Analgesic and antipruritic pharmacertical composition and application thereof

Abstract

An analgesic and antipruritic pharmaceutical composition, including PF-05089771 shown as ##STR00001##
and PF-04885614 shown as ##STR00002##
An application of the analgesic and antipruritic pharmaceutical composition in the treatment of a disease in which both a voltage-gated sodium channel 1.7 (Na.sub.v1.7) and a voltage-gated sodium channel 1.8 (Na.sub.v1.8) are involved.

Claims

1. An analgesic and antipruritic pharmaceutical composition, comprising: PF-05089771, which is ##STR00006## or a salt thereof; and PF-04885614, which is ##STR00007## or a salt thereof.

2. The analgesic and antipruritic pharmaceutical composition of claim 1, wherein a weight ratio of the PF-05089771 to the PF-04885614 is (100-1):(1-100).

3. The analgesic and antipruritic pharmaceutical composition of claim 1, wherein a weight ratio of the PF-05089771 to the PF-04885614 is (50-1):1.

4. The analgesic and antipruritic pharmaceutical composition of claim 1, wherein a weight ratio of the PF-05089771 to the PF-04885614 is (20-30):1.

5. The analgesic and antipruritic pharmaceutical composition of claim 1, further comprising: a pharmaceutically-acceptable carrier; wherein the pharmaceutically-acceptable carrier is a solvent, an excipient, a dispersion medium, a coating, an iso-osmotic solution, a slow-release agent, or a combination thereof.

6. The analgesic and antipruritic pharmaceutical composition of claim 5, wherein the pharmaceutically-acceptable carrier is selected from the group consisting of starch, microcrystalline cellulose, lactose, sucrose, mannitol, inorganic salt, hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, sodium alginate, agar, hydroxypropyl methyl cellulose, methylcellulose, hydroxyethyl cellulose, carbopol, polyvinyl alcohol, acrylic resin, chitosan, beeswax, stearic acid, and a combination thereof.

7. The analgesic and antipruritic pharmaceutical composition of claim 6, wherein the inorganic salt is selected from the group consisting of calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulphate dihydrate, and a combination thereof.

8. The analgesic and antipruritic pharmaceutical composition of claim 1, wherein the analgesic and antipruritic pharmaceutical composition is for treatment of diseases which comprise pruritus and pain; wherein the pain is inflammatory pain, neuropathic pain or a combination thereof; the inflammatory pain is selected from the group consisting of postoperative and traumatic pain, musculoskeletal pain, menalgia, visceralgia and a combination thereof; the musculoskeletal pain comprises arthralgia; and the neuropathic pain is selected from the group consisting of hemicrania, odontalgia, trigeminal neuralgia, postherpetic pain, pain after spinal cord injury, sciatica, cancer-related pain, diabetic peripheral neuropathy pain, and a combination thereof.

9. The analgesic and antipruritic pharmaceutical composition of claim 1, wherein an administration route of the analgesic and antipruritic pharmaceutical composition comprises oral administration, intraoral administration, injection, respiratory administration, cutaneous administration, ophthalmic administration, nasal mucosal administration, rectal administration, vaginal administration, otic administration, or dialysis.

10. A pharmaceutical composition, comprising: PF-05089771, which is ##STR00008## or a salt thereof; and PF-04885614, which is ##STR00009## or a salt thereof; wherein the pharmaceutical composition is for treatment of diseases in which both a voltage-gated sodium channel 1.7 (Na.sub.v1.7) and a voltage-gated sodium channel 1.8 (Na.sub.v1.8) are involved.

11. The pharmaceutical composition of claim 10, wherein a weight ratio of the PF-05089771 to the PF-04885614 is (100-1):(1-100).

12. The pharmaceutical composition of claim 10, wherein a weight ratio of the PF-05089771 to the PF-04885614 is (50-1):1.

13. The pharmaceutical composition of claim 10, wherein a weight ratio of the PF-05089771 to the PF-04885614 is (20-30):1.

14. The pharmaceutical composition of claim 10, further comprising: a pharmaceutically-acceptable carrier; wherein the pharmaceutically-acceptable carrier is a solvent, an excipient, a dispersion medium, a coating, an iso-osmotic solution, a slow-release agent, or a combination thereof.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutically-acceptable carrier is selected from the group consisting of starch, microcrystalline cellulose, lactose, sucrose, mannitol, inorganic salt, hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, sodium alginate, agar, hydroxypropyl methyl cellulose, methylcellulose, hydroxyethyl cellulose, carbopol, polyvinyl alcohol, acrylic resin, chitosan, beeswax, stearic acid, and a combination thereof.

16. The pharmaceutical composition of claim 15, wherein the inorganic salt is selected from the group consisting of calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulphate dihydrate, and a combination thereof.

17. The pharmaceutical composition of claim 10, wherein the diseases comprise pruritus and pain; wherein the pain is inflammatory pain, neuropathic pain or a combination thereof; the inflammatory pain is selected from the group consisting of postoperative and traumatic pain, musculoskeletal pain, menalgia, visceralgia and a combination thereof; the musculoskeletal pain comprises arthralgia; and the neuropathic pain is selected from the group consisting of hemicrania, odontalgia, trigeminal neuralgia, postherpetic pain, pain after spinal cord injury, sciatica, cancer-related pain, diabetic peripheral neuropathy pain, and a combination thereof.

18. The pharmaceutical composition of claim 10, wherein an administration route of the pharmaceutical composition comprises oral administration, intraoral administration, injection, respiratory administration, cutaneous administration, ophthalmic administration, nasal mucosal administration, rectal administration, vaginal administration, otic administration, or dialysis.

19. A method of treating pain and itching, comprising administering to a subject in need a pharmaceutical composition, wherein the pharmaceutical composition comprises: PF-05089771, which is ##STR00010## or a salt thereof; and PF-04885614, which is ##STR00011## or a salt thereof.

20. The method of claim 19, wherein an administration route of the pharmaceutical composition comprises oral administration, intraoral administration, injection, respiratory administration, cutaneous administration, ophthalmic administration, nasal mucosal administration, rectal administration, vaginal administration, otic administration, or dialysis.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates comparison of paw withdrawal thresholds (PWT) of mice before and after spared nerve injury (SNI) operation in Example 1, where the PWTs of mice at 2 weeks, 4 weeks and 6 weeks post operation are significantly lower than the baseline threshold (n=20-28, ****P<0.0001, with Mann-Whitney test);

(2) FIG. 2 demonstrates an analgesic effect (expressed by APWT) of intraperitoneal injection of 2 mg/kg PF-05089771 (Nav1.7 inhibitor) in SNI mice in Example 1, where the analgesic effect gradually decreases from 2 weeks to 6 weeks post operation (n=20-28, *P<0.05, ****P<0.0001, with Mann-Whitney test);

(3) FIG. 3 demonstrates an analgesic effect of intraperitoneal injection of 45 g/kg PF-04885614 (Nav1.8 inhibitor) in SNI mice in Example 1, where the analgesic effect gradually decreases from 2 weeks to 6 weeks post operation (n=17-21, *P<0.05, ***P<0.001, ****P<0.0001, with Mann-Whitney test);

(4) FIG. 4 demonstrates the synergistic analgesic effect of 2 mg/kg PF-05089771 and 45 g/kg PF-04885614 (intraperitoneal injection) on mechanical pain of SNI mice at 6 weeks post operation in Example 2, where the combination of 2 mg/kg PF-05089771 and 45 g/kg PF-04885614 is superior to the alone use of PF-05089771 or PF-04885614 in efficacy (n=12, * P<0.05, *** P<0.001, with Mann-Whitney test);

(5) FIG. 5 demonstrates the synergistic analgesic effect of 2 mg/kg PF-05089771 and 90 g/kg PF-04885614 (intraperitoneal injection) on mechanical pain of SNI mice at 6 weeks post operation in Example 2, where the combination of 2 mg/kg PF-05089771 and 90 g/kg PF-04885614 is superior to the alone use of PF-05089771 or PF-04885614 in efficacy (n=12, * P<0.05, *** P<0.001, **** P<0.0001, with Mann-Whitney test);

(6) FIG. 6 demonstrates relieve effect of intraperitoneal injection of 100 mg/kg Gabapentin on mechanical pain of SNI mice at 6 weeks post operation in Example 2 (n=12, **** P<0.0001, with Mann-Whitney test);

(7) FIG. 7 demonstrates the synergistic analgesic effect of 1 mg/kg PF-05089771 and 45 g/kg PF-04885614 (intraperitoneal injection) on mechanical pain of SNI mice at 6 weeks post operation in Example 2, where the combination of 1 mg/kg PF-05089771 and 45 g/kg PF-04885614 is superior to the alone use of PF-05089771 or PF-04885614 (n=12, * P<0.05, with Mann-Whitney test);

(8) FIG. 8 demonstrates relationship between dose and analgesic effect on SNI mice in Example 2, where the analgesic effect (measured at 6 weeks post operation) of the high dose group (2 mg/kg PF-05089771 and 90 g/kg PF-04885614) is better than that of the low-dose group (1 mg/kg of PF-05089771 and 45 g/kg of PF-04885614) (n=11-12, ****P<0.0001, with Mann-Whitney test);

(9) FIG. 9 shows comparison of 20 g/kg GNE-0439, 90 g/kg PF-04885614 and a combination thereof (intraperitoneal injection) in terms of analgesic effect on SNI mice at 6 weeks post operation in Example 3 (n=12, *P<0.05, ***P<0.001, with Mann-Whitney test); and

(10) FIG. 10 shows comparison of 2 mg/kg PF-05089771, 10 mg/kg PF-04531083 and a combination thereof (intraperitoneal injection) in terms of analgesic effect on SNI mice at 6 weeks post operation (n=12, ***P<0.001, ****P<0.0001, with Mann-Whitney test).

DETAILED DESCRIPTION

(11) As is well known in the art, voltage-gated sodium channels (Navs) play an important role in the itch and pain transmission. Sodium channel 1.7 (Nav1.7) and sodium channel 1.8 (Nav1.8) are involved in the itch and pain transmission under physiological and pathological conditions.

(12) It has been observed from the investigation on the role of Nav1.7 and Nav1.8 in SNI-induced neuropathic pain mice that as the time course of the disease prolonged, the analgesic effect of Nav1.7 inhibitor PF-05089771 and Nav1.8 inhibitor PF-04885614 significantly diminished, and the individual response rate also decreased. In addition, individuals who showed a poor response to PF-05089771 had a good response to PF-04885614. Thus, the therapeutic effect of Nav1.7 inhibitor in combination with Nav1.8 inhibitor on chronic neuropathic pain was studied, and the results demonstrated that there was synergistic analgesic effect on chronic neuropathic pain when combining PF-05089771 with PF-04885614 in different dose ratios, and the individual response rate was improved. The combined administration of PF-05089771 and PF-04885614 at the optimal dose brought not only an obvious analgesic effect, but also a high response rate (up to 100%). However, there was no synergistic effect between GNE-0439 and PF-04885614. Though the combined use of PF-05089771 and PF-04531083 showed a synergistic analgesic effect, it was observed that the effective dose of PF-04531083 was also accompanied by obvious side effects such as sedation and weight loss. Therefore, it was concluded that the combined use of PF-05089771 and PF-04885614 can significantly relieve the neuropathic pain, and the efficacy was superior to the single use of PF-05089771 or PF-04885614. Under the optimal dose, the combination of PF-05089771 and PF-04885614 exerted an analgesic effect equivalent to the clinical drug Gabapentin, and had no side effects (such as sedation) which occurred in the case of administering the equivalent dose of Gabapentin.

(13) This application will be described in detail below with reference to the accompanying drawings and embodiments.

Example 1

(14) The efficacy of individual inhibitors used alone was tested herein.

(15) The relieve effect of Nav1.7 inhibitor and Nav1.8 inhibitor on SNI-induced neuropathic pain at different time points was investigated. C57/BJ6 mice aged 5-6 weeks were purchased from Shanghai SLAC Laboratory Animal Co., Ltd and fed for 6 months. After that, the mice were placed in a transparent plexiglass chamber on an iron support. 30 minutes later, the baseline mechanical threshold (paw withdrawal threshold, PWT) of the mice was detected by Von Frey (DanMicGlobal, CA, USA). The average threshold of the mice was 1.54+0.07 g (see FIG. 1). The spared nerve injury (SNI)-induced neuropathic pain C57/BJ6 mouse model was established according to Pertin, M et al (Pertin, M., Gosselin, RD., Decosterd, I. (2012). The Spared Nerve Injury Model of Neuropathic Pain. In: Luo, Z. (eds) Pain Research. Methods in Molecular Biology, vol 851. Humana Press). The SNI-induced neuropathic pain mice were measured for the mechanical pain threshold using Von Frey respectively at 2 weeks, 4 weeks and 6 weeks post operation. The results were presented in FIG. 1, from which it can be observed that the thresholds post operation were significantly lower than the baseline threshold, and the means of threshold at 2 weeks, 4 weeks and 6 weeks post operation were 0.14+0.02 g, 0.06+0.01 g, and 0.12+0.02 g, respectively. Further, the analgesic effect of intraperitoneal injection of 2 mg/kg PF-05089771 (Nav1.7 inhibitor, Bio-Techne) or 45 g/kg PF-04885614 (Nav1.8 inhibitor, Bio-Techne) on SNI mice respectively at 2 weeks, 4 weeks, and 6 weeks post operation was analyzed.

(16) The mechanical pain threshold of mice was tested 1 hour after injection. The results showed that the injection of 2 mg/kg PF-05089771 could significantly relieve neuropathic pain in SNI mice at 2 weeks post operation, and increase the mechanical pain threshold by 0.77+0.10 g (PWT=post-administration thresholdpre-administration threshold). Among them, the mice with poor response (PWT 0.2 g) accounted for 10% (2/20) of all tested mice. However, the efficacy of 2 mg/kg PF-05089771 gradually decreased with the extension of time post operation. At 4 weeks post operation, the mechanical pain threshold of mice could only be increased by 0.39+0.07 g, and the mice with poor response (PWT0.2 g) accounted for 41.7% (10/24); and at 6 weeks post operation, the mechanical pain threshold of mice could only be slightly increased by 0.17+0.03 g, and the proportion of mice with poor response (PWT 0.2 g) rose to 57.1% (16/28), as shown in FIG. 2.

(17) Similar to PF-05089771, the injection of 45 g/kg PF-04885614 can also significantly relieve the neuropathic pain in SNI mice at 2 weeks post operation, and elevate the mechanical pain threshold by 0.86+0.14 g. Moreover, the mice with poor response (PWT 0.2 g) accounted for 11.1% (2/18). However, the efficacy of 45 g/kg of PF-04885614 sharply diminished over time post operation. At 4 weeks post operation, the mechanical pain threshold of mice was only improved by 0.21+0.04 g, and there was no statistically significant difference compared with the control group. Additionally, the mice with poor response (PWT0.2 g) accounted for 52.6% (10/19). At 6 weeks post operation, the mechanical pain threshold was only improved by 0.10+0.04 g, and the mice with poor response (PWT0.2 g) accounted for 76.5% (13/17), as shown FIG. 3.

Example 2

(18) In this example, the efficacy of a combined administration of inhibitors was investigated.

(19) Based on Example 1, it was further found that 2/3 of the total mice (8/12, see Table 1) poorly responded (PWT0.2 g) to 2 mg/kg PF-05089771 at 6 weeks post SNI operation, while half of them well responded to 90 g/kg PF-04885614 (see rows 7-10 in Table 1), suggesting that the combined use of PF-05089771 and PF-04885614 might enhance the analgesic effect. It was experimentally demonstrated that the intraperitoneal injection of 2 mg/kg PF-05089771 and 45 g/kg or 90 g/kg PF-04885614 can significantly relieve neuropathic pain in SNI mice at 6 weeks post operation, and the analgesic effect was significantly higher than that of the single administration group, as shown in FIGS. 4-5. 100% (12/12) of the mice well responded to the combined administration of 2 mg/kg PF-05089771 and 90 g/kg PF-04885614 (elevated threshold PWT>0.5 g for each mouse), see Table 1. The efficacy of combination of PF-05089771 and PF-04885614 was equivalent to that of 100 mg/kg Gabapentin (See FIG. 6), but without sedative side effects which were caused by 100 mg/kg Gabapentin. The analgesic effect of the combination of PF-05089771 and PF-04885614 at low doses was tested. The results showed that the intraperitoneal injection of 1 mg/kg PF-05089771 and 45 g/kg PF-04885614 could also significantly increase the mechanical pain threshold by 0.45 g, which was significantly higher than that of the single administration group, as shown in FIG. 7. Through comparative analysis, it was found that the analgesic effect of the high-dose combined administration (2 mg/kg PF-05089771 and 90 g/kg PF-04885614) was significantly better than that of the low-dose combined administration (1 mg/kg PF-05089771 and 45 g/kg PF-04885614). Thus, the analgesic effect of the combined administration of PF-05089771 and PF-04885614 had a dose-dependent effect, as shown in FIG. 8.

(20) TABLE-US-00001 TABLE 1 Response of SNI mice to PF-05089771 and PF-04885614 at 6 weeks post operation 6 weeks post PF-05089771 PF-04885614 PF-05089771 (2 mg/kg) + operation (2 mg/kg) (90 g/kg) PF-04885614 (90 g/kg) Number PWT (g) PWT (g) PWT (g) 1 0.36 0.36 0.56 2 0.33 0.53 1.33 3 0.33 0.53 1.33 4 0.33 0.53 1.93 5 0.2 1.6 1 6 0.05 0.58 0.98 7 0.09 0.53 1.93 8 0 0.44 1.84 9 0 0.2 1.6 10 0 0.2 1.6 11 0.12 0.12 1.96 12 0.09 0.03 0.53

Example 3

(21) To find the optimal combination of Nav1.7 inhibitor and Nav1.8 inhibitor in terms of pain relieve effect, the combination of another Nav1.7 inhibitor GNE-0439 and PF-04885614 was tested. 20 g/kg GNE-0439 and 90 g/kg PF-04885614 were intraperitoneally injected into SNI mice at 6 weeks post operation. One hour later, the mechanical threshold of mice was measured using Von Frey. It was found that the analgesic effect of the co-administration of GNE-0439 and PF-04885614 was not significantly better than that of the single administration of GNE-0439 (PWT=0.77+0.14 g, see FIG. 9), and was inferior to that of co-administration of 2 mg/kg PF-05089771 and 90 pg/kg PF-04885614 (PWT=1.38+0.15 g). Moreover, the analgesic effect of the combination of another Nav1.8 inhibitor PF-04531083 and PF-05089771 was tested. 2 mg/kg PF-05089771 and 10 mg/kg PF-04531083 were intraperitoneally injected into SNI mice at 6 weeks post operation, and the mechanical threshold of the mice was measured using Von Frey one hour later. It was observed that the co-administration of PF-05089771 and PF-04531083 achieved better relieve effect than the single administration of PF-05089771 or PF-04885614 (see FIG. 10), but the injection of 10 mg/kg PF-04531083 will result in significant side effects such as sedation and weight loss.