EP0735878A1

EP0735878A1 - Pharmaceuticals

Info

Publication number: EP0735878A1
Application number: EP95905068A
Authority: EP
Inventors: Ronald James SmithKline Beecham Pharmac. BOON; David Ronald John Griffin
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 1993-12-22
Filing date: 1994-12-14
Publication date: 1996-10-09
Also published as: GB9326177D0; CN1142769A; CN1084622C; ZA9410113B; AU1383495A; JPH09506883A; WO1995017190A1; CA2179282A1; AU697290B2

Abstract

A method for the treatment (including prophylaxis) of ZAP in mammals, including humans, which method comprises administering to the mammal in need of such treatment, an effective amount of a compound of formula (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing and the use of a compound of formula (A): or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing in the manufacture of a medicament for use in the treatment (including prophylaxis) of ZAP.

Description

PHARMACEUTICALS

This invention relates to treatment of zoster associated pain, and to the use of compounds in the preparation of a medicament for use in the treatment of this condition.

When used herein, 'treatment' includes prophylaxis as appropriate.

EP-A-141927 (Beecham Group p. I.e.) discloses penciclovir, the compound of formula (A):

(A)

and salts, phosphate esters and acyl derivatives thereof, as antiviral agents. The sodium salt hydrate of penciclovir is disclosed in EP-A-216459 (Beecham Group p. I.e.). Penciclovir and its antiviral activity is also disclosed in Abstract P.N11-5 p.193 of 'Abstracts of 14th Int. Congress of Microbiology¹, Manchester, England 7-13 September 1986 (Boyd et. al.). Orally active bioprecursors of the compound of formula (A) are of formula (B):

(B) and salts and derivatives thereof as defined under formula (A); wherein X is C\→ alkoxy. NH2 or hydrogen. The compounds of formula (B) wherein X is C g alkoxy or NH2 are disclosed in EP-A-141927 and the compounds of formula (B) wherein X is hydrogen, disclosed in EP-A- 182024 (Beecham Group p. I.e.) are preferred prodrugs. A particularly preferred example of a compound of formula (B) is that wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative, described in Example 2 of EP-A- 182024, hereinafter referred to as famciclovir.

The compounds of formulae (A) and (B) and salts and derivatives thereof have been described as useful in the treatment of infections caused by herpes viruses, such as herpes simplex type 1, herpes simplex type 2, varicella-zoster and Epstein-Barr viruses.

Zoster associated pain (ZAP) is considered to consist of the pain associated with zoster infection and includes the acute phase pain and post-heφetic neuralgia (PHN), which is by far the most common complication of heφes zoster infection and one of the most intractable pain disorders (Strommen et al, Pharmacotherapy. 1988;8:52-68). Patients who develop PHN suffer from a debilitating and often intractable pain which can persist for months or even years. Although rare in patients under 50 years of age, the frequency of PHN rises steeply with increasing age.

Huff et al, Journal of Medical Virology, Supplement 1:93-96 (1993) and Crooks et al, Scand J Infect - Suppl. 78:000-000, 1991 describe the effects of acyclovir in ZAP.

It has now been discovered that the above compounds are particularly effective in reducing the duration of ZAP when given to the patient during the acute infection.

Accordingly, the present invention provides a method of treatment of ZAP in humans, which method comprises the administration to the human in need of such treatment, an effective amount of a compound of formula (A):

(A)

or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing. The term 'acyl derivative' is used herein to include any derivative of the compounds of formula (A) in which one or more acyl groups are present. Such derivatives are included as bioprecursors of the compounds of formula (A) in addition to those derivatives which are per se biologically active.

The compound of formula (A) may be in one of the forms disclosed in EP-A-216459 (Beecham Group p. I.e.).

Examples of bioprecursors, pharmaceutically acceptable salts and derivatives are as described in the aforementioned European Patent references, the subject matter of which are incoφorated herein by reference.

A particular compound of formula (B) of interest is 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-aminopurine, known as famciclovir (FCV), the well- absorbed oral form of penciclovir (PCN).

The compound of formula (A), bioprecursors, salts and derivatives may be prepared as described in the aforementioned European Patent references.

The compound, in particular, famciclovir, may be administered by the oral route to humans and may be compounded in the form of syrup, tablets or capsule. When in the form of a tablet, any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk. The compound may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups. Sustained release formulations, for example tablets containing an enteric coating, are also envisaged.

For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.

Preferred parenteral formulations include aqueous formulations using sterile water or normal saline, at a pH of around 7.4 or greater, in particular, containing penciclovir sodium salt hydrate.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

A suitable dosage unit might contain from 50mg to lg of active ingredient, for example 100 to 500mg. Such doses may be administered 1 to 4 times a day or more usually 2 or 3 times a day. The effective dose of compound will, in general, be in the range of from 0.2 to 40mg per kilogram of body weight per day or, more usually, 10 to 20 mg/kg per day. in the case of famciclovir, the dosage unit would be 250 mg, 500 mg or 750 mg, preferably 250 mg or 500 mg.

The treatment is preferably carried out as soon as possible after symptoms appear usually within 72 hours, preferably within 48 hours of rash onset.

The treatment period is usually 7 days.

The treatment is particularly effective in the case of patients of greater than 50 years of age, and efficacy would be expected to be demonstrated further in patients greater than 60 years of age, especially patients of greater than 70 years of age.

The present invention also provides the use of a compound of formula (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, in the preparation of a medicament for use in the treatment of ZAP. Such treatment may be carried out in the manner as hereinbefore described.

The present invention further provides a pharmaceutical composition for use in the treatment of ZAP, which comprises an effective amount of a compound of formula (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinafter described.

The compound of formula (A) and its prodrugs show a synergistic antiviral effect in conjunction with interferons; and treatment using combination products comprising these two components for sequential or concomitant administration, by the same or different routes, are therefore within the ambit of the present invention. Such products are described in EP-A-271270 (Beecham Group p.l.c).

The following clinical data illustrate the invention.

Clinical Data

Study 1 is described in Degreef et al, 'International Journal of Microbial Agents, Volume 4, No. 4 (1994), pp 241-246. A prospective, randomized, double-blind study (study 2) was conducted to compare FCV dosed at 500 mg and 750 mg tid for 7 days with placebo in the treatment of uncomplicated heφes zoster. 419 immunocompetent patients, aged >_ 18 years whose zoster rash had been present for _<. 72 hours were enrolled. Patients were assessed for lesion condition and pain pre-therapy, daily during week 1, daily until full crusting during week 2 and then weekly until all crust had been lost. Both FCV doses were equally effective and significantly reduced the duration of VZV recovery from zoster lesions and the time to healing of zoster lesions compared with the placebo-treated group. In addition, a statistically significant decrease in the duration of acute phase pain was detected for famciclovir-treated patients presenting with severe rash when compared with placebo. The effect of famciclovir on PHN (defined as pain at or after healing) was evaluated by assessing pain at 5 monthly visits after healing. The duration of PHN for all age groups was significantly reduced from 128 days to 62 and 55 days following treatment with FCV 500 mg and 750 mg, respectively. There were no significant differences in the safety profiles between famciclovir and placebo. "The median time to loss of pain from enrolment (i.e. time to loss of ZAP) was 21 days and 27 days for famciclovir doses of 500 mg and 750 mg respectively compared with 30 days for placebo. In conclusion, this study demonstrates that famciclovir dosed tid is an effe; ^;ve and well tolerated treatment for patients with acute heφes zoster infection, significantly decreasing the time to cutaneous lesion resolution and the duration of pain measured both as PHN and as ZAP.

The table below summarises the results in ZAP from clinical studies with famciclovir.

Endpoint Sub-group ACV FCV FCV FCV PCB

(Study /Population) 250 500 750

TLZAP (Study 1/EE) ≥SO¹ 60 49 28 29 -

TLZAP (Study 1/EE) <48hrs² 69 12* 17* 28* -

TLZAP (Study 1/EE) <48/≥50³ 69 28*¹ 56*² 29 -

TLZAP (Study 2/EE) <48hrs² - - 26* 28* 64

TLZAP (Study 2/EE) ≥SO¹ - - 28* 57* 76

1 = Patients aged 50 years or more treated within 72 hours

2 = Patients of all ages treated within 48 hours of rash onset

3 = Patients aged 50 years or more who were treated within 48 hours of rash onset * 1 = Significant by Wilcoxon test

*2 = Significant by Log Rank Test

ITT = Intention to treat population

EE = Efficacy evaluable population

ACV = Acyclovir 800mg five times daily for seven days

PCB = Placebo treatment

TLZAP = Time to loss of ZAP (time to loss of pain from enrolment)

Claims

1. A method for the treatment (including prophylaxis) of ZAP in mammals, including _t humans, which method comprises administering to the mammal in need of such treatment, an effective amount of a compound of formula (A):

(A)

or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.

2. The use of a compound of formula (A):

(A)

or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing in the manufacture of a medicament for use in the treatment (including prophylaxis) of ZAP.

3. A pharmaceutical composition for use in the treatment (including prophylaxis) of

ZAP, which comprises a compound of formula (A):

(A)

or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier.

4. A method, use or composition according to claim 1, 2 or 3 wherein the treatment is first administered within 72 hours of rash onset.

5. A method, use or composition according to claim 4 wherein the treatment is within 48 hours of rash onset.

6. A method, use or composition according to any one of claims 1 to 5 where the treatment period is 7 days.

7. A method, use or composition according to any one of claims 1 to 6 wherein the treatment is carried out on patients of greater than 50 years of age.

8. A method, use or composition according to claim 7 wherein the treatment is carried out on patients of greater than 60 years of age.

9. A method, use or composition according to claim 8 wherein the treatment is carried out on patients of greater than 70 years of age.

10. A method, use or composition according to any one of claims 1 to 9 wherein the Compound is famciclovir.

11. A method, use or composition according to claim 10 wherein famciclovir is administered at a dose of 250 mg, 500 mg or 750 mg three times a day.

12. A method, use or composition according to claim 11 wherein famciclovir is administered at a dose of 250 mg three times a day.

13. A method, use or composition according to claim 11 wherein famciclovir is administered at a dose of 500 mg three times a day.