AU697612B2 - Post exposure prevention of HIV - Google Patents

Description

w OPI DATE 21/12/95 AOJP DATE.01/02/96 APL.ID 26331/95 lII iiIlIIIll1tHI N PCT NUMBER PCT/SE95/00524 AU9526331 (51) International Patent Ciassification 6: (11) International Publication Number: WO 95132983 C07H 19106t 19/073 Al (4)ItrainlPublication Date: 7 December 1995 (07.12,95) (21) International Application Number: PCT/SE95/00524 (81) Designated States: AM, AT, AU, BB, BO, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, Fl, GB, GE, HlU, IS, JP, KE, (22) International Filing Date: I11 May 1995 (11,05.95) KG, KP, KR, KZ, LK, LR, LT, LU, Lv, MD, MG, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TTr, UA, UG, US, UZ, VN, European patent (AT, Priority Data: BE, CH, DE, DK, ES, FR, GB, GR, IB, IT, LU, MC, NL, 08/251,316 31 May 1994 (31.05,94) us PT, SE), OAPI patent (BF, BJ, CF. CO, Cl, CM, GA, GN, 9500348-9 1 February 1995 (01.02.95) SE ML, MR, NE, SN, TD, TG), ARIPO patent (KB, MW, SD, SZ, UG).

(71) Applicant (for all designated States except US): MEDIVIR AD Lunastigen 7, S-141 44lluddinge Published With International search report.

(72) Inventor; and Inventor/Applicant (for US only): ()BERO, Do (SE/SE]; Askviigen 27, S-756 53 Uppsala (SE).

(74) Agent: MORRISON, lain, Medivir AB, Patentavodelningen, Lunastigen 7, S-141 44 Huddinge (SE).

(54) Title: POST EXPOSURE PREVENTION OF IIIV (57) Abstract A method of preventing the establishment of MIV Infection and/or HIV seroconversion in a human or simian NH 2 comprising the administration of an effective amount of the compound 1 -[2',3'-dideoxy-3'C(hydroxymethyl)-/3-D-erythropentofuranosyl]-cytosine having formula after exposure of saidN human or simian to HPl.N Ho1 0

HO

jl POST EXPOSURE PREVENTION OF HIV Technical Field This invention relates to preventing the establishment of HIV infection and/or HIV seroconversion in a human or simian after exposure to HIV, Several subpopulations of society, notably health care workers, surgical patients, medical researchers and law enforcement officials are subject to an enhanced risk of coming into accidental contact with human immunodeficiency virus (HIV). For instance, there are dozens of documented seroconversions in health care workers following accidental injury from syringes or surgical instruments previously used by HIVinfected individuals ("needle sticks"). While much can be done to reduce the risk of exposure there remains a need for an effective agent for protecting such individuals and other victims of inadvertant exposure to HIV-positive material from establishing an HIV infection or HIV seroconversion.

Description of Related Art A small number of antiviral agents, notably AZT (zidovudine) and ddl (dideoxy inosine), have been developed and shown to have a clinically significant action in the suppression of AIDS development or reducing viral loads in HIV-infected individuals. There is some evidence from animal studies that AZT may alter the pattern of lentivirus infections if administered prophylactically. i.e. prior to exposure to HIV or SIV(simian immunodeficiency virus) to delay the onset of viraemia and one report (Van Rompey et al 1992 Antimicrob Agents Chemotherapy 36 2381-2386) suggests that SI infection was prevented in 2 infant macacques with AZT given from 2 hours before inoculation, however the low infectious dose renders the significance of the report hard to assess. A further report Li__ WO 95/32983 PCT/SE95/00524 2 (Bbttiger et al AIDS Res Hum Retroviruses 1992; 7:1235-1238 suggests that FLT (3'-fluorothymidine) administered from 8 hours prior to virus inoculation may provide some protection against SIV. However the majority of literature references point to an inability to prevent infection with SIV with prophylactically, i.e. pre-exposure administered AZT, ddl, ddC, d4T and PFA (Lundgren et al, Antiviral Chemistry Chemotherapy 1990;5:299- 306, B6ttiger et al, Antiviral Chemistry Chemotherapy 1991;6:357-361, Lundgren et al, J AIDS 1991;4:498-498) The SIV and HIV-2 infections in monkeys bear a close resemblance to HIV-1 infections in humans.

"Prophylaxis" as used in this technical field generally refers to the administration of an active agent to an at-risk individual in sufficient time to achieve and maintain effective concentrations in the target tissues before the individual enters the risk environment. This is the classic meaning of prophylaxis. The position with regard to postexposure administration of anti-HIV agents is even less satisfactory than the above mentioned prophylactic attempts. There are currently 13 published accounts (Niu et al; J Inf Dis 1993:168:1490-501) of seroconversion after accidental exposure to HIV notwithstanding rapid and sustained postexposure administration of' large doses of AZT. Despite many attempts, postexposure treatment has not prevented any HIV-1, HIV-2 or SIV infections (Niu et al, ibid). In other words after extensive research into postexposure infection prevention and FDA consideration of approval criteria (J AIDS 1991;4:513-515), not a single agent has been reported which has proven to prevent the establishment of HIV infection or seroconversion in individuals already exposed to HIV. Not even those experimental agents such as soluble CD4 and heparin sulphate which act in vitro by preventing virus entering target cells and would thus WO 95/32983 PCTSE95/00524 3 appear to better candidates for prophylaxis than the nucleoside analogues, have proven to have any effect in vivo.

In the therapeutic context (as distinct from prophylaxis), European patent application 0 391 411 A2 describes a family of nucleoside analogues, including the active agent defined below, which family is implicated in the treatment of herpes infections and to some extent exhibits in vitro activity against HIV in a already infected cell line. No teaching or suggestion as to any prophylactic activity is apparent, which is in line with classical expectations as to the efficacy of nucleoside analogues, as discussed above.

International patent application nos. WO 88/08001 and WO 92/06102 extend to various nucleoside analogues of this type and demonstrate their activity against established retroviral and HIV infections. However, there is no teaching or suggestion that any of their compounds can be administered after exposure to HIV and yet prevent the establishment of HIV infection or seroconversion.

Summary of the invention The present invention provides a method for preventing the establishment of I-IV infection and/or HIV seroconversion in a human or simian comprising the administration of an effective amount of the compound 1-[2',3'-dideoxy- 3'C-(hydroxymethyl)-p-D-erythro-pentofuranosyl-cytosine having the formula 4 N H2

N

0 N) HO 0 57P

HO

after exposure of said human or simian to HIV. The invention further provides pharmaceutical compositions for use in this method, comprising an effective amount of the above defined active agent and a pharmaceutically acceptable diluent or carrier therefor.

Alternatively expressed, the invention relates to the use of the above defined active agent in the manufacture of a medicament for postexposure administration to a human or simian to prevent the establishment of 1-V infection or seroconversion.

As explained above, not even those prior art antivirals with an established therapeutic activity agaii HIV-infected cells or with antiviral effects in HIV/AIDS patients can prevent infection when administered after exposure of an individual to HIV, or indeed a monkey to SV, thus the above defined property of this particular nucleoside anomer is quite unexpected.

The method and composition of the invention should be contrasted with such agents as AZT and ddI which at most appear to delay seroconversion until shortly after "treatment" is concluded and do not prevent the establishment of an HIV infection and ultimately the resulting disease.

WO 95/32983 PCT/SE95/00524 The method and compositions of the present invention will be particularly useful for individuals at risk of accidental occupational exposure to HIVpositive material such as the staff or inmates of establishments such as hospitals, prisons and diagnostic or research laboratories. Such establishments can keep supplies of the compositions of the invention for rapid postexposure deployment in the event of accidental exposure to HIV.

The accidental exposure may comprise a needle stick or other surgical injury incurred by health care workers but in a wider context may result from any inadvertant exposure such as through sexual transmission, assault, body fluid splashes, erroneous blood transfusion or reuse of medical implements.

An advantage of postexposure administration, as distinct from prophylactic prevention of infection is that it avoids long term administration with potentially expensive agents and improves safety. The currently used HIV agents such as AZT and ddl require life long administration if seroconversion is to be avoided. Additionally, postexposure administration can be extended to individuals not belonging to a high-risk occupation or subpopulation.

Preferably the above defined active agent is adminstered as soon as practicable following the exposure of the human or simian to HTV.

Advantageously administration is commenced within about one day following exposure, especially within eight hours. Preferably administration of the active agent is commenced within about 3 hours following exposure and most preferably within about 1 hour. This timescale allows the above defined active agent to be administered as an oral preparation, such as tablets or syrups or percutaneously as a lotion, suppository or enema.

Preferably, however, at least the initial administration following discovery of 6 the accidental exposure is parenteral, eg by subcutaneous, intramuscular or intravenous routes.

While it is possible for the active agent to be admistered alone, it is preferable to present it as part of a pharmaceutical formulation. Such a formulation will comprise the above defined active agent together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.

The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

The formulations may conveniently be presented in unit dosage form, e.g.

tablets and sustained release capsules, and may be prepared by any mehtods well known in the art of pharmacy.

Such methods include the step of bringing into association the above defined adtve agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous WO 95/32983 PCT/SE95/00524 7 liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.

With regard to compositions for oral administration tablets and capsules), the term suitable carrier includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate and other metallic stearates, stearic add, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.

i" xU -ci- 8 Formulations suitable for topical administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agc.if in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.

Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels, and pastes comprising the active agent and a pharmaceutically active carrier. An exemplary topical delivery system is a transdermal patch containing the active agent.

Formulations for rectal or vaginal administration may be presented as a suppository or pessary with a suitable base comprising, for example, cocoa buter or a salicylate. Other vaginal preparations can be presented as tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active agent, such carriers as are known in the art to be appropriate.

Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range to 500 microns which is adminstered in the manner in which snuff is taken, i.e. by rapid inhalation from a container of the powder held up close to the nose. Suitable formulations wherein the carrier is a liquid for adminstration, for example, as a nasal spray or as nasal drops, include aqueous or oily solutions of the active agent.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, 7 WO 95/32983 PCT/SE95/00524 9 buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

In view of the understandable shock attendant upon either the exposure to HIV, i.e. a needle stick, or its discovery, e.g. that a contaminated syringe has been been reused, the above defined active agent is advantageously presented in an easily adminstered, rapidly acting form. An example of such a dosage form or package is a self-administered spring-loaded syringe currently used for nerve gas antidotes.

Several administration routes may be administered simultaneously, for instance a vaginal preparation, an intramuscular injection and a tablet may be contemporaneously taken, e.g. in the event of a suspected sexual transmission, to provide effective doses immediately at the site of exposure and in the circulatory system and for a more sustained rate via the oral route.

The above defined active agent is adminstered following exposure to HIV in an amount effective to prevent HIV infection or HIV seroconversion. Suitable amounts include about 0.1 mg/Jg bodyweight/day, preferably at least about 0.5 mg/kg/day and more preferably about 10 mg/kg/day. This I i WO 95/32983 PCTSE95/00524 corresponds to a preferred dosage amount of about 10 mg to about 10 g per day. Larger dosage regimes will tend to be indicated where a particularly large inoculum is suspected to have been transmitted, such as through a contaminated blood line or transfusion, where sustained administration is impractical, such as in a military environment, where the active agent is administered as a single dose "morning after pill" by clinics lacking follow up facilities or where there has been extended delay before the active agent is first administered.

The maximum dosage of the active agent is of course dependent on toxicity and the bioavailablity of the dosage route employed but it is noted that unlike therapeutic treatment for established HIV infections with the currently available agents which must be administered indefinitely in order to suppress viraemia, the present invention contemplates administration during a finite period following exposure to HIV. Accordingly transient toxicity which would be intolerable to a long term therapeutic regime may be tolerated in the method of the present invention. Cell culture results indicate that the above defined compound is generally well tolerated by human cells, for instance the ID 5 0 in MT4 cells appears to be around 45 u g/ml. In vivo simian experiments indicate no detectable toxidty short term at 30 mg/kg/day and bearing in mird the finite administration period, dosages of 100 mg/kg/day or more are feasible.

Accordingly, in view of the two immediately preceding paragraphs, preferred dosage amounts include a range of from 0.1 to 100 mg/kg bodyweight/day, particularly 0.5 mg/kg/day to 50 mg/kg/day and more particularly 1.0 to 25 mg/kg/day.

IV

WO 95/32983 PCT/SE95/00524 The finite period of time mentioned in the penultimate paragraph above will be the period of time which is sufficient to prevent the establishment of HWV infection or HV seroconversion when administered after exposure to HIV, but is not so long as to incur unnecessary expense or risk cumulative toxiity in atypically sensitive individuals, The finite period of admninstration will preferably be at least about one day, preferably about 3 days and may be 1 or two weeks, especially where there has been significant delay between exposure to HIV and initial administration of the active agent. Sustained release dosage forms can of course be formulated to release the active agent for the period intended, either as a single dose, or as a twice daily, daily or weekly dosage unit.

In keeping with sound pharmaceutical practice in relation to antiviral agents, the compositions of the invention may comprise one or more auxilliary antivirals or antimicrobials as congeners etc, either against other common infective agents in HIV positive body fluids or samples, such as hepatitis B or C, or those in use in conventional double or multiple therapy against HIV. Examples of such auxilliaries include interferon, gamma-globulin, RT and protease inhibitors, AZT and ddl. The compositions of the invention may alternatively or additionally comprise an abortificient such as the oestrogen derivatives employed in "morning after pills" or RU 486.

Detailed description Embodiments of the invention will now be described by way of example only with reference to the following Examples.

I

4#/2 WO 95/32983 PCT/SE95/00524 12 Example 1 Preparation of 1-[2,3'-dideoxy-3'C-(hydrox~rmethyl)-p-D-erythropentofuranosylj-cytosine The benzoyl protected sugar residue, methyl-5-O-benzoyl-3-[ (benzoyioxy)methy1]-2,3-dideoxy-D-erythro-pefltafurafloside is prepared according to the method of Svensson et al; 1991, 56, 2993-2997. The base residue is prepared by suspending 120 mg, 1.-08 inmol cytosine in 0.2 nil trimethyichiorosilane and 2 ml hexamethyldisilazane along with crystalline amimonium sulphate, refluxing until clear, vacuum concentration and coevaporation with dry xylene. This preparation is dissolved in 2 ml dichioroethane in a nitrogen atmosphere before 170 mg, 0.46 mmol of the sugar residue is added followed by 0.22 ml, 0.96 mmol t-butyl-dimethyltriflate, Reaction proceeds for 24 hours at room temperature and is quenched with saturated hydrogen carbonate during agitation for half an hour.

This solution is diluted with dichloroethane, washed in the saturated carbonate and concentrated following drying and filtration. The resultant concentrate is subjected for 24 hours at room temperature to 20 ml of saturated methanolic ammonia, before being concentrated, dissolved in water and extracted with dichioroethane. A C18 column is used for reverse phase semi preparative chromatography on the concentrated aqueous phase and eluted with 2% methanol in water. The P3 anomer, 1-[2',3'-dideoxy-3'C- (hydroxymethyl)-p -D-erythro-pentofuranosyl]-cytosine follows the a anomer and collected fractions yielded 27 mg with the following NMR spectra in ppm. (using TMS and TSP or dioxane as internal standards) [a] 26 +640 (c o.27, H 2 LUV (H 2 0) X max: 272 rim (E 9208); IH-NMR (270 MHz, D 2 2.2-2.46 (in, 3H, IJ-2); 3.68 J3, 6 .5 Hz, 2H, H-61); 3.76 (dd, 4,,5'a =12.5 H~z, 1H, H-5a;" 192 (dd, J4,5'b =2.9 Hz, Si WO 95/32983 PCISE95/00524 13 12.5 Hz, 1H, 4.01 J3', 4' 8.1 Hz, J'a, 4' 5.5 Hz, J5'b, 4' 2.9 Hz, I H, 6.05 J5,6 7.3 Hz, 1H, 6.11 (dd, J 1 2'a 7.0 Hz, Jl', 2'b Hz, 1H, 7.91 Js, 6 7.3 Hz, 1H, 1 3 C-NMR (25.05 vHiz,

D

2 36.1 40.8 62.7, 63.1 84.7, 87.1 96.5 142.2 158.2 166.8 The chromatographically pure compound is prepared into a subcutaneous preparation by dissolving 3.00 g in 300 ml 0.9 NaC1 in pyrogen free water followed by sterile filtration to give a 10 mg/ml solution which is administered subcutaneously at the rate of 1 mg/kg bodyweight.

Example 2a Animal Experiments: HIV.

Inoculation: The control and test animals, 2 year old macquaque monkeys were inoculated subcutaneously with a moderate (10 monkey infectious doses MIID 5 0 as determined by Bbttiger et al Antiviral Chemistry and Chemotherapy 1992;3:269-271) dose preparation of HIV-2 (SBL 6669strain) in phosphate buffer minutes after inoculation, the test animals were injected subcutaneously with a 10 mg/kg preparation of Example 3 or the con'esp'onding AZT preparation. Treatment was repeated three times per day for 4.5 days. After 8, 10, 14, 17,24 and 30 days blood samples were assayed for the presence of viral antigen (absorbance at 492 nm) and the presence or absence of virus in the 30 day sample was assayed.

P..

WO095/32983 PCTSE9$IOOS24 14 All four uninoculated control animals exhibited 1-flyantigen in the blood between days 14 and 17 and virus could be isolated after 30 days (2 months in one animal). Both of the AZT treated animals showed minor rises in absorbance at day 17 which later declined. However virus was isolated from both animals at day 30 and in keeping with the usual pattern following cessation of AZT maintenance therapy, it would be expected that the antigen (and free virus titre) would rise in following weeks and months, In contrast, none of the four animals treated wNith the preparation of the invention showed any rise in absorbance and nor could virus be isolated after 30 days. It is thus clear that the administration of the invention prevented the infection establishing itself, whereas AZT, the most efficacious therapeutic agent known to date has no such ability.

After several months, each of the protected test animals was reinoculated with HIV and became infected in the usual way, thus indicating that it was the active agent which was responsible for the failure of the infection to establish itself and not a peculiarity of the test animals.

Examrle 2b Animal Experiments: SIV Example 2a demonstrates that the activ.- agredient of the invention prevents the establishment of IV infection in the cynomnegalous monkey model. SIV, whose native host is the monkey and which results in a more aggressive infection than I-fl was then used to investigate appropriate dosages and regimes. Efficacy in the morie aggressive SIV model will more than reflect efficacy in the milder HIV infection in humans, siven from 2 hours before Inoculation, however the low infectious dose renders the sign~ficance of the report hard to assess. A further report WO 95/32903 PCTISE95IOOS24 is Control and test animals were 2 year old macquaque monkeys as above which were Inoculated intravenously with 10, 100 or 1 000 MID of SIN' sm as listed in Table 1 below.

One, 3,8, or 24 hours after inoculation with SIVsm, paired test animals wvere injected subcutaneously with 10 mg/kg of the preparation of Example 4, repeated three times per day for 1 day or 3 days as listed in table 1. Blood samples were extracted from the test and control animals on days 0, 17, 23 and 30 for determination of SIV antibody, SIV p26 antigen and presence of infective virus. The methods have been described by B~ttiger et al, AIDS Res Hum Retroviruses 1992;7:1235-1238.

With reference to table 1, it is clear that the administration of the present 1s active agent prevents the infection establishing itself in the test animals, as monitored by the presence of viral antigen or antibody to the virus in the blood or ability to culture virus. All of the control animals exhibited positive SIV antibody and antigen titres within the first 23 days and within 30 days infectious SIV virus could be cultivated.

Infection was prevented in all of the animals treated for three days, whether adminstration was first commenced one hour, 3 or 8 hours after inoculation with 10 ID 50 Even waiting for as long as 24 hours before first administering the preparation of the invention prevented infection in one of the two animals.

With treatments which were only of one day's duration, three of the four animals showed no signs of the establishment of infection if treatment

II

WO 95132983 PCTISE9500524 16 commenced within I hour of inoculation with 10 ID 3 0 Waiting for three hours increased the infection rate but some protective effect is still apparent.

Clearly a lower infectious dose, less aggressive virus, for instance HIV, or higher active concentration of the preparation will enhance this protective effect.

It should be noted that an inoculum of 10 infectious doses is a significantly greater amount of virus than a victim is exposed to in a normal needle stick accident. However the establishment of infection can be prevented even following very high infectious doses (100 M1ID3 0 as can be seen from the combination administration within 1 hour plus treatment for three days (three of four animals protected). This dosage regime also protected one of the two animals subjected to the extremely high inoculum of 1000 MID 50 The combination of adminstration within 3 hours plus treatnent for only 1 day prevented infection from 100 MID 50 virus in one of four monkeys which is a pronounced protective effect bearing in mind the inoculum, time to first adminstration and duration (results not shown in Table 1).

Table 1.

Monkey No.

Inftective dose M ID50) Treatmnent start post inoculation ho~urs Treatment durafltion days Detected during 30 (lays post virus inoculation SIV Ab SIV Ag Sly 41 42 4,1 44 46 4-4 48 49 51 -3 52-3 7-4 8-4 5-4 6-4 54 57 9-4 10-4 W.-O WON 14mhoi i i o4om Table 1. (continued) Monkey No- Infective dose

MID

50 Treatment start post inoculation hours Treatment duration days Detected during 30 days post virus inoculation SIV Ab SIV Ag Sly 17-4 18-4 29-4 30-4 31-4 32-4 53 58 13-4 14-4 15-4 16-4 1000 awpri Qor iyrup or preu yusi y 4 aa iuon, upposimyry ui, W i.

Preferably, however, at least the initial administration following discovery ot WO 95/32983 PCT/SE95/00S24 19 Example 3 Injectable preparation 750 mg of lyophilized active agent, as prepared in Example 1, is dissolved in 100 ml of pyrogen free isotonic saline. The pH of the preparation is adjusted to 7.5 with 0.1 M NaOH/HCl and the preparation sterile filtered and aseptically decanted into 10 10 ml sterile vials having a rubber diaphragm in the lid for rapid withdrawal of the contents. Each vial represents a dosage form containing 75 mg of active ingredient suitable for providing a dosage of 1 mg/kg for a normal adult male.

Example 4 Capsules 12 g of active agent, as prepared in Example 1, is seived through US 60 mesh along with 12 g of dessicated lactose and 0.1 g of magnesium stearate. The resultant fine powder is dosed in 500 mg amounts into hard gelatin capsules to form dosage units of 245 mg representing a dosage of about 32 mg/kg for a normal adult male.

Example Sustained release preparation The following materials are wet granulated in a 300 mg povidone aqueous base: 5000 mg active agent j 1000 mg HPMC (Methocel K4M premium) 500 mg lactose (pharmaceutical grade) The granules are compressed with a trace of magnesium stearate into 700 mg tablets suitable for twice daily administration.

ii vr4nlt; as a soiuon or a suspension ot weO Active agent in an aqueous j,4jOppRpj)jjj26)31-95XW 2017198 20 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

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Claims (12)

1. 2. A method according to claim 1 wherein said administration commences within about 8 hours following said exposure.
2. 3. A method according to claim 2 wherein said administration commences within about 3 hours.
3. 4. A method according to claim 3 wherein said administration commences within about 1 hour. A method according to claim 1 wherein said administration is continued over at least 1 day.
4. 6. A method according to claim 5 wherein said administration is continued over at least 3 days. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antoxidants, P!\OPBR\PDn\6331.95,CLM. 17/898 -22-
5. 7. A method according to claim 5 wherein said administration is continued for less than two weeks.
6. 8. A method according to claim 1 wherein said effective amount comprises at least 0.1 mg/kg body weight/day,
7. 9. A method according to claim 8 wherein said effective amount comprises at least mg/kg body weight/day. A method according to claim 1 wherein said exposure results from a needle stick or surgical injury.
8. 11. A method according to claim 1 wherein said exposure results from blood transfusion or reuse of contaminated medical apparatus.
9. 12. A method according to claim 1 wherein said exposure results from sexual transmission.
10. 13. A method according to claim 1 wherein at least the initial administration of said compound is intravenous, subcutaneous or intramuscular.
11. 14. A method according to claim 1 substantially as hereinbefore described with reference to the Examples. Use of 1-[2',3'-dideoxy-3'C-(hydroxymethyl)-P3-D-erythro-pentofuranosyl]-cytosine in the manufacture of a medicament for post-exposure administration to a human or simian to prevent the establishment of HIV infection or seroconversion. DATED this SEVENTEENTH day of AUGUST, 1998 MEDIVIR AB \by DAVIES COLLISON CAVE "atent Attorneys for the Applicants 9 I 9 *9 9 9. *9 9 9 9 9 9 9999 9 9t 9. 99 9 .9 9 9 9 9. 99 9 99 .9 9* 9, *9 LI VA% r#WUA4 V TC W. 4 ,JA& V Tita ,t Lfl&V~1V WA~ QU&~AI amounts include about 0A1 mg/,lkg bodyweight/day, preferably at least about 035 mg/kg/day and more preferably about '10 m$/kg/day. This INTERNATIONAL SEARCHI REPORT Intermnational application No. PCT/SE 95/00524 A. CLASSIFICATION OF SUBJECT MATT'ER IPC6: C07H 19/06 C07H 19/073 According to International lOatent. Classification (IPC) or to both national classification and Ipc B. FIELDS SEARCHED Minimum documentation searched (classificatilon system followed by classillcatios' symbols) IPC6: C07H Documentation searched other than minimum iocumcntation to the exterii that such documcnts are included In ti. ,elds searched SE,DK,FI,NO classes as above Electronic data base consulted during the international search (name or data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages JRelevant to claim No. X WO0 9206102 Al (MEDIVIR AB), 16 April 1992 1 14-16 (16.04.92) X WO0 8808001 Al (AKTIEBOLAGET ASTRA), 14-16 October 1988 (20.10.88) X EP 0391411 AZ (BRISTOL-MYERS SQUIBB COMPANY), 14-16 October 1990 (10.10.90) 0 Further documents are listed in the continuation of Box C. 1:X] See patent family annex. Special categories of cited documents: 'T later document published after the international iling date or priority ocuentder te gnerl sateof he n wichis ot onsdaudate and not in conflict with the application but cited to understand douen efinn th renealnae ofteatthces o osie.. principle or theory underlying the invention erlier document hut published 0n0cr after the international filing date dnum fpclrrtvance: the claimed invention ca-not be 'U document which may throw doubts on priority clam) or which is cosier2:ovl6r=1no be considered to involve an inventive cited to establish th% publication date of another =iatn or other step when the document is taken alone special reason (as rpiecified) document of particular retevance: the claimed invention cannot be document referring to an oral disclosure. use, cichibition or other considered to involve an inventive step when the document is meanscombined with one or more other such documents, such combination document published prior to. the international filing date but later dmn being obvious to a person skilled in the art the priority date claimed W' documnt member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 14 Jul 199517 -07- 1995 Name and mailing address of the ISA/ Authorized officer Swedish Pat, ii ',fice Box 5055, S-1%i"v 12 STOCKHOLM Eva Johanssan Facsimile No. 46 8:666 02 86 Telephone No. 46 8 782 25 00 i Form PCT/ISA/210 (second sheet) (July 1992) Particularly 1,0 to 25 mng/kg/day. I c 't INTERNATIONAL SEARCH REPORT International application No. PCT/SE 95/00524 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category" Citation of document, with indication, whore appropriate, of the relevant Passage$ Relevant to claim No. It is pointed out that a known compound may in many countries be claimed by a product claim restricted to the first medical use and in many of these countries by a use claim for other medical indications. F~orm PCrISA/210 (continuation or second sheetQ(uly 1992) e I 1 -41 1 1 INTERNATIONAL SEARCH REPORT lnlcmilloniaI application No, IPC T/SE 95/00524 SBox I Observations where certain claims were found unsearchable (Continuation of Item 1 of first sheet) This international search report has not been established in respectof certain claimniunder Article 17(2)(s) for the following reasonts: i. MU1 ClisNce.: 1-13 L- J r-zuse they relate to subject matter not required to be searched by this Authority. namely: See PCT Rule 39.1(iv) Methods for treatment of the human or animal body by surgery or therapy, as well as diagnostic methods. 2. FlClaims Nocs.- because they relate to parts of the international application that do not comiply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specific-ally: '~because they are depenadent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Obser-vationts wherr unity of invention Is lacking (Continuation of Item 2 of flrst sheet) This International Search iig Authority found multiple inventions in this international application, as follows: 1. Fl As all required additional search fees were timely paid by the applicant, this international search report covers all '~searchable claims. 2. MAs all searchable claims could bt; searchied without effort justifyini!, an additional fee, this Authority did not invite payMent of any additional fee. 3. ,J As only some of the required additional search fees were timely paid by tlm applicant, this international search report covers only those claims for which fets wevre paid, specifcally claims Nos.: 4. EJ No required additional search fees were timely paid by the applicant. Consequently, this international search repor is restricted to the invention first mentioned in the claims; it is covered by claimus Nor.: Remark on Protest The additional search fees were accompanied by the applicant's protest. No protest accompanied the payment of additional search fees. Form PCT/ISAI2I0 (continuation of first sheet (July 21992) MHz, D 2
12. 22-2.2-46 3H, IJ-2); 3.68 J3',6' x 5 5 Hz, 211, 3.76 (dd, J 4 5'a 12.5 Hz, 3.92 (dd, J4, 5'b 2.9 liz, J5'a, 5'b it rr i (1 4 INTERNATIONAL SEARCH REPORT Information on patent family members Inw, national application No, PCT/SE 95/00524 Patent document Publication Pateant family Publication cited in search report data member(s) date WO-Al- 9206102 16/04/92 AU-A- 8641091 28/04/92 CA-A- 2093020 03/04/92 EP-A- 0554274 11/08/93 JP-T- 6501261 10/02/94 WO-Al- 8808001 20/10/88 AT-T- 115958 15/01/95 AU-B- 614082 22/08/91 AU-A- 1689988 04/11/88 DE-D- 3852531 00/00/00 DK-A- 104994 13/09/94 DK-B- 168443 28/03/94 EP-A,B- 0309560 05/04/89 ^E-T3- 0309560 EP-A,A,A 0516186 02/12/92 EP-A- 0615975 21/09/94 US-A- 5215970 01/06/93 US-A- 5409906 25/04/95 EP-A2- 0391411 10/10/90 AU-B- 633065 21/01/93 AU-A- 5256090 11/10/90 CA-A- 2013874 06/10/90 FI-A,D- 942676 07/06/94 FI-A,D- 942677 07/06/94 FI-A,D- 942678 07/06/94 JP-A- 2290895 30/11/90 Form PCT/ISAP 10 (patent family annex) (July 1992) a-