Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-06-05
2001-03-20
Clardy, S. Mark (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S435000, C424S445000, C424S447000, C424S449000, C424S465000, C424S466000, C424S468000, C424S469000
Reexamination Certificate
active
06203817
ABSTRACT:
FIELD OF INVENTION
This invention relates to the passive transdermal delivery of drugs at acceptable skin irritation levels. More particularly, this invention relates to novel methods, compositions, and devices for the reduction or elimination of irritation and/or sensitization caused by an irritating or sensitizing drug when it is delivered transdermally. Still more particularly, but without limitation thereto, this invention relates to the passive transdermal delivery of drug salts possessing a combination of surface activity and low octanol-water partition coefficients whereby the drug salts may be transdermally administered at therapeutically effective drug fluxes and acceptable irritation and/or sensitization levels to the drug being delivered.
BACKGROUND OF THE INVENTION
The transdermal route of parenteral drug delivery provides many advantages over other administrative routes. Transdermal systems for delivering a wide variety of drugs or other beneficial agents are described in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,698,062; 4,704,282; 4,725,272; 4,781,924; 4,788,062; 4,816,258; 4,849,226; 4,904,475; 4,908,027; 4,917,895; 4,938,759; 4,943,435; 5,004,610; 5,071,656; 5,122,382; 5,141,750; 5,284,660; 5,314,694; 5,342,623; 5,411,740; and 5,635,203, which are hereby incorporated in their entirety by reference.
The factors influencing transdermal permeability of the stratum corneum can be classified into three major categories: 1) physicochemical properties of the penetrant; 2) physicochemical properties of the drug delivery system; and 3) physiological and pathological conditions of the skin. Various models based upon physicochemical data have been proposed to predict the transdermal flux of pharmaceutically active agents. Such models correlate the permeability of the skin to a specific penetrant (K
p
) with the diffusion coefficient of the penetrant through the skin (D
s
) and partition coefficient (k) between the lipophilic stratum corneum and more aqueous in nature viable tissue. These models are based upon Fick's Law of Diffusion and may be represented by the following simplification:
K
p
=(
D
s
)(
k
m
)/l (1)
where k
m
represents the partition coefficient of the penetrant between membrane m and the contacting solution and l represents the diffusion path length.
Because the measurement of k
m
is difficult, the more readily available octanol-water partition coefficient, k
oct
, is often used and is often expressed as the logarithm, log P. In general, drugs with high log P values are more likely to permeate through skin. Based upon such models, it has been concluded that drugs of high water solubility and a strong tendency to partition into oils can be expected to be quite skin permeable. It has also been concluded that one would expect the specific permeability of skin to the non-ionized form of a drug to be substantially greater that that of the ionized form. However, if the water solubility of the free base, non-ionized form of the drug is much less than that of its ionized salt, its rate of permeation in non-ionized form may be lower than that of its salt, even though the intrinsic permeability of the skin for the free base may be much greater. See Y. W. Chien,
Transdermal Controlled
-
Release Drug Administration,
Novel Drug Delivery systems—Fundamentals, Development Concepts, Biomedical Assessments, Marcel Dekker Inc., N.Y. 1982; and Guy et al.,
Physicochemical Aspects of Percutaneous Penetration and Its Enhancement,
Pharmaceutical Research, Vol. 5, No. 12, 1988, which are hereby incorporated in their entirety by reference.
More recent models have refined the correlation between the partition coefficient k
m
in equation (1) with the octanol-water partition coefficient k
oct
(log P). Potts et al. express the relationship as:
k=[k
oct
]
f
(2)
where the coefficient f accounts for the difference between the partitioning domain presented by octanol and that presented by the stratum corneum lipids.
Additionally, the functional dependence of D
s
on molar volume has been taken into account in contrast to the assumption in Equation (1) that it remain constant for all permeants. For many compounds, the molecular weight is a reasonable approximation for molar volume, thus the molar volume term may be approximated by using the molecular weight. As a result, these parameters have been used to develop quantitative structure-activity relationships (QSARs) which can be useful in predicting skin permeability coefficients for various chemicals. See Potts et al.,
Predicting Skin Permeability,
Pharmaceutical Research, Vol. 9, no. 5, 1992 and Kirchner et al.,
The Prediction of Skin Permeability by Using Physicochemical Data,
ATLA 25, 1997, which are hereby incorporated in their entirety by reference.
Unfortunately, many drugs that are candidates for transdermal delivery based upon such models have a tendency to cause skin irritation to human patients, particularly when maintained in contact with the skin under occlusion for sustained periods of time. These irritating drugs can cause undesirable skin reactions, such as itching and erythema. Therefore, despite the development of the transdermal drug delivery art, there remains a continuing need for an improved method of overcoming irritation caused by transdermal delivery of an irritating drug while transdermally delivering drugs at therapeutically effective rates.
Skin irritation can be caused by a variety of factors including, but not limited to, physical factors, eg, chafing or occluding the skin in an airtight manner; exposure to certain chemicals; exposure to pH outside normal pH of the skin or mucosa; and bacterial overgrowth. The skin reacts to many topically applied substances, particularly those maintained under occlusion, by blistering or reddening accompanied by unpleasant burning, itching, and stinging sensations. There is a wide interpersonal variation and susceptibility to irritation. An agent must be minimally irritating in a large percentage of the potential patient population in order to be suitable for safe and effective transdermal administration. Generally, tissue irritation is the manifested result of damage or toxicity to cells in the skin or mucosa caused by their response to a cytotoxic, i.e., irritating, agent.
There are known methods available to decrease the incidence of drug and permeation enhancer induced irritation and sensitization. Such methods include the codelivery of methyl nicotinate as disclosed in U.S. Pat. No. 5,451,407; codelivery of an anti-inflammatory agent as disclosed in U.S. Pat. Nos. 5,171,576 and 5,077,054; codelivery of a lysosomal uptake inhibitor as disclosed in U.S. Pat. Nos. 5,130,139 and 5,160,741; codelivery of a metabolic modulator as disclosed in U.S. Pat. No. 5,304,379; codelivery of an antigen processing-inhibiting agent as disclosed in U.S. Pat. Nos. 5,120,545 and 5,149,539; codelivery of glycerine as disclosed in U.S. Pat. No. 4,855,294; controlling the pH in the drug reservoir in order to deliver the non-ionized form of the drug at reduced irritation as disclosed in U.S. Pat. No. 4,756,710 and delivery of a non-irritating pro-drug. All of the above patents are hereby incorporated in their entirety by reference.
If a method involves codelivery of an agent and drug, precise codelivery of both the agent and drug is necessary. Not only might the precise codelivery of the drug and agent be difficult to achieve, but also codelivery of the irritation inhibitor may cause regulatory concerns. With respect to the delivery of a nonirritating pro-drug, although this method may potentially be efficient, the method for delivery is cumbersome and a new chemical entity is being delivered, thus causing regulatory concerns.
Reduction of irritation likely also results in a decrease in the sensitization reaction. Sensitization is an allergic reaction which is induced when an agent is first ap
Cormier Michel J. N.
Daddona Peter E.
Johnson Juanita A.
ALZA Corporation
Bates Owen J.
Clardy S. Mark
Date Vandana
Shelborne Kathryne E.
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