EP3538129A1 - A new formulation for intranasal administration - Google Patents
A new formulation for intranasal administrationInfo
- Publication number
- EP3538129A1 EP3538129A1 EP17809374.6A EP17809374A EP3538129A1 EP 3538129 A1 EP3538129 A1 EP 3538129A1 EP 17809374 A EP17809374 A EP 17809374A EP 3538129 A1 EP3538129 A1 EP 3538129A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ngf
- brain
- composition
- administration
- molecules
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to pharmaceutical compositions comprising NGF or molecules with NGF-like activity for use in the treatment of traumatic brain injury by means of intranasal administration, a method for treating traumatic brain injury by means of intranasal administration of NGF or molecules with NGF-like activity, and an associated pharmaceutical kit.
- Traumatic brain injury is a common event in children and young adults, particularly in developed countries, and is responsible for a high level of morbidity and mortality.
- the clinical outcome of TBI is determined not only on the basis of the primary brain injury, but also on the basis of secondary brain damage.
- a lesion forms which is the result of the mechanical destruction of the inter-neuronal connections and of the death of neurons, glial cells and vascular tissues at the trauma site. Damage to the cell membranes also causes a rise in their permeability, which leads to neuronal swelling, hypoperfusion of the tissue, and the triggering of a cascade of neurotoxic events.
- Secondary brain damage is caused by the reperfusion of the damaged tissue, by the hypoxia subsequent to the interruption in breathing, and by the reduced blood flow towards the brain, all of which are events that can have devastating effects and that can have a significant influence on the development of the clinical picture.
- hypoxic-ischemic brain injury is one of the main complications of TBI and is often associated with a negative clinical and neurological outcome in survivors.
- HIBI causes a loss of brain neurons and can be associated with a progressive decline in cognitive and motor functions.
- newborns and children who suffer from these conditions experience long-term problems, which are most pronounced in respect of neurobehavioral and neuropsychological functions.
- Nerve growth factor is a neurotrophin that supports neurogenesis, neuronal growth, and differentiation and survival of neurons, and that can prove to be useful in treating the damage caused by TBI or other hypoxic-ischemic brain injuries, promoting the growth of new cells in the brain tissue and revascularisation of the ischemic areas. NGF allows neurites to grow and helps to restore the function of the damaged neurons. NGF present in the cerebrospinal fluid (CSF) is a useful indicator of brain damage after major head trauma, and an increase of NGF in the CSF correlates to a favorable neurological outcome.
- CSF cerebrospinal fluid
- the main obstacles preventing the development of clinical therapies based on the use of NGF are the lack of ability of the molecules to diffuse through the blood-brain barrier (BBB), which limits the use of NGF to systemic administration, and the high invasiveness of the current methods of direct administration in the brain, for example intracerebroventricularly.
- BBB blood-brain barrier
- Nerve growth factor promotes the survival and growth of neurons, both of the central and peripheral nervous systems.
- exogenous NGF is able to prevent or significantly reduce the acute loss of cholinergic cells and the subsequent deficiencies sustained as a result of metabolic, traumatic and hypoxic-ischemic lesions.
- the authors of the present invention have surprisingly found that the administration of NGF in accordance with the methods presented in the present description has a therapeutic effect on the short-, medium- and long-term consequences of hypoxic-ischemic syndromes produced as a result of changes to the vascular/circulatory system.
- the mechanisms involved in this function, and also the involved genes and metabolic pathways are still largely unknown, even today.
- NGF neurotrophic factor
- SVZ subventricular zone
- SGZ subgranular zone
- DCX doublecortin
- a close link between NGF and DCX in neurogenesis has been demonstrated, since both the proteins are synthesized primarily in the hippocampus and prosencephalic neurons, and since both have a specific role in the neuroprotection and repair of nerve cells damaged by ischemic and traumatic injury.
- NGF vascular endothelial growth factor
- NGF neurotrophic factor
- arteriogenesis which consists of the proliferation of pre-existing arterial connections in collateral arteries
- arteriogenesis which consists of the proliferation of pre-existing arterial connections in collateral arteries
- capillary network which supplies oxygenated blood to the ischemic tissues.
- Other studies have also demonstrated that NGF is able to promote the growth of pre-existing capillaries from sympathetic ganglia in developing rats and to improve cerebral circulation in children with hypoxic-ischemic brain injury.
- the patients affected by injuries of this kind immediately display severe motor and cognitive losses, which limit their quality of life, with significant economical and social repercussions. Any non-invasive treatment able to improve such losses could therefore have very important repercussions from both a clinical and social viewpoint.
- NGF administered intranasally is innovative and particular insofar as drugs having neuroprotective action and used in the therapy of hypoxic- ischemic brain injury (i.e. antiepileptic drugs, dietary supplements, antiplatelet drugs, anticoagulants, antiedemic drugs, etc.) are currently unable to stimulate simultaneously cerebral perfusion and also an improvement in the glucidic metabolism of brain cells, as demonstrated by NGF (figures 1-3).
- the invention therefore relates to the use of NGF administered intranasally as active ingredient able to induce an improvement in blood perfusion by way of the brain parenchyma and, as a result of this effect, also able to indirectly stimulate a rise in the glucidic metabolism by way of the brain cells with a subsequent partial or total restoration of the neurophysiological functionalities altered by the vascular damage or by the hypoxic event.
- the invention therefore also relates to the use of NGF as active ingredient for use in therapy of pathologies that recognize an etiopathogenesis in respect of the cardiovascular system able to determine hypoxic-ischemic suffering of tissues in general and of the brain in particular.
- Such administration in the doses and in the ways described hereinafter, has allowed the drug to be carried to the brain parenchymal in a non-invasive way; a relatively quick diffusion of NGF in the central nervous system; with significant therapeutic effects and with subsequent reduction or lowering of the possible side effects associated with the action of NGF on peripheral nociceptive and autonomic neurons.
- Administrating NGF intranasally is a quick and safe way of transporting drugs into areas of the CNS that are difficult to access on account of the presence of the blood-brain barrier.
- This process does not require particular equipment, patient collaboration or preparation, is minimally invasive, is quick, and has an excellent safety profile, guaranteeing optimum bioavailability of the drug, in view of virtually absent and in any case minimal adverse effects or side effects.
- the invention is absolutely novel, since there are currently no pharmacological preparations available for use in the treatment of conditions or pathologies that require the therapeutic effect of neuronal regeneration, such as the treatment of the neurological outcomes of primary hypoxic-ischemic brain injuries or such injuries caused by brain trauma.
- composition for the use described in the invention and the kit described here represent not only the first pharmaceutical product aimed at treating the above-described clinical pictures, but also the first pharmacological therapeutic approach that can be placed on the market for intra-hospital and extra- hospital treatment of the neurological outcomes of hypoxic-ischemic brain injuries.
- the present invention therefore relates to a pharmaceutical composition
- a pharmaceutical composition comprising NGF and/or one or more molecules with NGF-like activity and at least one pharmaceutically acceptable carrier for use in the treatment of traumatic brain injuries, of conditions derived therefrom, or of sporadic and non-sporadic neurodegenerative pathologies by intranasal administration to a human patient.
- the present invention also relates to a therapeutic treatment of traumatic brain injuries, of conditions derived therefrom, or of sporadic and non-sporadic neurodegenerative pathologies by intranasal administration to a human patient of a pharmaceutical composition comprising NGS and/or one or more molecules with NGF-like activity.
- the present invention furthermore relates to a kit for the intranasal administration of NGF and/or molecules with NGF-like activity comprising one or more aliquots of a pharmaceutical composition comprising NGF and/or molecules with NGF-like activity and one or more devices for the topical administration of drugs to the nasal mucosa by atomization of said drugs.
- Figure 1 shows transverse PET images of brain sections with 18F-FDG taken before treatment and after four cycles of intranasal administration of NGF, showing a significant increase in brain metabolism in many valued cortical regions.
- Cerebral PET there is a progressive increase in brain metabolism from the time TO (before starting therapy by means of intranasal administration of NGF), to the times T1 , T2, T3 and T4 relating, respectively, to the checks performed after the first, second, third and, lastly, fourth administration of NGF.
- FIG. 2 shows the development of cerebral perfusion before and after intranasal administration of NGF.
- the initial SPECT scan (TO, before treatment with NGF) revealed moderate hypoperfusion in the anterior right-hand temporal region and in the left-hand portion of the front cortex, and also in the cerebral hemispheres.
- T1 after the first treatment with NGF
- the cerebral perfusion was slightly improved in the front right-hand and left-hand cortex, and also in the right-hand portion of the anterior temporal cortex, and there was an improvement in both cerebral hemispheres.
- T2 and T3 a further improvement was observed in the right-hand and left-hand front cortex and in the right-hand anterior temporal cortex.
- This figure which relates to the cerebral perfusion data, also shows a progressive increase in cerebral perfusion from the time TO (before the therapy by means of intranasal administration of NGF was started) to the times T1 , T2, T3 and T4 relating, respectively, to the checks performed after the first, second, third and, lastly, fourth administration of NGF.
- Figure 3 shows nuclear magnetic resonance images taken before and after intranasal administration of NGS and showing both a significant reduction of the extent of parenchymal brain lesions and an enlargement of the ventricular system, with a corresponding enlargement of the periencephalic spaces, evidencing an improved trophism of the brain parenchyma.
- This figure relates to cerebral NMR before (a-d) and after treatment with intranasal NGF (e-h). The images are shown with various cuts of the brain parenchyma: axial (a, e), axial FLAIR (b), axial T1w (c, g), and coronal T2w (d, h), so as to be able to examine the entire brain parenchyma in greater detail.
- the NMR before treatment with NGF shows areas of pathological T2w and FLAIR hyperintensity (a, b, outlined arrows) and of T1w hypointensity, which is also pathological at the basal ganglia (c, outlined arrow), and also the presence of hydrocephalus d, white arrows), a reduction of hydrocephalus (h, white arrows) and a subsequent enlargement of the thickness of the periventricular grey matter, which confirms a reduction of the softened areas of the brain parenchyma with subsequent improvement of cellular trophism.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising NGF and/or one or more molecules with NGF-like activity and at least one pharmaceutically acceptable carrier for use in the treatment of pathologies caused by changes to the vascular/circulatory cerebral system, such as traumatic brain injuries or also neurodegenerative diseases caused by changes to the vascular/circulatory system.
- pathologies according to the present invention are generally pathologies characterized also by the mechanical and/or pathological destruction (for example degenerative) of the interneuronal connections and death of neurons, glial cells and optionally also vascular tissues at the site affected by such destruction.
- a non- limiting example of pathologies or conditions according to the present description is constituted by pathologies/conditions deriving from a traumatic event involving the central nervous system, such as traumatic brain injuries (TBIs) or pathologies/conditions associated therewith or directly derived therefrom, such as hypoxic/ischemic brain injuries (HIBIs), or hypoxic-ischemic encephalopathy in neonatal patients, infantile cerebral paralysis, or other pathologies/conditions caused by mechanical traumas or by cerebral hypoxia/ischemia.
- TBIs traumatic brain injuries
- HIBIs hypoxic/ischemic brain injuries
- hypoxic-ischemic encephalopathy in neonatal patients, infantile cerebral paralysis, or other pathologies/conditions caused by mechanical traumas
- Brain hypoxic-ischemic injuries mean injuries caused by ischemic episodes following a reduction of the amount of oxygen supplied to the brain. These injuries can be primary or secondary effects of head trauma.
- the therapeutic treatment with NGF is limited to pathologies caused by changes to the vascular/circulatory system and results in an objective and quantifiable improvement of cerebral perfusion and metabolism.
- TBI for the purposes of the present description and as reported in the literature, is constituted by damage to the brain caused by the application of an external physical force which leads to a temporary or permanent structural and functional impairment of the brain.
- traumatic brain injuries represent risk factors for sporadic neurodegenerative diseases.
- the pathologies/conditions associated with TBIs according to the invention thus also include sporadic neurodegenerative diseases (more specifically not resulting from genetic causes).
- Injuries such as hypoxic/ischemic encephalopathy secondary damage, perinatal damage, infantile cerebral paralysis, brain injuries caused by cerebral ischemia of various type, including brain aneurysm ruptures, brain arteriovenous malformations, and brain sinus thrombosis, are also included.
- pathologies caused by changes to the vascular/circulatory system include, for example, hypoxic-ischemic syndromes which include, as will be defined in greater detail hereinafter, traumatic injuries; hemorrhagic injuries; atherosclerotic injuries; cardiogenic injuries; hypertensive injuries.
- pathologies include, for example, fetal and/or neonatal hypoxia/asphyxiation; major head trauma; acute cerebral hemorrhage, poisoning (carbon monoxide, cyanide); brain sinus thrombosis; coagulation factor deficiency; or also genetic diseases.
- examples of such pathologies include ictus; TIA; chronic vascular encephalopathy; major head trauma; acute brain hemorrhage; poisoning (carbon monoxide, cyanide); atherosclerosis; atrial fibrillation; arterial hypertension; embolism; Alzheimer's disease.
- the formulation according to the invention is also intended for use in the treatment of neurodegenerative pathologies/conditions generally also brought about by genetic causes.
- neurodegenerative diseases according to the invention include Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), multiple sclerosis, and muscular dystrophy.
- the formulation of the present invention in its doses and methods of administration, is suitable for the therapeutic treatment of pathologies/conditions of this kind insofar as it allows the drug to be carried to the brain parenchyma in a non-invasive manner; allows relatively quick diffusion of NGF in the central nervous system; allows minimal systemic diffusion of the drug, with significant therapeutic effects and with a subsequent reduction or lowering of the possible side effects associated with the action of NGF on peripheral nociceptive and autonomic neurons.
- nerve growth factor is a neurotrophin able to stimulate repair of damage of the nervous system by means of its trophic action on the neurons and ancillary cells as a result of its action promoting neurogenesis and vascularisation and perfusion of the damaged brain parenchyma.
- NGF is able to influence the supply and reperfusion of the damaged brain parenchyma, both at fluid-dynamic level and also by means of its ability to improve the amount of oxygen and nutrients transported by blood to the brain cells, restoring their "viability", and is therefore able at the same time to stimulate cerebral perfusion and also an improvement in the glucidic metabolism of the brain cells.
- mouse NGF nerve growth factor
- human NGF molecules with NGF-like activity which act on cells that express the receptors (TrkA and p75) of NGF, molecules which promote endogenic production or the activity of endogenically produced NGF, or mixtures thereof.
- molecules with NGF-like activity or molecules with an amino acid/protein structure similar to that of NGF or compounds able to function as agonists of NGF receptors can be used optionally in combination with one or more of the molecules described above.
- the term 'molecules with NGF-like activity' means: protein molecules, natural or synthetic peptides, natural or synthetic chemical compounds that act by directly activating (through the ligand-receptor bond) or indirectly influencing the biological activity of the receptors of NGF, more specifically the tyrosine receptor kinase A (TrkA) and the p75 pan-neurotrophic receptor (p75NTR), alone or in combination with one another in any stoichiometric ratio.
- TrkA tyrosine receptor kinase A
- p75NTR pan-neurotrophic receptor
- molecules with neurotrophic activity similar to that exerted by NGF interpreted as an ability to induce cellular survival and/or proliferation and/or growth and/or differentiation, both in neuronal cells and in non-neuronal cells that express receptors for NGF, and also activity in promoting vascular trophism, angiogenesis and blood perfusion of tissues, in accordance with that reported in the literature (Nico, Mangieri et al. 2008).
- the cited substances can be produced by direct synthesis of peptides from amino acids, by extraction and/or purification from biological tissues or cells, derived from biotechnologies, such as recombinant DNA techniques, or can be acquired from producers of these substances.
- Such molecules can be, for example: besides the protein NGF, as per the protein sequence reported in the UNIPROT references (www.uniprot.org) P01138 (http://www.uniprot.org/uniprot/P01138) and/or P01139
- the composition can be formulated as a liquid composition or as a lyophilized composition + carrier so as to be able to be restored just before use by the user.
- the carrier can be an isotonic solution, optionally buffered, such as saline solution or phosphate buffer, and can further comprise, if necessary, appropriate preservatives or other excipients suitable for the formulation of compositions for intranasal administration.
- the composition shall comprise, as sole active ingredient, NGF and/or one or more molecules with NGF-like activity.
- the pharmaceutical composition according to the invention is thus formed of NGF and/or one or more molecules with NGF-like activity and at least one pharmaceutically acceptable carrier.
- the human patient can be an adult patient, of any age, or can be a patient of pediatric age or even neonatal age.
- the intranasal administration will be performed preferably by means of suitable devices for topical administration, which act by means of atomization of the drugs through the nasal mucosa, preferably by the formation of atomized particles with a diameter between 10 and 50 micrometers.
- An example of devices suitable for intranasal administration of the composition of the invention is constituted by devices of the MAD (mucosal atomizer device) type or by devices that act with similar mechanisms and are commercially available.
- the application of the MAD to a syringe enables atomization of the drug as a whole, thus guaranteeing optimal absorption thereof at the nasal mucosa and reducing dispersion to the external environment and at pulmonary level to a minimum. Its structure makes it a device that is simple to use and extremely effective.
- NGF intranasally by means of an MAD device
- administration of NGF intranasally by means of an MAD device is a valid and accessible way of granting this active ingredient access at CNS level.
- NGF is carried through the nasal mucosa by means of the nose-brain pathway at fluid level, reaching areas usually inaccessible to the vast majority of drugs.
- the device loaded with the composition as described here can thus be used for the administration of NGF (or the molecules having NGF-like action) at the nasal mucosa and olfactory epithelium, with the objective of carrying it through the olfactory pathways and/or nerve endings, towards the brain parenchyma.
- the device, combined with the drug can therefore be used in clinical practice with the objective of inducing neuronal regeneration in the brain, for example for the treatment of the outcomes of brain hypoxic-ischemic injuries or neurodegenerative diseases, treating pathologies or conditions that currently cannot be treated pharmacologically.
- the compositions described here can be administered in one or more daily doses, with amounts of from 0.05 to 0.4 mg of NGF and/or molecules with NGF-like action per kg of body weight of the patient per dose.
- the administration can be performed for example 1 , 2, 3, 4, 5, 6, 7 or more times per day, depending on the patient's needs, and each time the dose can be, as described above, from 0.05 to 0.4 mg of NGF and/or molecules with NGF-like action per kg of body weight of the patient.
- the composition can be administered 2-4 times per day, for example 3 times per day, at a dose of 0.05-0.2 mg of NGF and/or molecules with NGF-like action per kg of body weight of the patient per administration.
- the composition can be administered 3 times per day in a dose of 0.1 mg of NGF and/or molecules with NGF-like action per kg of body weight of the patient.
- composition can be administered in any of the ways and doses described above for one or more therapeutic cycles.
- Such therapeutic cycles for example can last between one and two weeks.
- the pharmaceutical composition can be provided in the form of a number (for example any number from 10 to 20) of pre-prepared aliquots, each containing, by way of non-limiting example, 1 ml of physiological solution or any other suitable carrier, in which 0.5-4 mg of NGF are diluted.
- Such aliquots can be contained in phials, or also, in an embodiment offering particular ease of use, in pre-dosed syringes suitable for connection to an MAD device.
- the embodiment of the aliquots is provided so as to give a possibility of administering a dose between 0.05 and 0.4 mg of NGF and/or molecules with NGF-like action per kg of body weight of the patient.
- the composition of the invention can comprise, for example, 1 ml aliquots containing 1 mg of NGF and/or molecules with NGF-like action, this type of formulation being particularly suitable for children with a body weight around 10 kg.
- the composition can comprise 1 ml aliquots of a suitable carrier with 2 mg of NGF and/or molecules with NGF-like action to be used, for example, for children with a body weight around 20 kg, and so on.
- preparing suitable aliquots in the pharmaceutical composition by body weight range is a simple implementation for a person skilled in the art.
- the dose range used in rats is between 0.5 and 1.3 micrograms/kg, and administration is performed in a single treatment cycle with one-time daily administration for a duration varying from 3 to 14 days.
- Doses of this kind although they influence some biochemical parameters in relation to the development of neuronal suffering (for example accumulation of beta-amyloid protein, phosphorylation of the protein tau, rise in aquaporin, etc.), they do not always induce "clinical” improvements.
- the use of these methods of administration in addition does not make it possible to assess the possibility of the onset of side effects (neuropathic pain, hyperalgesia) already demonstrated in previous preclinical studies and clinical trials with peripheral administration of NGF.
- the dose administered by single cycle was from 0.05 to 0.4 mg/kg of body weight, in particular 0.1 mg/kg administered for a period of 10 days, and the administration in more daily doses was repeated for 4 cycles.
- this absolutely innovative administration protocol not developed on the basis of previous preclinical studies, a significant improvement both of metabolism and cerebral perfusion and of the clinical characteristics of the patient treated by the applicants (see examples hereinafter) was observed.
- the invention also relates to a kit for the intranasal administration of NGF and/or molecules with NGF-like activity comprising one or more aliquots of a pharmaceutical composition comprising NGF and/or molecules with NGF-like activity and one or more devices for topical administration, by atomization, of drugs through the nasal mucosa, in which kit said composition and said devices correspond to any one of the embodiments described above.
- the kit can be suitable for defined body weight ranges, and said one or more aliquots can be already pre-loaded in containers to be applied to, or forming part of, devices for topical administration as defined above.
- said one or more aliquots can be pre- calibrated for pediatric administration or for administration in adults and can be subdivided into single doses per body weight range comprising a suitable amount of NGF and/or molecules with NGF-like activity.
- said one or more aliquots can be multi-dose aliquots, for example "daily” or “weekly” aliquots which can be subdivided into a suitable dose based on patient weight.
- said one or more devices for administration of the composition can be devices of the MAD (mucosal atomizer device) type.
- the kit of the invention can comprise a number (for example any number from 10 to 20) of pre-prepared aliquots, each containing, by way of non-limiting example, 1 ml of physiological solution, in which 1-2 mg of NGF and/or molecules with NGF-like action, are diluted, which, for the 10 pre-dosed syringes, gives the possibility of administering 0.1 mg/kg of NGF in total.
- aliquots can be already contained in sterile syringes optionally already equipped with the MAD device for intranasal administration of the neurotrophin.
- the kit of the invention for example can comprise 10 syringes with 1 mg of NGF for children of body weight around 10 kg, or 10 syringes with 2 mg of NGF for children of body weight around 20 kg, or a kit of 20 syringes with 1 mg of NGF for children of body weight around 20 kg.
- preparing a suitable pharmaceutical kit for body weight ranges is a simple implementation for a person skilled in the art.
- kits of this kind would allow the intranasal administration of NGF at home and by the parents of children (given the simplicity and safety of the methodology), significantly improving the quality of life of these children.
- compositions, the kits, and the method of the invention can be used not only for patients (including patients of pediatric or neonatal age) suffering from neurological deficiencies caused by major head trauma, but also by all children affected by cerebral damage caused by hypoxic-ischemic encephalopathy brought about by perinatal damage and by patients affected generally by infantile cerebral paralysis and secondary brain injuries and cerebral ischemia of various nature (for example brain aneurysm rupture, brain arteriovenous malformations and brain sinus thrombosis).
- PICU Paediatric Intensive Care Unit
- Gemelli university hospital in Rome after a cardiac arrest, following a major head trauma caused by a car accident. Cardiopulmonary resuscitation was performed immediately on the child, and a tracheal tube fitted. After 7 minutes of cardiorespiratory arrest, a return of spontaneous circulation was established and the child was brought to our Pediatric Intensive Care Unit, where the neurological examination revealed a GCS of 4.
- the TAC total-body revealed the presence of blood in the lateral ventricles of the brain, deep and diffuse hemorrhagic petechiae at white matter level, as experienced with diffuse axonal injury, occipital fracture, left pulmonary contusion, and bilateral pleural effusion.
- a mild therapeutic hypothermia 34°C was established for 24 hours. After four days from the trauma, the sedation was interrupted and the child opened their eyes, but without any respiratory trigger.
- the emergency MRI of the spinal column revealed a frontal cortical-subcortical hemorrhagic contusion, and signs of axonal injury at the corpus callosum trunk and splenium.
- the neurological examination revealed a relatively comatose child with complete tetraplegia, severe communicative and neuropsychological impairment, and respiratory insufficiency.
- the child was fed by gastrostomy.
- the child was unable to control the bladder and intestinal functions due to the magnitude of the injury to the spinal cord.
- the ASIA scale yielded a result of "A", which confirmed complete lesion of the spinal cord.
- the EEG recordings revealed basic theta activity with poor electrical organization.
- the functional assessment was performed using the SCIM (spinal cord independence measure), version III and gave a final score of 11 (from 0 to 100, where 100 is total independence of movements). Focused management of the spasticity in specific muscular groups with botulinum toxin was performed, with no improvement.
- the patient was also subjected to numerous cycles of physiotherapy, but without any sign of improvement either in communicative capabilities or motor capabilities.
- NGF was administered in a dose of 0.1 mg/kg (2 mg of NGF diluted in 20 ml of saline solution, three times per day for 10 consecutive days) by means of an MAD (mucosal atomization device), used to administer drugs by atomization thereof in the nasal cavity.
- MAD molecular atomization device
- Such an amount of NGF was considered sufficient to reach and stimulate the NGF receptors, primarily the tyrosine kinase of receptor A (TrkA), in the majority of the cholinergic and serotoninergic brain areas.
- the nostrils were washed with 1 ml of physiological solution, then were sprayed, so as to avoid any interference with the absorption of the drug.
- the verbal dyspraxia demonstrated a progressive improvement, particularly in respect of the control of oral motility, such as opening the mouth, motility of the tongue, chewing and swallowing.
- the possibility to feed oneself improved; in fact, the child was able to eat small amounts of food and the parents communicated an improvement in the ability to distinguish between different tastes.
- improvements were also observed in phonation abilities, with formulation of more explicit sounds.
- a progressive and constant improvement in movements of the head primarily lateral rotational movements and, to a lesser extent, flexion-extension.
- some movements of the fingers of the hand have been observed during playtime, with characteristics of voluntary control and with improved muscle tone and trophism.
- the brain SPECT revealed the development of the cerebral perfusion before and after intranasal administration of NGF.
- brain hypoperfusion was present, evident most clearly at the frontal and temporal cortex dx, in the cerebral cortex sx, and at the brain hemispheres.
- a progressive and significant improvement of the cerebral perfusion was observed in the areas described above, with the exception of the brain hemispheres, where, instead, zones of vascular hypoperfusion still persisted.
- the visual interpretation of the SPECT images was confirmed by a semiquantitative analysis, using the statistical parametric mapping 8 (SPM8) system and the volumes of interest (VOIs) positioned at the grey brain matter ( Figure 2)
- the EEG examinations were performed before and after the treatment with intranasal administration of NGF and revealed a constant and progressive reduction of slow-wave activity with partial recovery of a normal electrophysiological rhythm.
- ERPs were recorded at the start and at the end of the treatment with NGF, in accordance with a technique already standardized.
- the ERPs in both eyes demonstrated a significant increase in the phase/latency ratio (>90° percentile) of the test-retest variability established in healthy children and in children with serious pathologies of the optical nerve caused by glioma, with a change of 60 and 100 degrees respectively for the right and left eye.
- This change corresponds to an advance of latency response between 20 and 30 milliseconds, indicating faster and more efficient visual cortical responses to light after treatment with NGF.
- the NGF ELISA was performed on samples of CSF collected by lumbar puncture, performed under deep sedation of the patient, before (pre-treatment) and at the end of the administration of the NGF.
- the levels of the NGF were significantly increased in the CSF after intranasal administration of NGF.
- an increase of 30% and of 44% of the NGF content in the CSF was observed, respectively.
- DCX protein doublecortin
- the presence and variation of the concentrations of DCX in the fluid was thus analyzed, by means of Western blot, before and after intranasal administration of NGF.
- the levels of DCX in the CSF were increased in both the post-treatment samples compared to their respective pre-treatment controls.
- the initial content of DCX in the CSF has risen over time, as demonstrated by a comparison with the pre-treatment samples.
- the nasal preparations were liquid, semi-solid, or solid preparations to be administered in the nasal cavities to obtain a systemic or local effect.
- the nasal preparation with NGF used in the treatment of the clinical case described above contained a single active ingredient in isotonic solution and was provided in a single dose, in a syringe with a system for nasal nebulation.
- the nasal solution was produced by the pharmacy of the Agostini Gemelli university hospital using:
- the lyophilized NGF was restored using 0.9% NaCI sterile physiological solution by means of an aseptic technique, in a sterile environment, under a vertical laminar flow hood, as indicated by the Good Preparation Practices of the Official Pharmacopoeia, edition XII.
- the solution was then divided into sterile syringes, each containing 1 ml of solution formed by 0.07 mg of NGF in physiological solution (0.9% NaCI).
- the prepared preparations were then introduced into sterile bags to ensure, at the moment of use, the absence of microbiological contamination and were labeled, noting all of the data requested by the Good Preparation Practices of the Official Pharmacopoeia, edition XII.
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- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hospice & Palliative Care (AREA)
- Inorganic Chemistry (AREA)
- Otolaryngology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IT102016000112420A IT201600112420A1 (en) | 2016-11-08 | 2016-11-08 | NEW FORMULATION BY INTRANASALE |
PCT/IB2017/056945 WO2018087656A1 (en) | 2016-11-08 | 2017-11-07 | A new formulation for intranasal administration |
Publications (1)
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EP3538129A1 true EP3538129A1 (en) | 2019-09-18 |
Family
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Family Applications (1)
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EP17809374.6A Withdrawn EP3538129A1 (en) | 2016-11-08 | 2017-11-07 | A new formulation for intranasal administration |
Country Status (3)
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EP (1) | EP3538129A1 (en) |
IT (1) | IT201600112420A1 (en) |
WO (1) | WO2018087656A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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BR112023019289A2 (en) | 2021-03-25 | 2024-01-30 | Chiesi Farm Spa | COMBINED TREATMENT OF BRAIN INJURY |
EP4342485A1 (en) * | 2022-09-23 | 2024-03-27 | Dompe' Farmaceutici S.P.A. | Ngf for the treatment of spasticity |
-
2016
- 2016-11-08 IT IT102016000112420A patent/IT201600112420A1/en unknown
-
2017
- 2017-11-07 EP EP17809374.6A patent/EP3538129A1/en not_active Withdrawn
- 2017-11-07 WO PCT/IB2017/056945 patent/WO2018087656A1/en unknown
Also Published As
Publication number | Publication date |
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WO2018087656A1 (en) | 2018-05-17 |
IT201600112420A1 (en) | 2018-05-08 |
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