Drug – bio-affecting and body treating compositions – Live skin colorant containing – Lip
Reexamination Certificate
2000-04-07
2002-04-02
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
Live skin colorant containing
Lip
C424S401000, C514S558000, C514S579000
Reexamination Certificate
active
06365138
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention resides in the field of topical compositions for use in treating lips suffering from cracking, fissuring, or scaling as a result of xeric stress, and for preventing the occurrence of such conditions.
2. Description of the Prior Art
The lips are a mucosal epithelium, unique among other mucosal tissues because the constant exposure of the lips to the environment requires the lips to function as epidermal tissue. Lips demonstrate a less efficient barrier function than other epidermal tissues, however, and are therefore more susceptible to moisture loss and the detrimental effects that result from xeric stress.
SUMMARY OF THE INVENTION
This invention arises from the discovery that a reason for the inability of the lips to provide an efficient barrier function is that they are low in certain lipid processing enzymes that are needed to generate some of the lipids that contribute to an effective barrier function. In particular, the lips have relatively low levels of endogenous &bgr;-cerebrosidase and phospholipases, and accordingly the lips contain relatively large amounts of glucosylceramides and phospholipids that have not been converted by these enzymes to ceramides and free fatty acids. Since the resulting lipid mixture is low in its levels of these lipids, it is not an efficient composition for supporting the barrier function. This renders hence lips more susceptible to dehydration, which leads to cracking, fissuring and scaling.
In accordance with this invention, therefore, it has been discovered that xeric stress of the lips can be treated or prevented by the application of any of several topical formulations, as follows:
(1) Formulations in which the only lipids included in the formulations that are physiologically active in affecting the moisture content of the lips are:
(a) one or more ceramides,
(b) one or more essential free fatty acids, and
(c) one or more nonessential free fatty acids; and
(2) Formulations that contain:
(a) a &bgr;-glucocerebrosidase or an analog thereof that has substantially similar activity in converting glucosylceramides to ceramides, and/or
(b) a phospholipase A
2
or an analog thereof that has substantially the same activity in converting phospholipids to free fatty acids.
DETAILED DESCRIPTION OF THE INVENTION AND SPECIFIC EMBODIMENTS
The term “ceramides” refers to a class of compounds that are otherwise known as “sphingoid” compounds or “sphingolipids.” These compounds have a backbone of sphingosine or a closely related structure, with fatty acids linked to the backbone through an amide linkage at the amino group of the sphingosine structure. The generic formula for ceramides is as follows:
in which:
R
1
is alkyl or &agr;-hydroxyalkyl;
R
2
is either
R
3
is C
10
-C
20
alkyl.
The term “alkyl” as it is used herein includes both straight-chain and branched-chain groups, saturated and unsaturated (i.e., containing one or more double bonds), and monovalent or divalent as indicated by the position of the group in the structural formula. Straight-chain groups are generally preferred. The term “&agr;-hydroxyalkyl” as it is used herein refers to groups derived from &agr;-hydroxy fatty acids, the &agr;-position denoting the carbon adjacent to the carboxyl group of the fatty acid. By “fatty acid residue” is meant the portion of a fatty acid remaining after removal of the —COOH group.
Preferred groups for R
1
are C
10
-C
36
alkyl and &agr;-hydroxy-C
10
-C
36
alkyl, or either of the two subgroups C
14
-C
20
alkyl and &agr;-hydroxy-C
14
-C
20
alkyl or C
20
-C
36
alkyl and &agr;-hydroxy-C
20
-C
36
alkyl. Particularly preferred are C
20
-C
36
alkyl, and the most preferred are saturated C
20
-C
36
alkyl.
The preferred group for R
2
is
Preferred groups for R
3
are C
12
-C
16
saturated straight-chain alkyl, particularly C
13
-C
15
saturated straight-chain alkyl, with C
13
and C
15
saturated straight-chain alkyl as the most preferred.
Many ceramides are naturally occurring in certain plant tissues such as yeast, and also in the mammalian stratum corneum and in other mammalian tissues such as brain tissue and nervous tissue. Ceramides can be extracted from these tissues by methods known in the art. Bovine brain tissue and human spleen tissue are common commercial sources. A mixture termed “ceramides type III” is prepared by the action of phospholipase C on bovine brain sphingomyelin, and the R
3
moiety is primarily stearic (saturated 18-carbon) and nervonic (unsaturated 24-carbon) acids. A mixture termed “ceramides type IV” is similar to ceramides type III except that it contains &agr;-hydroxy acids rather than stearic and nervonic acids. Both mixtures are commercially available from chemicals suppliers such as Sigma Chemical Company, St. Louis Mo., USA, and those which are not direct extracts are capable of being prepared by techniques described in the literature, such as Morrison, W. R.,
Biochem. Biophys. Acta
176:537 (1979), and Carter, H. E., et al.,
J. Lipid Res.
2:228 (1961). In general, seven types of ceramides are known, and all are believed to be useful in the practice of this invention.
The components designated herein as “free fatty acids” include &agr;-hydroxy fatty acids and &ohgr;-hydroxy fatty acids, and non-hydroxylated fatty acids, both saturated and unsaturated, and both straight-chain and branched-chain. Straight-chain, &agr;-hydroxy and non-hydroxylated fatty acids are preferred. The fatty acids are generally up to 36 carbon atoms in length. Preferred lengths are 12 to 20 carbon atoms.
The essential free fatty acids are linoleic acid (18 carbon atoms, two double bonds) and linolenic acid (18 carbon atoms, three double bonds), including the various isomers of these acids. Nonessential free fatty acids are all other fatty acids, notably those of 12 to 20 carbon atoms. Preferred nonessential free fatty acids are those of 16 to 18 carbon atoms, and the most preferred are stearic and palmitic acids. The free fatty acids may also be supplied in the form of their glycolipid precursors such as triglycerides.
The enzyme &bgr;-glucocerebrosidase (&bgr;-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of glucocerebrosides to glucose and ceramides. This enzyme is a naturally occurring human enzyme that is available from commercial suppliers. Certain analogues of the enzyme with similar activity are also commercially available and can likewise be used in this invention. One such analogue is CEREZYME®, which is produced by recombinant DNA technology using mammalian cell culture. This analogue, which is also known is imiglucerase, is a momeric glycoprotein of 497 amino acids, differing from placental glucocerebrosidase by the substitution of histidine for arginine at position 495, and by the modification of the oligosaccharide chains at the glycosylation sites such that they terminate in mannose sugars. Another analogue is CEREDASE® (alglucerase), produced by modification of the oligosaccharide chains of human &bgr;-glucocerebrosidase to alter the sugar residues at the non-reducing ends so that they are predominantly terminated with mannose residues. Each of these analogues is available from Genzyme Corporation, Cambridge, Mass., USA.
Phospholipase A
2
is a class of enzymes that specifically catalyzes the hydrolysis of the sn-2 acyl or alkyl ester of phosphoglycerides, producing equimolar quantities of lysophospholipids and free fatty acids. Preferred phospholipase A
2
(PLA
2
) enzymes for use in this invention are mammalian secretory PLA
2
enzymes and particularly pancreatic Type 1 or Type 5 secretory PLA
2
enzymes. Porcine, bovine and human pancreatic PLA
2
are commercially available from chemical suppliers, such as Sigma Chemical Company, St. Louis, Mo., USA.
The enzymes &bgr;-glucocerebrosidase (or its analogs) and secretory phospholipase A
2
can also be applied individually rather than in combination. Application of either one individually will provide partial relief of xeric stress
Dudash Diana
The Regents of the University of California
Yu Gina C
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