Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-05-01
2003-06-03
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S171000, C514S002600, C514S008100, C424S450000
Reexamination Certificate
active
06573249
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
This invention relates the treatment of decubitus ulcers, burns, open sores, incisions and wounds in mammals. In particular, it relates to topical wound therapeutic formulations containing a cromolyn compound alone or the combination of hyaluronic acid (hyaluronan) and a cromolyn compound. The formulations can also be used in combination with elements found in amniotic fluid.
2. Description of the Prior Art
Adult wound repair is characterized by fibrosis, scarring, and sometimes by contracture. The results of this deforming process affect every form of surgery and can have devastating consequences. In contrast fetal wound healing proceeds without such fibrosis or scar formation, Michael T. Longaker, M.D., Ernie S. Chiu, B.S., N. Scott Adzick, M.D., Michael Stern, D.D.S., Michael R. Harrison, M.D., and Robert Stern, M.D.,
Studies in Fetal Wound Healing, V. A Prolonged Presence of Hyaluronic Acid Characterizes Fetal Wound Fluid, Ann Surg,
April 1991, pp. 292-296.
It is known that hyaluronic acid bonds with fibronectin and together they have a powerful effect on the body's cellular matrix. It is also known that urea, produced by the fetus has an effect on cell migration. Elements such as glucose, protein, sodium, potassium, calcium, magnesium, phosphate and chloride that form the amniotic fluid, work together with an inseparable bond and synergy.
Fibronectin is important in wound healing. However, the presence of certain proteases in excess binds with the fibronectin and prevents its activity in healing.
Several prior art patents disclose therapeutic formulations including hyaluronic acid. Lindblad, “Hyaluronic Acid Preparation used for Treating Inflammations of Skeletal Joints”; U.S. Pat. No. 4,801,619 disclosed the use of hyaluronic for intra-articular administration for the treatment of steroid arthropathy and progressive cartilage degeneration caused by protoglycan degradation. Langerman, “Spare Parts for Use in Ophthalmic Surgical Prodecures: U.S. Pat. No. 4,888,016 disclosed the use of hyaluronic acid in ophthalmic surgery as an artificial “spare part” for surgical implantation in the eye during an extracapsular cataract extraction. Alvarez, “Three Step Wound Treatment Method and Dressing Therefor”; U.S. Pat. No. 4,813,942, which is herein incorporated by reference, disclosed the use of hyaluronic acid in the third step of a three-step treatment. The invention calls for hyaluronic acid to be in a hydrocolloid dressing which will provide controlled delivery over a period of 24 to 96 hours to promote thickening of the epidermal cells, thus strengthening the wound. Balazs et al, “Cross-Linked Gels of Hyaluronic Acid and Products Containing Such Gels”; U.S. Pat. Nos. 4,582,865, 4,636,524 and 4,636,865 disclosed the use of cross-linked gels of hyaluronic acid as a drug delivery system.
None of these prior art references claim to use hyaluronic acid and a cromolyn compound in the treatment of burns, open sores, incisions, and wounds and there is no combination with calcium, phosphate, uric acid, urea, sodium, potassium, chloride, and magnesium to simulate amniotic fluid.
U.S. Pat. Nos. 5,190,917 and 5,290,762, which are herein incorporated by reference disclose the roles of serine protease inhibitors in treatment of inflammation.
U.S. Pat. No. 4,970,298 which is herein incorporated by reference discloses a biodegradable matrix which comprises collagen, hyaluronic acid and fibronectin which enhance healing of wounds. Collagen, which is oversecreted by the body in response to an injury or wound, is known to be responsible for scar formation. Georgalas et al., “Skin Treatment Composition and Method for Treating Burned Skin,” U. S. Pat. No. 4,839,019, discloses a composition, which counteracts moisture loss and promotes healing of burned or sunburned skin comprised of polyglycerylmethacrylate, glycerine, allantoin, panthenol, amino acid complex, and fibronectin.
BRIEF SUMMARY OF THE INVENTION
The invention relates to formulations containing a cromolyn compound selected from the group consisting of cromolyn, cromolyn sodium, disodium cromolyn and esters thereof. There is also provided combinations of a cromolyn compound and hyaluronic acid. The mixture can be further combined with calcium, phosphate, uric acid, urea, sodium, potassium, chloride and magnesium, all elements found in amniotic fluid, to provide a unique synergy that is effective in the treatment of burns, open sores, incisions and wounds in mammals.
The invention is used for wound therapeutic formulations, for topical application, for treating decubitus ulcers, burns, traumatic damage caused by irradiation of the skin, the deleterious effects of open sores, incisions and wounds on skin and further provides a mixture which simulates the fetal in utero wound healing matrix in a safe and effective amount.
Hyaluronic acid or the cromolyn compound alone in a pharmaceutical base, are sufficient for treating minor injuries. The combination of a cromolyn compound and hyaluronic acid, speeds healing. Additional elements comprising a mixture of constituents selected from the group of calcium, phosphate, uric acid, urea, sodium, potassium, chloride and magnesium, which are found in amniotic fluid, promote healing in more serious injuries.
The cromolyn compounds are inhibitors of PAR-2 (proteinase activator receptor-2) and prevent the degranulation of mast cells so as to control the release of chymase and tryptase that may cause scarring.
A preferred topical composition for use in serious injuries such as burns comprises by weight of the mixture: 0.01% to 1.50% calcium; 0.01% to 0.10% phosphate; 0.01% to 2.00% uric acid, 0.01% to 2.00% urea; 0.02% to 1.50% sodium; 0.01% to 0.10% potassium; 0.01% to 0.70% chloride; 0.001% to 0.01% magnesium; 0.01% to 2.50% hyaluronic acid; and 1.0% to 5.00% of a cromolyn compound.
In the best mode, the hyaluronic acid comprises by weight about 0.10% to 2.50% of the mixture and the cromolyn compound about 1.0 to 5.0% in the mixture or alone.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention is a means for delivery of cromolyn alone or the combination of hyaluronic acid and a cromolyn compound in a topical preparation for the treatment of decubitus ulcers, burns, open sores, incisions and wounds for optimum healing.
In accordance with the invention, there is provided herein formulations useful for topical application comprising a cromolyn compound alone or in combination with hyaluronic acid and/or at least four members of the group consisting of calcium, phosphate, uric acid, urea, sodium, potassium, chloride, and magnesium, all elements healing matrix and a safe and effective amount of a topical carrier, in combinations described below.
Tissue repair in the mammalian fetus is fundamentally different from normal adult healing. In adult humans, injured tissue is repaired by collagen deposition, collagen remodeling and eventual scar formation, whereas fetal wound healing appears to be more of a regenerative process with minimal or no scar formation. The adult wound heals by the replacement of normal dermis with a scar that consists of excessive and abnormally organized collagen. In marked contrast, the fetal wound contains a persistent abundance of hyaluronic acid while collagen deposition is rapid and nonexcessive, Bruce A Mast, M.D., Robert F. Diegelmann, Ph.D.,
Healing in the Mammalian
Fetus, Surg. Gyn. And Ob., Vol. 174, pp. 441-451, May 92.
What is known is that hyaluronic acid has a definite role in harnessing and manipulating the natural reparative capacity of tissue fibroblasts and the hyaluronic acid protein complexes play a significant role in vivo organization or scar tissue, D. A. R. Burd, R. M. Greco, S. Regaurer, M. T. Longaker, J. W. Siebert and H. G. Garg,
Hyaluronan and Wound Healing: a New Perspective,
Journal of Plastic Sutery, 1991, pp. 579-584.
Hyaluronic acid has played a very limited role in the care and treatment of burns, open sores, incisions and wounds because there has not been an effective delivery sy
Lezdey Darren
Lezdey John
AlphaMed Pharmaceutical Corp.
Jagoe Donna
Lezdey John
Weddington Kevin E.
LandOfFree
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