Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2002-07-25
2004-06-08
Lankford, Jr., Leon B. (Department: 1654)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S744000, C424S757000, C424S774000, C424S778000, C424S447000, C424S448000, C514S646000
Reexamination Certificate
active
06746689
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods and compositions for intradermal administration of local anesthetics with the aid of an intradermal-penetration agent.
BACKGROUND OF THE INVENTION
Drug administration by topical skin application offers distinct advantages over conventional administration methods. For example, some drugs cannot be absorbed in the digestive tract and intravenous and subcutaneous administration by injection is painful and invasive. Furthermore, when treating localized conditions by oral and intravenous administration, the drug is circulated systemically rather than restricted to the diseased area.
But, unfortunately, because of the skin's drug penetration resistance, only a limited number of drugs are bioavailable via topical application (Ghosh, T. K.; Pfister, W. R.; Yum, S. I.
Transdermal and Topical Drug Delivery Systems
, Interpharm Press, Inc. p. 7). 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).
In general, drug administration via the skin is divided into two categories: 1) transdermal administration and 2) intradermal administration. Transdermal administration involves transport through the skin and into the blood stream to treat systemic diseases. One the other hand, intradermal administration is intended to impart a cutaneous effect, while keeping the pharmocological effects of the drug localized to the intracutaneous regions of drug penetration and deposition. Ideally, intradermal absorption occurs with little or no systemic absorption or accumulation.
The following sequence of mechanisms has been proposed for intradermal absorption: 1) partitioning of the drug from the applied vehicle into the stratum corneum; 2) diffusion through the stratum corneum; 3) partitioning from the stratum into the epidermis. On the other hand, transdermal absorption further involves: 4) diffusion through the epidermis; and 5) capillary uptake (Potts et al. (1992)
Percutaneous Absorption: Pharmacology of the Skin
, Ed. Mukhtar, H. CRC Press, pp. 13-27).
Because of the skins intrinsic resistance to drug penetration, penetration agents are essential to assist intradermal and transdermal drug administration. The term penetration agent has generally been applied to the class of chemicals that increase the partitioning and diffusion of the active agent. (for example see, Ghosh, T. K. et al. (1993),
Pharm. Tech.
17(3):72-98; Ghosh, T. K. et al. (1993),
Pharm. Tech.
17(4): 62-89; Ghosh, T. K. et al. (1993),
Pharm. Tech.
17(5):68-76; Pfister et al.
Pharm. Tech.
14(9):132-140, all of are incorporated herein by reference). Ideally penetration agents should be pharmacologically inert, non-toxic, non-irritating and non-allergenic, compatible with the formulation components, have rapid onset of action, and be reversible in their reduction of skin-barrier properties. The penetration agent should also spread well on the skin with a suitable skin feel. In practice, all of these ideal requirements are rarely met, and a need exists for improved penetration agents. (Aungst (1991)
Skin Permeation Enhancers for Improved Transdermal Drug delivery. In: High Performance Biomaterial: A Comprehensive Guide to Medical and Pharmaceutical Applications
, Ed. M. Szycher, pp. 527-538)).
The majority of dermal drug formulations and penetration agents for have been developed for transdermal administration. For example, U.S. Pat. No. 5,229,130 relates to the use of vegetable oils to enhance transdermal penetration of drugs through the skin into the blood stream. U.S. Pat. No. 5,229,130 teaches that vegetable oils (e.g., almond oil, babassu oil, castor oil, Clark A oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower-seed oil and wheat germ oil) as transdermal penetration agents for broad classes of pharmaceutically active compounds amenable to transdermal administration (e.g., antiinfectives; analgesics; anorexics; antihelminthics; antiarthritics; antiasthmatics; anticonvulsants; antidepressants; antidiabetics; antidiarrheals; antihistamines; antiinflammatories; antimigraine preparations; and tranquilizers).
Although transdermal systems can deliver drugs for the treatment of systemic disease, they are not practical for controlling the administration of drugs when the skin is the target site (i.e., intradermal administration). The controlled release of drugs into the epidermis or dermis, with the assurance that the drug remains primarily localized and does not enter the blood stream in significant amounts requires innovative approaches ((Ghosh, T. K.; Pfister, W. R.; Yum, S. I. (1997)
Transdermal and Topical Drug Delivery Systems
, p. 521)). Further complicating the matter, the behavior of a penetration agent is strongly dependant on the drug. That is, a given penetration agent does not necessarily increase the penetration of all drugs (Hori et al. (1989) Classification of
Percutaneous Absorption: Mechanisms
-
Methodology
-
Drug Delivery,
2nd ed., Eds. R. L. Bronaugh and H. I. Maibach pp. 197-211).
Certain aesthetics are advantageous for local administration. Especially amide and ester type local anesthetics (e.g., lidocaine, tetracaine, bupivacaine, prilocaine, mepivacaine, procaine, chloroprocaine, ropivacaine, dibucaine, etidocaine, and benzocaine). Traditionally, pain relief with local anesthetics involves injection into the area of the nerve fibers to be blocked (Jones M. Gregg A K, Anaesthesia February 1999; 54(2):200). While topical application of local anesthetics might overcome the disadvantages associated with injection (especially systemic dangers), this method has not been widely used, mainly, as discussed above, because of the difficulty to get significant concentrations of local anesthetics through skin barrier. But if a penetration agent is used, the danger of systemic absorption increases and this is significant because amide and ester anesthetics are systemically toxic.
Thus a need exists for penetration agents for intradermal local anesthetic administration. The agent should have balanced penetration properties such the intradermal penetration is maximized and transdermal penetration is minimized. Additionally, the agent should be pharmacologically inert, non-toxic, non-irritating and non-allergenic, compatible with the formulation components, have rapid onset of action, and spread well on the skin with a suitable skin feel.
SUMMARY OF THE INVENTION
It has now been found that triglycerides and aloe compositions are intradermal-penetration agents for enhancing penetration of topically applied local anesthetics through the stratum corneum and into the epidermis or dermis, in the absence of systemic absorption of the anesthetic.
In one embodiment, the invention comprises a method for administering a local anesthetic in a subject in need of a local anesthetic. The method comprises applying to the subject's skin a pharmaceutically acceptable topical formulation comprising a therapeutically effective amount of the local anesthetic or a pharmaceutically acceptable salt thereof and a penetration enhancing amount of an intradermal-penetration agent selected from t
Fischer Wilfried
Huber Petra
Mason Paul
Coe Susan D.
Day Jones
EpiCept Corporation
Lankford , Jr. Leon B.
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