Oral veterinary composition with gabapentin

Abstract

The present invention relates to a solid veterinary pharmaceutical composition, of oral administration comprising: a) a drug selected from gabapentin and/or fluoxetine or a pharmaceutically acceptable salt thereof, preferably gabapentin or an acceptable salt thereof in a concentration from 10 to 1000 mg; b) from 10% to 80% of the composition total weight of at least one silicon salt selected preferably from silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate or combinations thereof; c) from 1% to 20% of the composition total weight of at least one polyoxyethylenated sorbitan ester, preferably selected from sorbitan monolaurate, sorbitan monooleate and sorbitan trioleate, or combinations thereof; and d) one or more pharmaceutically acceptable excipients; such that it is optimally prepared as a veterinary pharmaceutical product that exhibits safety and efficacy in mammalian animals, preferably in companion animals.

Claims

1. A stable solid veterinary composition for oral administration, wherein the composition is in the form of a segmentable tablet and comprising: a) gabapentin or a pharmaceutically acceptable salt thereof in a concentration of 1 to 1000 mg; b) from 10% to 80% of the composition total weight of silicon dioxide or colloidal silicon dioxide, in a concentration of no more than 80% of the total weight; c) from 1% to 20% of the total weight of the composition of sorbitan monolaurate; d) from 13.3% to 60.9% of the total weight of the composition of a diluent selected from cellulose microcrystalline, mannitol, lactose and combinations thereof; e) from 1.0% to 14.0% of the total weight of the composition of a disintegrant selected from croscarmellose, crospovidone and a combination thereof; f) one lubricating agent; and g) optionally one coloring agent.

2. A The solid veterinary composition for oral administration according to claim 1, wherein the gabapentin or a pharmaceutically acceptable salt thereof is in a concentration of 100 to 400 mg.

3. The solid veterinary composition for oral administration according to claim 1 or 2, useful for the pain treatment and/or epilepsy wherein the gabapentin or a pharmaceutically acceptable salts thereof is in a dose range of 10 to 20 mg/Kg by weight of the veterinary patient, and preferably in a dose range of 1.5 to 10 mg/Kg by weight of the veterinary patient.

4. The solid veterinary composition for oral administration according to claim 1, wherein the colorant is selected from caramel, ferric oxide, red, yellow, titanium oxide, carmoisine, bluish black of naphthol, erythrosine, amaranth and combinations thereof.

5. The solid veterinary composition for oral administration according to claim 1, wherein optionally contains vitamin B1, vitamin B2, vitamin B12 or the combination thereof.

6. The solid veterinary composition according to claim 1, wherein the tablet is adapted to be segmented into equal parts, and wherein: a) Each segment retains a specific amount of gabapentin or a pharmaceutically acceptable salt thereof; b) The integrity of the doses is not compromised; c) The segmentation of the tablet is made manually or by a mechanical process; and d) The segments comprise no more than four and not less than two segments.

7. The solid veterinary composition according to claim 1, and which wherein the composition is useful for treating pain and/or epilepsy in mammalian animals of different weight and/or size.

8. The solid veterinary composition according to claim 1, wherein the composition is useful for treating pain or epilepsy in companion animals with different weight and/or size.

9. The solid veterinary composition according to claim 1, useful for the treatment of mild, moderate and/or severe pain.

10. The solid veterinary composition according to claim 1, useful for the treatment of epilepsy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1. Graph of the seizure number after administration of phenobarbital to the G0-E group.

(2) FIG. 2. Graph of the seizure number after administration of gabapentin in a dose of 10 mg/Kg of weight divided 3 times a day, to the G1-E group.

(3) FIG. 3. Graph of the seizure number after administration of gabapentin in a dose of 20 mg/Kg of weight divided 3 times a day, to the G2-E group.

DETAILED DESCRIPTION OF THE INVENTION

(4) The present invention relates to a solid veterinary pharmaceutical composition for oral administration comprising: a) a drug selected from gabapentin and/or fluoxetine or an acceptable salt thereof in a concentration of 1 to 1000 mg; b) from 10% to 80% of the composition total weight of at least one silicon salt selected preferably from silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate or combinations thereof; c) from 1% to 20% of the composition total weight of at least one polyoxyethylenated sorbitan ester, preferably selected from sorbitan monolaurate, sorbitan monooleate and sorbitan trioleate, or combinations thereof; and d) one or more pharmaceutically acceptable excipients; such that it is optimally prepared as a veterinary pharmaceutical product that exhibits safety and efficacy in mammalian animals, preferably not limited to companion animals.

(5) The solid oral veterinary pharmaceutical composition with potentiated analgesic effect comprises: a) gabapentin and/or an acceptable salt thereof; b) at least one silicon salt; c) at least one disintegrant; d) at least one anti-binding agent; e) at least one diluent, f) at least one lubricant and, optionally, g) at least one colorant.

(6) Where the disintegrant may be at least one of the following excipients: microcrystalline cellulose, alginic acid, sodium croscarmellose, crospovidone, hydroxypropyl cellulose, potassium polacrilin, pullulan, starch, sodium starch glycolate, gelatinized starch, among others.

(7) Where the anti-binding agent can be at least one of the following excipients: calcium silicate, magnesium silicate, colloidal silicon dioxide, talc, hydrophobic colloidal silica, among others.

(8) Where the diluent can be at least one of the following excipients: calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, dextrose, fructose, kaolin, mannitol, lactose, maltodextrin, maltose, starch, sorbitol, sucrose, among others.

(9) Where the lubricant may be at least one of the following excipients: calcium stearate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monopalmitate, polysorbate, talc, starch, stearic acid, ether oleyl polyoxyl 10, polyoxyl 35 castor oil, zinc stearate, among others.

(10) Where the colorant can be at least one of the following excipients: caramel, ferric oxide, red, yellow, titanium oxide, carmoisine, bluish black of naphthol, erythrosin, amaranth or mixtures.

(11) The inclusion of at least one drying agent in the composition resulted, in an unexpected manner, in obtaining a composition with greater stability compared to a composition obtained without the inclusion of said component.

(12) The drying agent is selected in a non-restrictive manner from calcium chloride, silicon dioxide and calcium sulfate, preferably silicon dioxide.

(13) It was obtained as a product of the present invention a composition of high stability, which additionally potentiates the analgesic effect of gabapentin when administered orally to animals, preferably not limited to companion animals.

(14) Within the state of the art, is reported the use of gabapentin for the pain treatment in humans (MX223993); the combination of gabapentin and meloxicam, but focus on the pain treatment by castration, dehorning and marking of ruminant and pre-ruminant animals (US2013123245), however, the inclusion of meloxicam, which is an NSAID, a composition is obtained with a high level of toxicity for animals that has an analgesic effect; additionally, the studies described in said document were carried out in ruminant calves and cattle and do not describe a specific composition.

(15) Another combination described in the state of the art comprises gabapentin and carprofen for use in cats, dogs and horses suffering from pain or inflammation (WO2006123247); as reported in the state of the art, are the patents referenced above as well as products commercially available pharmaceuticals, however, is not described in the state of the art an oral pharmaceutical composition for the pain prevention and/or treatment or epilepsy for veterinary use.

(16) Within the literature regarding the use of gabapentin is a series of articles that mention it in studies for veterinary species. Among which there are: studies to determine the effectiveness of an analgesic method in which is administrated meloxicam (1 mg/Kg oral), gabapentin (15 mg/Kg oral), meloxicam (1 mg/Kg intravenous), gabapentin (15 mg/Kg oral), flunixin (2.2 mg/Kg intravenous) and a placebo for the treatment of calf dehorning, obtaining that gabapentin alone or with meloxicam significantly decreases the concentration of substance P and the average daily gain compared to the control (Glynn H D, 2012).

(17) In addition, studies have been conducted to determine the pharmacokinetic and behavioral profile in horses for gabapentin, for which 20 mg/kg of gabapentin was administered orally or intravenously to six horses using a randomized cross-over design, the concentration of the compound in plasma was measured in samples collected in 0-48 hours post-administration using a mass spectrometer by liquid chromatography, obtaining a half-life of 8.5 h IV and 7.7 h p.o. Gabapentin administered orally had a relatively low absorption (bioavailability 16.2.sup.+-2.8%); in terms of behavior, drinking water was consistently greater and staying at rest was lower in the animals that took intravenous gabapentin. Another study about the pharmacokinetics of gabapentin in horses shows that when administering a dose of 5 mg/Kg oral it is quickly absorbed and with a half-life of 3.4 h, and when compared said results with those obtained in humans, rats and monkeys, the Cmax is higher in these than in horses, which also indicates that the absorption of gabapentin is relatively slow and rapidly metabolized in horses, unlike other species, and in the case of the half-life this is relatively similar to that reported in dogs (3.4 h) (Terry R L, et al., 2010).

(18) There is a study in which gabapentin is administered intraperitoneally in rats 100-1000 mg/kg, after administration the rats eat and drink freely, after two hours they are administered 100 mg/kg of phenobarbital and 0.4 ml 2N of 3-mercaptopropanoic acid, and the brain of the animal is obtained by separating it from the cerebellum and freezing it with liquid nitrogen, the blood is also collected from the body, when performing the analysis of the samples it was obtained that the gabapentin and its isoform pregabalin with antiepileptic effects decrease the cellular concentrations of glutamate (0.6-0.9% mN, 4-7%), which indicates that although the decrease was modest, these compounds could decrease cortical glutamate associated with epilepsy states (Errante L D and Petroff O A C, 2003).

(19) Another article of interest is that in which studies are done with gabapentin to evaluate its functionality in the treatment of neuropathic pain, in that article it is administered subcutaneously individually morphine 3.2 mg/Kg and gabapentin 17.8 mg/Kg reaching its maximum effect at 60 minutes post-treatment, producing an antihyperalgesic effect of 51.7% and 55%. While the combined administration produced an almost total antihyperalgesic effect at 30 minutes (96.7%) and 100% at 60 minutes (Arciniega M O, et al., 2007).

(20) For the development of this invention, studies were carried out to determine the safest and most effective dose and veterinary composition in order to provide a representative improvement to the existing compositions in the state of the art, the effectiveness of the composition being tested in two main treatments, the pain treatment and epilepsy.

(21) The present invention relates to various veterinary pharmaceutical compositions for the oral administration of gabapentin, among which are, but are not limited to: tablets, sublingual tablet, chewable tablets, modified-release tablets, bolus, hard and soft gelatin capsules, powder, granules and/or effervescent tablets; preferably segmentable tablets that comprise the same physical, chemical and therapeutic characteristics in each segment obtained.

(22) The above described compositions contain at least one pharmaceutically acceptable excipient selected from the following group: release polymers, binder, lubricant, solvent, diluent, dissolving modifying agent, desiccant, colorant, glidant, solubility enhancing agent, disintegrant, superdisintegrant, anti-binding agent, among others known in pharmaceutical practice.

(23) In the following, the compositions used during the development of the invention are described by way of illustrative, but not limiting, examples:

EXAMPLES

Example 1. Composition of Gabapentin with 50% Silicon Salt and 14% Polyoxyethylenated Sorbitan Ester

(24) TABLE-US-00001 Content % w/w Components A B C D Gabapentin 5 5 5 5 Silicon dioxide 50 0 0 0 Colloidal silicon dioxide 0 50 0 0 Calcium silicate 0 0 50 0 Magnesium silicate 0 0 0 50 Mannitol 10 10 10 10 Cellulose 8 8 8 8 Sodium croscarmellose 5.9 5.9 5.9 5.9 Crospovidone 5 5 5 5 Sorbitan monolaurate 14 14 14 14 Talc 2 2 2 2 Colorant 0.1 0.1 0.1 0.1

Example 2. Composition of Gabapentin with 10% Silicon Salt

(25) TABLE-US-00002 Components Content % w/w Gabapentin 5 Colloidal silicon dioxide 10 Mannitol 20 Cellulose 15 Sodium croscarmellose 12.9 Crospovidone 5 Sorbitan monolaurate 30 Talc 2 Colorant 0.1

Example 3. Composition of Gabapentin with 10% Desiccating Agent

(26) TABLE-US-00003 Components Content % Gabapentin 5 Silicon dioxide 10 Lactose 40 Cellulose 20.9 Hydroxypropylmethyl cellulose 18 Povidone 3 Sodium stearyl fumarate 2 Sodium lauryl sulfate 1 Colorant 0.1

Example 4. Composition of Gabapentin with 80% Desiccating Agent

(27) TABLE-US-00004 Components Content % Gabapentin 5 Silicon dioxide 80 Lactose 8.3 Cellulose 5 Hydroxypropylmethyl cellulose 0 Povidone 1 Magnesium stearate 0.5 Talc 0.1 Colorant 0.1

Example 5. Composition of Fluoxetine with 10% Silicon Salt

(28) TABLE-US-00005 Components Content % w/w Fluoxetine 1 Colloidal silicon dioxide 10 Mannitol 24 Cellulose 15 Sodium croscarmellose 12.9 Crospovidone 5 Sorbitan monolaurate 30 Talc 2 Colorant 0.1
Efficiency Evaluation of the Composition in the Treatment of Epilepsy.

(29) In order to comply with the various objectives of the present invention, studies were carried out to demonstrate the efficacy of gabapentin as treatment against idiopathic epilepsy in dogs, in said studies participated 30 animals of different races, aged from 1 to 5 years, variable weights and diagnosed with idiopathic epilepsy; the animals that had diseases were discarded and the following groups were formed:

(30) a) G0-E Group: treated with phenobarbital at dose of 2 mg/Kg of body weight, every 12 hours.

(31) b) G1-E Study Group: treated with gabapentin of 10 mg/Kg of body weight, divided 3 times a day by oral administration.

(32) c) G2-E Study Group: treated with gabapentin of 20 mg/Kg of body weight, divided 3 times a day by oral administration.

(33) Patients were monitored for 3 consecutive months, quantifying seizure episodes for each of the patients, obtaining the following:

(34) TABLE-US-00006 TABLE 1 Evaluation of Gabapentin and Phenobarbital for the treatment of epilepsy (seizure number) Seizure number Seizure number per month per month Group Patient prior to the study after the study G0-E 0-E-I 2 0 0-E-II 1 1 0-E-III 3 0 0-E-IV 11 4 0-E-V 13 1 0-E-VI 2 0 0-E-VII 8 0 0-E-VIII 7 0 0-E-IX 2 1 0-E-X 10 1 G1-E 1-E-I 11 0 1-E-II 4 RESCUED 1-E-III 5 0 1-E-IV 8 RESCUED 1-E-V 5 1 1-E-VI 10 0 1-E-VII 6 0 1-E-VIII 1 0 1-E-IX 3 0 1-E-X 9 0 G2-E 2-E-I 8 2 2-E-II 2 0 2-E-III 12 1 2-E-IV 2 1 2-E-V 8 0 2-E-VI 8 RESCUED 2-E-VII 6 0 2-E-VIII 4 3 2-E-IX 4 0 2-E-X 3 2

(35) FIG. 1 shows the seizure number obtained by the administration of phenobarbital, while FIGS. 2 and 3 show the effect on the seizure number with oral administration of gabapentin in doses of 10 mg/kg and 20 mg/kg, respectively. From these results, it is important to highlight that the administration of oral compositions in doses evaluated, allows a control of seizure episodes, being unexpectedly, the dose of 10 mg/kg, the concentration that best result shows with a significant reduction of seizures at the month 3 of treatment.

(36) Given the previous result, Table 2 shows the changes observed in the seizures of the patients in each group, as well as the clinical adverse effects that were observed during the treatment.

(37) TABLE-US-00007 TABLE 2 Evaluation of Gabapentin and Phenobarbital for the treatment of epilepsy (changes and adverse effects) Changes in the Clinical adverse Group Patient type of seizure effects observed G0-E 0-E-I NONE LIGHT SEDATION 0-E-II PARTIAL CONVULSIONS NONE 0-E-III NONE NONE 0-E-IV CLONIC TONIC NONE 0-E-V CLONIC TONIC HYPER- EXCITATION 0-E-VI NONE NONE 0-E-VII PARTIAL CONVULSIONS LIGHT SEDATION 0-E-VIII CLONIC TONIC NONE 0-E-IX PARTIAL CONVULSIONS NONE 0-E-X PARTIAL CONVULSIONS LIGHT SEDATION G1-E 1-E-I NONE NONE 1-E-II NONE NONE 1-E-III PARTIAL CONVULSIONS NONE 1-E-IV NONE NONE 1-E-V PARTIAL CONVULSIONS LIGHT SEDATION 1-E-VI PARTIAL CONVULSIONS NONE 1-E-VII PARTIAL CONVULSIONS NONE 1-E-VIII NONE NONE 1-E-IX NONE NONE 1-E-X NONE NONE G2-E 2-E-I PARTIAL CONVULSIONS LIGHT SEDATION 2-E-II NONE NONE 2-E-III CLONIC TONIC SOMNOLENCE 2-E-IV CLONIC TONIC NONE 2-E-V NONE NONE 2-E-VI PARTIAL CONVULSIONS LIGHT SEDATION 2-E-VII NONE LIGHT SEDATION 2-E-VIII CLONIC TONIC NONE 2-E-IX NONE NONE 2-E-X PARTIAL CONVULSIONS NONE

(38) It is clear that the reduction of the treatment dose in the composition shows less adverse effects than those obtained by the administration of the dose of 20 mg/Kg, additionally and unexpectedly, has less adverse effects than the composition containing phenobarbital.

(39) Efficiency Evaluation of the Composition in the Pain Treatment.

(40) In addition to the tests performed for the treatment of epilepsy, the effect of gabapentin in the pain treatment in dogs caused by osteoarthritis was evaluated, 30 animals of race, age, weight and variable sex were used, with 3/5 of body condition and clinical and radiological signs from moderate to severe of osteoarthritis, according to the Bioarth scale. Two study groups were formed:

(41) a) G0-D Group: treated with fluoxetine at dose of 1 mg/Kg of body weight, every 12 hours, orally.

(42) b) G1-D Group: treated with gabapentin of 1.5-10 mg/Kg of body weight, every 12 hours, orally.

(43) The dogs were monitored 8 consecutive weeks by applying the questionnaires of the Subjective Clinical Evaluation System, Liverpool Osteoarthritis in Dogs and the Helsinki Chronic Pain Index to the owners of the dogs, before and after administration of the treatments.

(44) The Subjective Clinical Evaluation System includes the following evaluation points:

(45) 1) Claudication: (0) in normal statics and walking normally, (1) in normal statics and slight claudication when walking (barely noticeable), (2) in normal statics, but moderate claudication when walking (raises the affected limb several times), (3) abnormal posture in static and severe claudication when walking (does not lean on the affected limb) and (4) reluctant to get up and does not take more than 5 steps.

(46) 2) Posture: (0) is maintained in a normal manner on all members at rest and when walking, (1) is maintained in a normal way at rest, but when walking gives preference to the affected member, (2) change of position at rest and when walking, (3) change of position at rest and does not lean on the affected limb when walking and (4) does not lean on the affected limb at rest or when walking.

(47) 3) Mobility of the affected joint: (0) No limitation of movement and no crepitus is palpable, (1) slight decrease in range of motion (10-20%), no crepitus is palpable, (2) slight decrease in range of motion (10-20%) with palpable crepitation, (3) moderate decrease in range of motion (20-50%) and (4) severe decrease in range of motion (>50%) with palpable crepitus.

(48) 4) Hold the contralateral limb high: (0) quickly accept to raise the contralateral limb, (1) offer resistance to the contralateral limb elevation, but maintain its weight on the affected limb for more than one minute, (2) offer moderate resistance to the elevation of the contralateral limb and replaces it after 30 seconds, (3) it offers resistance to the elevation of the contralateral limb and replaces it after 10 seconds and (4) refuses to elevate the contralateral limb.

(49) 5) Pain sign in the affected joint: (0) no response, (1) mild response (turns the head towards the affected joint), (2) moderate response (removes the affected joint member), (3) severe response (vocalizes and is aggressive) and (4) does not allow manipulation or palpation of the affected joint.

(50) The results obtained are presented as global observations made with the Subjective Clinical Evaluation System expressed in MediansEE, to these results the Wilcoxon ranks test was performed using the SPSS Statistics program. Statistically significant values were considered for a level of p<0.05.

(51) TABLE-US-00008 TABLE 2 Evaluation of Gabapentin and Fluoxetine for the pain treatment GROUP WEEK 0 WEEK 4 WEEK 8 G0-D 8.5 0.51 8.5 1.19 8 1.79 G1-D 9 0.86 4 1.02 6 0.73

(52) The results of the global observations made by the owners with the Liverpool Osteoarthritis in Dogs questionnaire expressed in MediansEE are presented in Table 3. The Wilcoxon ranks test was performed using the SPSS Statistics program considering statistically significant values for a level of p<0.05.

(53) TABLE-US-00009 TABLE 3 Evaluation of Gabapentin and Fluoxetine for the pain treatment. Questionnaire Liverpool Osteoarthritis in Dogs TIME G0-D G1-D WEEK 0 26 2.2 27 2.85 WEEK 1 23.5 5.4 24 2.26 WEEK 2 26 5.19 22 2.35 WEEK 3 22.5 4.52 23 3.15 WEEK 4 22.5 4.38 22 3.56 WEEK 5 23 2.95 26 3.15 WEEK 6 23 2.56 26 2.86 WEEK 7 22.5 1.95 23 2.67 WEEK 8 20.5 1.35 20 2.35

(54) The results of the global observations made by the owners with the Helsinki Chronic Pain Index questionnaire expressed in MediansEE are presented in Table 3. The Wilcoxon ranks test was performed using the SPSS Statistics program considering statistically significant values for a level of p<0.05.

(55) TABLE-US-00010 TABLE 4 Evaluation of Gabapentin and Fluoxetine for the pain treatment. Helsinki Chronic Pain Index questionnaire TIME G0-D G1-D WEEK 0 21.5 2.43 22 1.75 WEEK 1 20.5 3.66 15 3.23 WEEK 2 20 3.1 20 2.87 WEEK 3 15.5 3.1 15 3.06 WEEK 4 15.5 2.56 18 2.98 WEEK 5 15 1.54 17 3.68 WEEK 6 14 2.35 18 3.03 WEEK 7 13.5 1.55 18 2.8 WEEK 8 13.5 1.41 16 2.42

(56) As can be observed, the results obtained with the administration of Gabapentin or Fluoxetine were significantly favorable for the pain treatment once different pain assessment questionnaires were applied, where the dose of useful administration is 0.1 to 2 mg/Kg of Fluoxetine or 1.5 to 10 mg/Kg of Gabapentin.

(57) As a final point to the description of the invention, are presented below the main advantages that in a novel but non-limitative manner show the developed compositions: Stable composition Effective and efficient composition Comprehensive management of epilepsy Comprehensive management of pain Use of low doses of gabapentin. Decrease in the adverse effects of gabapentin. Composition with less adverse effects compared to compositions with NSAIDs. Veterinary composition easy to administer. It does not produce dependence. Decreases or eliminates the side effects of the active principle.