Topical preparation for introducing insulin in living organisms

Details Topical preparation for introducing insulin in living organisms Topical preparation for introducing insulin in living organisms

1999-06-03

2002-06-04

Borin, Michael (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C530S330000

Reexamination Certificate

active

06399566

ABSTRACT:

The invention relates to topically applicable pharmaceutical preparations which enable one to introduce peptidaceous pharmacons in living organisms by transdermal resorption. The topically applicable pharmaceutical preparations according to the invention may be e.g. ointments, creams, gels, lotions, solutions suspensions and similar formulations routinely utilized in topical treatments. Which can be applied onto the skin surface optionally in supported forms. Particularly preferred representatives of them are those wherein the topically applicable formulation is applied onto a support capable of adhering to skin, i.e. plasters (patches), which enable safe dosing and easy handling.
Topically applicable pharmaceutical preparations are outstandingly preferred formulations with respect to the treatment comfort of the patient. In contrast to parenteral formulations, like injections, the introduction of which is painful or at least unpleasant and requires either assistance of a doctor or of a nurse, or, when self-administered, requires practice and skill from the patient, a topical formulation can be applied to the place of treatment easily and painless even by the patient. Topical formulations are also more preferred than oral ones for patients who suffer from dysphagia or are averse to the taste of the medicine. A specific advantage of topical formulations is that the patient can, either at first sight or by touching his skin, easily ascertain whether he has applied the medicine or not, thereby the risk of inadvertent overdosing or underdosing considerably decreases
Despite of these advantages topically applicable formulations are utilized in medical practice in a rather narrow range, generally only for the treatment of external injuries and local inflammations. The reasons of this fact lie primarily on the physiological features of active agent resorption. In order to enable a topically applied active agent to reach the target organ in an appropriate concentration the active agent should penetrate not only through the skin but also through the walls of the subdermal blood vessels. Even skin and vessel walls are of highly restricted permeability owing to their physical structures (porosity and semipermeable membrane nature). Further significant hindrance arises from the so-called barrier function of the horny layer, which latter serves essentially to protect living organisms from foreign substances contacting the skin.
There have already been elaborated some topical formulations which can successfully replace oral ones for the introduction of the active agent concerned. One of them is an antirheumatic patch marketed in Hungary since about 15 years under the name MOTTO
(R)
, which comprises formic acid (as an antirheumatic agent) salicylic acid and optionally a pain-relieving agent in an emulsion formed with
Unguentum emulsificans
(a cream comprising nonionic tensides, Ph.Hg.V.), which is applied on a support capable of adhering to skin. NITRODERM
(R)
, a composition sold by Ciba-Geigy Co. (German Federal Republic), comprises nitroglycerol (as a cardiac agent) in a gel formed with methyl or carboxymethyl cellulose, which is applied on small polyurethane sponges capable of adhering to skin. SALONPAS
(R)
, a composition sold by Hisamitsu Pharmaceutical Co. Inc. (Japan), comprises methyl salicylate (as an anti-inflammatory agent) and menthol in a thick mass formed with polyvinyl alcohol, which is applied on small polyurethane sponges capable of adhering to skin. The active agents in these known compositions are strongly polar substances of relatively low molecular weights. thus they have much more chance for resorption than less polar substances with higher molecular weights.
Peptidaceous compounds form an important group of pharmaceutically active substances. In the specification and claims the term “peptidaceous compound” or “peptidaceous pharmacon” refers generally to any pharmaceutically active substance the molecule of which comprises at least two amino acids bound together by a peptide bond. A narrower group of them with outstanding pharmaceutical importance is the group of polypeptides, of which natural hormones and artificial analogues and derivatives thereof are of particular interest. A member of this latter group with outstanding importance from the aspects of public health is insuline. Hormones and hormone analogues which regulate fine balances of the organism are hazardous substances, thus with these substances it is particularly necessary to decrease the risks of inadvertent overdosing or underdosing. Some representatives of hormones and hormone analogues, in particular insuline, can be introduced only parenterally. Thus it would be highly desirable to introduce these active agents topically in the living organism. However, topical preparations applicable for introducing peptidaceous pharmacons in living organisms have not been disclosed before.
Based on my studies I have found that, upon utilizing specific auxiliary agents, peptidaceous pharmacons can be brought to a form capable of transdermal resorption. This recognition enables one to produce topically applicable pharmaceutical preparations comprising peptidaceous pharmacons
Thus, the invention relates to a topically applicable preparation for introducing a peptidaceous pharmacon in a living organism. The preparation according to the invention comprises
(i) a peptidaceous pharmacon,
(ii) capsaicine, histamine and/or cantharis extract. and
(iii) an epithelizing agent, in admixture with carriers and/or diluents conventionally applied in topical pharmaceutical preparations, optionally applied onto a support capable of adhering to skin.
The preparations according to the invention may comprise as peptidaceous pharmacon preferably a natural hormone or a synthetic analogue or derivative thereof, particularly preferably insuline. The amounts of peptidaceous pharmacons contained in a unit dose (i.e. in a dose for a single treatment) of the preparations according to the invention (such as in a single plaster) may be about the same as present in the conventional oral or parenteral unit dose forms. Thus, as an example, plasters according to the invention applicable in the treatment of diabetes mellitus may comprise 0.1-50 IU of insuline for one plaster or for a unit plaster fragment (e.g. for 1 cm
2
of plaster surface).
Capsaicine, histamine and cantharis extract (the active agent of
Tinctura cantharidis)
, which form component (ii) of the preparations according to the invention, are rubefacient local vasodilators. These substances have been applied for a long time in the therapy as external rubs for stimulating subdermal circulation e.g for the treatment of chilblains, extremital pains, rheuma and the like [Kiráy, Rácz, Török: Bör- és nemibetegsegek (Skin and Venereal Diseases, in Hungarian); 1927 and subsequent pages (Medicina Könyvkiadó, Budapest, 1986)]. As epithelizing agent, which is component (iii) of the preparation according to the invention, any agent known to be applied in the therapy to loosen the upper epithelial layer of skin can be utilized. Characteristic representatives of such agents are listed e.g in the textbook cited above. Salicylic acid, sodium chloride, urea and resorcinol are examples of epithelizing agents which can be utilized with good results in the preparations according to the invention.
Although, as it appears from the textbook cited above, components (ii) and (iii) of the preparation according to the invention have already been utilized before separately in compositions for topical treatment, no data can be found in the literature on their combined use and on their prospective combined effects. No data can be found in the literature, either, that component (ii) or component (iii) would have been utilized before in combination with a peptidaceous pharmacon for the purpose of topical treatments.
In the preparations according to the invention components (i) and (ii) interact with one another, which is verified e.g. by the observation that when capsaicine is added to an insuline suspen

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