Pharmaceutical composition for the treatment of neuropathic pain

Abstract

The present invention relates to a pharmaceutical composition for use in the treatment of neuropathic pain, comprising: (a) a combination of (i) trazodone or a salt thereof, and (ii) gabapentin or pregabalin or mirogabalin or a salt or a prodrug thereof, and (b) at least one pharmaceutically acceptable excipient, wherein the weight ratio of trazodone to gabapentin or pregabalin or mirogabalin is between 1:40 and 1:100, preferably lower than 1:40 and at most 1:100.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising a combination of trazodone and gabapentin or pregabalin or mirogabalin, which has an improving effect in the treatment of neuropathic pain, particularly pain caused by diabetic neuropathy.

Background Art

[0002] Physiological pain is an important protective mechanism designed to warn of danger from potentially harmful stimuli from the external environment. Neuropathic pain is defined as pain that is initiated or caused by primary damage or dysfunction of the nervous system. Neuropathic pain often debilitates, causing loss of the ability to work and a decline in quality of life. It also leads to economic and social harm.

[0003] Analgesics currently used in the treatment of neuropathic pain include non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, narcotic analgesics, and anticonvulsants [Woolf CJ, Mannion RJ, Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999;353: 1959-1964].

[0004] However, neuropathic pain is well known to be difficult to treat with currently available pharmaceuticals. As a result, the development of new drugs has always been one of the major goals of the pharmaceutical industry.

[0005] Diabetic neuropathy is one of the most common long-term symptomatic complications seen in patients with both type 1 and type 2 diabetes. At the time of initial diagnosis, 7.5% of patients are already suffering from painful diabetic peripheral neuropathy, and approximately 45-50% are suffering from this complication after 25 years.

[0006] Diabetic neuropathic pain is generally described as a tingling, burning, stabbing, pricking, or even an electric shock-like sensation. It is usually considered moderate to severe and often worsens at night, causing sleep disturbances. The pain is constant and may be accompanied by allodynia of the skin, which can substantially affect the patient's quality of life, the ability to perform daily activities, and may have a negative impact on mood. The pain can also be a reason for withdrawal from recreation and social activities and may be associated with depression.

[0007] Traditionally, the first step in the management of diabetic neuropathic pain was to improve and optimize glycemic control, but usually additional pain control medications are required.

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

[0009] Gabapentin is a known anti-seizure medication and is currently approved as a treatment for epilepsy and neuropathic pain. Gabapentin is effective in the management of neuropathic pain, and the management of diabetic neuropathy has found the best balance between safety and efficacy in gabapentin.

[0010] Gabapentin is currently widely recommended as a first-line treatment for peripheral diabetic neuropathy by several guidelines, such as those of the American Academy of Neurology, the National Institute for Health and Care Excellence in the UK, 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 a single more effective drug, and monotherapy rarely provides adequate pain relief. The clinical management of painful diabetic neuropathy continues to pose therapeutic challenges, and responses to existing treatments are often inadequate. A wide range of drugs, used alone or in combination, have been shown in randomized comparative trials to significantly reduce neuropathic pain compared to placebo, but pain relief remains inadequate for most patients.

[0012] Trazodone is a well-known antidepressant with a multi-receptor mechanism of action and has been proposed as an alternative treatment to approved analgesics as one of the potentially effective unapproved drugs. Low-dose trazodone has already been used in the treatment of neuropathic pain.

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

[0014] Subsequently, 31 adult diabetic patients with painful distal symmetric polyneuropathy were treated with oral trazodone doses of 50 or 100 mg / day. After 2 weeks of treatment, symptom relief was seen in 61.3% of the patients, and 22.6% were completely alleviated. After the end of the study, all patients who had achieved symptom relief continued to take trazodone without a decline in results or occurrence of side effects. The authors concluded that trazodone appears to be an excellent alternative to tricyclic antidepressants considering 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).

[0015] EP1663398B1 describes a combination for the treatment of neuropathic pain of an alpha-2-delta ligand such as gabapentin or pregabalin and a selective norepinephrine reuptake inhibitor such as (S,S)-reboxetine.

[0016] WO2013 / 002584 describes an analgesic composition comprising two or more components selected from (a) a 5-HT2 receptor antagonist, (b) a P2X receptor antagonist, and (c) either a glycine receptor agonist, a glycine transporter antagonist, a gamma-aminobutyric acid receptor agonist (GABA), and a GABA 1 transporter antagonist (GABA1).

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

[0018] A review on 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. Ris. (2013) 36:237-251. Excellent effects have been observed by the combination of gabapentin and venlafaxine in a neuropathic pain model, and by the co-administration of gabapentin and donepezil and / or duloxetine against neuropathic pain induced by spinal nerve ligation in a nerve injury model.

[0019] Trazodone, and the combination of trazodone and pregabalin, have been studied in the 12-week and 24-week treatment of fibromyalgia as disclosed by 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.

[0020] As disclosed in Fernandez-Duenas 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 combination of trazodone with fentanyl and paracetamol has been studied in a mouse model of visceral pain and shows a potent synergistic antinociceptive effect. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0021] The applicant faces the problem of providing a pharmaceutical composition having an activity superior to that of compositions known in the art for treating neuropathic pain, particularly pain caused by diabetic neuropathy. MEANS FOR SOLVING THE PROBLEM

[0022] Considering the results known in the art, the applicant hypothesized that the combination of trazodone and gabapentin could be used for the treatment of painful diabetic neuropathy and, generally, neuropathic pain.

[0023] The applicant has surprisingly discovered that trazodone can be used in combination with gabapentin in very small relative amounts, where the weight ratio of trazodone to gabapentin is between 1:40 and 1:100, preferably lower than 1:40 and up to 1:100.

[0024] In particular, the applicant has surprisingly discovered that a combination of trazodone and gabapentin, where the weight ratio is between 1:40 and 1:100, preferably lower than 1:40 and up to 1:100, improves the effect of reducing pain due to diabetic neuropathy in subjects treated for 9 weeks with a progressive gabapentin therapy to which concurrent administration of trazodone has been added.

[0025] In a combination where the weight ratio of trazodone to gabapentin exceeds 1:40 (for example, 1:30), there was little improvement in reducing the pain of diabetic neuropathy. Therefore, the effects discovered by the applicant are even more remarkable.

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

[0027] Considering the results obtained with gabapentin, the applicant believes that pregabalin or milogabalin, which are active ingredients similar to gabapentin, when used in combination with trazodone at the same weight ratio, will have the same therapeutic effect and mechanism of action, but will show a stronger and similar effect.

[0028] Accordingly, in a first aspect, the present invention relates to a pharmaceutical composition for use in the treatment of pain due to diabetic neuropathy, comprising (a) (i) a first active ingredient selected from the group consisting of trazodone or a salt thereof, and (ii) a second active ingredient selected from the group consisting of gabapentin, pregabalin, milogabalin, salts thereof, and prodrugs thereof, and (b) at least one pharmaceutically acceptable excipient, wherein the first and second active ingredients are included in a weight ratio represented as a trazodone:gabapentin or pregabalin or milogabalin weight ratio of 1:40 to 1:100, preferably lower than 1:40 and up to 1:100.

[0029] In a second aspect, the present invention relates to a pharmaceutical composition comprising (a) (i) a first active ingredient selected from the group consisting of trazodone or a salt thereof, and (ii) a second active ingredient selected from the group consisting of gabapentin, pregabalin, mirogabalin, salts thereof and prodrugs thereof, and (b) at least one pharmaceutically acceptable excipient, the first and second active ingredients being present in a weight ratio represented as a trazodone:gabapentin or pregabalin or mirogabalin weight ratio of 1:40 to 1:100, preferably lower than 1:40 and up to 1:100, and the method for treating pain due to diabetic neuropathy in a subject in need thereof, which comprises administering an effective amount of the pharmaceutical composition containing the first and second active ingredients.

Brief Description of the Drawings

[0030]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0031] As used in the present specification and claims, the expression "represented as the weight ratio of trazodone: gabapentin or pregabalin or mirogabalin" means that the ratio between the first active ingredient and the second active ingredient is always represented between the equivalent amount of trazodone itself contained in the pharmaceutical composition (even when present as a salt) and the equivalent amount of gabapentin or pregabalin or mirogabalin itself contained in the pharmaceutical composition (even when present as a salt or prodrug).

[0032] As used in the present specification and claims, the term "trazodone" represents the active ingredient 2-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one having the following structural formula (I): [Chemical formula] (I)

[0033] As used in the present specification and claims, the term "gabapentin" represents the active ingredient 2-[1-(aminomethyl)cyclohexyl]acetic acid having the following structural formula (II): [Chemical formula] (II)

[0034] As used in the present specification and claims, the term "pregabalin" represents the active ingredient (S)-3-(aminomethyl)-5-methylhexanoic acid having the following structural formula (III): [Chemical formula] (III)

[0035] As used in the present specification and claims, the term "mirogabalin" 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): [Chemistry]

[0036] The pharmaceutical composition according to the present invention provides a weight ratio of a first active ingredient to a second active ingredient represented by a weight ratio of trazodone: gabapentin or pregabalin or mirogabalin of 1:40 to 1:100, preferably lower than 1:40 and up to 1:100, more preferably 1:50 to 1:90, and even more preferably 1:60 to 1:80, and comprises (i) a first active ingredient selected from the group consisting of a specific amount of trazodone or a salt thereof, and (ii) a first active ingredient selected from the group consisting of a specific amount of gabapentin, pregabalin, mirogabalin, a salt thereof and a prodrug thereof.

[0037] According to the present invention, any value within the above-described trazodone: gabapentin or pregabalin or mirogabalin weight ratio can be used, 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.

[0038] The amounts of the first active ingredient and the second active ingredient contained in the pharmaceutical composition according to the present invention can vary according to the dosage required to achieve the desired effect, but the weight ratio of the first active ingredient and the second active ingredient represented by the weight ratio of trazodone: gabapentin or pregabalin or mirogabalin remains 1:40 to 1:100, preferably less than 1:40, up to 1:100, more preferably 1:50 to 1:90, and even more preferably 1:60 to 1:80.

[0039] It is advantageous for the pharmaceutical composition according to the present invention to contain an amount of a first active ingredient corresponding to an amount of trazodone of 2.50 to 1.00 mg, preferably 2.00 to 1.11 mg, more preferably 1.67 to 1.25 mg, relative to the amount of a second active ingredient corresponding to 100 mg of gabapentin or pregabalin.

[0040] Preferably, the pharmaceutical composition according to the present invention contains an amount of a first active ingredient corresponding to an amount of trazodone of 0.250 to 0.100 mg, preferably 0.200 to 0.111 mg, more preferably 0.167 to 0.125 mg, relative to the amount of a second active ingredient corresponding to 10 mg of milgabalin.

[0041] 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 present invention, trazodone can be added to such compositions to provide a weight ratio represented as a trazodone:gabapentin weight ratio of 1:40 to 1:100, preferably less than 1:40, up to 1:100, more preferably 1:50 to 1:90, even more preferably 1:60 to 1:80, for combination use in the treatment of painful diabetic neuropathy.

[0042] Thus, according to a first embodiment, the pharmaceutical composition according to the present invention contains an amount of a second active ingredient corresponding to 100 mg of gabapentin, and an amount of a first active ingredient corresponding to an amount of trazodone of 2.50 to 1.00 mg, preferably 2.00 to 1.11 mg, more preferably 1.67 to 1.25 mg.

[0043] Thus, according to a second embodiment, the pharmaceutical composition according to the present invention contains an amount of a second active ingredient corresponding to 300 mg of gabapentin, and an amount of a first active ingredient corresponding to an amount of trazodone of 7.50 to 3.00 mg, preferably 6.00 to 3.33 mg, more preferably 5.00 to 3.75 mg.

[0044] Accordingly, according to the third embodiment, the pharmaceutical composition according to the present invention comprises an amount of a second active ingredient corresponding to 400 mg of gabapentin, and an amount of a first active ingredient corresponding to an amount of trazodone of 10.00 to 4.00 mg, preferably 8.00 to 4.44 mg, more preferably 6.67 to 5.00 mg.

[0045] Other embodiments of the pharmaceutical composition according to the present invention can be considered to be within the scope of the present invention as long as the weight ratio of trazodone:gabapentin is maintained.

[0046] Compositions of pregabalin 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 of pregabalin. According to the present invention, trazodone can be added to such compositions to provide a weight ratio represented as a weight ratio of trazodone:pregabalin of 1:40 to 1:100, preferably less than 1:40, up to 1:100, more preferably 1:50 to 1:90, even more preferably 1:60 to 1:80 for combination use in the treatment of diabetic neuropathic pain.

[0047] Accordingly, according to the first embodiment, the pharmaceutical composition according to the present invention comprises an amount of a second active ingredient corresponding to 50 mg of pregabalin, and an amount of a first active ingredient corresponding to an amount of trazodone of 1.25 to 0.50 mg, preferably 1.00 to 0.56 mg, more preferably 0.83 to 0.63 mg.

[0048] Accordingly, according to the second embodiment, the pharmaceutical composition according to the present invention comprises an amount of a second active ingredient corresponding to 100 mg of pregabalin, and an amount of a first active ingredient corresponding to an amount of trazodone of 2.50 to 1.00 mg, preferably 2.00 to 1.11 mg, more preferably 1.67 to 1.25 mg.

[0049] Accordingly, according to the third embodiment, the pharmaceutical composition according to the present invention comprises an amount of a second active ingredient corresponding to 300 mg of pregabalin and an amount of a first active ingredient corresponding to an amount of trazodone of 7.50 to 3.00 mg, preferably 6.00 to 3.33 mg, more preferably 5.00 to 3.75 mg.

[0050] Other embodiments of the pharmaceutical composition according to the present invention can be considered to be within the scope of the present invention as long as the weight ratio of trazodone:pregabalin is maintained.

[0051] Compositions of milogabalin known in the art generally contain 2.5 mg to 30 mg of milogabalin, particularly 2.5 mg, 5 mg, 10 mg, 15 mg and 30 mg of milogabalin. According to the present invention, trazodone can be added to such compositions to provide a weight ratio represented as a weight ratio of trazodone:milogabalin of 1:40 to 1:100, preferably less than 1:40, up to 1:100, more preferably 1:50 to 1:90, even more preferably 1:60 to 1:80 for combination use in the treatment of diabetic neuropathic pain.

[0052] Accordingly, according to the first embodiment, the pharmaceutical composition according to the present invention comprises an amount of a second active ingredient corresponding to 5 mg of milogabalin and an amount of a first active ingredient corresponding to an amount of trazodone of 0.125 to 0.050 mg, preferably 0.100 to 0.056 mg, more preferably 0.083 to 0.063 mg.

[0053] Accordingly, according to the second embodiment, the pharmaceutical composition according to the present invention comprises an amount of a second active ingredient corresponding to 10 mg of milogabalin and an amount of a first active ingredient corresponding to an amount of trazodone of 0.250 to 0.100 mg, preferably 0.200 to 0.111 mg, more preferably 0.067 to 0.125 mg.

[0054] Accordingly, according to the third embodiment, the pharmaceutical composition according to the present invention comprises an amount of a second active ingredient corresponding to 15 mg of milogabalin, and an amount of a first active ingredient corresponding to an amount of trazodone of 0.375 to 0.150 mg, preferably 0.300 to 0.167 mg, more preferably 0.250 to 0.187 mg.

[0055] Other embodiments of the pharmaceutical composition according to the present invention can be considered to be within the scope of the present invention as long as the weight ratio of trazodone: milogabalin is maintained.

[0056] Gabapentin or pregabalin or a milogabalin prodrug is included within the scope of the present invention. Chemically modified drugs or prodrugs have a pharmacokinetic profile different from that of the parent drug, allow for easier absorption through the mucosal epithelium, improve the formulation of salts and / or solubility, and improve systemic stability (for example, due to an increase in plasma half-life).

[0057] Such chemical modifications can be (i) ester derivatives, (ii) amide derivatives, (iii) carbamate derivatives, (iv) N-acyl-oxyalkyl derivatives, (v) N-acyl-oxyalkoxycarbonyl derivatives, (vi) peptides, and (vii) any combination thereof.

[0058] Esters can be derived from the carboxyl group of the drug molecule by known means. Amides can be derived from the carboxyl group or amine group of the drug molecule by known means. Derivatives of esters or amides can be decomposed, for example, by esterases or lipases.

[0059] The number of carbon atoms present in the compounds used to produce these ester, amide, carbamate, N-acryloxyalkyl, and N-acryloxyalkoxycarbonyl derivatives is 10 or less, preferably 7 or less, more preferably 5 or less. Useful examples of the compounds are alcohols, carboxylic acids, and amines having 1 to 5 carbon atoms.

[0060] The peptide can be coupled to a drug molecule via the formation of an amide bond with the carboxyl or amine group of the drug molecule by known means. The peptide can be recognized by specific or non-specific proteases.

[0061] The number of amino acids present in the compounds used to obtain these peptide derivatives is 5 or less, preferably 4 or less, more preferably 3 or less.

[0062] Carbamates, N-cyclooxyalkoxyalkyl derivatives and N-cyclooxyalkoxycarbonyl derivatives can be derived from the amino group of a drug molecule by known means. These derivatives can be decomposed by esterases and / or may decompose spontaneously.

[0063] 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.

[0064] A particularly useful example of a gabapentin prodrug is gabapentin enacarbil, IUPAC chemical name 2-(1-{[({1-[(2-methylpropanoyl)oxy]ethoxy}carbonyl)amino]methyl}cyclohexyl)acetic acid, and has the following structural formula:

Chemical formula

[0065] The salts of trazodone, gabapentin, pregabalin and mirogabalin are included within the scope of the present invention. The salts can be formed from physiologically acceptable organic and inorganic compounds having an acidic or basic function.

[0066] Typical examples of suitable physiologically acceptable inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid.

[0067] 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.

[0068] 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.

[0069] 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, glucamine, glucosamine, histidine, N-(2-hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, theobromine, triethylamine, trimethylamine, tripropylamine and tromethamine.

[0070] Preferably, the pharmaceutical composition according to the present invention is for systemic use.

[0071] More preferably, the pharmaceutical composition according to the present invention is formulated for oral or parenteral administration.

[0072] Preferably, the pharmaceutical composition according to the present invention is prepared in a suitable dosage form.

[0073] Examples of suitable dosage forms are tablets, capsules, coated tablets, granules and solutions for oral administration, as well as syrups; creams, ointments and disinfectant patches for topical administration; suppositories for rectal administration; and sterile solutions for injection, aerosol or ophthalmic administration.

[0074] Preferred dosage forms are tablets, coated tablets, capsules and solutions for oral administration.

[0075] The dosage form of the pharmaceutical composition according to the present invention can be prepared according to techniques well known to pharmaceutical chemists, including mixing, granulation, compression, dissolution, sterilization, etc.

[0076] These dosage forms are advantageously formulated to ensure a controlled release of the active ingredient over time. In particular, depending on the type of treatment, the required release time can be very short, normal or long.

[0077] Preferably, the pharmaceutical composition according to the present invention is included in a single dosage form.

[0078] The present invention also provides a plurality of dosage forms comprising an amount of the first active ingredient and the second active ingredient to be simultaneously ingested, respectively, for administration in a weight ratio of the first active ingredient to the second active ingredient represented as a weight ratio of trazodone: gabapentin or pregabalin or mirogabalin of 1:40 to 1:100, preferably lower than 1:40 and up to 1:100, more preferably 1:50 to 1:90, even more preferably 1:60 to 1:80.

[0079] For example, for combination use in the treatment of painful diabetic neuropathy, a dosage form containing gabapentin or pregabalin 100 mg can be combined with a dosage form containing trazodone of 2.50 - 1.00 mg, preferably 2.00 - 1.11 mg, more preferably 1.67 - 1.25 mg.

[0080] Similarly, for combination use in the treatment of painful diabetic neuropathy, a dosage form containing mil Gabapentin 10 mg can be associated with a dosage form containing trazodone of 0.250 - 0.100 mg, preferably 0.200 - 0.111 mg, more preferably 0.167 - 0.125 mg.

[0081] Pharmaceutically acceptable excipients can be selected from the group consisting of thickeners, glidants, binders, disintegrants, fillers, diluents, preservatives, stabilizers, surfactants, buffers, fluidizing agents, lubricants, wetting agents, absorbents, salts for adjusting osmotic pressure, emulsifiers, fragrances, colorants, sweeteners, etc.

[0082] Particularly preferred excipients are sodium carbonate, magnesium carbonate, magnesium stearate, talc, saccharides, lactose, pectin, dextrin, starch (especially corn starch), sodium starch glycolate, gelatin, microcrystalline cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, povidone, cocoa butter, titanium dioxide (E171), red iron oxide, yellow iron oxide (E172), etc.

[0083] The pharmaceutical composition according to the present invention has been proven to be surprisingly useful for the treatment of pain caused by diabetic neuropathy, but is also considered to be usable for the treatment of pain caused by other types of neuropathy, particularly postherpetic neuralgia and postoperative neuropathic pain.

[0084] The following examples are intended to further illustrate the present invention, but do not limit the present invention.

Example

[0085] Example 1 - Clinical Research The clinical study was conducted in a population of 142 patients aged 18 to 75 years, both male and female, suffering from diabetic neuropathy. The patients were divided into three groups and subjected to a randomized, double-blind, placebo-controlled, parallel-group clinical trial, with the patients in Group 2 as the subjects.

[0086] Group 1 was treated with 20 mg of trazodone (10 drops of 6% trazodone hydrochloride solution) three times a day for 8 weeks, for a total of 60 mg per day.

[0087] Group 2 was treated with 10 mg of trazodone (5 drops of 6% trazodone hydrochloride solution) three times a day for 8 weeks, for a total of 30 mg per day.

[0088] Group 3 was treated with placebo, 10 drops of oral placebo solution, three times a day for 8 weeks.

[0089] In the 9th week after the clinical trial ended, Group 1 was treated with 10 mg of trazodone three times a day, for a total of 30 mg / day, and both Group 2 and Group 3 were treated with placebo.

[0090] The 6% trazodone hydrochloride solution contained 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, if necessary, 100 mL of purified water. The placebo solution was the same as the trazodone solution but did not contain the active ingredient.

[0091] Gabapentin was administered at a gradually increasing dose to all patients treated according to the dosing schedule shown in Table 1 below, using commercially available gabapentin (Neurontin®, Pfizer) capsules containing 100 mg, 300 mg, and 400 mg. The capsules contained lactose monohydrate, corn starch, and talc as excipients, as well as a combination of colors E171 and E772.

[0092] Table 1 [Table 1]

[0093] The following Table 2 shows the trazodone:gabapentin ratio for each of Groups 1 and 2 during treatment: Table 2 [Table 2]

[0094] At the start of treatment and at the end of each treatment week, patients in treatment completed a Brief Pain Inventory-Short Form (BPI-SF) that included a series of questions regarding self-assessment of pain (Zelman DC, et al., "Validation of a modified version of the pain inventory brief for painful diabetic peripheral neuropathy", J. Pain Symptom Manage. 2005 Apr;29(4):401-10).

[0095] Specifically, patients rated the average pain intensity during the week prior to assessment (Question 5) and at the time of assessment (Question 6) on a scale of 0-10, where 0 represents "no pain" and 10 represents "pain as bad as you can imagine".

[0096] At each clinic visit, assessments were collected and processed to determine the deviation from the mean value obtained for each group at the start of treatment. The results were compiled in Tables 3 and 4 below, from which the graphs shown in Figures 1 and 2 were obtained, respectively.

[0097] Table 3 [Table 3] * p<0.05 vs Group 3 ** p<0.1 vs Group 3 *** p<0.5 vs Group 3

[0098] Table 4

Table 4

[0099] Figure 1 shows the deviation from the value of the initial pain intensity in the week before the assessment (Question 5). At the end of the 4th and 5th weeks, Group 2 had a pain reduction of nearly 1 point compared to Groups 1 and 3, and remained at about half a point for the following weeks.

[0100] Figure 2 shows the deviation from the initial pain intensity value at the time of assessment (Question 6). Throughout the end of the 4th week and the period until the end of subsequent treatment, Group 2 showed a significant reduction in pain of nearly 1 point compared to Group 3 and about half as much compared to Group 1.

[0101] Within the range where the synergistic effect related to the relative amounts of trazodone and gabapentin at ratios of less than 1:40 is valid, all the effects obtained in the patients of Group 2 are even more surprising considering that the amount of trazodone administered to Group 2 was half the amount administered to Group 1.

[0102] The effects obtained in the patients of Group 2 also showed a tendency to decrease linearly and progressively in the last few weeks of treatment. Thus, different from the tendency brought about by the patients of Groups 1 and 3 where the curve shows a certain tendency and appears to flatten after 6 weeks, it gives the impression that an extension of the treatment may lead to a further reduction in the perception of pain.

[0103] Finally, Table 5 below shows, for each patient group and the responses to Question 5, (i) the sum of all the deviations obtained at each visit, (ii) the proportion of patients who had at least a 50% reduction compared to the initial value, and (iii) the relative NNT (number needed to treat) index.

[0104] Table 5

Table 5

[0105] These results confirmed the surprising effect of the treatment in Group 2, with a substantial increase in overall pain reduction and a very favorable and promising NNT value, when compared to both Group 1 and Group 3.

[0106] Patients during treatment also answered the SF-36 Health Status 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).

[0107] The SF-36 questionnaire consists of a set of 36 questions that define eight different aspects of general health, namely physical activity (PF - Physical Function), role and physical health (RP - Role Participation), physical pain (BP - Bodily Pain), general health (GH - General Health), vitality (VT - Vitality), social activity (SF - Social Function), role and emotional state (RE - Emotional Role), and mental health (MH - Mental Health).

[0108] The information obtained from these eight aspects is aggregated to define a summary of the physical components (PCS) and a summary of the mental components (MCS) of the health status.

[0109] MCS is mainly related to the aspects of vitality (VT), social activity (SF), role and emotional state (RE), and mental health (MH), and is an indicator used to estimate the proportion of patients with a positive risk of depression and anxiety compared to the normal general population.

[0110] The results are summarized in Table 6 below, from which the graph shown in Figure 3 has been obtained.

[0111] The results are presented as the percentage of patients with a positive risk of depression or anxiety compared to a normal general population in which 18 normal values are estimated.

[0112] Table 6

Table 6

[0113] A marked effect of group 2 treatment has been shown to reduce the risk of depression in patients with diabetic neuropathy. A marked effect of group 2 treatment has been shown to reduce the risk of depression in patients with diabetic neuropathy.

[0114] At the start of treatment (clinic visit 0), a higher percentage (52%) of group 2 patients showed a positive risk of depression compared to group 1 (31%) and group 3 (38%), but at the end of treatment (clinic visit 8), the risk percentage for group 2 decreased to 21% (compared to 25% for group 1 and 29% for group 3). This value is very close to the estimated risk of depression in the general population (indirect control) of 18%.

[0115] The results in Table 6 for 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.

[0116] Example 2 - Formulation The following Tables 7 and 8 provide some non - comprehensive examples of trazodone and gabapentin formulations for use according to the present invention. Table 7

Table 7

[0117] Table 8

Table 8

Claims

1. A pharmaceutical composition for use in the treatment of pain selected from the group consisting of pain due to diabetic neuropathy, postherpetic neuralgia, and postoperative neuropathic pain, comprising (a) (i) a first active ingredient selected from the group consisting of trazodone or a salt thereof, and (ii) a second active ingredient selected from the group consisting of gabapentin, a salt thereof, and a prodrug thereof, and (b) at least one pharmaceutically acceptable excipient, wherein the prodrug is gabapentin enacarbil, and the weight ratio of the first active ingredient to the second active ingredient is lower than 1:40 and at most 1:100, expressed as a weight ratio of trazodone:gabapentin.

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

90.

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

80.

4. The pharmaceutical composition for use according to claim 1, comprising an amount of the first active ingredient corresponding to an amount of trazodone of 2.50 to 1.00 mg, preferably 2.00 to 1.11 mg, more preferably 1.67 to 1.25 mg, relative to the amount of the second active ingredient corresponding to 100 mg of gabapentin.

5. The pharmaceutical composition for use according to claim 1, comprising an amount of the second active ingredient corresponding to 100 mg of gabapentin, and an amount of the first active ingredient corresponding to an amount of trazodone of 2.50 to 1.00 mg, preferably 2.00 to 1.11 mg, more preferably 1.67 to 1.25 mg.

6. The pharmaceutical composition for use according to claim 1, comprising an amount of a second active ingredient corresponding to 300 mg of gabapentin and an amount of a first active ingredient corresponding to an amount of trazodone of 7.50 to 3.00 mg, preferably 6.00 to 3.33 mg, more preferably 5.00 to 3.75 mg.

7. The pharmaceutical composition for use according to claim 1, comprising an amount of a second active ingredient corresponding to 400 mg of gabapentin and an amount of a first active ingredient corresponding to an amount of trazodone of 10.00 to 4.00 mg, preferably 8.00 to 4.44 mg, more preferably 6.67 to 5.00 mg.

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the salt is formed with a physiologically acceptable organic and inorganic acid or base.

9. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the first active ingredient and the second active ingredient are incorporated into a single dosage form or each is incorporated into a first dosage form containing the first active ingredient and a second dosage form containing the second active ingredient.

10. The pharmaceutical composition according to claim 9, wherein the dosage form is selected from the group consisting of tablets for oral administration, coated tablets, capsules and solutions.

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