Oral solution of a hydromorphone salt

Abstract

Oral solution containing a pharmaceutically acceptable salt of hydromorphone in a concentration of at least 1.5 mg / ml (calculated as hydromorphone hydrochloride) based on the total solution, at least one sweetener, glycerol, buffer and at least one antimicrobial preservative.

Description

[0001] The invention relates to an oral solution of a hydromorphone salt, in particular the hydrochloride, which has a high active ingredient concentration, is stable, and has a pleasant taste, making it easy to swallow even for patients with swallowing difficulties, such as elderly and / or severely debilitated patients. Furthermore, the oral solution according to the invention allows for easy dosage adjustment, in particular using a dosing syringe. The invention also relates to a kit of parts comprising the above oral solution, as well as the use of the oral solution or kit of parts in pain therapy. background

[0002] Hydromorphone is a μ-selective opioid analgesic with predominantly analgesic, anxiolytic, antitussive, and sedative properties. It is a semi-synthetic variant of morphine, and like morphine, hydromorphone is an agonist of the μ-opioid receptors, but approximately 7.5 times more potent than morphine. It is effective for severe and even severe pain and is therefore classified as Level III in the WHO pain classification system. Severe pain can be triggered, for example, by tumors or occur after surgery. Hydromorphone is a prescription drug and is subject to the German Narcotics Act.

[0003] Hydromorphone hydrochloride is chemically 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride or (5R,9R,13S,14R)-3-hydroxy-17-methyl-4,5-epoxymorphinan-6-one hydrochloride with the formula C 17 H 20 ClNO3 or C 17 H 19 NO3·HCl and a molecular weight of 321.8 g / mol.

[0004] Hydromorphone hydrochloride is a white to almost white, crystalline powder with a bitter taste. It is easily soluble in water, very slightly soluble in 96% ethanol, and practically insoluble in dichloromethane.

[0005] The active ingredient hydromorphone hydrochloride is listed in monographs in the European Pharmacopoeia, the British Pharmacopoeia, and the US Pharmacopoeia. In addition to the drug itself, the US Pharmacopoeia also describes a hydromorphone hydrochloride solution.

[0006] Some hydromorphone preparations are marketed in Germany in solid form, e.g., Palladon® 1.3 / 2.6 mg hard capsules from Mundipharma GmbH or Hydromorphon Aristo Long 4 / 8 / 16 / 32 mg prolonged-release tablets. There are prolonged-release tablet preparations and immediate-release hard gelatin capsules. These solid oral dosage forms are often very difficult for patients to swallow, especially for elderly or very weak patients. Furthermore, the dosage of solid dosage forms is much less flexible than that of liquid preparations.

[0007] Therefore, there is a need for liquid oral opioid and especially oral liquid hydromorphone preparations.

[0008] The following infusion or injection solutions are known as liquid hydromorphone preparations: WO 2023 / 183055 A1 discloses a ready-to-use solution for intravenous (IV) infusion. Hydromorphone hydrochloride is present in a saline solution in a polyvinyl acetate (PVA) plastic bag. The introduction to the document refers to common injection solutions offered in glass ampoules, with an active ingredient concentration of 2 mg / ml, and ampoules with 1 ml and 20 ml contents available. In addition, 1 ml pre-filled syringes with hydromorphone hydrochloride concentrations of 0.2 mg / ml, 1 mg / ml, or 2 mg / ml are available. However, larger volumes usually have to be prepared for use, causing problems such as dilution errors, time expenditure, and the unintentional introduction of impurities. Furthermore, the stability of the solutions obtained by dilution is limited, according to the document. The document therefore proposes a ready-to-use hydromorphone hydrochloride infusion solution that can be stored for 6 months at approximately 20 to 25 °C at not more than 40% relative humidity.Humidity is stable because the solution was packaged in a plastic bag and then terminally sterilized, i.e., autoclaved. The concentration of hydromorphone hydrochloride according to WO 2023 / 183055 A1 is 0.2 mg / ml, and the serving size is 50 ml or 100 ml. The pH is, for example, 3.5 to 4.5. The solution contains a tonicity agent such as NaCl and a buffer.

[0009] WO 2013 / 134362 discloses a sterile, buffer-free hydromorphone hydrochloride solution for injection. This is particularly suitable for intrathecal administration by direct injection into the cerebrospinal fluid and the extracellular fluid in the brain, and has a pH close to 7.3 for this purpose. The document mentions common hydromorphone hydrochloride injection solutions with a concentration of 10 mg / ml, which contain no preservatives but do contain 0.2% sodium nitrate and 0.2% citric acid solution. The buffers are disadvantageous because they could lead to potential complications such as toxicity, side effects, and allergic reactions. Furthermore, they increase the cost of the preparations. The document therefore proposes buffer-free injection solutions.The terminal sterilization of hydromorphone solutions is also disadvantageous, as hydromorphone is heat-labile and forms byproducts such as hydromorphone N-oxide (HNO), 6-β-tetrahydrooripavine (THO), dihydromorphone (DHM), and pseudohydromorphone (PHM) when heated. This reduces the available amount of hydromorphone in the solution. Furthermore, the degradation products of hydromorphone lead to undesirable side effects, including toxicity.

[0010] Due to their low stability and often also their unpleasant taste, injection solutions are generally not suitable as oral solutions, which are intended to be used over a longer period of time after the container has been opened and therefore must guarantee a certain shelf life after opening.

[0011] In addition, oral solutions are often preferred over infusions or injections for easier administration.

[0012] A liquid oral hydromorphone hydrochloride preparation is available in the USA: Dilaudid® oral liquid from Abbott Laboratories. This preparation contains methyl 4-hydroxybenzoate and propyl 4-hydroxybenzoate as preservatives, sucrose and glycerol as sweeteners, and sodium etabisulfite as an antioxidant. The hydromorphone hydrochloride concentration in this preparation is 1 mg / ml. The product is taken teaspoonful by teaspoonful. According to the manufacturer, one teaspoonful of solution contains 5 mg of hydromorphone hydrochloride. This dosage method is subject to considerable variation and is extremely imprecise because the size of teaspoons is not standardized. In cases of severe pain, relatively large volumes of the medicinal solution must be taken due to the low concentration of the solution.Due to the inaccuracy of the dosage, there is a risk of overdose, which must be avoided at all costs given the dangerous side effects of hydromorphone, particularly respiratory depression / respiratory arrest. On the other hand, too low a dosage is also detrimental, as in this case, sufficient pain relief is not achieved.

[0013] Hydromorphone HCl drops from Streuli are also available in a concentration of 1 mg / ml. They contain disodium EDTA as a chelating agent, methyl 4-hydroxybenzoate and propyl 4-hydroxybenzoate as preservatives, and ethanol and water as solvents. The taste of the drops is very bitter and unpleasant due to the active ingredient itself and the ethanol. Taking ethanol together with an opioid drug appears to be disadvantageous, as alcohol consumption is generally strictly discouraged when taking opioid medication because ethanol increases the opioid effect. Due to the low concentration of the drops, large amounts must be measured for severe pain, which can easily lead to miscounting and thus dosing errors.

[0014] The object of the invention was therefore to provide a highly concentrated oral solution of a hydromorphone salt that can be dosed easily and accurately, has a pleasant taste, and is stable when stored in a light-protected container (such as a brown glass bottle) for at least 12 months at 25°C and 60% relative humidity and for at least 1 month at 40°C and 75% relative humidity. In this description, the term "container" is used synonymously with "vessel."

[0015] The object is achieved by the oral solution according to claim 1. Preferred embodiments are specified in claims 2 to 8. The invention also encompasses a kit of parts comprising the oral solution, as well as the use of the oral solution or the kit of parts for pain therapy. Description of the figure

[0016] Fig.Figure 1 shows mean (arithmetic) plasma concentration-time curves of hydromorphone after administration of the oral solution according to the invention (light diamonds, referred to as “test”) with a concentration of 2.6 mg / ml hydromorphone hydrochloride compared to a capsule of the reference product Palladon® 2.6 mg hard capsules (black diamonds, referred to as “reference”). Disclosure of the invention

[0017] The oral solution according to the invention contains hydromorphone as a salt. The hydrochloride is preferred, but other salts, such as sulfate or mesylate, are also possible.

[0018] Hydromorphone hydrochloride is a well-known active ingredient and can be manufactured using known methods or purchased from various manufacturers.

[0019] The oral solution according to the invention contains the hydromorphone salt in a concentration of at least 1.5 mg / ml, calculated as hydromorphone hydrochloride. This means that when using a different salt, e.g., the sulfate, the amount of active ingredient salt in mg is converted according to the molar mass. For example, 10 mg of hydromorphone hydrochloride corresponds to 8.9 mg of hydromorphone (as the free base). Hydromorphone is usually used as a medicinal product in the form of the hydrochloride.

[0020] The concentration of hydromorphone hydrochloride in the oral solution according to the invention is preferably at least 2.0 mg / ml based on the total solution, more preferably at least 2.5 mg / ml, and most preferably 2.6 mg / ml, especially 2.60 mg / ml. This is significantly higher than the concentration of previously available oral solutions or drops, which is only 1.0 mg / ml.

[0021] The maximum concentration of the hydromorphone salt in the solution according to the invention is determined by its solubility therein. The maximum concentration is, for example, 10 mg / ml, preferably 5 mg / ml, and more preferably 3 mg / ml.

[0022] A 2.6 mg / ml hydromorphone hydrochloride solution has an efficacy equivalent to 20 mg / ml of orally administered morphine sulfate. The dose of the solution according to the invention is normally determined by titration starting from 0.5 ml of hydromorphone hydrochloride solution (i.e., 1.3 mg hydromorphone hydrochloride) or 1.0 ml of hydromorphone hydrochloride solution (i.e., 2.6 mg hydromorphone hydrochloride) every 4 hours. As pain severity increases, higher doses of the solution according to the invention, alone or in combination with extended-release hydromorphone preparations or other analgesics, will be required to achieve the desired pain relief.

[0023] Surprisingly, the oral solution according to the invention is sufficiently stable for use as an oral solution despite the high active ingredient concentration.

[0024] In particular, the solution according to the invention contains no ethanol. This has an unpleasantly bitter taste, which should be avoided according to the invention, and is also generally unsuitable for administering opioids, as their effect could be undesirably enhanced by ethanol. The use of ethanol is also disadvantageous due to the abuse potential of hydromorphone.

[0025] The solution according to the invention has a pleasant sweet taste and can therefore be taken without any problems, especially by elderly patients. The bitter taste of the active ingredient is no longer, or at least barely, perceptible in the solution according to the invention. It contains at least one sweetener. Sucrose (also known as table sugar) is preferably used as the sweetener. The solution also contains glycerol, which also has a sweet taste and simultaneously acts as a viscosity enhancer.

[0026] The applicant tested various sweeteners and flavorings and found that, surprisingly, raspberry flavoring led to the undesirable formation of hydromorphone degradation products. The best taste results, however, were achieved with sucrose as the sweetener and with glycerol.

[0027] Glycerol (also known as E 422) is a clear, colorless, odorless, viscous, hygroscopic liquid; it has a sweet taste, approximately 0.6 times sweeter than sucrose (table sugar). Glycerol is commonly used in a variety of pharmaceutical formulations, including oral, otic, ophthalmic, topical, and parenteral preparations. In oral solutions, glycerol is used as a solvent, sweetener, antimicrobial preservative, and viscosity-increasing agent. In the formulation according to the invention, glycerol is preferably used in an amount of approximately 5% by weight of the final formulation, particularly to increase viscosity, but also as a sweetener. The amount of glycerol according to the invention is, for example, 20 to 70 mg / ml, preferably 30 to 60 mg / ml, more preferably 30 to 55 mg / ml, and most preferably 50 mg / ml, based on the total solution. Pharmacopoeial-grade glycerol is preferred.

[0028] Sucrose is a sugar obtained from sugar cane (Saccharum officinarum Linne' (Fam. Gramineae)), sugar beet (Beta vulgaris Linne' (Fam. Chenopodiaceae)), and other sources. It is a disaccharide composed of glucose and fructose. Sucrose occurs as colorless crystals, as crystalline masses or blocks, or as a white crystalline powder; it is odorless and has a sweet taste. Sucrose is frequently used in oral pharmaceutical formulations. It can serve, for example, as a binder for moist granulated tablets or as a viscosity improver and sweetener in oral solutions. In the formulation according to the invention, sucrose is preferably used as a sweetener in an amount of approximately 0.1% by weight. The amount of sucrose in the total solution is not limited and is, for example, 1.0 to 1.6 mg / ml, more preferably 1.2 to 1.4 mg / ml, particularly preferably 1.3 mg / ml, in particular 1.30 mg / ml, each based on the total solution.

[0029] Other sweeteners such as sorbitol, mannitol, xylitol, sucralose, aspartame, sodium cyclamate, acesulfame potassium, acesulfame aspartame salt, neohesperidin, thaumatin, fructose, glucose, trehalose, erythritol, isomalt, lactitol, maltitol, or sodium saccharin, as well as other sweet-tasting solvents such as polyethylene glycol (with low molecular weight, such as PEG 400) or propylene glycol, are also suitable according to the invention. However, sucralose is somewhat less suitable than sucrose because a higher increase in impurities during storage is observed than with sucrose. The amounts of sweetener are adjusted according to the desired taste or sweetness of the oral solution.

[0030] According to the invention, a preservative is understood to mean an antimicrobial preservative. Methyl 4-hydroxybenzoate, also known under the designation E 218, is particularly preferably used as an antimicrobial preservative. Propyl 4-hydroxybenzoate is also suitable as an antimicrobial preservative. Other antimicrobial preservatives suitable according to the invention include, for example, benzoic acid, benzyl alcohol, butyl 4-hydroxybenzoate, chlorobutanol, ethyl 4-hydroxybenzoate, potassium sorbate, propylene glycol, sorbic acid, and benzalkonium chloride.

[0031] The amount of antimicrobial preservative in the oral solution according to the invention, in particular methyl 4-hydroxybenzoate, is selected to ensure sufficient storage stability. It is generally approximately 0.1 to 2.0 mg / ml, e.g., 1.0 to 1.5 mg / ml, more preferably 1.1 to 1.3 mg / ml, particularly preferably 1.2 mg / ml, especially 1.20 mg / ml, based in each case on the total solution.

[0032] Methyl 4-hydroxybenzoate occurs as colorless crystals or a white crystalline powder. It belongs to the so-called parabens. These are 4-hydroxybenzoic acid and its derivatives, such as salts and esters. Methyl 4-hydroxybenzoate is odorless or almost odorless and has a slightly burning taste. It is widely used in cosmetics, food, and oral and pharmaceutical formulations as an antimicrobial preservative. Parabens are effective over a wide pH range and have a broad spectrum of antimicrobial activity, although they are most effective against yeasts and molds. For oral solutions and suspensions, it is typically used in a concentration of 0.015–0.2% by weight. In the formulation according to the invention, methyl 4-hydroxybenzoate is particularly preferably used in an amount of 0.1% by weight as an antimicrobial preservative.Its concentration is particularly preferably 1.2 mg / ml based on the total solution, in particular 1.20 mg / ml.

[0033] The applicant tested other preservatives and surprisingly found that sodium metabisulfite, which is frequently used as an antioxidant and preservative in pharmaceuticals, is unsuitable for the invention because it leads to increased formation of undesirable hydromorphone degradation products. The applicant therefore classified sodium metabisulfite as incompatible with hydromorphone and therefore unsuitable for the invention.

[0034] The solution according to the invention therefore does not contain sodium metabisulfite.

[0035] The oral solution according to the invention is essentially free of sodium, since it contains less than 1 mmol (23 mg) of sodium per ml.

[0036] The oral solution according to the invention contains a buffer to adjust the pH to the desired range and to increase the stability of the solution.

[0037] A citrate buffer is particularly preferred. This buffer comprises one or more citrates and citric acid.

[0038] Sodium citrate (also known as E 331) is preferably used as citrate, but other pharmaceutically acceptable citrates are also possible, e.g. magnesium citrate, calcium citrate, zinc citrate, potassium citrate, etc. In the context of this application, sodium citrate is understood to mean trisodium citrate dihydrate in accordance with the pharmacopoeia.

[0039] Sodium citrate consists of odorless, colorless, monoclinic crystals or a white crystalline powder with a cooling, salty taste. It is easily deliquescent in humid air and efflorescent in warm, dry air. Sodium citrate, either as the dihydrate or as the anhydrous material, is widely used in pharmaceutical formulations. In food, it is primarily used to adjust the pH of solutions. It is also used as a sequestering agent. The anhydrous material is used in effervescent tablet formulations. As a buffering agent, it is usually used in a concentration of 0.3–2.0 wt.%. In the formulation according to the invention, sodium citrate is preferably used in an amount of 0.5 wt.% and serves as the base component of the citrate buffer. The amount of sodium citrate is particularly preferably 5.45 mg / ml based on the total solution.

[0040] According to the invention, citric acid is preferably used as citric acid monohydrate (also known as E 330). Citric acid monohydrate occurs as colorless or translucent crystals or as a white, crystalline, efflorescent powder. It is odorless and has a strongly acidic taste. Citric acid (as monohydrate or anhydrous material) is frequently used in pharmaceutical formulations, primarily to adjust the pH of solutions. In food, citric acid is used as a flavor enhancer due to its tart, sour taste. Citric acid monohydrate is used as a sequestering agent and antioxidant synergist. As a buffer, it is usually used in a concentration of 0.1 to 2.0% by weight. In the formulation according to the invention, citric acid monohydrate is preferably used in an amount of approximately 0.9% by weight and acts as the acidic component of the citrate buffer.The amount of citric acid monohydrate is particularly preferably 9.07 mg / ml.

[0041] In a preferred embodiment, the buffer is present in the solution according to the invention in an amount of 1.4 wt.% based on the total solution, in particular the solution contains 0.9 wt.% citric acid monohydrate and 0.5 wt.% sodium citrate.

[0042] In a preferred embodiment, the solution according to the invention contains a citrate buffer consisting of citric acid monohydrate and sodium citrate, and the antimicrobial preservative methyl 4-hydroxybenzoate.

[0043] The applicant has demonstrated in experiments that if no buffer is added to the oral solution, more impurities occur after storage, and the pH values of the formulation exhibit greater fluctuations than in buffered systems. Therefore, a buffer is used according to the invention.

[0044] The impurity content after storage increases with increasing storage temperature and pH. The applicant tested various pH values adjusted with different amounts of citrate buffer (pH 3.0, pH 3.5, pH 4.0, pH 4.8, and pH 6.0). Surprisingly, it was found that pH 3.5, rather than pH 4.8, was optimal in terms of storage stability and the formation of hydromorphone degradation products.

[0045] The solution according to the invention therefore has a pH of 2.5 to 4.8, preferably 3.0 to 4.2, more preferably 3.2 to 4.0, and particularly preferably 3.5. The pH values are to be understood as ± 0.1.

[0046] In addition to citrate buffer, any buffer system that allows adjustment of the above pH range can be used according to the invention. In particular, acetate buffer, which comprises acetic acid and an acetate salt, e.g., sodium acetate or potassium acetate, or phosphate buffer, comprising phosphoric acid and potassium dihydrogen phosphate, can be used. Citric acid-disodium hydrogen phosphate buffer, for example, can also be used.

[0047] The target pH is adjusted by selecting the appropriate amount of buffer.

[0048] The solution according to the invention does not contain any sequestering agent such as EDTA or salts of EDTA such as Na-edetate.

[0049] The solution according to the invention is an oral solution containing a pharmaceutically acceptable salt of hydromorphone in a concentration of more than 1.5 mg / ml, calculated as hydromorphone hydrochloride, based on the total solution, at least one sweetener, preferably sucrose, glycerol, buffer and at least one antimicrobial preservative.

[0050] Hydromorphone decomposes during storage into various degradation products, as mentioned above. Of particular importance are pseudohydromorphone (referred to herein as Impurity A or PHM) and hydromorphone N-oxide (referred to herein as Impurity B or HNO).

[0051] In order to meet the specification as a ready-to-use oral solution, the proportion of impurity B (HNO) must be ≤ 0.2 wt.% and the proportion of impurity A (PHM) ≤ 0.5 wt.% in the oral solution according to the invention after storage in a container protected from light, such as a brown glass bottle, under certain conditions (25 °C / 60% rel. humidity / 12 months and / or 40 °C / 75% rel. humidity / 1 month). The total proportion of impurities, including unknown impurities other than A and B, must be ≤ 2.0 wt.%. The proportion of each individual unknown impurity must be ≤ 0.2 wt.%. If these conditions are met, the solution is stable within the meaning of the invention. The solution is particularly preferably stable after 21 months when stored at 25 °C / 60% rel. humidity and / or after 3 months when stored at 40 °C / 75% relative humidity.

[0052] The impurities are quantified in a known manner by high-performance liquid chromatography (HPLC).

[0053] The oral solution according to the invention is stable, particularly storage-stable. Immediately after preparation, the solution is a clear, colorless, slightly viscous liquid.

[0054] According to the invention, a distinction is made between chemical stability, ie, the occurrence of degradation products only in the amounts defined above and an unchanged appearance, and microbiological storage stability, ie, the presence of microorganisms such as bacteria, fungi, etc. only in the maximum amounts defined below. The solution according to the invention is both chemically stable and microbiologically stable during storage.

[0055] Chemical stability here means, on the one hand, that the solution, after storage in a light-protected container at 25°C and 60% relative humidity, after at least 12 months and / or after storage at 40°C and 75% relative humidity after at least 1 month, particularly preferably after 21 months at 25°C / 60% relative humidity and / or 3 months at 40°C / 75% relative humidity, still displays an appearance when viewed with the naked eye that is unchanged from its initial state. In particular, no cloudiness, flocculation, and / or discoloration occur.

[0056] On the other hand, chemical stability also means that the amounts of impurities after storage at 25°C / 60% RH after at least 12 months or at 40°C / 75% RH after at least 1 month, particularly preferably after 21 months at 25°C / 60% RH and / or 3 months at 40°C / 75% RH, are still below the limits specified above. These are ≤ 0.5 wt% for impurity A (PHM), ≤ 0.2 wt% for impurity B (HNO), ≤ 0.2 wt% for each individual unknown impurity, and ≤ 2.0 wt% for the total impurities.

[0057] According to the invention, chemical preservatives and antioxidants (=stabilizers), sodium EDTA (chelating agents), and the like can be omitted. The solution according to the invention is chemically stable, even though it does not contain chemical preservatives such as antioxidants.

[0058] The solution according to the invention furthermore complies with the criteria for microbiological testing according to Ph. Eur. 2.6.12, 2.6.13 and 5.1.4 "Aqueous solutions for oral administration." The total yeast and mold count (TYMC) must be ≤ 10 1 CFU / g, the number of aerobic microbes (TAMC, total aerobic microbial count) must be ≤ 10 2 CFU / g, and E. coli must be absent in 1 g. CFU means the number of colony-forming units on a solid nutrient medium (agar).

[0059] The oral solution according to the invention is an aqueous solution for oral administration and does not possess sufficient antimicrobial activity on its own. Therefore, antimicrobial preservatives are added to limit microbial contamination that may occur under normal storage and use conditions, particularly in multi-dose containers, i.e., to ensure microbiological storage stability. Microbial contamination could pose a risk to the patient through infection and spoilage of the preparation. To ensure that the determined preservative concentration in the final formulation is sufficient, the antimicrobial preservative efficacy test for oral preparations was carried out according to Ph. Eur. 5.1.3. For this purpose, samples of the final formulation were analyzed with a target pH of 3.5 and pH 4.0, each containing different concentrations of methyl 4-hydroxybenzoate.In particular, the bacterial count ([CFU / g]) expressed as CFU (colony forming units) was determined at the beginning, after 7, 14, and 28 days, respectively, of the following microorganisms: Staphylococcus aureus ATCC 6538, Pseudomonas aeruginosa ATCC 9027, Candida albicans ATCC 10231, Aspergillus brasiliensis ATCC 16404, and Escherichia coli ATCC 8739. The solution according to the invention, with both a pH of 3.5 and a pH of 4.0, reliably complies with the specifications of the Ph. Eur. as mentioned above. This means that the solution according to the invention contains sufficient antimicrobial preservative and is thus microbiologically stable during storage.

[0060] The microbiological storage stability of the solution according to the invention in sealed, light-protected containers when stored below 25°C is at least 12 months. After opening, the microbiological storage stability, also referred to here as shelf life, is at least 1 month, preferably at least 2 months.

[0061] The solution according to the invention is bioequivalent to Palladon® 2.6 mg hard capsules with regard to the mean arithmetic plasma concentration-time curve of hydromorphone. This is Fig. 1 and the following Table 1.

[0062] The dissolution of the reference product Palladon® 2.6 mg hard capsules was analyzed in 0.1 N HCl and in buffer at pH 4.5 and pH 6.8 using a Ph. Eur. Apparatus 1 at 100 rpm in 500 ml of solvent. The study showed that at pH 1.0, 4.5, and 6.8, more than 90% of the active ingredient was dissolved after 15 minutes. Palladon® 2.6 mg hard capsules are therefore an immediate-release product.

[0063] Table 1: Calculated 90% confidence intervals, geometric means (T / R) and CV res (%) from the analysis of the pivotal bioequivalence study with hydromorphone HCl 2.6 mg / ml oral solution versus Palladon® 2.6 mg hard capsules (N = 50) parameter 90% confidence interval (%) Test / reference ratio (%) CV res (%) AUC (0-t) 93.42 - 108.38 100.62 18.85 C max 83.26- 103.63 92.89 28.07

[0064] AUC (area under the curve) is defined as the area enclosed between the curve and the x-axis. To measure bioavailability, the plasma concentration is measured at various time points after oral administration of a drug. These measurements result in a typical curve that shows the uptake of the active ingredient. The area under this curve is called AUC (area under the curve).

[0065] C max means the highest concentration of an active substance achieved in the blood plasma after its administration.

[0066] The confidence intervals determined for the oral solution according to the invention are within the acceptable range of 80.00 to 125.00%. Therefore, the oral solution according to the invention is bioequivalent to Palladon® 2.6 mg hard capsules.

[0067] The oral solution according to the invention is produced by a conventional manufacturing process. Preferably, the preservative, in particular methyl 4-hydroxybenzoate, is first dissolved in a portion of the calculated volume of water, e.g., 80% of the final volume, while heating to 85 to 90°C with stirring. A protective gas, e.g., argon or nitrogen, preferably argon, is bubbled through the liquid before the preservative is added and throughout the entire process to remove oxygen from the solution. After cooling to room temperature, the active ingredient and any other excipients are added and dissolved, likewise with stirring and in a protective gas. The solution is then diluted with water to the desired final volume. Finally, the pH is adjusted with an additional buffer, in particular sodium citrate. The solution is poured into the container under a protective gas, and the container is sealed. The process is preferably carried out with protection from light.

[0068] The invention also provides a kit of parts comprising the oral hydromorphone solution according to the invention in a suitable conventional container, e.g., a light-protective vessel such as a brown glass bottle, and a matching dosing device. This is preferably a plastic dosing syringe with a 1 ml or 3 ml filling volume and a 0.1 ml graduation. The bottle or container has an adapter adapted for the dosing device, into which the device, in particular the dosing syringe, is inserted to withdraw the desired dose (amount) of the oral solution. The bottle or container, including the adapter, is closed with a conventional lid, in particular a screw cap provided with a conventional child-proof lock, which is further designed to indicate that the bottle / container has already been opened (e.g., by a tear-off ring or strip that must be removed before first opening).The bottle / container has a capacity of 20, 50 or 100 ml, for example.

[0069] The dosing syringes were tested for accuracy in delivering hydromorphone HCl 2.6 mg / ml oral solution at the required dose. For this purpose, the uniformity and accuracy of the delivered doses were determined according to Ph. Eur. 2.9.27.

[0070] The dosage of hydromorphone HCl 2.6 mg / ml oral solution depends on the severity of the pain and the patient's previous analgesic history. The usual starting dose, as defined in the product information for the reference product Palladon® 2.6 mg hard capsules, is 0.5 ml (equivalent to 1.3 mg hydromorphone hydrochloride) or 1.0 ml (equivalent to 2.6 mg hydromorphone hydrochloride) every 4 hours. The ability to deliver the minimum dose per single administration can be achieved with both dosing syringes (i.e., 1 ml and 3 ml). Therefore, the uniformity of the delivered doses was tested with a 1 ml dosing syringe with 0.25 ml and 1.0 ml and with a 3 ml dosing syringe with 0.5, 1.0, and 3.0 ml of the oral solution according to the invention. The method and specifications are described in Ph. Eur., Chapter 2.9.27. The results for the 1 ml and 3 ml syringes are shown in the following table.

[0071] Table 2: Summary of dosing accuracy according to Ph. Eur. 2.9.27 with 1 ml and 3 ml dosing syringe Total % RSD 1 ml syringe 3 ml syringe dose 1 ml 0,25 ml 3 ml 1 ml 0,5 ml SD 0,02 0,007 0,02 0,01 0,01 RSD 2,31 % 2,88 % 0,59 % 1,04 % 1,98 % * SD: standard deviation, RSD: relative standard deviation

[0072] The results are well within the specification limits, so that the accuracy and reproducibility of the product dosing using the dosing aid according to the invention is very high.

[0073] Compared to drops or solutions that are measured with an unspecified teaspoon, the hydromorphone salt solution according to the invention contained in the kit of parts according to the invention can therefore be dosed much more precisely and safely.

[0074] According to the invention, the oral hydromorphone salt solution is used for pain therapy, particularly for the treatment of severe and extremely severe pain, such as that which occurs in cancer or after surgery. If appropriate, pain therapy can also be carried out according to the invention by administering a combination of the oral hydromorphone solution according to the invention with other analgesics. Examples

[0075] All substances used comply with the Ph. Eur. specifications. Water is used in the form of purified water. Example 1

[0076] Liquid hydromorphone formulations with different pH values were prepared, and chemical stability data were determined under various storage conditions. The levels of impurities A and B were determined by HPLC chromatography. The results are summarized in the following tables. HPLC chromatography:

[0077] Eluent A (buffer pH 2.5): Dissolve 0.9 g of sodium heptanesulfonic acid in 1000 ml of water and add 1 ml of triethylamine. The pH of the solution is adjusted to 2.5 ± 0.05 with phosphoric acid. HPLC system: Waters Column: Symmetry Shield RP18; 5µm; 150×3.9mm Eluent A: Buffer pH 2.5 Eluent B: Methanol (Gradient grade) gradient Time [min] Flow [ml / min] Eluent A [%] Eluent B [%] Curve 0,0 1,0 95 5 6 (linear) 60 75 25 75 75 25 80 95 5 85 95 5 Column temperature: 30 °C Sample temperature: 15 °C Injectable volume: 80 µl Detection: 220 nm Evaluation: substance RT [min] RRT RRF Contamination B approx. 27 0,9 1,07 Hydromorphone HCl approx. 30 - 1,00 Contamination A approx. 60 2,0 0,69 RRT = relative retention time RRF = relative response factor Table 3 Hydromorphone hydrochloride solutions with different pH values component Concentration [mg / ml] Hydr2206 (pH 3.0) Hydr2202d and 2107805 (pH 3.5) Hydr2205a (pH 4.0) Hydr2202a (pH 4.8) Hydr2202c (pH 6.0) Hydromorphone hydrochloride 2,60 2,60 2,60 2,60 2,60 Methyl 4-hydroxybenzoate 1,20 1,20 1,20 1,20 1,20 Sucrose 1,30 1,30 1,30 1,30 1,30 Glycerol 50,0 50,0 50,0 50,0 50,0 Citric acid monohydrate 9,33 9,07 8,07 3,59 0,04 Sodium citrate 2,46 5,45 7,42 7,23 0,26 Water, purified qs qs qs qs qs

[0078] The storage stability of the corresponding solutions is summarized in the following tables: Table 4 Storage stability of the solution Hydr2206 (pH 3.0) 25 °C / 60 % relative humidity 40 °C / 75% rel. air humidity . specification Beginning 6 months 3 months PH value 3,0 3,0 3,0 Impurity A (PHM) (wt%) ≤ 0,5 0,21 0,31 0,40 Impurity B (HNO) (wt%) ≤ 0,2 < 0,05 < 0,05 < 0,05 Individual unknown impurities (wt%) ≤ 0,2 < 0,05 0,05 0,05 0,05 Total impurities (wt%) ≤2,0 0,21 0,36 0,5 Table 5 Storage stability of the solution Hydr2202d (pH 3.5) 25 °C / 60% rel. air humidity . 40 °C / 75% rel. air humidity . specification Beginning 6 months 3 months PH value 3,6 3,6 3,6 Impurity A (PHM) (wt%) ≤ 0,5 0,19 0,21 0,23 Impurity B (HNO) (wt%) ≤ 0,2 < 0,05 < 0,05 < 0,05 Individual unknown impurities (wt%) ≤ 0,2 < 0,05 < 0,05 < 0,05 Total impurities (wt%) ≤2,0 0,19 0,21 0,23 Table 6 Storage stability of solution 2107805 (pH 3.5) 25 °C / 60% rel. air humidity . specification Beginning 3 months 6 months 9 months 12 months 21 months PH value 3,5 3,5 3,5 3,5 3,5 3,5 Impurity A (PHM) (wt%) ≤ 0,5 < 0,05 < 0,05 0,06 0,08 0,12 0,18 Impurity B (HNO) (wt%) ≤ 0,2 < 0,05 < 0,05 < 0,05 < 0,05 < 0,05 < 0,05 Individual unknown impurities (wt%) ≤ 0,2 < 0,05 < 0,05 0,06 0,08 0,10 0,15 Total impurities (wt%) ≤2,0 < 0,05 < 0,05 0,12 0,16 0,22 0,33 Table 7 Storage stability of the solution Hydr2205a (pH 4.0) 25 °C / 60% rel. air humidity . 40 °C / 75% rel. air humidity . specification Beginning 6 months 3 months PH value 4,0 4,0 4,0 Impurity A (PHM) (wt%) ≤ 0,5 0,20 0,25 0,30 Impurity B (HNO) (wt%) ≤ 0,2 < 0,05 < 0,05 < 0,05 Individual unknown impurities (wt%) ≤ 0,2 < 0,05 0,10 0,23 Total impurities (wt%) ≤2,0 0,20 0,35 0,58 Table 8 Storage stability of the solution Hydr2202a (pH 4.8) 25 °C / 60% rel. air humidity . 40 °C / 75% rel. air humidity . specification Beginning 3 months 1 month PH value 4,8 4,8 4,8 Impurity A (PHM) (wt%) ≤ 0,5 0,19 0,25 0,21 Impurity B (HNO) (wt%) ≤ 0,2 < 0,05 < 0,05 < 0,05 Individual unknown impurities (wt%) ≤ 0,2 < 0,05 0,12 0,19 Total impurities (wt%) ≤2,0 0,22 0,33 0,40 Table 9 Storage stability of the solution Hydr2202c (pH 6.0) 25 °C / 60% rel. air humidity . 40 °C / 75% rel. air humidity . specification Beginning 3 months 1 month PH value 6,0 6,0 6,0 Impurity A (PHM) (wt%) ≤ 0,5 0,19 0,18 0,16 Impurity B (HNO) (wt%) ≤ 0,2 < 0,05 < 0,05 < 0,05 Individual unknown impurities (wt%) ≤ 0,2 0,03 0,09 0,36* 0,08 0,06 0,05 0,33* 0,49* 0,07 0,12 0,08 Total impurities (wt%) ≤2,0 0,22 0,82 1,25 *:out of specification

[0079] It can be seen from the tables that above pH 4.8 the solution is no longer sufficiently stable. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] WO 2023 / 183055 A1

[0008] WO 2013 / 134362

[0009] Cited non-patent literature

[0000] Ph. Eur., Chapter 2.9.27

[0070]

Claims

[1] Oral solution containing a pharmaceutically acceptable salt of hydromorphone in a concentration of at least 1.5 mg / ml (calculated as hydromorphone hydrochloride) based on the total solution, at least one sweetener, glycerol, buffer and at least one antimicrobial preservative. [2] Oral solution according to claim 1, wherein the concentration of the hydromorphone salt calculated as hydromorphone hydrochloride, based on the total solution, is at least 2.0 mg / ml, more preferably at least 2.5 mg / ml, particularly preferably 2.6 mg / ml. [3] Oral solution according to claim 1 or 2, wherein the hydromorphone salt is hydromorphone hydrochloride or hydromorphone sulfate, preferably hydromorphone hydrochloride. [4] Oral solution according to one or more of the preceding claims, wherein the buffer is a citrate buffer consisting of citric acid monohydrate and sodium citrate, and / or the preservative is methyl 4-hydroxybenzoate. [5] Oral solution according to one or more of the preceding claims, wherein the buffer is present in an amount of 1.4 wt.% based on the total solution, in particular 0.9 wt.% citric acid monohydrate and 0.5 wt.% sodium citrate. [6] Oral solution according to one or more of the preceding claims, which has a pH in the range of 2.5 to 4.8, preferably pH 3.0 to 4.2, more preferably pH 3.2 to 4.0, particularly preferably pH 3.

5. [7] Oral solution according to one or more of the preceding claims, characterized by that it is stable for at least 12 months when stored in a light-protected container at 25°C and 60% relative humidity and / or for at least 1 month when stored at 40°C and 75% relative humidity. [8] Oral solution according to one or more of the preceding claims, characterized by that the shelf life is at least 1 month after opening. [9] Kit-of-parts comprising the oral solution according to one or more of the preceding claims in a suitable container and a dosing device designed accordingly. [10] Use of the oral solution according to one or more of the preceding claims 1 to 8 or of the kit-of-parts according to claim 9 for pain therapy, in particular for the therapy of severe and most severe pain.

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