NL2017559B1 - Method for preparing pulverized palmitoylethanolamide particles, particles obtainable by the method, and apharmaceutical or neutraceutical composition comprising saidparticles - Google Patents

Abstract

The present invention relates to a method for preparing a pharmaceutical and/or neutraceutical composition for human and/or veterinary use, comprising a therapeutically effective amount of palmitoylethanolamide (PEA) in pulverized form. The present invention also relates to a method for producing PEA particles. The present invention also relates to the PEA obtainable with the method, and to PEA for use in a method for treating a disorder characterized by inflammation and/or pain.

Description

METHOD FOR PREPARING PULVERIZED PALMITOYLETHANOLAMIDE PARTICLES, PARTICLES OBTAINABLE BY THE METHOD, AND A PHARMACEUTICAL OR NEUTRACEUTICAL COMPOSITION COMPRISING SAID PARTICLES

FIELD OF THE INVENTION

The present invention relates to a method for preparing a pharmaceutical and / or neutraceutical composition for human and / or veterinary use, including a therapeutically effective amount or palmitoylethanolamide (PEA) in pulverized form. The present invention also relates to a method for producing PEA particles. The present invention also relates to the PEA available with the method, and to PEA for use in a method for treating a disorder characterized by inflammation and / or pain.

BACKGROUND OF THE INVENTION

Palmitoylethanolamide (PEA; also referred to as palmidrol or N- (2-hydroxyethyl) hexadecanamide or N-palmitoylethanolamide) is an endogenous lipid. This lipid is currently pharmaceutically formulated in various ways such as tablets, sachets, capsules and suspensions. Based on known characteristics, PEA bears the promise to be beneficial in the treatment or prevention of a wide range of diseases and disorders characterized by inflammation and / or pain. However, said beneficial use of PEA in treatment or prevention regimens is severely hampered by encountered drawbacks related to the physical appearance of PEA. That is to say, the specific lipophilic and crystalline nature of PEA, and PEA's low melting temperature, hamper the preparation or a formulation containing a sufficient amount, i.e. a therapeutically effective amount, or pulverized PEA particles. Currently, such pulverized PEA particles are produced by sub-optimal and costly, laborious and sophisticated pulverization techniques. Moreover, subsequent processing or pulverized "sticky" PEA compositions such as those including for example (other) lipid or fat, is often also cumbersome. Regularly, during and after subsequent pharmaceutical processes involving pulverized particles, such as tableting or coating, the extent of pulverization is largely reversed due to fatty agglomeration or the pulverized particles or the active pharmaceutical ingredient. These limitations currently also occur when pulverized PEA particles are further processed. After pulverization procedures, tableting or a composition comprising pulverized PEA particles and excipients does indeed result in partial or complete loss or said initially pulverized PEA particles. Also coated or pulverized PEA particles with sorbitol results in a similar partial or complete loss or said pulverized PEA particles.

United States patent application 20110171313 discloses that it is hard to subject PEA to pulverization methods, due to the tendency of the fatty compound PEA to form aggregates. Aggregation of PEA hampers the production of fine PEA particles, whereas such fine PEA particles are aimed at enhancement or surface-volume ratio and for enhancement or absorption or PEA in vivo once administered to the animal or human body.

These drawbacks encountered during PEA formulation lead to various alternative formulation methods, as described in international patent application W02001010434 and in international patent application WO2011027373. In these patent applications, methods are disclosed for formulating PEA in pulverized formulations (W02001010434) and in ultra-pulverized formulations (WO 2011027373).

Although the said patent applications define specific pulverization techniques to enable the industrial production of PEA (such as PEA provided in tablets, capsules or sachets), the procedures described do still not prevent occurrence of waxy agglomerates or PEA in final formulations on the market, as has been addressed in Dutch patent NL2009474.

The waxy agglomerates or PEA occur during and after final steps or pharmaceutical processes. Due to the agglomeration of PEA, part of the pulverized PEA particles is lost during these pharmaceutical processes, leading to a reduced pulverization degree or the final formulations. The reduction of the degree of pulverization or PEA due to pharmaceutical processing is a well-known problem in the art, and is observed for example during the process of compressing, which is necessary during tableting (See for example: S. Potharaju, PhD thesis University Tennessee, USA, 2012). Thus, agglomerization of PEA particles negatively influences the pulverization degree of final (marketed) PEA formulations. Indeed, pulverized PEA particles with 99.9% of all PEA particles having a diameter smaller than 10 microns, lost more than 50% of its pulverization state after compressing the PEA particles into tablets in the presence of excipients.

In the international patent application W001 / 10434 pulverization methods are described that are based on specific techniques such as the air jet spray technique. Pulverization using air jet spray does not conserve the pulverized state of the particles once pulverized particles are subsequently processed, e.g., tableted.

Moreover, techniques such as the air jet spray technique have to be modified and extended with additional techniques to compensate for reduction of the initially higher achieved degree of pulverization, once the pulverized PEA is in a final formulation, such as in compressed tablets.

Thus, summarizing the current art, currently no adequate method is available for conserving initially pulverized (PEA) particles in their pulverized state during required subsequent (pharmaceutical) processes. (Re-) Agglomerization of pulverized PEA particles severely hampers the exploitation of the full (therapeutic) potential or PEA in its use in methods or treatment or its use in methods or prevention of various diseases.

SUMMARY OF THE INVENTION

It is the aim of the current invention to provide a solution to the problem of (re-) agglomerization of initially pulverized PEA, for the purpose of providing the ability to beneficially use the therapeutic potential or pharmaceutical or nutraceutical formulations including pulverized PEA.

This solution to the problem of agglomerization or initially pulverized PEA is provided by the method for producing PEA particles according to the invention. A first aspect of the invention is therefore a method for producing PEA particles comprising the steps of: a. providing pulverized PEA powder; b. simultaneously subjecting said pulverized PEA powder to milling and sieving.

For further processing of pulverized PEA particles, it is sometimes beneficial to have PEA particles free or excipients. These PEA particles free or excipients are provided by a method according to the invention. A second aspect of the invention is therefore a method for producing PEA particles, whether the particles are free of excipients, said method including the following steps: (i) providing PEA flakes; (i) pulverizing PEA flakes in the absence of pharmaceutical excipients; and iii (iii) forced sieving the pulverized PEA flakes on a metal sieve with mesh size of 10-14, preferably 12 providing PEA particles with a particle size distribution in which: - at least 50% of the particles have a diameter smaller than 25 pm, and - at least 25% of the particles have a diameter smaller than 10 pm, and - at least 10% of the particles have a diameter smaller than 5 pm.

Applying the method according to the invention provides PEA particles suitable for further pharmaceutical processing. A third aspect of the invention are therefore PEA particles characterized in that: - at least 50% of the particles have a diameter smaller than 25 pm; - at least 25% of the particles have a diameter smaller than 10 µm; and - at least 10% of the particles have a diameter smaller than 5 µm. A fourth aspect of the invention is thus a pharmaceutical or nutraceutical composition comprising PEA particles according to the invention or including PEA particles provided by any of the methods according to the invention.

Now that the methods of the invention provide for pulverized PEA particles according to the invention that remain stable, that is to say, that keep their pulverized state upon pharmaceutical processing, the current invention also provides for a pharmaceutical composition comprising the pulverized PEA particles according to the invention, for use in a method for the treatment of diseases and disorders characterized by inflammation and / or pain. A fifth aspect of the invention is therefore a pharmaceutical or nutraceutical composition comprising PEA particles according to the invention for use in the treatment of a disorder selected from an immune disorder, a chronic inflammatory disorder, a neuroinflammatory disorder or a chronic pain disorder.

DEFINITIONS

The term 'pulverization' used as used has its normal scientific meaning and refers to the process of reducing the size of particles, such as flakes and for the sake of this invention we define 'pulverization' as size reduction to at least 50% of all particles smaller than 25 microns.

The term 'pulverization-degree', or the equal term 'degree of pulverization', as used have their normal scientific meaning and are used here to indicate the amount of particles below 25 microns, as measured with a Malvern mastersizer and after wet dispersion and in-line sonication for 5 minutes. If at least 50% of all particles are narrower than 25 microns, the pulverization degree is (more than) sufficient for clinically meaningful effects.

The term 'pharmaceutical composition' used used has normal scientific meaning and encompasses all compositions meant to cure or treat or prevent a disorder or disease, and refers to a composition including one or more pharmaceutically active constituents which are suitable for administration to mammals, including humans.

The term "neutraceutics" as used here has its normal scientific meaning and encompasses the term "supplements" as well as "food supplements", and "nutritional compositions" as well as "food for medical purposes".

The term "forced sieving" used used has normal scientific meaning and describes the process of forcing particles through a (metal) sieve by mechanical force. In the context of the invention, the term "forced sieving" for example refers to the process of forcing PEA particles after mechanical milling through a metal sieve by mechanical force.

The current art, as outlined above, does not disclose any method of pulverization or PEA involving classical pulverization techniques, which results in commercially viable PEA formulations. Furthermore, the current art also does not present alternative PEA pulverization methods. Thus, in the relevant technical field of pulverization, there is a felt need for a technique that would solve the problem or a lost degree or initially achieved pulverization or PEA. The current invention, now, surprisingly led to an improved pulverized formulation with PEA. Indeed, according to the current invention, the problem of losing an initially achieved pulverization degree with PEA upon applying pharmaceutical procedures such as tableting to pulverized PEA has been solved by the method of the invention. The PEA particles produced according to the invention, are particularly suitable for use in pharmaceutical processes resulting in a pharmaceutical formulation. It is an important benefit of the current invention that pharmaceutical processes are applied to pulverized PEA particles, without reducing or losing the initially introduced pulverization degree or PEA in the obtained formulation.

Surprisingly, a method for producing stable pulverized particles was found. Applying said stable pulverized particles in a formulation process results in a stable formulation with regard to the initial degree of applied pulverized particles. Thus, application of the stable pulverized particles in (pharmaceutical) processes is without any loss of the pulverized state. This beneficial effect of a stable pulverization degree is based on a combination of mechanical milling and forced sieving for example by applying a metal sieve. When this combination of mechanical milling and forced sieving is applied to PEA, it results in a pulverized PEA powder including an amount of approximately 50% PEA particles with a particle size smaller than 25 microns (measured with a Malvern Mastersizer 2000 after 5 minutes of sonication and expressed as the D50, ie the Distribution Percentile of the median particle size). In addition, beneficially, the combination of mechanical milling and forced sieving preventing formation or waxy agglomerates being formed in a formulation and preventing reduction of the pulverization degree or PEA in the formulation. The combination of the milling method and the sieving method according to the invention provides a formulation comprising pulverized PEA, that maintains its therapeutic activity. Examples of therapeutic effects or administering (pharmaceutical) formulations including pulverized PEA to patients are provided in the Examples section.

The inventors of the present invention provide a method for producing pulverized PEA powder based on a combination of mechanical milling and forced sieving that was hitherto not exploited for the purpose of providing stable pulverized PEA particles. A first aspect of the invention is thus a method for producing PEA particles comprising the steps of: a. providing pulverized PEA powder; b. simultaneously subjecting said pulverized PEA powder to milling and sieving.

In a preferred embodiment of the present invention the degree of PEA pulverization of the marketed and final formulation including PEA after subjection of the pulverized PEA particles to pharmaceutical processes, not reduced compared to the degree of PEA pulverization obtained by applying a pulverization method according to the invention.

The sieving procedure has been adapted from an originally passive sieving technique, into an active forced sieving technique. In the forced sieving technique, the particles with a diameter larger than 1.5 mm (mesh size sieve 12, according to US Standard Mesh) remain on the sieve as sediments and are forced through the sieve by rubbing techniques. All mesh sizes are given according to the US Standard Mesh. Due to the specific physical characteristics of the soft, waxy PEA crystals, the rubbing surprisingly leads to further fracturing of the waxy PEA crystals and further all PEA particles pass through the sieve in the pulverized form.

This pulverization method of the invention is based on the unique combination of size reduction using a Freewitt hammer mill, in which the PEA particles are reduced in size and in which PEA crystals are fractured, together and subsequently combined and followed by forcefully rubbing the crushed PEA crystals through a 12 mesh metal sieve. In sieves or smaller sizes (greater than mesh 12) the rubbing technique results in the (partial) blockage of the sieve by the waxy agglomerates or PEA. Therefore, applying sieves with a mesh size or 14 or smaller is beneficial.

Thus, an embodiment of the invention is a method according to the invention, according to the milling is hammer milling. A second embodiment of the invention is a method according to the invention, the sieving is forced sieving. A third embodiment of the invention is a method according to the invention, according to the pulverized PEA powder is sieved using a metal sieve with a mesh size of 10-14, preferably 12.

In a comparative experiment the inventors revealed that the particle size distribution measured directly after applying a conventional PEA particle production method known in the art, as measured using a Malvern Mastersizer 2000, was non-optimal, due to a large degree of agglomeration of the PEA . When the method for producing PEA particles according to the invention was compared, the D50 (median particle size) or PEA was highly improved, showing a superior particle size distribution. 12. Applying a sieve with a bigger grid, thus with mesh size less than 12, in the method of the invention results in the PEA crystals being less pulverized, and more course PEA particles and PEA agglomerates pass through the sieve. The presence of course PEA particles and PEA agglomerates hampers for example filling or capsules with a constant and controllable amount of the active ingredient PEA. Preferably, therefore, in the method for producing PEA particles according to the invention, mesh size is preferably not less than 10, more preferably larger than 10. More preferably, the mesh size of the (metal) sieve is about 10-14. Thus, it is part of the invention that the combined steps of mechanical milling and forced sieving encompass milling with the hammer mill are defined or a comparable orthodox milling device, followed by forceful sieving in a metal sieve or mesh 10-14, preferably mesh 12 .

Applying the methods for producing PEA particle shows that it is possible to prepare a pulverized powder with optimal rheological properties and without forming aerosols during capsule or sachet filling procedures, at an industrial size with batches reaching from several kilograms up to more than a thousand kilograms. When applying a pulverization method known in the art, aerosols develop during pulverization which severely fill hampers or capsules or sachets with the pulverized PEA particles. Certain additional technical and costly measures are required in order to be able to fill the capsules in a robust and constant fashion. For example, certain excipients have been added to the PEA, as well as safety measures have been implemented (e.g. prevention of exposure to aerosols in the PEA preparation). Furthermore, for compounds like PEA, a pharmaceutical or nutraceutical composition free of excipients is preferred. It is now due to the present invention that a method of the invention for producing PEA particles provides for excipient free PEA particles suitable for application in a pharmaceutical composition according to the invention.

The inventors found a method for preparing fine pulverized particles or PEA, including the following steps: (i) providing PEA flakes; (ii) pulverizing the PEA flakes into PEA particles according to the present invention, using a combination of a mechanical mill and forced sieving via a metal sieve, in the absence of pharmaceutical excipients, in such a way that the PEA particles have obtained a particle size distribution, in which: - at least 50% of the particles have a diameter smaller than 25 microns, and - at least 25% of the particles have a diameter smaller than 10 microns, and - at least 10% of the particles have a diameter smaller than 5 µm. A second aspect of the invention is thus a method for producing PEA particles, whether the particles are free of excipients, said method including the following steps: (i) providing PEA flakes; (i) pulverizing PEA flakes in the absence of pharmaceutical excipients; and iii (iii) forced sieving the pulverized PEA flakes on a metal sieve with mesh size of 10-14, preferably 12 providing PEA particles with a particle size distribution in which: - at least 50% of the particles have a diameter smaller than 25 pm, and - at least 25% of the particles have a diameter smaller than 10 pm, and - at least 10% of the particles have a diameter smaller than 5 pm.

It has been determined by the inventors that the methods for producing PEA particles according to the invention are conveniently suitable for application at room temperature. Therefore, pulverization or PEA according to the methods of the invention is preferably performed at room temperature. Of course, other temperatures below the melting point of the PEA (approximately 59.5 ° C) are also applicable. A fourth embodiment of the invention is thus a method according to the invention, in which pulverization of the PEA flakes is by milling at room temperature.

In a fifth embodiment of the invention, the milling in the method according to the invention is oscillating and rotating sieve milling or the milling is hammer milling.

The inventors also found a method for preparing PEA particles, in which at least 25% of all particles have a size of 10 microns or less, by: i) providing PEA flakes; ii) pulverizing the PEA flakes according to this invention, using a combination of milling and forced sieving, into PEA particles in such a way that the particles have a particle size distribution, in which: - at least 50% of the particles have a diameter narrower than 25 µm .; - at least 25% of the particles have a diameter smaller than 10 µm .; - at least 10% of the particles have a diameter smaller than 5 µm. A third aspect of the invention are thus PEA particles characterized in that: - at least 50% of the particles have a diameter smaller than 25 pm; - at least 25% of the particles have a diameter smaller than 10 µm; and - at least 10% of the particles have a diameter smaller than 5 µm.

Thus, it is part of the present invention that the PEA particles have a size distribution in which: - at least 50% of the particles have a diameter smaller than 25 pm, and - at least 25% of the particles have a diameter smaller than 10 microns, and - at least 10% of the particles have a diameter smaller than 5 µm.

The particle size distribution has been assessed with a Malvern Mastersizer 2000 in combination with the Large Sample Presentation Unit for measuring in water. The configuration for measuring in liquids has a measuring range from 0.02 pm up to 2000 pm. The used optical model is Lorentz-Mie, taking into account the optical characteristics of the particles, in accordance with ISO 13320-1: 2009 standard. The applied optical model has a Particle Refractive Index [n] / Absorption Index 1.52 / 0.1. A milled and sieved PEA preparation is measured directly after subjecting a method for producing PEA particles, and after applying 5 minutes of ultrasonic to the PEA particles. Each result is the average of three dependent measurements and the complete procedure is investigated as an independent duplicate.

By applying a method for producing PEA particles according to the invention, one is thus able to obtain PEA particles having a particle size distribution, in which - at least 50% of the particles have a diameter smaller than 25 pm, and - at least 25 % of the particles have a diameter of less than 10 pm, and - at least 10% of the particles have a diameter of less than 5 pm.

Now that PEA particles with such a size distribution are easily available with a method of the invention, has a positive effect on production costs. Importantly, PEA particles and compositions according to the invention are now available, which are also suitable for filling capsules or sachets according to the invention.

The inventors found that pharmaceutical or nutraceutical compositions comprising PEA particles obtained by a method for preparing PEA particles according to the invention, thus said method including the steps of milling and sieving or PEA particles, are particularly suitable for use in a method of treatment or for use in a method for prevention of various (neuro-) inflammatory diseases and disorders.

Thus, a fourth aspect of the invention is a pharmaceutical or nutraceutical composition comprising PEA particles according to the invention or including PEA particles provided by any of the methods according to the invention.

The inventors provided the surprising insight that follows a method for preparing PEA particles according to the invention, it is now for the first time possible to prepare a fine PEA powder with a clinically relevant degree of pulverization. 'Clinically relevant' in the context of the invention has been understood as PEA particles that are provided in a pharmaceutical or nutraceutical formulation in a way suitable for the PEA being able to exert a therapeutically relevant activity once administered to a patient for treatment or prophylactic purposes. PEA is a compound devoid or dose-limiting side-effect (See: Esposito E, Cuzzocrea S. Mini Rev. Med. Chem. 2013 Feb; 13 (2): 237-55). Doses up to 100 mg / kg body weight are administerable to humans without inflicting side effects. Thus, a formulation comprising PEA with a sufficient degree of pulverization according to the invention, is particularly useful for application in therapeutic treatment regimes, being it curing treatments for prophylactic treatments, as for example illustrated by some of the examples given in the Examples section, below .

Furthermore, according to the invention, it is thus preferred to present the (pharmaceutical) composition of the invention in a capsule or in a sachet for sublingual use.

Thus, a sixth embodiment of the invention is a pharmaceutical or nutraceutical composition according to the invention, in which the composition is presented in a capsule or in a sachet.

Preferably, the pharmaceutical or nutraceutical composition according to the present invention is for use in the treatment or in the prevention of disorders in humans or animals, based on chronic (neuro-) inflammation or in chronic pain. In addition, and equally preferred, the pharmaceutical or nutraceutical composition according to the present invention is for use in a method of treatment or in a method of prevention of disorders in humans or animals, based on chronic (neuro-) inflammation or on chronic pain . The pharmaceutical composition according to the present invention is also suitably used to counteract or prevent neurotoxicity induced by neurotoxic drugs during chemotherapy, examples of such neurotoxic drugs being cisplatin and taxanes.

Thus, a fifth aspect of the invention is a pharmaceutical or nutraceutical composition according to the invention for use in the treatment of a disorder selected from an immune disorder, a chronic inflammatory disorder, a neuroinflammatory disorder or a chronic pain disorder. A seventh embodiment of the invention is said pharmaceutical or nutraceutical composition for use in the treatment or a disorder according to the invention, where the treatment is prophylactic.

An eighth embodiment of the invention is a pharmaceutical or nutraceutical composition for use in the treatment or a disorder according to the invention, the treatment is in mammals, preferably humans.

In a series of illustrative experiments, in which PEA production batches were scaled up to generate 1 kg or PEA powder, using a cross beater mill and a hammer mill (TA 0202; Freewitt), finely grained PEA was produced, which was forced through a 12 mesh metal sieve yielding the pulverized PEA product according to the invention, without leading to waxy (PEA) agglomerates and without resulting in dysfunctional sieves due to obstructions, for example by such agglomerates. In a separate experiment, the grained PES was forced through a US Sieve No. 14 sieve, providing the pulverized PEA product according to the invention.

Thus, the invention provides PEA particles obtained by applying the methods according to the invention, and as said before, the pulverized PEA particles are particularly suitable for use in a pharmaceutical or neutraceutical composition.

Now, further insight into the invention will be provided and the invention will be further illustrated and described more elaborately by means of the non-limiting examples, outlined below.

EXAMPLES

Example 1 A vegetable capsule or a gelatin-based capsule are filled with 300, 400, 500 or 600 mg or pulverized PEA according to the invention.

Example 2 A sachet for sublingual use, filled with 400 or 800 mg or pulverized PEA according to the invention is provided.

Example 3 A Food mix for horses and cattle is provided according to the invention containing 2 grams of PEA per unit dose or food mix. 10 grams or lupine feed or any other acceptable fodder, which lupine feed or fodder contains approximately 2 grams or pulverized PEA according to the invention.

Example 4

Containers with feed for dogs and cats are provided, said containers containing 150 mg or pulverized PEA according to the invention per serving, mixed with freeze-dried meat powder.

The following examples provide clinical examples with powdered, pulverized PEA according to the invention in 400 mg capsules.

Example 5

Small fiber neuropathy and pain. PEA is formulated according to the present invention for use in a method for treating small fiber neuropathic pain.

Pulverized PEA according to the invention is provided as capsules containing 400 mg PEA per capsule. For topical use, pulverized PEA according to the invention is provided as cream including 15 mg PEA particles per milliliter.

Small fiber neuropathy manifests in a variety of different diseases and often results in symptoms of burning pain, shooting pain, allodynia, and hyperesthesia. Patients suffering from idiopathic small fiber neuropathies were reported to respond to prednisone, presumably because these neuropathies were caused by inflammatory mechanisms. Prednisone, however, gives rise to multiple side effects and cannot be administered during longer periods or time without cumulating side-effect problems. A 67-year-old woman suffering from neuropathic pain resulting from chronic small fiber neuropathy. Patient suffered for several years from severe burning and stinging pains in both feet up to the knee, which pain proved to be unresponsive to pregabalin, amitriptyline and physiotherapy. Taking PEA (3 times per day 1 capsule with 400 mg PEA; administered orally) for 4 weeks reduced her burning pain after 4 weeks with approximately 40% compared to base line pain scores. 40% pain reduction is considered as a clinically significant effect.

The effect of combination therapy when combining the orally administered PEA as described above for this Example 5, with topically administered cream including PEA particles, was analyzed. Adding topically administered PEA to the treatment regimen of this Example 5 reported in the pain being equally further reduced, from approximately 40% to approximately 50%.

Example 6

Severe hay fever and asthma.

Therapeutic utility or pulverized PEA according to the invention, formulated according to the present invention, in hay fever and asthma.

Hay fever and allergic asthma are known to be provoked by mast cell activation. As PEA down-regulated over-active mast cells, hay fever is a good paradigm to explore the therapeutic effects of the said PEA formulation according to the invention.

This case description concerns a 57-year old woman who has had chronic severe hay fever and chronic asthma since many decades. During the hay-fever season she has to stay inside and none of the prescribed anti-asthma and anti-allergic medication lead to sufficient symptom relieve. Even nasal filters did not result in clinical sufficient effects for this patient, although these nasal filters are meant to prevent inhalation or pollen and reduce symptoms or hay fever, as well as reduce the symptoms or outdoor and indoor nasal allergies.

The patient started on a daily dose of 1200 mg PEA (3 times one capsule with 400 mg PEA) one month before the pollen season started. For the first time since the allergic responses to pollen, the patient experienced a nearly symptom free hay fever season and could walk outside and even sit under a tree while the grass was cut. PEA was prescribed according to the formulation according to the present invention, to tasks 3 times a day. The dose form was a capsule with 400 mg PEA.

During the pollen season she lowered the dose to 800 mg PA daily, but this induced mild to moderate shortness of breath and hay fever attacks within 4 days of the start or taking the reduced dose. The patient then increased the daily dose again to 1200 mg PEA per day and after a week was again symptom free.

Example 7

Diabetic neuropathic pain. A 60 year old man suffered from type 1 diabetes. The patient uses insulin. The patient also suffered from rheumatoid arthritis, for which prednisone was given during exacerbations. Pregabalin did not relief pain to a satisfactory level, and pain scores were still around 9 (on a scale from 1-10). Capsules with 400 mg PEA according to the invention were administered 3 times a day, and pain was reduced within several weeks to around 7. The daily PEA dose was increased to 2400 mg / daily. Pain was reduced to a score of 6. However, during the holiday patient forgot to take PEA, and pain intensified. After the holiday, the patient reported that the increase in pain was around 50%. A daily dose or 2400 mg PEA was re-installed and pain was reduced to a pain score or around 4.

Claims (11)

A method for producing palmitoylethanolamide (PEA) particles comprising the steps of: a. Providing pulverized PEA powder; b. simultaneously subjecting the pulverized PEA powder to milling and sieving, wherein the pulverized PEA powder is sieved using a metal sieve with a mesh size of 10-14, preferably 12, and wherein pulverizing the PEA provided in step a. resulted in a decrease in the size of the powder particles until at least 50% of all particles are smaller than 25 microns. The method of claim 1, wherein the milling is hammer milling. The method of claim 1 or 2, wherein the sieving is forced sieving. A method for producing PEA particles, wherein the particles are from excipients, the method comprising the steps of: i) providing PEA flakes; ii) pulverizing the PEA flakes in the absence of pharmaceutical excipients; and then iii) forced sieving of the pulverized PEA flakes on a metal sieve with a mesh size of 10-14, preferably of 12, thereby providing PEA particles with a particle size distribution wherein: - at least 50% of the particles have a diameter of less than 25 micrometer, and - at least 25% of the particles have a diameter of less than 10 micrometers, and - at least 10% of the particles have a diameter of less than 5 micrometers, in which the pulverization of the PEA in step ii) resulted in the decrease from the size of the flakes to at least 50% of all particles smaller than 25 microns. The method of claim 4, wherein the PEA flakes are pulverized by milling at room temperature. The method of claim 5, wherein the milling is oscillating and rotating screen milling or hammer milling. A pharmaceutical or nutraceutical composition comprising PEA particles provided by the method of any one of claims 1-6. A pharmaceutical or nutraceutical composition according to claim 7, wherein the composition is presented in a capsule or in a sachet. A pharmaceutical or nutraceutical composition according to claim 7 or 8 for use in the treatment of a disorder selected from an immune disorder, a chronic inflammatory disorder, a neuro-inflammatory disorder or a chronic pain disorder. A pharmaceutical or nutraceutical composition for use in the treatment of a condition according to claim 9, wherein the treatment is prophylactic. A pharmaceutical or nutraceutical composition for use in the treatment of a condition according to claim 9 or 10, wherein it is the treatment of animals, preferably of humans.