Patent Description:
The concept of targeted drug delivery is based on cell receptors which are overexpressed in the target cell in contrast to the not-to-be-targeted cells. If a drug has a binding site to those overexpressed cell receptors it allows the delivery of the drug after its systemic administration in high concentration to those target cells while leaving other cells, which are not of interested, unaffected. For example, if tumor cells are characterized by an overexpression of a specific cell receptor, a drug with binding affinity to said receptor will after intravenous infusion accumulate in high concentration in the tumor tissue while leaving the normal tissue unaffected.

This targeted drug delivery concept has also been used in radiomedicine to deliver radionuclides selectively to the target cells for diagnostic or therapeutic purposes.

For this radiomedicinal application the target cell receptor binding moiety is typically linked to a chelating agent which is able to form a strong complex with the metal ions of a radionuclide. This radiopharmaceutical drug is then delivered to the target cell and the decay of the radionuclide is then releasing high energy electrons, positrons or alpha particles as well as gamma rays at the target site.

One technical problem with those radiopharmaceutical drug products is that the decay of the radionuclide occurs constantly, e.g. also during the manufacturing and during storage of the drug product, and the released high energy emissions induce the cleavage of the chemical bonds of the molecules which form part of the drug product. This is often referred to as radiolysis or radiolytic degradation. The radiolytic degradation of the receptor binding moiety of the drug may lead to a decrease in its efficacy to act as a diagnostic and/or therapeutic.

The poor stability of those radiopharmaceutical drug products and their lack of any significant shelf-life required that those drugs have so far to be manufactured as an individual patient's dose unit in the laboratories at the hospital and administered immediately to the patient who had to be present at that hospital already awaiting the radiological treatment. To facilitate such drug preparation in the hospital laboratories, "cold" (i.e. non-radioactive) freeze-dried kits have been developed which comprise the cell receptor binding moiety linked to a chelating agent without the radionuclide. The freeze-dried content of those kit vials is then to be reconstituted with an solution of the radionuclide short before administration (<NPL>; <NPL>; <NPL>). However, those kits are not "ready-to-use" as they require the reconstitution step and in addition further processing steps (e.g. applying heat for the complexation reaction) as well as purification and sterilization steps before the drug can be finally administered.

To reduce radiolysis of radiopharmaceutical drug products and thus improve stability, various strategies have been explored with more or less success: The drug product may be stored at low temperatures, or produced in high dilution, or stabilizers may be added.

Adding stabilizers however may be problematic as those chemicals may have a negative impact on the complexation of the radionuclide into the chelating agent or may have a limited solubility and precipitate from the solution. Ethanol has been reported as stabilizer against radiolysis (<CIT>). While ethanol might not have a negative impact on the complexation or a solubility issue, higher amounts of ethanol in an infusion solution may be physiologically problematic and may have a negative impact on the tolerability of the drug product.

Producing the drug product in high dilution has the disadvantage that large volumes of infusion solutions need to be administered to patients. For the convenience of patients and for drug tolerability reasons it would be highly desirable to provide the radiopharmaceutical drug product in a high concentration. Those highly concentrated solutions however are in particular prone to radiolysis. Therefore, there are contradictory positions between, on the one hand, avoiding radiolysis by dilution of the drug product but, on the other hand, avoiding patient discomfort during treatment by providing a concentrated drug solution. In <NPL> a product of high concentration has been reported and claimed as being ready-to-use. However, that composition may be problematic with respect to tolerability as it contains high amounts of ethanol.

It remains therefore a challenge to design a ready-to-use radiopharmaceutical drug product which can be produced at commercial scale and delivered as a sufficiently stable and sterile solution in a high concentration which leads to a patient-convenient small infusion volume and which has a composition of high physiological tolerability (e.g. a composition which does not contain ethanol).

<NPL>), describes <NUM>Lu-Tyr<NUM>-octreotide and <NUM>Lu-PSMA(inhibitor) radiopeptides obtained from lyophilized formulations after reconstitution with sterile solutions of <NUM>LuCl<NUM> (<NUM> GBq/mL), without the need for further purification or sterilization processes.

<NPL>, describes the production and quality control of <NUM>Lu-Tyr3-octreotate (<NUM>Lu-DOTATATE), using DOTA (<NUM>,<NUM>,<NUM>,<NUM>-tetrazacyclododecane-N,N',N",N"'-tetra acetic acid) as chelating agent.

The EMA Assessment Report for Lutathera describes the evaluation of Lutathera, authorized by the EMA via the centralized procedure, and includes product information.

The present inventors have now found a way to design and produce a highly concentrated radionuclide complex solution which is chemically and radiochemically very stable even if stored at ambient or short term elevated temperatures so that it can be produced on commercial scale and supplied as a ready-to-use radiopharmaceutical product.

In particular, the present invention provides:
A process for manufacturing a pharmaceutical aqueous solution,.

Preferably, said stabilizers, component (b), are present in a total concentration of at least <NUM>/mL.

The present invention provides the following advantages:
The high concentration allows administering a high dose within a short time frame. The high dose of <NUM> GBq is provided in a small volume of <NUM> to <NUM> which allows the IV infusion administration to be completed within about <NUM> to <NUM> minutes.

The use of suitable stabilizers, according to the present invention as described, herein ensures high stability, at least <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>% or <NUM>% chemical stability with respect to the chemical purity for the cell receptor-binding molecule after <NUM> hours at <NUM>, even if this molecule is a sensitive peptide molecule. For DOTA-TATE, <NUM>% chemical purity were found after <NUM> hours at <NUM> and even after <NUM> hours at <NUM> were found. Even under short term elevated temperature conditions (<NUM> for <NUM> and <NUM>° for <NUM>) such high stability was found with respect to chemical purity.

Further, the use of suitable stabilizers, according to the present invention as described, herein ensures high stability, at least <NUM>% radiochemical stability with respect to the radiochemical purity radionuclide complex. For <NUM>Lu-DOTA-TATE, at least <NUM>% radiochemical purity were found after <NUM> hours at <NUM>. Even under short term elevated
temperature conditions (<NUM> for <NUM> and <NUM>° for <NUM>) such high stability was found with respect to radiochemical purity.

While sufficient stability may be achieved already with one single stabilizer, the use of two stabilizers has been found to be of particular suitability in stabilizing sensitive radiopharmaceutical solutions. In particular, the presence of one stabilizer during complex formation and another stabilizer added after the complex formation is of advantage as it ensures that already during the complexation reaction, the cell receptor-binding molecule is protected against radiolysis and the other stabilizer enhances the protecting effect for the shelf-life period.

Further, by this sequential application of the two stabilizers it is ensured, that during complexation only a relatively small amount of stabilizer is present (which minimizes the potential interference of that stabilizer with the complexation reaction) and after complexation a large amount of a stabilizer combination is present (which strengthens the protective power of the stabilizers for the following drug product storage time period).

This sequential application of two stabilizers also reduces the overall thermal stress of those stabilizers as one of them is not present when the complexation reaction, which involves high temperatures, takes place.

Further, particularly the use of two different stabilizers is advantageous as this combination is more efficacious in reacting to the various different radicals possibly formed by the radiolysis of the cell receptor binding molecule than only one single stabilizer can do.

The composition of the radiopharmaceutical solution does not require the presence of ethanol. The solution is sufficiently stable without ethanol. The absence of ethanol is of advantage with respect to the physiological tolerability of the solution.

A shelf-life of at least <NUM> days is required to allow a radiopharmaceutical drug product to be manufactured from a centralized pharmaceutical production site and to commercialize it as a ready-to-use drug product.

Therefore, due to the high stability (<NUM> at <NUM>) the present invention allows centralized pharmaceutical production at highest quality standards (e.g. cGMP) and at industrial scale, e.g. at <NUM> GBq or <NUM> GBq batch size which provides the drug product in numerous dose units, e.g. enough dose units for the treatment of <NUM> to <NUM> patients at the same time.

Further, due to the high stability, there is sufficient time for the present invention to be shipped from a centralized pharmaceutical production site to remote clinical centers.

Even further, due to the high stability, the present invention can be provided as a ready-to-use infusion solution which can be immediately administered to the patient without a need for the clinical staff to perform any preparatory work before administration.

The present invention relates to the very sensitive somatostatin analogue octreotate which is in particular prone to degradation reactions. Further, the present invention relates to the radionuclide Lutetium-<NUM> with its specific radioactivity characteristics.

Herein after, the present invention is described in further detail and is exemplified.

In general, the present invention is concerned about a process for manufacturing a radiopharmaceutical aqueous solution. The solution is for intravenous (IV) use/application/administration. The solution is stable, concentrated, and ready-to-use.

The stability of the solution ascertained by the use of stabilizers against radiolytic degradation.

In general, the stabilizers used in accordance with the present inventions may be selected from gentisic acid (<NUM>,<NUM>-dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g. sodium ascorbate), methionine, histidine, melatonine, ethanol, and Se-methionine. Preferred stabilizers are selected from gentisic acid or salts thereof and ascorbic acid or salts thereof.

Ethanol is considered as less preferred stabilizer due to tolerability issues associated with it if present in higher concentrations. Ethanol should be ideally avoided in the solutions of the present invention (in other words: free of ethanol).

According to the invention the amount of ethanol is less than <NUM> % by weight (w/w%) in the final solution which is foreseen to be injected/infused. Even more preferably, the solution is free of ethanol.

The "complex formed by" may be alternatively worded: "complex of".

The "different" in "two different stabilizers" refers to a difference in the chemical entity of such stabilizers. "Two different stabilizers" has the meaning that the two stabilizers are different chemical entities, e.g. gentisic acid and ascorbic acid are two different stabilizers. "at least two" means two or more, however, preferably that just two stabilizers are present (not three or more). It is further preferred that ethanol is not one of the two stabilizers.

The herein indicated pH values are the pH values of the final solution. However, it also the pH during manufacturing of the solution, e.g. the pH during the complex formation.

"Shelf life" has herein its general meaning in the context of pharmaceutical products. The shelf life is the length of time that a pharmaceutical product may be stored while its product characteristics still comply with the product specification as defined during drug development and agreed by health authorities.

The present invention further provides the pharmaceutical aqueous solution as defined herein for use in the treatment of neuroendocrine tumors (NET).

Alternatively, the present invention provides the pharmaceutical aqueous solution of the invention for use in a method for the treatment of NET in human patients in need of such treatment which comprises administering an effective amount of the pharmaceutical aqueous solution as defined herein.

Neuroendocrine tumors (NET) which may be treated by the pharmaceutical aqueous solutions as defined here alone or in combinations in accordance with the present invention are selected from the group consisting of gastroenteropancreatic neuroendocrine tumor, carcinoid tumor, pheochromocytoma, paraganglioma, medullary thyroid cancer, pulmonary neuroendocrine tumor, thymic neuroendocrine tumor, a carcinoid tumor or a pancreatic neuroendocrine tumor, pituitary adenoma, adrenal gland tumors, Merkel cell carcinoma, breast cancer, Non-Hodgkin lymphoma, Hodgkin lymphoma, Head & Neck tumor, urothelial carcinoma (bladder), Renal Cell Carcinoma, Hepatocellular Carcinoma, GIST, neuroblastoma, bile duct tumor, cervix tumor, Ewing sarcoma, osteosarcoma, small cell lung cancer (SCLC), prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, supratentorial primitive, neuroectodermal tumor, and esthesioneuroblastoma.

Further NET tumors which may be treated by the pharmaceutical aqueous solutions as defined here alone or in combinations in accordance with the present invention may be selected from the group consisting of functional carcinoid tumor, insulinoma, gastrinoma, vasoactive intestinal peptide (VIP) oma, glucagonoma, serotoninoma, histaminoma, ACTHoma, pheocromocytoma, and somatostatinoma.

The present invention further provides the pharmaceutical aqueous solution of the invention for use in combination or in combination therapy together with one or more therapeutic agents as outlined in the following:
In certain instances, other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.

General Chemotherapeutic agents considered for use in combination therapies include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-<NUM>-deoxy-<NUM>-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), <NUM>-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), <NUM>-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan <NUM> with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), <NUM>-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

Anti-cancer agents of particular interest for combinations with the pharmaceutical aqueous solution of the present invention include:.

In an embodiment, the one or more therapeutic agents are selected from the group consisting of octreotide, lanreotide, vaproreotide, pasireotide, satoreotide, everolimus, temozolomide, telotristat, sunitinib, sulfatinib, ribociclib, entinostat, and pazopanib. In particular embodiments, those combinations are for use in the treatment of NET tumors, e.g. GEP-NET, pulmonary NET, pNET, lung NET, Carcinoid syndrome, SCLC.

In particular embodiments, the one or more therapeutics agents, are one or more immuno-oncology therapeutic agents selected from the group consisting of PD-<NUM>, PD-L1 and CTLA-<NUM> inhibitors, in particular the I-O therapeutic agents selected from Spartalizumab, Nivolumab, Pembrolizumab, Pidilizumab, Durvalumab, Atezolizumab, Avelumab, Ipilimumab, and Tremelimumab. In particular embodiments, those combinations are for use in the treatment of NET tumors, e.g. GEP-NET, pulmonary NET, pNET, lung NET, Carcinoid syndrome, SCLC.

In the following, terms as used herein are defined in their meaning.

The term "about" or "ca. " has herein the meaning that the following value may vary for ± <NUM>%, preferably ± <NUM>%, more preferably ± <NUM>%, even more preferably ± <NUM>%, even more preferably ± <NUM>%.

Unless otherwise defined, "%" has herein the meaning of weight percent (wt%), also refered to as weight by weight percent (w/w%).

The cell receptor binding moiety and the chelating agent form together the following molecule:
DOTA-TATE: [DOTA<NUM>,D-Phe<NUM>,Tyr<NUM>]octreotate, DOTA-Tyr<NUM>-Octreotate, DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cyclo <NUM>,<NUM>), oxodotreotide (INN), represented by the following formula :
<CHM>.

The "cell receptor binding moiety linked to the chelating agent" molecule for the present invention is DOTA-TATE.

For the present invention, the complex formed by (or the complex of) the radionuclide and the cell receptor binding moiety linked to the chelating agent is <NUM>Lu-DOTA-TATE, which is also referred to as Lutetium (177Lu) oxodotreotide (INN), i.e. hydrogen [N-{[<NUM>,<NUM>,<NUM>-tris(carboxylato-κO-methyl)-<NUM>,<NUM>,<NUM>,<NUM>-tetraazacyclododecan-<NUM>-yl-κ<NUM>N<NUM>,N<NUM>,N<NUM>,N<NUM>]acetyl-κO}-D-phenylalanyl-L-cysteinyl-tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoninato cyclic (<NUM>→<NUM>)-disulfide(<NUM>-)](177Lu)lutetate(<NUM>-)
and is represented by the following formulas:
<CHM>
<CHM>.

"Buffer for a pH from <NUM> to <NUM>": may be an acetate buffer, citrate buffer (e.g. citrate + HCl or citric acid + Disodium hydrogenphosphate) or phosphate buffer (e.g. Sodium dihydrogenphosphate + Disodium hydrogenphosphate), preferably said buffer is an acetate buffer, preferably said acetate buffer is composed of acetic acid and sodium acetate.

"Sequestering agent", a chelating agent suitable to complex the radionuclide metal ions, preferably DTPA: Diethylenetriaminepentaacetic acid.

"for commercial use": the drug product, e.g. a pharmaceutical aqueous solution, is able to obtain (preferably has obtained) marketing authorization by health authorities, e.g. US-FDA or EMA, by complying with all drug product quality and stability requirements as demanded by such health authorities, is able to be manufactured (preferably is manufactured) from or at a pharmaceutical production site at commercial scale followed by a quality control testing procedure, and is able to be supplied (preferably is supplied) to remotely located end users, e.g. hospitals or patients.

"Combination": refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present invention and a combination partner (e.g. another drug as explained below, also referred to as "therapeutic agent" or "co-agent") may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms "coadministration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term "fixed combination" means that the therapeutic agents, e.g. a compound of the present invention and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents, e.g. a compound of the present invention and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more therapeutic agent.

Hereinafter, the present invention is described in more details and specifically with reference to the examples, which however are not intended to limit the present invention.

Materials:
The <NUM>LuCl<NUM> may be obtained from commercial sources, e.g. I. Holland BV. The DOTA<NUM>-Tyr<NUM>-Octreotate may be obtained from commercial sources, e.g. by piCHEM Forschungs-und Entwicklungs GmbH, Austria. All other components of the drug product are commercially available from various sources.

The Drug Product (<NUM>Lu-DOTA<NUM>-Tyr<NUM>-Octreotate <NUM> MBq/mL solution for infusion) is designed as a sterile ready-to-use solution for infusion containing <NUM>Lu-DOTA<NUM>-Tyr<NUM>-Octreotate as Drug Substance with a volumetric activity of <NUM> MBq/mL at reference date and time (calibration time (tc)). Calibration time (tc) corresponds to the End of Production (EOP = t0) which is the time of measurement of the activity of the first QC vial. The shelf-life of Drug Product is defined as <NUM> hours after calibration time. Drug Product is a single dose vial, containing suitable amount of solution that allows delivery of <NUM> GBq of radioactivity at injection time.

(<NUM> mCi) after the end of production. Certificates of analysis reports both the exact activity provided and the time when this activity is reached. This value is declared as "Injection time: {DD MM YYYY} {hh:mm} UTC". Considering the variable injection time and constant decay of the radionuclide, the filling volume needed for an activity of <NUM> GBq at injection time is calculated and can range from <NUM> and <NUM>.

For a <NUM> GBq batch size (<NUM> Ci batch size) a <NUM>LuCl<NUM> solution, about <NUM> GBq in HCl, is mixed together with a DOTA-Tyr<NUM>-Octreotate (about <NUM>) solution, and a Reaction Buffer solution, containing an antioxidant agent (and stabilizer against radiolytic degradation) (i.e. Gentisic acid, about <NUM>) and a buffer system (i.e. Acetate buffer system), resulting in a total of about <NUM> solution, which is used for radiolabelling that occurs at a temperature of about <NUM> to about <NUM> within less than <NUM> minutes.

The synthesis is carried out using a single use disposable kit cassette installed on the front of the synthesis module which contains the fluid pathway (tubing), reactor vial and sealed reagent vials.

The obtained mother solution is diluted with a solution containing a chelating agent (i.e. DTPA), an antioxidant agent (i.e. Ascorbic acid) sodium hydroxide, and sodium chloride and, then sterile filtered through <NUM> to give the ready-to-use solution as described in Example <NUM> with a pH of <NUM>-<NUM>, in particular <NUM>-<NUM>. Finally, the solution is dispensed in volumes of from <NUM> to <NUM> into sterile vials. The stoppered vials are enclosed within lead containers for protective shielding.

Manufacturing Process can also be implemented for batch sizes higher than 74GBq. In this case the amount of the raw materials (Lutetium, peptide and Reaction Buffer) are multiplied to guarantee the same raw materials ratio.

The following table provides the stability test data for a batch produced at <NUM> GBq batch size according to the process described in Example <NUM>.

Claim 1:
A process for manufacturing a pharmaceutical aqueous solution,
wherein the pharmaceutical aqueous solution comprises:
(a) a complex formed by
(ai) the radionuclide <NUM>Lu (Lutetium-<NUM>), and
(aii) DOTA-TATE; and
(b) at least two different stabilizers against radiolytic degradation, wherein said component (b) comprises the stabilizers
(bi) gentisic acid or a salt thereof, wherein the gentisic acid is present in a concentration of from <NUM> to <NUM>/mL, and
(bii) ascorbic acid or a salt thereof, wherein the ascorbic acid is present in a concentration of from <NUM> to <NUM>/mL,
wherein:
said stabilizers are present in a total concentration of from <NUM> to <NUM>/mL,
said solution has less than <NUM>% ethanol by weight (w/w%),
the radiochemical purity (determined by HPLC) is maintained at ≥ <NUM>% for at least <NUM> when stored at <NUM>,
the pharmaceutical aqueous solution provides a radioactive dose of <NUM> GBq, and
the volume of the pharmaceutical aqueous solution is <NUM> to <NUM>,
and wherein the process comprises the process steps:
(<NUM>) Forming a complex of the radionuclide <NUM>Lu and DOTA-TATE by
(<NUM>) preparing an aqueous solution comprising the radionuclide;
(<NUM>) preparing an aqueous solution comprising the DOTA-TATE and at least one stabilizer against radiolytic degradation, wherein the at least one stabilizer comprises gentisic acid; and
(<NUM>) mixing the solutions obtained in steps (<NUM>) and (<NUM>) and heating the resulting mixture;
(<NUM>) Diluting the complex solution obtained by step (<NUM>) by
(<NUM>) preparing an aqueous dilution solution comprising at least one stabilizer against radiolytic degradation, wherein the at least one stabilizer comprises ascorbic acid; and
(<NUM>) mixing the complex solution obtained by step (<NUM>) with the dilution solution obtained by the step (<NUM>) to obtain the final solution.