Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-07-26
2003-05-06
Lovering, Richard D. (Department: 1712)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C424S450000, C436S064000, C436S172000, C514S863000, C514S864000, C516S056000
Reexamination Certificate
active
06559183
ABSTRACT:
The present invention relates to nanoemulsions which contain 5-aminolevulinic acid or its derivatives, precursors or metabolites.
Photodynamic therapy is a novel and promising method for treating various premalignant and malignant diseases which are connected to cell proliferation. The principle of photodynamic therapy is based on introducing what is termed the photosensitizer into the tumor tissue and using irradiation with light of a suitable wavelength to convert this photosensitizer into a cytotoxically active compound which in the end destroys the cells. The selectivity of this method is based on the sensitizer being concentrated to a greater extent in rapidly proliferating tumor cells than in normal tissue. Irradiation with light in a locally restricted manner can then be used to specifically activate the sensitizer which is present in the tumor cells, thereby destroying the cancer cells while to a large extent sparing the healthy tissue.
Until now, an intravenously administered mixture of hematoporphyrin derivatives has in the main been used as the photosensitizer. Despite the encouraging clinical successes which have been achieved in connection with a number of different types of cancer, these hematoporphyrin derivatives nevertheless suffer from a variety of disadvantages. In the first place, relatively high concentrations of the active compound appear in normal tissue due to the low degree of tumor selectivity and the fact that the active compound is only slowly eliminated from the body. Undesirable photochemical reactions therefore take place in healthy tissue in connection with the irradiation. In the second place, this treatment results in a general sensitivity to light such that the patient is not allowed to expose himself to daylight for a period of some four weeks.
In certain cases, it is possible, particularly in connection with dermatological and gynecological applications, to bring about a reduction in the high concentration of active compound in normal tissue, and therefore in the undesirable side-effects, by developing topically applicable active compound formulations in place of the known systemic formulations. Attempts are also being made to reduce the sensitivity to light by using photosensitizer precursors which are photochemically inactive and are only converted into a photosensitizer within the target cell.
5-Aminolevulinic acid is an endogenous substance which is synthesized from glycine and succinyl-CoA. In heme biosynthesis, the extremely photoactive protoporphyrin IX is formed from 5-aminolevulinic acid (5-ALA) in several rapidly proceeding reactions steps, and is then converted into heme in a slow reaction. If the heme concentration is too high, a natural control mechanism inhibits both the endogenous synthesis of 5-aminolevulinic acid and the breakdown of protoporphyrin IX.
This control mechanism is circumvented by exogenously administering synthetically prepared 5-aminolevulinic acid, thereby giving rise to an increased production of protoporphyrin IX. Since the breakdown of protoporphyrin IX is still inhibited by the natural control mechanism, this compound becomes concentrated in the cells. When irradiated with light, protoporphyrin IX is able to enter into a photochemical oxidation reaction and consequently acts as a photosensitizer. When the sensitizer molecule absorbs a quantum of light, it is first of all transferred into an electronically excited state (singlet state), which is relatively short-lived, and either releases its excess energy once again within a few nanoseconds by emitting a fluorescence photon or else passes over into a relatively long-lived triplet state. Energy from this triplet state can be transferred to oxygen molecules which are present in the cell. The singlet oxygen which is formed in this connection has a cytotoxic effect, in particular on proliferating cells, since it reacts with cell components, for example the cell membrane and the mitochondria, or triggers the formation of cell-damaging free radicals. Furthermore, irradiation of the photosensitizer gives rise to a characteristic fluorescence radiation which can be used for detection reactions, for example for detecting proliferating cells.
A number of investigations using topically applicable 5-aminolevulinic acid compositions are known from the prior art. While these investigations have the feature in common that the 5-aminolevulinic acid employed is in the form of an oil-in-water emulsion, differences exist with regard to other parameters, such as period of penetration, period of treatment, type of light employed and the dose of light applied.
B. Thiele et al. (H+G, Volume 69, No. 3, pages 161-164 (1994)) describe investigations which involve using 20% &dgr;-aminolevulinic acid in the form of an oil-in-water emulsion, with a penetration period of from 5 to 6 h, and subsequently irradiating with an argon ion-pumped dye laser (emission maximum 630 nm) giving a cumulative total dose of from 50 to 100 J/cm
2
.
Wolf et al. (Journal of the American Academy of Dermatology Vol. 28, pages 17 to 21, 1993) describe investigations which involve using 20% 5-aminolevulinic acid in the form of an oil-in-water emulsion, with a penetration period of 4, 6 or 8 h, and irradiating with unfiltered light or red light, giving a light dose of from 30 J/cm
2
to 100 J/cm
2
.
Although the investigations disclosed in the prior art clearly demonstrate the promising potential of photodynamic therapy using 5-aminolevulinic acid, oil-in-water emulsions which are so far known suffer from a number of disadvantages.
Thus, M. Novo Rodriguez et al. (SPIE, Vol. 2371, pages 204-209) showed that, in the high concentrations which are required for a clinical application, aminolevulinic acid is unstable in aqueous solutions in the neutral to basic pH range. In the time period of 25 h investigated, satisfactory results are only obtained at a pH of 5.01, and a concentration of 3% and a pH of 5 are specified as the optimal conditions for aqueous solutions of 5-aminolevulinic acid. However, for clinical use, it will in general also be necessary to provide compositions in a higher concentration range; furthermore, to be used commercially, the 5-ALA solutions have to be stable for a period which is of the order of weeks or months.
V. von Arx et al. (J. Pharm. Pharmacol. 49: 652-656, 1997) describe investigations relating to the topical application of 5-aminolevulinic acid in a variety of gels. This publication states that the best formulation for maintaining the stability of 5-aminolevulinic acid is a combination with Novion AA-1, a polyacrylic acid, at a pH <6.
Another disadvantage of the known oil-in-water emulsions is that the depth to which the photosensitizer penetrates into the damaged tissue is not optimal. As a result, the diseased tissue is in many cases only accessible to the photodynamic therapy in its superficial layers even though the depth to which the light employed for activating the photosensitizer penetrates would also enable more deeply lying layers to be treated.
The object of the present invention was therefore to make available 5-aminolevulinic acid-comprising compositions in which the disadvantages known from the prior art are at least partially eliminated and which, in particular, possess adequate stability and exhibit an improved ability to penetrate into tissue.
This object is achieved by a composition which is characterized in that it contains a nanoemulsion which comprises a substance selected from 5-aminolevulinic acid, or a derivative, a precursor and/or a metabolite thereof, and a carrier in an aqueous phase.
It was observed, surprisingly, that the stability of 5-aminolevulinic acid can be substantially increased when the acid is formulated into a nanoemulsion. While the reasons for this are not known, it appears that a microenvironment created by nanosomes has a particularly favorable effect on the stability of the 5-aminolevulinic acid.
It has furthermore been shown, surprisingly, that very high tissue penetration depths can be achieved with the nanoemulsions accor
Burmeister Gerd
Schmid Hans W.
ASAT AG Applied Science & Technology
Lovering Richard D.
Rothwell Figg Ernst & Manbeck
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