Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1999-04-27
2001-05-29
Williamson, Michael A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C604S890100, C604S892100, C604S030000, C604S031000, C060S039440, C060S039440
Reexamination Certificate
active
06238693
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to transdermal administration of fenoldopam and to methods for administering the compound.
BACKGROUND OF THE INVENTION
Fenoldopam is a dopamine agonist that causes peripheral vasodilation via stimulation of dopamine type-1 receptors. The drug is currently administered as an intravenous infusion of racemic fenoldopam mesylate (CORLOPAM®) and is typically used in clinical situations where, either due to underlying disease or induced by trauma or a medical procedure, an elevation in blood pressure occurs requiring immediate correction. In these situations, fenoldopam can be given at a dose of between about 0.01-1.6 &mgr;g/kg/min for up to 48 hours to achieve a dose-dependent steady-state plasma concentration in about 20 minutes.
In addition to producing a decrease in blood pressure, fenoldopam also causes renal vasodilation, diuresis and natriuresis. Intravenous infusion of therapeutic dosages of fenoldopam increases renal blood flow and decreases renal vascular resistance while maintaining glomerular filtration rate and increasing creatinine clearance, urinary flow and excretion of sodium and potassium (Brogden, R. N. and Markham, A.,
Drugs,
54(4):634-650 (1997)). These beneficial effects of fenoldopam on renal function are particularly desirable for hypertensive patients with compromised renal function.
However, the antihypertensive and renal effects of fenoldopam are short lasting, due to the 3,4-dihydroxy benzene ring in the molecule and therefore a high first-pass metabolism via sulfation and glucuronidation (Lokhandwala, M. F.,
Drug Development Research,
10:123-134 (1987)). The average clearance (CL) and half-life (t
½
) of racemic fenoldopam are 2.6 L/min and 4.6 min, respectively. Because of the high first-pass metabolism and short half-life, it is difficult to maintain a therapeutically effective concentration via oral administration and for a continuous therapeutic effect frequent dosing, i. e., intravenous infusion, is required. Intravenous administration has numerous drawbacks, including the need for a skilled professional, poor patient acceptance and the limitation on patient mobility.
There is, therefore, an interest in developing alternative modes of delivery for fenoldopam which provide a therapeutically effective blood concentration of the drug for a desired period of time, typically between 6-24 hours.
Transdermal administration of a drug is one approach to achieving a constant blood level of drug in a patient for a period of time. Transdermal administration is often considered as an alternative mode of delivery for some drugs, since in addition to the benefit of a more constant blood level, other benefits are realized, including more efficient utilization of the drug, the potential for localized, site specific delivery and less frequent administration (Baker, R. W.,
CONTROLLED RELEASE OF BIOLOGICALLY ACTIVE AGENTS,
John Wiley and Sons, New York, (1987) p. 5-10). More efficient utilization of the drug is an important benefit, since oftentimes less drug, when administered in a controlled release manner, is required to produce a given duration of effect than when administered conventionally. This is particularly true if the half-life of the drug is short compared with the desired treatment period. Since the drug is utilized more efficiently, a considerably lower dose may be required, depending on the drug half-life and the desired time of treatment
However, it is well known in the art of transdermal drug delivery that not all drugs can be successfully administered transdermally. Two of the common problems encountered with transdermal administration of an agent include (i) inability of the drug to penetrate the skin at a rate sufficient to achieve a therapeutic blood level and (ii) skin irritation.
One approach to predicting whether or not a selected drug will have a skin penetration rate sufficient for therapeutic efficacy is to correlate the melting point of the drug with the skin permeability (Baker, supra). The relationship between the skin flux rate of various drugs and their melting points is shown in
FIG. 1
(from Baker, supra). Fenoldopam mesylate has a melting point of 274° C., which corresponds to a predicted skin flux rate of less than 0.0001 &mgr;g/cm
2
·hr. The recommended daily dose of fenoldopam for hypertension is between 10-24 &mgr;g/day, which corresponds to a skin flux rate of 21-50 &mgr;/cm
2
·hr from a 20 cm
2
patch. Thus, to achieve this dose at the predicted skin flux rate would require either an impracticably large patch size or a very significant improvement in skin flux rate by a skin permeation enhancer.
The free base form of fenoldopam may have a different melting point which, if lower, would favor an increase in the predicted skin flux rate. However, it is unknown if any lowering in the melting point would be sufficient to achieve a skin flux rate sufficient to achieve a therapeutically effective dose. Moreover, the free base is readily oxidized, necessitating that precautions be taken to protect the drug from exposure to the atmosphere during storage of a transdermal dosage form, e.g., a oxygen impermeable storage packet or addition of an anti-oxidant to the formulation.
Fenoldopam is a chiral compound and is currently administered as a racemic mixture of its optical isomers, called enantiomers. Enantiomers are structurally similar compounds having identical physical properties, except for the direction in which they rotate polarized light. Although enantiomers are physically similar, they can have profoundly different effects in biological systems, where one enantiomer is biologically active while the other has little or no biological activity. This is the case for the enantiomers of fenoldopam, where the activity of the drug is due to the R-enantiomer, the S-enantiomer being relatively inactive.
It is unknown if the skin flux rate of the enantiomers is sufficient to achieve a therapeutic blood level for treatment of the indications, discussed herein, fenoldopam is typically administered.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to transdermally administer fenoldopam at a rate which attains a therapeutic blood level for treatment of conditions ameloriated by the drug fenoldopam, including but not limited to impaired renal function and hypertension.
It is another object of this invention to transdermally administer the active enantiomer of fenoldopam at a rate which attains a therapeutic blood level for treatment of such conditions.
It is another object of the invention to provide a transdermal patch that can deliver racemic fenoldopam or the pharmacologically active enantiomer of fenoldopam at a rate that attains a therapeutic blood level for treatment of a selected condition.
Another object of the present invention is to provide a fenoldopam transdermal patch that is less than or equal to 30 cm
2
in active surface area.
It is a further object of the invention to provide a transdermal patch for administration of fenoldopam, either the racemic mixture or the active R-fenoldopam enantiomer, that avoids or minimizes skin irritation. Another object of the invention is to provide a fenoldopam transdermal patch that is effective for a period of at least about 12 hours.
In one aspect, the invention includes a method of administering fenoldopam to a patient, comprising transdermally administering to the patient an amount of fenoldopam sufficient to achieve a therapeutic plasma concentration.
In one embodiment, racemic fenoldopam is administered transdermally to the patient, and in another embodiment, the active R-fenoldopam enantiomer is administered transdermally.
In another embodiment, R-fenoldopam is administered transdermally along with an amount of S-fenoldopam which is effective to enhance the skin permeation rate of R-fenoldopam.
In one embodiment, the method includes applying to the skin of the patient a transdermal patch effective to achieve a fenoldopam skin permeation rate sufficient to obtain the desired therapeutic plasma concentr
Ellis David J.
Luther Robert R.
Mathur Vandana
McGuire Dawn
Elan Pharmaceuticals Inc.
Iota Pi Law Group
Mohr Judy M.
Williamson Michael A.
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