Title of Invention

A TOPICAL COMPOSITION IN THE FORM OF AN OIL IN WATER EMULSION

Abstract A topical composition in the form of an oil in water emulsion comprising 0.1-10% (w/w) hydrocortisone and 1-7% (w/w) of an antiviral nucleoside analogue selected from acyclovir, penciclovir or 9-(4-hydroxy-2-(hydroxymethyl)butyl)guanine in a pharmaceutical carrier comprising propylene glycol and an isopropyl C12-C22 alkanoic acid ester, characterized in that the carrier comprises, relative to the total weight of the composition, 15-25% (w/w) propylene glycol and 10-25% (w/w) of an isopropyl C12-C22 alkanoic,acid ester
Full Text FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"A TOPICAL COMPOSITION IN THB FORM OF AN OIL IN
WATER EMULSION"
MEDIVIR AB, of Lunastigen 7, S-141 44 Huddinge, Sweden,
The following specification particularly describes the invention and the manner in which it is to be performed:




The present invention relates to a topical composition in the form of an oil in water emulsion.
Technical Field
This invention relates to topical antiviral formulations suitable for orofacial or genital application and comprising an antiinflammatory agent and an antiviral agent The invention further relates to the treatment or prophylaxis of herpesvirus diseases using such formulations and to their preparation.
Background Art
International patent application no WO 96/24355 decribes pharmaceutical compositions comprising a topically acceptable antiviral substance and an antiinflammatory glucocorticoid in a pharmaceutically acceptable carrier. The carriers disclosed in this application comprise conventional formulations for each of the respective^active agents, that is a conventional antiviral formulation is combined with a conventional glucocorticoid formulation. Such combined formulations have a large number of ingredients, with potential-for interreacting with each other, leading to unknown stability and physicochemical characteristics.
European patent application no. EP 44543 relates to oil in water formulations of the acyclic nucleoside antiviral agent acyclovir and describes that effective topicai penetration necessitates that the carrier comprises at least 30 weight percent, preferably at least 40 weight percent propylene glycol. This formulation, denoted the MAC formulation, forms the basis of the most widely marketed topical acyclovir preparation.
International patent application no WO 91/11187 relates to oil in water or aqueous topical formulations of the acyclic nucleoside antiviral agent penciclovir. These formulations must comprise at least 30 weight percent, preferably at least 35 weight percent, propylene glycol. European patent application no. EP 416 739 relates to topical formulations of penciclovir comprising at least 30 weight percent propylene glycol and a decyl methyl sulfoxide emulsifier. International patent application no. WO 93/00905
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relates to topical formulations of penciclovir comprising at least 30 weight percent, preferably at least 35 weight percent, propylene glycol and a cetomacrogol 1000 emulsifier.
Formulation of a combination product comprising a strongly lipophilic component such as hydrocortisone and a moderately lipophobic component such as an acyclic nucleoside analogue is difficult in the case of conventional pharmaceuticals, but is even more difficult in the case of a topical preparation where release rates of the active ingredients into the target tissue must be taken into account. As described in the publications in the two paragraphs immediately above, it has hitherto been regarded essential to utilise a high level of propylene glycol when formulating acyclic nucleosides in order to achieve adequate penetration of the antiviral agent into the skin or dermal mucosa. We have discovered, however, that while conventional, high concentration propylene glycol carriers can be used to prepare efficacious antiviral compositions within the scope of the above mentioned WO 96/24355 (that is compositions comprising a glucocorticoid and an antiviral agent), these conventional carriers result in the product having an undesirably short shelf life and less than optimal antiviral and therapeutic performance.
Disclosure of the Invention
In accordance with the invention there is provided a topical composition comprising an antiinflammatory glucocorticoid and a nucleoside analogue antiviral agent in a pharmaceutical carrier characterized in that the carrier comprises about 15 to about 25 weight % propylene glycol and about 10 to about 25 weight % isopropyl C12- C22 alkanoic acid ester.
In the context of the invention, this combination of a lower concentration of propylene glycol in conjunction with an isopropyl alkanoic acid ester allows for good penetration and release of the antiviral component, while at the same time avoiding the instability shown by conventional antiviral compositions.
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The compositions of the invention are useful for the treatment or prophylaxis of diseases caused by members of the herpesvirus family, such as herpes simplex type 1 (predominantly an orofacial infection), herpes simplex type 2 i (predominantly a genitoanal infection), varicella zoster virus primary infection (chicken pox) and secondary infection (shingles), human herpesvirus type 6 and 8 (implicated in the skin condition Kaposi's sarcoma) and the like. Prophylaxis in the context of the invention includes prevention of infection (including preventing spread to adjacent healthy tissue) and l) preventing reactivation of previous herpes virus infection, such as reactivation of herpes lying dormant in neural tissue.
A further aspect of the invention thus provides the use of the composition defined above in medicine, particularly in the manufacture of a topical
15 medicament for the treatment or prophylaxis of herpes virus infections in humans, especially herpes simplex type 1 and herpes simplex type 2. A related aspect of the invention provides a method for the treatment or prophylaxis of herpes virus infection in humans comprising the topical administration of the composition described above to a subject in need
20 thereof.
Weight percentages herein refer to the weight of the component relative to the weight of the composition.
25 Preferred antiviral agents include ganciclovir, N-7 ganciclovir, bis -
hydroxymethylcyclopropylmethylguanine, lobucovir, adefovir, cidofovir and the like. Particularly preferred antiviral agents include penciclovir, 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G) and especially acyclovir. The antiviral agent may be in the form of a prodrug which is metabolised in
30 situ, for instances with epidermal esterases or xanthine oxidases, to form an antiviral agent such as the ones listed above.
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The antiviral agent is included in the formulation in substantially conventional concentrations for the respective nucleoside, for example 0.5 to 15 weight per cent, preferably 1-7 weight percent such as around 4-5 weight per cent. Advantageously the formulation is largely or completely saturated with respect to the antiviral agent.
Examples of glucocorticoids include alclometasone, desonide, fluprednidene, flumethasone, hydrocortisone and its esters such as hydrocortisone butyrate or hydrocortisone acetate, clobetasone, triamcinolone acetonide, betmethasone, budenoside, desoximethasone, diflorosane, fluocinolone, fluoccinonide acetonide, fiuocortolone, fluticasone, methylprednisolone aceponate, mometasone, rofleponide and the like. Mild glucocorticoids, such as those in Nordic class I, are preferred. Hydrocortisone and its esters are particularly preferred.

The glucocorticoid is included in the formulation in substantially conventional concentrations for the respective glucocorticoid, which concentrations are well known in the glucocorticoid art and generally fall in the range 0.005 to 12 weight percent, such as 0.1 to 10 weight percent. For instance when employing a mild (Nordic class I) glucocorticoid such as hydrocortisone, the formulation may contain 0.1 to 10 weight per cent, preferably 0.5 to 2 weight per cent, such as about 1 weight per cent hydrocortisone.
The glucocorticoid and antiviral components may be in substantially
dissolved form, dependent upon the carrier, but are conveniently prepared from a micronised raw material, such as those having > 75 %, preferably greater than 90% of particles with less than a defined particle size. For instance the glucocorticoid hydrocortisone is conveniently prepared from a
raw material with a particle size less than 5 pm. The antiviral acyclovir or penciclovir is conveniently presented with a particle size less than 15 p.m, preferably less than 7 pm.
5

In general the compositions of the invention are biphasic and comprise discrete oil and aqueous phases, either as an oil in water or a water in oil emulsion. Preferably the composition comprises a dispersed oil phase and a continuous aqueous phase. The isopropyl alkanoic acid ester and the 5 typically lipophilic glucocorticoid component will be preferentially found in the oil phase, while the antiviral nucleoside will generally be found in the aqueous phase, typically in conjunction with the propylene glycol.
Components of the oil phase may include conventional fats and oils and 10 their esters, as found in the European and other pharmacopeaias. Oil phase components are preferably non-greasy, non staining and washable. Conventional pharmaceutical oil phase components include mineral oils such as vaseline, liquid paraffin and the like, alkanoic acids such as stearic acid and fatty alcohols such as cetostearyl alcohol, straight or branched 15 chain mono or dibasic alkyl esters such as di-isopropyl adipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, decyl oleate, butyl stearate, 2-ethylhexyl palmitate and other 2-ethylhexanoic acid esters and the like.
20 Preferred isopropyl alkanoic acid esters include the dodecanate, myristate, palmitate, stearate. eicosanate or behenoate esters, especially isopropyl myristate. The composition of the invention comprises about 10 to about 25 weight per cent of the isopropyl alkanoic acid ester, preferably about 12 to about 18 weight per cent, such as about 15 weight per cent.
25
The composition of the invention comprises about 15 to about 25 weight percent propylene glycol, such as around 18 to around 22 weight per cent. Conveniently the propylene glycol content is around 20 weight per cent as this concentration generally assures a good preservative effect without
30 needing exogenous preservatives in the composition.
The composition of the invention conveniently includes an emulsifier (surfactant), typically in an amount of 0.05 to 5, preferably 0.1 to 1 weight
6

per cent. The European Pharmacopeia describes a number of pharmaceutical^ acceptable emulsifiers including anionic, cationic and non-ionic emulsifiers.
5 Exemplary non-ionic emulsifiers include cetomacrogols, such as
cetomacrogol 1000, ethylene ordiethylene glycol monostearate, glyceryl esters such as the behenate, oleate, stearate etc, laureth compounds such as lauromacrogols, macrogol monomethyl ethers, mono- and diglycerides, nonoxinols. octoxinols, poloxamers such as poloxamer 407, polyoxyl castor 10 oils, polyoxyl stearates, polysorbates, polyvinyl alcohols, propylene glycol diacetates, sorbitan esters and the like. Poloxamer 188 is a preferred non-ionic surfactant.
Exemplary anionic emulsifiers include aluminium monostearate, calcium 15 stearate, sulphated castor oil, magnesium stearate, pendecamaine, sodium oleate, sodium stearate, sodium stearyl fumarate, sodium tetradecyl sulphate, zinc stearate and the like. A preferred anionic emulsifier is sodium lauryl sulphate
20 The compositions of the invention can also include conventional auxiliaries such as surface anaesthetics, sunscreens, flavours, scents, emollients or skin tone colourants and masks.
The compositions of the invention can be prepared by conventional 25 blending techniques. Preferably the compositions are prepared by conventional biphasic blending techniques, whereby the oil and aqueous/propylene glycol phases are separately blended and homogenised and brought to a common temperature before mixing. The active ingredients (that is the glucocorticoid and the nucleoside analogue) may be added to 30 their respective oil and aqueous phases before or after blending. Preferably, to minimize the tendency to recrystallisation, the active ingredients are added after blending of the two phases. This means that there is a greater
7

volume when the active ingredients are added, and additionally the biphasic mixture is generally at a lower temperature.
A further aspect of the invention thus provides a method for the preparation 5 of an antiviral composition comprising bringing an oil phase comprising 10-25 weight percent (relative to the total weight of the intended formulation) isopropyl alkanoic acid ester to a defined temperature, bringing an aqueous phase comprising 15-25 weight per cent (relative to the total weight of the intended formulation) propylene glycol to the defined temperature, blending 10 and optionally homogenising the two phases, optionally allowing the blend to cool to a lower temperature, adding effective amounts of an antiinflammatory glucocorticoid and a nucleoside analogue antiviral agent and homogenising the resultant blend.
15 The intended viral conditions, such as herpes simplex lesions on the lips and/or genitalia or herpes zoster (shingles), are episodic. As with all antiviral treatments it is desirable to commence application of the medicament as soon as possible after the reactivation of a dormant herpes infection into an incipient lesion is sensed or suspected. For instance many people
20 experience a warmth or tingling at the coming focal point one or more days before the first visual signs of a herpes lesion become discernable. Application of the composition of the invention is preferably commenced at this point. In some patients, exposure to certain stimuli, such as UV light when skiing or from tropical sun, severe emotional stress or menstruation,
25 can induce reactivation of herpes lesions in particular positions. The
composition of the invention can be applied in a prophylactic manner upon exposure to these stimuli. In either event it will be convenient for people prone to herpes lesions to keep a supply of the composition readily available for speedy application when needed. Accordingly it is desirable for
30 the composition of the invention to have a long shelf life without
refrigeration, so that the medicament can be kept at home or at work and/or packed for travel.
8

The composition will generally be applied to the incipient or apparent lesion two to twelve times per day during an episode, such as every three hours. Application preferably continues at least until the hard scab stage which
generally takes 3 to 10 days from the first sensation that an episode is
5 expected.
The composition of the invention is preferably presented in a tube containing 0.25 to 50 ml. Conveniently the tube contains sufficient for a single cold or genital sore episode, such as 1 to 5 ml. This will allow several 10 daily applications over no more than a week or ten days, the residue being discarded, thus minimizing potential contamination of the open tube and/or cross infection between individuals sharing the same tube.
Preclinical efficacy of compositions of the invention can be assayed as 15 shown in the examples or with the adoptive transfer of immunity model described in WO 96/24355 and WO 96/24963
Brief Description of the Drawings
Various embodiments of the invention will now be illustrated by way of 20 example only with reference to the following non-limiting examples and
drawings in which:
Fig 1 is a plot of lesion score against time for herpes infected guinea
pigs topically receiving a composition of the invention or a placebo;
Fig 2 is a plot of lesion score against time for herpes infected guinea 25 pigs topically receiving a composition comprising a conventional carrier or a
placebo;
Fig 3 is plot of lesion score against time for herpes infected guinea
pigs topically receiving a composition falling outside the scope of the
invention or a placebo;
30 Fig 4 is a micrograph showing crystal growth in a conventional
formulation;
Fig 5 is a micrograph showing the lack of crystal growth in a
formulation of the invention;
9

Fig 6 is a plot of lesion score against time for herpes infected guinea pigs topically receiving a composition of the invention or a composition prepared according to WO 96/24355, example 3;
Fig 7 is a plot of lesion score against time for herpes infected guinea pigs topically receiving an alternative composition of the invention or a composition prepared analogously to W096/24355.
Detailed Description
Example 1
A composition in accordance with the invention is prepared from the following ingredients:

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20
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oil phase
cetostearyl alcohol 6.75 g 6.75%
vaseline 10.00 g 10.0%
liquid paraffin 5.65 g 5.65%
isopropyl myristate 15.00g 15.0%
aqueous phase
propylene glycol 20.00 g 20.0%
sodium lauryl sulphate 0.80 g 0.8%
poloxamer 188 1.00 g 1.0%
aq. purif. 34.8 g 34.8%
active components
acyclovir 5.00 g 5.0%
hydrocortisone 1.00 g 1.0%

The particle size of the acyclovir (Recordati micronised, USP23/BP93/Eur Ph III) was 10% = 2 pm, 50% = 4 pm, 90% = 7 pm & 100% = 15 pm. The particle size of the hydrocortisone (Pharmacia & Upjohn micronised USP/EP/BP) was 100% 10

The oil phase and aqueous phase components are added to respective mixing vessels, which are each heated to 70°C under agitation. When the phases are at an identical temperature, the oil phase is poured onto the aqueous phase from above while continuing to agitate for 3-5 minutes at the highest possible speed which avoids drawing air into the mixture. The thus emulsified mixture is then homogenised and cooled, with continued agitation, to 32-25°C. The active ingredients are added and agitation continued until the active ingredients are wetted and blended in. The mixture is once again homogenised and cooled until the cream thickens, around 30°C, before packaging.
Example 2
A penciclovir/hydrocortisone composition according to the invention was
prepared from the following components:

20


oil phase
cetostearyl alcohol 6.75 g 6.75%
vaseline 10.00 g 10.0%
liquid paraffin 5.65 g 5.65%
isopropyl myristate 15.00 g 15.0%
aqueous phase
propylene glycol 20.00 g 20.0%
sodium lauryl sulphate 0.80 g 0.8%
poloxamer 188 1.00 g 1.0%
aq. purif. 34.8 g 34.8%
active components
penciclovir 5.00 g 5.0%
hydrocortisone 1.00 g 1.0%

The particle size of the hydrocortisone (Pharmacia & Upjohn micronised USP/EP/BP) was 100% 11

The oil phase and aqueous phase components are added to respective mixing vessels, which are each heated to 70°C under agitation. When the phases are at an identical temperature, the oil phase is poured onto the aqueous phase from above while continuing to agitate for 3-5 minutes at the highest possible speed which avoids drawing air into the mixture. The thus emulsified mixture is then homogenised and cooled, with continued agitation, to 32-25°C. The active ingredients are added and agitation continued until the active ingredients are wetted and blended in. The mixture is once again homogenised and cooled until the cream thickens, around 30°C, before packaging.
Comparative Example 1
An acyclovir/hydrocortisone composition employing the prior art MAC carrier described and claimed in EP 44543 was prepared from the following components:
oil phase
cetostearyl alcohol 33.75 g 6.75%
vaseline 50.0 g 10.0%
liquid paraffin 28.25 g 5.65%
aqueous phase
propylene glycol 200.0 g 40.0%
sodium lauryl sulphate 4.0 g 0.8%
poloxamer188 5.0 g 1.0%
aq purif 148.82 g 29.8%
active components
acyclovir 28.19 g 5.0%
hydrocortisone 5.02 g 1.0%
The ingedients were blended substantially as described in Example 1.

Comparative Example 2
An acyclovir/hydrocortisone composition employing a low propylene glycol (PG) concentration (relative to the prior art MAC formulation) but without the isopropyl alkanoic ester (IPM) of the composition of the invention was prepared from the following components:






oil phase
cetostearyl alcohol 6.75 g 6.75%
vaseline 10.00 g 10.0%
liquid paraffin 5.65 g 5.65%
aqueous phase
propylene glycol 25.00 g 25%
sodium lauryl sulphate 0.80 g 0.8%
poloxamer 188 1.00 g 1.0%
aq purif 44.8 g 44.8%
active components
acyclovir 5.00 g 5.0%
hydrocortisone 1.00 g 1.0%

The ingredients were blended substantially as described in Example 1.
Biological Example 1
Antiviral efficacy of compositions in accordance with the invention and comparative examples is assayed in a guinea pig model (Alenius et al, J. Inf. Dis. 145 569-573 (1982)). In summary, the model involves establishing a primary herpes simplex virus infection on depilated areas of the dorsal surface of guinea pigs. 24 hours after inoculation, the test and placebo compositions are smeared onto the incipient herpes lesions. This topical administration is repeated twice per day for 3 or 4 days. Lesion appearance

is scored daily in a double blinded fashion and the scores from multiple animals averaged, wherein
0 represents no development of lesions,
1 represents a few scattered lesions,
5 2 represents several lesions, some confluent
3 represents maximum development of confluent lesions
Figure 1 shows the results from a composition in accordance with the invention (Example 1) in comparison to a placebo formulation (the MAC
formulation analagous to Comparative Example 1, but without the active ingredients) which represents uninhibited viral growth. Figure 2 shows a substantially prior art composition (Comparative Example 1 - acyclovir & hydrocortisone in a MAC formulation) in comparison to the corresponding placebo. Figure 3 shows a composition falling outside the scope of the
15 invention (Comparative Example 2, low PG/IPM free) in comparison to the placebo.
Referring initially to the placebo formulations it will be apparent that in the absence of the combination of antiviral agent and glucocorticoid, severe 20 lesions form within 3 days and remain unhealed for over 8 days.
A composition embodying the antiviral/glucocorticoid combination broadly in accordance with the abovementioned WO 96/24355 (Comparative Example 1) was freshly produced and comprised an antiviral nucleoside analogue
25 and an antiinflammatory glucocorticoid in a conventional MAC formulation. This formulation displays a retarded development of serious lesions (days 1 to 5) and a somewhat diminished intensity of lesion (maximum score 2 at day 6). As suggested in WO 96/24355 such formulations are thus of utility in the treatment and prophylaxis of herpes infections. However, as described
30 in Assay Example 1, this MAC formulation is not practical in a commercial context for combination regimens.
14

Turning now to Comparative Example 2 in Fig 3, as would be predicted from the disclosure of the abovementioned EP 44543, WO 91/11187, EP 416 739 and WO 93/00905 directed to various aspects and applications of the MAC formulation, lowering the level of propylene glycol below the "at least 5 30 weight percent" advised by these patents and applications significantly reduces antiviral efficacy and results in a formulation which is only marginally better than the placebo. In particular, the lesion score is less that one half unit lower than the placebo with barely measurable decreases in time to lesion and time to heal.
10
In contrast, the compositions of the invention, as depicted in Fig 1, show a significantly improved efficacy relative to both the placebo and the substantially prior art formulation of Fig 2. In particular the lesion score remains at all times less than 1 and is below 0.5 at day 8. Clearly the 15 combination of a reduced propylene glycol concentration in conjunction with the addition of the isopropyl alkanoic acid ester, isporopyl myristate, significantly aids antiviral and therapeutic efficacy of combination products comprising an antiviral and an antiinflammatory glucocorticoid.
20 Figure 6 depicts lesion score as a function of days in the guinea pig model broadly as described above but employing a slightly more pathogenic strain of herpes simplex type 1, from an experiment comparing the composition of the invention (Example 1) with a composition also comprising hydrocortisone and acyclovir but prepared according to Example 3 of our
25 copending application W096/24355. It will be apparent that both
compositions provide good healing but the composition of the present invention has an improved performance as regards lesion severity in the early infection. When plotted to lesion disappearance, the area under the curve for the composition of the invention is approximately 10% less than
30 that of the prior art formulation.
Figure 7 depicts lesion score as a function of days in the guinea pig model described in relation to Fig. 6 from an experiment applying the cream of
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Example 2 containing an alternative antiviral penciclovir and the glucocorticoid hydrocortisone. For comparison, a cream was prepared analogously to the method described in our copending WO 96/24355 using commercially available Denavir® (penciclovir) (SmithKiine Beecham) cream 5 and ACO 1% hydrocortisone. The composition of the invention provides significantly less severe lesions score. The placebo animals treated with the corresponding active ingredient-free carrier are also depicted in Fig 7.
Assay Example 1 10 Figures 4 and 5 are photomicrographs at 40x magnification of a composition reflecting a substantially prior art formulation (Figure 4, Comparative Example 1) and a composition of the invention (Figure 5, Example 1).
15 Referring inititiaily to Fig 5, which depicts a composition of the invention after storage at 25°C for six months, it will be apparent that the crystalline acyclovir and the globules of the oil phase are well dispersed in the aqueous phase. The appearance of this formulation after 6 month's storage is effectively identical to when the formulation was freshly prepared.
In contrast, Fig 4 depicts a 40x magnification of a formulation comprising a glucocorticoid and an nucleoside analogue antiviral agent in a carrier which is formulated in accordance with prior art techniques, namely with around 40 weight % propylene glycol. When freshly prepared, this formulation was
25 microscopically indistinguishable from the corresponding formulation in Fig 5. However, after only 3 months and 3 weeks storage at 25°C, long needle like crystals have grown in this prior art formulation. Analysis shows that these needles comprise the hydrocortisone component of the formulation which has precipitated out of solution in the oil phase, leading to
30 significantly suboptimal topically bioavailable amounts of this component in the formulation. Additionally it will also be apparent that the oil phase is less distinctly dispersed than in the micrograph of Figure 5.
16

Although the invention has been illustrated with reference to certain proposed and concrete embodiments, exemplified by the antiviral agent acyclovir, the isopropyi alkanoic acid ester IPM etc, it will be appreciated that the invention is not limited by this disclosure and extends to the spirit and scope of the accompanying claims.
17

WE CLAIM:
1. A topical composition in the form of an oil in water emulsion comprising 0.1-10% (w/w) hydrocortisone and 1-7% (w/w) of an antiviral nucleoside analogue selected from acyclovir, penciclovir or 9-(4-hydroxy-2-(hydroxymethyl)butyl)guanine in a pharmaceutical carrier comprising propylene glycol and an isopropyl C12-C22 alkanoic acid ester, characterized in that the carrier comprises, relative to the total weight of the composition, 15-25% (w/w) propylene glycol and 10-25% (w/w) of an isopropyl C12-C22 alkanoic,acid ester.
2. The composition as claimed in claim 1, wherein the carrier comprises, relative to the total weight of the composition, 18-22% (w/w), preferably 20% (w/w) propylene glycol.
3. The composition as claimed in claim 1, wherein the carrier comprises, relative to the total weight of the composition, 12-18% (w/w), preferably 15% (w/w) of an isopropyl alkanoic acid ester.
4. The composition as claimed in claim 3, wherein the isopropyl alkanoic acid ester is selected from do-decanate, myristate, palmitate, stearate, eicosanate or behenoate esters, or mixtures thereof.
5. The composition as claimed in claim 4, wherein the isopropyl alkanoic acid ester is isopropyl myristate.
6. The composition as claimed in any of the preceding claims, wherein the nucleoside analogue is acyclovir.
7. The composition as claimed in claim 6, wherein the composition comprises 4-7 % (w/w) acyclovir and 0.5-2% (w/w) hydrocortisone.
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8. The composition as claimed in claim 1, wherein the composition comprises 1-7% (w/w) penciclovir and 0.5-2% (w/w) hydrocortisone.
Dated this 26th day of April, 2001.

[DIPAK MUNDRA]
OF REMFRY 8B SAGAR
ATTORNEY FOR THE APPLICANTS
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Documents:

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in-pct-2001-00461-mum-cancelled pages(19-12-2006).pdf

in-pct-2001-00461-mum-claims(granted)-(19-12-2006).doc

in-pct-2001-00461-mum-claims(granted)-(19-12-2006).pdf

in-pct-2001-00461-mum-correspondence(20-01-2008).pdf

in-pct-2001-00461-mum-correspondence(ipo)-(18-07-2007).pdf

in-pct-2001-00461-mum-drawings(19-12-2006).pdf

in-pct-2001-00461-mum-form 13(20-01-2006).pdf

in-pct-2001-00461-mum-form 18(28-12-2005).pdf

in-pct-2001-00461-mum-form 1a(19-12-2006).pdf

in-pct-2001-00461-mum-form 2(granted)-(19-12-2006).doc

in-pct-2001-00461-mum-form 2(granted)-(19-12-2006).pdf

in-pct-2001-00461-mum-form 3(25-04-2001).pdf

in-pct-2001-00461-mum-form 5(19-12-2006).pdf

in-pct-2001-00461-mum-form-pct-ipea-409(19-12-2006).pdf

in-pct-2001-00461-mum-petition under rule 137(9-12-2006).pdf

in-pct-2001-00461-mum-power of authority(19-12-2006).pdf


Patent Number 208153
Indian Patent Application Number IN/PCT/2001/00461/MUM
PG Journal Number 32/2007
Publication Date 10-Aug-2007
Grant Date 18-Jul-2007
Date of Filing 26-Apr-2001
Name of Patentee MEDIVIR AB
Applicant Address LUNASTIGEN 7, S-141 44 HUDDINGE, SWEDEN
Inventors:
# Inventor's Name Inventor's Address
1 GUNILLA LEKARE SOLHAGSGATAN 3, S-784 50 BORLANGE, SWEDEN
PCT International Classification Number A61K 47/44
PCT International Application Number PCT/SE99/02043
PCT International Filing date 1999-11-12
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 9803929.0 1998-11-18 Sweden