Patent Application
20230381121
This application claims the benefit of priority to Italian Patent Application No. 102022000007952, filed Apr. 22, 2022, the entire contents of which are hereby incorporated by reference herein.
The present invention relates to the use of N-palmitoylethanolamide (PEA) in association with melatonin or natural precursors thereof in the treatment of autism spectrum disorder (ASD) and other neurobehavioral disorders similarly accompanied by restlessness, irritability, sleep disorders, and potentially stereotypies.
ASD is a multifactorial-etiology neurodevelopmental disorder occurring through the impairment of social interaction, verbal and non-verbal communication, activities, and interest (definition from the American Psychiatric Association). The symptomatology begins within the first three years of life following a specific event and early diagnosis is very important to be able to adequately intervene on the various compromised areas.
Stereotypies are one of the main diagnostic features of ASD and can comprise self-stimulatory and self-harming behaviors, excitement, stimulation, stress, anxiety, boredom, fatigue, and social isolation.
Other neurobehavioral disorders associated with the autism spectrum are restlessness, irritability, and sleep disorders.
Although the cause is not known, the appearance of ASD is also due to an imbalance between inhibitory and excitatory synapses, as well as neuroinflammation responsible for the activation and pathological proliferation of non-neuronal cells which, by releasing cytokines (IL-1α, IL-1β, IL-6 and TNF-α) and pro-inflammatory chemokines (MCP-1 and RANTES) in the brain and cerebrospinal fluid of autistic patients, exacerbate the neuroinflammatory process.
Sleep is one of the essential needs for the development and maturation of the brain. Children with ASD and disturbed sleep have an exacerbation of developmental delays in cognitive functions such as attention, memory consolidation, mood regulation, and social interaction.
Furthermore, the involvement of altered myelination has recently been highlighted in both experimental models of autism and in human patients with ASD. It is known that the administration of melatonin, a hormone produced naturally by the pineal gland (or epiphysis), is an aid in regulating circadian rhythms and reducing sleep disturbances, stereotyped repetitive behaviors and attention deficit.
The endogenous molecule PEA is known to play an important role in the natural modulation mechanism of neuroinflammation. In pre-clinical and clinical settings, the administration of PEA, especially if in an ultra-micronized form (um-PEA), is capable of determining neuroinflammatory normalization activity; in particular, it has been demonstrated that um-PEA is capable of significantly counteract the general neuroinflammatory status of mice with a simil-autistic phenotype, reducing the expression of the pro-inflammatory hippocampal and serum cytokines IL-6, IL-1β and TNF-α, as well as modulating the altered behavioral status. Clinically, the 3-month treatment of autistic children with um-PEA 600 mg/day improves aggressiveness, cognitive and behavioral skills, and communication without adverse effects.
Therefore, there is a need to provide ASD therapy, and in particular for neurobehavioral disorders similarly accompanied by restlessness, irritability, sleep disorders, which is effective, non-invasive and safe and which, if possible, does not require the administration of high doses of active substances. In fact, taking into account that such therapy would be primarily dedicated to a child population, repeated administration and/or in large dosage forms (for example, large tablets for oral administration of high doses of active ingredients) would be difficult to accept by the patient.
The present invention derives from the surprising discovery that PEA, preferably when used in ultra-micronized form, when administered in association with melatonin, exhibits a synergistically relevant effect in improving the behavioral parameters of autistic subjects, in particular the parameters associated with restlessness, irritability, sleep disorders and stereotypies.
Therefore, the present invention relates to PEA for use in the treatment of ASD, where PEA is administered in association with melatonin, where said administration is separate, combined, or simultaneous.
The invention further relates to a composition containing PEA and melatonin, in particular when usable in the treatment of ASD.
These and further objects, as outlined in the appended claims, will be described in the following description. The text of the claims should be considered included in the description in order to assess the description sufficiency.
Further features and advantages of the invention will become apparent from the following description of preferred embodiments, given by way of non-limiting examples.
The present invention relates in a first aspect to PEA for use in the treatment of ASD, where PEA is administered in association with melatonin or natural precursors thereof, where said administration is separate, combined, or simultaneous.
The term “in association” means both a combination therapy and a therapy in which PEA and melatonin or natural precursors thereof are contained in a single dosage form.
“Separate” administration means an administration of PEA and melatonin or natural precursors thereof in separate dosage forms, administered at different times ranging from 1 minute to several hours, for example 8, 12 or 14 hours apart.
“Combined” administration means an administration of PEA and melatonin or natural precursors thereof contained in a single dosage form, i.e., a pharmaceutical or veterinary composition or formulation, supplement, dietary composition or food for special medical purposes.
“Simultaneous” administration means an administration of PEA and melatonin or natural precursors thereof in separate dosage forms, but administered simultaneously, i.e., within a separation time between the PEA and melatonin administration, or vice versa, not exceeding 1 minute.
PEA can be administered in any form, for example in a non-micronized form, in a micronized form or in an ultra-micronized form.
The term “palmitoylethanolamide (or PEA) in a non-micronized form” means PEA having a particle size distribution, defined as a percentage by volume and measured with the laser light scattering method, represented by a distribution curve having the mode above 10 microns, preferably above 20 microns.
The term “palmitoylethanolamide (or PEA) in a micronized form” means PEA having a particle size distribution, defined as a percentage by volume and measured with the laser light scattering method, represented by a distribution curve having the mode between 6 microns and 10 microns.
The term “palmitoylethanolamide (or PEA) in an ultra-micronized form” means PEA having a particle size distribution, defined as a percentage by volume and measured with the laser light scattering method, represented by a distribution curve having the mode below 6 microns and above 0.5 microns.
Preferably, the PEA is in an ultra-micronized form.
In an embodiment, the PEA in an ultra-micronized form has a particle size distribution as defined above, measured with a Malvern Mastersizer 3000 instrument with Fraunhofer calculation algorithm, where at least 95% by volume, more preferably at least 99% by volume, of particles has a particle size of less than 6 microns.
In a particularly preferred embodiment, the PEA in an ultra-micronized form has a particle size distribution as defined above, measured with a Malvern Mastersizer 3000 instrument with Fraunhofer calculation algorithm, having a mode between 2 and 4 microns and having 100% by volume of particles smaller than 10 microns and at least 60% by volume of particles smaller than 3 microns.
The micronization can be carried out in a fluid jet system (for example, Jetmill® model system) which operates with spiral technology with a compressed air or nitrogen jet capable of exploiting kinetic energy—instead of mechanical energy—to crush the particles. Such apparatuses are conventional and will therefore not be further described, except in relation to the following features:
Melatonin has the following structural formula:
Melatonin (chemically N-acetyl-5-methoxy tryptamine) is a hormone produced by the pineal gland (or epiphysis), the gland at the base of the brain. It acts on the hypothalamus and has the function of regulating the sleep-wake cycle. In addition to humans, it is also produced by other species of animals, plants (phytomelatonin) and microorganisms. Low-dose melatonin is used regularly in sleep-wake cycle disorder therapy.
The term “natural precursors” of melatonin means tryptophan (TRP) and 5-hydroxytryptophan (5H-TRP), which generate serotonin which in turn is converted into melatonin.
The biosynthetic diagram from TRP to 5H-TRP and serotonin is as follows:
The transformation of TRP into 5H-TRP is carried out by tryptophan hydroxylase, while the subsequent transformation of 5H-TRP into serotonin occurs by means of the aromatic L-amino acid decarboxylase.
Melatonin is finally synthesized by serotonin via N-acyltransferase and acetylserotonin O-methyltransferase.
A further object of the present invention is a composition comprising palmitoylethanolamide and melatonin or natural precursors thereof as defined above. Preferably, the composition of the invention consists of a dry mixture of PEA/melatonin and pharmaceutically acceptable excipients. More preferably, PEA is in micronized (m-PEA) or ultra-micronized (um-PEA) form, still more preferably the palmitoylethanolamide is um-PEA.
Whether administered separately or combined in a single formulation, the PEA and melatonin are administered in a weight ratio between at least 20:1 and 5:1, preferably between at least 12:1 and 8:1. More in particular, when the PEA is in ultra-micronized form, the weight ratio PEA/melatonin will preferably be between at least 11:1 and 8:1, more preferably between at least 10:1 and 9:1. When the PEA is in micronized or non-micronized form, the weight ratio PEA/melatonin will preferably be between at least 20:1 and 10:1, more preferably between at least 18:1 and 12:1.
Based on such weight ratios for which a significant synergistic effect has been highlighted and considering that the dose of melatonin normally considered safe in a subject is between 0.5 and 6 mg/day, the minimum daily dose of PEA, both in a combination therapy and in a PEA/melatonin composition, will be at least between 2.5 mg/day and 120 mg/day. Preferably, in the case of using um-PEA, the minimum daily dose of um-PEA will be between 4 mg/day and 66 mg/day, while in the case of using non-micronized PEA or m-PEA the minimum daily dose will be between 5 mg/day and 120 mg/day.
Such doses may vary depending on the subject and in particular if the subject is of child, adult or elderly age. In fact, in such cases, the daily doses of melatonin considered safe are 1-3 mg/day in children, 0.5-5 mg/day in adults and 0.1-2 mg/day in the elderly, whereby the minimum daily doses of PEA must be calculated accordingly.
When the precursors TRP and 5H-TRP are used in place of melatonin, the weight ratio PEA/TRP or PEA/5H-TRP will preferably be between at least 5:1 and 1:10, more preferably between at least 3:1 and 1:6.
The daily dose of TRP or 5H-TRP is preferably between 30 and 500 mg/day, whereby it will also be possible to calculate the minimum daily dose of PEA based on the weight ratios described above.
Given that, as is widely known from the literature, PEA has an anti-inflammatory activity in general and counteracts neuroinflammation both centrally and peripherally and that such a molecule has a low toxicity, it will be possible to use higher doses of PEA than those described above, which are sufficient to obtain a synergistic effect on autism spectrum disorders.
The additional PEA with respect to the amount of synergistic PEA with melatonin or the natural precursors thereof can also be present in a different form from that used in association with melatonin, TRP or 5H-TRP. For example, if the latter is in the form of um-PEA, the additional PEA may be either um-PEA, m-PEA or non-micronized PEA, or vice versa.
Therefore, the overall daily dose of PEA administered to a subject, either in the form of combination therapy or in the aforesaid composition with melatonin or the natural precursors thereof, can be between 200 and 1500 mg/day, preferably between 400 and 1200 mg/day.
Such daily doses can be divided into dose units for an administration, for example, from 1 to 4 times a day. The dose will also depend on the route chosen for administration. It should be considered that it may be necessary to continuously vary the dosage depending on the age and weight of the patient and also on the severity of the clinical condition to be treated. The exact dose and route of administration will ultimately be at the discretion of the attending physician.
In certain embodiments, the invention relates to the association of PEA, melatonin or natural precursors thereof and docosahexaenoic acid (DHA) or oils suitably titrated in DHA, where the PEA, melatonin and the natural precursors thereof are as defined above.
DHA, also called cervonic acid, is an omega-3 or PUFA n-3 fatty acid. Oceanic cold-water fish are rich in DHA. Most of the DHA present in fish and complex organisms, which live in cold ocean waters, comes from photosynthetic algae. DHA is also commercially produced by microalgae, Crypthecodinium cohnii which is a microorganism of the genus Schizochytrium. DHA produced using microalgae is of plant origin.
Also in this case a separate, combined or simultaneous administration can be made available and a composition comprising a ternary dry mixture of PEA, melatonin or natural precursors thereof and DHA can be made available, where the weight ratios PEA/melatonin, PEA/TRP and PEA/5H-TRP are as defined above and the weight ratio PEA/DHA is between 1:7 and 1:1, preferably between 1:5 and 1:2, when the PEA is um-PEA, and between 1:1 and 7:1, more preferably between 2:1 and 5:1 when the PEA is non-micronized PEA or m-PEA.
Preferably, the dosages of DHA administered to a patient of child or adolescent age are 700 mg/day or less, or more preferably 500 mg/day or less.
For the purposes of the invention, PEA alone, melatonin or the natural precursors thereof alone or the composition containing PEA and melatonin or natural precursors thereof, optionally in association with DHA, can be included in pharmaceutical or veterinary formulations and can be formulated in dosage forms for oral, buccal, parenteral, rectal, topical or transdermal administration.
For oral administration, the compounds of the invention can be found, for example, in the form of tablets or capsules, hard or soft, prepared in the conventional fashion with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized cornstarch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or inhibiting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art. The liquid preparations for oral administration can be, for example, in the form of solutions, syrups or suspensions or they can be freeze-dried or granulated products to be reconstituted, before use, with water or other suitable vehicles. Such liquid preparations can be prepared through conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or edible hydrogenated fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl- or propyl-p-hydroxybenzoates, sorbic acid, benzoic acid or salts thereof). The preparation can also conveniently contain flavorings, dyes, and sweeteners.
The preparations for oral administration can be appropriately formulated to allow the controlled release of the active constituent.
For buccal administration, the compounds of the invention can be in the form of tablets or pills formulated in the conventional manner, which are suitable for an absorption at the level of the buccal mucosa. Typical buccal formulations are tablets for sub-lingual administration.
The compounds of the invention can be formulated for parenteral administration by injection. The injection formulations can be presented as a single dose, for example in vials, with an added preservative. The compositions can appear in such a form as suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain agents of the formulation such as suspension, stabilizers and/or dispersants.
Alternatively, the active ingredient or the mixture of active ingredients can be found in the form of a powder to be reconstituted, before use, with a suitable vehicle, for example with sterile water.
The compounds of the invention can also be formulated according to rectal formulations such as suppositories or retention enemas, for example containing the basic components of the common suppositories such as cocoa butter or other glycerides.
In addition to the formulations described above, the compounds of the invention can also be formulated as a deposit preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously, transcutaneously or intramuscularly) or intramuscular injection. Therefore, for example, the composition can be formulated with appropriate polymer or hydrophobic materials (for example in the form of an emulsion in a suitable oil) or ion exchange resins or as minimally soluble derivatives.
The compounds or composition of the invention can also be administered in the form of oral sprays or nasal sprays.
The invention further relates to dietary compositions, food supplements, complementary feed and foods for special medical purposes (FSMPs) comprising PEA, preferably ultra-micronized PEA, and melatonin for use in the treatment of ASD. In such cases, the daily dose of melatonin must not exceed 1 mg/day.
The term “food for special medical purposes” means products authorized according to regulation (EU) 2016/128. Such a term refers to a product to be administered under medical supervision, thus assimilating such an FSMP to a drug.
The formulations according to the invention can be prepared according to conventional methods, such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA, 17th edition, 1985 o in Remington, The Science and Practice of Pharmacy, Edited by Allen, Loyd V., Jr, 22nd edition, 2012 or in subsequent editions.
Micronization Procedure
The PEA was micronized as previously described.
The ultra-micronization was carried out in a fluid jet system (in particular, the Jetmill® model system) which operates with compressed air jet “spiral technology”.
Optimal Micronization Conditions:
Determination of the Particle Size Distribution
The determination of the particle size distribution was carried out on a wet sample, after 1-minute sonication.
A Malvern Mastersizer 3000 instrument operating with the LALLS (Low Angle Laser Light Scattering) technique and a Fraunhofer calculation algorithm was used.
The particle size distribution graph is shown in
Biological Experimentation
a. Mixture of PEA-Um and Melatonin in VPA Mice
To evaluate the synergy of a combination PEA-um and melatonin, experimental tests were carried out by oral administration (gastric tube) of a mixture of um-PEA and melatonin (approximately 10:1 ratio) at a dose of 10 mg/kg for two weeks in mice in which an autistic phenotype was induced by a single injection of valproic acid in the form of sodium valproate (VPA).
Furthermore, experimental tests were carried out to determine the synergy of the PEA-Melatonin-DHA combination administered orally to genetically modified BTBR T+tf/J (BTBR) mice, an animal model of neurobehavioral disorders of the ASD type.
Healthy male C57/BL6 mice fed ad libitum and housed in cages with controlled sleep/wake cycles were used in the first experimentation. Before the start of the experimentation, the animals were subjected to an acclimatization period of 1 week considering all the experimental procedures and protocols, compliant with the principles of care and welfare of laboratory animals approved by the Italian Ministry of Health (Italian Legislative Decree 2014/26) and European directives (EU Directive 2010/63) and by the ARRIVE guidelines.
To induce the simil-autistic phenotype, 14-day-old animals were chemically treated with a single dose of subcutaneous (s.c.) VPA at a concentration of 400 mg/kg in 100 μl of saline.
The animals were randomized into 6 groups of 20 mice each and treated per os, starting from the 15th day of life, with 1.5% carboxymethyl cellulose (CMC) (vehicle used to suspend the molecules), with Melatonin (1 and 10 mg/kg), um-PEA (9 mg/kg) and um-PEA/Melatonin (10 mg/kg in 10:1 ratio, previously mixed dry) daily for 14 days:
b. Mixture of PEA-um, Melatonin and DHA in BTBR Mice
To determine the synergy of a PEA-um, melatonin and DHA combination, a second experimentation was performed, using a different animal model useful for the study of neurobehavioral disorders, and more precisely BTBR mice. These animals are genetically lacking the corpus callosum and have severely reduced hippocampal commissure. Over a period of time comparable to infant infancy, the animals develop behavioral deficits, reduced social interactions, altered play expressions, reduced exploratory behavior, unusual vocalizations, and anxiety.
The mice were randomized into 4 groups of 8 animals each (3 BTBR groups and 1 group of healthy C57 mice used as controls), and treated orally every day for 10 consecutive days, starting from the fourth month of life, according to the following groups of treatment:
The animals underwent the following behavioral tests:
At the end of the behavioral tests and treatments, the animals were sacrificed for brain sampling, immediately fixed in formalin and then cut into sagittal sections (7 μm) stained with hematoxylin and eosin (E/E).
Changes were studied in the density in the Purkinje cell layer (pcs) and neuronal damage in the CA1 and CA3 regions of the hippocampus (
The protein analyses (Western Blotting) were performed on hippocampal and cerebellar tissues using the primary antibodies anti-GFAP (1:500, Santa Cruz Biotechnology), anti-Iba1 (1:500, Santa Cruz Biotechnology), anti-IkB-α (1:500, Santa Cruz Biotechnology), anti-NF-kB (1:500, Santa Cruz Biotechnology), anti-Bax (1:1000, Santa Cruz Biotechnology), anti-Bcl-2 (1:1000, Santa Cruz Biotechnology) and anti-β-actin (1:5000, Santa Cruz Biotechnology). Protein expression was quantified by densitometry (BIORAD ChemiDocT™ XRS+software) and normalized to p-actin expression levels.
Immunohistochemical (IHC) analyses were performed at the level of the cerebellum in tissues derived from VPA animals to assess the number of positive cells for the primary antibodies anti-Period (per)-1, anti-per2 and anti-npas2, proteins involved in homeostatic regulation of sleep, circadian rhythm generation, and memory consolidation.
Due to the structural alterations present in the brain of BTBR animals, it was not possible to perform immunohistochemical analyses to evaluate the number of cells positive for the primary anti-Period (per)-1 and anti-npas2 antibodies. For this reason, Real Time (RT)-PCR analyses were performed to quantify and evaluate the gene expression of the aforementioned sleep genes, at the level of the cerebellum.
Briefly, a small portion of the cerebellum was preserved in RNALater and used for RNA extraction (Trizol, Invitrogen). The extracted RNA was treated with RNAsefree DNAse I (New England Biolabs, Ipswich, MA, USA) and 1 ug of total RNA of each sample was reverse transcribed using the RevertAid First Strand cDNA Synthesis Kit (Invitrogen). Complementary DNA (cDNA) was then used as a template to evaluate messenger RNA (mRNA) expression of the per1 and npas2 genes. All samples were tested in triplicate and b-actin was used as the house-keeping gene
Further analyses were conducted on hippocampal and cerebellar tissues to assess:
Finally, sagittal sections of the brain derived from VPA mice were stained with luxol fast blue (LFB) technique (Ghasemi-Kasman M et al. In vivo conversion of astrocytes to myelinating cells by miR-302/367 and valproate to enhance myelin repair. J Tissue Eng Regen Med 2018; 12:e462-e472) to quantify myelin sheath demyelination (
Statistical Analysis
All the values reported in the results were expressed as mean±standard error of the mean (SEM) of N observations (N=number of animals). Between-group statistical differences for the VPA mice experiments in behavioral score and molecular analyses were analyzed by ANOVA followed by Bonferroni's post-hoc test for multiple comparisons. For experiments conducted in BTBR mice, ANOVA analysis was used followed by Tukey's multiple comparison test.
The p-value <0.05 was considered significant.
Results of the Experiments
a. Mixture of PEA-Um and Melatonin in VPA Mice
From the experiments described above and as shown by the results reported in the graphs of
In the above study, conducted in a VPA injection model of autism, melatonin at 1 mg/kg was never shown to be active, but actually worsened pain insensitivity.
Based on the conversion of “mouse dose” to “human dose” (Reagan-Shaw S, et al., FASEB J. 2008; Nair A B, Jacob S., J Basic Clin Pharm 2016; 7: 27-31; FDA Guidelines), the 1 mg/kg dose of melatonin used in the mixture of the present study corresponds to an equivalent dose of 0.12 mg/kg in the child. For children weighing 10-20 kg, the daily dose of melatonin to be administered mixed with um-PEA would therefore be equal to 1.2 mg-2.4 mg, which falls within the daily doses envisaged according to the present invention.
Although at a dose of 10 mg/kg melatonin has been shown to be active in the present study, it should be considered that in a child weighing 10-20 kg, such a dose corresponds to a very high equivalent dose, and equal to 12-24 mg, therefore not usable.
In fact, as mentioned above, in most children with autism the dose of melatonin used is in the range of 1-3 mg/day. In adults, the recommended dose is 0.5-5 mg/day, while for the elderly it is recommended to start with a minimum dose of 0.1 mg/day. Therefore, in general terms, melatonin can be administered in a dose range from 0.1 mg/day to 5 mg/day.
High doses of melatonin can induce in children nightmares, drowsiness, headaches, stomach pain, dizziness and grogginess in the daytime, low blood pressure, nocturnal enuresis, more rarely hyperactivation and reduced sleep. Adults may experience side effects such as vivid dreams or nightmares, headaches, dizziness, daytime sleepiness, short-term feelings of depression, stomach cramps, irritability, decreased libido.
From the present study it is evident that the association between um-PEA and melatonin within the expected dose ranges, therefore at doses of both PEA and melatonin within the allowable and safe doses, is synergistically active in the treatment of autism spectrum disorders.
b. Mixture of PEA-Um, Melatonin and DHA in BTBR Mice
From the experiments described above and as shown by the results in
The present invention thus provides a method for treating neurobehavioral disorders, such as e.g. ASD comprising or consisting of administering to a subject, PEA, preferably in ultra-micronized form, and melatonin or natural precursors thereof, and optionally DHA, where said administration is separate, combined (i.e., in a single dosage form) or simultaneous and where at least the melatonin is administered at a dosage at which, when administered alone, it is inactive.
In particular, the disorders which can be treated according to the invention are neurobehavioral disorders accompanied by restlessness, irritability, sleep disorders, and potentially stereotypies and associated with:
It has also been seen that the administration of the compounds or compositions according to the invention is able to treat neuro-behavioral disorders accompanied by restlessness, irritability, sleep disorders and, potentially, stereotypies connected to dementias and senile dementias, also in dog and cat, such as the Cognitive Dysfunction Syndrome.
The invention will now be further described through the following formulation examples.
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| Number | Date | Country | Kind |
|---|---|---|---|
| 102022000007952 | Apr 2022 | IT | national |
