Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
1999-06-18
2003-11-11
Travers, Russell (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S400000, C514S152000, C514S039000, C514S474000, C514S937000, C514S944000
Reexamination Certificate
active
06645508
ABSTRACT:
BACKGROUND
The present invention relates to a composition containing a relatively high concentration of a water-sensitive pharmacologically active agent, such as L-Ascorbic acid, which composition is stable in this preparation for a commercially feasible time period and can be used, in particular, for topical cosmetic or medical therapeutic purposes to cleanse, care for, improve, or protect human tissue and skin.
The dermatological benefit of topical application of L-Ascorbic acid has been well established. A stable, skin-penetrable, high concentration composition of L-Ascorbic acid is needed for cosmetic and therapeutic purposes. Scientists have had difficulty for a long time formulating stable solutions of L-Ascorbic acid of high enough concentration which would be beneficial for cosmetic or dermatologic needs.
Although L-Ascorbic acid is more stable in some water-miscible organic solvents than in water itself, unfortunately its solubility in such non-aqueous media is very limited which prevents achieving a suitable concentration in an anhydrous medium. The desired level of stability and skin penetrability and therefore, efficacy are not attained. For this reason, presently unstable L-Ascorbic acid preparations have been used for cosmetic and therapeutic purposes at unsuitably low concentrations.
L-Ascorbic acid, C
6
H
8
O
6
, molecular weight 176.1, commonly known as Vitamin C or ascorbic acid, is an unsaturated lactone or cyclic ester. It is unstable and reversibly oxidized to give biologically active dehydroascorbic acid in aqueous solution. The oxidation rate is dependent on pH and on oxygen concentration and is catalyzed by metal ions, especially Cu (II) and Fe (III). Dehydroascorbic acid quickly undergoes irreversible degradation to biologically inactive diketogulonic acid and oxalic acid. Oxidation is also subject to buffer catalysis by both general acids and general bases. A three-fold rise in rate is observed in 0.5 M phosphate buffer even in the pH range 1 to 4. The decomposition rate increases with various buffers and depends upon concentration. At neutral or higher pH of a typical cosmetic formulation, L-Ascorbic acid becomes the notoriously unstable ascorbate anion.
Optimum stability of ascorbic acid solution occurs around pH 2.5 to 3.0 (K. A. Connors, G. L. Amidon and L. Kennon, Chemical Stability of Pharmaceuticals, John Wiley & Sons, 1979). B. R. Hajratwala published a paper entitled “Stability of ascorbic acid” in the Revue sciences Pharmaceutiques on Mar. 15, 1985 and observed stabilization of ascorbic acid in acidic aqueous solution after addition of a surface-active agent and a chelating agent, with packaging under nitrogen in the absence of light. Moreover the hydroalcoholic solution in the patent having a pH lower than 3.5 may produce side effects such as irritation or burning of the skin. In this preparation ascorbic acid is insufficiently stabilized for commercial purposes.
Ascorbic acid is also susceptible to dehydration degradation under anaerobic conditions, giving furfural and carbon dioxide. The pH-decomposition rate profiles for both aerobic and anaerobic degradation show maxima about pH 4 near to its pK
1
. Optimum stability occurs around pH 2.5 to 3.0 and pH 6.0 to 6.5. The catalytic degradation of ascorbic acid solution is particularly effective at lower pH values and can promote oxidation even in the absence of air. Catalysis by various other metal ions, such as Pb(II), Zn(II), and Al(III) has also been reported (P. Finholt et. al., J. Pharm. Sci. 55: 1435, 1966).
Although ascorbic acid is relatively soluble in aqueous media, it oxidizes rapidly in solution. On the other hand, ascorbic acid is relatively insoluble in organic solvents such as alcohol, glycol, fats, fat solvents and oils. Using high concentration of water miscible organic solvent, even in a co-solvent system, achieving a cosmetical and therapeutically desired concentration of ascorbic acid solution is difficult. Among pharmaceutical vehicles sorbitol, glycerin and propylene glycol can maintain about 90% potency of low concentration (about 1 to 10%) of ascorbic acid for one year, however this is still a short-term stabilization for commercial purposes.
The initial concentration of ascorbic acid in solution plays a key role in determining the rate of decomposition. It is reported that high concentrations, up to 5%-10%, show slightly better stability of ascorbic acid in water, propylene glycol or Syrup USP at room temperature.
U.S. Pat. No. 4,983,382 describes a stable composition of ascorbic acid for application to human skin as a cosmetic preparation. The preparation contains about 1 to 10% of ascorbic acid by weight, co-solvent of no more than 12% of water and water miscible organic solvents, emollients, fragrances, antioxidants and preservatives, or mixtures of the same. It specified a group of the alcohols, glycols, and polyols or mixtures thereof as second co-solvent comprising up to but no more than about 90% of the total weight of the composition in which propylene glycol is present in an amount by weight ranging from about 20% to 25% and ethanol is present in an amount by weight ranging from about 55% to 65%.
Kassem, et al. (M. A. Kassem et. al., Pharm. Acta Helv. 44: 611, 1969 and 47: 89, 1972) studied the effect of complexing agents and autoclaving of injectable ascorbic acid solutions. The stabilizing effectiveness of all metal complexing agents studied was limited.
Blaug and Hajratwala (S. M. Blaug et. al., J. Pharm. Sci. 63: 1240, 1974 ) observed an increase in aerobic oxidation rate of ascorbic acid with both surfactant, polysorbate 80, and polyoxalkol at low concentration of surfactant. At higher concentration, no change in rate was observed for polysorbate 80 but a 30% decrease in rate occurred for polyoxalkol.
Nixon and Chawla (J. R. Nixon et. al., J. Pharm. Pharmacol. 17: 558, 1965), using polysorbate 20, found an increase in decomposition rate with increasing viscosity at high concentration of surfactant. However, for the metal-catalyzed reaction, the rate decreased by a factor of 6 at about 70% w/w of polysorbate 20. The rate of copper-catalysed decomposition in the presence of polysorbate 80 has been found to decrease up to a concentration of 30% w/w polysorbate 80 in a study by Poust and Colaizzi (R. I. Poust et. al., J. Pharm. Sci. 57: 2119, 1968).
A monograph prepared by D. Madey (The Science Supporting Topical Vitamin C (L-Ascorbic Acid Products, no other publication information) also recognized that it is notoriously difficult to stabilize L-Ascorbic acid and it tends to break down rapidly. Instability restricts the only form of vitamin C body can use and its application to cosmetic preparations. The monograph also elaborates U.S. Pat. No. 5,140,043 (“the '043 Patent”) which teaches a stable L-Ascorbic acid formulation in an initial laboratory preparation at pH 3.5. The '043 Patent describes a stable topical composition consisting essentially of at least about 1% to up to about 20% L-Ascorbic acid (w/v) in 80% to 97% water and a carrier such as propylene glycol or combination of propylene glycol and hydroxypropylcellulose. This aqueous preparation with pH of 2.5 to 3.5 can be applied to the skin as a method of preventing, treating and retarding damage to skin by ultraviolet light.
A stable composition for topical application in U.S. Pat. No. 5,703,041 (“the '041 Patent”) contains at least 0.001 to 15% of one water-degradable active agent with a topical action including ascorbic acid, at least 30 to 99.9% by weight of one polyol, such as, glycerol or propylene glycol, and at least one structuring agent, such as glyceryl polyacrylate polymer and/or oil, such as mineral oil and water. The water-sensitive active agent can also be an enzyme. The composition obtained can be used for cleansing, caring for or protecting skin or keratinous fibers. A stabilized form of L-Ascorbic acid at low pH for cosmetic use has been marketed recently by SkinCeuticals (Dallas, Tex.).
Several stabilized derivatives, esters, and analogs of ascorbic acid in cream,
Jackson Walker L.L.P.
Sharareh Shahnam J
Travers Russell
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