AU1024299A - Use of delta-aminolaevulinic acid for the preparation of a topical medicament for the integral diagnosis and/or therapy of tumours in hollow organs - Google Patents

Abstract

The invention relates to a topically applied medicament for the integral diagnosis and/or treatment of tumours in hollow organs, with a delta -aminolevulinic acid base. The inventive medicament contains a physiologically compatible acid and sodium hydrogen phosphate as a buffer in addition to the active agent in an aqueous solution, and has a pH value of 4.8 to 5.2. The medicament is stable and particularly compatible.

Description

medac Gesellschaft ffr klinische Spezialpr~parate mbH Fehlandtstr. 3 20354 Hamburg 5 September 1998 P 48110 WE Use of 8-aminolaevulinic acid for the preparation of a topical medicament for the integral diagnosis and/or 10 therapy of tumours in hollow organs The invention relates to the use of 8-aminolaevulinic acid (ALA) for the preparation of a topical medicament for the integral diagnosis and/or therapy of tumours in hollow organs. 15 Malignant oncoses in hollow organs, such as, for example, urinary passages and airways, peritoneal cavity, gastrointestinal tract and female genital tract, are distinguished by high recurrence and progression rates. These are an expression of 20 precancerous and cancerous changes which already exist synchronously (early carcinomas), which cannot be diagnosed endoscopically and thus cannot be treated in the early stage. In the case of early carcinomas of the urinary 25 bladder, for example, the recurrence and progression rates are up to 90%. A potential degeneration in the area of the entire bladder mucous membrane is therefore to be postulated. The precancerous and cancerous changes, such as, for example, severe urothelial 30 dysplasias, carcinoma in situ and multifocal micropapillary tumours, cannot be recognized endoscopically or can only be recognized with great difficulty. For a curative treatment, a prerequisite is to 35 recognize all tumour foci comprehensively, on the other hand a complete and integral treatment of the entire bladder mucous membrane is required. None of the diagnostic procedures known until now is able to recognize tumour foci completely and 1 ~specifically, even in the early stage. Until now, -2 medicaments (cytostatics, BCG) have been instilled into the urinary bladder for the therapy of the bladder mucous membrane. Although -the recurrence intervals can be prolonged in this manner, a final cure, however, is 5 not possible within the framework of the therapeutic processes known until now (J. Urol. 1987, 138, 1363 1368). Alternatively to the conservative diagnosis and therapy methods, photodynamics is employed. It is based 10 on light absorption by a chemical compound, the so called photosensitizer, which on the one hand leads to emission of fluorescence, which can be utilized for diagnosis, and on the other hand causes a cytotoxic reaction, which is of use for therapy. 15 In the context of photodynamics, porphyrin mixtures of different compositions, which have to be administered intravenously, are at present used as photosensitizers. The intravenous administration of 20 photosensitizers of this type involves two crucial disadvantages. On the one hand, it leads to a concentration of the porphyrin mixtures in the entire skin and thus triggers a phototoxic reaction on exposure to light, 25 which manifests itself in the form of reddening, swelling and erosion of the skin and by pain. The patients are therefore forced to protect themselves from strong irradiation by light for several weeks; in practice a diagnosis or therapy of this type means a 30 month-long stay in darkened rooms for the affected! On the other hand, the low tumour-selective concentration of the porphyrin mixtures crucially restricts the efficiency of fluorescence detection. To date, this fluorescence difference can only be shown 35 with expensive computer-assisted image analysis systems, since it is not visible with the naked eye. In addition, the therapeutic use of intravenously administered photosensitizers is restricted on account of the low tumour selectivity, - 3 and local-type side effects, such as contracted bladder formation, were observed. The use of S-aminolaevulinic acid (ALA) for the production of a topical medicament for the integral 5 diagnosis and/or therapy of tumours in hollow organs has also already been proposed, cf. DE-A 42 28 106 and US Patent 5 079 262. ALA is generally known in the formation of haemoglobin (haem biosynthesis) as a precursor of 10 protoporphyrin IX. The previous clinical use of ALA was restricted to certain metabolic disorders (porphyrias), where, however, it proved unsuccessful. Thus Okuda et al. (Hepatology 1991, 14, 1153-1160) report on the treatment of patients with Gilbert's syndrome (Behcet's 15 disease) and on healthy subjects. As a substance, ALA is innocuous. On intravenous administration of 0.23 mg of ALA, no toxic reactions were observed (Okuda et al., Hepatology 1991, 14, 1153-1160, cf. also Kennedy et al., J. Photochem. 20 Photobiol. B., 1990, 6, 143-148) . According to Berlin et al. (Biochem. J. 1956, 64, 80-90 and 90-100), phototoxic reactions were observed only for 1 to 2 days in healthy subjects at relatively high dosage. In the context of various toxicity investigations in animals 25 (Lima et al., Can. J. Neur. Sci. 1981, 8, 105-114; Arnold et al., Food Cosmet. Toxicol. 1975, 13, 63-68; Kennedy et al., ibid 1976, 14, 45-48) it was not possible to observe any negative symptoms with respect to direct toxicity, photosensitivity, teratogenicity or 30 sub-acute toxicity. The recently described topical use of ALA in the treatment of superficial skin tumours (especially basaliomas), cf. Kennedy et al., (J. Photochem. Photobiol. B., 1990, 6, 143-148), relates primarily to 35 the visually recognizable tumours, which are brought locally into contact with the substance in a controlled manner. The action of ALA is based on the stimulation R N of endogenous porphyrin formation. The use of ALA - 4 according to DE-A 42 28 106 is 'based on the knowledge that ALA is selectively absorbed and concentrated by tumour tissue on topically integral administration to the mucous membranes of hollow organs and only leads to 5 increased porphyrin formation and concentration therein, while the healthy tissue essentially remains unaffected. It was shown that according to the invention the concentration factor relative to healthy tissue is up to 20:1, with the result that the 10 fluorescence of the tumour or pretumour islets is recognizable even with the naked eye. The expensive image processing systems formerly necessary can in this case be dispensed with. Other than in the earlier applications, ALA is 15 in this case not specifically applied to the already recognized tumours to be treated, but the whole mucous membrane lining the hollow organ is homogeneously wetted. As a result of the tumour-selective deposition of ALA, on subsequent Aintegral irradiation of the 20 urinary bladder only tumourous lesions fluoresce (diagnosis) or are destroyed (therapy). Compared with the earlier processes for the diagnosis of tumours in hollow organs, which were restricted to visible tumours in advances stages, the 25 use of ALA has crucial advantages. The selective concentration in the tumour tissue taking place on instillation of ALA into hollow organs, such as, for example, the urinary bladder, is expressed in comparison with earlier therapeutic attempts in very 30 much higher difference factors compared with healthy tissue. While in the intravenous administration of porphyrin derivatives which were used for diagnosis as undefined mixtures, difference factors of 2 to 5:1 between tumour and healthy tissue were observed, the 35 difference factor in comparison with healthy tissue in the integral treatment of the urinary bladder is, for example, 20:1. As a result of the strong fluorescence of tumourous tissue connected therewith on irradiation, or the first time the diagnosis of precancerous - 5 lesions, which until now were not detectable endoscopically, is successful. The side effects of photosensitization, which in the case of intravenous administration of 5 photosensitizers in practice made necessary a month long stay of the patients in darkened rooms, do not occur with the use of ALA for the integral treatment of the urinary bladder. Furthermore, complicated image processing systems for diagnosis can be dispensed with 10 as a result of the improved difference factor. Owing to the stimulation of endogenous porphyrin formation as a result of tumour-selective absorption in the use of ALA, it is possible not only to recognize bladder carcinomas in the early stage 15 (integral fluorescence labelling), but also selectively to destroy the tumourous lesions by subsequent integral irradiation of the urinary bladder (integral therapy). Thus for the first time a therapy is available per se for precancerous and cancerous lesions which until now 20 were not treated in early disease stages on account of the lacking possibility of making a diagnosis. The recurrence and progression rates observed until now for, for example, bladder tumours can be decisively lowered by the use of ALA for diagnosis and/or therapy. 25 According to US Patent 5 079 262, topical highly concentrated ALA solutions having an active compound content of between 10 and 33% by weight are used. ALA solutions of this type are not stable even when prepared immediately before use and decompose in a 30 very short time. DE-A 42 28 106 proposes the use of ALA in 3% strength aqueous solution which is adjusted to a neutral pH by means of sodium bicarbonate as a buffer for diagnostic application. For therapeutic 35 applications, the concentration of the neutral buffered ALA solution should be up to 10%. However, it has been shown that ALA solutions adjusted to the physiological pH of approximately 7 are not stable. Even at a pH of above 5.2, a decomposition of the active compound takes - 6 place with simultaneous yellow colouration of the solution. On the other hand, solutions of 6 aminolaevulinic acid hydrochloride, which have a pH between 2.2 and 3.2 even at a concentration of 1%, lead 5 to severe burning, which is difficult for the patient to bear. It has now been found that the pH of the ALA solution must be between 4.8 and 5.2 in order to achieve both good tolerability and adequate stability. 10 A pH of above 5.2 leads to the instability of the S-aminolaevulinic acid; at a pH of below 4.8 the side effect profile worsens significantly. For the preparation of the ALA solution, the physiologically tolerable buffer solution is preferably added to the 15 sterile ALA lyophilizate only shortly before use. In this case certain concentration variations inevitably occur, which can be in an order of magnitude of +10%. In other words, this means that in the preparation of a 3% strength solution the actual content can vary 20 between 2.7 and 3.3%. It was found that in particular using sodium hydrogen phosphate (Na 2 HPO4-12 H20) adjustment to the desired pH range from 4.8 to 5.2 is successful, while this is not possible without difficulty with other buffers, such as sodium 25 bicarbonate, utilizable per se physiologically. The invention accordingly relates to a topically administrable medicament, for the integral diagnosis and/or therapy of tumours in hollow organs, based on S-aminolaevulinic acid, the medicament being 30 characterized in that it contains S-aminolaevulinic acid in an aqueous solution which is adjusted to a pH of 4.8 to 5.2 by means of a physiologically tolerable buffer solution. The pH is preferably adjusted to a pH of 4.8 to 5.2 by means of a physiologically tolerable 35 acid and sodium hydrogenphosphate. The physiologically tolerable acid is preferably hydrochloric acid. A particularly advantageous embodiment of the invention consists in employing S-aminolaevulinic acid as the )TF R hydrochloride.

- 7 Favourably, the pharmaceutical solution is only prepared immediately before use from S-aminolaevulinic acid hydrochloride in the-form of a lyophilizate with addition of the sodium hydrogenphosphate buffer 5 solution, the medicament being made available to the physician in the form of a combination pack. Preferably, the combination pack already contains the parts of an arrangement which, on use, can serve for the instillation of the medicament. 10 The use according to the invention of ALA is suitable for the diagnosis and/or therapy of the urinary tract epithelium and of the central nervous system (preferably the various brain areas) and for the integral diagnosis and/or therapy of hollow organs such 15 as the urinary bladder (urinary tract), the airways, the peritoneal cavity, the gastrointestinal tract, or of the female genital tract, the urinary bladder and the female genital tract preferably being suitable. Administration can be carried out - for example d 20 in the urinary bladder - either topically intravesically or in a preferred embodiment by instillation of the ALA solution. For diagnosis, the hollow organ or the affected area is integrally irradiated with light of the 25 wavelength 390 to 430 nm, preferably 410 nm, such that tumourous lesions fluoresce. Light of a wavelength of 406 nm refracted by filters can preferably be used. For integral diagnostic irradiation, a krypton ion laser is particularly suitable. 30 In order to destroy the tumourous lesions, after instillation of the medicament according to the invention the affected area is extensively irradiated or the hollow organ is integrally irradiated with light of the wavelength 600 to 650 nm, preferably 630 nm. In 35 particular, an Nd:Yag laser (neodymium:yttrium aluminium garnet laser) is used in therapeutic local irradiation. The invention is illustrated below by means of example. J\h - 8 Example A sterile solution of 5.4% by weight of Na 2

HPO

4 -12H 2 0 in sterile water was prepared. The pH of this phosphate solution was about 9. 5 3 g of S-aminolaevulinic acid hydrochloride were added to 100 ml of this buffer solution. The pH was adjusted to 4.85 by this means. The osmolality of this solution was 700 mOsm/kg. The solution showed no discolouration even after standing at room temperature 10 for several hours, while a solution of pH > 5.2 turned yellowish within minutes; at a pH of > 6 the discolouration clearly visibly commenced even during the formation of the solution; after standing for one hour a solution of this type is coloured strongly 15 orange-yellow. Further experiments showed that the pH range from 4.8 to 5.2 can still be adhered to using the 5.4% strength sodium hydrogenphosphate solution even if the ALA concentration varies by ±10%, i.e. between 2.7 and 3.3% by weight. 20 The 3% strength ALA solution having a pH of 4.85 was well tolerated on instillation into the bladder of patients. In particular, no unpleasant burning occurred, as is observed with unbuffered ALA solutions.

Claims (5)

1. Topically administrable medicament, for the integral diagnosis and/or .therapy of tumours in hollow organs, based on 8-aminolaevulinic acid, characterized 5 in that it contains 8-aminolaevulinic acid in an aqueous solution which is adjusted by means of a physiologically tolerable acid and sodium hydrogen phosphate to a pH of 4.8 to 5.2.

2. Medicament according to Claim 1, characterized 10 in that it contains hydrochloric acid as the acid.

3. Medicament according to Claims 1 or [sic] 2, characterized in that it contains S-aminolaevulinic acid as the hydrochloride.

4. Medicament according to one of Claims 1 to 3, 15 characterized in that, for preparation immediately before use, it is present in the form of a pack unit of lyophilized S-aminolaevulinic acid hydrochloride on the one hand and the sodium hydrogenphosphate solution on the other hand. 20

5. Medicament according to one of Claims 1 to 4, characterized in that it is formulated for instillation.