Transdermal delivery system

Details Transdermal delivery system Transdermal delivery system

1999-11-23

2001-08-14

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S448000, C424S443000

Reexamination Certificate

active

06274166

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a transdermal delivery system containing an active ingredient selected from the group consisting of peptides, proteins and mixtures thereof. More particularly the present invention provides systems and compositions which are pharmaceutically accepted and easy-to-use topical systems containing an active ingredient selected from the group consisting of peptides, proteins and mixtures thereof. These systems incorporate further components that assist in stabilizing the active material, e.g., by preventing the inactivation thereof and facilitating the penetration thereof as active molecules through the skin layers.
It has been discovered in the present invention that oxidizing agents such as iodine, potassium permanganate, peroxides and silver protein enable the application of formulations containing proteins and peptides and especially insulin onto the skin.
BACKGROUND ART
Insulin is secreted from beta cells of pancreatic Langerhans islet in its active form. The human insulin is composed of two polypeptides, the A and B chain, usually of 21 and 30 amino acids residues, respectively, with a molecular mass of about 5800 DA. The peptides are interconnected by disulfide bonds of the cysteine residues at A7-B7, A20-B19 and A6-A11. Insulin exerts a wide variety of biological activities including controlling the uptake, utilization, and storage of cellular nutrients such as glucose, amino acids and fatty acids. The important target tissues of insulin are liver, muscle and fat but many other cell types are also influenced by this hormone. [Davis, S N; Granner, D K (1996) In: Goodman & Gilman's The Pharmacological Basis of Therapeutics. ninth edition ed. (Eds: Hardman, J G et al.) McGraw-Hill, 1487—1517].
Diabetes and Insulin: One of the main physiological roles of insulin is stimulation of glucose transport into muscle and adipose tissues. A defect in this system leads to the diabetes mellitus syndrome characterized by hyperglycemia, changes in the metabolism of carbohydrates, lipids and proteins, and by elevated incidence of vascular disorders. There are two main diabetes, insulin-dependent diabetes mellitus (IDDM) with an incidence of 1-43 per 100,000 inhabitants in the Western countries, and the non-insulin-dependent diabetes mellitus (NIDDM) whose incidence is between 100-800 per 100,000 inhabitants in the Western countries (The above reference).
Insulin is the main treatment of all IDDM and many NIDDM patients. Long-term treatment is predominantly based on subcutaneous administration of insulin formulations. There are long-, short- and intermediate-acting preparation which are used according to the special requirements of the patient. However, apart from the discomfort and troublesome feelings and the possibility of infection associated with daily injections along the entire lifetime (particularly with IDDM, formerly termed juvenile-onset diabetes mellitus), this kind of therapy has serious clinical problems mainly with the maintenance of the appropriate blood levels of the hormone resulting in non-physiological blood glucose levels and other complications. Although much effort has been made in developing insulin analogs [Brange, J; et al. (1990) Diabetes 13, 923-954] and genetic engineering methodologies [Sutherland, DER et al. (1989) Diabetes 38 Suppl 1, 46-54], there are no successful findings for solving the clinical problems associated with parenteral insulin injections.
One of the approaches aimed to cope with the aforementioned difficulty was to deliver the hormone non-invasively, via transdermal route of administration. By this procedure, the annoyance and inconvenience of the parenteral injections can be avoided, moreover, much steadier blood hormone levels can be achieved due to prolonged delivery of the drug. Several low molecular weight drugs have been formulated and are being clinically used as transdermal preparations. However, apart from a few medicines, many drugs, particularly peptides and proteins, are not successfully formulated for transdermal delivery. In vitro experiments have shown that &agr;-melanocyte stimulating hormone analog can penetrate across human and mouse, but cannot penetrate rat skin [Dawson, B V et al. (1990) J. Invest. Dermatol. 94, 432-435; Dawson, B V et al. (1988) Life. Sci. 43, 1111-1117] and that enkephaiin can penetrate hairless mouse skin but in the presence of the enhancer n-decylmethyl sulfoxide and proteinase inhibitors [Choi, H K et al. (1990) Pharm. Res. 7, 1099-1106]. However, apart from one study with small number of mice which showed reduced levels of blood glucose after 4 hours of cutaneous application of insulin with enhancer [Liedtke, R K et al. (1990) Drug Res. 40, 880-883], no efficient in vivo transdermal penetration of peptides and proteins, by chemical means (e.g. enhancer or proteinase inhibitors) have been published. Transdermal penetration of various peptides and proteins can be enhanced by iontophoresis using electrical current for delivering charged agents across the skin. Various peptides and small proteins including insulin, calcitonin, vasopressin, luteinizing hormone-releasing hormone, (LHRH) leuprolide, thyrotropin-releasing hormone and cholecystokinin were tested in in vitro iontophoresis assays and some of them also in in vivo systems [Heit, M C et al. (1993) J Pharm Sci 1993 82(3):240-243; Srinivasan, V et al. (1990) J. Pharm. Sci. 79, 588-591; Burnette, R R and Marrero, D (1986) J. Pharm. Sci. 75, 738-743; Banga, A K and Chien, Y W (1993): Pharm. Res. 10, 697-702; Mao, X M et al. (1995) Yao. Hsueh. Hsueh. Pao. 30, 302-306; Mao, X M et al. (1995) Yao. Hsueh. Hsueh. Pao. 30, 881-885; Meyer, B R et al. (1989) Am. J. Med. Sci. 297, 321-325]. Additional technique to facilitate transdermal delivery of insulin by ultrasound vibration, termed sonophoresis, was used in both in vitro and in vivo systems [Tachibana, K and Tachibana, S (1991): J. Pharm. Pharmacol. 43, 270-271; Tachibana, K (1992) Pharm. Res. 9, 952-954; Mitragotri, S et al. (1995) Science. 269(5225), 850-853]. Although transdermal penetration of insulin and other proteins and peptides was enhanced by the sonophoretic and iontophoretic techniques, these procedures require complicated and an uneasy way of operation. Furthermore, the safety of long-term, daily use of this techniques was not confirmed. The fact that only one report, describing unsatisfactory results on the use of penetration enhancer in type II diabetic patients [Liedtke, R K et al. (1990): Drug Res. 40, 884-886] has been published, indicates the problematic issues of the above methods.
DISCLOSURE OF THE INVENTION
According to the present invention there is now provided a transdermal delivery system comprising an active ingredient selected from the group consisting of peptides, proteins and mixtures thereof and a pharmaceutically acceptable oxidizing agent.
As will be discussed hereinafter it is believed that said oxidizing agent serves to oxidize reduced glutathione thereby preventing it functioning as an inactivating agent.
Assuming that this hypothesis is correct then also a component such as buthionine sulfoximine which also prevent the formation of glutathione can be used in the present invention alone or in combination with an oxidizing agent to achieve the desired effect.
In preferred embodiments of the present invention said active ingredient is insulin.
A first series of experiments, using the in vitro Franz Cells, showed that insulin penetrates skin of several species including the rat, hairless mouse and human. However, in the parallel in vivo system, employing the insulin-containing well on rat abdominal skin, no reduction in blood glucose levels was observed. The in vivo/in vitro discrepancy may be associated with the ability of reduced glutathione (GSH) (and of other cellular SH groups) to inactivate insulin by reducing its disulfide bond(s) [Rafter, G W (1990) Biochem. Int. 20, 817-820] followed by aggregation of sever

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