dordrecht, 1988 and references therein.
Previous art concerning doubling cavity size by using two cyclodextrin moieties relied on connection of these moieties by chemical (covalent) bonds. Specific chemical connection is required for such designs to be effective (K. Fujita et al., J. Chem. Soc. Chem. Commun., 1277-1278, 1984; R. Breslow et al., J. Amer. Chem. Soc., 118, 8495-8496, 1996). Additionally, molecules of some guests are known to form complexes with two molecules of the same cyclodextrin derivative. Such complexes are termed 1:2 complexes and often accompany the usual 1:1 complexes. The present invention shows that some combinations of two different cyclodextrin derivatives lead to better inclusion by host molecules.
Previous art describing complex formation by ionic guests is extensive. A review of those systems, in which parent cyclodextrins were used, counts 271 systems for alpha-cyclodextrin and 342 for beta-cyclodextrin alone (K. A. Connors, J. Pharm. Sci., 84, 843-848, 1995). Statistically, the complexes of anionic guests have about twice the stability compared to corresponding uncharged guests, but there are numerous cases where the situation is reversed and the uncharged guest is preferred. It is not possible to predict whether a specific guest will have greater stability in charged or uncharged state. In previous art, the bases used to form anions of guests were non-volatile and inorganic; many of the guests described there have been used as drugs.
U.S. Pat. No. 4,727,064 discloses that ionization of guest molecules may be an important factor in formation of inclusion complexes of hydroxypropyl derivatives of cyclodextrins and that formation is affected by counterions. Solubilization of retinoic acid in its acidic form and in the form of its sodium, choline and ethanolamine salts were compared and found to increase in that order. The patent also teaches how to prepare such complexes in solid form.
U.S. Pat. No. 5,120,720 and an article by Pitha, Hoshino, Torres-Labandeira and Irie (International Journal of Pharmaceutics, 80, 255-258, 1992) describe a method for preparing inclusion complexes in which a volatile base, ammonia, was used to bring fast dissolution of acidic guests wherein the cyclodextrin derivative was added immediately after the dissolution. The majority of the volatile base was removed with water after solid complexes were prepared.
Related work described later taught addition of bases or organic acids facilitated the solubilization of drugs while cyclodextrins or cyclodextrin derivatives were already present in solutions (E. Fenyvesi et al., The 7th International Cyclodextrins Symposium, Tokyo 1994, Proceedings, pp. 414-418; E. Fenyvesi et al., The 8th International Cyclodextrin Symposium, Budapest 1996, Programme and Abstracts 3-p48; Italian Patent Application M193 A000 141; PCT WO 95/28965; U.S. Pat. No. 5,773,029). The inventors call their system a multiple complex formation by cyclodextrin derivatives. In their claims, they specify that the characteristic of multicomponent inclusion complexes is the simultaneous salt formation and complexation.
SUMMARY OF THE INVENTION
The present invention discloses new methods which have wide applicabilit
Azpuru Carlos A.
Di Nola-Baron Liliana
Hendricks Glenna
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