Claims:1. A composition comprising palmitoylethanolamideor salts and the one or more probiotics with pharmaceutically acceptable salts thereof.
2. The composition as claimed in claim 1 wherein the one or more probiotics is / are, respectively, chosen from the group consisting of includes species of Lactobacillus and Bifidobacterium, yeast Saccharomyces cerevisiae, E. coli and Bacillus species, Lactic acid bacteria, including Lactobacillus species, Oligofructose, Inulin, Galacto-oligosaccharides, Lactulose, Breast milk oligosaccharides or mixtures thereof.
3. The composition as claimed in any of the claims 1 to 2, wherein the compositioncomprises between 30% and 3000% of the recommended daily intake of probiotic, preferably 3 billion per unit of composition.
4. The composition as claimed in any of the claims 1 to 3, wherein the compositioncomprises between 100 and 800 mg palmitoylethanolamide, preferably between300 mg and 600 mg palmitoylethanolamide, per unit of composition; optionally, containing said palmitoylethanolamide in an oil matrix, in a volume ratio of 5%- 20% (volume/volume), preferably 10% (volume/volume) palmitoylethanolamide / olive oil.
5. The composition as claimed in any of the claims 1 to 4, wherein the composition is formulated as a pharmaceutical composition or a nutraceutical composition.
6. The composition as claimed in any of the preceding claims, wherein the composition is formulated as an oral formulation, a sublingual formulation, a transdermal or a topical formulation.
7. A method for preparing the composition as claimed in any of the claims 1 to 6.
8. The method as claimed in claim 7, wherein the palmitoylethanolamideor salts and one or more probiotics thereof have been granulated into particles with an average particle size (D50) of between 10 and 1000 micron, preferably between 10 and 100 micron.
9. The method as claimed in claim 7, comprising the step of adding thepalmitoylethanolamide particles to an oil, preferably any vegetable oil or any fish oil comprising omega-3 fatty acids, preferably olive oil, such that a composition comprising palmitoylethanolamide in an oil matrix, in a volume ratio of 5%-20% (volume/volume), preferably 10% (volume/volume) palmitoylethanolamide / vegetable oil, preferably palmitoylethanolamide / olive oil, is obtained.
10. The composition as claimed in any of the claims 1 to 6, for use as a medicament, chronic pain coincides with an axonal neuropathy such as diabetic neuropathy, a demyelinating neuropathy, chemotherapy induced neuropathy, HIV neuropathy, post herpetic neuropathy or postoperative pain.
, Description:FORM 2

THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

Title of the Invention: “NOVEL COMPOSITION FOR THE TREATMENT OF
CHRONIC PAIN”

Applicant Name: LYCEUM LIFE SCIENCES PRIVATE LIMITED

Applicant Nationality: An Indian Company

Address: 14/13B, Ground Floor, Bosepukur Road, Kasba, Behind Kasba
Police Station, Talbagan Bus Stop, Kolkata – 700 042,
West Bengal, India

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a composition comprising of palmitoylethanolamide (PEA) and probiotic. The present invention also relates to such a composition for use as a medicament, for use as an analgesic pharmaceutical, and more specifically for use as an analgesic pharmaceutical in the alleviation of chronic pain, and to a method for preparing such a composition.
BACKGROUND ART
The prevalence of chronic pain (CP) is well described in Europe, America, and Australia. However, little knowledge is available of the prevalence of CP within Asia or Southeast Asia. Given the cultural and genetic variation in pain causation, manifestation, and reporting, the findings of previous western studies cannot be extrapolated to Asian countries. A prevalence study was needed to be carried out to quantify the magnitude and impact of CP in the adult population in India.
This Indian adults' population survey about CP found a higher prevalence of CP as compared to other Asian pain prevalence studies; however, the impact of pain was just as significant. In a rapidly aging population, CP is emerging as a significant healthcare problem which may likely to exert an increasing toll on the existing social infrastructure within the next two decades.
Chronic pain is one of the most prevalent and disabling conditions in the clinical setting with both physical and psychological symptoms. In the past three decades, there has been a better understanding of the underlying pathophysiological mechanisms that cause chronic pain, yet it still remains a significant problem. Multiple levels of the nervous system with multiple neurotransmitters are involved in pain transmission. Therefore, it is not so easy to plan effective pharmacological therapy for chronic pain and pain treatment often involves the use of one or a combination of agents with analgesic action. Chronic pain may be nociceptive or chronic. Nociceptive pain usually is treated with anti-inflammatory or analgesic medications. Chronic pain typically is treated with medications that influence neurotransmitters (e.g., antidepressants, antiepileptic drugs), and treatment with opioids is reserved for patients with refractory chronic pain. There are no truly effective medicines for certain types of pain; thus, a better understanding of the existing ones [opioids: methadone and tramadol; antidepressants: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenalin reuptake inhibitors (SNRIs); anticonvulsants: gabapentin and pregabalin or the search for new or perhaps the oldest form of medicine (cannabis) is needed.
Chronic pain is of concern to health professionals, patients, society, and negatively impacts quality of life (QOL). The present epidemiologic study identified point prevalence of chronic pain in India, impact on individual's QOL, unveiling current pain treatment practices, and levels of satisfaction with treatment. This epidemiological telephonic survey consisted of two questionnaires: screening questionnaire that assessed prevalence of pain, its frequency during the past week, intensity during last episode, sites of pain, and main causes, and in-depth questionnaire that evaluated demography, frequency, duration, and intensity of pain; impact of pain on QOL; respondent's perception regarding the attitude of their family, friends, and doctors toward their pain. A total of 5004 respondents were included from eight cities across India. The overall point prevalence of chronic pain was 13%, and the mean intensity of pain on NRS scale was 6.93. Respondents with chronic moderate and chronic severe pain were 37% and 63%, respectively. Pain in knees (32%), legs (28%), and joints (22%) was most prevalent. Respondents with chronic pain were no longer able to exercise, sleep, maintain relationships with friends and family, and maintain an independent lifestyle. About 32% of patients lost =4 hours of work in the past 3 months. Majority (68%) of respondents were treated for pain with over the counter (OTC) drugs, and most were taking NSAIDs (95%). A significant population of India suffers from chronic pain, and their QOL is affected leading to disability. A proportion of respondents receiving pain treatment were taking non-prescription medications with a majority of respondents on NSAIDs. A very few were consulting pain management specialists.
Indeed, currently, various drugs are used to combat chronic pain, though without reaching the desired level of success for the patient. Side effects induced by current prescribed pain-relieving drugs limit their use by making it impossible to reach effective dose levels. So, there is a need for effective and safe treatment options for patients suffering from chronic pain. Accordingly, research continues into new or alternative methods for treating chronic pain in a manner that is long lasting, effective, with few side effects and good tolerability.
The present scenario of Pain Management:
Persistent pain is an escalating public health problem. Traditionally, clinicians have conceptualized chronic pain as a symptom of disease or injury. Treatment was focused at addressing the underlying cause with the expectation that the pain would then resolve. It was thought that the pain itself could not kill. There is mounting evidence that ‘pain can kill’. It has been demonstrated that uncontrolled pain compromises immune function, promotes tumour growth, and can compromise healing with an increase in morbidity and mortality following surgery. Constant pain at moderate to severe levels, especially when associated with depression, can increase suicide risk. Often, chronic pain may cause more suffering and disability than the injury or illness that caused it in the first place. Alarming figures recently emphasized during the Global Day Against Pain (cosponsored by the World Health Organization, the International Association for the Study of Pain and the European Foundation of International Association for the Study of Pain Chapters) stated that more than 50% of patients still suffer severe and intolerable pain after surgery and trauma.
Studies have demonstrated that 30% to 50% of patients suffer from chronic pain 1.5 to more than two years after such surgeries as open inguinal hernia repair or thoracotomy, and that acute pain after surgery predicts long-term pain two years later.
We now recognize that the treatment of pain must be given high priority in India. The American Board for Hospital Accreditation has adopted pain as ‘the fifth vital sign’. This has resulted in mandated routine assessment and treatment of pain in hospital settings in all populations across the life cycle. The Canadian Pain Society has successfully advocated for a similar approach in Canada. Beginning in 2005, the Canadian Council on Health Services Accreditation now includes pain assessment and management in the Achieving Improved Measurement Standards.
Exponential growth in pain research in the past three decades has increased our understanding of underlying mechanisms of the pathophysiology of chronic pain. It is now known that peripheral and central events related to disease or injury can trigger long-lasting changes in the spinal cord and brain that lead to continued generation of afferent information through pain conducting systems. By such means, pain can persist beyond the point where normal healing takes place.
The system involved in pain transmission has ascending and descending branches at multiple levels. Complex interactions take place with feedback loops and multiple neurotransmitters involved. As described by Patrick Wall, “sensory systems are not dedicated and hard wired but are held in a steady state by elaborate dynamic control mechanisms”. Under normal or physiological conditions, it is nociceptors, sensory neurons and their projections that transmit patterns of impulses that are ultimately interpreted by the brain as pain. Following tissue damage, a number of changes take place within pain conducting systems. These changes can be broadly categorized as due to sensitization, structural reorganization and disinhibition. Neurons in this system can be pushed outside of their normal working range. Thus, nociceptors that are normally only responsive to noxious stimuli can begin to fire in response to stimuli that do not normally cause pain (eg, light touch), and receptors that normally respond to light touch can now evoke activity in the nociceptive system. This abnormal pattern of transmission assists in the understanding of clinical symptoms and signs such as allodynia, hyperalgesia, anesthesia dolorosa, phantom limb and phantom visceral pain.

Pharmacological Approach:
In the past two decades, many preclinical works have been carried out assisting in our understanding of the underlying pathophysiological mechanisms that cause chronic pain. Chronic pain involves multiple pathophysiological mechanisms with peripheral and central components. This research in basic and clinical research has greatly expanded the options for analgesic pharmacotherapy. The major classes of medication used to assist in the management of chronic pain, including nonopioids analgesics such as NSAIDs and acetaminophen, opioids analgesics, antidepressants and anticonvulsants and an emerging area as the field of cannabinoids is. Importantly, chronic pain treatment encompasses multiple agents to take advantage of synergistic mechanism of actions, but drug-drug interactions have to be taken into account in order to avoid lack of efficacy or toxicity.
Lyceums Objective:
Looking at the present picture and modalities of chronic chronic pain management, we at Lyceum worked extensively for an innovative idea and looking for formulation, which will not only take care the present limitation of pharmacotherapy but also correct the root cause of chronic pain along with highest level of safety. Our research team, has come out with an evidence based suggestion that any chronic pain is being primarily caused by process called inflammation. Nauroinflammation is characterized by an excessive activation of cells like mast cells and glial cells which releases pro inflammatory signals. Activation of these glial cells and mast cell cause Neuroinflamation. It is found in research that these activation of these cells happens due to the decline of an amide called Palmitoylethanolamide (PEA),which is bodys natural analgesic, when there is deregulation or decline of this PEA, the glial cells and mast cells release pro inflammatory factors and cells gets activated and that cause inflammation or neuro inflammation which in turn sustain chronic pain. By giving this PEA from outside that improves body’s own deficit of PEA level and that inhibits the activation of cells.
On the other hand we found that human body’s 70-80% immunity system is situated in human gut. The human gut is consist of trillions of bacteria which control the gut mechanism. Gut –Brain axis is an established hypothesis today by many research. It is found that probiotics are live organisms that confer health benefit when administered sufficient amount. It is also found that Probiotics can arrest inflammatory pain by regulating pro inflammatory factors like cytokines and cox-2 expressions.
Research has also observed that much chronic pain gets relieved by use of probiotics after seven days of therapy. Probiotics also has the capacity to heals the damages caused by negative side effects of use of NSAIDs and Coxibs.
When we look at present treatment mode in chronic chronic pain across globe, it is mostly being treated with drugs like Gabapentine, Pregabaline (Anti-epileptic Drugs), and TCAs like Amitryptyline or nor tryptiline or SNRI drugs like Duloxetine (Antidepressants).
All these above mentioned drugs cause various side effects which affects seriously to patients quality of life (QOL) in long run. There are confirm studies that has shown that majority of analgesics OTC use causes end organ damage. One of the largest cause for renal disorder and cardiac complications are due to rampant use of analgesics without prescriptions.
In summary, several members of the commonly prescribed drugs of the classes of anti-depressants, gabapentinoids and opioids are only partial effective at best, when treatment of pain is considered, achieving only a partial reduction of pain: 25-40% pain reduction in 40-60% of patients. Moreover, application of these drugs in chronic pain treatment regimens is accompanied by numerous undesirable side effects, which limit, or even prohibit, their use.
Due to increasing insight in the complex patho-mechanisms underlying chronic and chronic pain, more and more combinations of analgesic compounds are prescribed to chronic pain patients. However, such combinations are based on combining two or more pharmaceutical compounds of the classes of anti-epileptics (for example pregabalin, gabapentin), anti-depressants (e.g. amitriptyline, duloxetine), nonsteroidal analgesic anti-inflammatory compounds (e.g. ibuprofen), and opioids (e.g. tramadol, oxycodin), all with their far from optimal safety profile. Due to the side effects, related for example to the inhibition of neuronal activity, most patients indeed heavily suffer when treated with such combinations (drowsiness, confusion, impairment of driving skills).
In a search for improved efficacy accompanied with less side effects and a better safety profile, attention was focused on therapy combining the aforementioned analgesics with a stimulatory co-factor compound having an acceptable safety profile and being able to enhance the pain relieving activity of the analgesic, potentially allowing for the application of a lower effective dose of the analgesic.
Compositions comprising anti-depressant agomelatine or a different member of agomelatine related compounds together with palmitoylethanolamide (PEA) as a co-factor, have been described in international patent application WO2013063263. In this application, a pharmaceutical composition for the prevention or treatment of chronic pain is disclosed, wherein the composition comprises an agomelatine-like naphthalene compound, such as agomelatine itself, together with PEA.
Patients suffering from chronic pain and previously treated with analgesic only, have subsequently been treated with the analgesics combined with PEA as a co- factor (J. Keppel Hesselink & T. Hekker, J. Pain Res. 2012:5 437-442).
An analgesic effect is seen in patients on gabapentin therapy now in combination with vitamins from the B-complex family as a co-factor for enhancing gabapentin efficacy (R. Medina-Santillan et al, Proc. West. Pharmacol. Soc. 47: 109-112 (2004)). Treatment of patients with gabapentin is associated with a high frequency of adverse effects.
Thus, although some improvements related to enhanced efficacy were observed, treatment of patients with analgesic drug compounds known for their high risk for side effects and unfavorable safety profile, is still continued.
Concluding, all of these aforementioned compositions comprising prescribed drugs with analgesic activity do not provide for a highly effective relieve of pain in chronic pain patients, including patients suffering from chronic pain, accompanied with good tolerability at an effective dose and a good safety profile. Thus, there exists a need for compositions which are effective in sufficiently relieving chronic pain, accompanied by an acceptable safety profile and with no or minimal side effects, which does not hamper reaching the aimed effective dose.
SUMMARY OF THE INVENTION
A first aspect of the present invention relates to a composition comprising palmitoylethanolamide and probiotic thereof.
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide. PEA is classified as a food for medical purposes, and as a dietary supplement Probiotics are live bacteria and yeasts that are good for humans, especially digestive system. Probiotics are called "good" or "helpful" bacteria because they help keep your gut healthy, also present in various food products.
Therefore, a preferred embodiment of the present invention relates to a composition comprising PEA and Probiotics or salts thereof, wherein the composition is a pharmaceutical composition or a nutraceutical composition.
Preferably, PEA and the one or more Probiotcs or salts thereof are the only pharmaceutically active ingredients in the composition according to the invention.
Both PEA and the Probiotics are in separate occasions applied as a co-factor in pharmaceutical compositions comprising an analgesic compound. The current invention now provides for pharmaceutical compositions containing or comprising both co-factors PEA and one or more Probiotics or salts thereof, together.
A second aspect of the present invention relates to a method for preparing the composition according to the present invention.
A third aspect of the present invention relates to a composition comprising PEA and one or more probiotics or salts thereof, for use as a medicament.
As per another aspect the method includes step wherein the palmitoylethanolamide and one or more probiotics or salts thereof are granulated into particles with an average particle size (D50) of between 10 and 1000 micron, preferably between 10 and 100 micron.
As per yet the method includes the step of adding the palmitoylethanolamide particles to an oil, preferably any vegetable oil or any fish oil comprising omega-3 fatty acids, preferably olive oil, such that a composition comprising palmitoylethanolamide in an oil matrix, in a volume ratio of 5%-20% (volume/volume), preferably 10% (volume/volume) palmitoylethanolamide / vegetable oil, preferably palmitoylethanolamide / olive oil, is obtained.
Compositions of the invention comprising PEA and one or more Probiotics or salts thereof, are particularly suitable for use in the alleviation of pain, especially the alleviation of chronic pain.
Therefore, a further aspect of the invention relates to a composition comprising PEA and one or more Probiotics or salts thereof, for use in pain alleviation, preferably chronic pain alleviation.
DEFINITIONS
The term "chronic pain" as used herein has its conventional meaning and has been defined by the International Association for the Study of Pain (IASP, 201 1) as 'Pain caused by a lesion or disease of the somatosensory nervous system'. The IASP further specifies: 'Chronic pain is a clinical description (and not a diagnosis) which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. The presence of symptoms or signs (e.g., touch-evoked pain) alone does not justify the use of the term chronic. Some disease entities, such as trigeminal neuralgia, are currently defined by their clinical presentation rather than by diagnostic testing. Other diagnoses such as post-herpetic neuralgia are normally based upon the history.
Chronic pain can be divided according to the IASP in two different pain states:
1. Central chronic pain, defined by the IASP as 'pain caused by a lesion or disease of the central somatosensory nervous system'; and
2. Peripheral chronic pain, defined by the IASP as 'pain caused by a lesion or disease of the peripheral somatosensory nervous system'.
The term "lesion" as used herein has its conventional meaning and refers to a situation when diagnostic investigations (e.g. imaging, neurophysiology, biopsies, lab tests) reveal an abnormality or when there was obvious trauma.
The term "Probiotic" as used herein has its conventional meaning and includes species of Lactobacillus (Fig. 1) and Bifidobacterium, yeast Saccharomyces cerevisiae and some E. coli and Bacillus species are also used as probiotics. Other probiotics include Lactic acid bacteria, including Lactobacillus species, Oligofructose, Inulin, Galacto-oligosaccharides, Lactulose, Breast milk oligosaccharides etc.
The term "somatosensory" as used herein has its conventional meaning and refers to information about the body per se including visceral organs, rather than information about the external world related to the body (e.g., vision, hearing, or olfaction).
The term "synergy" as used herein has its conventional meaning and refers to two or more compounds that interact in a way that enhance or magnify one or more effects of those compounds.
The term "optimal" in the context of "optimal tolerability" as used herein has its conventional meaning and refers to an amount of a compound administered to a subject, which effectively reliefs pain in the subject to a desired level, whereas side- effects stay below an acceptable threshold.
The term "dose-limiting side-effects" as used herein has its conventional meaning and refers to unacceptable side effects that would occur in a subject when a dose of a compound would be administered, high enough for effective pain relief in a subject to a desired level.
The term "classical analgesic drug" as used herein has its conventional meaning and refers to the types of analgesic drugs commonly prescribed to chronic pain patients up to the date of filing of the current application and up to the priority date.
The term "recommended daily allowances" ("RDA"), "Recommended daily intake" ("RDI") or "Recommended daily dose" ("RDD"), as used herein have their conventional meaning in the context of Probiotic uptake by a human.
The term "dosage" as used herein has its conventional meaning and refers to the giving of a single dose of a compound to a subject.
The term "daily dosage" as used herein has its conventional meaning and refers to the giving of a total dose of a compound to a subject per day, administered as a single dose, or as several doses throughout the day.
The term "unit of composition" as used herein shall mean a ready to use unit of composition in any form, either as food product, a drink, a food additive, a food supplement, or as a formulation, such as a tablet, a chewing tablet, a capsule or a liquid, a suspension, or a sublingual formulation or any formulation for mucosal absorbance of the active ingredients of said composition, such as a lozenge or a quick dissolving powder, or a transdermal or topical formulation wherein the composition isadministered in a cream, an ointment or a gel.
The term a "single compounded cream or gel" as used herein has its conventional meaning and refers to a cream or a gel comprising two or more active ingredients mixed together in a cream or gel, thereby providing a multi- compound compounded pharmaceutical or nutraceutical.
The term "fixed-dose combination" as used herein has its conventional meaning and refers to the bulk fixed-dose combination as well as single dosages of the fixed- dose combination, retrieved from this bulk.
The terms "pharmaceutically acceptable" and "nutraceutically acceptable" as used herein have their conventional meaning and refer to compounds, material, compositions and/or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
The term "salt" as used herein has its conventional meaning and includes the acid addition and base salts.
The term "treatment" as used herein has its conventional meaning and refers to curative, palliative and prophylactic treatment.
The term "only active ingredient" as used herein has its conventional meaning and means that a given compound is present as the sole pharmaceutically active ingredient and that no other compounds are present in an amount which renders a pharmaceutically relevant effect in the human or animal body.
BRIEF DESCRIPTION OF THE DRAWING
FIGURE 1: Electron micrograph of Lactobacillus salivarius adhering to Caco-2 cells in accordance with the present invention.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
Numerous attempts have been conducted to overcome the current drawbacks seen with classical analgesic drugs when applied in the treatment of pain, e.g. chronic pain, though with limited success. Chronic pain patients treated with a classical analgesic drug or with an analgesic drug from the classes of anti-depressants, gabapentinoids and opioids, commonly suffer from adverse effects, while efficacy of the treatment is in many occasions suboptimal at best.
Following one line of reasoning, in order to reach an effective dose of an analgesic drug, however accompanied with acceptable side effects, co-stimulatory factors were searched for. These co-stimulatory factors, or "co-factors", ideally enhance the efficacy of the analgesic drug in such a way that relief of pain is reached in the patient already at a drug dose at which dose-limiting side-effects do not yet hamper the treatment. Co-factors that were analyzed for their co-stimulatory activity towards analgesic drugs are, amongst others, palmitoylethanolamide (PEA) and, in separate research programs, probiotics providing synergy in efficacy. Although providing some improvement, an efficacious drug for the treatment of chronic pain, without side effects, has not been obtained until now.
In order to overcome the sub-optimal ratio between treatment efficacy and adverse effects due to the treatment, a novel composition omitting classical analgesic drugs is developed by the current inventors. It is surprisingly found that combining PEA and one or more probiotics as the only pharmaceutically active ingredients, previously separately known for their co- factor activity towards analgesic drugs, provided a composition according to the invention with improved analgesic efficacy already only by themselves, and thus when omitting the incorporation of a classical analgesic drug in the composition of the invention. Moreover, the inventors found that treatment of patients with such a composition comprising the two co-factors PEA and probiotics did not induce the side-effects commonly seen when patients are treated with a classical analgesic drug. In addition, surprisingly, such a composition comprising the two co-factors PEA and a probiotic results in a much faster onset of action, when administered to a patient.
Therefore, a first aspect of the present invention relates to a composition comprising PEA and one or more probiotics or salts thereof. According to the present invention, both PEA and one or more probiotics or salts thereof are now used as the pharmaceutically active ingredients and no longer as co-factors.
In one embodiment of the present invention, PEA and the one or more probiotics or salts thereof are the only pharmaceutically active ingredients present in the composition.
PEA belongs to a group of endogenous molecules (lipid autacoids) known as N- acylethanolamines. PEA has a beneficial pharmacological profile based on its antiinflammatory, analgesic and neuroprotective properties. PEA is described in patent application EP0550006 as a compound able to down regulate overactive mast cells, and international patent application WO2001010434 describes micronized pharmaceutical compositions containing PEA. A pharmaceutical formulation containing PEA, co-ultramicronized with antioxidants such as quercetin, resveratrol, polydatin, luteolin, tocopherol, and thioctic acid, is known based on patent application US20110171313: 'Composition containing ultra-micronized palmitoyl-ethanolamide.' The addition of such antioxidants, however, has never been clinically proven to bring synergies for efficacy, and most of these antioxidants, especially the antioxidants of herbal origin, do not have well known safety profiles.
The family of Probiotics are live microbes that can be formulated into many different types of product, including foods, drugs, and dietary supplements. Species of Lactobacillus (Fig. 1) and Bifidobacterium are most commonly used as probiotics, but the yeast Saccharomyces cerevisiae and some E. coli and Bacillus species are also used as probiotics. Lactic acid bacteria, including Lactobacillus species, which have been used for preservation of food by fermentation for thousands of years, can serve a dual function by acting as agents for food fermentation and, in addition, potentially imparting health benefits. Strictly speaking, however, the term “probiotic” should be reserved for live microbes that have been shown in controlled human studies to impart a health benefit. Fermentation of food provides characteristic taste profiles and lowers the pH, which prevents contamination by potential pathogens. Fermentation is globally applied in the preservation of a range of raw agricultural materials (cereals, roots, tubers, fruit and vegetables, milk, meat, fish etc.).
Preferably, the composition according to the present invention comprises PEA and one or more probiotics or a salts thereof, wherein the one or more probiotics is, or respectively, are chosen from undermentioned list including :
Examples of probiotic strains in products
Bifidobacteriumanimalis DN 173 010
Bifidobacteriumanimalis subsp. lactis Bb-12
Bifidobacterium breve Yakult
Bifidobacteriuminfantis 35624
Bifidobacteriumlactis HN019 (DR10)
Bifidobacteriumlongum BB536
Enterococcus LAB SF 68
Escherichia coli Nissle 1917
Lactobacillus acidophilus LA-5
Lactobacillus acidophilus NCFM
Lactobacillus casei DN-114 001
Lactobacillus casei CRL431
Lactobacillus casei F19
Lactobacillus caseiShirota
Lactobacillus johnsonii La1 (Lj1)
Lactococcuslactis L1A
Lactobacillus plantarum 299V
Lactobacillus reuteri DSM 17938
Lactobacillus rhamnosus ATCC 53013 (LGG)
Lactobacillus rhamnosus LB21
Lactobacillus salivarius UCC118
Saccharomyces cerevisiae (boulardii) lyo
Mixture:
Lactobacillus acidophilus CL1285 &L.casei Lbc80r
Lactobacillus rhamnosus GR-1 & L. reuteri RC14
VSL#3 (mixture of one strain of Streptococcus thermophilus, four Lactobacillus spp., & three Bifidobacterium spp. strains
Lactobacillus acidophilus CUL60 &Bifidobacteriumbifidum CUL 20
Lactobacillus helveticus R0052 & L. rhamnosus R0011
Bacillus clausii strains O/C, NR, SIN, and T

Typically, the compositions of the invention comprise one or more probiotics at a dose expressed as a percentage of the recommended daily allowances per unit. Preferably, the compositions of the invention comprise between 30% and 3000% of the recommended daily intake of Probiotic, and more preferably between 50%> and 1000%), most preferably between 20%> and 500%, per unit of composition.
In patients suffering from chronic idiopathic axonal neuropathy, dosages of 400 mg PEA, administered thrice per day, 600 mg PEA administered twice per day, and 2400 mg PEA, administered once a day, were shown to be effective and well tolerated by the patients. Therefore, suitable compositions comprising an effective dose of PEA according to the invention, comprise between 100 and 800 mg PEA, preferably between 300 mg and 600 mg PEA per unit of composition. Thus, an important aspect of the present invention is a composition comprising PEA and one or more probiotics or salts thereof, wherein the composition is a pharmaceutical composition or a nutraceutical composition. An equally important aspect of the invention is a composition comprising PEA and one or more probiotics or salts thereof, wherein the composition is a food product, a drink, a food additive, a food supplement or a food ingredient. It is now due to the current invention that it has been found that a composition comprising both PEA and one or more probiotics or salts thereof, is an efficacious combination drug, even when omitting a classical drug. Thus, for the first time, a combination drug of PEA and at least one Probiotic, or a salt thereof as the only pharmaceutically active ingredients, has now become available as a medicament.
In one embodiment the composition according to the present invention comprises between 100 and 800 mg PEA, preferably between 300 mg and 600 mg PEA, per unit of composition; optionally, containing said PEA in an oil matrix, in a volume ratio of 5%-20% (volume/volume), preferably 10% (volume/volume) PEA / olive oil.
The composition according to the present invention has preferably been formulated as a pharmaceutical composition or as a nutraceutical composition.
Furthermore, the composition according to the present invention has preferably been formulated as an oral formulation, such as a tablet, chewing tablet, a capsule, a liquid or a suspension. The composition according to the present invention may also be formulated as a sublingual formulation or any formulation suitable for mucosal absorbance of the active ingredients of said composition, such as a lozenge or a quick dissolving powder. Alternatively, the composition according to the present invention may be formulated as a transdermal or topical formulation, wherein the composition is administered as a cream, an ointment or a gel.
Preferably, the composition has been formulated as a single compounded cream or gel comprising a cream basis or gel basis selected from Cremorcetomacrogolis FNA or Lanette cream FNA.
In an alternative embodiment, the composition according to the present invention comprises one or more analgesic compounds, besides PEA and the one or more probiotics or salts thereof. Preferably, such composition comprises 1-20% by weight analgesic compounds. Preferred analgesic compounds are ketamine ((RS)-2-(2-Chlorophenyl)-2- (methylamino)cyclohexanone), gabapentin (l-(aminomethyl)cyclohexaneacetic acid), pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid), amitriptyline (3-(10,l l- Dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethylpropan-l-amine), duloxetine ((+)-(S)-N-Methyl-3-(naphthalen- 1 -yloxy)-3-(thiophen-2-yl)propan- 1 - amine), baclofen ((RS)-4-Amino-3-(4-chlorophenyl)butanoic acid) or a combination of any of these analgesic compounds.
A second aspect of the present invention relates to a method for preparing the compositions as has been described above.
Preferably, the PEA and one or more probiotics or salts thereof have been granulated into particles with an average particle size (D50) of between 10 and 1000 micron (micrometer), preferably between 10 and 100 micron (micrometer). In the art, several methods are readily available to the skilled person to prepare particles with the above mentioned particle size.
The method according to the present invention, preferably comprises the step of adding the PEA particles to an oil, preferably any vegetable oil or any fish oil comprising omega-3 fatty acids, preferably olive oil, such that a composition comprising PEA in an oil matrix, in a volume ratio of 5%-20% (volume/volume), preferably 10% (volume/volume) PEA / vegetable oil or PEA / fish oil, containing omega-3 fatty acids, preferably PEA / olive oil, is obtained, wherein the oil is with or without enrichment with omega-3 fatty acids.
A further aspect of the invention relates to a composition comprising PEA and one or more probiotics or salts thereof, for use as a medicament, preferably for use in pain alleviation.
In this regard, it is noted that preferably, no other pharmaceutically active compounds are present in the composition.
It is now due to the achievements of the present inventors that an efficacious and safe treatment of patients suffering from pain, without undesired side effects, has become available. Thus, the composition according to the invention is efficiently used in the treatment of pain.
Hence, the composition according to the present invention is preferably used in pain alleviation. Since in particular pain alleviation in chronic patients is hampered by limited treatment options with reasonable efficacy and acceptable side effects, the current invention particularly provides a composition for use in chronic pain alleviation.
One of the advantages of a composition according to the invention is effective treatment of pain, especially chronic pain, without side-effects commonly hampering the use of classical analgesic drugs. One other advantage of a composition according to this invention over a fixed combination between PEA and co-factors such as antioxidants, is the long-standing safety profile of one or more probiotics or salts thereof.
Since chronic pain is often the result of an underlying disease or health problem, the compositions according to the invention are suitable for relieving the chronic pain in patients suffering from such diseases or health problems. Examples of diseases and health problems accompanied by chronic pain that is effectively treated by the compositions according to the invention, are an axonal neuropathy such as diabetic neuropathy, a demyelinating neuropathy, chemotherapy inducedneuropathy, HIV neuropathy, post herpetic neuropathy or postoperative pain.
The compositions according to the invention exhibit synergies between PEA and one or more vitamins belonging to the B vitamin family, providing analgesic efficacy in the absence of troublesome CNS related side effects or other tolerability issues. Various embodiments of the invention disclose a number of effective, tolerable and safe combinations of PEA and probiotics, based on the endogenous molecule PEA and one or more probiotics family.
The present innovative formulation of Palmitoylethanolamide (PEA) 600mg along with Probiotic 30 Billion is a revolutionary approach to treat Chronic pain without having any serious side effects. Both PEA and Probiotic Combination tablet corrects the root cause of chronic chronic pain. It is Lyceums own intellectual property right to combine these two elements in a tablet form for the first time in the world. We are confident on the basis of these two elements efficacy and safety recorded that combination of these two would exert synergistic efficacy in treating chronic chronic pain at the root cause with no serious side effects.
It is also evident that probiotic and PEA both contribute a greater benefit to patient’s immunity system also. This enhanced immunity in turn helps patients to prevent chronic pain associated with co morbid conditions.
Preferably, the composition for use according to the present invention has been formulated as an oral formulation such as a tablet, a chewing tablet, a capsule or a liquid, a suspension, or a sublingual formulation or any formulation for mucosal absorbance of the active ingredients of said composition, such as a lozenge or a quick dissolving powder, or a transdermal or topical formulation wherein the composition is administered in a cream, an ointment or a gel.
In a particular embodiment of the invention, the composition is provided as a tablet, wherein the tablet comprises PEA 600 mg and Probiotic 30 Billion.
The present invention will be illustrated further by means of the following non- limiting examples.
Example 1
A female patient born in 1975, suffering from diabetes treated with metformin (?,?-Dimethylimidodicarbonimidicdiamide) and insulin, presented with severe proximal asymmetrical chronic pains in left upper leg, pain score 10 on the Numeric Rating Scale (NRS). Patient was unable to walk.
Treatment with amitriptyline induced drowsiness. The patient was treated with PEA 600 mg and probiotic 20 – 30 billion three times per day and the pain score decreased to 8. Pain scores decreased 2 more points and overall improvement in quality of life was 60%>. She could again walk, ride the bicycle and take up social contacts.
Example 2
A female patient, born in 1969 and suffering from diabetes type II, treated with metformin. Since 2 years he had increasing complaints of burning pain, itching and tingling of feet and legs. Therapy with PEA (1200 mg/day) was started for 1 month. This decreased the symptoms from a score of 8 to 7 on the NRS. Increasing PEA to 2400 mg/day improved scores to 5. Adding probiotics, at a dose of 30 million RDI / day, resulted in complete vanishing of all chronic positive symptoms: pain, tingling and itching.
Although the foregoing description of the present invention has been shown and described with reference to particular embodiments and applications thereof, it has been presented for purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the particular embodiments and applications disclosed. It will be apparent to those having ordinary skill in the art that a number of changes, modifications, variations, or alterations to the invention as described herein may be made, none of which depart from the spirit or scope of the present invention. The particular embodiments and applications were chosen and described to provide the best illustration of the principles of the invention and its practical application to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such changes, modifications, variations, and alteration should therefore be seen as being within the scope of the present invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly, legally, and equitably entitled.