Pharmaceutical compositions comprising trazodone for the treatment of neuropathic pain

Abstract

The present invention relates to a pharmaceutical composition comprising (a) (i) a combination of Trazodone or a salt thereof, and (ii) Gabapentin or Pregabalin or Milnacian or a salt thereof or a prodrug thereof, and (b) at least one pharmaceutically acceptable excipient, for the treatment of neuropathic pain, wherein the pharmaceutical composition comprises Trazodone:Gabapentin or Pregabalin or Milnacian in a weight ratio of between 1:40 and 1:100, preferably below 1:40 and up to 1:100.

Description

Invention Field

[0001] This invention relates to pharmaceutical compositions comprising a combination of trazodone and gabapentin or pregabalin or mirogabalin, which have a beneficial effect in treating neuropathic pain, particularly pain caused by diabetic neuropathy. Background Technology

[0002] Physiological pain is an important protective mechanism designed to warn of potential dangers from external environmental stimuli. Neuropathic pain is defined as pain caused by or triggered by primary damage to or dysfunction of the nervous system. Neuropathic pain is often debilitating, leading to loss of work capacity and poor quality of life. It also results in economic and social harm.

[0003] Currently used analgesics for treating neuropathic pain include nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, opioid analgesics, and anticonvulsants [Woolf CJ, Mannion RJ, Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353:1959-1964].

[0004] However, neuropathic pain is notoriously difficult to treat with currently available drug therapies. Therefore, developing new drugs has always been one of the main goals of the pharmaceutical industry.

[0005] Diabetic neuropathy is one of the most common long-term symptomatic complications in patients with type 1 and type 2 diabetes. At initial diagnosis, 7.5% of patients already have painful diabetic peripheral neuropathy, and approximately 45-50% will develop this complication 25 years later.

[0006] Diabetic neuropathic pain is generally described as tingling, burning, stinging, sharp, or even electric shock-like sensations. It is typically considered moderate to severe and often worsens at night, causing sleep disturbances. The pain can be persistent and accompanied by abnormal pain in the skin, which can substantially impact a patient's quality of life, affecting their ability to perform daily activities and negatively affecting their mood. The pain may also be a reason for withdrawal from recreational and social activities and may be associated with depression.

[0007] While the first step in managing diabetic neuropathic pain has traditionally been to improve and optimize glycemic control, additional pain management medications are often required.

[0008] Current treatment options include antidepressants (such as tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors), gamma-aminobutyric acid (GABA) analogs (such as pregabalin, gabapentin, and milobalin), opioids, and topical treatments.

[0009] Gabapentin is a known anticonvulsant and is currently approved for the treatment of epilepsy and neuropathic pain. Gabapentin is effective in managing neuropathic pain, and in the management of diabetic neuropathy, gabapentin has been found to strike the best balance between safety and efficacy.

[0010] Gabapentin is now widely recommended as a first-line treatment for peripheral diabetic neuropathy by multiple guidelines, including those from the American Academy of Neurology, the National Institute for Health and Care Excellence, the European Federation of Neurological Societies, and the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain.

[0011] Unfortunately, there is no consensus on which single drug is more effective, and monotherapy rarely provides adequate pain relief. Clinical management of diabetic neuropathic pain continues to pose a treatment challenge, and responses to existing treatments are often inadequate. In randomized controlled trials, multiple drugs, used alone or in combination, have shown significant reductions in neuropathic pain compared to placebo, but pain relief remains insufficient for most patients.

[0012] Trazodone is a well-known antidepressant with a multi-receptor mechanism of action and has been proposed as an alternative to approved pain medications, as one of the potentially effective off-label drugs. Low doses of trazodone have been used to treat neuropathic pain.

[0013] Khurana observed that trazodone had a good effect on pain relief and numbness when administered in divided doses of 100 mg / day in six diabetic patients with peripheral diabetic neuropathy (Khurana RC., "Treatment of painful diabetic neuropathy with trazodone", JAMA vol.250, no.11, 1983).

[0014] Subsequently, 31 adult diabetic patients with painful distal symmetrical polyneuropathy received oral trazodone at doses of 50 or 100 mg / day. After 2 weeks of treatment, 61.3% of patients experienced symptom relief, and 22.6% achieved complete remission. At the end of the study, all patients with symptom relief continued to take trazodone without any adverse effects or remission. The authors concluded that, given the efficacy, safety, and rapid onset of trazodone, it appears to be a good alternative to tricyclic antidepressants (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).

[0015] EP1663398B1 describes a combination of α-2-δ ligands (such as gabapentin and pregabalin) with selective norepinephrine reuptake inhibitors (such as (S,S)-reboxetine) for the treatment of neuropathic pain.

[0016] WO2013 / 002584 describes pain relief compositions comprising two or more components selected from the following: (a) a 5-HT2 receptor antagonist, (b) a P2X receptor antagonist, and (c) any of a glycine receptor agonist, a glycine transporter antagonist, a γ-aminobutyric acid receptor agonist (GABA), and a GABA 1 transporter antagonist (GABA1).

[0017] WO2017 / 067870 describes a pharmaceutical composition comprising, for example, an amount of trazodone provided at a dose equal to or less than 1 mg / kg and an amount of gabapentin provided at a dose equal to or less than 15 mg / kg, wherein the weight ratio of trazodone to gabapentin is between 1:15 and 1:5, for the treatment of chronic pain, particularly acetic acid injection-induced inflammatory pain in mice and sciatic nerve ligation-induced neuropathic pain in rats.

[0018] Kukkar A. et al. published a review on the use of gabapentin in the treatment of neuropathic pain, “Implications and mechanism of action of gabapentin in neuropathic pain”, Arch. Pharm. Ris. (2013) 36:237-251. Superior efficacy has been observed in the combination of gabapentin and venlafaxine in neuropathic pain models, as well as in the treatment of neuropathic pain induced by spinal nerve ligation, and in the co-administration of gabapentin with donepezil and / or duloxetine in a spared nerve injury model.

[0019] As reported 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, trazodone and the combination of trazodone and pregabalin have been studied in 12-week and 24-week treatments of fibromyalgia.

[0020] As in As disclosed in “Fentanyl–trazodone–paracetamol tripledrug combination: Multimodal analgesia in a mouse model of visceral pain”, Pharmacology, Biochemistry and Behavior 98 (2011) 331–336, the combination of trazodone with fentanyl and paracetamol has been studied in a mouse model of visceral pain, showing effective anti-antinociceptive effects. Invention Summary

[0021] The applicant faces the challenge of providing pharmaceutical compositions for treating neuropathic pain, particularly pain caused by diabetic neuropathy, that have better activity than compositions known in the art.

[0022] Based on results known in the art, the applicant hypothesizes that the combination of trazodone and gabapentin can be used to treat diabetic neuropathic pain and neuropathic pain in general.

[0023] The applicant has surprisingly discovered that trazodone can be used in combination with gabapentin in very low relative amounts, with a weight ratio between trazodone and gabapentin between 1:40 and 1:100, preferably below 1:40 and up to 1:100.

[0024] In particular, the applicant has surprisingly found that in subjects treated with escalating gabapentin therapy (to which trazodone is added and co-administered) for nine weeks, the combination of trazodone and gabapentin in a weight ratio between 1:40 and 1:100, preferably below 1:40 and up to 1:100, has an improving effect on reducing pain from diabetic neuropathy.

[0025] The applicant found even more surprising results, as a combination of trazodone and gabapentin in a weight ratio greater than 1:40 (e.g., 1:30) showed little improvement in reducing pain associated with diabetic neuropathy.

[0026] The applicant also found a surprisingly positive effect in reducing the risk of depressive or anxiety disorders in the same subjects treated with the aforementioned combination of gabapentin and trazodone.

[0027] Based on the results obtained with gabapentin, the applicant believes that similar effects can be observed when pregabalin or milobalin (with similar active ingredients to gabapentin, the same therapeutic effects and mechanisms of action but with greater efficacy) is used in combination with trazodone in the same weight ratio.

[0028] Therefore, in a first aspect, the present invention relates to a pharmaceutical composition comprising (a)(i) a first active ingredient selected from trazodone and its salts, and (ii) a combination of a second active ingredient selected from gabapentin, pregabalin, milobalin, their salts and their prodrugs, and (b) at least one pharmaceutically acceptable excipient for treating pain caused by diabetic neuropathy, wherein the pharmaceutical composition comprises the first active ingredient and the second active ingredient in a weight ratio between 1:40 and 1:100, preferably less than 1:40 and up to 1:100, the weight ratio being expressed as the weight ratio of trazodone:gabapentin or pregabalin or milobalin.

[0029] In a second aspect, the present invention relates to a method for treating pain caused by diabetic neuropathy in a subject in need of such treatment, the method comprising administering an effective amount of a pharmaceutical composition comprising (a)(i) a first active ingredient selected from trazodone and its salts, and (ii) a combination of a second active ingredient selected from gabapentin, pregabalin, milobalin, their salts and their prodrugs, and (b) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises the first active ingredient and the second active ingredient in a weight ratio between 1:40 and 1:100, preferably less than 1:40 and up to 1:100, the weight ratio being expressed as the weight ratio of trazodone:gabapentin or pregabalin or milobalin. Attached Figure Description

[0030] Figures 1 to 3 The results of the clinical study described in Example 1 are displayed in graphs. Figure 1 and Figure 2 In the diagram, the average deviation of the treated subjects from their pain perception values ​​at the start of treatment is represented on the y-axis, while the x-axis shows the number of treatment weeks. Figure 3 In the figure, the y-axis shows the percentage of patients with a positive risk of depression or anxiety in the normal population (reference) and the three treatment groups (groups 1-3) at the start and end of treatment. Invention Details

[0032] The expression "represented as a weight ratio of trazodone: gabapentin or pregabalin or milobalin" as used in this specification and claims means that the ratio between the first active ingredient and the second active ingredient is always expressed as the equivalent weight of trazodone (even if present as a salt) in the pharmaceutical composition and the equivalent weight of gabapentin or pregabalin or milobalin (even if present as a salt or prodrug) in the pharmaceutical composition.

[0033] The term "trazodone" as used in this specification and claims represents the active ingredient 2-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-[1,2,4]triazol[4,3-a]pyridine-3(2H)-one having the following structural formula (I):

[0034]

[0035] The term "gabapentin" as used in this specification and claims represents the active ingredient 2-[1-(aminomethyl)cyclohexyl]acetic acid having the following structural formula (II):

[0036]

[0037] The term "pregabalin" as used in this specification and claims represents the active ingredient (S)-3-(aminomethyl)-5-methylhexanoic acid having the following structural formula (III):

[0038]

[0039] The term "milobalin" as used in this specification and claims represents the active ingredient (1R,5S,6S)-6-(aminomethyl)-3-ethyl-bicyclo(3.2.0)hept-3-ene-6-acetic acid having the following structural formula (IV):

[0040]

[0041] The pharmaceutical composition according to the invention contains (i) a certain amount of a first active ingredient selected from trazodone and its salts, and (ii) a certain amount of a second active ingredient selected from gabapentin, pregabalin, milobalin, their salts and their prodrugs, such as to provide the first active ingredient and the second active ingredient in a 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, the weight ratio being expressed as the weight ratio of trazodone:gabapentin or pregabalin or milobalin.

[0042] According to a preferred aspect of the invention, any value within the aforementioned weight ratio of trazodone to gabapentin or pregabalin or milobalin can 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.

[0043] The amounts of the first and second active ingredients contained in the pharmaceutical composition according to the invention can vary according to the dosage necessary to achieve the desired effect, provided that the weight ratio of the first active ingredient to the second active ingredient is maintained between 1:40 and 1:100, preferably below 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, wherein the weight ratio is expressed as the weight ratio of trazodone: gabapentin or pregabalin or milobalin.

[0044] Advantageously, the pharmaceutical composition of the present invention comprises a first active ingredient in an amount equivalent to trazodone in an amount 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, and a second active ingredient in an amount equivalent to 100 mg of gabapentin or pregabalin.

[0045] Preferably, the pharmaceutical composition of the present invention comprises a first active ingredient in an amount equivalent to trazodone between 0.250 and 0.100 mg, more preferably between 0.200 and 0.111 mg, and even more preferably between 0.167 and 0.125 mg, and a second active ingredient in an amount equivalent to 10 mg of milobalin.

[0046] Compositions of gabapentin known in the art generally contain 100 mg to 800 mg of gabapentin, particularly 100 mg, 300 mg, 400 mg, 600 mg, or 800 mg of gabapentin. According to the invention, trazodone can be added to such compositions to provide a weight ratio combination for treating diabetic neuropathic pain between 1:40 and 1:100, preferably below 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, expressed as a trazodone:gabapentin weight ratio.

[0047] According to the first embodiment, the pharmaceutical composition according to the invention thus comprises a second active ingredient in an amount equivalent to 100 mg of gabapentin and a first active ingredient in an amount equivalent to trazodone in an amount between 2.50 and 1.00 mg, preferably 2.00 to 1.11 mg, and more preferably 1.67 to 1.25 mg.

[0048] According to a second embodiment, the pharmaceutical composition according to the invention thus comprises a second active ingredient in an amount equivalent to 300 mg of gabapentin and a first active ingredient in an amount equivalent to trazodone in an amount between 7.50 and 3.00 mg, preferably 6.00 to 3.33 mg, and more preferably 5.00 to 3.75 mg.

[0049] According to a third embodiment, the pharmaceutical composition according to the invention thus comprises a second active ingredient in an amount equivalent to 400 mg of gabapentin and a first active ingredient in an amount equivalent to trazodone in an amount between 10.00 and 4.00 mg, preferably 8.00 to 4.44 mg, and more preferably 6.67 to 5.00 mg.

[0050] Other embodiments of the pharmaceutical composition according to the invention can be considered within the scope of the invention, provided that the weight ratio of trazodone to gabapentin is maintained.

[0051] Pregabalin compositions known in the art generally contain 25 mg to 300 mg of pregabalin, particularly 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 combination for treating diabetic neuropathic pain between 1:40 and 1:100, preferably below 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, expressed as a trazodone:pregabalin weight ratio.

[0052] According to the first embodiment, the pharmaceutical composition according to the invention thus comprises a second active ingredient in an amount equivalent to 50 mg of pregabalin and a first active ingredient in an amount equivalent to trazodone in an amount between 1.25 and 0.50 mg, preferably 1.00 to 0.56 mg, and more preferably 0.83 to 0.63 mg.

[0053] According to a second embodiment, the pharmaceutical composition according to the invention thus comprises a second active ingredient in an amount equivalent to 100 mg of pregabalin and a first active ingredient in an amount equivalent to trazodone in an amount between 2.50 and 1.00 mg, preferably 2.00 to 1.11 mg, and more preferably 1.67 to 1.25 mg.

[0054] According to a third embodiment, the pharmaceutical composition according to the invention thus comprises a second active ingredient in an amount equivalent to 300 mg of pregabalin and a first active ingredient in an amount equivalent to 7.50 to 3.00 mg, preferably 6.00 to 3.33 mg, and more preferably 5.00 to 3.75 mg of trazodone.

[0055] Other embodiments of the pharmaceutical composition according to the invention can be considered within the scope of the invention, provided that the weight ratio of trazodone to pregabalin is maintained.

[0056] Milobalin compositions known in the art generally contain 2.5 mg to 30 mg of milobalin, particularly 2.5 mg, 5 mg, 10 mg, 15 mg, and 30 mg of milobalin. According to the invention, trazodone can be added to such compositions to provide a weight ratio combination for treating diabetic neuropathic pain between 1:40 and 1:100, preferably below 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, expressed as trazodone:milobalin.

[0057] According to a first embodiment, the pharmaceutical composition according to the invention thus comprises a second active ingredient in an amount equivalent to 5 mg of milobalin and a first active ingredient in an amount equivalent to trazodone in an amount between 0.125 and 0.050 mg, preferably 0.100 to 0.056 mg, and more preferably 0.083 to 0.063 mg.

[0058] According to a second embodiment, the pharmaceutical composition according to the invention thus comprises a second active ingredient in an amount equivalent to 10 mg of milobalin and a first active ingredient in an amount equivalent to trazodone in an amount between 0.250 and 0.100 mg, preferably 0.200 to 0.111 mg, and more preferably 0.067 to 0.125 mg.

[0059] According to a third embodiment, the pharmaceutical composition according to the invention thus comprises a second active ingredient in an amount equivalent to 15 mg of milobalin and a first active ingredient in an amount equivalent to trazodone in an amount between 0.375 and 0.150 mg, preferably 0.300 to 0.167 mg, and more preferably 0.250 to 0.187 mg.

[0060] Other forms of the pharmaceutical compositions according to the invention may be considered within the scope of the invention, provided that the weight ratio of trazodone to milobalin is maintained.

[0061] Gabapentin, pregabalin, or milobalin prodrugs are included within the scope of this invention. Chemically modified drugs or prodrugs should have different pharmacokinetic characteristics from the parent drug, allowing for easier absorption through mucosal epithelium, improved saline formulations and / or solubility, and improved systemic stability (e.g., increased plasma half-life).

[0062] Such chemical modification can be (i) ester derivatives, (ii) amide derivatives, (iii) carbamate derivatives, (iv) N-acyloxyalkyl derivatives, (v) N-acyloxyalkoxycarbonyl derivatives, (vi) peptides, and (vii) any combination thereof.

[0063] The ester can be derived from the carboxyl group of the drug molecule in a known manner. The amide can be derived from the carboxyl or amino group of the drug molecule in a known manner. The derivatives of the ester or amide can be decomposed, for example, by esterases or lipases.

[0064] The compounds used to prepare these esters, amides, carbamates, N-acryloyloxyalkyl and N-acryloyloxyalkoxycarbonyl derivatives contain 10 or fewer carbon atoms, preferably 7 or fewer, more preferably 5 or fewer. Useful examples of compounds are alcohols, carboxylic acids and amines having 1 to 5 carbon atoms.

[0065] The peptide can be coupled to a drug molecule via a known mechanism by forming an amide bond with the carboxyl or amino group of the drug molecule. The peptide can be recognized by specific or non-specific proteases.

[0066] The compounds used to obtain these peptide derivatives contain 5 or fewer amino acids, preferably 4 or fewer, and more preferably 3 or fewer.

[0067] Carbamates, N-cyloxyalkoxyalkyl derivatives, and N-cyloxyalkoxycarbonyl derivatives can be derived from the amino group of a drug molecule in known ways. These derivatives may be broken down by esterases and / or spontaneously decomposed.

[0068] Useful examples of suitable drugs are described, for example, in Stella VJ et al., “Prodrug Strategies to overcome poor water solubility”, Advance Drug Delivery Reviews 59 (2007) 677-694, and in Simpliciio AL et al., “Prodrugs for Amines”, Molecules 2008, 13, 519-547.

[0069] A particularly useful example of a gabapentin prodrug is gabapentin enacarbil, with the IUPAC chemical name 2-(1-{[({1-[(2-methylpropanoyl(propanoil))oxy]ethoxy}carbonyl)amino]methyl}cyclohexyl)acetic acid, represented by the following structural formula:

[0070]

[0071] Salts of trazodone, gabapentin, pregabalin, and milobalin are included within the scope of this invention. These salts may be formed from physiologically acceptable organic and inorganic compounds having acid or base functions.

[0072] Typical examples of suitable physiologically acceptable inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid.

[0073] 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.

[0074] Typical examples of physiologically acceptable inorganic bases are hydroxides, carbonates, and bicarbonates of ammonium, calcium, magnesium, sodium, and potassium, such as ammonium hydroxide, calcium hydroxide, magnesium carbonate, sodium carbonate, and potassium bicarbonate.

[0075] Typical examples of suitable physiologically acceptable organic bases are: arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, N-methylglucamine, glucosamine, histidine, N-(2-hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, theobromine, triethylamine, trimethylamine, tripropylamine, and trometamine.

[0076] Preferably, the pharmaceutical composition according to the invention is for systemic use.

[0077] More preferably, the pharmaceutical composition according to the invention is formulated for oral or parenteral administration.

[0078] Preferably, the pharmaceutical composition according to the invention is prepared in a suitable dosage form.

[0079] Examples of appropriate dosage forms are: tablets, capsules, coated tablets, granules, and solutions, as well as syrups, for oral administration; creams, ointments, and antimicrobial patches for topical administration; suppositories for rectal administration; and sterile solutions for injection, aerosol, or ophthalmic administration.

[0080] Preferred dosage forms are tablets, coated tablets, capsules, and solutions for oral administration.

[0081] The dosage forms of the pharmaceutical compositions of the present invention can be prepared according to techniques well known to medicinal chemists, including mixing, granulation, compression, dissolution, sterilization, etc.

[0082] These dosage forms are advantageously formulated to ensure controlled release of the active ingredient over time. In particular, depending on the type of therapy, the required release time can be short, normal, or long.

[0083] Preferably, the pharmaceutical composition of the present invention is contained in a single dosage form.

[0084] The present invention also includes multiple dosage forms, each containing amounts of first and second active ingredients that can be taken simultaneously, so as to administer the first and second active ingredients at a weight ratio of 1:40 to 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, wherein the weight ratio is expressed as the weight ratio of trazodone:gabapentin or pregabalin or milobalin.

[0085] For example, a formulation containing 100 mg gabapentin or pregabalin can be combined with a formulation containing 2.50 to 1.00 mg, preferably 2.00 to 1.11 mg, and more preferably 1.67 to 1.25 mg trazodone, for the treatment of diabetic neuropathic pain.

[0086] Similarly, a formulation containing 10 mg of milobalin can be combined with a formulation containing 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 the treatment of diabetic neuropathic pain.

[0087] Pharmaceutically acceptable excipients can be selected from thickeners, gliders, binders, disintegrants, fillers, diluents, preservatives, stabilizers, surfactants, buffers, fluidizing agents, lubricants, wetting agents, absorbents, salts that regulate osmotic pressure, emulsifiers, flavoring agents, coloring agents, sweeteners, etc.

[0088] The particularly preferred excipients are sodium carbonate, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch (especially corn starch), sodium glycolate starch, gelatin, microcrystalline cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, povidone, cocoa butter, titanium dioxide (E171), red iron oxide and yellow iron oxide (E172), etc.

[0089] The pharmaceutical compositions according to the invention have been shown to be surprisingly effective in treating pain caused by diabetic neuropathy, but it is also believed that they can be used to treat pain caused by other types of neuropathy, particularly postherpetic neuralgia and post-surgical neuropathic pain.

[0090] The following examples are intended to further illustrate the present invention, but do not limit the invention. Example

[0091] Example 1 – Clinical Study

[0092] This clinical study was conducted in a cohort of 142 patients with diabetic neuropathy, spanning both sexes and aged 18 to 75 years. Patients were randomly assigned to three groups and complied with a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Group 2 patients participated in a double-dummy modality.

[0093] Group 1 received 20 mg trazodone (10 drops of 6% trazodone hydrochloride solution) three times a day for 8 weeks, for a total of 60 mg per day.

[0094] Group 2 received 10 mg trazodone (5 drops of 6% trazodone hydrochloride solution) three times a day for 8 weeks, for a total of 30 mg per day.

[0095] Group 3 received placebo treatment, 10 drops of oral solution three times a day for 8 weeks.

[0096] At week 9, when the clinical trial concluded, group 1 received 10 mg trazodone three times daily for a total of 30 mg daily, while groups 2 and 3 received placebo.

[0097] A 6% trazodone hydrochloride solution contains trazodone hydrochloride (6%), polyethylene glycol (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 to a final volume of 100 mL. The placebo solution is identical to the trazodone solution but does not contain the active ingredient.

[0098] For all patients treated according to the dosage regimens shown in Table 1 below, commercially available gabapentin in doses of 100 mg, 300 mg, and 400 mg was used. Pfizer's capsules administer gabapentin in escalating doses. The capsules contain lactose monohydrate, corn starch, and talc as excipients, as well as a combination of E171 and E772 colorants.

[0099] Table 1

[0100]

[0101]

[0102] Table 2 below shows the trazodone:gabapentin ratio in each of Group 1 and Group 2 during the treatment period:

[0103] Table 2

[0104] Group 1 Group 2 Week 1 1:5 1:10 Week 2 1:10 1:20 Week 3 1:15 1:30 Week 4 1:20 1:40 Week 5 1:30 1:60 Week 6 1:40 1:80 Week 7 1:40 1:80 Week 8 1:40 1:80 Week 9 1:80 na

[0105] At the start of treatment and at the end of each treatment week, patients receiving treatment completed the Brief Pain Inventory-Short Form (BPI-SF), which included question groups related to pain self-assessment (Zelman DC et al., “Validation of a modified version of the pain inventory brief for painful diabetic peripheralneuropathy”, J. Pain Symptom Manage. 2005 Apr; 29(4):401-10).

[0106] In particular, patients rated the average pain intensity on a scale of 0 to 10 during the week before the assessment (issue 5) and during the assessment (issue 6), where 0 represents “no pain” and 10 represents “more pain than you can imagine”.

[0107] At each visit, the evaluations were collected and processed to determine the deviation from the mean obtained for each group at the start of treatment. The results are collected in Tables 3 and 4 below, from which the following information was obtained: Figure 1 and 2 The chart shown.

[0108] Table 3

[0109]

[0110] *Compare with the third group, p<0.05

[0111] **Compare with the third group, p<0.1

[0112] ***Compare with the third group, p<0.5

[0113] Table 4

[0114]

[0115] *Compare with the third group, p<0.05

[0116] **Compare with the third group, p<0.1

[0117] ***Compare with the third group, p<0.5

[0118] Figure 1 The deviation from the initial pain intensity values ​​in the week prior to assessment is described (Question 5). At the end of weeks 4 and 5, group 2 showed a significant reduction of nearly one point in pain compared to groups 1 and 3, which remained at approximately half a point thereafter.

[0119] Figure 2 The deviation from the initial pain intensity value at the time of assessment was described (Question 6). At the end of week 4 and throughout the subsequent period until the end of treatment, group 2 showed a significant reduction of nearly 1 point in pain compared to group 3, and a reduction of about half a point compared to group 1.

[0120] Given that the amount of trazodone administered to group 2 was half that administered to group 1, the effect obtained in group 2 patients was more surprising. To some extent, it seems reasonable that the synergistic effect is related to the relative ratio of trazodone to gabapentin being less than 1:40.

[0121] In the final weeks of treatment, the effects achieved by Group 2 patients also showed a linear and gradually decreasing trend, giving the impression that prolonged treatment might lead to further reduction in pain perception. This differed from the trends observed in Groups 1 and 3, whose curves appeared to show a constant trend, flattening out after the sixth week.

[0122] Finally, Table 5 below shows the sum of all deviations obtained at each visit for each patient group and for the answers given to Question 5 (i), (ii) the percentage of patients who achieved at least a 50% reduction compared to the initial value, and (iii) the relative NNT index (the number of treatments required).

[0123] Table 5

[0124] Group 1 Group 2 Group 3 Total Deviation -116.3 -142.5** -117.6 Relief of 50% of patients 54.0 62.8 45.8 NNT 12.2 5.9 -

[0125] **Compare with the third group, p<0.5

[0126] These results confirm the surprising effectiveness of the second group of treatments. Compared with the first and third groups, the second group showed a significant increase in overall pain reduction and had a very favorable and promising NNT value.

[0127] Patients receiving treatment also completed the SF-36 health status 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).

[0128] The SF-36 questionnaire comprises a set of 36 questions that define eight different aspects of good general health: physical activity (PF – physical functioning), role and physical health (RP – role participation), bodily pain (BP – bodily pain), general health (GH – general health), vitality (VT – vitality), social activity (SF – social functioning), role and emotional state (RE – emotional role), and mental health (MH – mental health).

[0129] Information from these eight aspects has been compiled to define the Body Component Summary (PCS) and Mental Component Summary (MCS) of health status.

[0130] MCS is primarily associated with vitality (VT), social activity (SF), role and emotional state (RE), and mental health (MH), and is a measure used to estimate the percentage of patients with a positive risk of depression or anxiety compared to the general population.

[0131] The results have been collected in Table 6 below, from which the following information has been obtained. Figure 3 The charts shown.

[0132] Results are expressed as the percentage of patients with a positive risk of depression or anxiety compared to the normal general population with an estimated normal value of 18.

[0133] Table 6

[0134] Group 1 Group 2 Group 3 0th visit 31 52 38 8th visit 25 21 29

[0135] The significant effects of the second treatment group have been shown to reduce the risk of depression in patients with diabetic neuropathy.

[0136] Although at the start of treatment (visit 0), Group 2 had a higher percentage of patients with a positive risk of depression (52%) compared to Group 1 (31%) and Group 3 (38%), this percentage decreased to 21% at the end of treatment (visit 8) (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), which is 18%.

[0137] The results in Table 6 of Group 2 further confirm the hypothesis of a synergistic effect related to the relative amounts of trazodone and gabapentin at a ratio of less than 1:40.

[0138] Example 2 - Formulation

[0139] Tables 7 and 8 below provide some non-complete examples of trazodone and gabapentin formulations for use according to the present invention:

[0140] Table 7

[0141]

[0142]

[0143] Table 8

[0144] tablet mg mg mg Gabapentin 100 300 400 Trazodone 1.50 4.50 6.00 lactose 200 600 600 starch 50 50 50 Sodium glycolate starch 15 45 45 Povidone 5 5 5 magnesium stearate 4 4 4

Claims

1. Use of a pharmaceutical composition in the manufacture of a medicament for treating pain caused by diabetic neuropathy, postherpetic neuralgia, or postoperative neuropathic pain, said pharmaceutical composition comprising (a) (i) a first active ingredient selected from trazodone and its salts and (ii) a second active ingredient selected from gabapentin, its salts, and its prodrugs, wherein said prodrug is gabapentin ester, and (b) at least one pharmaceutically acceptable excipient, wherein said pharmaceutical composition comprises the first active ingredient and the second active ingredient in a weight ratio of less than 1:40 and up to 1:100, said weight ratio being expressed as the weight ratio of trazodone:gabapentin.

2. The use according to claim 1, wherein the pharmaceutical composition comprises the first active ingredient and the second active ingredient in a weight ratio between 1:50 and 1:90, the weight ratio being expressed as the weight ratio of trazodone:gabapentin.

3. The use according to claim 1, wherein the pharmaceutical composition comprises the first active ingredient and the second active ingredient in a weight ratio between 1:60 and 1:80, the weight ratio being expressed as the weight ratio of trazodone:gabapentin.

4. The use according to claim 1, wherein the pharmaceutical composition comprises a first active ingredient in an amount equivalent to trazodone in an amount between 2.50 and 1.00 mg, and a second active ingredient in an amount equivalent to 100 mg gabapentin.

5. The use according to claim 1, wherein the pharmaceutical composition comprises a second active ingredient in an amount equivalent to 100 mg of gabapentin and a first active ingredient in an amount equivalent to trazodone in an amount between 2.50 and 1.00 mg.

6. The use according to claim 1, wherein the pharmaceutical composition comprises a second active ingredient in an amount equivalent to 300 mg of gabapentin and a first active ingredient in an amount equivalent to trazodone in an amount between 7.50 and 3.00 mg.

7. The use according to claim 1, wherein the pharmaceutical composition comprises a second active ingredient in an amount equivalent to 400 mg of gabapentin and a first active ingredient in an amount equivalent to trazodone in an amount between 10.00 and 4.00 mg.

8. The use according to claim 1, wherein the salt is formed using a physiologically acceptable organic or inorganic acid or a physiologically acceptable organic or inorganic base.

9. The use according to claim 1, wherein the first active ingredient and the second active ingredient are incorporated into a single dosage form or respectively incorporated into a first dosage form containing the first active ingredient and a second dosage form containing the second active ingredient.

10. The use according to claim 9, wherein the dosage form is selected from tablets, capsules, and solutions for oral administration.

11. A pharmaceutical composition comprising (a) (i) a first active ingredient selected from trazodone and its salts and (ii) a second active ingredient selected from gabapentin, its salts and its prodrugs, wherein the prodrug is gabapentin ester, and (b) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises the first active ingredient and the second active ingredient in a weight ratio of less than 1:40 and up to 1:100, the weight ratio being expressed as the weight ratio of trazodone:gabapentin.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition comprises the first active ingredient and the second active ingredient in a weight ratio between 1:50 and 1:90, the weight ratio being expressed as the weight ratio of trazodone to gabapentin.

13. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition comprises the first active ingredient and the second active ingredient in a weight ratio between 1:60 and 1:80, the weight ratio being expressed as the weight ratio of trazodone to gabapentin.

14. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition comprises a first active ingredient in an amount equivalent to trazodone in an amount between 2.50 and 1.00 mg, and a second active ingredient in an amount equivalent to 100 mg gabapentin.

15. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition comprises a second active ingredient in an amount equivalent to 100 mg of gabapentin and a first active ingredient in an amount equivalent to trazodone in an amount between 2.50 and 1.00 mg.

16. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition comprises a second active ingredient in an amount equivalent to 300 mg of gabapentin and a first active ingredient in an amount equivalent to trazodone in an amount between 7.50 and 3.00 mg.

17. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition comprises a second active ingredient in an amount equivalent to 400 mg of gabapentin and a first active ingredient in an amount equivalent to trazodone in an amount between 10.00 and 4.00 mg.

18. The pharmaceutical composition of claim 11, wherein the salt is formed using a physiologically acceptable organic or inorganic acid or a physiologically acceptable organic or inorganic base.

19. The pharmaceutical composition of claim 11, wherein the first active ingredient and the second active ingredient are incorporated into a single dosage form or into a first dosage form containing the first active ingredient and a second dosage form containing the second active ingredient, respectively.

20. The pharmaceutical composition of claim 19, wherein the dosage form is selected from tablets, capsules, and solutions for oral administration.

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