EA005497B1 - One-day pharmaceutical composition containing brivudine - Google Patents

Abstract

There is disclosed the activity of brivudine once-a-day in acute herpes zoster infections and post-herpetic neuralgia and the compositions thereof.

Description

Field of Invention

The present invention relates to pharmaceutical compositions for once-daily administration intended for the treatment of acute herpes zoster infections containing antiviral Brivudin, and to their use in preventing the occurrence of postherpetic neuralgia.

State of the art

Over the past ten years, the number of clinically useful drugs introduced for chemotherapy of viral diseases has increased significantly. Since its introduction in 1982, oral acyclovir has been widely used in the treatment of acute herpes zoster in immunocompetent patients. However, the main disadvantage of acyclovir therapy is that because of its limited bioavailability, frequent and high doses are required, which often leads to poor patient compliance.

This led to the development of a new antiviral drug (penciclovir) and the so-called prodrugs, such as valaciclovir (acyclovir prodrug) and famciclovir (penciclovir prodrug). To date, famciclovir provides the most convenient treatment for acute herpes zoster in elderly patients with a dosage of three tablets or capsules daily compared to five tablets of acyclovir daily or six tablets of valaciclovir daily. Famciclovir alleviates the acute signs and symptoms of herpes zoster, like acyclovir, and provides protection against prolonged herpes zoster pain or postherpetic neuralgia (ΡΗΝ). When taking the medicine less often, at lower doses and without an increased risk of side effects compared with acyclovir, this treatment is preferred and more convenient, especially for elderly patients. The recommended daily dose varies between 750 and 1500 mg (EGG E1 a1., 1994, Ιηΐ. 1. Ap11t1sto. Adep1k 4, 241-246; Tuttd e1 a1., 1995, App. 1p1etp. Meb. 123, 89-96 ; O \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ ек ек have to кт, т т кт кт е 1 а а 1 1.,, 1995 1995 1995 1995 1995 1995 1995 1995 1995 1995 1995 1995 1995 1995 1995 1995;;,; кт е еке., Еке еке еке еке еке еке еке еке. )

Brivudin, a nucleoside analogue, is a potent virostatic agent with selective activity against varicella zoster virus (Wapsa 11a hok1eg νίπικ. Νζν) and herpes simplex virus type 1 (Jettr ytp1ex νίπικ 1ure 1, Ηδν-1ес (Е1 | 1979, Proc. No. 11. Asab. 8s1. I8A, 76, 2947-2951; Ee S1egss. | E1 a1, 1980, 1. 1nGes1. Όίκ. 141, 563-574). While viral DNA synthesis is inhibited, cellular functions remain largely unaffected. The ongoing development of brivudine over the past ten years has been directed towards treating νζν infections in immunocompetent patients.

Based on the results of a number of controlled and uncontrolled studies, brivudine was registered in Germany in 1990 with the purpose of treating Ηδν-1 and νζν infections in immunocompromised patients at a dosage of 125 mg three or four times a day (Ee C1etcd e1 a1, 1980, Vg. Furniture. 1, 281, 1178; Tpso1 e1 a1, 1986, 1. Furniture. Tol1uu, 18, 11-20; \ U1x1sg e1 a1, 1995, 1. Furniture. Tol0, 46, 252 -257; see also GaschGottayop with the pharmaceutical product He1rsch®, sold in Germany in 1992).

Description of the invention

In recent significant multinational studies in immunocompetent patients with herpes zoster, it was unexpectedly shown that the once-daily dosage regimen in the form of 125 mg of brivudine per day for 7 days was statistically better than standard oral treatment with 800 mg five times a day acyclovir in relation to dermatological end points (5-Ho-L / 007BC). A post-trial examination of patients aged 50 years and older who took part in these trials and transferred ΡΗΝ after the end of the study showed a significantly lower incidence ΡΗΝ after treatment with brivudine compared with acyclovir (5-Ηo [a + b + c] ΡΗV / 0078BC).

Therefore, brivudine unexpectedly provides the possibility of treating patients with herpes zoster using a single tablet of 125 mg per day instead of the large and frequent regimen for the use of acyclovir, valacyclovir or famciclovir. One 125 mg tablet once a day is even more unexpected if we consider it against the previously planned 125 mg four times a day, as was recorded in Germany in 1990 for the treatment of Ηδν-1 and νζν infections in immunocompromised patients. With this application once a day, another unexpected result was achieved: a decrease in the incidence of postherpetic neuralgia.

The present invention provides the use of a pharmaceutical composition containing from 50 to 300 mg of brivudine for the treatment of herpes zoster infections or postherpetic neuralgia by administering such a composition once a day. In a preferred aspect, such a composition comprises 125 mg of brivudine.

Also provided is a method of treating herpes zoster infections or postherpetic neuralgia, in which 50 to 300 mg of brivudine, preferably 125 mg of brivudin, are administered once a day.

Preferably, an oral composition containing 125 mg of brivudine selected from the group consisting of:

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125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of lactose monohydrate, 6.5 mg of povidone with a K value of 25, 2.5 mg of magnesium stearate, purified water up to 245 mg in total;

125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of corn starch, 6.5 mg of povidone with a K value of 25, 2.5 mg of magnesium stearate, purified water up to 245 mg in total;

125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of lactose, 6.5 mg of povidone with a value of 25, 2.5 mg of magnesium stearate, purified water up to 245 mg in total;

125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of corn starch, 6.5 mg of sovovidone UL 64, 2.5 mg of magnesium stearate, purified water up to 245 mg in total;

125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of lactose, 6.5 mg of copovidone UA 64, 5.0 mg of collidone CI, 2.5 mg of magnesium stearate, purified water up to 250 mg in total;

125 mg of brivudine, 122.5 mg of microcrystalline cellulose / aerosil, 2.5 mg of magnesium stearate, purified water up to 250 mg in total;

125 mg of brivudine, 100.5 mg of microcrystalline cellulose / aerosil, 22.0 mg of collidone Cb, 2.5 mg of magnesium stearate, purified water up to 250 mg in total;

125 mg of brivudine, 122.5 mg of microcrystalline cellulose, 2.5 mg of magnesium stearate, purified water up to 250 mg in total (immediate release);

125 mg of brivudine, 74 mg of microcrystalline cellulose, 32.0 mg of lactose monohydrate, 5.0 mg of aerosil, 6.5 mg of copovidone UA 64, 2.5 mg of magnesium stearate, 1.5 mg of macrogol 6000, 4.5 mg of titanium dioxide (immediate release coated tablets).

experimental part

In order to evaluate the efficacy and safety of brivudine in immunocompetent adult patients with herpes zoster, large critical studies have recently been carried out (studies of 5No-a, 5-Ho-b and 5-Ho-s) in accordance with the standard of the Soviet Socialist Republic (Soob С11шса1 РтасДсе). All four studies were expected and had multicenter, double-blind, randomized, parallel planning.

Patients were followed up to 35 days to assess the disappearance of skin rash and acute phase pain. All patients were immunocompetent. Only adult patients 18 years of age or older were involved.

The primary parameter for evaluating efficacy in all three studies was the time from the start of treatment to the last rash of new vesicles. This parameter corresponds to viral replication in the skin and therefore conveys the virostatic efficacy of the drug. It is accepted in the literature and is considered the most reliable clinical sign in relation to other skin manifestations. Additional parameters for assessing the disappearance of a skin rash were the time from the start of treatment to the start of crust formation, the time from the start of treatment to the completion of crust formation, and the time from the start of treatment to the disappearance of crusts.

The spread of pathological skin changes and the appearance of other complications were also evaluated.

In the literature, the most commonly used measures to evaluate the benefits of antiviral therapy for herpes zoster are the duration of the skin rash and the appearance and intensity of pain during the acute phase of the infection. Recently, however, postherpetic neuralgia has become of great importance in assessing the benefits of antiviral therapies. Thus, in order to make a preliminary assessment of the possible effect of brivudine in reducing the incidence of postherpetic neuralgia, after the studies, retrospective examinations of patients aged 50 years and older who were involved in the main studies were additionally conducted.

In the table. 1 presents tests conducted on immunocompetent patients with herpes zoster. Previous uncontrolled studies in immunocompromised patients who provided early evidence of the potential benefits of brivudine will not be discussed.

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Table 1. Clinical Trials Overview

Study code Description Means of treatment and daily dosage (treatment for 7 days, unless otherwise indicated) 5-but Dose Establishment Study (Phase II) Brivudin 125 mg 1 Brivudine 62.5 mg x 1 Brivudine 31.25 mg 1 Acyclovir 800 mg x 5 5-but-b Effectiveness Study (Phase III) Brivudin 125 mg 1 Acyclovir 800 mg x 5 5-But-s Effectiveness Study (Phase III) Brivudine 125 mg x 1 for 3 days Acyclovir 800 mg x 5 5-But-a + b- ΡΗΝ На examination after Brivudin 125 mg 1 Acyclovir 800 mg x 5

research 5-but-with- ΡΗΝ Post-test на examination Brivudine 125 mg x 1 for 3 days Acyclovir 800 mg x 5

These clinical trials are presented below in chronological order.

Study 5-No-a

Since the concentration of brivudine in the plasma of a man receiving 125 mg once a day is 10-50 times higher than the 1C _{50 of the} clinical strain of chickenpox virus and, in addition, pharmacokinetic data for humans have shown that the concentration of brivudine in the plasma remains above 1C ₅₀ within 24 hours after a single injection of 125 mg of brivudine, it was reasonably suggested that once daily use of 125 mg of brivudine would be sufficient to treat herpes zoster.

The 5-No-a study, a phase II study, was performed on 642 patients; therefore, once-daily administration of 125 mg of brivudine for 7 days was evaluated tentatively compared to 5 x 800 mg of acyclovir for 7 days. Two trials with once-daily dosing of 62.5 mg and 32.25 mg brivudine for 7 days were added to evaluate the effectiveness of lower doses.

This study showed that the administration of 1 x 125 mg of brivudine for 7 days for patients with acute herpes zoster is as effective as treatment with the 5 x 800 mg acyclovir regimen for 7 days, with respect to the primary parameter, the time from the start of treatment to the last rash of new vesicles, as well as in relation to all secondary parameters, including the time from the start of treatment to the cessation of pain (intensity is weak or zero) as a clinically more important secondary parameter. Statistical analysis of the primary efficacy parameter and pain parameter showed that brivudine according to the 1 x 125 scheme is not inferior to acyclovir. For the parameter, the time from the beginning of treatment to the completion of cortical formation of superiority can be achieved by testing. A graphical representation of the risk factors calculated using the Cox proportional risk model for the 1 x 125 mg brivudine group compared to the 5 x 800 mg group of acyclovir is shown in FIG. one.

Brivudine has a linear dose-response relationship. The superiority over placebo in a statistically and clinically significant degree was shown in immunocompetent patients with acute herpes zoster infection. Treatment with brivudine using a dose of 1 x 125 mg for seven days is at least as effective as treatment with acyclovir according to the 5 x 800 mg regimen for seven days with respect to the duration of blistering and acute pain. These results, together with previous pharmacokinetic findings, led to the recognition of 125 mg of brivudine once a day as the treatment of choice.

Study 5-But-b

A study of 5-Phase III phase III was performed on 1227 patients to obtain supporting statistics for comparing the use of 1 x 125 mg of brivudine for seven days and 5 x 800 mg of acyclovir for seven days in immunocompetent patients with herpes zoster. A subgroup of patients aged 50 years and older was also evaluated separately.

A graphical representation of risk ratios calculated using the Cox proportional risk model for the 1 x 125 mg brivudine group compared to the 5 x 800 mg group of acyclovir is shown in FIG. 2.

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Study 5-No-s: reduction in treatment duration

In order to evaluate the effectiveness of a three-day treatment for patients with herpes zoster with taking 125 mg of brivudine once a day, another large study was conducted using exactly the same scheme as in the 5-Ho-L study. We compared the intake of 125 g of brivudine once a day for three days (followed by placebo for four days) with 800 mg of acyclovir 5 times a day for 7 days.

A total of 1336 patients were involved. The results show that this regimen of brivudine is not inferior to treatment with acyclovir using a standard dosage in relation to the primary variable effectiveness. However, superiority could not be established.

Therefore, these data on the reduced duration of treatment support the belief that brivudine once daily is certainly an effective treatment for herpes zoster in immunocompetent adults, and confirm the correctness of the results obtained in previous studies.

Primary variable of effectiveness

For the primary parameter, it was possible to establish the superiority of the brivudine group compared with acyclovir. The confirmation test procedure was statistically significant at 5%. The calculated risk factor was 1.14 (for the population according to the protocol), showing a 14% better effect (the endpoint was achieved faster) for patients treated with 1 x 125 mg of brivudine, compared with patients treated with acyclovir. The corresponding apparent average value for the time from the start of treatment to the last rash of herpes zoster vesicles was 25% less for brivudine (average: 13.5 hours) than for acyclovir (average: 18.0 hours).

Thus, as was shown in confirmation, for the primary variable efficacy, treatment with brivudine is statistically significantly better than treatment with acyclovir.

Secondary Performance Variables

Statistical tests for all secondary efficacy variables, including clinically important pain parameters, showed equivalence of 1 x 125 mg of brivudine compared to 5 x 800 mg of acyclovir.

The spread of skin lesions (brivudin: 1; acyclovir: 2) and other complications (brivudin: 0; acyclovir: 6) were found in less than 1% of patients in both groups.

An analysis of a subgroup of patients aged 50 years and older yielded results similar to those obtained for the entire population, with a 18% better treatment effect for the primary variable efficacy in patients treated with brivudine compared with patients treated with acyclovir.

The superiority of brivudine over acyclovir could be demonstrated by supporting statistics for the primary efficacy variable. At a significance level of 5% for all secondary efficacy variables, including pain parameters, it was possible to demonstrate that brivudine is not inferior to acyclovir.

For a subpopulation of patients 50 years of age and older, an even greater advantage was found for brivudine compared with acyclovir with respect to the primary efficacy parameter.

Post-Herpetic Neuralgia Examination

Two retrospective examinations after the studies were conducted in double-blind conditions according to the OCP standard in order to study the appearance of postherpetic neuralgia (ΡΗΝ) in patients aged 50 years and older:

1) selected from studies of 5-No-a and 5-No-b (7-day treatment with brivudine compared with 7-day treatment with acyclovir)

2) 5-No-s selected from the study (3-day treatment with brivudine compared with 7-day treatment with acyclovir).

Patients who, during a telephone interview, reported pain associated with herpes zoster, were invited to the center at the end of the study and examined by the researcher to confirm the incidence of ΡΗΝ and to answer questions related to the nature of the pain. ΡΗΝ was defined as pain in dermatomes affected by herpes zoster after the end of an individual study (patients had to complete the studies 5-No-a, 5-No-b and 5-No-s, when all the crusts disappeared or on the 35th day from the start of treatment, depending on what happened first).

The studies were carried out under blind conditions (both patients and researchers did not know what treatment was carried out during the studies of 5-Ho-a, 5-Ho-b and 5-Ho-s), which gives considerable strength to the results of these studies.

1. Post-test examination for отношении after seven-day treatment with brivudine

A large group of 608 male and female patients aged 50 years and older after 5-No-a and 5-No-L studies were retrospectively re-examined (between 8 and 17 months after treatment) to assess the benefits of brivudine in preventing the occurrence of postherpetic neuralgia. In a group of patients who had previously been treated with 125 mg of brivudine for seven days, 32.7% reported that

- 4 005497 suffer from postherpetic neuralgia at the end of treatment, while in the group treated with acyclovir this proportion was 43.5%. Thus, the relative risk of postherpetic neuralgia was 25% lower in the 125 mg brivudine group compared with the acyclovir group. This is a statistically significant decrease, which can be considered as an important clinical benefit of brivudine.

2. Post-test examination for отношении after three days of treatment with brivudine.

This study included patients 50 years of age or older who received a three-day course of 125 mg of brivudine or had a standard seven-day regimen of acyclovir in the 5-No-s study. Patients were interviewed between 3 and 8 months after treatment.

The results show that the incidence of postherpetic neuralgia in patients receiving a three-day course of 125 mg of brivudine once a day is comparable to the incidence of patients receiving standard dosage for acyclovir for seven days (41.6% versus 39.7%, respectively). These additional data confirm the evidence that 125 mg of brivudine given once a day for three days is not inferior to acyclovir in the treatment of herpes zoster.

Examples

The following can be considered as a non-limiting example of the present invention: Example 1. 1 tablet containing 125 mg of brivudine - immediate release tablets

No. raw materials mg / tablet one brivudine 125.0 2 microcrystalline cellulose 74.0 3 lactose monohydrate 37.0 4 povidone. K value 25 6.5 5 magnesium stearate 2,5 6 purified water

245.0

Example 2

No. raw materials mg / tablet one brivudine 125.0 2 microcrystalline cellulose 74.0 3 corn starch 37.0 4 povidone. K value 25 6.5 5 magnesium stearate 2,5 6 purified water

245.0

Example 3

No. raw materials mg / tablet one brivudine 125.0 2 cellulose powder 74.0 3 lactose 37.0 4 povidone. K value 25 6.5 5 magnesium stearate 2,5 6 purified water

245.0

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Example 4

Example 7

No. raw materials mg / tablet one brivudine 125.0 2 microcrystalline cellulose / Aerosil 98/2 100.5 3 call and don 22.0 4 magnesium stearate 2,5 5 purified water 250,0

Example 8. Capsule immediate release

No. raw materials mg / tablet one brivudine 125.0 2 microcrystalline cellulose 122.5 3 magnesium stearate 2,5 4 purified water 250,0

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EXAMPLE 9 Coated Immediate Release Tablet

No. raw materials mg / tablet one brivudine 125.0 2 microcrystalline cellulose 74.0 3 lactose monohydrate 32,0 4 aerosil 5,0 5 sopovidone. UA 64 6.5 6 magnesium stearate 2,5 7 hydroxypropylmethyl l cellulose 5,0 8 macrogol 6000 1.5 nine titanium dioxide 4.5 256,0

CLAIM

Claims (5)

CLAIM 1. The use of a pharmaceutical composition containing from 50 to 300 mg of brivudine for the treatment of herpes zoster infections or postherpetic neuralgia by administering such a composition once a day. 2. The use according to claim 1, where the content of brivudine is 125 mg. 3. A method for the treatment of herpes zoster infections or postherpetic neuralgia, in which 50 to 300 mg of brivudine is administered once a day. 4. The method according to claim 3, wherein 125 mg of brivudine is used. 5. The method according to claim 3 or 4, wherein an oral composition containing 125 mg of brivudine is used, said composition being selected from the group consisting of 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of lactose monohydrate, 6.5 mg of povidone with a K value of 25, 2.5 mg of magnesium stearate, purified water up to 245 mg in total; 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of corn starch, 6.5 mg of povidone with a K value of 25, 2.5 mg of magnesium stearate, purified water up to 245 mg in total; 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of lactose, 6.5 mg of povidone with a value of 25, 2.5 mg of magnesium stearate, purified water up to 245 mg in total; 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of corn starch, 6.5 mg of sovovidone UA 64, 2.5 mg of magnesium stearate, purified water up to 245 mg in total; 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of lactose, 6.5 mg of copovidone UA 64, 5.0 mg of collidone SB, 2.5 mg of magnesium stearate, purified water up to 250 mg in total; 125 mg of brivudine, 122.5 mg of microcrystalline cellulose / aerosil, 2.5 mg of magnesium stearate, purified water up to 250 mg in total; 125 mg of brivudine, 100.5 mg of microcrystalline cellulose / aerosil, 22.0 mg of collidone SB, 2.5 mg of magnesium stearate, purified water up to 250 mg in total; 125 mg of brivudine, 122.5 mg of microcrystalline cellulose, 2.5 mg of magnesium stearate, purified water up to 250 mg in total (immediate release); 125 mg of brivudine, 74 mg of microcrystalline cellulose, 32.0 mg of lactose monohydrate, 5.0 mg of aerosil, 6.5 mg of copovidone UA 64, 2.5 mg of magnesium stearate, 1.5 mg of macrogol 6000, 4.5 mg of titanium dioxide (immediate release coated tablets). - 7 005497 1.5 cortex formation rash beginning complete disappearance cessation of pain (primary parameter) co-formation ^no or weak no FIG. one 0.5 * Risk factors calculated using Cox regression using covariates. A risk factor greater than 1 shows the best effect of treatment with brivudine compared with acyclovir. The lower limit of the one-sided 95% confidence interval above the 0.8 line (dashed line) shows that brivudine is not inferior to acyclovir, and above the 1.0 line (continuous line) shows superiority of 1 x 125 mg of brivudine compared to 5 x 800 mg acyclovir. ♦ lower risk coefficient 95% CI Time from initiation of treatment to ¹ T - g t ₁ ¹ I II last beginning complete disappearance of pain cessation rash crusting no or weak no (primary parameter) FIG. 2 * Risk factors calculated using Cox regression using covariate. A risk factor greater than 1 shows the best effect of treatment with brivudine compared with acyclovir. The lower limit of the one-sided 95% confidence interval above the 0.8 line (dashed line) shows that brivudine is not inferior to acyclovir, and above the 1.0 line (continuous line) shows superiority of 1 x 125 mg of brivudine compared to 5 x 800 mg acyclovir. f risk factor lower 95% CI