Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
1999-05-04
2003-03-11
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S400000, C424S047000
Reexamination Certificate
active
06531140
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to topical anti-irritant compositions which contain a phosphodiesterase inhibitor. In particular, the invention relates to topical skin care compositions containing 2′-deoxy adenosine 3 ′5′ cyclic monophosphate which exhibit inhibitory action toward phosphodiesterase.
BACKGROUND OF THE INVENTION
Irritation and inflammation are complex processes that involve various factors such as, for example, prostaglandins, leukotrines, cytokines, proteases. Another factor is the intracellular level of cyclic adenosine monophosphate (hereinafter referred to as “cAMP”), and therefore, it is possible to control inflammation and irritation by modulating the levels of cAMP. Modulation can be achieved by employing one of two methods. One method involves the inhibition of new cAMP synthesis and the other method entails the removal of existing cAMP. One known removal method involves the use of an enzyme, cyclic nucleotide phosphodiesterase (hereinafter referred to as “PDE”). This isoenzyme is the catalyst for the hydrolytic reaction whereby cAMP is converted to adenosine 5′ monophosphate (hereinafter referred to as “AMP”). A family of isoenyzmes is formed by various PDEs and is categorized into seven types, known as Types I-VII whereby the type is determined by the inhibitor sensitivity. Human epidermal keratinocytes have been shown to contain both Type IV and Type V phosphodiesterase activity.
As a result of its relationship with cAMP, it is also known in the prior art that PDE plays a role in inflammatory response. There is an abnormal elevated activity of PDE in leukocytes of patients with skin disorders such as atopic dermatitis. The presence of elevated PDE activity causes a deficiency in cAMP control and results in exaggerated immune and inflammatory responses in the blood and tissue. Since elevated PDE activity is known to have a correlation with irritation and inflammation, means of inhibiting PDE activity have, therefore, been sought.
PDE inhibitors have been shown to reduce the inflammation associated with atopic dermatitis. For example, there are “classical” inhibitors of PDE such as methylxanthines like caffeine, pentoxifylline and theophylline, and theobromine. However, methylxanthines may also exhibit numerous pharmacological activities which do not directly inhibit phosphodiesterase. Other active inhibitors include alkaloids, papaverine, and imidazolone derivatives, which are among the most potent PDE inhibitors known. Cosmetic use of cAMP and PDE inhibitors has been disclosed in U.S. Pat. No. 3,978,213. However, the presence of cAMP is not disclosed as a PDE inhibitor, and derivatives or analogs of cAMP are not disclosed as having any particular ability to inhibit PDE.
It has been recognized in recent years that 2′-deoxy cAMP and 2′-deoxy cGMP are specific and potent in vitro inhibitors of cAMP-PDE and cGMP-PDE, respectively. Helfman, D. M., et al.,
Biochemical Pharmacology,
vol. 31, no. 1, pp. 43-47 (1982). Further, 2′-deoxy cyclic UMP may also be a specific PDE inhibitor. Id. In addition, a type IV PDE inhibitor CP80,633 has been tested in vivo and has been found to demonstrate a significant reduction of inflammatory parameters. Hanifin, J. M., et al., “Type 4 Phosphodiesterase Inhibitors Have Clinical and In Vitro Anti-inflammatory Effects in Atopic Dermatitis”, The Journal of Investigative Dermatology, vol 104, no. 1, pgs. 51-56 (1996). The PDE inhibitors in this study are enantiomeric and racemic compounds and it is not disclosed in this study that topical application of 2′-deoxy cAMP exhibits inhibitory action toward PDE. Therefore, the ability of 2′-deoxy cAMP compounds to inhibit PDE when formulated in a topical cosmetic or pharmaceutical composition has not, until now, been demonstrated. The present invention now provides such a topical composition.
SUMMARY OF THE INVENTION
It has now been discovered that a topical cosmetic or pharmaceutical composition containing a cyclic nucleotide PDE inhibitor has effective anti-inflammation and/or anti-irritation properties when applied to the skin. The present invention thus relates to cosmetic or pharmaceutical topical compositions comprising a cyclic nucleotide having a 2′ hydroxyl group replaced by a hydrogen atom as the phosphodiesterase inhibitor in combination with a cosmetically or pharmaceutically acceptable carrier. The invention also relates to a methods for treating or preventing symptoms of inflammation or irritation caused, in whole or in part by phosphodiesterase activity, as found in atopic dermatitis, by applying to the skin the compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Cells contain the enzyme, phosphodiesterase (hereinafter referred to as “PDE”). A hydrolytic reaction which converts cyclic nucleotides into their corresponding non-cyclic nucleotide structure is catalyzed by PDE by specifically attacking the 3′-phosphoester or P-O(3′) bond. Cyclic nucleotides are produced by the action of adenylate cyclase, which can be activated or inhibited to increase or decrease the steady state cAMP concentration. “Cyclic AMP and the Skin”,
Front. Matrix Biol
., vol. 6, pgs. 85-100 (1978). Cyclic nucleotides such as cAMP are major second messengers which mediate biological responses elicited by a vast number of extracellular signals. This requires a transport of exogenous cAMP into the cytoplasm of the cell. As a strong acid having a pK of 3.80, cAMP is completely dissociated under biological conditions. Further, it is commonly known that diffusion through the cell membrane of a phospho-organic anion is challenging and therefore, exogenous cAMP is known to have a weak action on intact cells. Therefore, synthetic analogs of cAMP, such as 2′-deoxy cAMP, have been prepared and studied to either better penetrate the cell membrane or to have better resistance to the action of PDE. Id., pp. 96-97, Posternak, “Cyclic AMP and Cyclic GMP”, Annu. Rev. Pharmacol., vol. 14, pp. 23-33, 28 (1974). In general, synthetic compounds of cAMP have been found to be less active than exogenous cAMP, but they have also been found to be more active when applied to intact tissues. Robison, et al.,
Cyclic AMP,
Chapter 5 “Some Actions of Cyclic AMP”, p. 98 (Academic, New York 1971). The 2′ hydroxyl (—OH) group is one of the reactive functions of cAMP that is capable of being transformed. Id., Chapter 3 “Chemistry of Cyclic Nucleotide Phosphates”, pp. 64. Through such research, it became known that the hydrophobic and obstructing group in the 2′ position of the ribose considerably hinders the action of PDE. However, the free hydroxyl (—OH) group in the 2′ position is not considered to participate in the breakage of the phosphodiester bond, nor in the attachment to the active site of PDE as greater hydrolysis of 2′-deoxy cAMP than cAMP was found. Id.
It has now been surprisingly discovered that topically applied cosmetic or pharmaceutical compositions comprising a phosphodiesterase inhibitor in the form of a cyclic nucleotide having its 2′ hydroxyl group (—OH) replaced by a hydrogen atom have anti-inflammatory and anti-irritating activities on the skin. The effects of cAMP are not consistent in all tissues. Chapter 5 “Some Actions of Cyclic AMP” pp. 92. Different derivatives and analogs of cAMP have varying abilities, if any at all, to inhibit PDE. Therefore, it is surprising to discover that a topical cosmetic or pharmaceutical composition can be prepared comprising a 2′-deoxy cyclic nucleotide as a PDE inhibitor.
In a typical formulation, the PDE inhibitor is present in a PDE inhibiting amount. As used in the present context, an “inhibiting amount” of the inhibitor is an amount which is sufficient to function as an anti-inflammatory or an anti-irritant by inhibiting PDE activity. Exemplary amounts are concentrations of from about 0.01 to about 10.00 percent by weight of the composition. Preferably, the concentration is about 0.1 to about 5.0 percent and
Goyarts Earl C.
Mammone Thomas
Muizzuddin Neelam
E-L Management
Jones Dameron L.
Price, Esq. Darene M.
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