CA2530904A1 - Pharmaceutical agents for the treatment of pain associated with spinal cord injury - Google Patents

Abstract

The invention relates to the use of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid for the treatment of pain associated with spinal cord injury.

Description

PHARMACEUTICAL AGENTS FOR THE TREATMENT OF PAIN ASSOCIATED
WITH SPINAL CORD INJURY

This invention relates to a method of treating pain associated with spinal cord injury with (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin).

BACKGROUND OF THE INVENTION
Pregabalin ((S)-(+)-3-(aminomethyl)-5-methylhexanoic acid) is a compound that exhibits activity as an alpha2delta ligand (a28 ligand). As such, it has affinity for the a28 subunit of a calcium channel.
Pregabalin and methods of synthesizing it are referred to in U.S. Patent 6,197,819, which issued on March 6, 2001. Methods of treating pain using pregabalin are referred to in U.S. Patent 6,001,876, which issued on December 14, 1999. Other pharmaceutical uses for pregabalin and methods for synthesizing pregabalin, as well as pharmaceutical formulations of pregabalin, are referred to in the following patents and patent applications: World Patent Application WO 99/59572, which was published on November 25, 1999; World Patent Application WO 99/59573, which was published on November 25, 1999; World patent Application WO 01/55090, which was published on August 2, 2001; World Patent Application WO 04/054559, which was published on July 1, 2004; U.S. Patent 5,629,447, which issued on May 13, 1997; U.S. Patent 5,616,793, which issued on April 1, 1997; U.S. Patent 5,637,767, which issued on June 10, 1997; U.S. Patent 6,046,353, which issued on April 4, 2000; and U.S. Patent 5,840,956, which issued on November 24, 1998. All of the foregoing patents and patent applications are incorporated herein by reference in their entireties.

Pregabalin is structural analogue of the mammalian neurotransmitter, GABA, that is being investigated for various indications, including neuropathic pain. Pregabalin is an alpha-2delta (a28) ligand that has analgesic, anxiolytic, and antiepileptic activity. Alpha-2-delta is an auxiliary protein associated with voltage-gated calcium channels. Pregabalin binds potently to the a26 subunit of such calcium channels. Potent binding at this site reduces stimulus induced calcium influx at nerve terminals and reduces the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. Binding to the alpha-2-delta is required for the full pharmacologic activity in animal models of neuropathic pain, epilepsy and anxiety. Pregabalin is inactive at GABAA and GABAB

receptors, it is not converted metabolically into GABA or a GABA antagonist, and it does not alter GABA uptake or degradation.

SUMMARY OF THE INVENTION
Pregabalin has been demonstrated to have particular efficacy in treating pain associated with spinal cord injury.

This invention relates to a method of treating pain associated with spinal cord injury in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of pregabalin or a pharmaceutically acceptable salt thereof.
This invention also relates to a pharmaceutical composition for treating pain associated with spinal cord injury in a mammal, preferably a human, comprising a therapeutically effective amount of pregabalin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

This invention also relates to the use of pregabalin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pain associated with spinal cord injury in a mammal, preferably a human.

The term "treating", as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or preventing one or more symptoms of such condition or disorder. The term "treatment", as used herein, refers to the act of treating, as "treating" is defined immediately above.

The term "therapeutically effective amount", as used herein, refers to an amount of pregabalin that is effective, when administered in a treatment regimen as described in this document, in treating pain associated with spinal cord injury.

Pregabalin is an amino acid and is therefore capable of forming a wide variety of both base and acid addition salts. Pregabalin is capable of forming salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate pregabalin from the reaction mixture in which it was synthesized as a pharmaceutically unacceptable salt and then simply convert such salt to the free base compound by treatment with an alkaline reagent, and then convert the pregabalin free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of pregabalin are readily prepared by treating pregabalin with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts pregabalin are those that form nontoxic salts derived from inorganic acids such as he following salts: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like.
Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J. of Pharma.
Sci., 1977;66:1).

Pregabalin is also capable of forming pharmaceutically acceptable base addition salts. Such salts can be prepared by contacting the free acid form of the compound with a nontoxic metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine. Examples of suitable metal cations include sodium cation (Na+), potassium cation (K+), magnesium cation (Mg2+), calcium cation (Ca2+), and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, supra., 1977).

501.90-174 DETAILED DESCRIPTION OF THE INVENTION

The method of this invention is practiced by administering pregabalin, or a pharmaceutically acceptable salt thereof, in an amount that is therapeutically effective to treat pain associated with spinal cord injury. Typical dosages will range from about 10 to about 5000 mg/day for an adult subject of normal weight. A daily dosage of about 1 mg/kg to about 50 mg/kg is preferred. In a clinical setting, regulatory agencies such as, for example, the Food and Drug Administration ("FDA") in the U.S. may require a particular therapeutically effective amount.

In determining what constitutes an effective amount, i.e., a therapeutically effective amount, of pregabalin, or a pharmaceutically acceptable salt thereof, for treating pain associated with spinal cord injury, a number of factors will generally be considered by the medical practitioner or veterinarian in view of the experience of the medical practitioner or veterinarian, published clinical studies, the subject's age, sex, weight and general condition, as well as the severity of the spinal cord injury pain being treated, and the use of other medications, if any, by the subject. As such, the administered dose may fall within the ranges or concentrations recited above, or may vary outside, i.e., either below or above, those ranges depending upon the requirements of the individual subject, the severity of the condition being treated, and the particular therapeutic formulation being employed. Determination of a proper dose for a particular situation is within the skill of the medical or veterinary arts. Generally, treatment may be initiated using smaller dosages of pregabalin, or a pharmaceutically acceptable salt thereof, that are less than optimum for a particular subject. Thereafter, the dosage 501.90-174 can be increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

Pharmaceutical compositions of pregabalin, or a pharmaceutically acceptable salt thereof, are produced by formulating the active compound in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses.

Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules;
sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc;

stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol;
polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations.

The compositions to be employed in the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic 501.90-174 agents commonly employed to treat the disorder or condition being treated.

The percentage of pregabalin in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of pregabalin is present, for example, up to about 95%.

Preferred routes of administration of pregabalin and its pharmaceutically acceptable salt are oral routes or parenteral routes such as intravenous, intramuscular, or subcutaneous injection as a liquid formulation.

For example, a useful intravenous dose is between 5 and 50 mg, and a useful oral dosage is between 20 and 800 mg.

A clinical study was conducted to evaluate the efficacy of pregabalin relative to placebo for the treatment of spinal cord injury pain in men and women with a diagnosis of nonprogressive spinal cord injury (paraplegia or tetraplegia) and chronic central neuropathic pain.
Study Design The study was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study with 2 phases:
(1) a 1-week baseline phase, and (2) a 12-week double-blind treatment phase. Eligible subjects completed a 1-week baseline phase and then were randomly assigned to 1 of 2 treatment groups in a 1:1 ratio: (1) escalating doses of pregabalin 150, 300, and 600 mg/day administered BID which were adjusted based on subject response and tolerability at weekly intervals; or (2) placebo administered BID, following the same blinded adjustment schedule as the pregabalin group, for the 12-week double-blind treatment. The daily dosage of study medication was adjusted for the first 3 weeks, and then remained stable for the rest of the study.
Dosage and Administration Subjects were to take 150 mg/day (75 mg BID) of pregabalin or the placebo equivalent during Days 1-7. The daily dosage was to be adjusted (based on response and tolerability) to 300 mg/day (150 mg BID) during Days 8-14.
From Days 15-84, the target daily dosage was 600 mg/day (300 mg BID). Subjects who could not tolerate the target dosage were allowed to have their dosage reduced. The details regarding dosage reductions are described below.
During Week 2, subjects who experienced intolerable adverse events were allowed to reduce the target daily dosage from 300 mg/day to 150 mg/day as directed by the investigator. During Week 3, subjects who experienced intolerable adverse events during the week the dose was increased were allowed to reduce their target dose by 1 level (e.g., 600 mg/day to 300 mg/day, or 300 mg/day to 150 mg/day) as directed by the investigator. Subjects with dosage reductions were to be maintained on the reduced dosage for the remainder of the study.

Beginning at Visit 3 (end of Week 1), subject whose pain was reduced by at least 50% during the preceding week could have been maintained on the same dosage of study medication for the remainder of the study or could have been further adjusted to achieve further pain reduction as directed by the investigator. The same applied to Visit 4 (end of Week 2). The subject's daily dosage was to have been stabilized by no later than Visit 5 (end of Week 3).
Efficacy Results A total of 136 subjects were randomly assigned to a double-blind treatment group, took at least 1 does of study medication, and had at least 1 post-randomization efficacy evaluation on any efficacy scale. These 136 subjects (67 in the placebo group and 69 in the pregabalin group) were included in the intent-to-treat population for efficacy analyses (one subject in the pregabalin group discontinued due to an adverse event after 3 days of double-blind treatment, had no post-baseline efficacy data, and was excluded from the intent-to-treat population).

Pain was reported in this study on a 0 to 10 numerical scale (0 indicating no pain, 10 indicating worst possible pain). Pain scores for each week (7 days) were averaged to obtain the mean pain scores. Endpoint mean pain scores were computed based on the last 7 days (or fewer if 7 postbaseline entries were not available) of treatment regardless of when the subject exited the study. A negative change in mean pain score at each week and at endpoint indicates a reduction (i.e., improvement) in mean pain score.

Table I presents the results of the ANCOVA to compare the endpoint mean pain scores of the placebo and pregabalin groups. At baseline, the LS mean pain scores were comparable (6.615 in the placebo group vs. 6/430 in the pregabalin group). At endpoint, the pregabalin group had a larger reduction from baseline in mean pain score than the placebo group (LS mean change, -0.433) in the placebo group vs. -1.967 in the pregabalin group). Results of the analysis of covariance (ANCOVA) model showed that the treatment difference (1.533 [S.E. 0.312], 95% CI [0.916, 2.150] was statistically significant in favor of pregabalin (p<0.001) .

Table I. Primary Efficacy Analysis: Mean Pain Score at Baseline and Endpoint Intent-to-Treat Population Treatment Difference (Placebo-Pregabalin)a Placebo Pregabalin Estimate (S.E.) 95% Cl p-value Baseline Mean (SD) 6.727 (1.446) 6.540 (1.253) LS Mean (S.E.) 6.615 (0.174) 6.430 (0.170) .185 (0.230) -0.27, 0.641 0.423 Endpoint Mean Change -0.454 -1.917 LS Mean (S. E. ) 6.199 (0.235) 4.665 (0.231) LS Mean Change -0.433 -1.967 1.533 (0.312) 0.916 2.150 <0.001 LS Mean = Least squares mean; S.E.= Standard error; LS Mean Change = Least square mean of change from baseline;
SD=Standard deviation; Mean Change = Mean change from baseline, 95% Cl = 95%
Confidence Interval.

e Placebo - Pregabalin difference in LS Means from the ANCOVA Model with Treatment, Center, and Baseline (Baseline not included at baseline time point) as factors.

Pregabalin was shown to be superior to placebo with respect to pain reduction in subjects with central neuropathic pain based on the subjects' mean weekly pain scores. The differences between groups were apparent as early as Week 1(at a daily dosage of 150 mg/day) and were sustained for the duration of the study. These findings were consistently supported by other measures of pain reduction. Pregabalin was also shown to be superior to placebo with respect to alleviating sleep interference due to pain. Supporting data are listed below.

= At endpoint, the pregabalin group had a significantly greater reduction in mean pain score from baseline (LS mean change, -0.433 in the placebo group vs. -1.967 in the pregabalin group). Treatment differences with respect to reductions in mean pain scores were apparent as early as Week 1 and a statistically significant treatment difference was maintained at each week, through Week 12 of double-blind treatment.

= The proportion of subjects who had a?30o reduction in mean pain score from baseline to endpoint was significantly higher in the pregabalin group (42.0%) compared to the placebo group (16.4%). Similarly, the proportion of subjects who had a _50% reduction in mean pain score from baseline to endpoint was significantly higher in the pregabalin group (21.7%) compared to the placebo group ( 7 . 5 0 ) .

= Significantly greater reductions in pain-related sleep interference scores occurred in the pregabalin group than in the placebo group (-1.478 versus -0.109). The treatment difference in favor of pregabalin was apparent at Week 1 and remain statistically significant at each week, through Week 12 of treatment.

= At endpoint, there were statistically significant treatment differences in favor of pregabalin with respect to the sensory, affective, and total scores of the Short Form McGill Pain Questionaire (SF-MPQ).

= Greater improvements in the SF-MPQ PPI index and Visual Analog Scale (VAS) of the SF-MPQ scores were apparent in the pregabalin group compared to the placebo group at endpoint. Statistically significant treatment differences in favor of pregabalin were apparent at all but 1 time point (Week 12) measured for the PPI index.

= At endpoint, the change from baseline in the Medical Outcomes Study (MOS) Sleep Questionaire sleep disturbance score (-3.937 in the placebo group and -17.218 in the pregabalin group), overall sleep problems score (-3.001 in the placebo group and -9.405 in the pregabalin group), and sleep quantity (0.017 in the placebo group and 0.582 in the pregabalin group) were statistically significant in favor of pregabalin. The treatment differences at endpoint with respect to the MOS measures of snoring, awaken short of breath, sleep adequacy, and somnolence were not statistically significant.

Claims (3)

1. A pharmaceutical composition for treating pain associated with spinal cord injury in a mammal, comprising a therapeutically effective amount of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. Use of pregabalin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pain associated with spinal cord injury in a mammal.

3. Use of pregabalin, or a pharmaceutically acceptable salt thereof, for the treatment of pain associated with spinal cord injury in a mammal.