METHOD OF TREATING NEUROPATHIC PAIN WITH A SYNERGISTIC PHARMACEUTICAL COMPOSITION COMPRISING PALMITOYLETHANOLAMIDE AND L-ACETYLCARNITINE

Abstract

A method of controlling the inflammatory and/or neuropatic pain of various origins by administering a pharmaceutical composition containing palmitoylethanolamide, to a human or animal patient. In particular, the present invention relates to the administration of a pharmaceutical composition comprising palmitoylethanoiamide (PEA) and L-acetylcarnitine (LAC), optionally in addition with an antioxidant compound, such as a polyphenol, alpha-lipoic acid, or L-acetylcysteine to a patient.

Claims

1. A method of treating neuropathic pain, comprising administering to a patient a synergistic pharmaceutical daily dosage form comprising: palmitoylethanolamide (PEA), and L-acetylcarnitine (LAC) in a finely pulverized form; and the pharmaceutical daily dosage form is for oral or buccal use, and palmitoylethanolamide (PEA) and L-acetylcarnitine (LAC) are contained in the daily dosage form in doses in which the palmitoylethanolamide (PEA) and L-acetylcarnitine (LAC) are inactive when used singularly.

2. The method of claim 1, wherein the synergistic pharmaceutical daily dosage form further comprises one or more compounds with an antioxidant activity.

3. The method of claim 2, wherein the one or more compounds with the antioxidant activity is selected from the group consisting of polyphenols, alpha-lipoic acid, and L-acetylcysteine.

4. The method of claim 3, wherein the one or more compounds with the antioxidant activity, is or comprises a polyphenol selected from the group consisting of polydatin, resveratrol, luteolin, quercetin, and rutin.

5. The method of claim 2, wherein the synergistic pharmaceutical daily dosage form further comprises: an active dosage of palmitoylethanolamide in an amount of about 5 mg/kg; an active dosage of L-acetylcarnitine in an amount of about 10 mg/kg; and an active dosage of one or more compounds with an antioxidant activity in an amount of about 0.5 mg/kg such that the synergistic pharmaceutical daily dosage form is a dosage tablet, a capsule, or liquid form of a pharmaceutical composition having palmitoylethanolamide in weight percentages ranging between 20 and 35%, L-acetylcarnitine in weight percentages ranging between 20 and 55%, and the one or more compounds with the antioxidant activity in total weight percentages ranging from about 20% or less.

6. The method of claim 2, wherein the one or more compounds with the antioxidant activity is co-micronized with the palmitoylethanolamide.

7. The method of claim 1, wherein the neuropathic pain results from a disease selected from: both acute and chronic painful peripheral neuropathies of dysmetabolic, compressive, traumatic, toxic, infectious, iatrogenic origin; pain associated with vertebral column and spinal cord diseases of traumatic, dysmetabolic, degenerative, infectious, iatrogenic origin; pain associated with small fibre diseases of infectious, traumatic, dysmetabolic, iatrogenic origin; acute and/or chronic pain associated with diseases in the pelvic area, such as Endometriosis, Interstitial Cystitis, Recurrent Cystitis, Irritable Bowel Syndrome, Prostatites, Vaginites, Vulvovaginites, primary and secondary Dysmenorrhoea, Vulvodynias, Vestibulodynias; pain associated with traumatic and degenerative joint diseases; and pain associated with arthritic diseases.

8. The method of claim 1, wherein the pharmaceutical composition is for human or veterinary use.

9. The method of claim 1, wherein the palmitoylethanolamide is in ultra-micronized form (PEA-um) with a particle size ranging between 0.8 and 6.0 microns.

10. A method of treating neuropathic pain, comprising administering to a patient a dosage tablet, a capsule, or a liquid form of a synergistic pharmaceutical composition, wherein each dosage tablet, capsule, or liquid form of the pharmaceutical composition comprises an active dosage of palmitoylethanolamide in an amount not to exceed 5 mg/kg; an active dosage of L-acetylcarnitine in an amount not to exceed 10 mg/kg; and an active dosage of one or more compounds with an antioxidant activity in an amount not to exceed 0.5 mg/kg such that each dosage tablet, capsule, or liquid form of the synergistic pharmaceutical composition has palmitoylethanolamide in weight percentages ranging between 20 and 35%, L-acetylcarnitine in weight percentages between 20 and 55%, and the one or more compounds with the antioxidant activity in total weight percentages not to exceed 20%, wherein the combination of palmitoylethanolamide, L-acetylcarnitine and the one or more compounds with the antioxidant activity does not exceed a weight percent of 100% and a combined amount of palmitoylethanolamide (PEA) and L-acetylcarnitine (LAC) does not exceed about 1 g per each dosage tablet, capsule, or liquid form of the pharmaceutical composition.

11. The method of claim 10, wherein said palmitoylethanolamide is in non-micronized form with a particle size ranging between 50.0 and 100.0 μm, in micronized form (PEA-m) with a particle size ranging between 2.0 and 10.0 μm, or in ultra-micronized form (PEA-um) with a particle size ranging between 0.8 and 6.0 μm, or in a mixture of such forms.

12. The method of claim 11, wherein said L-acetylcarnitine is in a finely pulverized form.

13. The method of claim 10, wherein the one or more compounds with the antioxidant activity is selected from the group consisting of polyphenols, alpha-lipoic acid, and L-acetylcysteine.

14. The method of claim 10, wherein the one or more compounds with the antioxidant activity, is or comprises a polyphenol selected from the group consisting of polydatin, resveratrol, luteolin, quercetin, and rutin.

15. The method of claim 11, wherein the one or more compounds with the antioxidant activity is co-micronized with palmitoylethanolamide.

16. The method of claim 10, wherein the pharmaceutical composition is for human or veterinary use.

17. The method of claim 10, wherein the neuropathic pain results from a disease selected from: both acute and chronic painful peripheral neuropathies of dysmetabolic, compressive, traumatic, toxic, infectious, iatrogenic origin; pain associated with vertebral column and spinal cord diseases of traumatic, dysmetabolic, degenerative, infectious, iatrogenic origin; pain associated with small fibre diseases of infectious, traumatic, dysmetabolic, iatrogenic origin; acute and/or chronic pain associated with diseases in the pelvic area, such as Endometriosis, Interstitial Cystitis, Recurrent Cystitis, Irritable Bowel Syndrome, Prostatites, Vaginites, Vulvovaginites, primary and secondary Dysmenorrhoea, Vulvodynias, Vestibulodynias; pain associated with traumatic and degenerative joint diseases; and pain associated with arthritic diseases.

18. A method of treating neuropathic pain comprising administering to a patient a daily dosage tablet for oral or buccal use, the tablet comprising: palmitoylethanolamide in a weight percentage ranging between 20 and 35% of a total weight of the tablet; L-acetylcarnitine in a weight percentage ranging between 20 and 55% of the total weight of the tablet; and a compound with antioxidant activity in a weight percentage ranging between 20% or less of the total weight of the tablet; wherein palmitoylethanolamide (PEA) and L-acetylcarnitine (LAC) are contained in the daily dosage from in doses in which the palmitoylethanolamide (PEA) and L-acetylcarnitine (LAC) are inactive when used singularly.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 shows a Table illustrating the data regarding a mechanical allodynia test following a sciatic nerve ligation in mouse.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The invention relates to the use of a pharmaceutical composition comprising palmitoylethanolamide (PEA), alternatively in non-micronized form (non-micronized PEA), or in micronized form (PEA-m), or in ultra-micronized form (PEA-um), and L-acetylcarnitine in finely pulverized form.

[0015] Palmitoylethanolamide can be synthetized as described in Example no. 25 of U.S. Pat. No. 5,990,170.

[0016] Non-micronized PEA can be obtained by finely grounding the product from the synthesis; product with a particle size ranging between 50.0 and 100.0 μm can be obtained.

[0017] PEA-m. can be obtained as described in the patent U.S. Pat. No. 6,548,550 B1 and it has a particle size ranging between 2.0 and 10.0 μm.

[0018] PEA-um can be obtained as described in the patent Application PCT issued with no. WO 2011/027373 A1 and it has a particle size ranging between 0.8 and 6.0 μm.

[0019] More indications on said forms of PEA are present in the above-mentioned patent publications, the content of which relating to the characterization of the product is incorporated herein by reference.

[0020] Pharmaceutical grade L-acetylcarnitine is a commercially available product.

[0021] The pharmaceutical composition of the invention comprises palmitoylethanolamide in weight percentages ranging between 20 and 35%, L-acetylcarnitine in weight percentages between 20 and 55%, and one or more compounds with antioxidant activity total weight percentages ranging between 0 and 20%.

[0022] The compound with antioxidant activity is preferably selected from the group comprising polyphenols, alpha-lipoic acid (or thioctic acid), and the L-acetylcysteine.

[0023] When the antioxidant compound is or comprises a polyphenol, it is preferably selected polydatin, resveratrol, luteolin, quercetin and rutin.

[0024] The molecules having an antioxidative activity may also be co-micronized with palmitoylethanolamide according to the teachings described in U.S. Pat. No. 6,548,550 E1.

[0025] The antioxidative compounds are commercially available products.

[0026] The inventive composition can further contain pharmaceutically acceptable excipients and additives, selected as a function of the desired pharmaceutical form.

[0027] The diseases which can be treated with the composition of the present invention comprise:

[0028] Both acute and chronic painful peripheral neuropathies of dysmetabolic, compressive, traumatic, toxic, infectious, iatrogenic origin;

[0029] Pain associated with vertebral column and spinal cord diseases of traumatic, dysmetabolic, degenerative, infectious, iatrogenic origin;

[0030] Pain associated with small fiber diseases of infectious, traumatic, dysmetabolic, iatrogenic origin;

[0031] Acute and/or chronic pain associated with diseases in the pelvic area, such as Endometriosis, Interstitial Cystitis, Recurrent Cystitis, Irritable Bowel Syndrome, Prostatites, Vaginites, Vulvovaginites, primary and secondary Dysmenorrhoea, Vulvodynias, Vestibulodynias;

[0032] Pain associated with traumatic and degenerative joint diseases; and

[0033] Pain associated with arthritic diseases.

[0034] The pharmaceutical composition according to the present invention can be formulated for an oral, a buccal, or a rectal administration.

[0035] For the oral administration, the pharmaceutical compositions can be, for example, in the form of tablets or capsules prepared in a conventional manner with pharmaceutically acceptable excipients, such as binders (e.g., pre-gelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); filling agents (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrating agents (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 in the form of lyophilized products to be reconstituted, before their use, with water or other suitable vehicles. Such liquid preparations can be prepared by conventional methods with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or edible hydrogenated fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated plant-based oils); and preservatives (e.g., methyl- or propyl-p-hydroxybenzoates or sorbic acid). The preparation may also suitably contain flavors, colorants, and sweeteners.

[0036] The preparations for oral administration can be suitably formulated to allow the controlled release of the active ingredient.

[0037] For the buccal administration, the compositions can be in the form of tablets or lozenges formulated in a conventional manner, suitable for an absorption by the buccal mucosae. Typical buccal formulations are the tablets for sub-lingual administration.

[0038] According to the present invention, the compounds can also be formulated in rectal compositions, such as suppositories or retention enema, for example containing the base components of typical suppositories, such as cocoa butter or other glycerides.

[0039] In addition to the compositions described above, the compounds can also be formulated as depot preparations. Such long-acting formulations can be administered by an implant (for example, subcutaneously, transdermally, or intramuscularly) or by intramuscular injection. Thus, for example, the compounds, according to the present invention, can be formulated with suitable polymeric or hydrophobic materials (e.g., in the form of an emulsion in a suitable oil) or ionic exchange resins, or as minimally soluble derivatives, for example, as a minimally soluble salt.

[0040] According to the present invention the dose of the compounds proposed for the administration to a human being (with a body weight of about 70 Kg) ranges from 10 mg to 1 g, and preferably from 100 mg to 500 mg of the active ingredients per dose unit. The dose unit can be administered, for example, 1 to 4 times/day. The dose will depend on the selected administration route. It shall be considered that it could be necessary to continuously vary the dosage as a function of the age and weight of the patient, and also of the severity of the clinical condition to be treated. Finally, the precise dose and the administration route will be at discretion of the attending physician or veterinary.

[0041] The formulations described above can be prepared according to conventional methods, such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA.

Experimental Section

Experimental Model of Neuropathic Pain

[0042] The experiments were carried out using male mice the C57BL/6J strain with a weight ranging between 25 and 30 g; 10 animals per group were used. The animals were anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and subjected to a surgical procedure of sciatic nerve ligation capable of inducing neuropathic pain in accordance with the method described by Bennet and Xie (1988, Pain; 33:87-107). Sham animals were used as a control.

[0043] The products were administered p.o. with a tube, suspended in 2% Carboxymethyl Cellulose.

[0044] The mechanical allodynia was measured by using the Dynamic Plantar Aesthesiometer equipment of the Company Ugo Basile—Varese, Italy.

[0045] Data are set forth in Table of FIG. 1. The values in the table are referred to the weight, expressed in grams, to which the animal object of the experiment, subjected thereto, withdraws its paw when feeling pain. It is pointed out from the data set forth in the table that LAC alone or PEA-um alone cause a significant alleviation of the neuropathic pain when used at doses, of 100 mg/kg and 10 mg/kg, respectively, while, at a dose of 10 mg/kg for LAC alone and of 5 mg/kg for PEA-um alone, the two substances do not cause a significant activity.

[0046] Vice versa, PEA-um at a dose from 5 mg/kg in association with LAC at a dose of 10 mg/kg, causes a very high decrease of the neuropathic pain after 8 days of treatment.

[0047] Finally, the association of PEA (5 mg/kg) co-micronized with polydatin (0.5 mg/kg) and in association with LAC (10 mg/kg) cause an almost complete remission of neuropathic pain after 8 days of treatment.

[0048] Therefore, data show a markedly synergic effect of the combination of PEA, in particular PEA-um, and LAC, above all when in association with an antioxidant.

[0049] The invention will be now further described by some formulation examples, given by way of exemplary, non-limiting examples of the protection scope of the invention as defined by the appended claims.

Formulation Examples

Example A

Tablets for Oral Use

[0050] Each tablet contains:

[0051] 150.0 mg PEA-um

[0052] 300.0 mg LAC

[0053] 80.0 mg Microcrystalline Cellulose

[0054] 45.0 mg Croscarmeilose Sodium

[0055] 10.0 mg Polyvinylpyrrolidone

[0056] 4.0 mg Magnesium Stearate

Example B

Tablets for Oral Use

[0057] Each tablet contains:

[0058] 200.0 mg PEA-m

[0059] 300.0 mg LAC

[0060] 90.0 mg Microcrystalline Cellulose

[0061] 65.0 mg Croscarmellose Sodium

[0062] 15.0 mg Polyvinylpyrrolidone

[0063] 4.0 mg Magnesium Stearate

Example C

Tablets for Oral Use

[0064] Each tablet contains:

[0065] 200.0 mg PEA-m (co-micronized with Polydatin)

[0066] 20.0 mg Polydatin (co-micronized with PEA-m)

[0067] 300.0 mg LAC

[0068] 90.0 mg Microcrystalline Cellulose

[0069] 65.0 mg Croscarmellose Sodium

[0070] 15.0 mg Polyvinylpyrrolidone

[0071] 4.0 mg Magnesium Stearate

Example D

Tablets for Oral Use

[0072] Each tablet contains:

[0073] 200.0 mg PEA-m (co-micronized with Quercetin)

[0074] 25.0 mg Quercetin (co-micronized with PEA-m)

[0075] 300.0 mg LAC

[0076] 90.0 mg Microcrystalline Cellulose

[0077] mg 65.0 Croscarmellose Sodium

[0078] 15.0 mg Polyvinylpyrrolidone

[0079] 4.0 mg Magnesium Stearate

Example E

Tablets for Oral Use

[0080] Each tablet contains:

[0081] 200.0 mg PEA-um

[0082] 50.0 mg Acetylcysteine

[0083] 300.0 mg LAC

[0084] 90.0 mg Microcrystalline Cellulose

[0085] 65.0 mg Croscarmellose sodium

[0086] 15.0 mg Polyvinylpyrrolidone

[0087] 4.0 mg Magnesium Stearate

Example F

Tablets for Oral Use

[0088] Each tablet contains:

[0089] 150.0 mg PEA-m

[0090] 100.0 mg α-Lipoic Acid

[0091] 200.0 mg LAC

[0092] 100.0 mg Microcrystalline Cellulose

[0093] 80.0 mg Croscarmellose sodium

[0094] 10.0 mg Polyvinylpyrrolidone

[0095] 15.0 mg Magnesium. Stearate

Example G

Microgranules for Sublingual Use

[0096] Each sachet of microgranules contains:

[0097] 300.0 mg PEA-um

[0098] 100.0 mg Acetylcysteine

[0099] 300.0 mg LAC

[0100] 380.0 mg Sorbitol powder

[0101] 15.0 mg Saccharose Palmitate

[0102] 5.0 mg Polysorbate 80 (plant-based).