Particulate formulation of 5-amino levulinic acid for oral administration

Abstract

The invention relates to a solid pharmaceutical composition in form of a powder for oral administration comprising or essentially consisting of 5-amino levulinic acid or a physiologically acceptable salt thereof and a primary packaging comprising such composition.

Description

Particulate formulation of 5-amino levulinic acid for oral administration

[0001] Priority is claimed of European patent application no. 24 165 407.8 that was filed on March 22, 2024.

[0002] The invention relates to a solid pharmaceutical composition in form of a powder for oral administration comprising or essentially consisting of 5-amino levulinic acid or a physiologically acceptable salt thereof and a primary packaging comprising such composition.

[0003] 5 -Amino levulinic acid (5 -ALA) is an endogenous non-proteinogenic amino acid involved in the porphyrin synthesis pathway. Heme generation from 5-ALA is completed by binding iron to a center. Protoporphyrin IX (PpIX) is produced in just one step before iron combination. PpIX has unique characteristics, because it reflects red light when it is irradiated with blue light of a specific wavelength.

[0004] Cancer cells have acquired the ability to proliferate indefinitely and have abnormalities in the heme production mechanism. Cancer cells that have absorbed large amounts of 5-ALA are found to be unable to produce heme properly and accumulate PpIX one step before. Therefore, it is possible to make only cancer cells glow red using blue light by administering 5-ALA to subjects with cancer, since 5- ALA is converted into heme in ordinary cells but remains as PpIX in cancer cells.

[0005] Based upon these principles, 5 -aminolevulinic acid induced PpIX has proven its rational in fluoro-guided resection of malignant gliomas due to a selective tumor uptake and minimal skin sensitization (photodynamic diagnosis (PDD)). Moreover, the relatively specific accumulation of photosensitizing PpIX within the tumor cells has also gained interest in therapy of malignant glioma of malignant gliomas. When exposed to light, PpIX produces reactive oxygen species (ROS), a substance that is highly toxic to cells. Treatment that uses this phenomenon to selectively kill cancer has attracted attention as photodynamic therapy (PDT) (see e.g. M-Ch Tetard et al., Photodiagnosis and Photodynamic therapy of malignant glioma, 2014, pp. 319-30).

[0006] -Amino levulinic acid is marketed under the tradename Gliolan® as powder for oral solution (photonamic GmbH & Co. KG, Germany). It is provided in form of a lyophilizate in bottles containing 1.5 g 5-amino levulinic acid hydrochloride. The recommended dose is 20 mg 5-ALA HC1 per kilogram body weight. The oral solution is prepared by dissolving the amount of powder of one bottle in 50 ml of drinking water. One bottle of Gliolan® 30 mg / ml powder for oral solution reconstituted in 50 ml of drinking water corresponds to a total dose of 1,500 mg 5 -aminolevulinic acid hydrochloride (5-ALA HC1). Gliolan® is for single use only and any content remaining after first use must be discarded.

[0007] Another product also containing 1.5 g of 5-amino levulinic acid is marketed under the tradename Alaglio® for visualization of non-muscle invasive bladder cancer during transurethral resection (ChugaiPharmaceutical Co., SBI Pharmaceuticals Co., Japan) The recommended dose for adult patients is likewise 20 mg of 5 -aminolevulinic acid hydrochloride per kg body weight, dissolved in water.

[0008] 5 -Amino levulinic acid is comparatively expensive. Thus, it is not cost efficient to discard residual amounts that were not used in view of the body weight of the patient to be treated.

[0009] US 2003 0124191 Al relates to the use of a powder comprising at least one active substance, at least one surfactant, at least one wetting agent and at least one diluent, for preparing a pharmaceutical or nutraceutical composition, this composition allowing rapid and immediate release of the active substance.

[0010] US 11,026,909 Bl relates to a method for amelioration of, or prophylaxis against, a viral infection comprising administering to a patient in need of treatment a therapeutically effective amount of 5- aminolevulimc acid, optionally with at least one of cucumarin nano, zinc, vitamin C and methylene blue, and compositions thereof. Such compositions may be used for the treatment of coronavirus infections, including the SARS-CoV-2 virus, and / or rhinoviruses.

[0011] EP 0 759 746 Bl relates to a wipe, comprising an absorbent woven or non-woven fabric, cloth or tissue substrate, impregnated with a pharmaceutically active agent, wherein the agent is a substance effective in stimulating melanocytes to produce melanin and / or is effective in a topical treatment of a skin condition in combination with electromagnetic radiation falling in the range of 220-700 nm.

[0012] JP 2018 153428 A relates to an oral agent package of aminolevulinic acid hydrochloride. The oral agent package includes a non-lyophilized solid formulation containing aminolevulinic acid hydrochloride in a screw cap type container. The container including the solid formulation is stored in a packaging bag. The solid formulation contains at least aminolevulinic acid hydrochloride. The solid formulation 10 is in a non-lyophilized state, and is packed in a solid state into the container.

[0013] Dusa Pharmaceuticals, "Levulan Kerastick (aminolevulinic acid HCl) for topical solution, 20% Initial U.S. Approval: 1999", 1 March 2018, Highlights of Prescribing Information relates to a topical solution for photodynamic therapy. The topical solution contains 20% aminolevulinic acid hydrochloride, ethanol, water, laureth-4, isopropyl alcohol, and polyethylene glycol.

[0014] "Public Assessment Report - Scientific Discussion 5-ALA", 26 March 2015 relates to medicated plaster containing 5 -aminolevulinic acid indicated for the treatment of mild to moderate actinic keratoses lesions on the face and scalp (hairless areas). After topical application of 5 -aminolevulinic acid (5-ALA), its metabolite protoporphyrin IX (PPIX) accumulates intracellularly in the treated actinic keratoses lesion. The intracellular PPIX is a photoactive, fluorescing compound and, upon light activation in the presence of oxygen, single oxygen is formed which causes damage to cellular compartments of the light- exposed target cells, in particular the mitochondria.

[0015] It is an object of the invention to provide pharmaceutical compositions and pharmaceutical dosage forms of -amino levulinic acid and its physiologically acceptable salts, preferably the hydrochloride salt, that have advantages compared to the prior art.

[0016] The pharmaceutical compositions and pharmaceutical dosage forms should allow for adjustable dosing in view of the individual body weight of the patient to be treated thereby avoiding the need to discard excessive amounts of the active ingredient. The pharmaceutical compositions and pharmaceutical dosage forms should facilitate transport and storage and should provide storage stability for extended periods of time, preferably several years. Furthermore, processes for preparing the pharmaceutical compositions and pharmaceutical dosage forms should be easy and cost efficient The pharmaceutical compositions and pharmaceutical dosage forms should be easily packable into primary packaging with high dose accuracy and likewise be easily as well as completely withdrawable from such primary packaging.

[0017] This object has been achieved by the subject-matter of the patent claims.

[0018] It has been found that 5-amino levulinic acid and its physiologically acceptable salts can be provided in dose units (pharmaceutical compositions, pharmaceutical dosage forms, primary packaging) that can be used as hospital products. For example, it has been found that 3 dose units each containing 500 mg of 5-amino levulinic acid or a physiologically acceptable salt thereof have advantages compared to 1 dose unit containing 1500 mg. Dosing is adjustable to body weight in a facilitated manner thereby reducing waste.

[0019] For example, when the dose unit is provided in a primary packaging, e.g. a sachet, containing 500 mg of the active ingredient, individualized dosing per body weight can easily be achieved.

[0020] Further, waste can be reduced and the active ingredient can be used more efficiently. When the body weight is within the range of from 50 kg to 75 kg, three primary packaging contain the appropriate dose and the amount of excessive active ingredient to be discarded is minimized. When the body weight exceeds 75 kg, only one additional dose unit is needed for body weights of up to 100 kg. In contrast, with conventional dose units containing 1500 mg, a second dose unit would be needed for treating patients having body weights of up to 100 kg and said second dose unit would contain a considerably higher amount of excessive active ingredient to be discarded.

[0021] Still further, compared to a lyophilizate that is provided as a cake in a bottle or a vial, a free flowing powder that is contained in a primary packaging such as a sachet allows for better individualized dosing, easier transport, easier storage, and less expensive manufacture, because lyophilization is a laborious and time consuming process.

[0022] Furthermore, it has been found that the pharmaceutical compositions and dosage forms can be packed in primary packaging such as sachets, preferably stick-packs, that provide long term storage stability. The pharmaceutical compositions and pharmaceutical dosage forms should can be easilypacked into such primary packaging with high dose accuracy and it is easy to completely withdraw the pharmaceutical compositions and pharmaceutical dosage forms should such primary packaging.

[0023] In case that a primary packaging contains a higher amount of the pharmaceutical composition or pharmaceutical dosage form than is needed in view of the body weight of the patient to be treated, the individual dose to be administered can be easily adjusted because the solid pharmaceutical composition is a powder that can be easily divided.

[0024] A first aspect of the invention relates to a solid pharmaceutical composition in form of a powder for oral administration comprising or essentially consisting of 5-amino levulinic acid or a physiologically acceptable salt thereof; preferably wherein the weight content of the 5-amino levulinic acid or the physiologically acceptable salt thereof is at least 43.0 wt.-%, relative to the total weight of the composition.

[0025] 5-Amino levulinic acid (ATC L01XD04) has the following structure:

[0026] Unless expressly stated otherwise, all percentages are percent by weight.

[0027] Unless expressly stated otherwise, all parameters relating to the amount, quantity, content and the like of 5-amino levulinic acid or the physiologically acceptable salt thereof refer to the actual weight of the given form, i.e. either the weight of the given non-salt form (5-ALA (CAS 106-60-5) Mr 131.13 g / mol), or the weight of the given pharmaceutically acceptable salt (e.g., 5-ALA HC1 (CAS 5451-09-2) Mr 167.59 g / mol). Thus, the weight contribution of the salt is considered and included within the quantitative value for amount, quantity, content and the like.

[0028] Preferably, the 5-amino levulinic acid is present as 5-amino levulinic acid hydrochloride salt.

[0029] Preferably, the weight content of the 5-amino levulinic acid or the physiologically acceptable salt thereof is at least 43.0 wt.-%, relative to the total weight of the composition.

[0030] Preferably, the weight content of the 5-amino levulinic acid or the physiologically acceptable salt thereof is at least 45.0 wt.-%, relative to the total weight of the composition; preferably at least 50.0 wt.-%, more preferably at least 55.0 wt.-%, still more preferably at least 60.0 wt.-%, yet more preferably at least 65.0 wt.-%, even more preferably at least 70.0 wt.-%, most preferably at least 75.0 wt.-%, and in particular at least 80.0 wt.-%.

[0031] Preferably, the weight content of the 5-amino levulinic acid or the physiologically acceptable salt thereof is at least 85.0 wt.-%, relative to the total weight of the composition; preferably at least 90.0 wt.-%, more preferably at least 92.5 wt.-%, still more preferably at least 95.0 wt.-%, yet more preferablyat least 97.0 wt.-%, even more preferably at least 98.0 wt .-%, most preferably at least 99.0 wt.-%, and in particular about 100 wt.-%.

[0032] It is contemplated that the pharmaceutical composition may contain one or more excipients such as carriers, fdlers, diluents, binders, disintegrants, glidants, dispersants, lubricants, preservatives, antioxidants, surfactants, colorants, flavors, aromas, sweeteners, taste masking substances and the like. Preferably, however, the pharmaceutical composition consists of 5 -amino levulinic acid or the physiologically acceptable salt thereof, i.e. does not contain any excipients.

[0033] Preferably, the powder has a bulk density of at least 0.720 g / ml, determined according to Ph. Eur. 2.9.34.

[0034] Preferably, the powder has a bulk density of at most 0.840 g / ml, determined according to Ph. Eur. 2.9.34.

[0035] Preferably, the bulk density is at least 0.730 g / ml, preferably at least 0.740 g / ml, more preferably at least 0.750 g / ml, still more preferably at least 0.760 g / ml, yet more preferably at least 0.770 g / ml, even more preferably at least 0.780 g / ml, most preferably at least 0.790 g / ml, and in particular at least 0.800 g / ml.

[0036] Preferably, the bulk density is at most 0.830 g / ml, preferably at most 0.820 g / ml, more preferably at most 0.810 g / ml, still more preferably at most 0.800 g / ml, yet more preferably at most 0.790 g / ml, even more preferably at most 0.780 g / ml, most preferably at most 0.770 g / ml, and in particular at most 0.760 g / ml.

[0037] In preferred embodiments, the bulk density is within the range of from 0.720 to 0.840 g / ml.

[0038] In preferred embodiments, the bulk density is within the range of from 0.720 to 0.760 g / ml.

[0039] In preferred embodiments, the bulk density is within the range of from 0.740 to 0.780 g / ml.

[0040] In preferred embodiments, the bulk density is within the range of from 0.760 to 0.800 g / ml.

[0041] In preferred embodiments, the bulk density is within the range of from 0.780 to 0.820 g / ml.

[0042] In preferred embodiments, the bulk density is within the range of from 0.800 to 0.840 g / ml.

[0043] Preferably, the powder has a tapped density of at least 0.760 g / ml, determined according to Ph. Eur. 2.9.34.

[0044] Preferably, the powder has a tapped density of at most 0.970 g / ml, determined according to Ph. Eur. 2.9.34.

[0045] Preferably, the tapped density is at least 0.770 g / ml, preferably at least 0.780 g / ml, more preferably at least 0.790 g / ml, still more preferably at least 0.800 g / ml, yet more preferably at least 0.810 g / ml, even more preferably at least 0.820 g / ml, most preferably at least 0.830 g / ml, and in particular at least 0.840 g / ml.

[0046] Preferably, the tapped density is at most 0.960 g / ml, preferably at most 0.950 g / ml, more preferably at most 0.940 g / ml, still more preferably at most 0.930 g / ml, yet more preferably at most 0.920 g / ml, even more preferably at most 0.910 g / ml, most preferably at most 0.900 g / ml, and in particular at most 0.890 g / ml.

[0047] In preferred embodiments, the tapped density is within the range of from 0.760 to 0.970 g / ml.

[0048] In preferred embodiments, the tapped density is within the range of from 0.760 to 0.830 g / ml.

[0049] In preferred embodiments, the tapped density is within the range of from 0.795 to 0.865 g / ml.

[0050] In preferred embodiments, the tapped density is within the range of from 0.830 to 0.900 g / ml.

[0051] In preferred embodiments, the tapped density is within the range of from 0.865 to 0.970 g / ml.

[0052] Preferably, the powder has a Hausner ratio of at least 1.00, determined according to Ph. Eur. 2.9.34.

[0053] Preferably, the powder has a Hausner ratio of at most 1.25, determined according to Ph. Eur. 2.9.34.

[0054] Preferably, the Hausner ratio is at least 1.02, preferably at least 1.04, more preferably at least 1.06, still more preferably at least 1.08, yet more preferably at least 1.10, even more preferably at least 1.12, most preferably at least 1.14, and in particular at least 1.16.

[0055] Preferably, the Hausner ratio is at most 1.24, preferably at most 1.22, more preferably at most 1.20, still more preferably at most 1.18, yet more preferably at most 1.16, even more preferably at most 1.14, most preferably at most 1.12, and in particular at most 1.10.

[0056] In preferred embodiments, the Hausner ratio is within the range of from 1.00 to 1.25.

[0057] In preferred embodiments, the Hausner ratio is within the range of from 1.05 to 1.15.

[0058] Preferably, the powder is free flowing; preferably wherein the powder has at least good flow properties according to Ph. Eur. 2.9.36, more preferably excellent flow properties according to Ph. Eur. 2.9.36.

[0059] Preferably, the powder has a particle size distribution characterized by a D10 value, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 20 to 65 pm.

[0060] Preferably, the powder has a particle size distribution characterized by a D50 value, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 150 to 350 pm.

[0061] Preferably, the powder has a particle size distribution characterized by a D90 value, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 380 to 780 pm.

[0062] Preferably, the powder has a particle size distribution characterized by a span value (D90- D10) / D50, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 1.85 to 2.25.

[0063] Preferably, the powder has a sphericity of particles, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 0.805 to 0.820.

[0064] Preferably, the powder has an aspect ratio of particles, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 0.645 to 0.670.

[0065] Preferably, the powder has a true density according to Ph. Eur. 2.2.42 within the range of 1.438±0.008 g / ml, preferably 1.438±0.006 g / ml, more preferably 1.438±0.006 g / ml, still more preferably 1.438±0.002 g / ml, and yet more preferably 1.438±0.001 g / ml.

[0066] Preferably, the powder has a specific surface area according to Ph. Eur. 2.9.26 within the range of 0.020 to 0.065 m2 / g.

[0067] In preferred embodiments, the 5-amino levulinic acid or a physiologically acceptable salt thereof is at least partially crystalline. Preferably, the 5-amino levulinic acid or a physiologically acceptable salt thereof is crystalline.

[0068] Preferably, the crystalline salt of 5-amino levulinic acid is the hydrochloride salt. Preferably, the 5-amino levulinic acid hydrochloride salt is polymorph form A according to JP 50 10 840 B2

[0069] Polymorphic forms are described in patents JP 49 15 724 B2 and JP 50 10 840 B2. 2 polymorphic forms are distinguished based on characteristic peaks at certain diffraction angles 20: Form A according to JP 50 10 840 B2 is a crystal of 5 -aminolevulinic acid hydrochloride having characteristic peaks at diffraction angles 20 of 20.7°±0.1°, 21.1°±0.1°, and 23.7°±0.1°. Form B according to JP 50 10 840 B2 is a crystal of 5 -aminolevulinic acid hydrochloride having characteristic peaks in their powder X-ray diffraction spectrum at diffraction angles 20 of 18.8°±0.2°, 20.1°±0.2°, 21.4°±0.2°, 23.3°±0.2°, and 25.8°±0.2°.

[0070] In other preferred embodiments, the 5-amino levulinic acid or a physiologically acceptable salt thereof is at least partially amorphous.

[0071] Another aspect of the invention relates to the composition according to the invention as described above for use in photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or in photodynamic therapy of a cancerous conditions, preferably malignant glioma.

[0072] For the purpose of the specification, malignant tissue and the cancerous condition is preferably selected from carcinoma, sarcoma, myeloma, leukemia, and lymphoma.

[0073] Analogously, the invention relates to the use of 5-amino levulinic acid or a physiologically acceptable salt thereof for the manufacture of a composition according to the invention as described abovefor photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or for photodynamic therapy of a cancerous conditions, preferably malignant glioma.

[0074] Analogously, the invention relates to a method for photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or for photodynamic therapy of a cancerous conditions, preferably malignant glioma, the method comprising administering an effective amount of a composition according to the invention as described above to a subject in need thereof.

[0075] The visualization of malignant tissue, preferably during surgery for malignant glioma is particularly preferred.

[0076] Another aspect of the invention relates to a pharmaceutical dosage form comprising or essentially consisting of the pharmaceutical composition according to the invention as described above.

[0077] In preferred embodiments, the pharmaceutical dosage form is identical to the pharmaceutical composition, whereas its amount or dose of 5 -aminolevulinic acid or the physiologically acceptable salt thereof is specified (administration unit). For the purpose of the description of preferred embodiments of the invention, the terms "composition" and "dosage form" are interchangeable.

[0078] It is contemplated that the pharmaceutical dosage form may contain one or more excipients such as carriers, fillers, diluents, binders, disintegrants, glidants, dispersants, lubricants, preservatives, antioxidants, surfactants, colorants, flavors, aromas, sweeteners, taste masking substances and the like. Preferably, however, the pharmaceutical dosage form consists of the pharmaceutical composition, which in turn more preferably consists of 5 -amino levulinic acid or the physiologically acceptable salt thereof, i.e. neither the pharmaceutical composition nor the pharmaceutical dosage form contain any excipients.

[0079] Preferably, the amount of the pharmaceutical composition in the dosage form is within the range of 500±400 mg, preferably 500±350 mg, more preferably 500±300 mg, still more preferably 500±250 mg, yet more preferably 500±200 mg, even more preferably 500±150 mg, most preferably 500±100 mg, and in particular 500±50 mg.

[0080] Preferably, the amount of 5 -aminolevulinic acid or the physiologically acceptable salt thereof in the dosage form is within the range of 500±400 mg, preferably 500±350 mg, more preferably 500±300 mg, still more preferably 500±250 mg, yet more preferably 500±200 mg, even more preferably 500±150 mg, most preferably 500±100 mg, and in particular 500±50 mg

[0081] In preferred embodiments, the amount of the pharmaceutical composition in the dosage form is at least 1000 mg, preferably at least 1200 mg, more preferably at least 1400 mg, still more preferably at least 1600 mg, yet more preferably at least 1800 mg, even more preferably at least 2000 mg, most preferably at least 2200 mg, and in particular at least 2400 mg.

[0082] Preferably, the amount of 5 -aminolevulinic acid or the physiologically acceptable salt thereof in the dosage form is at least 1000 mg, preferably at least 1200 mg, more preferably at least 1400 mg,still more preferably at least 1600 mg, yet more preferably at least 1800 mg, even more preferably at least 2000 mg, most preferably at least 2200 mg, and in particular at least 2400 mg

[0083] Another aspect of the invention relates to the pharmaceutical composition or the pharmaceutical dosage form according to the invention as described above for use in photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or in photodynamic therapy of a cancerous conditions, preferably malignant glioma.

[0084] Analogously, the invention relates to the use of 5-amino levulinic acid or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical composition or a pharmaceutical dosage form according to the invention as described above for photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or for photodynamic therapy of a cancerous conditions, preferably malignant glioma.

[0085] Analogously, the invention relates to a method for photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or for photodynamic therapy of a cancerous conditions, preferably malignant glioma, the method comprising administering an effective amount of a pharmaceutical composition or a pharmaceutical dosage form according to the invention as described above to a subject in need thereof.

[0086] The visualization of malignant tissue, preferably during surgery for malignant glioma is particularly preferred.

[0087] Preferably, the pharmaceutical composition or dosage form is administered orally.

[0088] Preferably, prior to oral administration the pharmaceutical composition or dosage form is dissolved in a sufficient volume of water.

[0089] Preferably, the pharmaceutical composition or dosage form is administered to a patient having a body weight, wherein the amount of the pharmaceutical composition in the dosage form is within the range of from 15 to 25 mg / kg body weight, preferably 16 to 24 mg / kg body weight, more preferably 17 to 23 mg / mg body weigh, still more preferably 18 to 22 mg / mg body weight, yet more preferably 1 to 21 mg / kg body weight, and even more preferably about 20 mg / kg body weight.

[0090] Another aspect of the invention relates to a multitude of pharmaceutical dosage forms according to the invention as described above for use in photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or in photodynamic therapy of a cancerous conditions, preferably malignant glioma.

[0091] The visualization of malignant tissue, preferably during surgery for malignant glioma is particularly preferred.

[0092] Preferably, the multitude of dosage forms is administered all at once to a patient having a body weight, wherein the total amount of the pharmaceutical composition in the multitude of dosage forms iswithin the range of from 15 to 25 mg / kg body weight, preferably 16 to 24 mg / kg body weight, more preferably 17 to 23 mg / mg body weigh, still more preferably 18 to 22 mg / mg body weight, yet more preferably 19 to 21 mg / kg body weight, and even more preferably about 20 mg / kg body weight.

[0093] In preferred embodiments, at least two dosage forms of the multitude of dosage forms have a different content of the pharmaceutical composition.

[0094] In other preferred embodiments, all dosage forms of the multitude of dosage forms have the same content of the pharmaceutical composition.

[0095] Another aspect of the invention relates to a primary packaging comprising the pharmaceutical composition according to the invention as described above or the pharmaceutical dosage form according to the invention as described above.

[0096] In preferred embodiments, the primary packaging contains 500±400 mg (i.e. 100 to 900 mg) of the solid pharmaceutical composition according to the invention, which is in form of a powder for oral administration and which comprises or essentially consists of 5 -amino levulinic acid or a physiologically acceptable salt thereof.

[0097] Preferably, the primary packaging is a sachet, pouch or pad, preferably a stick-pack.

[0098] The primary packaging may be equipped with various opening options.

[0099] In preferred embodiments, the primary packaging comprises a mark where it is to be opened by cutting with a pair of scissors.

[0100] In other preferred embodiments, the primary packaging comprises a laser cut or a punctual laser perforation facilitating opening by manual tearing.

[0101] In further preferred embodiments, the primary packaging comprises an opening notch facilitating opening by manual tearing.

[0102] In preferred embodiments, the primary packaging contains 250±200 mg, preferably 250±175 mg, more preferably 250±150 mg, still more preferably 250±125 mg, yet more preferably 250±100 mg, even more preferably 250±75 mg, most preferably 250±50 mg, and in particular preferably 250±25 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0103] In preferred embodiments, the primary packaging contains 500±400 mg, preferably 500±350 mg, more preferably 500±300 mg, still more preferably 500±250 mg, yet more preferably 500±200 mg, even more preferably 500±150 mg, most preferably 500±100 mg, and in particular preferably 500±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0104] In preferred embodiments, the primary packaging contains 750±400 mg, preferably 750±350 mg, more preferably 750±300 mg, still more preferably 750±250 mg, yet more preferably 750±200 mg, even more preferably 750±150 mg, most preferably 750±100 mg, and in particular preferably 750±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0105] In preferred embodiments, the primary packaging contains 1000±400 mg, preferably 1000±350 mg, more preferably 1000±300 mg, still more preferably 1000±250 mg, yet more preferably 1000±200 mg, even more preferably 1000±150 mg, most preferably 1000±100 mg, and in particular preferably 1000±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0106] In preferred embodiments, the primary packaging contains 1250±400 mg, preferably 1250±350 mg, more preferably 1250±300 mg, still more preferably 1250±250 mg, yet more preferably 1250±200 mg, even more preferably 1250±150 mg, most preferably 1250±100 mg, and in particular preferably 12 0±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0107] In preferred embodiments, the primary packaging contains 1500±400 mg, preferably 1500±350 mg, more preferably 1500±300 mg, still more preferably 1500±250 mg, yet more preferably 1500±200 mg, even more preferably 1500±150 mg, most preferably 1500±100 mg, and in particular preferably 1500±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0108] In preferred embodiments, the primary packaging contains 1750±400 mg, preferably 1750±350 mg, more preferably 1750±300 mg, still more preferably 1750±250 mg, yet more preferably 1750±200 mg, even more preferably 1750±150 mg, most preferably 1750±100 mg, and in particular preferably 1750±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0109] In preferred embodiments, the primary packaging contains 2000±400 mg, preferably 2000±350 mg, more preferably 2000±300 mg, still more preferably 2000±250 mg, yet more preferably 2000±200 mg, even more preferably 2000±150 mg, most preferably 2000±100 mg, and in particular preferably 2000±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0110] In preferred embodiments, the primary packaging contains 16±15 mg, preferably 16±13 mg, more preferably 16±11 mg, still more preferably 16±9 mg, yet more preferably 16±7 mg, even more preferably 16±5 mg, most preferably 16±3 mg, and in particular preferably 16±1 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0111] In preferred embodiments, the primary packaging contains 32±30 mg, preferably 32±26 mg, more preferably 32±22 mg, still more preferably 32± 18 mg, yet more preferably 32=1=14 mg, even more preferably 32±10 mg, most preferably 32±6 mg, and in particular preferably 32±2 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0112] In preferred embodiments, the primary packaging contains 64±60 mg, preferably 64±52 mg, more preferably 64±44 mg, still more preferably 64±36 mg, yet more preferably 64±28 mg, even more preferably 64±20 mg, most preferably 64±12 mg, and in particular preferably 64±4 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0113] In preferred embodiments, the primary packaging contains 128±120 mg, preferably 128±104 mg, more preferably 128±88 mg, still more preferably 128±72 mg, yet more preferably 128±56 mg,even more preferably 128±40 mg, most preferably 128±24 mg, and in particular preferably 128±8 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0114] In preferred embodiments, the primary packaging contains 256±240 mg, preferably 256±208 mg, more preferably 256±176 mg, still more preferably 256±144 mg, yet more preferably 256±112 mg, even more preferably 256±80 mg, most preferably 256±48 mg, and in particular preferably 256±16 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0115] In preferred embodiments, the primary packaging contains 512±400 mg, preferably 512±350 mg, more preferably 512±300 mg, still more preferably 512±250 mg, yet more preferably 12±200 mg, even more preferably 512±150 mg, most preferably 512±100 mg, and in particular preferably 512±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0116] In preferred embodiments, the primary packaging contains 1024±400 mg, preferably 1024±350 mg, more preferably 1024±300 mg, still more preferably 1024±250 mg, yet more preferably 1024±200 mg, even more preferably 1024±150 mg, most preferably 1024±100 mg, and in particular preferably 1024±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0117] In preferred embodiments, the primary packaging contains 2048±400 mg, preferably 2048±350 mg, more preferably 2048±300 mg, still more preferably 2048±250 mg, yet more preferably 2048±200 mg, even more preferably 2048±150 mg, most preferably 2048±100 mg, and in particular preferably 2048±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

[0118] Preferably, the primary packaging according to the invention absorbs UV light.

[0119] Preferably, the primary packaging according to the invention is intransparent for UV light.

[0120] Preferably, the primary packaging according to the invention has a water vapor transmission, determined by electro analysis according to ISO 15106-3 (38°C / 90% r.h.), below the detection limit of <0.001 g m-2d-'.

[0121] Preferably, the primary packaging according to the invention has an oxygen transmission, determined by manometric analysis according to ISO 15105-2 (23°C / 50% r.h.), below the detection limit of <0.005 ml m2d ' bar '.

[0122] Preferably, the primary packaging according to the invention besides the pharmaceutical composition or the pharmaceutical dosage form comprises or essentially consists of a packaging material in form of a film or sheet material.

[0123] Preferably, the film of sheet material is multilayered.

[0124] Preferably, the film or sheet material is a laminate.

[0125] The laminate according to the invention may comprise 2, 3, 4, 5 or more layers.

[0126] In preferred embodiments, the laminate comprises a metal layer and at least one polymer layer. Preferably, an adhesive layer is present between the metal layer and the at least one polymer, wherein the adhesive layer is preferably also based on a polymer, preferably on a polyurethane adhesive.

[0127] For the purpose of the description "based on" means that the specified constituent has the greatest weight content of all constituents of the material, here layer. Preferably, the weight content of the specified constituent is at least 50 wt.-%, more preferably at least 60 wt.-%, still more preferably at least 70 wt-%, yet more preferably at least 80 wt.-%, even more preferably at least 90 wt.-%, most preferably at least 95 wt.-%, and in particular at least 99 wt.-%, relative to the total weight of the material, here layer.

[0128] In preferred embodiments, the laminate comprises a metal layer that is sandwiched between a first polymer layer and a second layer, preferably a second polymer layer. Preferably, a first adhesive layer is present between the metal layer and the first polymer layer. Preferably, a second adhesive layer is present between the metal layer and the second layer, preferably second polymer layer. Preferably, the first adhesive layer and the second adhesive layer independently of one another are also based on a polymer, preferably on a polyurethane adhesive.

[0129] Preferably, the film or sheet material comprises or essentially consists of a metal layer, preferably an aluminum layer. For the purpose of the specification "aluminum" also covers alloys of aluminum wherein aluminum is the predominant metal of the alloy. Preferred aluminum alloys are in accordance with EN AW- 1200 and EN AW-8079.

[0130] Preferably, the metal layer, preferably aluminum layer, has a thickness of at least 10 pm, more preferably at least 15 pm, still more preferably at least 20 pm.

[0131] Preferably, the metal layer, preferably aluminum layer, has a number of pores per m2, measured as defined in EN 546-4 (corresponding to AFCO recommendation B), of less than 1000, preferably less than 400, more preferably less than 20, still more preferably less than 5, and yet more preferably leas than 0.5; wherein pores are defined as pin holes with a size of less than 0.2 mm.

[0132] Preferably, the film or sheet material comprises or essentially consists of layer of a web, fabric, woven, nonwoven, netting, scrim, or paper.

[0133] Preferably, the film or sheet material comprises or essentially consists of one or more polymer layers.

[0134] In preferred embodiments, at least one of the one or more polymer layers is based on a polyolefin, preferably polypropylene or polyethylene, more preferably polyethylene, still more preferably low density polyethylene (LDPE).

[0135] In preferred embodiments, at least one of the one or more polymer layers is based on a polyester, preferably polyethylene terephthalate (PET).

[0136] Preferably, the film or sheet material is selected from paper layered foils, aluminum foils, polyethylene foils, desiccant foils, needled foils, laser perforated foils, and layered foils.

[0137] In preferred embodiments, the film or sheet material is a laminate, wherein a metal layer, preferably aluminum layer, is sandwiched between a first polymer layer and a second layer, preferably a second polymer layer.

[0138] In preferred embodiments, the film or sheet material is a laminate of paper, aluminum and polymer, preferably paper, aluminum and polyethylene.

[0139] In preferred embodiments, the film or sheet material is a laminate having from the outside to the inside of the primary packaging(a) optionally an outer lacquer layer that may be printed with printing ink(s);(b) a first polymer layer, preferably based on polyester, more preferably based on polyethylene terephthalate (PET);(c) a first adhesive layer, preferably based on a polyurethane adhesive;(d) a metal layer, preferably aluminum layer;(e) a second adhesive layer, preferably based on a polyurethane adhesive; and(f) a second polymer layer, preferably based on polyolefin, more preferably polyethylene, still more preferably low density polyethylene (LDPE).

[0140] Preferably, the optional lacquer layer (a) has a thickness of at most 10 pm, more preferably at most 5 pm.

[0141] In preferred embodiments, the first polymer layer (b) has athickness within the range of 25±15 pm, more preferably 25±10 pm, still more preferably 25±5 pm.

[0142] In other preferred embodiments, the first polymer layer (b) has a thickness within the range of 12.5±10 pm, more preferably 12.5±7.5 pm, still more preferably 12.5±5 pm.

[0143] Preferably, the second polymer layer (f) has a thickness that is greater than the thickness of the first polymer layer, preferably within the range of 50±15 pm, more preferably 50±10 pm, still more preferably 50±5 pm.

[0144] Preferably, the first adhesive layer (c) and the second adhesive layer (e) independently of one another have a thickness of at most 10 pm, preferably at most 5 pm.

[0145] Preferably, the metal layer (d) has a thickness of 20±15 pm, more preferably 20±10 pm, still more preferably 20±5 pm.

[0146] Another aspect of the invention relates to a secondary packaging comprising a multitude of primary packaging according to the invention as described above.

[0147] In preferred embodiments, at least two primary packaging of the multitude of primary packaging have a different content of the pharmaceutical composition or the pharmaceutical dosage form.

[0148] In other preferred embodiments, all primary packaging of the multitude of primary packaging have the same content of the pharmaceutical composition or the pharmaceutical dosage form.

[0149] Particularly preferred embodiments of the invention are compiled as clauses hereinafter:Clause 1 : A solid pharmaceutical composition in form of a powder for oral administration comprising or essentially consisting of 5 -amino levulinic acid or a physiologically acceptable salt thereof; preferably wherein the weight content of the 5 -amino levulinic acid or the physiologically acceptable salt thereof is at least 43.0 wt.-%, relative to the total weight of the composition.Clause 2: The composition according to clause 1, wherein the 5 -amino levulinic acid is present as 5- amino levulinic acid hydrochloride salt.Clause 3: The composition according to clause 1 or 2, wherein the weight content of the 5 -amino levulinic acid or the physiologically acceptable salt thereof is at least 45.0 wt.-%, relative to the total weight of the composition; preferably at least 50.0 wt.-%, more preferably at least 55.0 wt.-%, still more preferably at least 60.0 wt.-%, yet more preferably at least 65.0 wt.-%, even more preferably at least 70.0 wt.-%, most preferably at least 75.0 wt.-%, and in particular at least 80.0 wt.-%; preferably wherein the weight content of the 5-amino levulinic acid or the physiologically acceptable salt thereof is at least 85.0 wt.-%, relative to the total weight of the composition; preferably at least 90.0 wt.-%, more preferably at least 92.5 wt.-%, still more preferably at least 95.0 wt.-%, yet more preferably at least 97.0 wt.- %, even more preferably at least 98.0 wt.-%, most preferably at least 99.0 wt.-%, and in particular about 100 wt.-%.Clause 4: The composition according to any of the preceding clauses, wherein the powder has a bulk density of at least 0.720 g / ml, determined according to Ph. Eur. 2.9.34.Clause 5 : The composition according to any of the preceding clauses, wherein the powder has a bulk density of at most 0.840 g / ml, determined according to Ph. Eur. 2.9.34.Clause 6: The composition according to clause 4 or 5, wherein the bulk density is at least 0.730 g / ml, preferably at least 0.740 g / ml, more preferably at least 0.750 g / ml, still more preferably at least 0.760 g / ml, yet more preferably at least 0.770 g / ml, even more preferably at least 0.780 g / ml, most preferably at least 0.790 g / ml, and in particular at least 0.800 g / ml.Clause 7: The composition according to any of clauses 4 to 6, wherein the bulk density is at most 0.830 g / ml, preferably at most 0.820 g / ml, more preferably at most 0.810 g / ml, still more preferably at most 0.800 g / ml, yet more preferably at most 0.790 g / ml, even more preferably at most 0.780 g / ml, most preferably at most 0.770 g / ml, and in particular at most 0.760 g / ml.Clause 8: The composition according to any of clauses 4 to 7, wherein the bulk density is within the range of from 0.720 to 0.840 g / ml.Clause 9: The composition according to any of clauses 4 to 8, wherein the bulk density is within the range of from 0.720 to 0.760 g / ml.Clause 10: The composition according to any of clauses 4 to 8, wherein the bulk density is within the range of from 0.740 to 0.780 g / ml.Clause 11: The composition according to any of clauses 4 to 8, wherein the bulk density is within the range of from 0.760 to 0.800 g / ml.Clause 12: The composition according to any of clauses 4 to 8, wherein the bulk density is within the range of from 0.780 to 0.820 g / ml.Clause 13: The composition according to any of clauses 4 to 8, wherein the bulk density is within the range of from 0.800 to 0.840 g / ml.Clause 14: The composition according to any of the preceding clauses, wherein the powder has a tapped density of at least 0.760 g / ml, determined according to Ph. Eur. 2.9.34.Clause 15: The composition according to any of the preceding clauses, wherein the powder has a tapped density of at most 0.970 g / ml, determined according to Ph. Eur. 2.9.34.Clause 16: The composition according to clause 14 or 15, wherein the tapped density is at least 0.770 g / ml, preferably at least 0.780 g / ml, more preferably at least 0.790 g / ml, still more preferably at least 0.800 g / ml, yet more preferably at least 0.810 g / ml, even more preferably at least 0.820 g / ml, most preferably at least 0.830 g / ml, and in particular at least 0.840 g / ml.Clause 17: The composition according to any of clauses 14 to 16, wherein the tapped density is at most 0.960 g / ml, preferably at most 0.950 g / ml, more preferably at most 0.940 g / ml, still more preferably at most 0.930 g / ml, yet more preferably at most 0.920 g / ml, even more preferably at most 0.910 g / ml, most preferably at most 0.900 g / ml, and in particular at most 0.890 g / ml.Clause 18: The composition according to any of clauses 14 to 17, wherein the tapped density is within the range of from 0.760 to 0.970 g / ml.Clause 19: The composition according to any of clauses 14 to 18, wherein the tapped density is within the range of from 0.760 to 0.830 g / ml.Clause 20: The composition according to any of clauses 14 to 18, wherein the tapped density is within the range of from 0.795 to 0.865 g / ml.Clause 21: The composition according to any of clauses 14 to 18, wherein the tapped density is within the range of from 0.830 to 0.900 g / ml.Clause 22: The composition according to any of clauses 14 to 18, wherein the tapped density is within the range of from 0.865 to 0.970 g / ml.Clause 23: The composition according to any of the preceding clauses, wherein the powder has a Haus- ner ratio of at least 1.00, determined according to Ph. Eur. 2.9.34.Clause 24: The composition according to any of the preceding clauses, wherein the powder has a Haus- ner ratio of at most 1.25, determined according to Ph. Eur. 2.9.34.Clause 25: The composition according to clause 23 or 24, wherein the Hausner ratio is at least 1.02, preferably at least 1.04, more preferably at least 1.06, still more preferably at least 1.08, yet more preferably at least 1.10, even more preferably at least 1.12, most preferably at least 1.14, and in particular at least 1.16.Clause 26: The composition according to any of clauses 23 to 25, wherein the Hausner ratio is at most 1.24, preferably at most 1.22, more preferably at most 1.20, still more preferably at most 1.18, yet more preferably at most 1.16, even more preferably at most 1.14, most preferably at most 1.12, and in particular at most 1.10.Clause 27: The composition according to any of clauses 23 to 26, wherein the Hausner ratio is within the range of from 1.00 to 1.25.Clause 28: The composition according to clause 27, wherein the Hausner ratio is within the range of from 1.05 to 1.15.Clause 29: The composition according to any of the preceding clauses, wherein the powder is free flowing; preferably wherein the powder has at least good flow properties according to Ph. Eur. 2.9.36, more preferably excellent flow properties according to Ph. Eur. 2.9.36.Clause 30: The composition according to any of the preceding clauses, wherein the powder has a particle size distribution characterized by a D10 value, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 20 to 65 pm.Clause 31 : The composition according to any of the preceding clauses, wherein the powder has a particle size distribution characterized by a D50 value, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 150 to 350 pm.Clause 32: The composition according to any of the preceding clauses, wherein the powder has a particle size distribution characterized by a D90 value, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 380 to 780 pm.Clause 33 : The composition according to any of the preceding clauses, wherein the powder has a particle size distribution characterized by a span value (D90-D10) / D50, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 1.85 to 2.25.Clause 34: The composition according to any of the preceding clauses, wherein the powder has a sphericity of particles, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 0.805 to 0.820.Clause 35 : The composition according to any of the preceding clauses, wherein the powder has an aspect ratio of particles, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 0.645 to 0.670.Clause 36: The composition according to any of the preceding clauses, wherein the powder has a true density according to Ph. Eur. 2.2.42 within the range of 1.438±0.008 g / ml, preferably 1.438±0.006 g / ml,more preferably 1.438±0.006 g / ml, still more preferably 1.438±0.002 g / ml, and yet more preferably 1.438±0.001 g / ml.Clause 37: The composition according to any of the preceding clauses, wherein the powder has a specific surface area according to Ph. Eur. 2.9.26 within the range of 0.020 to 0.065 m2 / g.Clause 38: The composition according to any of the preceding clauses, wherein the 5-amino levulinic acid or a physiologically acceptable salt thereof is at least partially crystalline.Clause 39: The composition according to any of the preceding clauses, wherein the 5-amino levulinic acid or a physiologically acceptable salt thereof is crystalline.Clause 40: The composition according to any of clauses 1 to 38, wherein the 5-amino levulinic acid or a physiologically acceptable salt thereof is at least partially amorphous.Clause 41: The composition according to any of the preceding clauses for use in photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or in photodynamic therapy of a cancerous conditions, preferably malignant glioma; particularly preferably for use in visualization of malignant tissue, preferably during surgery for malignant glioma.Clause 42: A pharmaceutical dosage form comprising or essentially consisting of the pharmaceutical composition according to any of the preceding clauses.Clause 43: The dosage form according to clause 42, wherein the amount of the pharmaceutical composition in the dosage form is within the range of 500±400 mg, preferably 500±350 mg, more preferably 500±300 mg, still more preferably 500±250 mg, yet more preferably 500±200 mg, even more preferably 500±150 mg, most preferably 500±100 mg, and in particular 500±50 mg.Clause 44: The dosage form according to clause 42 or 43, wherein the amount of the pharmaceutical composition in the dosage form is at least 1000 mg, preferably at least 1200 mg, more preferably at least 1400 mg, still more preferably at least 1600 mg, yet more preferably at least 1800 mg, even more preferably at least 2000 mg, most preferably at least 2200 mg, and in particular at least 2400 mg.Clause 45: The dosage form according to any of clauses 42 to 44 for use in photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or in photodynamic therapy of a cancerous conditions, preferably malignant glioma; particularly preferably for use in visualization of malignant tissue, preferably during surgery for malignant glioma.Clause 46: The dosage form for use according to clause 45, which is administered orally.Clause 47: The dosage form for use according to clause 45 or 46, wherein prior to oral administration the dosage form is dissolved in a sufficient volume of water.Clause 48: The dosage form for use according to any of clauses 45 to 47, wherein the dosage form is administered to a patient having a body weight, wherein the amount of the pharmaceutical composition in the dosage form is within the range of from 15 to 25 mg / kg body weight, preferably 16 to 24 mg / kg body weight, more preferably 17 to 23 mg / mg body weigh, still more preferably 18 to 22 mg / mg bodyweight, yet more preferably 19 to 21 mg / kg body weight, and even more preferably about 20 mg / kg body weight.Clause 49: A multitude of pharmaceutical dosage forms according to any of clauses 42 to 48 for use in photodiagnosis, preferably visualization of malignant tissue, preferably during surgery for malignant glioma, or in photodynamic therapy of a cancerous conditions, preferably malignant glioma; particularly preferably for use in visualization of malignant tissue, preferably during surgery for malignant glioma.Clause 50: The multitude of dosage forms for use according to clause 49, wherein the multitude of dosage forms is administered all at once to a patient having a body weight, wherein the total amount of the pharmaceutical composition in the multitude of dosage forms is within the range of from 15 to 25 mg / kg body weight, preferably 16 to 24 mg / kg body weight, more preferably 17 to 23 mg / mg body weigh, still more preferably 18 to 22 mg / mg body weight, yet more preferably 19 to 21 mg / kg body weight, and even more preferably about 20 mg / kg body weight.Clause 51: The multitude of dosage forms for use according to clause 49 or 50, wherein at least two dosage forms of the multitude of dosage forms have a different content of the pharmaceutical composition.Clause 52: The multitude of dosage forms for use according to clause 49 or 50, wherein all dosage forms of the multitude of dosage forms have the same content of the pharmaceutical compositionClause 53: A primary packaging comprising the pharmaceutical composition according to any of clauses 1 to 41 or the pharmaceutical dosage form according to any of clauses 42 to 48.Clause 54: The primary packaging according to clause 53, which is a sachet, pouch or pad, preferably a stick-pack.Clause 55: The primary packaging according to clause 53 or 54, which comprises a mark where it is to be opened by cutting with a pair of scissors.Clause 56: The primary packaging according to any of clauses 53 to 55, which comprises a laser cut or a punctual laser perforation facilitating opening by manual tearing.Clause 57: The primary packaging according to any of clauses 53 to 56, which comprises an opening notch facilitating opening by manual tearing.Clause 58: The primary packaging according to any of clauses 53 to 57, which contains 250±200 mg, preferably 250±175 mg, more preferably 250±150 mg, still more preferably 250±125 mg, yet more preferably 250±100 mg, even more preferably 250±75 mg, most preferably 250±50 mg, and in particular preferably 250±25 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 59: The primary packaging according to any of clauses 53 to 57, which contains 500±400 mg, preferably 500±350 mg, more preferably 500±300 mg, still more preferably 500±250 mg, yet more preferably 500±200 mg, even more preferably 500±150 mg, most preferably 500±100 mg, and in particular preferably 500±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 60: The primary packaging according to any of clauses 53 to 57, which contains 750±400 mg, preferably 750±350 mg, more preferably 750±300 mg, still more preferably 750±250 mg, yet more preferably 750±200 mg, even more preferably 750±150 mg, most preferably 750±100 mg, and in particular preferably 750±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 61: The primary packaging according to any of clauses 53 to 57, which contains 1000±400 mg, preferably 1000±350 mg, more preferably 1000±300 mg, still more preferably 1000±250 mg, yet more preferably 1000±200 mg, even more preferably 1000±150 mg, most preferably 1000±100 mg, and in particular preferably 1000±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 62: The primary packaging according to any of clauses 53 to 57, which contains 1250±400 mg, preferably 1250±350 mg, more preferably 1250±300 mg, still more preferably 1250±250 mg, yet more preferably 1250±200 mg, even more preferably 1250±150 mg, most preferably 1250±100 mg, and in particular preferably 12 0±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 63: The primary packaging according to any of clauses 53 to 57, which contains 1500±400 mg, preferably 1500±350 mg, more preferably 1500±300 mg, still more preferably 1500±250 mg, yet more preferably 1500±200 mg, even more preferably 1500±150 mg, most preferably 1500±100 mg, and in particular preferably 1500±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 64: The primary packaging according to any of clauses 53 to 57, which contains 1750±400 mg, preferably 1750±350 mg, more preferably 1750±300 mg, still more preferably 1750±250 mg, yet more preferably 1750±200 mg, even more preferably 1750±150 mg, most preferably 1750±100 mg, and in particular preferably 1750±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 65: The primary packaging according to any of clauses 53 to 57, which contains 2000±400 mg, preferably 2000±350 mg, more preferably 2000±300 mg, still more preferably 2000±250 mg, yet more preferably 2000±200 mg, even more preferably 2000±150 mg, most preferably 2000±100 mg, and in particular preferably 2000±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 66: The primary packaging according to any of clauses 53 to 57, which contains 16±15 mg, preferably 16±13 mg, more preferably 16±11 mg, still more preferably 16±9 mg, yet more preferably 16±7 mg, even more preferably 16±5 mg, most preferably 16=1=3 mg, and in particular preferably 16±1 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 67: The primary packaging according to any of clauses 53 to 57, which contains 32±30 mg, preferably 32±26 mg, more preferably 32±22 mg, still more preferably 32±18 mg, yet more preferably32±14 mg, even more preferably 32±10 mg, most preferably 32±6 mg, and in particular preferably 32±2 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 68: The primary packaging according to any of clauses 53 to 57, which contains 64±60 mg, preferably 64±52 mg, more preferably 64±44 mg, still more preferably 64±36 mg, yet more preferably 64±28 mg, even more preferably 64±20 mg, most preferably 64±12 mg, and in particular preferably 64±4 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 69: The primary packaging according to any of clauses 53 to 57, which contains 128±120 mg, preferably 128±104 mg, more preferably 128±88 mg, still more preferably 128±72 mg, yet more preferably 128±56 mg, even more preferably 128±40 mg, most preferably 128±24 mg, and in particular preferably 128±8 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 70: The primary packaging according to any of clauses 53 to 57, which contains 256±240 mg, preferably 256±208 mg, more preferably 256±176 mg, still more preferably 256±144 mg, yet more preferably 256±112 mg, even more preferably 256±80 mg, most preferably 256±48 mg, and in particular preferably 256±16 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 71: The primary packaging according to any of clauses 53 to 57, which contains 512±400 mg, preferably 512±350 mg, more preferably 512±300 mg, still more preferably 512±250 mg, yet more preferably 512±200 mg, even more preferably 512±150 mg, most preferably 512±100 mg, and in particular preferably 512±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 72: The primary packaging according to any of clauses 53 to 57, which contains 1024±400 mg, preferably 1024±350 mg, more preferably 1024±300 mg, still more preferably 1024±250 mg, yet more preferably 1024±200 mg, even more preferably 1024±150 mg, most preferably 1024±100 mg, and in particular preferably 1024±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 73: The primary packaging according to any of clauses 53 to 57, which contains 2048±400 mg, preferably 2048±350 mg, more preferably 2048±300 mg, still more preferably 2048±250 mg, yet more preferably 2048±200 mg, even more preferably 2048±150 mg, most preferably 2048±100 mg, and in particular preferably 2048±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.Clause 74: The primary packaging according to any of clauses 53 to 73, which absorbs UV light.Clause 75: The primary packaging according to any of clauses 53 to 74, which is intransparent for UV light.Clause 76: The primary packaging according to any of clauses 53 to 75, which has a water vapor transmission, determined by electro analysis according to ISO 15106-3 (38°C / 90% r.h.), below the detection limit of <0.001 g m’^d1.Clause 77: The primary packaging according to any of clauses 53 to 76, which has an oxygen transmission, determined by manometric analysis according to ISO 15105-2 (23°C / 50% r.h ), below the detection limit of <0.005 ml m^ d ' bar1.Clause 78: The primary packaging according to any of clauses 53 to 77, which besides the pharmaceutical composition or the pharmaceutical dosage form comprises or essentially consists of a packaging material in form of a film or sheet material.Clause 79: The primary packaging material according to clause 78, wherein the film of sheet material is multilayered.Clause 80: The primary packaging according to clause 78 or 79, wherein the film or sheet material is a laminate.Clause 81: The primary packaging according to any of clauses 78 to 80, wherein the film or sheet material comprises or essentially consists of a metal layer, preferably an aluminum layer.Clause 82: The primary packaging according to clause 81, wherein the metal layer, preferably aluminum layer, has a thickness of at least 10 pm, more preferably at least 15 pm, still more preferably at least 20 pm.Clause 83: The primary packaging according to clause 81 or 82, wherein the metal layer, preferably aluminum layer, has a number of pores per m2, measured as defined in EN 546-4 (corresponding to AFCO recommendation B), of <1000, preferably <400, more preferably <20, still more preferably <5, and yet more preferably <0.5; wherein pores are defined as pin holes with a size < 0.2 mm.Clause 84: The primary packaging according to any of clauses 78 to 83, wherein the film or sheet material comprises or essentially consists of layer of a web, fabric, woven, nonwoven, netting, scrim, or paper.Clause 85: The primary packaging according to any of clauses 78 to 84, wherein the film or sheet material comprises or essentially consists of one or more polymer layers.Clause 86: The primary packaging according to clause 85, wherein at least one of the one or more polymer layers is based on a polyolefin, preferably polypropylene or polyethylene, more preferably polyethylene, still more preferably low density polyethylene (LDPE).Clause 87: The primary packaging according to clause 85 or 86, wherein at least one of the one or more polymer layers is based on a polyester, preferably polyethylene terephthalate (PET).Clause 88: The primary packaging according to any of clauses 78 to 87, wherein the film or sheet material is selected from paper layered foils, aluminum foils, polyethylene foils, desiccant foils, needled foils, laser perforated foils, and layered foils.Clause 89: The primary packaging according to any of clauses 78 to 88, wherein the film or sheet material is a laminate, wherein a metal layer, preferably aluminum layer, is sandwiched between a first polymer layer and a second layer, preferably a second polymer layer.Clause 90: The primary packaging according to any of clauses 78 to 89, wherein the film or sheet material is a laminate of paper, aluminum and polymer, preferably paper, aluminum and polyethylene.Clause 91: The primary packaging according to any of clauses 78 to 90, wherein the film or sheet material is a laminate having from the outside to the inside of the primary packaging (a) optionally an outer lacquer layer that may be printed with printing ink(s); (b) a first polymer layer, preferably based on polyester, more preferably based on polyethylene terephthalate (PET); (c) a first adhesive layer, preferably based on a polyurethane adhesive; (d) a metal layer, preferably aluminum layer; (e) a second adhesive layer, preferably based on a polyurethane adhesive; and (f) a second polymer layer, preferably based on polyolefin, more preferably polyethylene, still more preferably low density polyethylene (LDPE).Clause 92: The primary packaging according to clause 91, wherein the optional lacquer layer (a) has a thickness of at most 10 pm, more preferably at most 5 pm.Clause 93: The primary packaging according to clause 91 or 92, wherein the first polymer layer (b) has a thickness within the range of 25±15 pm, more preferably 25±10 pm, still more preferably 25±5 pm.Clause 94: The primary packaging according to clause 91 or 92, wherein the first polymer layer (b) has a thickness within the range of 12.5±10 pm, more preferably 12.5±7.5 pm, still more preferably 12.5±5 pmClause 95: The primary packaging according to any of clauses 91 to 94, wherein the second polymer layer (f) has a thickness that is greater than the thickness of the first polymer layer, preferably within the range of 50±15 pm, more preferably 50±10 pm, still more preferably 50±5 pm.Clause 96: The primary packaging according to any of clauses 91 to 95, wherein the first adhesive layer (c) and the second adhesive layer (e) independently of one another have a thickness of at most 10 pm, preferably at most 5 pm.Clause 97: The primary packaging according to any of clauses 91 to 96, wherein the metal layer (d) has a thickness of 20±15 pm, more preferably 20±10 pm, still more preferably 20±5 pm.Clause 98: A secondary packaging comprising a multitude of primary packaging according to any of clauses 53 to 97.Clause 99: The secondary packaging according to clause 98, wherein at least two primary packaging of the multitude of primary packaging have a different content of the pharmaceutical composition or the pharmaceutical dosage form.Clause 100: The secondary packaging according to clause 98, wherein all primary packaging of the multitude of primary packaging have the same content of the pharmaceutical composition or the pharmaceutical dosage form.

[0150] The following examples further illustrates the invention but is not to be construed as limiting its scope:Example 1:

[0151] A pharmaceutical composition was provided consisting of 5 -amino levulinic acid hydrochloride salt (5 -ALA HC1) in form of a free flowing powder having the following properties determined according to dynamic image analysis:

[0152] Additional properties were likewise determined in accordance with Ph. Eur.:

[0153] The specific surface area was 0.021 m2 / g.Example 2:

[0154] Off-line dosing trials were conducted with the material of Example 1 which was able to be dosed using slider technology with constant weight throughout an experiment of 1000 cycles. Considering a range of ±7.5 % (462.5 mg - 537.5 mg) a good Cpk value (Process Capability Index) was obtained indicating good dosing process capability for the dosing of a fill weight of 500 mg into stick-packs.

[0155] The Off-line dosing station (MERZ) was equipped with a slider dosing unit and a slider 001 for the 500 mg dose fill weight. Experimental set up and process parameter used for both experiments are described in the table here below:

[0156] Mass uniformity samples were taken by holding a tared weighing boat below the filling tube in the right moment for the correct amount of time to sample the complete dose of the cycle. All taken mass uniformity samples had been weighed out. Weighing boat number and total weight (weighing boat + sample) were documented to connect with the correct Tara value and to calculate the dose weight of each mass uniformity sample. A set up run of 300 cycles was performed before the experiment of 1000 cycles started. During the set up run the slider was adjusted to obtain the targeted fill weight in a steady state in the dosing process.

[0157] Process capability analysis was performed showing a process capability value (Cpk) of 2.59 for a 500.0 mg fill weight in the off- line dosing trials, confirming the appropriate processability of this material with the applied dosing parameter. Mass uniformity samples are all in a range of ± 7.5 from the average value.

[0158] The off-line dosing station results are summarized in the table here below:

[0159] The parametric details regarding to process capability report of 500 mg fill weight are compiled in the tables here below and also visualized in Figures 1 and 2:LSL = Lower Spec Limit; USL = Upper Spec Limit

[0160] Performance values were:

[0161] Figure 1 visualizes experimental results with regard to a 500 mg fill weight. The process spread is illustrated by 6 sigma. The solid line indicates "overall", the dotted line indicates "within" .

[0162] Figure 2 is a boxplot of the off-line dosing experiment.

[0163] Performed off-line dosing trials using the fill weight of 500.0 mg confirmed processability of the material with the slider dosing process at simulated production range of 45 Stick Pack / min and showed overall precise and consistent dosing. Mass uniformity analysis showed low variability in fill weight throughout a dosing process of app 1000 cycles.Example 3:

[0164] An ICH stability study was performed under different storage conditions. The material of Example 1 was packaged in a heat-sealed laminated packet (PET / aluminum foil / PE).

[0165] The table here below summarizes analytical data obtained after storage at 25±2°C / 60±5% RH:n.t. = not tested; LTRT= Lower Than Reporting Threshold 0.05%; (1) Impurity D: 2,5-Bis-(beta-car- boxyethyl) pyrazine (corresponds to Related Compound A of USP Monograph Aminolevulinic acid hydrochloride).

[0166] The table here below summarizes analytical data obtained after storage at 30±2°C / 65±5% RH:n.t. = not tested; LTRT= Lower Than Reporting Threshold 0.05%; (1) Impurity D: 2,5-Bis-(beta-car- boxyethyl) pyrazine (corresponds to Related Compound A of USP Monograph Aminolevulinic acid hydrochloride)

[0167] The table here below summarizes analytical data obtained after storage at 40±2°C / 75±5% RH:n.t. = not tested; LTRT= Lower Than Reporting Threshold 0.05%; (1) Impurity D: 2,5-Bis-(beta-car- boxyethyl) pyrazine (corresponds to Related Compound A of USP Monograph Aminolevulinic acid hydrochloride)

[0168] The table here below summarizes analytical data on in-use stability:n.a. = not applicable; LTRT= Lower Than Reporting Threshold 0.05%; (1) Impurity D: 2,5-Bis-(beta- carboxyethyl) pyrazine (corresponds to Related Compound A of USP Monograph Aminolevulinic acid hydrochloride)Example 4:

[0169] Polymorphism of 5-ALA HC1 was investigated by XRPD on both, the drug substance and the drug product.

[0170] Figure 3 compares a fresh batch of drug substance with a sample taken after 12 months long term stability storage. Relevant characteristic peak positions 20 (+ / - 0.2) are 10.5 / 15.8 / 19.0 / 20.7 / 21.1 / 23.7 / 28.2 / 30.9 / 31.3 / 31.8 / 33.6. Peaks with high intensity are similar to form A according to JP 50 10 840 B2, whereas characteristic peaks described for form B according to JP 50 10 840 B2 were not found.

[0171] Additional XRPD investigation was done with drug product to evaluate potential impact of the filling process and storage on the polymorphic form of 5-ALA HC1. Samples were tested after close to 12 months storage at long-term (25°C / 60%RH) conditions and after 6 months storage at accelerated (40°C / 75%RH) conditions. Relevant characteristic peak positions in drug product after up to 12 months storage 20 (+ / - 0.2°) are 10.5° / 15.8° / 19.0° / 20.7° / 21.1° / 23.7° / 28.2° / 30.9° / 31.3° / 31.8° / 33.6°.

[0172] Again, peaks with high intensity are similar to form A according to JP 50 10 840 B2, whereas characteristic peaks described for form B according to JP 50 10 840 B2 were not found. No change from drug substance to drug product XRPD was observed.

[0173] In conclusion, similar XRPD peak patterns were observed in both drug substance and drug product. Relevant characteristic peak positions 20 are similar to the postulated form A of ALA HC1. Characteristic peaks as described for form B were not found in both drug substance nor drug product.

Claims

Patent claims:

1. A primary packaging containing 500±400 mg of a solid pharmaceutical composition in form of a powder for oral administration comprising or essentially consisting of 5-amino levulinic acid or a physiologically acceptable salt thereof, wherein the weight content of the 5-amino levulinic acid or the physiologically acceptable salt thereof is at least 43.0 wt.-%, relative to the total weight of the composition.

2. The primary packaging according to claim 1, wherein the 5-amino levulinic acid is present as 5- amino levulinic acid hydrochloride salt.

3. The primary packaging according to claim 1 or 2, wherein the weight content of the 5-amino levulinic acid or the physiologically acceptable salt thereof is at least 45.0 wt.-%, relative to the total weight of the composition; preferably at least 50.0 wt.-%, more preferably at least 55.0 wt.- %, still more preferably at least 60.0 wt.-%, yet more preferably at least 65.0 wt.-%, even more preferably at least 70.0 wt.-%, most preferably at least 75.0 wt.-%, and in particular at least 80.0 wt.-%;4. The primary packaging according to any of the preceding claims, wherein the weight content of the 5-amino levulinic acid or the physiologically acceptable salt thereof is at least 85.0 wt.-%, relative to the total weight of the composition; preferably at least 90.0 wt.-%, more preferably at least 92.5 wt.-%, still more preferably at least 95.0 wt.-%, yet more preferably at least 97.0 wt.- %, even more preferably at least 98.0 wt.-%, most preferably at least 99.0 wt.-%, and in particular about 100 wt.-%.

5. The primary packaging according to any of the preceding claims, wherein the powder is free flowing; preferably wherein the powder has at least good flow properties according to Ph. Eur. 2.9.36, more preferably excellent flow properties according to Ph. Eur. 2.9.36.

6. The primary packaging according to any of the preceding claims, wherein the 5-amino levulinic acid or a physiologically acceptable salt thereof is at least partially crystalline.

7. The primary packaging according to any of the preceding claims, wherein the powder has a bulk density of at least 0.720 g / ml, determined according to Ph. Eur. 2.9.34.

8. The primary packaging according to any of the preceding claims, wherein the powder has a bulk density of at most 0.840 g / ml, determined according to Ph. Eur. 2.9.34.

9. The primary packaging according to claim 7 or 8, wherein the bulk density is at least 0.730 g / ml, preferably at least 0.740 g / ml, more preferably at least 0.750 g / ml, still more preferably at least 0.760 g / ml, yet more preferably at least 0.770 g / ml, even more preferably at least 0.780 g / ml, most preferably at least 0.790 g / ml, and in particular at least 0.800 g / ml.

10. The primary packaging according to any of claims 7 to 9, wherein the bulk density is at most 0.830 g / ml, preferably at most 0.820 g / ml, more preferably at most 0.810 g / ml, still more preferably at most 0.800 g / ml, yet more preferably at most 0.790 g / ml, even more preferably at most 0.780 g / ml, most preferably at most 0.770 g / ml, and in particular at most 0.760 g / ml.

11. The primary packaging according to any of claims 7 to 10, wherein the bulk density is within the range of from 0.720 to 0.840 g / ml.

12. The primary packaging according to any of claims 7 to 11, wherein the bulk density is within the range of from 0.720 to 0.760 g / ml.

13. The primary packaging according to any of claims 7 to 11, wherein the bulk density is within the range of from 0.740 to 0.780 g / ml.

14. The primary packaging according to any of claims 7 to 11, wherein the bulk density is within the range of from 0.760 to 0.800 g / ml.

15. The primary packaging according to any of claims 7 to 11, wherein the bulk density is within the range of from 0.780 to 0.820 g / ml.

16. The primary packaging according to any of claims 7 to 11, wherein the bulk density is within the range of from 0.800 to 0.840 g / ml.

17. The primary packaging according to any of the preceding claims, wherein the powder has a tapped density of at least 0.760 g / ml, determined according to Ph. Eur. 2.9.34.

18. The primary packaging according to any of the preceding claims, wherein the powder has a tapped density of at most 0.970 g / ml, determined according to Ph. Eur. 2.9.34.

19. The primary packaging according to claim 17 or 18, wherein the tapped density is at least 0.770 g / ml, preferably at least 0.780 g / ml, more preferably at least 0.790 g / ml, still more preferably at least 0.800 g / ml, yet more preferably at least 0.810 g / ml, even more preferably at least 0.820 g / ml, most preferably at least 0.830 g / ml, and in particular at least 0.840 g / ml.

20. The primary packaging according to any of claims 17 to 19, wherein the tapped density is at most 0.960 g / ml, preferably at most 0.950 g / ml, more preferably at most 0.940 g / ml, still more preferably at most 0.930 g / ml, yet more preferably at most 0 920 g / ml, even more preferably at most 0.910 g / ml, most preferably at most 0.900 g / ml, and in particular at most 0.890 g / ml.

21. The primary packaging according to any of claims 17 to 20, wherein the tapped density is within the range of from 0.760 to 0.970 g / ml.

22. The primary packaging according to any of claims 17 to 21, wherein the tapped density is within the range of from 0.760 to 0.830 g / ml.

23. The primary packaging according to any of claims 17 to 21, wherein the tapped density is within the range of from 0.795 to 0.865 g / ml.

24. The primary packaging according to any of claims 17 to 21, wherein the tapped density is within the range of from 0.830 to 0.900 g / ml.

25. The primary packaging according to any of claims 17 to 21, wherein the tapped density is within the range of from 0.865 to 0.970 g / ml.

26. The primary packaging according to any of the preceding claims, wherein the powder has a Haus- ner ratio of at least 1.00, determined according to Ph. Eur. 2.9.34.

27. The primary packaging according to any of the preceding claims, wherein the powder has a Haus- ner ratio of at most 1.25, determined according to Ph. Eur. 2.9.34.

28. The primary packaging according to claim 26 or 27, wherein the Hausner ratio is at least 1.02, preferably at least 1.04, more preferably at least 1.06, still more preferably at least 1.08, yet more preferably at least 1.10, even more preferably at least 1.12, most preferably at least 1.14, and in particular at least 1.16.

29. The primary packaging according to any of claims 26 to 28, wherein the Hausner ratio is at most 1.24, preferably at most 1.22, more preferably at most 1.20, still more preferably at most 1.18, yet more preferably at most 1.16, even more preferably at most 1.14, most preferably at most 1.12, and in particular at most 1 10.

30. The primary packaging according to any of claims 26 to 29, wherein the Hausner ratio is within the range of from 1.00 to 1.25.

31. The primary packaging according to claim 30, wherein the Hausner ratio is within the range of from 1.05 to 1.1532. The primary packaging according to any of the preceding claims, wherein the powder has a particle size distribution characterized by a D10 value, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 20 to 65 pm33. The primary packaging according to any of the preceding claims, wherein the powder has a particle size distribution characterized by a D50 value, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 150 to 350 pm.

34. The primary packaging according to any of the preceding claims, wherein the powder has a particle size distribution characterized by a D90 value, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 380 to 780 pm.

35. The primary packaging according to any of the preceding claims, wherein the powder has a particle size distribution characterized by a span value (D90-D10) / D50, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 1.85 to 2.25.

36. The primary packaging according to any of the preceding claims, wherein the powder has a sphericity of particles, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 0.805 to 0.820.

37. The primary packaging according to any of the preceding claims, wherein the powder has an aspect ratio of particles, determined by dynamic image analysis according to Ph. Eur. 2.9.48, within the range of from 0.645 to 0.670.

38. The primary packaging according to any of the preceding claims, wherein the powder has a true density according to Ph. Eur. 2.2.42 within the range of 1.438±0.008 g / ml, preferably 1.438±0.006 g / ml, more preferably 1.438±0.006 g / ml, still more preferably 1.438±0.002 g / ml, and yet more preferably 1.438±0.001 g / ml.

39. The primary packaging according to any of the preceding claims, wherein the powder has a specific surface area according to Ph. Eur. 2.9.26 within the range of 0.020 to 0.065 m2 / g.

40. The primary packaging according to any of the preceding claims, wherein the 5-amino levulinic acid or a physiologically acceptable salt thereof is crystalline.

41. The primary packaging according to claim 40, wherein the 5-amino levulinic acid is present as 5- amino levulinic acid hydrochloride salt.

42. The primary packaging according to claim 41, wherein the 5-amino levulinic acid hydrochloride salt is polymorph form A.

43. The primary packaging according to any of claims 1 to 39, wherein the 5-amino levulinic acid or a physiologically acceptable salt thereof is at least partially amorphous.

44. The primary packaging according to any of the preceding claims, which contains 500±350 mg, more preferably 500±300 mg, still more preferably 500±250 mg, yet more preferably 500±200 mg, even more preferably 500±150 mg, most preferably 500±100 mg, and in particular preferably 500±50 mg of the pharmaceutical composition or the pharmaceutical dosage form.

45. The primary packaging according to any of the preceding claims, which is a sachet, pouch or pad, preferably a stick-pack.

46. The primary packaging according to any of the preceding claims, which comprises a mark where it is to be opened by cutting with a pair of scissors.

47. The primary packaging according to any of the preceding claims, which comprises a laser cut or a punctual laser perforation facilitating opening by manual tearing.

48. The primary packaging according to any of the preceding claims, which comprises an opening notch facilitating opening by manual tearing.

49. The primary packaging according to any of the preceding claims, which absorbs UV light.

50. The primary packaging according to any of the preceding claims, which is intransparent for UV light.

51. The primary packaging according to any of the preceding claims, which has a water vapor transmission, determined by electro analysis according to ISO 15106-3 (38°C / 90% r.h ), below the detection limit of <0.001 g m ^d1.

52. The primary packaging according to any of the preceding claims, which has an oxygen transmission, determined by manometric analysis according to ISO 15105-2 (23°C / 50% r.h.), below the detection limit of <0.005 ml m ^d ’ bar1.

53. The primary packaging according to any of the preceding claims, which besides the pharmaceutical composition or the pharmaceutical dosage form comprises or essentially consists of a packaging material in form of a fdm or sheet material.

54. The primary packaging material according to claim 53, wherein the fdm of sheet material is multilayered.

55. The primary packaging according to claim 53 or 54, wherein the fdm or sheet material is a laminate.

56. The primary packaging according to any of claims 53 to 55, wherein the fdm or sheet material comprises or essentially consists of a metal layer, preferably an aluminum layer.

57. The primary packaging according to claim 56, wherein the metal layer, preferably aluminum layer, has a thickness of at least 10 pm, more preferably at least 15 pm, still more preferably at least 20 pm.

58. The primary packaging according to claim 56 or 57, wherein the metal layer, preferably aluminum layer, has a number of pores per m2, measured as defined in EN 546-4 (corresponding to AFCO recommendation B), of <1000, preferably <400, more preferably <20, still more preferably <5, and yet more preferably <0.5; wherein pores are defined as pin holes with a size < 0.2 mm.

59. The primary packaging according to any of claims 53 to 58, wherein the film or sheet material comprises or essentially consists of layer of a web, fabric, woven, nonwoven, netting, scrim, or paper.

60. The primary packaging according to any of claims 53 to 59, wherein the film or sheet material comprises or essentially consists of one or more polymer layers.

61. The primary packaging according to claim 60, wherein at least one of the one or more polymer layers is based on a polyolefin, preferably polypropylene or polyethylene, more preferably polyethylene, still more preferably low density polyethylene (LDPE).

62. The primary packaging according to claim 60 or 61, wherein at least one of the one or more polymer layers is based on a polyester, preferably polyethylene terephthalate (PET).

63. The primary packaging according to any of claims 53 to 62, wherein the film or sheet material is selected from paper layered foils, aluminum foils, polyethylene foils, desiccant foils, needled foils, laser perforated foils, and layered foils.

64. The primary packaging according to any of claims 53 to 63, wherein the film or sheet material is a laminate, wherein a metal layer, preferably aluminum layer, is sandwiched between a first polymer layer and a second layer, preferably a second polymer layer.

65. The primary packaging according to any of claims 53 to 64, wherein the film or sheet material is a laminate of paper, aluminum and polymer, preferably paper, aluminum and polyethylene.

66. The primary packaging according to any of claims 53 to 65, wherein the film or sheet material is a laminate having from the outside to the inside of the primary packaging (a) optionally an outer lacquer layer that may be printed with printing ink(s); (b) a first polymer layer, preferably based on polyester, more preferably based on polyethylene terephthalate (PET); (c) a first adhesive layer, preferably based on a polyurethane adhesive; (d) a metal layer, preferably aluminum layer; (e) a second adhesive layer, preferably based on a polyurethane adhesive; and (f) a second polymer layer, preferably based on polyolefin, more preferably polyethylene, still more preferably low density polyethylene (LDPE).

67. The primary packaging according to claim 66, wherein the optional lacquer layer (a) has a thickness of at most 10 pm, more preferably at most 5 pm.

68. The primary packaging according to claim 66 or 67, wherein the first polymer layer (b) has a thickness within the range of 25±15 pm, more preferably 25±10 pm, still more preferably 25±5 pm.

69. The primary packaging according to claim 66 or 67, wherein the first polymer layer (b) has a thickness within the range of 12.5±10 pm, more preferably 12.5±7.5 pm, still more preferably 12.5±5 pm.

70. The primary packaging according to any of claims 66 to 69, wherein the second polymer layer (f) has a thickness that is greater than the thickness of the first polymer layer, preferably within the range of 50±15 pm, more preferably 50±10 pm, still more preferably 50±5 pm.

71. The primary packaging according to any of claims 66 to 70, wherein the first adhesive layer (c) and the second adhesive layer (e) independently of one another have a thickness of at most 10 pm, preferably at most 5 pm.

72. The primary packaging according to any of claims 66 to 71, wherein the metal layer (d) has a thickness of 20±15 pm, more preferably 20±10 pm, still more preferably 20±5 pm.

73. A secondary packaging comprising a multitude of primary packaging according to any of the preceding claims.

74. The secondary packaging according to claim 73, wherein at least two primary packaging of the multitude of primary packaging have a different content of the pharmaceutical composition or the pharmaceutical dosage form.

75. The secondary packaging according to claim 73, wherein all primary packaging of the multitude of primary packaging have the same content of the pharmaceutical composition or the pharmaceutical dosage form.

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