FR2818907A1 - USE OF BRIVUDINE FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

The invention relates to the use of brivudine for the preparation of a pharmaceutical composition intended to be administered once a day. pharmaceutical field.

Description

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The present invention relates to the use of brivudine for the preparation of a pharmaceutical composition intended to be administered once a day, in particular for the treatment or the prevention of acute zosterial infections or postherpetic neuralgia.

State of the art
Over the past decade, the number of clinically useful drugs introduced for the chemotherapy of viral diseases has increased significantly. Since its introduction in 1982, oral acidovir has been widely used in the treatment of acute herpes zoster in immunocompetent patients. However, a major disadvantage of aciclovir therapy is that high and frequent doses are required because of the limited bioavailability of this drug, which often results in poor compliance.

(penciclovir) et de substances appelées des prodrogues telles que le valaciclovir (la prodrogue de l'aciclovir) et le famciclovir (la prodrogue du penciclovir). A ce jour, le famciclovir offre le traitement le plus commode du zona aigu chez les patients âgés, avec une administration de trois comprimés ou capsules par jour, au lieu de cinq comprimés par jour pour l'aciclovir et de six comprimés par jour pour le valaciclovir. Le famciclovir atténue les signes et symptômes aigus du zona, comme le fait l'aciclovir, et apporte une protection contre la douleur prolongée associée au zona ou PHN. Avec des prises moins fréquentes, en doses plus faibles et sans risque accru d'événements défavorables comparativement à l'aciclovir, ce traitement est avantageux et plus commode, notamment pour les patients âgés. La dose quotidienne recommandée varie entre 750 mg et 1500 mg (Degreef et coti., 1994, lut. J. This problem led to the development of a new antiviral agent

(penciclovir) and substances called prodrugs such as valaciclovir (the prodrug of aciclovir) and famciclovir (the prodrug of penciclovir). To date, famciclovir offers the most convenient treatment for acute herpes zoster in elderly patients, with three tablets or capsules daily, instead of five tablets per day for aciclovir and six tablets per day for valaciclovir. Famciclovir relieves the acute signs and symptoms of shingles, as does aciclovir, and provides protection against the prolonged pain associated with shingles or PHN. With less frequent doses, lower doses and no increased risk of adverse events compared to aciclovir, this treatment is advantageous and more convenient, especially for elderly patients. The recommended daily dose varies between 750 mg and 1500 mg (Degreef et al., 1994, J.-L.

Antimicrob. Agents 4,241-246; Tyring et al., 1995, Ann. Intern. Med. 123.89-96; Dworkin et al., 1995, Antiviral Res. 26.344; Dworkin et al., 1996, Bread 67, 241-251; Dworkin et al., 1998, Antiviral Research 33, 73-85).

Acad. Sci. USA 76, 2947-2951 ; De Clercq et coli., 1980, J. Infect. Dis. 141, 563-574). Bien que la synthèse de l'ADN viral soit inhibée, les fonctions cellulaires restent largement inaltérées. La poursuite du développement de la brivudine pendant ces dernières années a été orientée vers le traitement Brivudine, a nucleoside analogue, is a potent virostatic agent with selective activity against varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) (De Clercq et al., 1979, Proc Nat.

Acad. Sci. USA 76, 2947-2951; De Clercq et al., 1980, J. Infect. Dis. 141, 563-574). Although the synthesis of viral DNA is inhibited, cell functions remain largely unaltered. The further development of brivudine in recent years has been directed towards the treatment

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d'infections à VZV chez des patients immunocompétents.

VZV infections in immunocompetent patients.

Based on the results of a number of controlled and uncontrolled studies, brivudine was registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in patients with immunodeficiency at 125 mg three or four times daily (De Clercq et al., 1980, Br Med Med J. 281, 1178, Tricot et al., 1986, J. Med Virology 18, 11-20, Wutzler et al., 1995, J. Med Virology 46, 252-257, see also the information leaflet attached to the drug product Helpin @ marketed in Germany in 1992).

PHN après le traitement par la brivudine comparativement à l'aciclovir (5Ho [a+b+c] PHN/0078BC). Presentation of the invention
In large recent multinational studies in immunocompetent patients with shingles, a single dose regimen of 125 mg brivudine daily for 7 days was surprisingly statistically superior to standard oral five times a day with 800 mg of aciclovir, with regard to the dermatological endpoints (5-Ho-b / 0078BC). Post-study surveillance of patients aged 50 years or older who had participated in these studies and who had undergone PHNs after graduation indicated a significantly lower incidence of

PHN after treatment with brivudine compared to aciclovir (5Ho [a + b + c] PHN / 0078BC).

Brivudine therefore offers, surprisingly, the possibility of treating patients with zoster with a single 125 mg tablet per day, instead of the high-dose and frequent dosages of aciclovir, valaciclovir or famciclovir. A single 125 mg tablet a day is even more surprising when compared with the 125 mg previously prescribed four times a day, as recorded in Germany in 1990 for the treatment of HSV-1 and VZV infections in patients with immune deficiency. With this once-a-day dosing regimen, another surprising result is that of reducing the incidence of post-herpetic neuralgia. The pharmaceutical composition containing brivudine may be in a form selected from a group consisting of capsules, tablets and oral modified release forms.

 The present invention also extends to the use of brivudine for the preparation of a pharmaceutical composition for administration once a day, the amount of active ingredient being 50 to 300 mg, preferably 100 to 200 mg. mg.

Experimental part
To evaluate the efficacy and safety of brivudine in immunocompetent adult patients with herpes zoster, three major pivotal studies (5-Ho-a, 5-Ho-b and 5-Ho-c studies) were conducted recently according to rules of good clinical practice. The four studies were all

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prospectives et organisées en parallèle avec randomisation, en double insu, dans des centres multiples.

Prospective and organized in parallel with randomization, double blind, in multiple centers.

Patients were observed for up to 35 days to assess the resolution of the acute rash and pain. All patients were immunocompetent. Only adult patients aged 18 years or older were enrolled in the study.

The main parameter for evaluating efficacy in the three studies was "time from the start of treatment to the last new vesicle eruption". This parameter varies in parallel with the viral replication in the skin and thus describes the virostatic power of a drug. It is accepted in the literature and considered the most reliable clinical sign compared to other cutaneous manifestations. Other parameters used to evaluate the resolution of the rash are the "time from the start of treatment to the onset of crust formation", the "time from the start of treatment to the complete formation of crusts. "the time" from the beginning of the treatment until the fall of the crusts ". Dissemination of skin lesions and the appearance of other complications were also evaluated.

 In the literature, the most common measures used to judge the benefit of antiviral therapy in shingles are the duration of rash and the onset and intensity of pain during the acute phase of the infection. . However, post-herpetic neuralgia has recently gained increasing importance in evaluating the value of antiviral therapies.

Thus, to evaluate in a preliminary way the possible effect of brivudine on the decrease in the incidence of post-herpetic neuralgia, retrospective post-study surveillance studies were also conducted on patients aged 50 or over. more who had been engaged in the studies.

 Table 1 summarizes the tests performed on immunocompetent patients with shingles. The first uncontrolled studies of patients with immunodeficiency, who gave early indications of the potential benefit of brivudine, will not be examined.

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TABLE 1 OVERVIEW OF CLINICAL TRIALS

<Tb>
<tb> Study <SEP> Code <SEP> Description <SEP> Treatment <SEP> and <SEP> Dosage <SEP> Daily
<tb> (SEP treatment) of <SEP> 7 <SEP> days
<tb> except <SEP> mention <SEP> opposite)
<tb> 5-Ho-a <SEP><SEP> Study of <SEP> Brivudine <SEP> 125 <SEP> mg <SEP> x <SEP> 1
<tb> determination <SEP> Brivudine <SEP> 62.5 <SEP> mg <SEP> x <SEP> 1
<tb><SEP> dose <SEP> Brivudine <SEP> 31.25 <SEP> mg <SEP> x <SEP> 1
<tb> (Phase <SEP> II) <SEP> Aciclovir <SEP> 800 <SEP> mg <SEP> x <SEP> 5
<tb> 5-Ho-b <SEP><SEP> Study of <SEP> Confirmation <SEP> Brivudine <SEP> 125 <SEP> mg <SEP> x <SEP> 1
<tb> Efficacy <SEP> Aciclovir <SEP> 800 <SEP> mg <SEP> x <SEP> 5
<tb> (Phase <SEP> fit)
<tb> 5-Ho-c <SEP><SEP> Study of <SEP> Confirmation <SEP> Brivudine <SEP> 125 <SEP> mg <SEP> x <SEP> 1 <SEP> During <SEP> 3
<tb> efficiency <SEP> days
<tb> (Phase <SEP> III) <SEP> Aciclovir <SEP> 800 <SEP> mg <SEP> x <SEP> 5
<tb> 5-Ho-a + b-Surveillance <SEP> after <SEP> Brivudine <SEP> 125 <SEP> mg <SEP> x <SEP> 1
<tb> PHN <SEP> study <SEP> on <SEP> PHN <SEP> Aciclovir <SEP> 800 <SEP> mg <SEP> x <SEP> 5
<tb> 5-Ho-c-PHN <SEP> Monitoring <SEP> after <SEP> Brivudine <SEP> 125 <SEP> mg <SEP> x <SEP> 1 <SEP> during <SEP> 3
<tb> study <SEP> on <SEP> PHN <SEP> days
<tb> Aciclovir <SEP> 800 <SEP> mg <SEP> x <SEP> 5
<Tb>

These clinical trials are presented below in chronological order.

Study 5-Ho-a Since plasma concentrations of brivudine in a man receiving 125 mg once daily are 10 to 50 times the Ci, clinical strains of varicella-zoster virus and in addition, the pharmacokinetic results showed that plasma concentrations of brivudine are maintained above Ciso for 24 hours after a single 125 mg dose of brivudine, it was reasonable to assume that a single daily brivudine was sufficient for the treatment of shingles.

 The 5-Ho-a Phase II study in 642 patients, therefore, prospectively evaluated a single daily administration of 125 mg brivudine for seven days compared to 5 x 800 mg aciclovir for seven days. Two study branches with daily doses

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uniques de brivudine de 62, 5 mg et 32, 25 mg pendant sept jours ont été ajoutées pour évaluer également l'efficacité de doses inférieures.

Single doses of brivudine 62, 5 mg and 32, 25 mg for seven days were added to also evaluate the effectiveness of lower doses.

primaire du "temps depuis le début du traitement jusqu'à la dernière éruption de nouvelles vésicules" et également au regard de tous les paramètres secondaires, y compris le "temps depuis le début du traitement jusqu'à la cessation de la douleur (intensité nulle ou modérée)"comme paramètre secondaire cliniquement plus pertinent. Une analyse statistique du paramètre primaire d'efficacité et du paramètre de douleur a démontré la non-infériorité de 1 x 125 mg de brivudine comparativement à l'aciclovir. Pour le paramètre "temps depuis le début du traitement jusqu'à formation complète de croûtes", la supériorité a pu être établie d'une manière exploratrice. La Figure 1 donne une représentation graphique des coefficients de risque calculés d'après le modèle des risques proportionnels de Cox pour le groupe à 1 x 125 mg de brivudine comparé au groupe à 5 x 800 mg d'aciclovir. This study demonstrated that 1 x 125 mg brivudine for 7 days in patients with acute herpes zoster is as effective as treatment with 5 x 800 mg aciclovir for 7 days with respect to the parameter

primary "time from start of treatment to last new vesicle eruption" and also to all secondary endpoints, including "time from start of treatment to cessation of pain (zero intensity) or moderate) "as a secondary parameter clinically more relevant. A statistical analysis of the primary efficacy endpoint and the pain parameter demonstrated the non-inferiority of 1 x 125 mg brivudine compared with aciclovir. For the parameter "time since the beginning of the treatment until complete crust formation", the superiority could be established in an exploratory way. Figure 1 provides a graphical representation of the risk coefficients calculated from the proportional hazards model of Cox for the 1 x 125 mg brivudine group compared to the 5 x 800 mg aciclovir group.

 Brivudine has a linear dose-response relationship. The superiority over placebo has been demonstrated to a statistically and clinically significant extent in immunocompetent patients with acute herpes zoster infection. Brivudine at a dose of 1 x 125 mg for seven days is at least as effective as treatment with aciclovir 5 x 800 mg for seven days with respect to the duration of vesicle onset and acute pain. . These results, taken in conjunction with previous pharmacodynamic considerations, led to the selection of 125 mg brivudine once daily as an elective treatment.

Study 5-Ho-b
The study of Phase tt! 5-Ho-b was performed on 1227 patients to obtain confirmatory statistics for the comparison of 1 x 125 mg brivudine for seven days with 5 x 800 mg aciclovir for seven days in immunocompetent patients with shingles. A subgroup of patients aged 50 and older was also assessed separately.

 Figure 2 provides a graphical representation of the risk coefficients calculated from the proportional hazards model of Cox for the 1 x 125 mg brivudine group compared to the 5 x 800 mg aciclovir group.

Study 5-Ho-c: Reduction of the duration of treatment
To estimate the effectiveness of a three-day treatment with 125 mg

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de brivudine une fois par jour chez des patients atteints de zona, une autre grande étude a été conduite en utilisant exactement la même organisation d'étude que pour l'étude 5-Ho-b. On a comparé 125 mg de brivudine une fois par jour pendant trois jours (suivis par quatre jours de placebo) avec 800 mg d'aciclovir 5 fois par jour pendant 7 jours.

of brivudine once daily in patients with shingles, another large study was conducted using exactly the same study organization as for the 5-Ho-b study. 125 mg of brivudine was compared once daily for three days (followed by four days of placebo) with 800 mg of aciclovir 5 times daily for 7 days.

 A total of 1,336 patients were enrolled in the study. The results show that this brivudine dosing regimen is not inferior to conventional treatment with aciclovir with respect to the primary efficacy variable. Superiority could not be established, however.

 These results obtained with a reduced duration of treatment thus support the idea that brivudine is indeed an effective once-daily treatment for shingles in immunocompetent adults and confirm the validity of the results obtained in previous studies.

Primary efficacy variable
For the primary endpoint, the superiority of brivudine treatment compared to aciclovir treatment could be established. The confirmation test procedure was statistically significant at the 5% level. The estimated risk coefficient was 1.14 (for the population per protocol), indicating a better effect of 14% (the endpoint was reached faster) for patients treated with 1 x 125 mg brivudine compared to patients treated with aciclovir. The corresponding descriptive mean for "time from treatment start to last zoster vesicle eruption" for brivudine (mean: 13.5 hours) was 25% lower than for aciclovir (mean: 18 , 0 hours).

 Thus, with respect to the primary efficacy variable, it was conclusively demonstrated that brivudine treatment was statistically significantly superior to aciclovir treatment.

Secondary efficacy variables
Statistical tests for all secondary efficacy variables, including clinically relevant pain parameters, demonstrated the equivalence of 1 x 125 mg brivudine compared with 5 x 800 mg aciclovir.

 Dissemination of cutaneous lesions (brivudine: 1, aciclovir: 2) and other complications (brivudine: 0, aciclovir: 6) occurred in less than 1% of patients in both groups.

 Subgroup analysis of patients aged 50 years or older

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donné des résultats similaires à ceux obtenus dans la population globale, avec un effet de traitement supérieur de 18 % pour la variable d'efficacité primaire chez les patients traités par la brivudine comparés à ceux traités par l'aciclovir.

similar results to those obtained in the overall population, with a treatment effect greater than 18% for the primary efficacy variable in patients treated with brivudine compared to those treated with aciclovir.

 The superiority of brivudine over aciclovir was demonstrated by confirmatory statistics for the primary efficacy variable. Noninferiority could be demonstrated at the 5% significance level for all secondary variables, including pain parameters.

 For the subpopulation of patients aged 50 years and older, an even greater benefit regarding the primary efficacy endpoint was found in favor of brivudine compared to aciclovir.

Post-Zosterian neuralgia post-herpes surveillance
Two post-study retrospective follow-ups were performed under double-blind conditions consistent with the rules of good clinical practice to investigate the occurrence of post-herpetic neuralgia (PHN) in patients aged 50 years or older: 1) selected from studies 5-Ho-a and 5-Ho-b (7-day comparative treatments with brivudine and 7 days with aciclovir) 2) selected in the 5-Ho-c study (3-day comparative treatments with brivudine and 7 days by aciclovir)
Patients who, following telephone contact, reported pain associated with shingles after the end of the study were asked to visit the center and reviewed by the experimenter to confirm the incidence of PHN and to respond to questions about the characteristics of the pain.

PHNs were defined as pains in dermatomes affected by shingles after completion of individual studies (patients had completed 5-Ho-a, 5-Ho-b and 5-Ho-c when all crusts were had fallen, ie day 35 after the start of treatment, whichever came first).

 Studies were performed under blind conditions (all patients and experimenters were unaware of the treatment that had been administered during studies 5-Ho-a, 5-Ho-b and 5-Ho-c), which validated strongly the results of these studies.

1. Monitoring after PHN study after seven-day treatment with brivudine
A large sample of 608 male and female subjects aged 50

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ans ou plus provenant des études 5-Ho-a et 5-Ho-b a été réexaminé rétrospectivement (entre 8 et 17 mois après traitement) pour estimer l'intérêt offert par la brivudine pour prévenir l'apparition de névralgies post-zostériennes.

years or older from the 5-Ho-a and 5-Ho-b studies was retrospectively reviewed (between 8 and 17 months after treatment) to estimate the interest of brivudine in preventing post-herpetic neuralgia.

In the group of patients initially treated with 125 mg brivudine for seven days, 32.7% reported post-herpetic neuralgia after the end of the study, while the proportion was 43.5% in the group. of patients treated with aciclovir. Thus, the relative risk of post-herpetic neuralgia incidence was 25% lower in the 125 mg brivudine group compared to the aciclovir-treated group.

This reduction was statistically significant and may be considered a clinically interesting benefit of brivudine.

de trois jours par la brivudine
Cette étude incluait les patients âgés de 50 ans ou plus qui avaient été soumis à la cure de trois jours avec 125 mg de brivudine ou au régime posologique classique de sept jours d'aciclovir dans l'étude 5-Ho-c. Les patients ont été interrogés entre 3 et 8 mois après le traitement. 1. Monitoring after PHN study after treatment

three days by brivudine
This study included patients aged 50 years or older who had undergone the three-day course with 125 mg brivudine or the conventional seven-day aciclovir regimen in the 5-Ho-c study. Patients were interviewed between 3 and 8 months after treatment.

 The results show that the incidence of post-herpetic neuralgia in patients undergoing three-day treatment with 125 mg brivudine once daily is comparable to that of patients who received aciclovir at the conventional dosage for seven days (41 , 6% and 39.7 fa).

 These additional results confirm that the 125 mg dose of brivudine administered once a day for only three days is not inferior to aciclovir in the treatment of shingles.

Examples
The following may be considered as non-limiting examples of the present invention:

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Exemple 1 : Comprimé dosé à 125 mg de brivudine-comprimés à libération immédiate

Example 1: 125 mg tablet of brivudine-immediate release tablets

<Tb>
<tb> NO <SEP> Ingredient <SEP> mg / tablet
<tb> 1 <SEP> brivudine <SEP> 125.0
<tb> 2 <SEP> cellulose <SEP> microcrystalline <SEP> 74.0
<tb> 3 <SEP> lactose <SEP> monohydrate <SEP> 37.0
<tb> 4 <SEP> povidone, <SEP> index <SEP> K <SEP> 25 <SEP> 6.5
<tb> 5 <SEP> stearate <SEP> of <SEP> magnesium <SEP> 2,5
<tb> 6 <SEP> purified water <SEP>
<tb> 245, <SEP> 0
<Tb>
Example 2

<Tb>
<tb> N <SEP> Ingredient <SEP> mg / tablet
<tb> 1 <SEP> Brivudine <SEP> 125.0
<tb> 2 <SEP> cellulose <SEP> microcrystalline <SEP> 74.0
<tb> 3 <SEP> starch <SEP> of <SEP> corn <SEP> 37.0
<tb> 4 <SEP> povidone, <SEP> index <SEP> K <SEP> 25 <SEP> 6.5
<tb> 5 <SEP> stearate <SEP> of <SEP> magnesium <SEP> 2,5
<tb> 6 <SEP> purified water <SEP>
<tb> 245, <SEP> 0
<Tb>
Example 3

<Tb>
<tb> N <SEP> ingredient mg / tablet
<tb> 1 <SEP> brivudine <SEP> 125.0
<tb> 2 <SEP> cellulose <SEP> microcrystalline <SEP> 74.0
<tb> 3 <SEP> lactose <SEP> 37.0
<tb> 4 <SEP> povidone, <SEP> Index <SEP> K <SEP> 25 <SEP> 6.5
<tb> 5 <SEP> stearate <SEP> of <SEP> magnesium <SEP> 2,5
<tb> 6 <SEP> purified water <SEP>
<tb> 245, <SEP> 0
<Tb>

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Exemple 4

Example 4

<Tb>
<tb> NO <SEP> Ingredient <SEP> mg / tablet
<tb> 1 <SEP> brivudine <SEP> 125.0
<tb> 2 <SEP> cellulose <SEP> microcrystalline <SEP> 74.0
<tb> 3 <SEP> starch <SEP> of <SEP> corn <SEP> 37.0
<tb> 4 <SEP> Copovidone <SEP> VA <SEP> 64 <SEP> 6.5
<tb> 5 <SEP> stearate <SEP> of <SEP> magnesium <SEP> 2,5
<tb> 6 <SEP> purified water <SEP>
<tb> 245, <SEP> 0
<Tb>
Example 5

<Tb>
<tb> NO <SEP> ngrédientmg / tablet
<tb> 1 <SEP> brivudine <SEP> 125.0
<tb> 2 <SEP> cellulose <SEP> microcrystalline <SEP> 74.0
<tb> 3 <SEP> lactose <SEP> 37.0
<tb> 4 <SEP> Copovidone <SEP> VA <SEP> 64 <SEP> 6.5
<tb> 5 <SEP> collidone <SEP> CL <SEP> 5, <SEP> 0
<tb> 6 <SEP> stearate <SEP> of <SEP> magnesium <SEP> 2,5
<tb> 7 <SEP> purified water <SEP>
<tb> 250, <SEP> 0
<Tb>
Example 6

<Tb>
<tb> NO <SEP> Ingredient <SEP> mg / tablet
<tb> 1 <SEP> brivudine <SEP> 125.0
<tb> 2 <SEP> cellulose <SEP> microcrystalline / Aerosil <SEP> 98/2 <SEP> 122, <SEP> 5
<tb> 3 <SEP> stearate <SEP> of <SEP> magnesium <SEP> 2,5
<tb> 4 <SEP> purified water <SEP>
<tb> 250.0
<Tb>

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Exemple 7

Example 7

<Tb>
<tb> N <SEP> Ingredient <SEP> mg / tablet
<tb> 1 <SEP> brivudine <SEP> 125.0
<tb> 2 <SEP> cellulose <SEP> microcrystalline / Aerosil <SEP> 98/2 <SEP> 100.5
<tb> 3 <SEP> collidone <SEP> CL <SEP> 22.0
<tb> 4 <SEP> stearate <SEP> of <SEP> magnesium <SEP> 2,5
<tb> 5 <SEP> purified water <SEP>
<tb> 250.0
<Tb>
Example 8 Immediate Release Capsule

<Tb>
<tb> NO <SEP> Ingredient <SEP> mg / capsule
<tb> 1 <SEP> brivudine <SEP> 125.0
<tb> 2 <SEP> cellulose <SEP> microcrystalline <SEP> 122.5
<tb> 3 <SEP> stearate <SEP> of <SEP> magnesium <SEP> 2,5
<tb> 4 <SEP> purified water <SEP>
<tb> 250.0
<Tb>
Example 9: Immediate Release Coated Tablet

<Tb>
<tb> N <SEP> Ingredient <SEP> mg / tablet
<tb> 1 <SEP> brivudine <SEP> 125.0
<tb> 2 <SEP> cellulose <SEP> microcrystalline <SEP> 74.0
<tb> 3 <SEP> lactose <SEP> monohydrate <SEP> 32.0
<tb> 4 <SEP> Aerosil <SEP> 5.0
<tb> 5 <SEP> Copovidone <SEP> VA <SEP> 64 <SEP> 6.5
<tb> 6 <SEP> stearate <SEP> of <SEP> magnesium <SEP> 2,5
<tb> 7 <SEP> hydroxypropyl methylcellulose <SEP> 5.0
<tb> 8 <SEP> Macrogol <SEP> 6000 <SEP> 1.5
<tb> 9 <SEP> dioxide <SEP> of <SEP> titanium <SEP> 4, <SEP> 5
<tb> 256.0
<Tb>

Claims (7)

1. Use of brivudine for the preparation of a pharmaceutical composition intended to be administered once a day.  2. Use according to claim 1, characterized in that the amount of active ingredient is 50 to 300 mg.  3. Use according to claim 2, characterized in that the amount of active ingredient is 100 to 200 mg.  4. Use according to claim 3, characterized in that the amount of active ingredient is 125 mg.  5. Use according to any one of the preceding claims, characterized in that said pharmaceutical composition is in a form selected from a group consisting of capsules, tablets and oral forms with modified release.  6. Use according to any one of the preceding claims, characterized in that said pharmaceutical composition is chosen from the following compositions: 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of lactose monohydrate, 6.5 mg of povidone K 25.2, 5 mg magnesium stearate, and purified water to a total of 245 mg; 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of corn starch, 6.5 mg of 25.2 K povidone, 5 mg of magnesium stearate, and purified water to a total of 245 mg; 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of lactose, 6.5 mg povidone K-value 25.2 mg magnesium stearate and purified water to a total of 245 mg; 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of corn starch, 6.5 mg of copovidone VA 64.2, 5 mg of magnesium stearate, and purified water to a total of 245 mg; 125 mg of brivudine, 74 mg of microcrystalline cellulose, 37 mg of lactose, 6.5 mg of copovidone VA 64.5, 0 mg of collidone CL, 2.5 mg of magnesium stearate, and purified water to a total of 250 mg; 125 mg of brivudine, 122.5 mg of microcrystalline cellulose / Aerosil 98/2, 2.5 mg of magnesium stearate, and purified water up to a total of 250 mg; 125 mg of brivudine, 100.5 mg of microcrystalline cellulose / Aerosil 98/2, 22.0 mg of collidone CL, 2.5 mg of magnesium stearate, and purified water to a total of 250 mg; <Desc / Clms Page number 13> 2.5 mg magnesium stearate, 1.5 mg Macrogol 6000.5, 0 mg hydroxypropyl methylcellulose, 4.5 mg titanium dioxide (immediate release coated tablets).  125 mg brivudine, 122.5mg microcrystalline cellulose, 2.5mg magnesium stearate, and purified water to a total of 250mg (immediate release); 125 mg of brivudine, 74.0 mg of microcrystalline cellulose, 32.0 mg of lactose monohydrate, 5.0 mg of Aerosil, 6.5 mg of copovidone VA 64,

 7. Use according to any one of the preceding claims for the treatment or prevention of zoster infections or postherpetic neuralgia.