Reexamination Certificate
1999-09-10
2001-05-29
Page, Thurman K. (Department: 1615)
C156S327000, C156S283000, C424S443000, C424S448000
Reexamination Certificate
active
06238284
ABSTRACT:
DESCRIPTION
The invention relates to a transdermal therapeutic system for application to the skin and/or mucosa consisting of at least one active substance in the form of a solid dispersion in combination with at least one destructuring agent and/or at least one structuring agent in a common matrix.
The invention thus relates to a method for improving the cutaneous permeation of active substances, which can be employed in particular for producing a transdermal therapeutic system (TTS) intended for application to the skin or mucosa.
The term “TTS” describes an administration device which adheres to the target organ which is the skin or mucosa and moreover allows the contained medicinal substance to exert systemic activity in the body by passing through the target organ.
The terms destructuring agent and structuring agent derive from the “ice” theory of hydrogels as described, for example, by Hüttenrauch et al. (Pharmazie 40, p. 427, 1985).
Compositions used for transdermal administration of active substances are known in a wide variety of forms:
U.S. Pat. No. 4,777,047 describes formulations for transdermal administration which contain a calcium channel blocker and surface-active auxiliaries such as isopropyl myristate or ethyl oleate in a solvent. The solvents generally mentioned are propylene glycol, linolenic acid, oleyl alcohol, Solketal or dimethyl sulphoxide.
U.S. Pat. No. 5,422,361 describes a cream or lotion which contains a lipophilic pharmaceutical active substance. The basic material used in this case is a physically and chemically stable oil-in-water emulsion which has a content of N-methyl-2-pyrrolidone, dimethyl sulphoxide, Solketal or oleyl alcohol. The basic materials described for Solketal and dimethyl sulphoxide have a maximum content of these substances of 10% by weight.
DE-C 43 09 830 describes an active substance plaster for delivering estradiol to the skin. The active substance plaster has an active substance reservoir consisting of a contact adhesive. A penetration accelerant, namely monoisopropylideneglycerol (MIPG, Solketal) or monoisopropylidenediglycerol (MIPD) is present in the polymer matrix of the contact adhesive to improve the bioavailability of estradiol.
Akhter, S. A. et al. (J. Pharm. Pharmacol. 36, Suppl., p. 7 (1984)) describe solutions of an active substance in the solvent Solketal to which 7% oleic acid is added as penetration-enhancing agent.
Dosage forms of these types for transdermal administration may be adequate for certain purposes, in particular for active substances for which the permeability of the skin is relatively good. However, as a rule, the epidermis, for example of humans, has relatively low permeability for active substances. Accordingly, on use of the known formulations, ordinarily too little active substance is transported through the skin into the bloodstream. In addition, cutaneous intolerance is common, such as, for example, skin irritation or even allergic effects. This is particularly true when steroid hormones are to be employed as active substances.
The preferred area of use of transdermal medicinal forms are symptoms, diseases, deficiency states and similar needs, such as nausea, heart/circulatory failure, hormone deficiency, the wish for contraception. These needs require provision of the active substance which is longer lasting, uniform or adapted to the biological rhythm of the blood level.
Typical TTSs release the contained medicinal substance uniformly over a prolonged period. However, additionally more complicated systems and mixed types (mixed systems) have also been described. Examples of TTSs mentioned by D'Mello (Transdermal Patch Drug Delivery, Scrip report BS750, PJB Publications Ltd., 1995) or in the “Rote Liste” (publisher: Bundesverband der pharmazeutischen Industrie (BPI), 1996) are:
Nicotine patches,
Hyoscine patch,
Glyceryl trinitrate patches,
NSAID patches,
Fentanyl patch,
Clonidine patch,
Oestradiol patch,
Oestradiol/Norethisterone patch,
Estradiol vaginal rings,
Isosorbide dinitrate ointments,
Isosorbide dinitrate transdermal sprays,
Glyceryl trinitrate ointments.
TTSs for insulin and other peptide active substances, including certain “releasing hormones”, are being developed.
The production of the TTSs disclosed to date already in many cases takes account of the fact that not all active substances permeate through the skin to a sufficient extent. However, satisfactory functioning of the systems depends crucially on ensured permeation.
According to the recent review (Ghosh T. K., Banga, A. K., Pharm. Technol., 17 (March) 72-96 (1993) and 17 (April) 62-87 (1993)), there are physical, chemical and biological possibilities for improving cutaneous permeation. The use of so-called penetration promoters is to be regarded as a chemical possibility. These substances penetrate into the skin and interact with the constituents of the stratum corneum, which is the main impediment to penetration of the active substance. Penetration promoters reduce the resistance of the skin and thus increase the passage (flux) of the active substance through the skin. In most cases they also beneficially affect the active substance partition ratio between skin and vehicle (Franz, T. J., Tojo, K., Shah, K. R., Kydonieus, A., Transdermal Delivery, in Kydonieus, A. (Ed.) Treatise on Controlled Drug Delivery, Marcel Dekker, Inc., 341-422 (1992); Loth, H., Meth. and Find. Exp. Clin. Pharmacol., 11 (3), 155-164, (1989); Robson, D. L., Thesis, University of Bradford, Postgraduate School of Studies in Pharmacy, 1988, p. 1-25).
The transdermal flux takes place mainly intercellularly. This involves the permeating substance penetrating through the lipophilic cell structures (lipophilic route) so that penetration promoters which affect this route ought, depending on the region of the cell structure (cf. Fartasch, M. The nature of the epidermal barrier: Structural aspects. Advan. Drug Delivery Rev. 18(3), 273-282 (1996)), to have three sites of action (Barry, B. W., J. Controlled Release, 15, 237-248, (1991)), namely
in the direct vicinity of polar head groups (region A)
in the aqueous region between the head groups (region B) and
within the nonpolar constituents of the lipid bilayers (region C).
The site of action of most permeation promoters is known, but details are still lacking for some substances (Table 1).
TABLE 1
Classification of penetration promoters according to the
site of action
Site of action
(predominant)
Penetration promoter
Region A
Water, dioxolane derivatives, ethyl
acetate, urea*, ethanol and short-chain
monohydric alcohols (C
2
-C
6
)*, propylene
glycol*
Region B
Ethanol
Region C
DMSO*, DMF**, laurocapram and derivatives,
fatty acids (e.g. oleic acid), surfactants
(e.g. decyl methyl sulphoxide), terpenes
Unclear
Isopropanol, glycerol, monohydric alcohols
assignment
(C
8
-C
14
), alkanes, alkyl halides, amides,
pyrrolidone derivatives, fatty acid esters,
cyclodextrins, polyethylene glycols
Additionally affects:
*keratin fibrils
**region A (solvation)
The overview in Table 1 makes it very clear that regions A and C are almost exclusively the sites of action of the well-known permeation promoters. These promoters aim at affecting either the head groups or the lipophilic chains. Only ethanol is thought to act in the aqueous region in the vicinity of the head groups. It can thus be said that the well-known permeation promoters, with the exception of ethanol, affect in particular the lipophilic regions and promote the lipophilic flux.
On the other hand, it is known that an alteration in the lipophilic regions is associated with serious impairments of the condition of the skin. These impairments extend from drying out and embrittlement to cracks, marked irritation, reddening, exzema and similar skin damage. This also applies to ethanol, the concentration of which is therefore limited on dermal application. In addition, ethanol has the disadvantage of ease of evaporation so that supersaturation states occur, the disadvantages of which will be explained later.
It is, however, known that the flux is possible by tw
Ahrens Kathrin
Dittgen Michael
Fricke Sabine
Gerecke Hagen
Köpke Kai
Ghali Isis
Hochberg D. Peter
Holt William H.
JENAPHARM GmbH & Co. KG
Page Thurman K.
LandOfFree
Transdermal compositions with enhanced skin penetration... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Transdermal compositions with enhanced skin penetration..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Transdermal compositions with enhanced skin penetration... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2526985