Pharmaceutical infusion solution containing dopamine

Abstract

The present disclosure relates to a pharmaceutical infusion solution comprising dopamine or a pharmaceutically acceptable salt thereof, preferably dopamine hydrochloride, dissolved in water for injection, the pharmaceutical infusion solution having a pH between 3.0 and 5.5 and an oxygen content of 0.008% (8 ppm) or less, and uses thereof.

Description

[Technical Field]

[0001] The present disclosure relates to a pharmaceutical infusion solution comprising dopamine hydrochloride dissolved in water for injection, the pharmaceutical infusion solution having a pH between 3.0 and 5.5 and an oxygen content of 0.008% (8 ppm) or less. [Background technology]

[0002] Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting the nervous system, particularly the nigrostriatal system, which contains dopaminergic neurons. Progressive neurodegeneration in the substantia nigra pars compacta (SNpc) results in a decrease in dopamine in the striatum, which in turn causes motor symptoms.

[0003] Pharmacological treatments for Parkinson's disease can be divided into neuroprotective therapy and symptomatic therapy. Neuroprotective therapy for Parkinson's disease is based on protecting dopaminergic neurons in the human substantia nigra and striatum from the complex degenerative process that causes premature cell death and dopamine depletion. However, in reality, almost all available treatments are symptomatic in nature and do not appear to slow or reverse the natural course of the disease. In fact, there are currently no neuroprotective treatments available on the market.

[0004] Therefore, many symptomatic treatments have focused on attenuating this dopamine deficiency (Chaudhuri et al., 2009; Devos et al., 2013) (Chaudhuri KR1, Schapira AH. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009;8:464-74; Devos D, Lejeune S, Cormier-Dequaire F, Tahiri K, Charbonnier-Beaupel F, Rouaix N, Duhamel A, Sablonniere B, Bonnet AM, Bonnet C, Zahr N, Costentin J, Vidailhet M, Corvol JC. Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in Parkinson's disease. Parkinsonism Relat Disord. 2014;20:170-5).

[0005] Because dopamine does not cross the gastrointestinal mucosa or the blood-brain barrier, its lipophilic precursor, L-dopa (levodopa), was developed as an orally administered drug to relieve the symptoms of Parkinson's disease.

[0006] However, many pharmacokinetic drawbacks are associated with the use of L-dopa, leading to the occurrence of L-dopa-related complications (LDRCs). L-dopa has a short plasma half-life and produces dopaminergic pulse stimulation. Under normal conditions, dopaminergic neurons in the substantia nigra pars compacta (SNpc) fire tonically, maintaining a relatively constant level of dopamine in the striatum (Miler and Abercrombie, 1999; Venton et al., 2003; Olanow et al., 2006) (Miller DW, Abercrombie ED. Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats. J Neurochem. 1999;72:1516-22; Venton BJ, Zhang H, Garris PA, Phillips PE, Sulzer D, Wightman RM. Real-time decoding of dopamine concentration changes in the caudate-putamen during tonic and phasic firing. J Neurochem. 2003;87:1284~95; Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications. Lancet Neurol. 2006;5:677-87).However, intermittent oral administration of levodopa in dopamine-depleted states induces discontinuous stimulation of striatal dopamine receptors, contributing to dysfunction of dopaminergic pathways after long-term treatment and leading to the development of motor complications (Fahn and Parkinson study group, 2005; Parkinson study group, 2009) (Fahn S, Parkinson Study Group. Does levodopa slow or hasten the rate of progression of Parkinson's disease? J Neurol. 2005;252 Suppl 4:IV37-IV42; Parkinson Study Group CALM Cohort Investigators. Long-term effect of initiating pramipexole vs. levodopa in early Parkinson's disease. Arch Neurol. 2009;66:563-70). This oral pulse administration, resulting in alternating periods of under- and over-dosing, may contribute to exacerbating disease progression (Devos et al., 2013). Indeed, intermittent oral administration of L-dopa fails to restore sustained nigrostriatal dopaminergic neurotransmission.

[0007] Sustained dopamine administration may be more physiological and may prevent large fluctuations in dopamine levels that can cause adverse outcomes.

[0008] Therefore, some treatments have focused on continuous dopamine administration. However, direct delivery of levodopa gel to the duodenum (Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, Vanagunas A, Othman AA, Widnell KL, Robieson WZ, Pritchett Y, Chatamra K, Benesh J, Lenz RA, Antonini A, LCIG Horizon Study Group. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomized, controlled, double-blind, double-dummy study. Lancet Neurol. 2014;13:141-9; Devos D, French DUODOPA Study Group. Patient profile, indications, efficacy and safety of duodenal levodopa infusion in advanced Parkinson's disease. Mov Disord. 2009;24:993-1000) or subcutaneous injection of the dopamine agonist apomorphine (Manson AJ, Turner K, Lees AJ. Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson's disease: long-term follow-up study of 64 patients. Mov Disord. 2002;17:1235-41; Drapier S, Gillioz AS, Leray E, Peron J, Rouaud T, Marchand A, Verin M.Apomorphine infusion in advanced Parkinson's patients with subthalamic stimulation contraindications. Parkinsonism Relat Disord. 2012;18:40-4) has shown modest efficacy in reducing LDRC and poor ergonomics due to external pumps (Syed N, Murphy J, Zimmerman T Jr, Mark MH, Sage JI. Ten years' experience with enteral levodopa infusions for motor fluctuations in Parkinson's disease. Mov Disord. 1998;13:336-8; Devos D, French DUODOPA Study Group. Patient profile, indications, efficacy and safety of duodenal levodopa infusion in advanced Parkinson's disease. Mov Disord. 2009;24:993-1000). The use of long-acting dopamine agonists (Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N Engl J Med. 2000;342:1484-91) or L-dopa administered with a catechol-O-methyltransferase inhibitor (COMTI) to prolong dopamine elimination half-life (Stocchi F, Rascol O, Kieburtz K, Poewe W, Jankovic J, Tolosa E, Barone P, Lang AE, Olanow CW).Initiating levodopa / carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol. 2010;68:18-27) failed to significantly improve severe LDRC.

[0009] The spatial distribution of dopamine and methotrexate during continuous intracerebral microperfusion has also been studied (Sendelbeck SL and Urquhart J. Spatial Distribution of Dopamine, Methotrexate, and Antipyrine During Continuous Intracerebral Microperfusion. Brain Research 1985;328:251-258). Infusions were performed into brain tissue, more specifically into the mesothalamic region of the diencephalon, using Alzet 2001 miniosmotic pumps filled with dopamine hydrochloride and methotrexate sodium dissolved in deoxygenated artificial cerebrospinal fluid containing sodium fluorescein. The miniosmotic pumps were filled with the solution at least 16 hours before implantation. However, under these conditions, oxygen would inevitably penetrate the pump, rendering the dopamine toxic. Furthermore, this study was not intended for any therapeutic purposes; it was conducted solely to analyze the diffusion of various drugs according to their lipid solubility and polarity.

[0010] Sustained release of dopamine from a mesoporous matrix of TiO2 is disclosed in MX2012012559. Dopamine is embedded in a matrix produced by a sol-gel method. However, the matrix must be implanted into the caudate nucleus of the brain, which is invasive and quite inconvenient for patients. Furthermore, the sustained release of dopamine from this mesoporous matrix only allows the symptoms of Parkinson's disease to be controlled, but does not produce any neuroprotective effect.

[0011] Another therapeutic strategy involves continuous dopamine infusion directly into the striatum or lateral ventricles of animals.

[0012] Yebenes et al. (1987) evaluated the effects of dopamine or dopamine agonists by intracerebroventricular infusion in rats with unilateral lesions of the nigrostriatal pathway and in MPTP-treated monkeys. Infusions were administered into the lateral ventricle ipsilateral to the lesion using a catheter connected to an Alzet 2001 pump loaded with dopamine in various vehicles, including sodium metabisulfite. Sodium metabisulfite was used to reduce dopamine autooxidation. Decreased motor symptoms and increased brain dopamine concentrations were observed. However, infusion of dopamine or dopamine agonists induced contralateral rotation, which peaked 2 days after implantation and slowly decreased over the 5-day infusion period. These effects suggest that continuous infusion induces a tachyphylaxis effect, supported by the reduced number of DA receptors in the infused animals. This suggests that the treatment induces an adaptation phenomenon to the progressive loss of efficacy. Therefore, titration of the dopamine dose is necessary to maintain maximal efficacy (de Yebenes JG1, Fahn S, Lovelle S, Jackson-Lewis V, Jorge P, Mena MA, Reiriz J, Bustos JC, Magarinos C, Martinez A. Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson's disease. Mov Disord. 1987;2:143-58).

[0013] Furthermore, oxidation problems were observed. Dopamine autoxidation induces the formation of highly cytotoxic quinones and free radicals. This dopamine autoxidation leads to the oxidation of surrounding tissues and cell walls. Such oxidation has been shown to induce neurotoxicity, which may ultimately contribute to the exacerbation of Parkinson's disease. This autoxidation problem was reduced when dopamine was dissolved in sodium metabisulfite, but remained. Furthermore, sodium metabisulfite induces tolerance issues, such as allergic reactions to sulfite. In addition, it has been shown that the use of sulfite induces exacerbation of neurodegeneration in pyramidal neurons (Akdogan I, Kocamaz E, Kucukatay V, Yonguc NG, Ozdemir MB, Murk W. Hippocampal neuron number loss in rats exposed to ingested sulfite. Toxicol Ind Health. 2011;27:771-778). This suggests the potential toxicity of sodium metabisulfite in Parkinson's disease models.

[0014] The treatment studied by Yebenes et al. was merely symptomatic and failed to achieve protection of dopaminergic neurons in the human substantia nigra and striatum.

[0015] EP 3142651 B1 discloses a pharmaceutical solution containing at least dopamine for use in Parkinson's disease, which is maintained under anaerobic conditions from its formulation until its administration.

[0016] EP 3453388 A1 discloses a pharmaceutical solution consisting of dopamine hydrochloride dissolved in saline, the solution having a pH between 5.5 and 7, the solution being injectable, oxygen-free and preservative-free, the saline consisting of water and mono- or di-sodium phosphate, sodium chloride, potassium chloride, calcium chloride or magnesium chloride or a mixture of such salts.

[0017] However, the present inventors have discovered that the dopamine solutions disclosed in EP 3142651 B1 and EP 3453388 A1 cannot be stored for extended periods at a temperature of 37° C. due to stability issues, which is inconvenient when using the solutions with a pump that is in continuous contact with the skin. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] MX 2012012559 [Patent Document 2] EP3142651B1 [Patent Document 3] EP3453388A1 [Patent Document 4] FR0114796 [Patent Document 5] US2005070613 A1 [Non-patent literature]

[0019] [Non-Patent Document 1] Chaudhuri KR1, Schapira AH. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009;8:464~74 [Non-patent document 2] Devos D, Lejeune S, Cormier-Dequaire F, Tahiri K, Charbonnier-Beaupel F, Rouaix N, Duhamel A, Sablonniere B, Bonnet AM, Bonnet C, Zahr N, Costentin J, Vidailhet M, Corvol JC. Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in Parkinson's disease. Parkinsonism Relat Disord. 2014;20:170 - 175

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[0020] Thus, there remains a need in the art for a treatment for medical conditions associated with low levels of dopamine, particularly Parkinson's disease or Parkinsonian syndrome, that does not suffer from the above-mentioned drawbacks.

[0021] More specifically, there is a need for stable pharmaceutical compositions that can be administered using a pump and that allow for the treatment of medical conditions associated with low levels of dopamine, particularly Parkinson's disease or parkinsonian syndromes. [Means for solving the problem]

[0022] The present inventors have now discovered that the above drawbacks can be overcome when dopamine or a pharmaceutically acceptable salt thereof, preferably dopamine hydrochloride, is dissolved in water for injection, and the resulting pharmaceutical infusion solution has a pH between 3.0 and 5.5 and an oxygen content of 0.008% (8 ppm) or less.

[0023] A first aspect of the present invention is directed to a pharmaceutical infusion solution comprising dopamine or a pharmaceutically acceptable salt thereof, preferably dopamine hydrochloride, dissolved in water for injection, the pharmaceutical infusion solution having a pH between 3.0 and 5.5 and an oxygen content of 0.008% (8 ppm) or less.

[0024] A second aspect of the present invention relates to the pharmaceutical infusion solution of the present invention for use in treating a medical condition associated with low levels of dopamine in a subject in need of such treatment. DETAILED DESCRIPTION OF THE INVENTION

[0025] definition The following definitions are given for terms used in this specification.

[0026] The term "about" or "ca.," as used herein, means that the value that follows it can vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0027] Unless otherwise specified, "%" herein has the meaning of weight percent (wt%), also known as weight / weight percent (w / w%).

[0028] As used herein, the term "effective amount" or "therapeutically effective amount" of a compound refers to that amount of compound that will elicit a biological or medical response in a subject, such as amelioration of symptoms, alleviation of a condition, slowing or delaying the progression of a disease, or prevention of a disease.

[0029] As used herein, the term "low levels of dopamine" refers to dopamine levels that are insufficient to ensure normal dopaminergic neurotransmission. This is clinically manifested by the appearance of disorders of automaticity, especially motor automaticity, in particular akinesia (i.e., slowness in the execution of voluntary but especially automatic movements), bradykinesia (i.e., abnormally slow and infrequent movements, especially in the automatic part of movements), the presence of muscle hypertonia, and sometimes the occurrence of resting tremor.

[0030] Pharmaceutical infusion solution containing dopamine The present disclosure relates to a pharmaceutical infusion solution comprising dopamine or a pharmaceutically acceptable salt thereof, preferably dopamine hydrochloride, dissolved in water for injection, the pharmaceutical infusion solution having a pH between 3.0 and 5.5 and an oxygen content of 0.008% (8 ppm) or less.

[0031] Indeed, the present invention is based on the surprising discovery that dopamine, when present in a pharmaceutical infusion solution dissolved in water for injection at a pH between 3.0 and 5.5 and containing an oxygen content of 0.008% (8 ppm) or less, is stable for administration to a subject using a pump while simultaneously enabling the treatment of medical conditions associated with low levels of dopamine.

[0032] This particular combination of pH and water for injection makes the aqueous solution of dopamine stable at 37°C for at least 7 days, preferably 14 days, more preferably 21 days, and even more preferably 28 days, and therefore can be stored anoxically in a pump in continuous contact with the skin for such extended periods. Thus, the solutions of the present invention are suitable for use in accordance with the present invention.

[0033] The pharmaceutical solutions of the present invention include those that are pharmaceutically acceptable, i.e., generally safe, non-toxic, not biologically or otherwise undesirable, and acceptable for human pharmaceutical use.

[0034] Dopamine is a sympathomimetic amine hypertensive agent and the natural precursor of norepinephrine. Dopamine is an important neurotransmitter in the brain. Dopamine can be in the form of its free base (4-(2-aminoethyl)benzene-1,2-diol) and its pharmaceutically acceptable salts, such as its hydrochloride salt.

[0035] The term "pharmaceutically acceptable salt" refers to any salt obtained from dopamine, which has slightly similar biological activity compared to that of the compounds of the present invention. Dopamine is an amine and can therefore form acid addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples of such acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, and maleic acid, of which hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and acetic acid are preferred. Therefore, suitable pharmaceutically acceptable salts are dopamine hydrobromide, dopamine sulfate, dopamine phosphate, dopamine methanesulfonate, dopamine acetate, dopamine fumarate, dopamine succinate, dopamine lactate, dopamine citrate, dopamine tartrate, and dopamine maleate, of which hydrochloride, hydrobromide, sulfate, phosphate, and acetate are preferred. More preferably, the pharmaceutically acceptable salt is dopamine hydrochloride. Pharmaceutically acceptable salts can be obtained, for example, using standard procedures well known in the pharmaceutical field. In certain embodiments, the pharmaceutical infusion solution according to the present invention comprises a pharmaceutically acceptable salt of dopamine.

[0036] According to the present invention, dopamine or a pharmaceutically acceptable salt thereof, preferably dopamine hydrochloride, is dissolved in water for injection (WFI), a pharmaceutically acceptable vehicle for injectable formulations. "Water for injection" (WFI) refers to ultra-high quality water free from significant contamination as defined by the world's pharmacopoeias, e.g., European Pharmacopoeia 10. Pharmaceutical Monographs 04 / 2017:0169.

[0037] When dopamine or a pharmaceutically acceptable salt thereof, preferably dopamine hydrochloride, is dissolved in water for injection (WFI), the dopamine thus obtained provides a stable acidic solution, having a pH between 3.0 and 5.5, preferably between 3.3 and 5.0, more preferably between 3.5 and 4.5, and even more preferably about 4.0. Thus, the pharmaceutical solution of the present invention is in the form of an aqueous solution.

[0038] The pharmaceutical infusion solution according to the present invention has an oxygen content of 0.008% (8 ppm) or less. In one embodiment, the pharmaceutical solution has an oxygen content of 0.0007% (7 ppm) or less, preferably 0.0006% (6 ppm) or less, more preferably 0.0005% (5 ppm) or less, and even more preferably about 0.0002% (2 ppm).

[0039] Such an oxygen content can be obtained by any method known in the art, for example, by deoxygenation with an inert gas such as nitrogen, freon, argon, xenon, (36)-krypton or neon or any other gas. To this end, dopamine, preferably dopamine hydrochloride, dissolved in water for injection is made up in an inert atmosphere as described in FR0114796.

[0040] In one embodiment, the concentration of dopamine in the solution is at least 50 mg / mL, preferably between 50 mg / mL and 1000 mg / mL, more preferably about 100 mg / mL, about 150 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, about 600 mg / mL, about 700 mg / mL, about 800 mg / mL, about 900 mg / mL, and even more preferably between 100 mg / mL and 400 mg / mL.

[0041] In certain embodiments, when dopamine is dopamine hydrochloride, for example, a concentration of 10 mg / mL requires the addition of salt to make it isotonic, and then it can be administered to a subject.However, when the concentration exceeds 50 mg / mL, the pharmaceutical solution inevitably becomes hyperosmotic.Adding any salt, such as sodium chloride, will further increase the osmolality of the solution, which may be harmful to the pharmaceutical solution.In particular, when the pharmaceutical solution contains a pharmaceutically acceptable salt of dopamine, which is dopamine hydrochloride, it is preferable not to add sodium chloride to the pharmaceutical solution.

[0042] Advantageously, the pharmaceutical infusion solution of the present invention does not contain a preservative, by which is meant any molecule, peptide, salt or other compound that has an antioxidant effect or is essential to preserve dopamine and other compounds that make up the pharmaceutical solution of the present invention.

[0043] In a preferred embodiment, the pharmaceutical infusion solution consists essentially of dopamine hydrochloride dissolved in water for injection, the solution having a pH between 3.0 and 5.5, preferably between 3.3 and 5.0, more preferably between 3.5 and 4.5, and even more preferably about 4.0, and an oxygen content of 0.008% or less, preferably 0.0007% (7 ppm) or less, more preferably 0.0006% (6 ppm) or less, even more preferably 0.0005% (5 ppm) or less, and even more preferably about 0.0002% (2 ppm). In a specific embodiment, the pharmaceutical infusion solution consists essentially of dopamine hydrochloride dissolved in water for injection, the solution having a pH of about 4.0 and an oxygen content of about 0.0002% (2 ppm). "Substantially consisting of" means only the referenced component and its eventual impurities, i.e., no other components are added.

[0044] Pharmaceutical solutions containing dopamine can be injectable, i.e., formulated for parenteral administration. When a pharmaceutical composition is injectable, it is administered parenterally, i.e., using a needle (usually a hypodermic needle) and a syringe, or by inserting an indwelling catheter. Examples of parenteral administration include intravenous, intramuscular, intranasal, transdermal, submucosal, intrathecal, subcutaneous, intraperitoneal, intraocular, intracerebral, e.g., intraventricular, etc.

[0045] Also provided herein is a pharmaceutical infusion solution adapted to be stored in a vial and stable at 5°C for at least 1 month, preferably 2 months, more preferably 3 months, even more preferably 4 months, even more preferably 5 months, even more preferably 6 months, even more preferably 9 months, even more preferably 12 months, even more preferably 18 months, and even more preferably 24 months.

[0046] Also provided herein is a pharmaceutical infusion solution adapted to be stored in an anaerobic pump and stable at 37°C for at least 7 days, preferably 14 days, more preferably 21 days, and even more preferably 28 days.

[0047] Methods of treatment using said medicinal infusion solutions In a second aspect of the present invention, the pharmaceutical infusion solution of the present disclosure is for use in treating a medical condition associated with low levels of dopamine in a subject in need of such treatment.

[0048] In other words, the present invention also relates to a method of treating a medical condition associated with low levels of dopamine, wherein a therapeutically effective amount of the pharmaceutical infusion solution of the present disclosure is administered to a subject in need thereof.

[0049] The present invention also relates to the use of a pharmaceutical infusion solution of the present disclosure for the manufacture of a medicament for treating a medical condition associated with low levels of dopamine in a subject in need of such treatment.

[0050] The form (especially the concentration), route of administration, dosage and regimen of a pharmaceutical infusion solution necessarily depend on the severity of the disease, age, weight and sex of the subject.

[0051] The terms "treatment," "treating," and derivatives thereof refer to the amelioration, alleviation, prevention, or prevention of medical conditions associated with low levels of dopamine. The term "treatment" also refers to prophylactic treatments that can delay the onset of medical conditions associated with low levels of dopamine.

[0052] Terms such as "patient," "subject," and "individual" are used interchangeably herein and refer to humans, more specifically humans over the age of 45, more preferably humans over the age of 50. In some embodiments, patients, subjects, or individuals in need of treatment include those who already have a disease, condition, or disorder, i.e., a medical condition associated with low levels of dopamine.

[0053] In preferred embodiments, the medical condition associated with low levels of dopamine is selected from the group consisting of Parkinson's disease, Parkinson's syndrome, restless legs syndrome, depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD), cerebral iron deposition neurodegeneration, and other vascular or degenerative brain diseases associated with dopa-responsive parkinsonism, and genetic disorders adversely affecting synthetic or metabolic enzymes. More preferably, the medical condition associated with low levels of dopamine is Parkinson's disease or Parkinson's syndrome.

[0054] In one embodiment, no more than 3 mL, preferably between 1 mL and 3 mL, preferably about 2 mL of said pharmaceutical infusion solution is administered to a subject daily.

[0055] In another embodiment, at least 25 mg, preferably between 25 mg and 500 mg, more preferably between 50 mg and 400 mg, even more preferably between 75 mg and 300 mg, even more preferably between 100 mg and 250 mg, and even more preferably about 200 mg of dopamine is administered to the subject daily.

[0056] Advantageously, the pharmaceutical infusion solution is suitable for intraventricular administration, more particularly, the pharmaceutical solution is adapted to be administered into the right lateral ventricle, preferably at the entrance of the interventricular foramen, so that the pharmaceutical solution can be administered into the third ventricle.

[0057] In fact, the inventors have surprisingly discovered that by placing a catheter in the right lateral ventricle, particularly at the entrance of the interventricular foramen, administration at the entrance of the interventricular foramen is possible, thereby allowing the pharmaceutical infusion solution to be administered directly into the third ventricle. This therefore allows bilateral concentration of dopamine into the striatum through the ventricular wall and the subventricular zone (SVZ). This administration significantly reduces motor complications, while dopamine, when administered into the frontal region of the brain, is concentrated outside in the frontal and caudate nuclei, which is unfavorable for the development of motor complications and psychiatric disorders.

[0058] For this purpose, and to carry out administration under anaerobic conditions, the medicinal infusion solution according to the invention is adapted to be administered using an anaerobic pump.

[0059] The term "anaerobic pump" refers to any device that allows controlled release of the solution of the present invention without exposing the solution to oxygen, thereby deteriorating its anoxic state. Generally, the pump must be compatible with the present invention, particularly capable of anoxically delivering the dopamine solution to the desired administration site. For example, the SYNCHROMED II pump (marketed by Medtronic, Ireland), the iPRECIO pump (marketed by ALZET, USA), or the ALZET pump (marketed by Alzet, USA), or the Siromedes pump (marketed by Tricumed, Germany), or the Prometra II pump (marketed by Flowonix, USA) can be used for this purpose. The Prometra II pump (marketed by Flowonix) is suitable for humans and is therefore preferably used in human patients. This pump allows for completely anaerobic conditions and excellent stability of dopamine. Therefore, the use of these pumps significantly reduces the risk of dopamine oxidation or auto-oxidation. The benefit / risk balance of using dopamine in the treatment of Parkinson's disease was negative prior to the development of these anaerobic pumps. When placed in a subject requiring it, the pump is in continuous contact with the skin. In fact, the pump is implanted subcutaneously at the paraumbilical level, above the rectus muscle. Therefore, the pump is at an internal body temperature of 37°C. The pump is connected to a subcutaneous catheter that extends to the frontal level, where the catheter penetrates the brain several centimeters into the anterior horn of the right lateral ventricle.

[0060] Administration of the solution of the present invention under anaerobic conditions can also be carried out by any other method known to those skilled in the art.

[0061] The inventors have discovered that when the concentration of dopamine in the solution exceeds 100 mg / mL, the pharmaceutical infusion solution becomes hyperosmolar, i.e., exceeds 295 mOsm / L. In this case, the subject's body may not tolerate it. In fact, the osmolarity depends on the volume of the infusion solution to be infused and the infusion compartment and its volume into which the infusion solution is infused. Generally, intolerance problems occur when the osmolarity of an intravenous infusion solution exceeds 600 mOsm / L. The inventors have discovered that injecting a pharmaceutical infusion solution having a dopamine concentration exceeding 100 mg / mL into a subject is possible only if the formulation to be infused into the subject's body, preferably into the cerebrospinal fluid (CSF), is directly diluted and the infusion rate is controlled so that it is tolerated by the subject. For example, 100 mg of dopamine hydrochloride in a volume of 2 mL, e.g., dopamine hydrochloride at a concentration of 100 mg / mL in a pharmaceutical infusion solution, will be diluted into a volume of cerebrospinal fluid (known to be about 150 mL), and since the production rate of cerebrospinal fluid is about 20 mL / hour and the drainage rate of cerebrospinal fluid increases with the volume of cerebrospinal fluid, the osmolality of the cerebrospinal fluid after administration of the pharmaceutical infusion solution will be close to 295 mOsm / L, i.e., between 295 mOsm / L and 350 mOsm / L, which is acceptable and does not pose a risk to the subject.

[0062] Thus, in one embodiment, the pharmaceutical infusion solution comprising dopamine hydrochloride has an osmolality of between 800 mOsm / L and 6400 mOsm / L, preferably between 1200 mOsm / L and 4800 mOsm / L, more preferably between 1600 mOsm / L and 3200 mOsm / L, more preferably about 1600 mOsm / L.

[0063] In certain embodiments, the pharmaceutical infusion solution is administered to a subject at a rate of between 1 mL / day and 3 mL / day, preferably about 2 mL / day.

[0064] In another embodiment, the pharmaceutical infusion solution for use is administered to a subject using an anaerobic pump at a flow rate of between 0.04 mL / hour and 0.125 mL / hour, preferably between 0.06 mL / hour and 0.10 mL / hour, and more preferably about 0.08 mL / hour.

[0065] Therefore, administering medicinal infusion solutions far exceeding the maximum recommended osmolality, i.e., 600 mOsm / L, was unexpected, and selection of the specific concentration of medicinal infusion solution and the flow rate of administration, particularly with an anaerobic pump, makes administration according to recommendations possible and acceptable.

[0066] The dose used for administration can be adapted depending on various parameters, in particular depending on the mode of administration used, depending on the pathology involved, or alternatively depending on the desired duration of treatment.

[0067] The present invention also provides the above-mentioned pharmaceutical infusion solution and its use, wherein the pharmaceutical solution is administered continuously with varying doses, preferably with a priority or limited to a diurnal dose.

[0068] "Preferentially in favor of a daytime dose" means that the nocturnal dose is lower than the daytime dose, preferably at least 70% lower than the daytime dose, more preferably at least 80% lower than the daytime dose, and more preferably at least 90% lower than the daytime dose.

[0069] "Limited to daytime doses" means there is no nighttime dose.

[0070] The administration protocol can be facilitated by use of an anaerobic pump, such as the Prometra II pump (commercially available from Flowonix, Inc.), as described above.

[0071] In certain embodiments, the pharmaceutical infusion solution is administered in the following dosage regimen: - sustained daytime dose, - optionally, a bolus administered in the morning, and - optionally, at least one bolus when needed, and / or - a sustained nighttime dose lower than the daytime dose, preferably with the nighttime dose being between 1% and 50% of the daytime dose, even more preferably between 2% and 30% of the daytime dose, even more preferably between 2.5% and 10% of the daytime dose; It is administered at .

[0072] By "bolus" is meant a single, relatively high dose of the pharmaceutical solution of the present invention administered to achieve immediate effect. Preferably, the bolus is as described above. The bolus is administered in the morning and optionally as needed, i.e., when the patient requires immediate effect of treatment.

[0073] The inventors have discovered that this administration protocol makes it possible to determine the minimum effective dose, which may vary from patient to patient. The motor and non-motor symptoms of Parkinson's disease are treated without any of the side effects (dyskinesia, fluctuations, psychosis, etc.) typically associated with peripherally administered dopaminergic treatments (i.e., oral pulse L-dopa, subcutaneous apomorphine, jejunal L-dopagel), and without the risk of autoxidation observed with central (intraventricular) administration of aerobic dopamine. Such complications or side effects can be prevented or even prevented if treatment with anaerobic dopamine according to the present invention is administered before such complications occur. The use of an anaerobic pump typically makes it possible to determine the minimum effective dose appropriate for each individual case.

[0074] By "minimum effective dose" is meant an amount sufficient to be effective at a reasonable benefit / risk ratio applicable to any medical treatment. However, it should be understood that the total daily dosage will be determined by the attending physician within the scope of sound medical judgment. The specific minimum effective dose for any particular patient in need thereof will depend on various factors, including the patient's age, weight, general health, sex, and diet, time of administration, route of administration, duration of treatment, concomitant or concurrent medications, and similar factors well known in the medical community. For example, it is well known within the art to initiate a dose of a compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. Dosages may also vary depending on the patient's dopa sensitivity. For example, a ratio of 1 / 100 to 1 / 300 between the required orally administered dose and the dose administered intracerebroventricularly (ICV) has previously been observed (e.g., morphine, baclofen). Furthermore, after preclinical studies in monkeys, it has been established in the literature that a dose of 40 mg / day of dopamine is sufficient to be effective in humans (Caroline Moreau et al., Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson's disease, Neurobiology of Disease, Vol. 139, 2020, pp. 104846; M.K. Horne et al., Intraventricular infusion of dopamine in Parkinson's disease, Ann Neurol 1989; 26: 792-794). However, the inventors have discovered that in order to obtain sufficient efficacy, i.e. to reduce the appearance of disorders of automaticity, in particular motor automaticity, preferably the presence of akinesia, dyskinesia, bradykinesia, hypertonia and resting tremor, as well as to reduce the appearance of behavioral and cognitive disorders, such as apathy, anxiety, sleep disorders, this estimated dose is totally underestimated and that this dose needs to be doubled or even tripled, i.e. to at least 100 mg / day. [Brief explanation of the drawings]

[0075] [Figure 1] This is a diagram showing the study design of the clinical trial. D means days. The schedule may be slightly changed depending on the patient's health condition (e.g., number of days of hospitalization) and medication satisfaction (e.g., length of dose adjustment period). [Figure 2] FIG. 1 shows the effect of A-dopamine on motor fluctuations and dyskinesias measured using patient diaries. [Example]

[0076] The present disclosure will now be described in more detail, particularly with reference to examples, which are not intended to limit the invention.

[0077] Example 1 Determining the optimal pH for compatibility with delivery pumps The inventors found that a dopamine solution containing dopamine hydrochloride in saline (0.9% NaCl) at pH 5.5 was not stable enough to allow for adequate storage in the pump at 37° C. Therefore, the inventors attempted to lower the pH of the solution to make it as acidic as possible.

[0078] The purpose of this test is to follow the aging of the pump during operation over a period of one year by filling the pump with saline (0.9% NaCl) buffered to pH 4, pH 3 and pH 2. The checks for proper functioning of the pump are as follows: - Monitoring the daily delivery rate of the fill solution set at the beginning of the study, - Investigation of possible degradation of the various materials that make up the pump, depending on the amount of metallic elements in the filler solution Includes.

[0079] Materials and Methods A 1:10 dilution of 2 mol / l (2N) HCl solution was used to buffer saline (0.9% NaCl) to obtain test solutions at pH 4, pH 3, and pH 2. The commercially available saline (0.9% NaCl) used to prepare the buffer solutions was prepared according to the following references: - B Braun Medical, reference number 432 858, lot number 20362404, expiry date August 2023, - Versol, Reference Number 600019, Lot Number C0669, Expiration Date April 2023, - Versol, Reference Number 600019, Lot Number C0826A01, Expiration Date November 2023 had the following characteristics:

[0080] Three pumps were placed in a 37°C oven. Each pump was filled with saline (NaCl 0.9%) buffered to one pH 4, one pH 3, and one pH 2. The densities of the three buffer solutions were checked to ensure there were no differences in fill volume between the three pumps.

[0081] The pump was set at a flow rate of 0.9 ml per day with a nominal fill of 20 ml. A new fill was carried out after a complete emptying of the tank, on average every 21 days. Portions of the recovered solution were used for investigation and determination of the released metal elements. The solutions analyzed were recovered after 7, 15, 29, 91, 238, 315, and 352 days.

[0082] Determining the Density of Buffered Saline Solutions The density of each of the pH 4, pH 3, and pH 2 buffer solutions was determined by weighing using the cut-flask method at a temperature of 37° C.±2° C. The cut-vial method involved the following steps:

[0083] A balance with a resolution of 0.0001g was used to measure three different quantities: - 25 ml pycnometer filled to the mark with buffered NaCl solution: M NaCl - 25ml pycnometer filled to the mark with water: M w - Empty and dry 25ml pycnometer: M E was carried out.

[0084] The balance was tared before each weighing. The density of the buffer solution is given by the following formula:

[0085]

number

[0086] The density results are shown in the following table in kg / m 3 It is expressed as:

[0087] [Table 1]

[0088] The density values ​​obtained for the three buffer solutions are very similar to each other. The average value for the three solutions is 1000 ± 2 kg / m 3 is equal to.

[0089] Monitoring pump operation Each time the pump was filled, various checks were performed.

[0090] Checking the residual volume in the pump: Sampling and measuring the volume remaining in the pump.

[0091] Check pump operation: INQUIRY Read out control module indication.

[0092] Visual inspection: - Appearance of the device: pump and catheter, - Appearance of the solution.

[0093] After a year of operation, no visible deterioration of the three pumps has been observed and all collected solutions are clear and transparent.

[0094] Investigation and determination of metal elements in the recovered solution Panoramic analysis was performed by inductively coupled plasma mass spectrometry (ICP-MS, Perkin Elmer, NEXION 300X). After calibrating the mass scale with representative standard solutions, the collected solutions were measured after 7 and 15 days of operation, and this technique provided an estimated content of all elements in the periodic table available. Although this analysis is not quantitative, it readily allows the identification of significantly present elements, which are then the subject of further analysis.

[0095] Depending on the elements detected by the exploratory panoramic analysis and the concentration levels observed, two analytical techniques are applied. - The element silicon is quantitatively determined in a 1 / 10 diluted solution by plasma optical emission spectroscopy (ICP-OES, HORIBA, ACTIVA-M) against a calibration line established in situ. - Other elements detected were quantitatively determined by inductively coupled plasma mass spectrometry (ICP-MS) in solutions after mineralization in a microwave oven in the presence of an appropriate acid mixture. The elements selected were barium, chromium, copper, iron, molybdenum, nickel, lead, titanium, tungsten, and zinc.

[0096] Three fill solutions buffered to pH 4, pH 3, and pH 2 were placed in amber glass vials and stored next to the three pumps in a 37°C oven for the duration of the test. These are referred to as "test blanks." Parallel analyses were performed on these "test blank" solutions for each analysis of the solutions collected during pump operation. The metal element results obtained for these "test blanks" served as the basis for the results obtained for the test solutions.

[0097] Metal element determinations were carried out on solutions collected after 7, 15, 29, 91, 238, 315 and 352 days of operation.

[0098] [Table 2]

[0099]

Table 3

[0100]

Table 4

[0101]

Table 5

[0102]

Table 6

[0103]

Table 7

[0104]

Table 8

[0105]

Table 9

[0106]

Table 10

[0107]

Table 11

[0108]

Table 12

[0109] Zinc was not determined for the first three samples because it was not detected as a free element in the panoramic analysis performed by inductively coupled plasma mass spectrometry (ICP-MS).

[0110] result Regarding the pump filled with a pH 4 solution During the first month of operation, a strong release of barium, nickel, tungsten, and silicon was observed, followed by a very clear decrease in some elements to constant or even undetectable levels, while other elements were not significantly detected.

[0111] For pumps filled with pH 3 solution: During the first month of operation, a strong release of barium, iron, nickel, and silicon was observed, followed by a very clear decrease in some elements to a constant or undetectable content. The release of lead increased gradually. The release of tungsten was gradual during the first three months, then decreased until it reached a constant content. The release of zinc began three months after operation and then increased strongly. The other elements were not significantly detected.

[0112] For pumps filled with pH 2 solution: During the first month of operation, the release of barium, chromium, iron, molybdenum, nickel, and titanium elements was stronger than for the pH 4 and pH 3 solutions, and then for certain elements, there was a very clear decrease until the content remained constant or even became undetectable. A strong release of silicon element was observed during the first month of operation, and then there was a clear decrease to a constant content. The release of tungsten element was gradual during the first three months, and then decreased to a constant content. Copper element was constantly released. The release of lead element gradually increased. The release of zinc element started after three months of operation, and then increased stronger than for the pH 4 and pH 3 solutions.

[0113] conclusion Lowering the pH of the solution to pH 2 resulted in the pump releasing large amounts of metals beyond the standard. At pH 3, the pump released excessive levels of metals, some of which exceeded the standard. At pH 4, the levels were acceptable.

[0114] Example 2 Six-month stability study of 100 mg / mL dopamine hydrochloride solution diluted in water for injection, pH 4, and stored at 5°C This stability study was performed on solutions of dopamine hydrochloride that were anoxically packaged in 20 mL Type I amber glass vials, sealed with elastomeric stoppers, and then crimped. Dopamine hydrochloride is sensitive to light and to oxygen naturally present in air. The preparation and filling of the solutions was performed under anaerobic conditions to avoid degradation of the active ingredient and to avoid the formation of degradation products, particularly its neurotoxic degradation product, 6-hydroxydopamine (6-OHDA).

[0115] Dopamine concentrations are always expressed as mean % of initial concentration (%C0) ± standard deviation in tabular and graphical formats.

[0116] The pH, absorbance at 320 nm, and osmolality of the solutions are presented in tabular form as the mean ± standard deviation of the analytical results.

[0117] Protocol for preparing a 100 mg / mL dopamine hydrochloride solution diluted in WFI, pH 4, and filling 20 mL glass vials The solution preparation process was carried out in an anaerobic environment in a nitrogen chamber with an oxygen level of less than 0.01%. The oxygen level in the chamber was checked before the start of each run.

[0118] Two liters of solution are required to fill 90 20 mL vials, and are placed in two 1 L volumetric flasks. 100 g of European Pharmacopoeia quality dopamine hydrochloride (Lot No. 62317 250, Reference No. 005765, INRESA, Bartenheim, France) are dissolved in 1 L of WFI (Reference No. DE0304, Baxter, Guyancourt, France). After visual control, two 1 L portions of the solution are placed in a beaker to homogenize the concentration. The pH of the solution was already 4.00, so no pH adjustment was required. The pH is measured using a handheld pH meter (HI9125 with a HI1333B semi-micro glass electrode, Hanna Instruments, Lingolsheim, France), which is calibrated before use.

[0119] The composition of the injection solution (per unit and per batch) is summarized in Table 13.

[0120] [Table 13]

[0121] Vials were also filled under anaerobic conditions. Vials were filled with 20 mL polypropylene luer-lock syringes (reference number: 300629, Becton Dickinson, Le Pont de Claix, France) equipped with 0.22 μm porosity filters equipped with a Supor® membrane (reference number: HP4642, Pall, Saint-Germain-En-Laye, France), allowing for filtration and sterilization before packaging. To respect the filter manufacturer's warranty, sterile filtration was performed using a different filter for each vial. A 2 L beaker of solution was required to fill 90 vials (1 batch = 90 20 mL vials). After removal from the laminar flow hood, the vials were then capped and crimped in a chamber. The crimping was checked manually. Vials were visually inspected before and after quarantine (15 days to perform sterility testing).

[0122] Terminal sterilization was not performed due to the presence of inert gases, especially nitrogen, in the vials. The vials were finally labeled and stored at 5°C for 6 months to perform stability testing.

[0123] Stability testing Analyses were performed every 7 days from months T0 to T1, then every 15 days from months T1 to T6. At each analysis, concentration, pH, osmolality, and absorbance at 320 nm were checked for three bottles.

[0124] Concentration measurement by HPLC-UV The initial concentration of dopamine hydrochloride diluted in water for injection was 101.98±0.28 mg / mL for a solution at pH 4. The percentage of dopamine hydrochloride remaining in solution relative to the initial concentration C0 at various test times is shown in Table 14.

[0125] [Table 14]

[0126] Dopamine hydrochloride concentrations remained well above our 90% limit after 6 months of storage at 5° C. Additionally, no trace of 6-OHDA was found, meaning that this degradation product remained at a concentration below 0.019 μg / mL.

[0127] pH measurement The pH was measured potentiometrically according to European Pharmacopoeia monograph 2.2.3 using a pH meter HI9125 equipped with a semi-micro glass electrode HI1333B (Hanna Instruments, Lingolsheim, France). Before each use, it was calibrated with standard solutions. At each test, the pH was measured for three vials.

[0128] Specification: The pH must not vary from the pH of the starting solution by more than 0.5 pH units or by less than 0.5 pH units.

[0129] Table 15 shows the evolution of pH over 6 months of storage at 5°C.

[0130] [Table 15]

[0131] The pH did not change in the vial during the 6 months of storage.

[0132] Osmolality measurement Osmolality was measured using a Fiske micro-osmometer model 210 (Advanced Instruments, Horsham, UK) according to European Pharmacopoeia monograph 2.2.35.

[0133] At each test, osmolality was measured for three vials. Specification: The osmolality must not vary from the osmolality of the starting solution to values ​​greater than or less than 10 mOsmol / kg.

[0134] Table 16 shows the evolution of osmolality over 6 months of storage at 5°C.

[0135] [Table 16]

[0136] This solution was hypertonic relative to plasma and the osmolality did not change in glass vials during 6 months of storage.

[0137] Solution contamination The degree of dopamine degradation was determined by measuring the absorbance of each solution at 320 nm using a UV spectrophotometer (UV2550, Shimadzu, Noisiel, France). At each assay time, absorbance was measured for three vials. The lower the absorbance, the greater the stability of the dopamine.

[0138] Table 17 shows the evolution of absorbance at 320 nm of a 100 mg / mL dopamine hydrochloride solution at pH 4 diluted in WFI over 6 months of storage.

[0139] [Table 17]

[0140] The solution remained stable for 6 months when stored at 5°C.

[0141] conclusion A 100 mg / mL solution of dopamine hydrochloride diluted in water for injection, pH 4, remained stable for 6 months when stored at 5°C for all parameters tested: concentration, pH, osmolality, and color. No 6-OHDA was detected.

[0142] Example 3 Stability study of 100 mg / mL dopamine hydrochloride solution diluted in water for injection, pH 4, in the Prometra II pump. For this treatment to be administered to patients, a 28-day stability study was conducted on a 100 mg / mL solution of dopamine hydrochloride diluted in water for injection (WFI) adjusted to pH 4. Pumps were filled using an "anoxic kit" prepared in an anoxic chamber. Dopamine hydrochloride is sensitive to light, oxygen, and temperature. As it degrades, it acquires color and forms 6-hydroxydopamine (6-OHDA), a neurotoxic dopamine degradation product. Instability is indicated as soon as 6-OHDA is detected in the solution and / or contamination occurs.

[0143] Protocol for preparation of Prometra II pump The manufacturing process for filling the pumps was carried out in an anaerobic chamber with an oxygen level of less than 0.01% and a temperature of 37°C.

[0144] The pump was immersed in a bath containing lard (pork fat) to mimic the layers of skin and fat that would be above and below the pump when implanted in a patient.

[0145] The pumps were filled with a 100 mg / mL solution of dopamine hydrochloride, pH 4, contained in a 20 mL glass vial (see Example 2, "Protocol for the Preparation of Amber Glass Vials Containing a Solution of 100 mg / mL Dopamine Hydrochloride Diluted in Water for Injection" report). The protocol for testing performed to track stability and the provisions for testing performed on manufactured batches for vial manufacturing and stability were performed in the open air. After filling, the pump tray was returned to the chamber, which was set to 37°C and 0.01% oxygen for testing.

[0146] Sample collection The purpose of this procedure was to program the pump to deliver 0.5 mL of solution per 24 hours. The experiment was carried out in anoxic conditions (0.01% oxygen) and at 37°C in the chamber. Liquid was collected at the catheter outlet into sealed Eppendorf TUBES® (DNA LoBind Tube 1.5 MI, ref. 0030 108.051, Eppendorf AG, Hamburg, Germany) (containing only a hole in the lid for the catheter) for the first 24 hours and then analyzed by HPLC-UV and UV spectrophotometry. In addition, liquid was collected inside the pump and analyzed by HPLC-UV and UV spectrophotometry. Collection and analysis were carried out every 7 days for 4 weeks. A control Eppendorf® tube containing 0.5 mL of 100 mg / mL dopamine hydrochloride solution adjusted to pH 4 was placed next to the collected Eppendorf® tube. The volume of the control solution was measured at the end of the 24-hour collection period to estimate sample evaporation.

[0147] result Concentration measurement by HPLC-UV During the stability study, dopamine hydrochloride concentration was monitored by a high-performance liquid chromatography (HPLC) assay coupled with a UV-visible detector. A range of dopamine hydrochloride concentrations was validated for a target concentration of 200 μg / mL. While the validation of this method was performed on a stock solution of dopamine hydrochloride diluted in 0.9% NaCl, our 100 mg / mL dopamine hydrochloride solution was diluted in water for injection. To perform the assay, this solution was diluted 1:500 under the same conditions as the validated method. Therefore, the change in diluent did not affect the results of the HPLC-UV assay.

[0148] Detection of dopamine at 280 nm and 6-OH dopamine (6-OHDA) at 291 nm.

[0149] N=3 determinations for collected samples.

[0150] Rule: A proven effect of the tested agent is considered to be present when the concentration of the active ingredient is less than 90% of the initial concentration. In addition, if 6-OHDA is detected, the test is stopped.

[0151] The initial concentration of dopamine diluted in water for injection is 98.39 ± 1.95 mg / mL. The percentage of the initial concentration of dopamine hydrochloride in solution, C, measured inside the pump and at the catheter outlet at various test times is shown in Table 19.

[0152] [Table 18]

[0153] Dopamine hydrochloride concentrations remained greater than 90% of the initial concentration at the catheter exit and in the Prometra II pump during 28 days of storage at 37° C. Furthermore, no trace of 6-OHDA was observed during the 28-day study by HPLC / UV assay.

[0154] Solution contamination limits The degree of dopamine degradation was determined by measuring the absorbance of each solution at 320 nm using a UV spectrophotometer (UV2550, Shimadzu, Noisiel, France). At each determination time, absorbance was measured for a sample taken from the sample. The lower the absorbance, the greater the stability of the dopamine.

[0155] Dopamine concentrations are always expressed as mean % of initial concentration (%C0) ± standard deviation in tabular and graphical formats.

[0156] The absorbance of the solution at 320 nm is expressed as the analytical result value in tabular form.

[0157] Table 20 shows the absorbance at 320 nm of a 100 mg / mL dopamine hydrochloride solution at pH 4.

[0158] [Table 19]

[0159] During 28 days of storage at 37°C, the absorbance at 320 nm remained stable at the catheter exit and within the Prometra II pump.

[0160] conclusion A 100 mg / mL dopamine hydrochloride solution diluted in water for injection, pH 4, is stable in the Prometra II pump (Flowonix) for 28 days at 37°C under the conditions tested and can therefore be administered to patients.

[0161] Example 4 Clinical Trial - Intracerebral Infusion of Dopamine in Parkinson's Disease Motor and non-motor disorders during the oral and moderate-dose A-dopamine phases Patients and Ethical Standards Two patients were prospectively enrolled at the PD Centre of Excellence, Lille, France (Table 21).

[0162] Patients 1 and 2 received moderate doses of A-dopamine, i.e., up to 150 mg / day, specifically 99 mg / day (5.5 mg / h), formulated as a solution of dopamine hydrochloride (50 mg / mL and 100 mg / mL) in water for injection at pH 4 in a sterile, anoxic nitrogen isolation system (<0.1% oxygen) without any other additives to avoid degradation by autoxidation of dopamine, and produced by the Central Pharmacy of the University Hospital of Lille.

[0163] [Table 20A]

[0164] [Table 20B]

[0165] [Table 20C]

[0166] The selection criteria were as follows: (i) A diagnosis of PD consistent with MDS criteria, with severe motor and non-motor L-dopa-related complications, including at least 2 hours of off-state and 1 hour of L-dopa-induced dyskinesia not controlled with optimized oral medication (i.e., with at least 5 doses of L-dopa). (ii) meet the criteria for an invasive secondary procedure; (iii) continuous subcutaneous apomorphine infusion is insufficiently effective, poorly tolerated, contraindicated, or rejected; (iv) Patients who prefer A-dopamine to two other currently effective treatments (i.e., deep brain stimulation (subthalamic or globus pallidus internal segment) or levodopa-carbidopa enteral gel).

[0167] The main non-selection criteria were as follows: (i) Subjects over 75 years of age; (ii) dementia (DSM IV criteria, MDS criteria, and MOCA score ≤22), and (iii) decompensated psychiatric disorders using the semi-structured psychiatric MINI interview;

[0168] Surgery and Implantable Systems The neurosurgical team performed the procedure of implanting a catheter (Flowonix™) into the right anterior horn near the foramen of Monro using stereotaxic catheter guidance by a Renishaw Neuro Mate robot. Catheter position was controlled intraoperatively using the O-Arm system. The catheter was attached to the right frontal bone of the skull using a Medtronic stim lock® system and then threaded under the skin to the abdomen, where it was connected to a 20 ml telemetered adjustable pump delivery system (Prometra II, Flowonix), which was implanted in a subcutaneous pocket. Postoperative scans were performed within 48 hours to verify the absence of hematoma and to confirm the correct catheter position after the surgery.

[0169] Preparation of A-dopamine A-dopamine was formulated as a solution of dopamine hydrochloride (50 mg / mL and 100 mg / mL) in water for injection at pH 4 in a sterile, anoxic nitrogen isolation system (<0.1% oxygen) to avoid degradation by autoxidation of dopamine, without any other additives, and was produced by the Central Pharmacy of the University Hospital of Lille.

[0170] Pre- and post-operative evaluation Comprehensive preoperative assessments of L-dopa-induced dyskinesias, L-dopa-related complications, and motor, cognitive, and behavioral symptoms were performed at the baseline visit. Assessments were performed sequentially in a dose-adjusted Phase I and a 1-month crossover Phase II, with the same comprehensive assessments performed before and after each period compared with usual, optimized oral treatment (Figure 1).

[0171] Phase I: Dose titration and dose finding An initial in-hospital dose titration was performed, increasing from 1 mg / day to 18 mg / day (up to 1 mg / hour over 18 hours during the day) for 3 to 5 days, followed by weekly 18 mg increments (1 mg / hour over 18 hours) under real-life conditions in the outpatient setting, until the dose achieved adequate motor control. Because of the need to ensure and manage A-dopamine quality, the pump was refilled every 7 to 15 days.

[0172] To ensure patient comfort and avoid transient motor deterioration, oral treatment was gradually tapered during dose adjustment. Patients were evaluated weekly for changes in pump speed and neurological, psychiatric, and cardiovascular safety monitoring (pulse, blood pressure, electrocardiogram). The ideal intermediate dose was defined as the dose that would result in a substantial reduction in oral therapy and a significant attenuation of L-dopa-related complications. The maximum tolerated dose without adverse reactions was also determined. Once the patient was successfully dose-adjusted and satisfied, they progressed to Phase 2. To ensure and control the quality of A-dopamine, the pump was refilled every 7 to 15 days.

[0173] Phase II: Evaluation during a randomized crossover trial A randomized, controlled, open-label study was conducted in a crossover design with two 4-week periods separated by a 21-day treatment changeover (see Figure 1). Two patients were randomized to one of two treatment sequences: (i) Period 1: A-dopamine treatment with remaining oral treatment, and (ii) Period 2: oral optimized oral treatment only; or the reverse. Comprehensive assessments were performed, including a one-week home assessment using a patient-completed diary and a one-week home activity measurement using a wristwatch (Parkinson Kinetograph™, GKC) worn on the most affected side.

[0174] At the end of Period 1, the previous treatment was discontinued and gradually replaced with the new treatment without interruption, ensuring that the patient was constantly on treatment. After stabilization and without adverse reactions, patients were discharged home, and evaluations for Period 2 began one week later to eliminate the possibility of residual effects from the first treatment. Using the same preoperative comprehensive assessment, the objective was to evaluate the effects of continuous intracerebroventricular administration of A-dopamine on L-dopa-related complications, motor, cognitive, and behavioral symptoms, compared with an optimized oral medication regimen excluding acute L-dopa administration. Weekly home evaluations were conducted during Weeks 1 and 4 of each period using a patient-completed daily diary. The diary included eight possible outcomes: sleep, dyskinesia (severe, moderate, mild), off periods (severe, moderate, mild), and complete control, and was checked hourly by the patient during the day. A learning process was conducted with patients and their neurologists before and during dose adjustments during Phase 1. Concurrent weekly home activity measurements were performed during the first and fourth weeks of each period using a wristwatch (Parkinson Kinetograph™, GKC) worn on the most affected side to record bradykinesia score (50th percentile: reference value = 18.6), dyskinesia score (50th percentile: reference value = 4.3), and dyskinesia score variability (an estimate of variability relative to optimal control, i.e., poor (bradykinesia) or excessive (dyskinesia) control).

[0175] An independent data and safety monitoring committee reviewed all data weekly. Total dopamine levels were measured in 24-hour urine samples during the oral treatment-only or A-dopamine combination. After randomization, patient 2 began a 1-month oral treatment-only phase and then transitioned to the A-dopamine phase, while patient 1 did the reverse.

[0176] result Slow dose titration and moderate dose setting in Phase I General anesthesia and stereotactic implantation did not result in any adverse reactions. For the first patient, dose adjustments were initiated slowly at a concentration of 10 mg / ml, starting at 1 mg / day up to 10 mg / day, followed by a maximum of 50 mg / day, then 54 mg / day up to 90 mg / day at 50 mg / ml. For patient 2, dose adjustments were initiated at 1 mg / hour over 18 hours of treatment (5 AM to 11 PM) (i.e., weekly increments of 18 mg). No adverse reactions related to A-dopamine were observed. The color of A-dopamine withdrawn from the pump always remained below the predetermined threshold for oxidation. The primary benefit reported by all patients was a significant reduction in L-dopa-induced dyskinesia and severe off periods, even before the first L-dopa dose reduction.

[0177] Rapid dose adjustment in Phase I Rapid dose titration, with hourly dose changes throughout the day, was performed in the first patient. Hourly dose increases from 1 mg / hour to 10 mg / hour were without adverse reactions. A mean dose of 10 mg / hour prevented the need for oral L-dopa between 8:30 am and 5 pm. In patient 1, doses of 12 mg / hour to 18 mg / hour resulted in dose-dependent somnolence and nausea, and orthostatic hypotension was observed from 15 mg / hour onward. Importantly, hallucinations, hypomania, and dyskinesias were not observed, even with very high doses of A-dopamine.

[0178] Phase II study with moderate doses over 2 months Patients received a daytime dose of 99 mg of A-dopamine (i.e., 5.5 mg / hour from 5 a.m. to 11 p.m.). Nighttime doses varied slightly between patients as needed to control nighttime off periods, starting at 3 mg and 2 mg for Patients 1 and 2, respectively. The most striking benefit was the significant reduction in L-dopa-induced dyskinesias and motor fluctuations, as seen by activity measurements, diaries, and scales (see Table 21). Nighttime dopamine requirements were minimal, and it was highly effective during periods of underdosing. The behavioral and cognitive effects of A-dopamine either showed improvement or no worsening. There was no induction or exacerbation of impulse control disorders or hypomania in any patient, and no deterioration of anxiety, depression, apathy, sleepiness, sleep quality, or cognition. Conversely, both patients reported a reduction in impulse control and irritability, a positive impact on quality of life, and an approximately 60% reduction in oral treatment. In all patients, urinary dopamine levels did not appear to differ during A-dopamine administration compared with the period limited to oral L-dopa treatment. Both patients desired to maintain A-dopamine long-term. Therefore, it was decided to resume titration at a higher dose to further evaluate the therapeutic potential.

[0179] Evaluation of longer-term, higher doses Four patients received oral treatment-limited and moderate and high doses of A-dopamine.

[0180] The midday dose was 5.5 mg / h (i.e., 99 mg daytime) of A-dopamine, formulated as a solution of dopamine hydrochloride (2 mg / mL and 10 mg / mL) in water for injection at pH 4 in a sterile, anoxic nitrogen-isolated device (<0.1% oxygen) without any other additives to avoid autoxidative degradation of dopamine, and manufactured by the Central Pharmacy of the University Hospital of Lille. The high daytime dose was 11.5 mg / h (i.e., 207 mg / 24 hours) of A-dopamine. The A-dopamine was formulated as a solution of dopamine hydrochloride (50 mg / mL and 100 mg / mL) in water for injection at pH 4 in a sterile, anoxic nitrogen isolation system (<0.1% oxygen) without any other additives to avoid autoxidative degradation of dopamine, and was produced by the Central Pharmacy of the University Hospital of Lille. The nighttime A-dopamine dose remained unchanged between the mid-day and high-daytime doses (Patient 1: 20 mg, Patients 2 and 3: 10 mg, Patient 4: 2.5 mg).

[0181] For two weeks, patients completed a home diary comparing oral treatment with moderate and high doses of A-dopamine. The motor fluctuation and dyskinesia diary included eight possibilities: sleep, dyskinesia (severe, moderate, mild), off periods (severe, moderate, mild), and complete control, and was checked by the patient hourly during the day.

[0182] The percentage of days with severe, moderate, or mild dyskinesia (upper left), severe, moderate OFF periods (upper right), complete control (lower left), and complete control or mild OFF (autonomic, lower right) are shown as means and standard deviations and histograms of values ​​for each patient (Figure 2). The follow-up period was 21 months for patient 1, 16 months for patient 2, 8 months for patient 3, and 6 months for patient 4.

[0183] When the dose was increased to a maximum of 10.5-11.5 mg / hour during daytime hours (5 a.m. or 7 a.m.-11 p.m.), a greater dose-effect benefit was observed with a near elimination of dyskinesias and moderate-to-severe off periods and a 70% reduction in oral treatment (Figure 2). Follow-up was 8 months for patient 1 and 6 months for patient 2.

[0184] Regarding the safety profile, no adverse reactions were observed at doses of α-dopamine below 11.5 mg / hour or with dose titrations below 2 mg / hour. However, with daytime doses above 11.5 mg / hour and rapid dose titrations above 2 mg / hour, excessive somnolence was observed in Patients 1, 2, and 4, and mild orthostatic hypotension was observed in Patients 1 and 3. Hallucinations, relapse of addictive behavior, hypomania, or dyskinesia were not observed, even at the highest dose; rather, inhibitory effects on motor skills and behavior were observed. When the nighttime dose was increased by 2 to 5 mg above the effective dose, nocturnal awakenings were observed, but these disappeared when the dose was reduced, demonstrating a low need for dopamine at night.

[0185] Consideration Given the confirmed depletion of nigrostriatal dopamine in PD, it seems reasonable to supplement it with continuous administration, following the example of organotherapy with insulin in diabetes. Controlling the oxidation of this neurotransmitter by producing and delivering it under strictly anaerobic conditions helps avoid tachyphylaxis, resulting in a stable and significant improvement in dopa-responsive clinical symptoms over several months. The use of a high-tech pump allows for fine-tuning of the dose and respect for circadian rhythms, further enhancing personalized benefit and ergonomic comfort. One of the most striking findings was the significant safety of intracerebroventricular infusion of α-dopamine. In fact, even the highest doses, even those exceeding the effective dose, for long periods of time only caused somnolence and nausea, without dyskinesia, hallucinations, hypomania, or other behavioral disturbances.

[0186] Along with the reduction in oral L-dopa, there was a dose-dependent effect of A-dopamine on the efficacy of L-dopa-related complications. At the highest dose, almost complete resolution of L-dopa-induced dyskinesias and severe OFF periods was possible despite maintaining L-dopa at a dose of 50 mg every 2–3 hours. Notably, two patients remained remarkably stable between complete control and mild OFF periods for most of the day. Similar effects were observed in nonmotor symptoms (reduced irritability, absence of hypomania, and absence of impulse control disorders) with a favorable safety profile when compared with L-dopa and dopaminergic agonists. This benefit was maintained over a long period of 6–8 months.

[0187] During the first few years of PD progression, oral L-dopa treatment improves motor symptoms by approximately 30–50% without the development of L-dopa-induced dyskinesias. Then, on average, after 5 years, L-dopa induces L-dopa-associated morbidity, during which patients appear to have fully recovered from PD, albeit at the expense of L-dopa-induced dyskinesias. However, the chorea associated with L-dopa-induced dyskinesias masks the residual bradykinesia and rigidity. A-dopamine administered via the intracerebroventricular route does not induce dyskinetic morbidity or produce the same clinical effects as oral L-dopa.

[0188] The mechanism by which A-dopamine affects dopaminergic neurotransmission remains poorly defined. A-dopamine crosses the ependymal layer and reaches the central nervous system, particularly the striatum, via the glymphatic system. A-dopamine can then persistently stimulate postsynaptic receptors. A-dopamine can also be recaptured by presynaptic dopaminergic neurons in the SNpc via the dopamine transporter. However, significant recapture by the norepinephrine transporter may also contribute to off-target activity. Urinary dopamine levels did not decrease during A-dopamine administration, despite a significant reduction in oral L-dopa. This suggests that a small proportion of A-dopamine infused into the cerebrospinal fluid is shed into the venous system and subsequently excreted via the kidneys.

[0189] These results support the clinical feasibility of intracerebral infusion of A-dopamine as a solution of dopamine hydrochloride in water for injection at pH 4 in a sterile, anoxic nitrogen isolation device (<0.1% oxygen) without any other additives in patients with PD at the stage of L-dopa-related complications.

[0190] Example 5 Clinical trial - high-dose intracerebral infusion of dopamine in Parkinson's disease Motor and non-motor disorders during the oral phase and the higher dose A-dopamine phase Patients and Ethical Standards One patient was prospectively enrolled at the PD Centre of Excellence, Lille, France (Table 22).

[0191] The patient received a high dose of 280 mg / day, i.e., a dose of 150 mg or more per day, specifically 240 mg during the day and 40 mg at night, of A-dopamine, formulated as a solution of dopamine hydrochloride (100 mg / mL) in water for injection at pH 4 in a sterile, anoxic nitrogen isolation system (<0.1% oxygen) without any other additives to avoid autoxidative degradation of dopamine, and produced by the Central Pharmacy of the University Hospital of Lille.

[0192] [Table 21]

[0193] For two weeks, patients completed home diaries comparing oral treatment (levodopa) with high-dose A-dopamine treatment: a two-week home diary with oral treatment and a two-week home diary with A-dopamine treatment. The motor fluctuations and dyskinesia diaries included eight possibilities: sleep, dyskinesias (severe, moderate, mild), off periods (severe, moderate, mild), and complete control, which were checked by the patient hourly during the day. Table 23 summarizes the results in the following categories: time with good autonomy, time with complete control, time with dyskinesia, time with severe dyskinesia, and time with severe off, with time with complete control being a subcategory of time with good autonomy.

[0194] [Table 22]

[0195] A-dopamine treatment can reduce oral levodopa treatment by 60%.

[0196] Regarding the safety profile, no adverse reactions were observed at the higher dose of A-dopamine, 280 mg / day. During the dose adjustment, i.e., during the dose escalation to 280 mg / day (2.5 months of dose adjustment), nausea was the only transient adverse event with A-dopamine. After the dose adjustment, no adverse events were observed. There were no neurosurgical adverse events, no ECG or blood medications, no adverse events with the device (administration pump), and no severe adverse events with A-dopamine.

[0197] Two additional patients with similar patient profiles were also treated with high-dose A-dopamine and completed similar home diaries for both oral levodopa and high-dose A-dopamine treatment. These two additional patients demonstrated an identical response profile to the first patient reported above.

[0198] conclusion Along with the reduction in oral L-dopa, there was a dose-effect of A-dopamine on its efficacy against L-dopa-related complications. A dose of 280 mg / day allowed for almost complete resolution of L-dopa-induced dyskinesias and a significant reduction in severe OFF periods. Remarkably, patients remained remarkably stable between complete control and mild OFF periods for most of the day. Furthermore, at this dose, no adverse events (nausea, dyskinesia, hallucinations, hypomania, or other behavioral disturbances) were observed after dose adjustment, which is important to note. These results support the clinical feasibility of intracerebral infusion of A-dopamine as a solution of dopamine hydrochloride dissolved in water for injection at pH 4 in a sterile, anoxic, nitrogen-isolated device (<0.1% oxygen) without any other additives in patients with PD who are at the stage of L-dopa-related complications.

[0199] Example 6 Comparative Example 3 of US2005070613 A1 The applicant repeated Example 3 (paragraphs

[0091] to

[0102] ) of application US2005070613 A1, preparing dopamine at a concentration of 10 mg / mL in water for injection. Osmolality was measured using a Fiske micro-osmometer model 210 (Advanced Instruments, Horsham, UK) in accordance with European Pharmacopoeia Monograph 2.2.35 (11th Edition (11.3) of July 2023). The measured osmolality was 97 mOsmol / kg, which is therefore less than the osmolality of a hypotonic, i.e., isotonic, solution. Because hypotonic solutions are not suitable for human administration, the 10 mg / mL solution of Example 3 of US2005070613 A1 is also not suitable for administration. Therefore, Example 3 teaches not to use water for injection to prepare an injectable dopamine solution.

Claims

1. A pharmaceutical infusion solution comprising dopamine or a pharmaceutically acceptable salt thereof, preferably dopamine hydrochloride, dissolved in water for injection, the pharmaceutical infusion solution having a pH between 3.0 and 5.5 and an oxygen content of 0.008% (8 ppm) or less.

2. 10. The pharmaceutical infusion solution of claim 1 having a pH of about 4.

0.

3. 3. The pharmaceutical infusion solution of claim 1, wherein the concentration of dopamine in the solution is at least 50 mg / mL, preferably between 50 mg / mL and 1000 mg / mL, more preferably about 100 mg / mL, about 150 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, about 600 mg / mL, about 700 mg / mL, about 800 mg / mL, about 900 mg / mL, and even more preferably between 100 mg / mL and 400 mg / mL.

4. 4. A pharmaceutical infusion solution according to any one of claims 1 to 3, in which there is no addition of sodium chloride, particularly when the pharmaceutically acceptable solution comprises a pharmaceutically acceptable salt which is dopamine hydrochloride.

5. 5. The pharmaceutical injection solution of claim 1, which is preservative-free.

6. 6. The pharmaceutical infusion solution of any one of claims 1 to 5, for use in treating a medical condition associated with low levels of dopamine in a subject in need of such treatment.

7. 7. The pharmaceutical infusion solution for use according to claim 6, wherein the medical condition associated with low levels of dopamine is selected from the group consisting of Parkinson's disease, Parkinson's syndrome, restless legs syndrome, depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD), cerebral iron deposition neurodegeneration and other vascular or degenerative brain diseases associated with dopa-responsive parkinsonism, and genetic disorders adversely affecting synthetic or metabolic enzymes.

8. 8. The pharmaceutical infusion solution for use according to claim 6 or 7, wherein no more than 3 mL, preferably between 1 mL and 3 mL, preferably about 2 mL of said pharmaceutical infusion solution is administered to a subject daily.

9. 9. The pharmaceutical infusion solution for use according to any one of claims 6 to 8, wherein at least 25 mg, preferably between 25 mg and 500 mg, more preferably between 50 mg and 400 mg, even more preferably between 75 mg and 300 mg, even more preferably between 100 mg and 250 mg, even more preferably about 200 mg of dopamine is administered to the subject daily.

10. 10. The pharmaceutical infusion solution for use according to any one of claims 6 to 9, adapted to be administered into a cerebral ventricle, preferably into the right lateral ventricle, preferably at the entrance of the interventricular foramen.

11. 11. The pharmaceutical infusion solution for use according to any one of claims 6 to 10, adapted to be administered by means of an anaerobic pump.

12. 12. The pharmaceutical infusion solution for use according to claim 11, wherein the pharmaceutical infusion solution according to claims 1 to 5 is administered to a subject using an anaerobic pump at a flow rate of between 0.04 mL / hour and 0.125 mL / hour, preferably between 0.06 mL / hour and 0.10 mL / hour, more preferably about 0.08 mL / hour.

13. 13. The pharmaceutical infusion solution for use according to any one of claims 6 to 12, which is administered continuously to a subject with varying doses.

14. 14. The pharmaceutical infusion solution for use according to any one of claims 6 to 13, administered as a predominantly or exclusively daytime dose.

15. The following dosing regimens: - sustained daytime dose, - optionally, a bolus administered in the morning, and - optionally, at least one bolus when needed, and / or - a sustained nighttime dose lower than the daytime dose, preferably with the nighttime dose being between 1% and 50% of the daytime dose, even more preferably between 2% and 30% of the daytime dose, even more preferably between 2.5% and 10% of the daytime dose; 15. The pharmaceutical infusion solution for use according to any one of claims 6 to 14, wherein the solution is administered intravenously.

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