EA046312B1 - PHARMACEUTICAL COMBINATION INCLUDING TRAZODONE FOR THE TREATMENT OF NEUROPATHIC PAIN - Google Patents

Description

Field of invention

The present invention relates to a pharmaceutical composition consisting of a combination of trazodone and gabapentin or pregabalin or mirogabalin, with improved effect in the treatment of neuropathic pain, in particular pain resulting from diabetic neuropathy.

State of the art

Physiological pain is an important defense mechanism designed to warn of danger from potentially harmful environmental stimuli. Neuropathic pain is defined as pain initiated or caused by a primary injury or dysfunction of the nervous system. Neuropathic pain is often debilitating and causes disability and poor quality of life. It also leads to economic and social harm.

Analgesic medications used in the treatment of neuropathic pain include nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, opiate analgesics, and anticonvulsants [Woolf CJ, Mannion RJ, Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353: 1959-1964].

However, neuropathic pain is notoriously difficult to treat with currently available medications. Consequently, the development of new drugs has always been one of the main objectives of the pharmaceutical industry.

Diabetic neuropathy is one of the most common late symptomatic complications in patients with type 1 and type 2 diabetes. At initial diagnosis, 7.5% of patients already suffer from painful diabetic peripheral neuropathy and about 45-50% will suffer from this complication after 25 years.

Diabetic neuropathic pain is commonly described as tingling, burning, stinging, stabbing, or even an electric shock sensation. It is usually considered moderate to severe and often worsens at night, causing sleep disturbances. The pain can be persistent and accompanied by cutaneous allodynia, which can significantly impact patients' quality of life, affecting their ability to carry out daily activities, and have a negative impact on their mood. Pain may also cause withdrawal from recreational and social activities and may be associated with depression.

Although traditionally the first step in the treatment of diabetic neuropathic pain is to improve and optimize glycemic control, additional medications are usually needed to treat pain.

Current treatments include antidepressants such as tricyclics and serotonin-norepinephrine reuptake inhibitors, γ-aminobutyric acid (GABA) analogues such as pregabalin, gabapentin and mirogabalin, opioids and topical medications.

Gabapentin is a well-known anticonvulsant currently approved for the treatment of epilepsy and neuropathic pain. Gabapentin is effective in the management of neuropathic pain, and in the treatment of diabetic neuropathy, gabapentin has found the best balance between safety and effectiveness.

Gabapentin is now widely recommended as a first-line treatment for peripheral diabetic neuropathy by several guidelines, such as the American Academy of Neurology, National Institute for Health and Care Excellence, European Federation of Neurological Societies and Neuropathic Pain Special Interest Group of the International Association for the Study. of Pain.

Unfortunately, there is no consensus on a single drug that is more effective, and monotherapy rarely provides adequate pain relief. The clinical management of diabetic neuropathic pain continues to pose a therapeutic challenge and response to existing treatments is often inadequate. A wide range of drugs, used alone or in combination, have demonstrated significant reductions in neuropathic pain compared with placebo in randomized controlled trials, but pain relief remains inadequate for most patients.

Trazodone is a well-known multireceptor antidepressant and has been proposed as an alternative treatment to approved pain medications as one of the potentially effective off-label drugs. Low doses of trazodone have already been used in the treatment of neuropathic pain.

Khurana observed good effect of trazodone in relieving pain and numbness in 6 diabetic patients suffering from peripheral diabetic neuropathy when administered at 100 mg/day in divided doses (Khurana RC., Treatment of painful diabetic neuropathy with trazodone, JAMA vol. 250, no 11, 1983).

Subsequently, 31 adult diabetic patients with painful distal symmetrical polyneuropathy were treated with oral doses of trazodone ranging from 50 to 100 mg/day. After 2 weeks of treatment, 61.3% of patients had symptomatic relief and 22.6% had complete relief. After completion of the study, all patients who received symptomatic relief continued

- 1 046312 take trazodone without reducing results or developing side effects. The authors concluded that trazodone is likely a good alternative to tricyclic antidepressants based on its efficacy, safety profile, and rapid onset of action (Wilson RC., The use of low dose Trazodone in the treatment of painful diabetic neuropathy, J. Am. Podiatr. Med. Assoc 1999 Sep;89(9):468-71).

EP1663398B1 describes the combination of an alpha-2-delta ligand such as gabapentin and pregabalin with a selective norepinephrine reuptake inhibitor such as (S,S)-reboxetine for the treatment of neuropathic pain.

WO2013/002584 describes a composition for pain relief that includes two or more components selected from (a) a 5-HT2 receptor antagonist, (b) a P2X receptor antagonist, (c) any of a glycine receptor agonist, a glycine transporter antagonist, a receptor agonist gamma-aminobutyric acid (GABA), and GABA transporter antagonist 1 (GABA1).

WO2017/067870 describes a pharmaceutical composition comprising a synergistic combination of trazodone in such an amount as to provide a dose equal to or less than 1 mg/kg, and gabapentin in such an amount as to provide a dose equal to or less than 15 mg/kg, with a mass a ratio of trazodone to gabapentin of 1:15 to 1:5, for use in the treatment of chronic pain, particularly inflammatory pain induced in mice by acetic acid administration and neuropathic pain induced in rats by sciatic nerve ligation.

A review of the use of gabapentin in the treatment of neuropathic pain was published by Kukkar A. et al, Implications and mechanism of action of gabapentin in neuropathic pain, Arch. Pharm. Fig. (2013) 36:237251. A superior effect was observed for the combination of gabapentin and venlafaxine in a model of neuropathic pain and co-administration of gabapentin with donepezil and/or duloxetine against neuropathic pain induced by spinal nerve ligation and in a nerve transection model.

Trazodone and the combination of trazodone and pregabalin were studied in the 12- and 24-week treatment of fibromyalgia, as described in Morillas-Arques et al., Trazodone for the treatment of fibromyalgia: an open label, 12-week study, BMC Musculoskeletal Disorders 2010, 11:204 and Calandre et al., Trazodone plus pregabalin combination in the treatment of fibromyalgia: a two-phase, 24-week, open-label uncontrolled study, BMC Musculoskeletal Disorders 2011, 12:95.

The combination of trazodone with fentanyl and paracetamol was studied in a mouse model of visceral pain, demonstrating a strong synergistic antinociceptive effect, as described in FernandezDuenas et al., Fentanyl-trazodone-paracetamol triple drug combination: Multimodal analgesia in a mouse model of visceral pain, Pharmacology, Biochemistry and Behavior 98 (2011) 331-336.

The essence of the invention

The Applicant is faced with the problem of providing a pharmaceutical composition for the treatment of neuropathic pain, in particular pain resulting from diabetic neuropathy, with better activity than compositions known in the art.

In light of the results known in the art, the applicant hypothesized that the combination of trazodone and gabapentin could be used for the treatment of diabetic neuropathic pain and neuropathic pain in general.

The Applicant has surprisingly discovered that trazodone can be used in combination with gabapentin in very relatively low amounts, with a weight ratio between trazodone and gabapentin between 1:40 and 1:100, preferably less than 1:40 and up to 1:100.

In particular, the applicant has unexpectedly discovered that a combination of trazodone and gabapentin with a weight ratio between 1:40 and 1:100, preferably less than 1:40 and up to 1:100, has an improving effect in reducing pain from diabetic neuropathy in patients treated in for nine weeks with increasing doses of gabapentin, to which was added co-administration of trazodone.

The effect found by the applicant is even more surprising, since combinations with a weight ratio between trazodone and gabapentin greater than 1:40 (eg, 1:30) showed almost no improvement in reducing diabetic neuropathic pain.

The applicant also found an unexpected positive effect in reducing the risk of depressive or anxiety disorders in the same patients receiving the above-mentioned combination of gabapentin and trazodone.

In light of the results obtained with gabapentin, the applicant believes that a similar effect could also be obtained with pregabalin or mirogabalin, active ingredients similar to gabapentin with the same therapeutic effect and mechanism of action, but greater effectiveness, when used in association with trazodone with the same mass ratio.

Therefore, in a first aspect, the present invention relates to a pharmaceutical composition that includes (a) a combination of (i) a first active ingredient selected from the group consisting of trazodone and a salt thereof, and (ii) a second active ingredient selected from the group consisting of gabapentin, pregabalin, mirogabalin, and their salts, and their prodrugs, and (b) according to

- 2 046312 at least one pharmaceutically acceptable excipient for use in the treatment of pain resulting from diabetic neuropathy, wherein said pharmaceutical composition comprises a weight ratio of said first active ingredient to said second active ingredient, expressed as a weight ratio of trazodone:gabapentin or pregabalin or mirogabalin , between 1:40 and 1:100, preferably less than 1:40 and up to 1:100.

In a second aspect, the present invention relates to a method for treating pain resulting from diabetic neuropathy in a patient in need thereof, which comprises administering an effective amount of a pharmaceutical composition that includes (a) a combination of (i) a first active ingredient selected from the group, consisting of trazodone and a salt thereof, and (ii) a second active ingredient selected from the group consisting of gabapentin, pregabalin, mirogabalin, their salt and prodrugs and (b) at least one pharmaceutically acceptable excipient, wherein said pharmaceutical composition includes a mass a ratio of said first active ingredient to said second active ingredient, expressed as a weight ratio of trazodone:gabapentin or pregabalin or mirogabalin, between 1:40 and 1:100, preferably less than 1:40 and up to 1:100.

Brief description of drawings

In fig. 1-3 graphically show the results of the clinical study described in Example 1.

In fig. 1 and 2, the mean deviations from the value of pain experienced at the beginning of treatment by patients receiving treatment are presented on the y-axis, while the x-axis shows the weeks of treatment.

In fig. 3, the y-axis shows the percentage of patients with a positive risk of depression or anxiety in the general population (control) and in the three treatment groups (group 1-3), at the beginning and at the end of treatment.

Detailed Description of the Invention

The expression expressed as a weight ratio of trazodone:gabapentin or pregabalin or mirogabalin, as used in the present description and claims, means that the ratio between the first active ingredient and the second active ingredient is always expressed between the equivalent weight of trazodone, as such, contained in the pharmaceutical composition ( even if present as a salt) and an equivalent mass of gabapentin or pregabalin or mirogabalin as such contained in the pharmaceutical composition (even if present as a salt or prodrug).

The term 'trazodone', as used in the present specification and claims, is the active ingredient 2-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-[1,2,4]triazole[4 ,3-a]pyridin3(2H)-one having the following structural formula (I):

(I)

The term 'gabapentin' as used in the present specification and claims is the active ingredient 2-[1-(aminomethyl)cyclohexyl]acetic acid having the following structural formula (II):

(II)

The term 'pregabalin', as used in the present description and claims, is the active ingredient ^)-3-(aminomethyl)-5-methylhexanoic acid having the following structural formula (III):

The term 'mirogabaline' as used in

OH (III) in the present description and claims is the active ingredient (^^^)-6-(aminomethyl)-3-ethylbicycle(3.2.0)ept-3-ene-6acetic acid having the following structural formula (IV) :

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The pharmaceutical composition of the present invention contains (i) an amount of a first active ingredient selected from the group consisting of trazodone and a salt thereof, and (ii) an amount of a second active ingredient selected from the group consisting of gabapentin, pregabalin, mirogabalin, a salt thereof and their prodrug, so as to provide a weight ratio of said first active ingredient to said second active ingredient, expressed as a weight ratio of trazodone:gabapentin or pregabalin or mirogabalin, between 1:40 and 1:100, preferably less than 1:40 and up to 1 :100, more preferably between 1:50 and 1:90, and even more preferably between 1:60 and 1:80.

In accordance with a preferred aspect of the present invention, any value within the above-mentioned weight ratio of trazodone:gabapentin or pregabalin or mirogabalin may be used, such as, for example, 1:41, 1:42, 1:43, 1:44, 1: 45, 1:46, 1:47, 1:48, 1:49, 1:50, 1:51,1:52,

1:53, 1:54, 1:55, 1:56, 1:57, 1:58, 1:59, 1:60, 1:61, 1:62, 1:63, 1:64, 1: 65, 1:66, 1:67, 1:68, 1:69, 1:70, 1:71,1:72,

1:73, 1:74, 1:75, 1:76, 1:77, 1:78, 1:79, 1:80, 1:81, 1:82, 1:83, 1:84, 1: 85, 1:86, 1:87, 1:88, 1:89, 1:90, 1:91,1:92,

1:93, 1:94, 1:95, 1:96, 1:97, 1:98, 1:99, and 1:100.

The amount of the first and second active ingredients contained in the pharmaceutical composition of the present invention may be varied according to the dosage required to achieve the desired effect, provided that the weight ratio of said first active ingredient to said second active ingredient, expressed as the weight ratio of trazodone : gabapentin or pregabalin or mirogabalin remains between 1:40 and 1:100, preferably less than 1:40 and up to 1:100, more preferably between 1:50 and 1:90, and even more preferably between 1:60 and 1:80.

Advantageously, the pharmaceutical composition of the present invention includes an amount of the first active ingredient equivalent to an amount of trazodone between 2.50 and 1.00 mg, preferably 2.00 to 1.11 mg, and more preferably 1.67 to 1.25 mg, for an amount of the second active ingredient equivalent to 100 mg of gabapentin or pregabalin.

Preferably, the pharmaceutical composition of the present invention includes an amount of the first active ingredient equivalent to an amount of trazodone between 0.250 and 0.100 mg, preferably between 0.200 and 0.111 mg, and more preferably between 0.167 and 0.125 mg, for an amount of the second active ingredient equivalent to 10 mg of mirogabalin.

Gabapentin compositions known in the art typically include 100 mg to 800 mg gabapentin, such as 100 mg, 300 mg, 400 mg, 600 mg or 800 mg gabapentin. According to the invention, trazodone can be added to such compositions to provide a weight ratio, expressed as a trazodone:gabapentin weight ratio, between 1:40 and 1:100, preferably less than 1:40 and up to 1:100, more preferably between 1 :50 and 1:90, and even more preferably between 1:60 and 1:80 for combined use in the treatment of diabetic neuropathic pain.

According to a first embodiment of the invention, the pharmaceutical composition of the present invention therefore comprises an amount of the second active ingredient equivalent to 100 mg of gabapentin and an amount of the first active ingredient equivalent to an amount of trazodone between 2.50 and 1.00 mg, preferably from 2.00 to 1.11 mg, and more preferably from 1.67 to 1.25 mg.

According to a second embodiment of the invention, the pharmaceutical composition of the present invention therefore includes an amount of the second active ingredient equivalent to 300 mg of gabapentin and an amount of the first active ingredient equivalent to an amount of trazodone between 7.50 and 3.00 mg, preferably from 6.00 to 3.33 mg, and more preferably from 5.00 to 3.75 mg.

According to a third embodiment of the invention, the pharmaceutical composition of the present invention therefore includes an amount of the second active ingredient equivalent to 400 mg of gabapentin and an amount of the first active ingredient equivalent to an amount of trazodone between 10.00 and 4.00 mg, preferably 8.00 -4.44 mg, and more preferably 6.67 to 5.00 mg.

Other embodiments of the pharmaceutical composition of the present invention may be contemplated within the scope of the invention as long as the trazodone:gabapentin weight ratio is maintained.

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Pregabalin compositions known in the art typically include 25 mg to 300 mg pregabalin, such as 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg and 300 mg pregabalin. According to the invention, trazodone can be added to such compositions to provide a weight ratio, expressed as a trazodone:pregabalin weight ratio, between 1:40 and 1:100, preferably less than 1:40 and up to 1:100, more preferably between 1 :50 and 1:90, and even more preferably between 1:60 and 1:80 for combined use in the treatment of diabetic neuropathic pain.

According to the first embodiment of the invention, the pharmaceutical composition of the present invention therefore includes an amount of the second active ingredient equivalent to 50 mg of pregabalin and an amount of the first active ingredient equivalent to an amount of trazodone from 1.25 to 0.50 mg, preferably from 1.00 to 0.56 mg, and more preferably from 0.83 to 0.63 mg.

According to a second embodiment of the invention, the pharmaceutical composition of the present invention therefore includes an amount of the second active ingredient equivalent to 100 mg of pregabalin and an amount of the first active ingredient equivalent to an amount of trazodone from 2.50 to 1.00 mg, preferably from 2. 00 to 1.11 mg, and more preferably 1.67 to 1.25 mg.

According to a third embodiment of the invention, the pharmaceutical composition of the present invention therefore includes an amount of the second active ingredient equivalent to 300 mg of pregabalin and an amount of the first active ingredient equivalent to an amount of trazodone between 7.50 and 3.00 mg, preferably from 6.00 to 3.33 mg, and more preferably from 5.00 to 3.75 mg.

Other embodiments of the pharmaceutical composition of the present invention may be considered within the scope of the invention as long as the weight ratio of trazodone:pregabalin is maintained.

Mirogabalin compositions known in the art include 2.5 mg to 30 mg mirogabalin, especially 2.5 mg, 5 mg, 10 mg, 15 mg and 30 mg mirogabalin. According to the invention, trazodone can be added to such compositions to provide a weight ratio, expressed as trazodone:mirogabaline, between 1:40 and 1:100, preferably less than 1:40 and up to 1:100, more preferably between 1: 50 and 1:90, and even more preferably between 1:60 and 1:80 for combined use in the treatment of diabetic neuropathic pain.

According to the first embodiment of the invention, the pharmaceutical composition of the present invention therefore includes an amount of the second active ingredient equivalent to 5 mg of mirogabalin and an amount of the first active ingredient equivalent to the amount of trazodone from 0.125 to 0.050 mg, preferably from 0.100 to 0.056 mg, or more preferably 0.083 to 0.063 mg.

According to a second embodiment of the invention, the pharmaceutical composition of the present invention therefore includes an amount of the second active ingredient equivalent to 10 mg of mirogabalin and an amount of the first active ingredient equivalent to an amount of trazodone from 0.250 to 0.100 mg, preferably 0.200 to 0.111 mg, and more preferably 0.067-0.125 mg.

According to a third embodiment of the invention, the pharmaceutical composition of the present invention therefore includes an amount of the second active ingredient equivalent to 15 mg of mirogabalin and an amount of the first active ingredient equivalent to an amount of trazodone from 0.375 to 0.150 mg, preferably from 0.300 to 0.167 mg, or more preferably 0.250 to 0.187 mg.

Other forms of the pharmaceutical composition of the present invention may be considered within the scope of the invention as long as the weight ratio of trazodone: mirogabaline is maintained.

Prodrugs of gabapentin or pregabalin or mirogabalin are included within the scope of the present invention. The chemically modified drug or prodrug should have a pharmacokinetic profile different from that of the parent drug, allowing easier absorption through the mucosal epithelium, improved salt composition and/or solubility, improved systemic stability (eg, for increased plasma half-life).

Such chemical modifications may be (i) ester derivatives, (ii) amide derivatives, (iii) carbamate derivatives, (iv) N-acyloxyalkyl derivatives, (v) Nacyloxyalkoxycarbonyl derivatives, (vi) peptides, and (vii) any combinations thereof.

An ester can be prepared from the carboxyl group of a drug molecule by known means. The amide can be obtained from the carboxyl or amino group of the drug molecule by known means. Ester or amide derivatives can be degraded, for example, from esterases or lipases.

The number of carbon atoms present in the compounds used to prepare such esters, amides, carbamates, N-acryloxyalkyl and N-acryloxyalkoxycarbonyl derivatives is equal to or less than 10, preferably equal to or less than 7, more preferably equal to or

- 5 046312 less than 5. Applicable examples of the compound are alcohols, carboxylic acids and amines having 1 to 5 carbon atoms.

The peptide can be linked to a drug molecule by forming amide bonds with the carboxyl or amino group of the drug molecule by known means. Peptides can be recognized by specific or nonspecific proteinases.

The number of amino acids present in the compounds used to prepare such peptide derivatives is equal to or less than 5, preferably equal to or less than 4, more preferably equal to or less than 3.

The carbamate derivative, N-cycloxyalkoxyalkyl derivative and N-cycloxyalkoxycarbonyl derivative can be prepared from the amino group of the drug molecule by known means. Such derivatives can be destroyed by esterases and/or decompose spontaneously.

Useful examples of suitable drugs are described, for example, in Stella V.J. et al., Prodrug Strategies to overcome poor water solubility, Advance Drug Delivery Reviews 59 (2007) 677-694, and in Simplicio A.L. et al., Prodrugs for Amines, Molecules 2008, 13, 519-547.

A particularly useful example of a gabapentin prodrug is gabapentin enacabil, IUPAC chemical name 2-(1-{[({1-[(2-methylpropanoyl)oxy]ethoxy}carbonyl)amino]methyl}cyclohexyl)acetic acid, represented by the following structural formula:

ABOUT

Salts of trazodone, gabapentin, pregabalin and mirogabalin are included within the scope of the present invention. The salt can be obtained from physiologically acceptable organic and inorganic compounds having an acidic or basic functional group.

Typical examples of suitable physiologically acceptable inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid.

Typical examples of suitable physiologically acceptable organic acids are acetic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-toluenesulfonic acid, benzenesulfonic acid, succinic acid, tannic acid and tartaric acid.

Typical examples of physiologically acceptable inorganic bases are the hydroxides, carbonates and bicarbonates of ammonium, calcium, magnesium, sodium and potassium, for example ammonium hydroxide, calcium hydroxide, magnesium carbonate, sodium carbonate and potassium bicarbonate.

Typical examples of physiologically acceptable organic bases are: arginine, betaine, caffeine, choline, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, Nmethylglucamine, glucamine, glucosamine, histidine, N( 2-hydroxyethyl)piperidine, N(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, theobromine, triethylamine, trimethylamine, tripropylamine and tromethamine.

Preferably, the pharmaceutical composition of the present invention is for systemic use.

More preferably, the pharmaceutical composition of the present invention is formulated for oral or parenteral administration.

Preferably, the pharmaceutical composition of the present invention is prepared in appropriate dosage forms.

Examples of suitable dosage forms are: tablets, capsules, film-coated tablets, granules and oral solutions and syrups; creams, ointments and antiseptic patches for local administration; suppositories for rectal administration and sterile solutions for injection, aerosol or ophthalmic use.

Preferred dosage forms are tablets, film-coated tablets, capsules and oral solutions.

Dosage forms of the pharmaceutically acceptable composition of the present invention can be prepared in accordance with techniques well known to pharmaceutical chemists, including mixing, granulation, compression, dissolution, sterilization and the like.

Such dosage forms are advantageously formulated to provide controlled release of the active ingredient over time. In particular, depending on the type of therapy, the required release time may be very short, normal or long.

Preferably, the pharmaceutical composition of the present invention is contained in a single dosage form.

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The present invention also includes multiple dosage forms containing amounts of first and second active ingredients, respectively, for administration simultaneously to administer said first and second active ingredients in a weight ratio between said first active ingredient and said second active ingredient, expressed as the weight ratio of trazodone: gabapentin or pregabalin or mirogabalin, between 1:40 and 1:100, preferably less than 1:40 and up to 1:100, preferably between 1:50 and 1:90, and even more preferably between 1:60 and 1:80.

For example, dosage forms containing 100 mg of gabapentin or pregabalin can be combined with dosage forms containing from 2.50 to 1.00 mg, preferably from 2.00 to 1.11 mg, and more preferably from 1.67 to 1 .25 mg trazodone for combined use in the treatment of diabetic neuropathic pain.

Similarly, dosage forms comprising 10 mg of mirogabalin may be associated with dosage forms comprising 0.250 to 0.100 mg, preferably 0.200 to 0.111 mg, and more preferably 0.167 to 0.125 mg of trazodone for combined use in the treatment of diabetic neuropathic pain.

The pharmaceutically acceptable excipient may be selected from the group which includes thickeners, gliders, astringents, disintegrants, fillers, thickeners, preservatives, stabilizers, surfactants, buffers, thinners, lubricants, humectants, adsorbents, control salts osmotic pressure, emulsifiers, flavors, dyes, sweeteners and the like.

Particularly preferred excipients are sodium carbonate, magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch (especially corn starch), sodium starch glycolate, gelatin, microcrystalline cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, povidone, oil cocoa, titanium dioxide (E171), red iron oxide and yellow iron oxide (E172), and the like.

The pharmaceutical composition of the present invention has found unexpected utility in the treatment of pain resulting from diabetic neuropathy, but is believed to also be useful in the treatment of pain resulting from other types of neuropathies, particularly post-herpetic neuralgia and post-surgical neuropathic pain.

The following examples are intended to further illustrate the present invention without limiting it.

Examples

Example 1 - clinical study.

The clinical study was conducted on a population of 42 patients of both sexes and aged 18 to 75 years with diabetic neuropathy. Patients were divided into three groups and a randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted, with double sham for patients in group 2.

Group 1 received 20 mg trazodone (10 drops of 6% trazodone hydrochloride solution) three times daily for 8 weeks, up to a total of 60 mg daily.

Group 2 received 10 mg trazodone (5 drops of 6% trazodone hydrochloride solution) three times daily for 8 weeks for a total of 30 mg daily.

Group 3 received placebo, 10 drops of an oral solution three times daily for 8 weeks.

During the ninth week, completing the clinical study, Group 1 received 10 mg of trazodone three times daily for a total of 30 mg per day, while Group 2 and Group 3 received placebo.

Trazodone hydrochloride 6% solution contains trazodone hydrochloride (6%), macrogol (35%), propylene glycol (30%), citric acid (0.5%), sucrose (0.15%), sodium hydroxide (0.125%), propyl gallate (0.10%), disodium edetate (0.05%), and purified water as needed up to 100 ml. The placebo solution is identical to the trazodone solution, but without the active ingredient.

Gabapentin was administered in increasing dosages to all patients treated according to the treatment regimen shown in Table. 1 below, using capsules containing 100 mg, 300 mg and 400 mg of commercially available gabapentin (Neurontin®, Pfizer). The capsules contain lactose monohydrate, corn starch and talc as excipients, and color combinations E171 and E772.

Table 1

Capsule contents (mg) Dosing Period Dosage (mg/day) 100 1 capsule 3 times a day ^1st week 300 100 2 capsules 3 times a day ^2nd week 600 300 1 capsule ^3rd week 900

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3 times a day 400 1 capsule 3 times a day ^4th week 1200 300 2 capsules 3 times a day ^5th week 1800 400 2 capsules 3 times a day ^{6th -8th} weeks 2400

In table Figure 2 below shows the trazodone:gabapentin ratio for each group 1 and 2 during treatment:

table 2

Group 1 Group 2 ^1st week 1:5 1:10 ^2nd week 1:10 1:20 ^3rd week 1:15 1:30 ^4th week 1:20 1:40 ^5th week 1:30 1:60 ^6th week 1:40 1:80 ^7th week 1:40 1:80 ^8th week 1:40 1:80 ^9th week 1:80 n.a.

At the start of treatment and at the end of each week of treatment, patients receiving treatment completed the Brief Pain Inventory - Short Form (BPI-SF), which includes questions regarding self-reported pain (Zelman DC, et al., Validation of a modified version of the pain inventory brief for painful peripheral neuropathy, J. Pain Symptom Manage. 2005 Apr;29(4):401-10).

Specifically, patients rated their average pain intensity in the week before the assessment (Item 5) and at the time of the assessment (Item 6) on a scale of 0 to 10, with 0 representing no pain and 10 representing more pain than you can imagine.

At each visit, scores were collected and processed to determine deviation from the mean for each group at baseline. The results are summarized in the following tables. 3 and 4, from which the graphs shown in FIG. 1 and 2, respectively.

Table 3

Question 5 Deviation of mean pain score from the start of treatment (visit 0) Group 1 Group 2 Group 3 Visit 1 -0.7 -1.1 -1.0 Visit 2 -1.4 -1.6 -1.7 Visit 3 -1.7 -2.0 -2.1 Visit 4 -2.1 -2.8 * -1.9 Visit 5 -2.2 -2.9** -2.1 Visit 6 -2.3 -2.8 *** -2.4 Visit 7 -2.6 -3.0 *** -2.4 Visit 8 -2.6 -3.1 *** -2.5 Visit 9 -2.7 -3.2** -2.5

* p<0.05 vs group 3;

** p<0.1 vs group 3;

*** p<0.5 vs group 3.

Table 4

Question 6 Deviation of mean pain score from the start of treatment (Visit 0) Group 1 Group 2 Group 3 Visit 1 -0.6 -1.0 -0.9 Visit 2 -1.4 -1.4 -1.4 Visit 3 -1.6 -1.9 -1.7 Visit 4 -2.2 -2.5 * -1.6 Visit 5 -2.2 -2.6** -1.8 Visit 6 -2.2 -2.7** -2.0 Visit 7 -2.6 -2.7** -1.9 Visit 8 -2.4 -2.9 * -2.0 Visit 9 -2.6 -3.1 * -2.0

* p<0.05 vs group 3;

** p<0.1 vs group 3;

*** p<0.5 vs group 3.

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In fig. Figure 1 shows the deviation from the initial pain intensity rating in the week preceding the assessment (item 5). At the end of weeks 4 and 5, group 2 showed a significant reduction in pain of almost one point compared to groups 1 and 3, which then remained at about half a point over the following weeks.

In fig. Figure 2 shows the deviation from the initial value of pain intensity (point 6). At the end of week 4 throughout the follow-up period until the end of treatment, group 2 showed a significant reduction in pain of almost one point compared to group 3 and about half a point compared to group 1.

The effect obtained for group 2 patients is increasingly surprising, considering that the amount of trazodone administered to group 2 is half the amount administered to group 1, to the extent that the synergistic effect associated with the relative amounts of trazodone and gabapentin for ratios of less than 1:40 is compelling.

The effect obtained for patients in group 2 also shows a linear and progressively decreasing trend in the last weeks of treatment, thus giving the impression that prolongation of treatment may lead to an additional reduction in pain sensation, in contrast to the trend in the result of patients in groups 1 and 3, where the curve shows a constant trend with flattening after the sixth week.

Finally, in table. Figure 5 below shows for each patient group and for the responses given to question 5 (i) the sum of all abnormalities obtained at each visit, (ii) the percentage of patients with a decrease of at least 50% from baseline, and (iii) relative NNT index (number of patients to be treated).

Table 5

Group 1 Group 2 Group 3 Deviation amount -116.3 -142.5** -117.6 Patients with a 50% reduction 54.0 62.8 45.8 NNT 12.2 5.9 -

** p<0.5 vs group 3.

The results confirm the unexpected treatment effect of group 2, with a significant increase in overall pain reduction relative to group 1 and group 3, and an extremely favorable and promising NNT value.

Patients receiving treatment also completed the SF-36 health assessment questionnaire (G. Apolone et al., Questionario sullo stato di salute SF-36. Manuale d'uso e guida all'interpretazione dei risultati, Editore Guerini e Associati, Nona Edizione , Gennaio 2005).

The SF-36 questionnaire includes a set of 36 questions measuring eight different aspects of general health, namely physical activity (PF - physical function), role and physical health (RP - role participation), physical pain (BP - body pain), general health (GH - general health), vitality (VT - vitality), social activities (SF - social functioning), role and emotional state (RE - emotional role), and mental health (MH - mental health).

Information obtained from these eight domains was collected to determine the physical component sum (PCS) and mental component sum (MCS) of the health status.

The MCS primarily relates to the aspects of vitality (VT), social functioning (SF), role and emotional state (RE), and mental health (MH), and is a measure used to assess the percentage of patients at positive risk for depression or anxiety compared with normal general population.

The results are collected in table. 6 below, from which the graph shown in FIG. 3.

Results are expressed as the percentage of patients at positive risk for depression or anxiety compared with the normal general population, in which the approximate normal value is 18.

Table 6

Group 1 Group 2 Group 3 Visit 0 31 52 38 Visit 8 25 21 29

A significant treatment effect in group 2 was shown to reduce the risk of depression in patients with diabetic neuropathy.

Although at the beginning of treatment (Visit 0) a greater percentage (52%) of patients in group 2 had a positive risk of depression compared with group 1 (31%) and group 3 (38%), at the end of treatment (Visit 8) the percentage of risk in the group 2 decreased to 21% (compared to 25% in group 1 and 29% in group 3). This value is very close to the estimated risk of depression in the general population (indirect control) of 18%.

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Claims (8)

Table results 6 for group 2 further supports the hypothesis of a synergistic effect associated with the relative amounts of trazodone and gabapentin for ratios less than 1:40. Example 2 - compositions. The following tables. 7 and 8 provide some non-limiting examples of trazodone and gabapentin compositions for use in the present invention: Table 7 Capsules mg mg mg G abapentin 100 300 400 Trazodone 1.25 3.75 5.00 Lactose 13 41 54 Corn starch 40 40 40 Talc 5 5 5 Table 8 Pills mg mg mg G abapentin 100 300 400 Trazodone 1.50 4.50 6.00 Lactose 200 600 600 Starch 50 50 50 Starch glycolate sodium 15 45 45 Povidone 5 5 5 Magnesium stearate 4 4 4 CLAIM 1. A pharmaceutical composition for the treatment of pain resulting from diabetic neuropathy, post-herpetic neuralgia and post-surgical neuropathic pain, which includes (a) a combination of (i) a first active ingredient selected from the group consisting of trazodone and a salt thereof, and (ii) a second an active ingredient selected from the group consisting of gabapentin, pregabalin, mirogabalin, a salt thereof and a prodrug thereof, wherein said prodrug is gabapentin enacarbil, and (b) at least one pharmaceutically acceptable excipient, wherein said pharmaceutical composition comprises a weight ratio of said first active ingredient to said second active ingredient, expressed as a weight ratio of trazodone:gabapentin or pregabalin or mirogabalin of less than 1:40 and up to 1:100. 2. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises a weight ratio of said first active ingredient and said second active ingredient, expressed as a weight ratio of trazodone:gabapentin or pregabalin or mirogabalin, between 1:50 and 1:90. 3. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises a weight ratio of said first active ingredient to the second active ingredient, expressed as a weight ratio of trazodone:gabapentin or pregabalin or mirogabalin, between 1:60 and 1:80. 4. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition includes an amount of the first active ingredient equivalent to an amount of trazodone from 2.50 to 1.00 mg, preferably from 2.00 to 1.11 mg, and more preferably from 1.67 up to 1.25 mg, for an amount of the second active ingredient equivalent to 100 mg of gabapentin or pregabalin. 5. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition includes an amount of the second active ingredient equivalent to 100 mg of gabapentin and an amount of the first active ingredient equivalent to the amount of trazodone from 2.50 to 1.00 mg, preferably from 2.00 to 1 .11 mg, and more preferably 1.67 to 1.25 mg. 6. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition includes an amount of the second active ingredient equivalent to 300 mg of gabapentin and an amount of the first active ingredient equivalent to the amount of trazodone from 7.50 to 3.00 mg, preferably from 6.00 to 3 .33 mg, and more preferably from 5.00 to 3.75 mg. 7. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition includes an amount of the second active ingredient equivalent to 400 mg of gabapentin and an amount of the first active ingredient equivalent to the amount of trazodone from 10.00 to 4.00 mg, preferably from 8.00 to 4 .44 mg, and more preferably 6.67 to 5.00 mg. 8. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises an amount of a second active ingredient equivalent to 50 mg of pregabalin and an amount of the first -