CN1845743A - Use of oxcarbazepine for the treatment of diabetic neuropathic pain and the improvement of sleep - Google Patents

Abstract

The present invention provides for novel uses of the carbamazepine derivative of formula (I) and its pharmaceutically acceptable salts, in particular an improved regimen for the administration of the carbamazepine derivative of formula (I) and the pharmaceutically acceptable salts thereof for the treatment of patients suffering from pain, in particular neuropathic pain, especially diabetic neuropathic pain, and the improvement of sleep; the use of oxcarbazepine for the manufacture of a pharmaceutical composition for the treatment of pain or the manufacture of a pharmaceutical composition for the improvement of sleep in human patients suffering from chronic pain; pharmaceutical compositions comprising oxcarbazepine as sole active ingredient for the treatment of pain or for the improvement of sleep in human patients suffering from chronic pain and to packages comprising a pharmaceutical composition comprising as sole active ingredient oxcarbazepine together with instructions for the treatment of pain or together with instructions for improvement of sleep in human patients suffering from chronic pain.

Description

Use of oxcarbazepine in treating diabetic neuropathic pain and improving sleep

The present invention relates to the new application of carbamazepine derivatives of formula I and pharmaceutically acceptable salts thereof, particularly relate to the carbamazepine derivatives of formula I and its pharmacy for treating patients suffering from pain and for improving sleep An improved dosing regimen of an acceptable salt above, especially neuropathic pain, especially diabetic neuropathic pain. Described formula (I) is as follows:

The compound of formula I is known as "oxcarbazepine" (10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide) and is known, for example, under the trade name Trileptal ^® listed.

Oxcarbazepine is a known anticonvulsant drug used to treat eg epileptic seizures. Its preparation method is disclosed in, for example, US Patent 3,642,775 and WO 01/56992, which are incorporated herein by reference.

Surprisingly, the applicant has found that the administration of oxcarbazepine according to one of the dosing regimens of the present invention results in an effective treatment of pain, especially neuropathic pain, in human patients, especially in the Caucasian patient population. Pain, especially diabetic neuropathic pain. Even more surprisingly, effective treatment of neuropathic pain can be obtained with relatively low daily doses of oxcarbazepine (eg, 450 or 600 mg/day), that is, with a total daily dose significantly lower than usual Total daily dose for the treatment of epilepsy.

In addition, the Applicant has surprisingly found that administration of oxcarbazepine, in particular according to one of the regimens according to the present invention, reduces pain in patients with chronic pain (in particular neuropathic pain, especially diabetic neuropathic pain) Improves sleep in human patients, reducing the number of awakenings from sleep due to pain on the one hand, and reducing delays in falling asleep or feeling restful after sleep due to pain on the other hand.

According to one embodiment of the present invention, oxcarbazepine or a pharmaceutically acceptable salt thereof may be administered as follows: for example, two or more times a day, such as two or three times, with a total dosage ranging from about 450 mg/day to About 900 mg/day, preferably a total dosage of about 550 mg/day to about 750 mg/day, particularly preferably 600 mg/day. Accordingly, the present invention relates to a method of also administering oxcarbazepine to a patient, the method comprising administering oxcarbazepine or a pharmaceutically acceptable salt thereof to a patient suffering from pain, especially neuropathic pain, especially diabetic neuropathic pain. For patients with sexual pain), preferably twice a day, the total dosage is about 450 mg/day to about 900 mg/day, preferably the total dosage is about 550 mg/day to about 750 mg/day, particularly preferably 600 mg/day.

In addition, the present invention relates to a method for improving sleep in patients suffering from chronic pain (especially neuropathic pain, especially diabetic neuropathic pain), the method comprising administering oxcarbazepine or a pharmaceutically acceptable salt thereof to said Patients are preferably administered twice a day with a total dose of about 450 mg/day to about 900 mg/day, preferably a total dose of about 550 mg/day to about 750 mg/day, particularly preferably 600 mg/day.

According to another embodiment of the present invention, oxcarbazepine or a pharmaceutically acceptable salt thereof may be administered as follows: for example, two or more times a day, such as two or three times, with a total dosage ranging from about 900 mg/day to about 1500 mg/day, preferably a total dosage of about 1050 mg/day to about 1350 mg/day, particularly preferably 1200 mg/day. Accordingly, the present invention relates to a method of administering oxcarbazepine to a patient, the method comprising administering oxcarbazepine or a pharmaceutically acceptable salt thereof to a patient suffering from pain, especially neuropathic pain, especially diabetic neuropathic pain. Pain), preferably twice a day, the total dosage is about 900mg/day to about 1500mg/day, preferably the total dosage is about 1050mg/day to about 1350mg/day, especially preferably 1200mg/day.

In addition, the present invention relates to a method for improving sleep in patients suffering from chronic pain (especially neuropathic pain, especially diabetic neuropathic pain), the method comprising administering oxcarbazepine or a pharmaceutically acceptable salt thereof to said Patients are preferably administered twice a day with a total dose of about 900 mg/day to about 1500 mg/day, preferably a total dose of about 1050 mg/day to about 1350 mg/day, particularly preferably 1200 mg/day.

According to another embodiment of the present invention, oxcarbazepine or a pharmaceutically acceptable salt thereof may be administered as follows: for example, two or more times a day, such as two or three times, with a total dosage ranging from about 1500 mg/day Up to about 2100 mg/day, preferably a total dosage of about 1650 mg/day to about 1950 mg/day, particularly preferably 1800 mg/day. Accordingly, the present invention relates to a method of administering oxcarbazepine to a patient, the method comprising administering oxcarbazepine or a pharmaceutically acceptable salt thereof to a patient suffering from pain, especially neuropathic pain, especially diabetic neuropathic pain. Pain), preferably twice a day, the total dosage is about 1500mg/day to about 2100mg/day, preferably the total dosage is about 1650mg/day to about 1950mg/day, especially preferably 1800mg/day.

In addition, the present invention relates to a method for improving sleep in patients suffering from chronic pain (especially neuropathic pain, especially diabetic neuropathic pain), the method comprising administering oxcarbazepine or a pharmaceutically acceptable salt thereof to said Patients are preferably administered twice a day with a total dose of about 1500 mg/day to about 2100 mg/day, preferably a total dose of about 1650 mg/day to about 1950 mg/day, particularly preferably 1800 mg/day.

The term "neuropathic pain" as used herein includes, but is not limited to, pain often associated with nerve damage arising from a range of pathologies including amputation or disease (diabetes, postherpetic neuralgia or trigeminal neuralgia).

Hyperalgesia and allodynia associated with neuropathic pain are clinically difficult to manage and treat with the administration of opioids or nonsteroidal anti-inflammatory drugs.

In appropriate clinical studies, as described in the Examples, for example, when the total daily dose of oxcarbazepine is 600 mg, 1200 mg or 1800, the effectiveness of oxcarbazepine in treating the above diseases including improving sleep quality can be confirmed. Those skilled in the relevant fields can choose relevant experiments to confirm the effectiveness. A suitable clinical study is preferably a randomized, double-blind, placebo-controlled, parallel experiment in patients with neuropathic pain.

Description of drawings

Figure 1 depicts the mean VAS scores (y-axis) during the last week of treatment in the clinical study described in Example 1. Dark areas represent scores obtained in a group of patients given oxcarbazepine at a daily dose of 1800 mg (N=68). Light colored areas represent scores of the placebo group (N=76).

2 depicts mean VAS scores (y-axis) per week (x-axis) for the clinical study described in Example 1. FIG. The upper line represents the score of the placebo group (N=76). The lower line represents the scores obtained in a group of patients given oxcarbazepine at a daily dose of 1800 mg (N=68).

According to one aspect of the invention, oxcarbazepine may be administered twice daily continuously, alone, or during and after other treatments, such as during diabetes treatment.

A single dose of oxcarbazepine may range from 150 to 1200 mg, for example 300 mg, 600 mg or 900 mg. For example, in one embodiment of the invention, two single doses of about 900 mg are administered, 6-12 hours apart, for example about 8 hours apart.

Oxcarbazepine can be administered by any conventional means, for example oral administration (eg in the form of tablets or capsules) or parenteral administration (eg in the form of injection solutions or suspensions).

In one embodiment of the invention, the pharmaceutical composition is preferably a tablet, more preferably a tablet as disclosed in US 4,353,887, most preferably a film-coated tablet as disclosed in WO 98/35681, The disclosures of the above two patent applications are hereby incorporated by reference, especially their work

Example.

In another embodiment of the present invention, the pharmaceutical composition is preferably an oral suspension, more preferably an oral suspension as disclosed in WO 01/45671, the content of which is incorporated herein by reference.

A unit dosage form may contain, for example, from about 2.5 mg to about 1000 mg of oxcarbazepine, such as 150 mg or 300 mg.

The present invention also provides the use of oxcarbazepine in the production of a pharmaceutical composition for the treatment of pain (especially neuropathic pain, especially diabetic neuropathic pain), characterized in that the composition contains 300 to 1200 mg of Oxcarbazepine.

The present invention further provides the use of oxcarbazepine in the production of a pharmaceutical composition for improving the sleep of patients suffering from chronic pain (especially neuropathic pain, especially diabetic neuropathic pain).

In addition, the present invention also provides:

A package comprising a pharmaceutical composition containing oxcarbazepine as the sole active ingredient and instructions for improving sleep in patients suffering from chronic pain, especially neuropathic pain, especially diabetic neuropathic pain ;and

• A pharmaceutical composition containing oxcarbazepine as the sole active ingredient for improving sleep in patients suffering from chronic pain, especially neuropathic pain, especially diabetic neuropathic pain.

a package comprising a pharmaceutical composition comprising oxcarbazepine as the sole active ingredient and instructions for use in the treatment of pain (in particular neuropathic pain, especially diabetic neuropathic pain); and

• A pharmaceutical composition comprising oxcarbazepine as the sole active ingredient for the treatment of pain (in particular neuropathic pain, especially diabetic neuropathic pain).

Example 1 - Clinical Study in Patients with Diabetic Neuropathic Pain

In the clinical study of the Caucasian patient population, a completely double-blind treatment period was used for 112 days. Patients with diabetic neuropathic pain were given placebo or oxcarbazepine. In the last week of double-blind treatment, pain severity was scored using the mean visual analogue scale (VAS), and the results showed that the total dose of 1800 mg/day oxcarbazepine was statistically significantly better than placebo (p=0.0108).

Additionally, the group treated with a total dose of 1800 mg/day oxcarbazepine had a statistically significantly higher percentage of responders (those who felt improved, significantly improved, or very significantly improved) compared to the placebo group (39.7%). Improved responder) (p=0.0003).

Example 2 - Effect of Oxcarbazepine on Sleep in Human Patients with Diabetic Neuropathic Pain

In a multicentre, placebo-controlled, double-blind, parallel-group study, the efficacy of oxcarbazepine administered up to 1800 mg per day was evaluated in patients suffering from diabetic neuropathic pain. The study consisted of three steps: a pre-randomization screening phase (2 weeks); a double-blind treatment phase (18 weeks); and an open-label extension phase (52 weeks). The double-blind treatment period was further divided into: a titration period of 4 weeks, a maintenance period of 12 weeks, and a follow-up period of 2 weeks. During the double-blind treatment period (16 weeks), patients meeting all inclusion criteria were randomized in a 1:1 ratio to receive the test drug or placebo. After random selection into the double-blind treatment period, the initial dose of oxcarbazepine or placebo was 300 mg/day, which was increased to 300 mg twice a day (600 mg/day) after 3 days. Then, during a 4-week titration phase, oxcarbazepine was titrated to a maximum target dose of 900 mg twice daily (1800 mg/day) as tolerated in increments of 300 mg every 5 days. During the subsequent 12-week study period (maintenance phase), oxcarbazepine was maintained at this dose until day 28. Sleep surveys were conducted daily using the following three questions to evaluate the sleep fluctuations of responding patients during the double-blind treatment period: 1) Did the pain make you fall asleep late last night? 2) Did the pain wake you up from sleep more than once last night? 3) After sleeping, did you feel calm this morning?

The mean proportion of days on which patients were awake at night due to pain was lower in the oxcarbazepine-treated group compared to the control group (31% vs. 49% of study days; P=0.02) (Table 1). Additionally, oxcarbazepine-treated patients had lower rates of sleep onset delay and higher rates of feeling calm after sleep compared with placebo-treated patients, but the differences did not reach statistical significance.

Table 1: Treatment Effects and Sleep Questionnaire ITT number Oxcarbazepine placebo P value (compared to placebo) Percentage of days in sleep survey double-blind phase, mean (SD) sleep delay n=6828(31)31(29)55(34) n=7638(38)49(38)46(37) 0.090.020.17

Abbreviations: ITT is to-be-treated; SD is standard deviation.

Claims (31)

1. oxcarbazepine is used for improving the purposes of the Pharmaceutical composition of the human patients sleep of suffering from chronic pain in production.

2. the purposes of claim 1, wherein said pain is diabetic neuropathic pain.

3. claim 1 or 2 purposes, wherein the accumulated dose of oxcarbazepine administration is between about 450mg/ days to about 2100mg/ days.

4. each purposes among the claim 1-3 is wherein improved sleep by reducing the number of times of waking up owing to pain.

5. each purposes among the claim 1-3 is wherein by reducing the slow sleep that improves because pain is fallen asleep.

6. each purposes among the claim 1-3 is wherein improved sleep by the aftersensation calmness of sleeping.

7. pack, this packing comprises Pharmaceutical composition and the description that contains as the oxcarbazepine of unique active component, and this packing is used to improve the human patients sleep of suffering from chronic pain.

8. Pharmaceutical composition, this Pharmaceutical composition contains the oxcarbazepine as unique active component, is used for improving suffering from the sleep of chronic pain human patients.

9. improve the method suffer from the sleep of chronic pain human patients, this method comprises total dose range is delivered medicine to described patient for about 1500mg/ days to about 2100mg/ days oxcarbazepine or its pharmaceutically acceptable salt.

10. the method for claim 9, the daily dose that wherein delivers medicine to the patient for from 1650mg to 1950mg.

11. the method for claim 10, wherein daily dose is about 1800mg.

12. improve the method suffer from the sleep of chronic pain human patients, this method comprises total dose range is delivered medicine to described patient for about 900mg/ days to about 1500mg/ days oxcarbazepine or its pharmaceutically acceptable salt.

13. the method for claim 12, the daily dose that wherein delivers medicine to the patient is to 1350mg from 1050mg.

14. the method for claim 13, wherein daily dose is about 1200mg.

15. improve the method suffer from the sleep of chronic pain human patients, this method comprises total dose range is delivered medicine to described patient for about 450mg/ days to about 900mg/ days oxcarbazepine or its pharmaceutically acceptable salt.

16. the method for claim 15, the daily dose that wherein delivers medicine to the patient is to 750mg from 550mg.

17. the method for claim 16, wherein daily dose is about 600mg.

18. claim 9,12 or 15 each methods, wherein oxcarbazepine is administered twice every day.

19. each method among the claim 1-18, wherein the patient suffers from neuropathic pain.

20. each method among the claim 1-19, wherein the patient is derived from the white race crowd.

21. the method for claim 19, wherein oxcarbazepine is with the form administration of film coating tablet.

22. the method for treatment human patients pain, this method comprise total dose range is delivered medicine to described patient for about 1500mg/ days to about 2100mg/ days oxcarbazepine or its pharmaceutically acceptable salt.

23. the method for claim 22, wherein daily dose is about 1800mg.

24. the method for treatment human patients pain, this method comprise total dose range is delivered medicine to described patient for about 900mg/ days to about 1500mg/ days oxcarbazepine or its pharmaceutically acceptable salt.

25. the method for claim 24, wherein daily dose is about 1200mg.

26. the method for treatment human patients pain, this method comprise total dose range is delivered medicine to described patient for about 450mg/ days to about 900mg/ days oxcarbazepine or its pharmaceutically acceptable salt.

27. the method for claim 26, wherein daily dose is about 600mg.

28. claim 22,24 or 26 each methods, wherein the patient suffers from diabetic neuropathic pain.

29. claim 22,24 or 26 each methods, wherein the patient is derived from the white race crowd.

30. oxcarbazepine is used for the treatment of purposes in the Pharmaceutical composition of diabetic neuropathic pain in production.

31. packing, this packing comprises Pharmaceutical composition and the description that contains as the oxcarbazepine of unique active component, is used for the treatment of pain.

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