Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1999-10-25
2002-05-07
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S448000
Reexamination Certificate
active
06383511
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a local method to prevent or ameliorate the pain associated with surgical incision by topically administering a local anesthetic.
BACKGROUND OF THE INVENTION
The skin is a complex multilayer organ with a total thickness of 2-3 mm. The panniculus adiposus, a variably thick fatty layer, is below the dermis. The dermis is a layer of dense connective tissue that supports the epidermis. The epidermis comprises a layer of epithelial cells and is about 100 &mgr;m thick. The epidermis is further classified into a number of layers, of which the outermost layer is the stratum corneum (15-20 &mgr;m thick). The stratum corneum comprises highly dense, keratinized tissue and is the skin's main source of penetration and permeation resistance (Montagna, W. and Parakkal, P. F. (1974)
The Structure and Function of Skin
, Academic Press, New York and Holbrook, K. A. and Wolf, K. (1993) The Structure and Development of Skin, In:
Dermatology in General Medicine
, Vol 1, 4th ed., Eds. T. B. Fitzpatrick, A. Z. Eisen, K. Wolff, I. M. Feedberg, and K. F. Austen, McGraw Hill, Inc., New York, pp. 97-145).
Because of the skin's drug permeation resistance, as little as about 1 percent and usually no more than about 15 percent of a drug in a dermatological formulation is bioavailable (Ghosh, T. K.; Pfister, W. R.; Yum, S. I.
Transdermal and Topical Drug Delivery Systems
, Interpharm Press, Inc. p. 7).
After a surgical procedure, pain results from pain receptor stimulation. Postoperative or post-traumatic pain is caused by stimulation of sub-dermal sensory nerve receptors (i.e., nociceptors). And trauma is increased over the first 24-48 hours by phases of reactive edema and by release of cytokines and chemo reactive agents.
After a wound is closed by a surgical professional, pain prevention options are limited, especially outpatient pain control and management. Traditionally, for post wound closure pain prevention, opiates and NSAIDs are administered systemically, i.e., throughout the organism via the circulatory system. Topical intradermal pain prevention has seen little application, likely because surgically closed wounds are expected to present a drug permeation barrier similar to intact skin.
Systemic administration of pain relief drugs usually is effected orally or intravenously, The AHCPR Guidelines suggested pain control options include: systemic administration of non-steroidal anti-inflammatory drugs (NSAIDs) or opiates using the traditional “as needed” schedule or around-the-clock administration (American Pain Society, 1989).
Systemic pharmacotherapies are, however, accompanied by adverse side effects, particularly with continuous use. With NSAIDs, there is a high risk of gastric disorders, erosions of the stomach lining and the intestinal mucus membrane and bleeding. Administration of opiates and narcotics presents a high dependency risk aside from other undesirable effects, like, respiratory depression, sedation, dizziness, nausea, and constipation. Furthermore, systemic use of these substances while taking other medications can result in detrimental pharmacologic interactions. Of course, pharmacological interactions become more significant in an ambulatory postoperative patient for whom polypharmacy is necessary.
In contrast to prevention of pain with systemic agents, pain can also be treated locally, that is, by delivering the pain reliever directly to the painful area. Thus, for example, a local anesthetic or NSAID might be injected at the pain area.
Local anesthetics reversibly block impulse conduction along nerve axons and other excitable membranes that utilize sodium channels as the primary means of action potential generation. This blocking action can be used clinically to block pain sensation at specific areas of the body (Strichartz, G. R. (Ed.) Local Anesthetics, Handbook of Experimental Pharmacology, Vol. 81, Springer, Berlin/New York, 1987). Furthermore, local anesthetics generally possess a good tissue tolerance, and in some cases, local anesthetics have bactericidal properties, and may impart a positive influence on the regional vessel innervation during wound healing and episodes of.
Traditionally, pain relief with local anesthetics—at least for the more painful wounds, such as surgically closed wounds—involves injection into the area of the nerve fibers to be blocked (Jones M. Gregg AK, Anaesthesia 1999 February; 54(2):200). But with this therapy, the medical professional is confronted with the risk/benefit consideration between the negative effects of systemic absorption versus achieving pain relieving concentrations at the pain site. Systemic absorption of injected local anesthetics is modified by several factors, including dosage, injection site, drug tissue binding. For example, local anesthetic injection to a highly vascular area results in more rapid systemic absorption and thus, adversely, higher drug blood levels are attained. In an analogy to injection, local anesthetics have also been infused directly into open wounds before surgical closure (e.g., U.S. Pat. Nos. 5,272,139 and 5,922,340).
In addition to systemic absorption risk, local injection is painful and invasive and also requires professional administration. Of course, with surgically closed wounds, which are very sensitive, injections should be avoided if possible.
While topical application of local anesthetics might overcome some of the problems associated with injection (especially systemic dangers), this method has not been widely used, mainly, as discussed above, by the difficulty to get significant concentrations through skin barrier. Further advantages of topical administration include improved patient compliance and reversible action (i.e., the action can be reversed by removing the anesthetic from the application site) (Ghosh, T. K.; Pfister, W. R.; Yum, S. I.
Transdermal and Topical Drug Delivery Systems
, Interpharm Press, Inc. pp. 33-112).
Thus, topical administration of local anesthetics has, in general, only been used to treat minor pain where small concentrations of the anesthetic will suffice. For example, for relief of minor pain from scrapes, skin irritations. Topical administration of local anesthetics is also indicated for topical anesthesia prior to needle insertion (e.g., blood sampling, vaccination, allergy testing), and superficial surgical procedures (Zook et al. U.S. Pat. No. 5,415,866; Royds, R. B. U.S. Pat. No. 5,466,465; Zhange et al. U.S. Pat. No. 5,919,479; and Berkovitch, et al.
J. Clin. Pharmacol
. 35: 295-297).
In addition to classic local anesthetics—i.e., amide and ester type—several of the more potent NSAIDs have been developed into topical products for local application to minor pain sites—for example, Cordran® Tape delivers flurandrenolide for relief of inflammatory and puritic conditions (Oclassen (1995) Cordon Tape Package Insert, Oclassen Pharmaceutical, San Rafael, Calif.).
But, in brief, topical application of local anesthetics is not known to treat the more intense pain associated with wounds after surgical closure. This is likely because a surgically closed wound is expected to present the same permeability difficulties associated with intact skin.
Surgically closed wounds are tightly welded. The most common techniques for closure of open wounds is suturing (with either non-absorbable and absorbable materials) and stapling. These mechanical closure methods provide tension on the skin tissue at the wound border that encourages epithelial tissue to migrate toward the wound and cover it. As the skin heals, the wound becomes even more impenetrable by pharmaceuticals, nonetheless, the pain persists. Also, modern surgical suturing techniques and intraoperative hemostasis, wound treatment has been greatly advanced by the use of suitable supplementary materials, such as tissue glues and adhesives, to accelerate hemostasis as well as to optimize conditions and control of wound closure. Fibrin-based biological glues have proven particularly advantageous over non-biological adhesives because fibrin-based glues
EpiCept Corporation
Rose Shep K.
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