IE20010413A1 - Once-a-day pharmaceutical composition containing Brivudine - Google Patents
Once-a-day pharmaceutical composition containing BrivudineInfo
- Publication number
- IE20010413A1 IE20010413A1 IE20010413A IE20010413A IE20010413A1 IE 20010413 A1 IE20010413 A1 IE 20010413A1 IE 20010413 A IE20010413 A IE 20010413A IE 20010413 A IE20010413 A IE 20010413A IE 20010413 A1 IE20010413 A1 IE 20010413A1
- Authority
- IE
- Ireland
- Prior art keywords
- brivudine
- brivudin
- magnesium stearate
- purified water
- treatment
- Prior art date
Links
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 title claims abstract description 82
- 229960001169 brivudine Drugs 0.000 title claims abstract description 77
- 239000008194 pharmaceutical composition Substances 0.000 title claims 3
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims abstract description 25
- 208000007514 Herpes zoster Diseases 0.000 claims abstract description 22
- 208000015181 infectious disease Diseases 0.000 claims abstract description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 36
- 235000019359 magnesium stearate Nutrition 0.000 claims description 18
- 239000008213 purified water Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 14
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 5
- 229920002261 Corn starch Polymers 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 235000010980 cellulose Nutrition 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000008120 corn starch Substances 0.000 claims description 4
- 229940099112 cornstarch Drugs 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 2
- 229960003511 macrogol Drugs 0.000 claims description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims 2
- 229960001375 lactose Drugs 0.000 claims 2
- 229960001021 lactose monohydrate Drugs 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 239000004408 titanium dioxide Substances 0.000 claims 1
- 239000008203 oral pharmaceutical composition Substances 0.000 abstract 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 34
- 229960004150 aciclovir Drugs 0.000 description 31
- 208000002193 Pain Diseases 0.000 description 12
- 239000002994 raw material Substances 0.000 description 9
- 230000001154 acute effect Effects 0.000 description 8
- 229940086177 acyclovir 800 mg Drugs 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 206010037844 rash Diseases 0.000 description 6
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 5
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960004396 famciclovir Drugs 0.000 description 4
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 4
- 208000010201 Exanthema Diseases 0.000 description 3
- 206010061598 Immunodeficiency Diseases 0.000 description 3
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 3
- 201000005884 exanthem Diseases 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 231100000046 skin rash Toxicity 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 229940093257 valacyclovir Drugs 0.000 description 3
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[(2r,3s,4r,5r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 2
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 2
- 206010039509 Scab Diseases 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229960001179 penciclovir Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 231100000444 skin lesion Toxicity 0.000 description 2
- 206010040882 skin lesion Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000000528 statistical test Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000001790 virustatic effect Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Use of brivudine in the preparation of an oral pharmaceutical composition for the once-a-day of herpes zoster infections or post-herpetic neuralgia. The amount of brivudine in each dose may be between 50 and 300mg. Use of a once daily dosage regimen improves patient compliance.
Description
^^•^The present invention refers to once-daily pll'ininaLTOtkal eompooitiea containing the antiviral Brivudine for the treatment of acute herpes zoster infections and their use in preventing the occurrence of post-herpetic neuralgia.
State of the art During the last ten years, the number of clinically useful drugs introduced for the chemotherapy of viral diseases has increased considerably.
Since its introduction in 1982, oral acyclovir has been widely used in the treatment of acute herpes zoster in immunocompetent patients. However, a major disadvantage of acyclovir therapy is that, due to its limited bioavailability, frequent and high doses are required, which often leads to poor compliance.
This has led to fhe development of a new antiviral (penciclovir) and to so-called prodrugs such as valaciclovir (the prodrug of acyclovir) and famciclovir (the prodrug of penciclovir). To date, famciclovir offers the most convenient treatment of acute herpes zoster in elderly patients, with a dosage of three tablets or capsule daily, compared to five tablets daily for acyclovir and six tablets daily for valaciclovir. Famciclovir relieves the acute signs and symptoms of herpes zoster as acyclovir does, and provides protection against the prolonged herpes zoster-associated pain or PHN. Taken less frequently, in lower dosages, and without an increased risk of adverse events compared to acyclovir, such treatment is advantageous and more convenient, particularly for elderly patients. The recommended daily dosage varies between 750 mg and 1500 mg (Degreef et al., 1994, Int. J. 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, Pain, 67, 241-251; Dworkin et al., 1998, Antiviral Research 33, 73-85).
Brivudin, 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. Natl. Acad.. Sci. USA, 76, 2947-2^51; De Clercq et al, 1980, J. Infect. Dis. 141, 563-574). While the synthesis of viral DNA is inhibited, the cellular functions remain largely unaffected. The continued development of brivudin during the last years has been directed at the treatment of N7N infections in immunocompetent .........patients. --------------Based on the results of a number of non-controlled and controlled studies Brivudine was registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in immunocompromised patients at a dosage of 125 mg three or four times daily (DeCIercq et al, 1980, Br. 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 Fachinformation united to the pharmaceutical product Helpin® marketed in the German territory in 1992). Disclosure of the invention In recent, large, multi-national studies on immunocompetent patients with herpes zoster, a once daily dosage regimen of 125 mg brivudin per day for 7 days was surprisingly shown to be statistically superior to the standard five times daily oral treatment with 800 mg acyclovir, with respect to dermatological endpoints (5-Ho-b/0078BC). A post-study surveillance of patients aged 50 years or older who had participated in these studies, and who had experienced PHN after study termination, indicated a significantly lower incidence of PHN after treatment with brivudin compared to acyclovir (5Ho[a+b+c]PHN/0078BC).
Brivudin therefore surprisingly offers the possibility of treating herpes zoster patients with a single 125 mg tablet per day, instead of the high and Ε 8 ΐ 0 4 u frequent dosage schedules of acyclovir, valaciclovir, or famciclovir. A single 125 mg tablet per day is even more surprising if considered in relation to the previously scheduled 125 mg four times daily as registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in immunocompromised patients. With this once daily dosage schedule a further surprising result was achieved: that of reducing the incidence of Postherpetic Neuralgia. Experimental To assess the efficacy and safety of brivudin in immunocompetent adult patients with herpes zoster, three large pivotal studies (studies 5-Ho-a, 5-Ho-b and-5-Ho-c) were recently performed according to GCP standard. All four studies were prospective and had a multicentre, double-blind, randomised parallel design.
The patients were observed for up to 35 days to evaluate resolution of skin rash and acute phase pain. All patients were immunocompetent. Only adult patients aged 18 years or older were enrolled.
The primary parameter to assess efficacy was ‘time from start of treatment to last eruption of new vesicles ’ in all three studies. This parameter parallels viral replication in the skin and therefore describes the virostatic potency of a drug. It is accepted in the literature and considered as the most reliable clinical sign with respect to other cutaneous manifestations. Further parameters to assess the resolution of skin rash were ‘time from start of treatment to start of crusting’, ‘time from start of treatment to complete crusting’ and ‘time from start of treatment to loss of crusts’. Dissemination of skin lesions and the occurrence of other complications were also assessed.
In the literature the most frequently used measures to judge the benefit of antiviral therapy in herpes zoster are the duration of skin rash and the occurrence and intensity of pain during the acute phase of the infection. Lately, however, postherpetic neuralgia has become of increasing importance in the assessment of the benefit of antiviral therapies. Thus, to assess the |£0 1 Μ 13 possible effect of brivudin on reducing the incidence of post-herpetic neuralgia in a preliminary manner, retrospective double-blind post-study surveillance studies were additionally conducted on patients aged 50 or older that had been enrolled into studies .
Table 1 lists the trials performed in immunocompetent patients with ~ herpes zoster. Former uncontrolled studies performed in immunocompromised patients, which provided early evidence of the potential benefit of brivudin, will not be discussed.
Table 1: O ver vie w of Clinical Trials Study code Description Treatment arms and daily dosage (7-day treatment unless otherwise specified) 5-Ho-a Dose-finding study (Phase II) Brivudin 125 mg x 1 Brivudin 62.5 mg x 1 Brivudin 31.25 mg x 1 Acyclovir 800 mg x 5 5-Ho-b Confirmatory efficacy study (Phase III) Brivudin 125 mg x 1 Acyclovir 800 mg x 5 5-Ho-c Confirmatory efficacy study (Phase III) Brivudin 125 mg x 1 for 3 days Acyclovir 800 mg x 5 5-Ho-a+b- PHN Post-study surveillance on PHN Brivudin 125 mg x 1 Acyclovir 800 mg x 5 5-Ho-c-PHN Post-study surveillance on PHN Brivudin 125 mg x 1 for 3 days Acyclovir 800 mg x 5 These clinical trials are presented below in a chronological order.
Study 5-Ho-a Since brivudin plasma concentrations in man receiving 125 mg once a day are 10 to 50-fold the IC50 of clinical strains of Varicella zoster virus and, additionally, human pharmacokinetic data showed that brivudin plasma concentrations are maintained above the IC50 for 24 hours following a single administration of brivudin 125 mg, the reasonable assumption was made that a once daily application of 125 mg brivudin would be sufficient for the treatment of herpes zoster.
Study 5-Ho-a, a Phase II study performed in 642 patients, therefore evaluated a once daily administration of brivudin 125 mg for seven days in comparison to 5 x 800 mg acyclovir for seven days in an exploratory manner. Two study arms with once daily brivudin doses of 62.5 mg and 32.25 mg for seven days were added to also assess the efficacy of lower doses.
This study demonstrated that 1 x 125 mg brivudin for 7 days in patients -with acute herpes-zoster is as effective as the treatment with 5 x 800 mg acyclovir for 7 days with respect to the primary parameter ’’time from start of treatment to last eruption of new vesicles" as well as with respect to all secondary parameters, including "time from start of treatment to cessation of pain (intensity none or mild) " as the clinically more relevant secondary parameter. Statistical analysis of the primary efficacy parameter and the pain parameter demonstrated non-inferiority of 1 x 125 mg brivudin compared to acyclovir. For the parameter ’’time from start of treatment to complete crusting superiority could be achieved in an exploratory manner. A graphical presentation of the risk ratios calculated from the Cox proportional hazards model for the 1 x 125 mg brivudin group compared to the 5 x 800 mg acyclovir group is presented in Figure 1.
Brivudin has a linear dose-effect relationship. Superiority to placebo was demonstrated to a statistically and clinically significant extent in immunocompetent patients with acute herpes zoster infection. Brivudin treatment with a dose of 1 x 125 mg for seven days is at least as effective as the treatment with 5 x 800 mg acyclovir for seven days as regards the duration of vesicle appearance and acute pain. These results, together with the previous pharmacokinetic considerations, led to the selection of brivudin 125 mg once daily as the treatment of choice.
Study 5-Ho-b The Phase III study 5-Ho-b was performed in 1227 patients to provide confirmatory statistics for the comparison of 1 x 125 mg brivudin for seven days and 5 x 800 mg acyclovir for seven days in immunocompetent patients with herpes zoster. A subgroup of patients aged 50 and older was also evaluated separately.
A graphical presentation of the risk ratios calculated from the Cox proportional hazards model for the l x 125 mg brivudin group compared to the 5 x 800 mg acyclovir group is presented in Figure 2.
Study 5-Ho-c: Reduction of treatment duration In order to assess the efficacy of a three day treatment with brivudin 125 mg once daily in patients with herpes zoster, another large study was performed using exactly the same study design as study 5-Ho-b. Brivudin 125 mg once daily for three days (followed by four days of placebo) was compared to acyclovir 800 mg 5 times daily for 7 days.
A total of 1336 patients were enrolled. The results show that this dosage regimen of brivudin is non-inferior to treatment with acyclovir at the standard dosage for the primary efficacy variable. Superiority could, however, not be established.
These data with a reduced treatment duration therefore support the notion that brivudin is indeed an effective treatment given once daily for herpes zoster in immunocompetent adults and support the validity of the results obtained in the previous studies.
Primary efficacy variable For the primary parameter superiority of the brivudin group compared with acyclovir could be established. The confirmatory test procedure was statistically significant at the 5% level. The estimated risk ratio was 1.14 (for the Per Protocol population), indicating a 14% better effect (endpoint was reached faster) for patients treated with 1 x 125 mg brivudin as compared to IEO 104 15 patients treated with acyclovir. The corresponding descriptive mean value for the ''time from start of treatment to last eruption of herpes zoster vesicles ’ was % smaller for brivudin (mean: 13.5 hours) than for acyclovir (mean: 18.0 hours).
Thus, for the primary efficacy variable brivudin treatment was i * demonstrated confirmatorily to be statistically significantly superior to acyclovir treatment.
Secondary efficacy variables The statistical tests for all secondary efficacy variables, including the clinically relevant pain parameters, showed equivalence of 1 x 125 mg brivudin as compared to 5 x 800 mg acyclovir.
Dissemination of skin lesions (brivudin: 1; acyclovir: 2) and other complications (brivudin: 0; acyclovir: 6) occurred in less than 1% of patients in both groups.
The subgroup analysis in patients aged 50 years and older yielded similar results to those obtained in the overall population, with an 18% better treatment effect for the primary efficacy variable in patients treated with brivudin as compared to those treated with acyclovir .
Superiority of brivudin over acyclovir could be demonstrated by confirmatory statistics for the primary efficacy variable. Non-inferiority could be demonstrated at the 5% significance level for all secondary variables, including pain parameters.
For the subpopulation of patients aged 50 or older an even greater benefit concerning the primary efficacy parameter was found for brivudin compared to acyclovir.
Post-study surveillance on Postherpetic Neuralgia Two retrospective post-study surveillances were performed under double-blind conditions to GCP standard to investigate the occurrence of postherpetic neuralgia (PHN) in patients aged 50 or older: ΙΕ ΰ ι a 11 j 1) selected from studies 5-Ho-a and 5-Ho-b (7-day brivudin vs. 7-day acyclovir treatment) 2) selected from study 5-Ho-c (3-day brivudin vs. 7-day acyclovir treatment) Patients who, following a telephone contact, reported zoster-related » pain after the end of the study were invited to the centre and examined by the investigator to confirm the incidence of PHN and to answer questions relating to the characteristics of pain. PHN was defined as pain in herpes zoster affected dermatomes after the individual study termination (patients had to io terminate studies 5-Ho-a, 5-Ho-b and 5-Ho-c when all crusts had fallen off, or' on day 35 after start of treatment, whichever occurred first).
The studies were performed under blinded conditions (both the patients and the investigators were still unaware of the treatment that had been administered during the studies 5-Ho-a, 5-Ho-b and 5-Ho-c), which strongly validates the results of these studies. 1. Post-study surveillance on PHN following a seven-day brivudin treatment A large sample of 608 male and female patients aged 50 or older from studies 5-Ho-a and 5-Ho-b were re-examined retrospectively (between 8 and 17 months following treatment) to assess the benefit of brivudin in preventing the occurrence of postherpetic neuralgia. In the patient group formerly treated with 125 mg brivudin for seven days, 32.7% reported suffering from postherpetic neuralgia after study termination, whereas in the acyclovir treatment group the proportion was 43.5%. Thus, the relative risk for the incidence of postherpetic neuralgia was 25% lower in the 125 mg brivudin group compared to the acyclovir group. This was a statistically significant reduction and can be regarded as a clinically relevant benefit of brivudin. 2. Post-study surveillance on PHN following a three-day brivudin treatment This study included patients aged 50 years or older who had received the three-dav course of brivudin 125 mg or the standard seven-day dosage schedule of acyclovir in study 5-Ho-c. Patients were questioned between 3 and 8 months following treatment.
The results show that the incidence of postherpetic neuralgia in patients who received a three-dav course of brivudin 125 mg once daily is comparable to that of patients who received acyclovir at the standard dosage for seven days (41.6% vs. 39.7%, respectively).
These additional data support the evidence that brivudin 125 mg, given once daily for only three days, is non-inferior to acyclovir in the treatment of herpes zoster. io Examples The following can be considered non-limitative example of the present invention: Example 1: 1 Brivudin 125 mg tablet-immediate release tablets No. raw material mg/ tablet 1 brivudin 125.0 2 microcrystalline cellulose 74.0 3 lactose-monohydrat 37.0 4 povidon. K-value 25 6.5 5 magnesium stearate 2.5 6 purified water 245.0 Exemple 2 No. Raw material Mg / tablet 1 Brivudin 125.0 2 microcrystalline cellulose 74.0 3 cornstarch 37.0 4? povidon. K-value 25 6.5 5. magnesium stearate 2.5 6 purified water 245.0 Exemple 3 No. Raw material mg/ tablet 1 brivudin 125.0 2 cellulose powder 74.0 3 Lactose 37.0 4 povidon, K-value 25 6.5 5 magnesium stearate 2.5 6 purified water 245.0 Example 4 No. raw material mg/ tablet 1 brivudin 125.0 2 microcrystalline 74.0 cellulose 3 cornstarch 37.0 4 copovidon VA 64 6.5 5 magnesium stearate 2.5 6 purified water 245.0 IE0USU3 Example 5 No. raw material mg/tablet 1 brivudin 125.0 2 microcrystalline cellulose 74.0 3 lactose 37.0 4? copovidon. VA 64 6.5 5. collidone CL 5.0 6 magnesium stearate 2.5 7 purified water 250.0 Example 6 No. raw material mg/ tablet 1 brivudin 125.0 2 microcrystalline cellulose/aerosil 98/2 122.5 3 magnesium stearate 2.5 4 purified water 250.0 Example 7 No. raw material mg/ tablet 1 brivudin 125.0 2 microcrystalline cellulose/aerosil 98/2 100.5 3 collidone CL 22.0 4 magnesium stearate 2.5 5 purified water 250.0 Example 8- immediate release capsule No. Raw material mg powder/ capsule 1 brivudin 125.0 2 microcrystalline cellulose 122.5 3 magnesium stearate 2.5 4 purified water 250.0 ΙΕ Ο 104 1 J Example 9- immediate release coated tablet No. raw material mg/ tablet 1 brivudin 125.0 2 microcrystalline 74.0 i - cellulose 3 lactose-Monohydrat 32.0 4 Aerosil 5.0 5 copovidon. VA 64 6.5 6 magnesium stearate 2.5 7 Hydroxypropyl-methyl- 5.0 cellulose 8 Macrogol 6000 1.5 9 Titandioxid 4.5 256.0
Claims (8)
1. The use of brivudine for the preparation of a pharmaceutical composition to be administered once-a-day.
2. Use according to claim 1, wherein the amount of brivudine is from 50 to 300 mg. Use according to claim 2, wherein said amount is from 100 to 200mg.
3. 4. Use according to claim 3, in which said use is 125 mg.
4.
5. Use according to any preceding claims, wherein the pharmaceutical composition is in a form selected from the group consisting of capsules, tablets and modified release oral forms. 10
6. Use according to claim 5, wherein said composition is selected from the group consisting of: (a) brivudine 125 mg, microcrystalline cellulose 74 mg, lactose monohydrate 37 mg, povidon K-value 25 6.5 mg, magnesium stearate 2.5 mg, purified water to 245 mg total; 15 (b) brivudine 125 mg, microcrystalline cellulose 74 mg, cornstarch 37 mg, povidon K-value 25 6.5 mg, magnesium stearate 2.5 mg, purified water to 245 mg total; (c) brivudine 125 mg, microcrystalline cellulose 74 mg, lactose 37 mg. povidon K-value 25 6.5 mg, magnesium stearate 2.5 mg, purified water to 245 mg total; 20 (d) brivudine 125 mg, microcryslalline cellulose 74 mg, cornstarch 37 mg, copovidon VA64 6.5 mg, magnesium stearate 2.5 mg, purified water to 245 mg total; (e) brivudine 125 mg, microcrystalline cellulose 74 mg, lactose 37 mg, copovidon VA64 6.5 mg, collidone C.L 5.0 mg, magnesium stearate 2.5 mg, purified water to 250 mg total; ΙΕΟ 104 15 (ί) brivudine 125 mg, microcrystalline cellulose/aerosil 122.5 mg, magnesium stearate 2.5 mg, purified water to 250 mg total; (g) brivudine 125 mg, microcrystalline cellulose/aerosil 100.5 mg, colidone CL ^270 mg, magnesium stearate 2.5 mg, purified water to 250 mg total; 5 (h) brivudine 125 mg, microcrystalline cellulose 122.5 mg, magnesium stearate 2.5 mg, purified water to 250 mg total (immediate release); (i) brivudine 125 mg, microcrystalline cellulose 74.0 mg, lactose-monohydrate 32.0 mg, aerosil 5.0 mg, copovidon VA64 6.5 mg, magnesium stearate 2.5 mg, macrogol 6000 1.5 mg, titanium dioxide 4.5 mg (immediate release coated io tablets),
7. Use of brivudine according to any preceding claim in the treatment and prevention of herpes zoster infections or post-herpetic neuralgia.
8. Use according to claim 1, substantially as hereinbefore described and exemplified.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2001MI000009A ITMI20010009A1 (en) | 2001-01-03 | 2001-01-03 | PHARMACEUTICAL COMPOSITIONS CONTAINING BRIVUDINA FOR SINGLE DAILY ADMINISTRATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE20010413A1 true IE20010413A1 (en) | 2003-04-16 |
Family
ID=11446384
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE20010413A IE20010413A1 (en) | 2001-01-03 | 2001-04-25 | Once-a-day pharmaceutical composition containing Brivudine |
Country Status (20)
| Country | Link |
|---|---|
| AT (1) | AT6141U1 (en) |
| BE (1) | BE1014522A5 (en) |
| CH (1) | CH695662A5 (en) |
| CZ (1) | CZ20012464A3 (en) |
| DK (1) | DK177084B1 (en) |
| ES (1) | ES2192456B1 (en) |
| FI (1) | FI20011446A (en) |
| FR (1) | FR2818907B1 (en) |
| GB (1) | GB2370771A (en) |
| GR (1) | GR1004012B (en) |
| HR (1) | HRPK20010345B3 (en) |
| HU (1) | HUP0102816A3 (en) |
| IE (1) | IE20010413A1 (en) |
| IT (1) | ITMI20010009A1 (en) |
| NL (1) | NL1018431C2 (en) |
| PL (1) | PL348480A1 (en) |
| PT (1) | PT102642B (en) |
| SE (1) | SE0102309L (en) |
| SK (1) | SK287043B6 (en) |
| UA (1) | UA76402C2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2239527B1 (en) * | 2004-03-01 | 2006-11-16 | M. Cruz Fernandez Gonzalez | PHARMACOLOGICAL COMPOSITION OF TOPICAL USE FOR THE TREATMENT OF HERPES ZOSTER. |
| CN113712928A (en) * | 2021-09-29 | 2021-11-30 | 重庆市力扬医药开发有限公司 | Brivudine drug absorbed through oral mucosa |
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|---|---|---|---|---|
| EP0104857A1 (en) * | 1982-09-28 | 1984-04-04 | Beecham Group Plc | Deoxyuridine compounds, methods for preparing them and their use in medicine |
| IT1170232B (en) * | 1983-10-31 | 1987-06-03 | Anna Gioia Stendardi | THERAPEUTIC COMPOSITIONS WITH ANTI-VIRAL ACTIVITY |
| US5446031A (en) * | 1991-04-24 | 1995-08-29 | Yamasa Shuyu Kabushiki Kaisha | 1-β-D-arabinofuranosyl-(E)-5-(2-halogenovinyl)uracil derivatives |
| WO1997025989A1 (en) * | 1996-01-19 | 1997-07-24 | Glaxo Group Limited | Use of valaciclovir for the manufacture of a medicament for the treatment of genital herpes by a single daily application |
-
2001
- 2001-01-03 IT IT2001MI000009A patent/ITMI20010009A1/en unknown
- 2001-04-25 IE IE20010413A patent/IE20010413A1/en not_active IP Right Cessation
- 2001-05-01 GB GB0110682A patent/GB2370771A/en not_active Withdrawn
- 2001-05-11 HR HR20010345A patent/HRPK20010345B3/en not_active IP Right Cessation
- 2001-05-29 CH CH00987/01A patent/CH695662A5/en not_active IP Right Cessation
- 2001-06-28 SE SE0102309A patent/SE0102309L/en not_active Application Discontinuation
- 2001-06-29 FR FR0108596A patent/FR2818907B1/en not_active Expired - Lifetime
- 2001-06-29 DK DKPA200101019A patent/DK177084B1/en not_active IP Right Cessation
- 2001-07-02 NL NL1018431A patent/NL1018431C2/en not_active IP Right Cessation
- 2001-07-03 FI FI20011446A patent/FI20011446A/en not_active Application Discontinuation
- 2001-07-04 SK SK957-2001A patent/SK287043B6/en not_active IP Right Cessation
- 2001-07-04 BE BE2001/0452A patent/BE1014522A5/en not_active IP Right Cessation
- 2001-07-04 CZ CZ20012464A patent/CZ20012464A3/en unknown
- 2001-07-04 UA UA2001074658A patent/UA76402C2/en unknown
- 2001-07-05 PT PT102642A patent/PT102642B/en active IP Right Grant
- 2001-07-05 ES ES200101566A patent/ES2192456B1/en not_active Expired - Fee Related
- 2001-07-05 GR GR20010100322A patent/GR1004012B/en unknown
- 2001-07-05 HU HU0102816A patent/HUP0102816A3/en unknown
- 2001-07-05 PL PL01348480A patent/PL348480A1/en not_active Application Discontinuation
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2002
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Also Published As
| Publication number | Publication date |
|---|---|
| ITMI20010009A0 (en) | 2001-01-03 |
| FR2818907B1 (en) | 2006-05-26 |
| ES2192456A1 (en) | 2003-10-01 |
| PT102642A (en) | 2002-07-31 |
| PL348480A1 (en) | 2002-07-15 |
| CZ20012464A3 (en) | 2002-08-14 |
| DK177084B1 (en) | 2011-07-11 |
| GB2370771A (en) | 2002-07-10 |
| FI20011446A (en) | 2002-07-04 |
| HRPK20010345B3 (en) | 2005-02-28 |
| AT6141U1 (en) | 2003-05-26 |
| DK200101019A (en) | 2002-07-04 |
| CH695662A5 (en) | 2006-07-31 |
| PT102642B (en) | 2003-06-30 |
| SE0102309L (en) | 2002-07-04 |
| UA76402C2 (en) | 2006-08-15 |
| HUP0102816A2 (en) | 2002-10-28 |
| FI20011446A0 (en) | 2001-07-03 |
| GB0110682D0 (en) | 2001-06-20 |
| HRP20010345A2 (en) | 2003-08-31 |
| FR2818907A1 (en) | 2002-07-05 |
| SE0102309D0 (en) | 2001-06-28 |
| SK9572001A3 (en) | 2003-03-04 |
| GR20010100322A (en) | 2002-10-08 |
| HUP0102816A3 (en) | 2005-01-28 |
| ES2192456B1 (en) | 2005-02-01 |
| SK287043B6 (en) | 2009-10-07 |
| HU0102816D0 (en) | 2001-09-28 |
| GR1004012B (en) | 2002-11-01 |
| ITMI20010009A1 (en) | 2002-07-03 |
| BE1014522A5 (en) | 2003-12-02 |
| NL1018431C2 (en) | 2002-07-05 |
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| MM9A | Patent lapsed through non-payment of renewal fee |