Pharmaceutical composition comprising (1R,4R)-6′- fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro [cyclohexane-1,1′-pyrano- [3,4,b ]indol] -4-amine and paracetamol or propacetamol

Abstract

The invention relates to a pharmaceutical composition comprising a first pharmacologically active ingredient selected from (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and the physiologically acceptable salts thereof, and a second pharmacologically active ingredient selected from paracetamol and propacetamol.

Claims

1. A pharmaceutical composition comprising: a first pharmacologically active ingredient which is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine or a physiologically acceptable salt thereof; and a second pharmacologically active ingredient which is paracetamol or propacetamol, wherein the first pharmacologically active ingredient and the second pharmacologically active ingredient are present in the pharmaceutical composition at a weight ratio such that the first pharmacologically active ingredient and the second pharmacologically active ingredient will exert a synergistic therapeutic effect when the pharmaceutical composition is administered to a patient.

2. The pharmaceutical composition according to claim 1, wherein the first pharmacologically active ingredient is (1 r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine hydrochloride, (1 r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine hemicitrate, or (1 r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine maleate.

3. The pharmaceutical composition according to claim 1, wherein the second pharmacologically active ingredient is paracetamol.

4. The pharmaceutical composition according to claim 1, wherein a relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is 1:30 to 1:1,000,000.

5. A method for treating pain comprising administering to a patient the pharmaceutical composition according to claim 1.

6. The method according to claim 5, wherein the pain is at least one of peripheral pain, central pain, musculoskeletal pain, acute pain, subacute pain, chronic pain, moderate to severe pain, neuropathic pain, psychogenic pain, nociceptive pain, mixed pain, lower back pain, visceral pain, headache pain, post-operative (post-surgical) pain, pain associated with cancer, and inflammatory pain.

7. A pharmaceutical dosage form comprising the pharmaceutical composition according to claim 1.

8. The pharmaceutical dosage form according to claim 7, wherein the first pharmacologically active ingredient is present at 10 to 1,200 μg.

9. The pharmaceutical dosage form according to claim 7, wherein the second pharmacologically active ingredient is present at 100 to 8,000 mg.

10. The pharmaceutical dosage form according to claim 7, wherein the first pharmacologically active ingredient is present in the dosage form in a dosage that is within a range of from 1:20 to 20:1 of an amount which is equieffective to a dosage of the second pharmacologically active ingredient contained in the dosage form.

11. The pharmaceutical dosage form according to claim 7, wherein the pharmaceutical dosage form is adapted for oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intrathecal administration, intramuscular administration, intranasal administration, transmucosal administration, subcutaneous administration, or rectal administration.

12. The pharmaceutical dosage form according to claim 7, wherein the pharmaceutical dosage form provides under in vitro conditions immediate release or controlled release of at least one of the first pharmacologically active ingredient and the second pharmacologically active ingredient.

13. A kit comprising: a first pharmaceutical dosage form comprising a first pharmacologically active ingredient selected from the group consisting of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine or a physiologically acceptable salt thereof; and a second pharmaceutical dosage form comprising a second pharmacologically active ingredient selected from the group consisting of paracetamol or propacetamol; wherein the first pharmacologically active ingredient and the second pharmacologically active ingredient are present in the kit at a weight ratio such that the first pharmacologically active ingredient and the second pharmacologically active ingredient will exert a synergistic therapeutic effect when they are both administered to a patient.

14. The kit according to claim 13, wherein the first pharmaceutical dosage form and the second pharmaceutical dosage form are adapted for simultaneous or sequential administration.

15. The kit according to claim 14, wherein the first pharmaceutical dosage form and the second pharmaceutical dosage form are adapted for administration by the same pathway of administration.

16. The kit according to claim 14, wherein the first pharmaceutical dosage form and the second pharmaceutical dosage form are adapted for administration by a different pathway of administration.

17. A pharmaceutical composition comprising a synergistic combination of: (1) a first pharmacologically active ingredient which is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine or a physiologically acceptable salt thereof; and (2) a second pharmacologically active ingredient which is paracetamol or propacetamol.

Description

EXAMPLE 1

Paw Incision Model in Rats (Postoperative Pain)

(1) The experiments were carried out in male albino rats (Sprague Dawley) with 170 g-230 g body weight from a commercial breeder (Janvier; France). The animals were housed under standardized conditions: light/dark rhythm (06.00 h-18.00 h light, 18.00 h-06.00 h dark); room temperature 20° C.-24° C.; relative air humidity 35%-70%; 15 air changes per hour, air movement <0.2 m/sec. The animals were given tap water and a diet of standard laboratory food (Ssniff R/M-Haltung, Ssniff Spezialdiäten GmbH, Soest, Germany) ad libitum. Both were withdrawn during the test. All rats were used only once. Ten rats were used per experimental group. There were at least five days between delivery of the animals and the day of surgery.

(2) The rats were placed in a plastic cage with a wire mesh bottom which allowed full access to the paws. Hind paw withdrawal threshold after mechanical stimulation was tested with electronic von Frey hairs (Somedic Sales AB, Hörby, Sweden). Animals were placed in a plastic cage with a wire mesh bottom which allowed full access to the paws. Behavioral accommodation was allowed for 30 min. In each case, withdrawal response was measured at an area adjacent to the wound (ipsilateral) and to the same area on the non-injured foot (contralateral). Two hours after surgery, primary hypersensitivity was tested as tactile withdrawal threshold shortly before drug administration and at different time points after drug application. Animals injected with vehicle served as controls. The pretest measurement was made prior to surgery and two thresholds were taken per test and averaged.

(3) Surgery was performed as previously described (Brennan T. J., Vandermeulen E. P., and Gebhart G. F., Characterization of a rat model of incisional pain, Pain 1996; 64:493-501). Briefly, rats were anaesthetised with isoflurane, and a 1 cm longitudinal incision was made, through skin and fascia of the plantar aspect of the foot, starting from the proximal edge of the heel and extending toward the metatarsal toes. The plantaris muscle was elevated and incised longitudinally. The muscle origin and insertion remained intact. After spreading of the muscle and haemostasis with gentle pressure, the skin was closed with two single interrupted sutures. After surgery, the rats were allowed to recover in their home cages and the animals regained consciousness within 2 to 5 minutes. In order to ensure a complete recovery from anaesthesia the baseline value of each individual animal was recorded not until 2 hours after surgery.

(4) The first pharmacologically active ingredient was dissolved in 5% DMSO and 95% glucose solution (5%). The second pharmacologically active ingredient was dissolved in 1% CMC in aqua dest. Intravenous (i.v.) and intraperitoneal (i.p.) applications were made in a volume of 5 mL/kg.

(5) Data were recorded and the median was calculated from five values of each animal and measurement.

(6) The median values of the individual latencies are calculated as the percentage of the Maximum Possible Effect (% MPE) according to the following formula: % MPE=100=[(value after application=pretest before surgery)/(pretest after surgery=pretest before surgery).Math.100]

(7) The individual % MPE values were averaged for the respective treatment group and expressed as mean % MPE±standard error of the mean (SEM).

(8) The pharmacologically active ingredients were administered using a logarithmically staggered dose scheme. The results are presented in graphs as means±SEM against the time after surgery.

(9) Data were analyzed by means of two-factor analysis of variance (ANOVA) with repeated measures. Significance of treatment-, time- or treatment×time interaction effects was analyzed by means of Wilks' Lambda statistics. In case of a significant treatment effect, pair-wise comparison was performed at the different time points effect by Fisher's least significant difference test. Results were considered statistically significant if p<0.05.

(10) The interaction studies presented herein were performed by comparison of the theoretically additive effect of defined doses of the first and the second pharmacologically active ingredient with the experimental determined effect of their combination.

(11) The application route was intravenous (i.v.) for the first pharmacologically active ingredient and intraperitoneal (i.p.) for the second pharmacologically active ingredient.

(12) Tests were performed using doses of 0.00464 mg/kg body weight to 0.0068 mg/kg body weight of the first pharmacologically active ingredient and 215 mg/kg body weight of Paracetamol as the second pharmacologically active ingredient.

(13) When administered in combination, the first pharmacologically active ingredient (0.00464 mg/kg body weight i.v.) and the second pharmacologically active ingredient (Paracetamol, 215 mg/kg body weight i.p.) showed an analgesic efficacy with a maximal effect of 33% MPE at 30 min. The analysis showed additive interaction of the first pharmacologically active ingredient and the second pharmacologically active ingredient.

(14) When administered in combination, a dose of 0.0068 mg/kg body weight (i.v.) of the first pharmacologically active ingredient and a dose of 215 mg/kg body weight (i.p.) of the second pharmacologically active ingredient led to side effects (sedation).

(15) FIG. 1 shows the withdrawal threshold in g in dependence of the time elapsed after administration.

(16) ##STR00003##

(17) FIG. 2 shows % MPE (Maximum possible effect) of the first and the second pharmacologically active ingredient and of the combined administration of the first and the second pharmacologically active ingredient, and the theoretical % MPE of the combined administration of the first and the second pharmacologically active ingredient in dependence of the time post administration.

(18) TABLE-US-00001 dose [mg/kg] first pharmacologically active ingredient 0.00464 second pharmacologically active ingredient 215 combined administration of first 0.00464 + 215 pharmacologically active ingredient + second pharmacologically active ingredient theoretical additive value of first pharmacologically active ingredient + second pharmacologically active ingredient

(19) Experimental results demonstrating additive effect of the combination of the first and the second pharmacologically active ingredient are summarized in the following tables 1 to 5.

(20) TABLE-US-00002 TABLE 1 % MPE (Maximum possible effect) of the combined administration of different doses of the first and the second pharmacologically active ingredient in dependence of the time post administration: % MPE 30 min. 60 min. 90 min. dose (n = 10) (n = 10) (n = 10) [mg/kg] Mean SEM Mean SEM Mean SEM vehicle    0.0 + 0.0 −0.48 ± 0.71  −1.14 ± 0.65  0.47 ± 1.45 Combination of first 0.00464 + 215 33.1 ± 6.71 6.13 ± 3.49 4.35 ± 2.40 pharmacologically active p ≤ 0.001 p ≤ 0.05  n.s. ingredient and second  0.0068 + 215 41.2 ± 8.14 17.0 ± 2.56 3.46 ± 1.32 pharmacologically active p ≤ 0.001 p ≤ 0.001 n.s. ingredient p: level of statistical significance; n.s.: not significant

(21) TABLE-US-00003 TABLE 2 % MPE: GLM Repeated Measures and Statistical evaluation of the data following two-factor analysis of variance (ANOVA) and Fisher's LSD: GLM (General Linear Model) %MPE treatment time interaction F(2, 22) = 15.465 F(2, 44) = 37.591 F(4, 44) = 11.904 p < 0.001 p < 0.001 p < 0.001 ANOVA [Fisher's LSD] dose [mg/kg] 30 min. 60 min. 90 min. 0.00464 + 215 p < 0.001 p = 0.043 p = 0.150  0.0068 + 215 p < 0.001 p < 0.001 p = 0.358 p: level of statistical significance.

(22) TABLE-US-00004 TABLE 3 ipsilateral: GLM Repeated Measures and Statistical evaluation of the data following two-factor analysis of variance (ANOVA) and Fisher's LSD: GLM (General Linear Model) ipsilateral treatment time interaction F(2, 22) = 11.006 F(2, 44) = 37.049 F(4, 44) = 12.008 p < 0.001 p < 0.001 p < 0.001 ANOVA [Fisher's LSD] dose [mg/kg] 30 min. 60 min. 90 min. 0.00464 + 215 p < 0.001 p = 0.111 p = 0.398  0.0068 + 215 p < 0.001 p < 0.01  p = 0.732 p: level of statistical significance.

(23) TABLE-US-00005 TABLE 4 contralateral: GLM Repeated Measures and Statistical evaluation of the data following two-factor analysis of variance (ANOVA) and Fisher's LSD: GLM (General Linear Model) contralateral treatment time interaction F(2, 22) = 6.464 F(2, 44) = 13.172 F(4, 44) = 4.617 p < 0.001 p < 0.001 p = 0.003 ANOVA [Fisher's LSD] dose [mg/kg] 30 min. 60 min. 90 min. 0.00464 + 215 p = 0.004 p = 0.059 p = 0.356  0.0068 + 215 p = 0.051 p = 0.057 p < 0.001 p: level of statistical significance.

(24) TABLE-US-00006 TABLE 5 % MPE (Maximum possible effect) of the first and the second pharmacologically active ingredient and of the combined administration of the first and the second pharmacologically active ingredient, and the theoretical % MPE of the combined administration of the first and the second pharmacologically active ingredient in dependence of the time post administration: % MPE 30 min. 60 min. 90 min. dose (n = 10) (n = 10) (n = 10) [mg/kg] Mean SEM Mean SEM Mean SEM first pharmacologically 0.00464 12.2 ± 2.69 10.6 ± 3.51  2.88 ± 2.27 active ingredient second pharmacologically 215 16.3 ± 3.06 4.35 ± 1.53 −0.21 ± 0.75 active ingredient combination of first 0.00464/215 33.1 ± 6.71 6.13 ± 3.49 4.35 ± 2.4 pharmacologically active (theoretical (theoretical (theoretical ingredient and second additive value: additive value: additive value: pharmacologically active 28.5 ± 4.07) 15.0 ± 3.83) 2.67 ± 2.39) ingredient p = 0.507 p = 0.032 p = 0.502

EXAMPLE 2

Randall Selitto Test in Rats (Chronic Inflammatory Pain)

(25) The weight ratios of the first and the second pharmacologically active ingredient that will lead to a supra-additive effect (synergistic effect) may be determined via the test of Randall and Selitto as described in Arch. Int. Pharmacodyn., 1957, 111: 409-419, which is a model for inflammatory pain. The respective part of the literature is hereby incorporated by reference and forms part of the present disclosure.

(26) By means of injection of 0.1 ml of Carrageenin-suspension ventrally into a hind paw of a rat an oedema is induced, on which pain is generated 4 hours later by continuously increasing pressure with a stamp (2 mm tip diameter). The antinociceptive and antihyperalgesic activity of the tested pharmacologically active ingredient is determined at different points in time after administration of the pharmacologically active ingredient. The measured value to be determined and at the same time also the end point of the pain test is the pressure at which the vocalisation reaction of the rat occurs. The percentage maximum possible effect (% MPE) is calculated. The maximum pressure of the stamp is 250 g. The group size is n=12.

(27) ED.sub.50-values were determined by regression analysis in case of dose-dependent results (according to Litchfield J. T. and Wilcoxon F. A., A simplified method of evaluating dose-effect experiments, J. Pharmacol. Exp. Ther. 1949; 96: 99-113). The analysis of the results with respect to a supra-additive effect of the first and the second pharmacologically active ingredient is carried out via statistical comparison of the theoretical additive ED.sub.50-value with the experimentally determined ED.sub.50-value of a so-called fixed ratio combination (isobolographic analysis according to Tallarida J. T., Porreca F., and Cowan A., Statistical analysis of drug-drug and site-site interactions with isobolograms, Life Sci. 1989; 45: 947-961).

(28) The interactions studies presented herein were performed using equieffective doses of the first and the second pharmacologically active ingredient, calculated from the ratio of the respective ED.sub.50 values of the first and the second pharmacologically active ingredient if administered alone.

(29) The application route was intravenous (i.v.) for the first pharmacologically active ingredient and intraperitoneal (i.p.) for the second pharmacologically active ingredient. The first and the second pharmacologically active ingredient were dissolved in 5% DMSO, 5% Cremophor, 90% glucose solution (5%) and in 1% CMC in aqua dest., respectively. Intravenous (i.v.) and intraperitoneal (i.p.) applications were made in a volume of 5 mL/kg.

(30) In case of the combined, simultaneous administration, the relative dose ratio of first pharmacologically active ingredient to the second pharmacologically active ingredient was 1:56,453.

(31) When the first pharmacologically active ingredient was applied alone, the peak effect was reached 15 min p. appl. (timepoint of first measurement) and ED.sub.50-value of 3.364 (2.896-3.815) μg/kg i.v. was calculated. The second pharmacologically active ingredient Paracetamol induced a dose-dependent analgesic effect with ED.sub.50-value of 189,914 (181,292-198,419) μg/kg i.p., reaching the peak effect 120 min p. appl. According to their respective timepoint of peak effect, the first pharmacologically active ingredient was applied 15 min and the second pharmacologically active ingredient 120 min before timepoint of measurement of the interaction-experiments (i. e. the second pharmacologically active ingredient was applied 105 min before the first pharmacologically active ingredient). Thus, the time point of ED.sub.50 calculation of the pharmaceutical composition according to the invention corresponds to the timepoint of the peak effect of the respective pharmacologically active ingredient. The isobolographic analysis revealed that in case of the combined administration of the first and the second pharmacologically active ingredient the experimental ED.sub.50-values were significantly lower than the respective theoretical ED.sub.50-values. Thus, the combination studies demonstrate significant synergistic interaction of the first pharmacologically active ingredient with the second pharmacologically active ingredient. The results of the isobolographic analysis are summarized in the following table 6.

(32) FIG. 3 shows the graphical analysis of experimental ED.sub.50-values corresponding to the single administration of the first pharmacologically active ingredient and the second pharmacologically active ingredient, respectively, and the corresponding theoretic additive values for the combined administration of the first and the second pharmacologically active ingredient compared to the experimental ED.sub.50-values determined for said combination.

(33) TABLE-US-00007 E050 (95% CI)[μg/kg] (i.v./i.p.) first pharmacologically active = 3.36 (2.90-3.82) ingredient second pharmacologically active = 189,914 (181,292-198,419) ingredient theoretical additive value = 94,957 (88,212-101,701) part of first pharmacologically = 1.68 (1.56-1.80) active ingredient part of second pharmacologically = 94,955 (88,211-101,700) active ingredient experimental value of the = 68,427 (64,864-71,835) combination part of first pharmacologically = 1.21 (1.05-1.38) active ingredient part of second pharmacologically = 68,426 (65,340-71,511) active ingredient

(34) TABLE-US-00008 TABLE 6 Experimental ED.sub.50 values of the first and the second pharmacologically active ingredient and isobolographic analysis of the interaction between the first and the second pharmacologically active ingredient: Substance/ED.sub.50 [μg/kg] (confidence interval) first second Theoretical ED.sub.50 Experimental ED.sub.50 pharmacologically pharmacologically [μg/kg] of the [μg/kg] of the active ingredient active ingredient combination combination Interaction 3.36 189,914 94,957 68,427 supra- (2.90-3.82) (181,292-198,419) (88,212-101,701) (64,864-71,835) additive (p < 0.001) p: level of statistical signifigance.