Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
1997-04-24
2002-07-09
Bockelman, Mark (Department: 3762)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S020000
Reexamination Certificate
active
06416503
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a new matrix for iontophoreses.
BACKGROUND OF THE INVENTION
Iontophoresis is a percutaneous absorption promoting system with electricity as an external stimulant. The principle behind it is that drug molecule penetration through the skin barrier is promoted as molecules charged positively in the electric field between the cathode and anode upon electric supply migrate from the anode to the cathode, while negatively charged molecules migrate from the cathode to the anode [see the Journal of Controlled Release, Vol. 18, pp. 213-220, 1992; Advanced Drug Delivery Review, Vol. 9, p. 119, 1992; Pharmaceutical Research, Vol. 3, pp. 318-326, 1986].
Recent advances in synthetic technology and gene engineering have made it possible to produce naturally-occurring peptides or proteins, or derivatives thereof obtained by altering the amino acid compositions thereof or chemically modifying them, in pure forms and in large amounts. Such substances are expected to be applied to pharmaceuticals. On the other hand, medication of these peptides or proteins, which exhibit various physiological activity in trace amounts, must be controlled rigorously to maximize their drug efficacy with minimum prevalence of side effects in particular diseases. For example, parathyroid hormone and active fragments thereof exhibit mutually opposite actions on bone, i.e., bone formation and bone destruction. These are used to treat osteoporosis by intermittent administration in which bone formation surpasses bone destruction.
However, such physiologically active peptides or proteins are generally known to be poorly absorbable because of decomposition by digestive juices in the gastrointestinal tract and hydrolysis by lytic enzymes secreted from the digestive wall. It is therefore common practice to administer these physiologically active peptides or proteins by injection, rather than oral administration, to obtain satisfactory efficacy. However, this practice poses significant pain on the patient, and a major burden associated with the impossibility of self-administration. This is especially true when intermittent multiple-dose administration is required as in the case of active fragments of parathyroid hormone.
In the field of pharmaceutical manufacture, iontophoresis, as a new drug delivery system potentially applicable to such physiologically active peptides and proteins, is now being extensively studied.
A device for iontophoresis equipped with a means of voltage control for switching the polarity of the voltage applied between a pair of electrodes each of which contains a drug is described in JP-A 224770/1992. A device for iontophoresis characterized by the containment of a drug in both cathode and anode, the cathode being kept at high pH and the anode at low pH is described in Canadian laid-open Patent Application No. 2042994. The effects of drug isoelectric point and electrode pH on drug absorbability in iontophoresis is described in U.S. Pat. No. 5,042,975. A plaster for iontophoresis wherein a water separation/supply layer is arranged between the electrode layer and the drug-containing layer with a tight-sealed inner cover outside the electrode layer is described in JP-A 102768/1988.
However, conventional methods of iontophoresis have a problem in practical use, because they possess drawbacks of unsatisfactory drug absorption and time-related reduction in absorbability. Against this background the present invention is aimed at providing a practical matrix for iontophoresis offering markedly improved drug availability.
SUMMARY OF THE INVENTION
While taking the present circumstances mentioned above into consideration, the present inventors pursued their studies on a matrix for iontophoresis offering markedly improved drug availability. As the result, the present inventors found that iontophoreisis with a matrix, which comprises a cationized drug on the anode side and a water-soluble acidic substance or a salt thereof on the cathode side, or which comprises a drug reservoir containing a drug or a salt thereof, the reservoir having a thickness of less than 0.05 mm, markedly improves the percutaneous absorbability of the drug or a salt thereof. Based on these findings, the present inventors made further studies to complete the present invention.
DETAILED DESCRIPTION OF THE INVENTION
By the following description, the detailed description of a system for iontophoreses, which comprises an anode side matrix and a cathode side matrix, wherein the anode side matrix contains a cationized drug and the cathode side matrix contains a water-soluble acidic substance, will be described.
This invention provides:
1) A system for iontophoreses, which comprises an anode side matrix and a cathode side matrix, wherein the anode side matrix contains a cationized drug and the cathode side matrix contains a water-soluble acidic substance;
2) A system according to 1), wherein the drug is cationized with a water-soluble carboxylic acid;
3) A system according to -2), wherein the carboxylic acid is an aliphatic carboxylic acid;
4) A system according to 1), wherein the acidic substance is a water-soluble organic acid;
5) A system according to 1), wherein the acidic substance is a water-soluble inorganic acid;
6) A system according to 1), wherein the acidic substance is an aliphatic carboxylic acid;
7) A system according to 3) or 6), wherein the aliphatic carboxylic acid is a C
2-6
aliphatic carboxylic acid;
8) A system according to 7), wherein the C
2-6
aliphatic carboxylic acid is citric acid;
9) A system according to 1), wherein the pH on the anode side is in the range of 1 to 5;
10) A system according to 1), wherein the drug is a physiologically active peptide having at least one basic functional group;
11) A system according to 10), wherein the molecular weight of the peptide is not more than 7,000;
12 A system according to 10), wherein the isoelectric point of the peptide is not less than 5.5;
13) A system according to 1), wherein the drug is a calcium regulatory hormone;
14) A system according to 13), wherein the calcium regulatory hormone is parathyroid hormone or its derivative, or salts thereof;
15) A system according to 13), wherein the calcium regulatory hormone is calcitonin or its derivative, or salts thereof;
16) A matrix for iontophoreses, which comprises a drug reservoir containing a drug, the reservoir having a thickness of less than 0.05 mm.
17) A matrix according to 16), wherein the drug reservoir is composed of a water-soluble polymer;
18) A matrix according to 17), wherein the polymer is a cellulose derivative;
19) A matrix according to 16), wherein the drug reservoir further comprises a water-soluble carboxylic acid;
20) A matrix according to 19), wherein the carboxylic acid is a C
2-6
aliphatic carboxylic acid;
21) A matrix according to 16), wherein the drug is a physiologically active peptide having at least one basic functional group;
22) A matrix according to 21), wherein the molecular weight of the peptide is not more than 7,000;
23) A matrix according to 21), wherein the isoelectric point of the peptide is not less than 5.5;
24) A matrix according to 16), wherein the drug is a calcium regulatory hormone;
25) A matrix according to 24), wherein the calcium regulatory hormone is parathyroid hormone or its derivative, or salts thereof;
26) A matrix according to 24), wherein the calcium regulatory hormone is calcitonin or its derivative, or salts thereof;
27) A method for iontophoreses, which comprises using the system as defined in 1) and supplying electric charge intermittently;
28) A method for iontophoreses, which comprises using the matrix as defined in 16) and supplying electric charge intermittently;
29) A method for iontophoreses according to 27) or 28), wherein the electric supply comprises a pulsating direct current;
30) A method for iontophoreses according to 27) or 28), wherein the electric supply comprises a continuous direct current; and
31) A method for iontophoreses according to 29) or 30), wherein the amperage of the direct current is
Iga Katsumi
Matsumoto Yukihiro
Okada Hiroaki
Suzuki Yasuyuki
Bockelman Mark
Hisamitsu Pharmaceutical Co. Inc.
Wenderoth , Lind & Ponack, L.L.P.
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