United States Patent: 5585379

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United States Patent	5,585,379
Sintov , et al.	December 17, 1996 =

Acyclovir antiviral gel composition

Abstract

An antiviral topical pharmaceutical composition for treating viral = diseases=20 of the skin or mucosa comprises a poorly soluble antiviral nucleoside=20 derivative, dispersed in an aqueous gel carrier containing a gelling = agent and a=20 water-soluble carboxylic or dicarboxylic acid salt.

Inventors:	Sintov; Amnon (Omer, = IL),=20 Uzan; Rina (Beer Sheva, IL)
Assignee:	AGIS Industries (1983) Ltd. = (Yerucham,=20 IL)
Appl. No.:	08/186,259
Filed:	December 28, = 1993

Foreign Application Priority Data


Dec 30, 1992 [IL]			104283

Current U.S. = Class: 514/263.38 ; = 424/677;=20 514/944; 514/946; 514/947

Current International = Class:=20 A61K = 31/52 (20060101); A61K=20 31/519 (20060101); A61K 47/12 (20060101); A61K=20 031/52 ()

Field of Search: = 514/49,50,256,261,944,946 424/677=20

References Cited [Referenced=20 By]

U.S. Patent Documents


4537776	August 1985	Cooper
4956184	September 1990	Kross

Foreign Patent Documents


0135312A2	Mar., 1985	EP
0397211A2	Nov., 1990	EP

Other References

Toshinobu Seki et al., Enchanced Transdermal = Delivery=20 of Zidovudine in Rats and Human Skin, Chem. Pharm. Bull., vol. 38, = No. 11,=20 1990 (pp. 3086-3089). .
Toshinobu Seki et al., Percutaneous = Absorption=20 of Azidothyumidine in Rats, International Journal of = Pharmaceutics, vol.=20 57, 1989 (pp. 73-75)..

Primary = Examiner:=20 Wilson; James O.
Attorney, Agent or Firm: Darby & = Darby=20

Claims

What is claimed is:

1. A non-emulsion antiviral topical=20 pharmaceutical composition comprising (a) 0.5-20%, based on 100% of said = composition, of a an antiviral agent comprising acyclovir, and (b) an = aqueous=20 gel carrier comprising 0.1-30% of an alkali oleate, 0-70% propylene = glycol,=20 0-50% glycerine and 0.1-5% of a gelling agent, based on 100% of said=20 composition, said acyclovir being dispersed in said carrier and said gel = forming=20 a continuous phase.

=20 Description

The present invention relates to an antiviral topical = pharmaceutical=20 composition.

More particularly, the present invention relates to = a=20 topical pharmaceutical composition containing a water-insoluble, = antiviral=20 nucleoside derivative dispersed in an aqueous gel carrier.

Many=20 antiviral nucleoside derivatives are known, which suffer from the = problem of low=20 solubility in water and almost total insolubility in hydrophobic = systems. The=20 antiviral nucleoside derivatives that are sparingly soluble in water = include:=20

1. Acyclovir [9-(2-hydroxyethoxymethyl)quanine]

2. = Vidarabine=20 (adenine arabinoside)

3. Azidothymidine (AZT, Retrovir, = Zidovudine,=20 3(-azido-3'-deoxythymidine

4. Ganciclovir=20 [9-(1,3-dihydroxy-2-propoxy)methylguanine, DHPG]

An especially = important=20 antiviral nucleoside derivative is acyclovir.

As described and = explained=20 in Israel Patent 63351:

"Acyclovir and pharmaceutically = acceptable salts=20 and esters thereof are known to have antiviral activity against various = classes=20 of DNA and RNA viruses, both in vitro and in vivo, see UK Patent No. = 1,523,865=20 (corresponding to Israel Patent 48035). In particular, the compound is = active=20 against herpes simplex virus, which causes herpetic keratitis in = rabbits,=20 herpetic encephalitis in mice, and cutaneous herpes in guinea pigs.=20

"Acyclovir suffers from the disadvantage that it has a low = solubility in=20 water and is almost totally insoluble in hydrophobic solvent systems. It = is=20 accordingly difficult to produce a topical formulation containing a = sufficiently=20 dissolved concentration of active ingredient for it to exert its full = effect and=20 also to optimise the flux of the compound into the skin. In addition to = ease of=20 release, it is also important that any formulation of a pharmaceutically = active=20 compound should be stable for long periods of time; should not lose its = potency;=20 should not discolour or form insoluble substances or complexes; and also = should=20 not be unduly irritating to the skin or mucosa."

Said patent = teaches=20 solving the above stated problem by providing an oil-in-water topical=20 pharmaceutical formulation for treating virus diseases of the skin or = mucosa, of=20 9-(2-hydroxyethoxymethyl)guanine (hereinafter referred to as acyclovir) = or a=20 pharmaceutically acceptable salt and ester thereof, having a dispersed = oil phase=20 and a continuous aqueous phase, characterised in that the aqueous phase=20 comprises water, at least 30% w/w of a water-miscible polyhydric alcohol = and=20 solubilized acyclovir or salt or ester thereof.

The present = invention=20 comes to challenge the accepted practice relating to penetration of = acyclovir=20 and other nucleoside analogues through biological membranes, using a = different=20 drug vehicle/dosage form.

As stated, acyclovir is a guanosine = analogue=20 with potent antiviral activity against herpes simplex virus. This agent = is a=20 prescription antiviral agent, currently marketed by Burroughs-Wellcome = under the=20 trade name ZOVIRAX.RTM., and is available for topical use as 5% (w/w) = ointment=20 or cream in a polyethylene glycol base.

The ability to deliver = acyclovir=20 to herpes simplex virus infections is a prerequisite of any dosage form=20 developed. There are a considerable amount of reports pointing out that = topical=20 acyclovir therapy lacks efficacy as compared to oral or parenteral=20 administrations. The lack of efficacy can most likely be related to the = poor=20 water-solubility and lipophilicity of acyclovir, resulting in its = inadequate=20 skin or mucous membrane partitioning ability.

The present = invention=20 relates to a novel composition consisting of poorly water-soluble active = ingredients in a gel formulation. Although this composition is an = aqueous gel,=20 it enhances the absorption of acyclovir and its related lipophilic = compounds to=20 the skin and through the skin, as well as mucous membranes of the nasal, = buccal,=20 sublingual and vaginal cavities. It is noteworthy that the delivery of = drugs=20 through the skin or mucous membranes offers a targeting of the drugs in = a local=20 manner to the affected area, accompanying a significant reduction in = side=20 effects and drug biodegradation.

Thus, according to the present=20 invention there is now provided an antiviral, topical pharmaceutical = composition=20 for treating viral diseases of the skin or mucosa, comprising a poorly=20 water-soluble, antiviral nucleoside derivative dispersed in an aqueous = gel=20 carrier containing a gelling agent and a carboxylic or dicarboxylic acid = salt,=20 such as a water solubilized C.sub.16 -C.sub.18 carboxylic acid salt, = e.g., a=20 linoleate, elaidate, palmitate, myristate or oleate, or a dicarboxylic = acid=20 salt, e.g., a malonate, succinate, adipate, pimelate, maleate, fumerate = or=20 azelate.

Said compositions can further comprise a carboxylic or=20 dicarboxylic acid in combination with said acid salt.

In=20 contradistinction to the approaches suggested in the prior art of = utilizing=20 water-in-oil or oil-in-water emulsions in an ointment or cream topical = delivery=20 system, it has now been found, according to the present invention, that = a gel=20 formulation containing a soluble salt of a carboxylic or dicarboxylic = acid, such=20 as sodium or potassium oleate, enhances the permeation of a poorly = absorbed drug=20 (e.g., acyclovir) through skin. A composition consisting of potassium = oleate is=20 superior over an o/w or w/o cream. As shown in the examples hereinafter, = ZOVIRAX=20 (o/w) cream delivers more drug than w/o cream. However, a continuous = aqueous=20 phase gel functions as an even more effective drug delivery system when=20 water-soluble carboxylic or dicarboxylic acid salt is included therein.=20 Therefore, the present invention in its preferred embodiment provides an = enhanced bioavailability of acyclovir and its poorly absorbed = derivatives, and=20 provides an unexpectable improved delivery of acyclovir from an aqueous = dosage=20 form to and through the skin and other mucous membranes, thus increasing = the=20 blood level of the active agent.

Thus the present invention, in=20 especially preferred embodiments, provides a topical pharmaceutical = composition=20 comprising an antiviral topical aqueous gel pharmaceutical composition = according=20 to the present invention, comprising 0.1-30% of an alkali oleate, = 0.5-20%=20 acyclovir, 0-70% propylene glycol, 0-50% glycerine and 0.1-5% of a = gelling=20 agent.

Preferably, said antiviral topical aqueous gel = pharamaceutical=20 composition will also comprise a polyhydroxy compound of the type known = in the=20 art such as glycerine, propylene glycol and polyethylene glycol. =

While=20 the invention will now be described in connection with certain preferred = embodiments in the following examples so that aspects thereof may be = more fully=20 understood and appreciated, it is not intended to limit the invention to = these=20 particular embodiments. On the contrary, it is intended to cover all=20 alternatives, modifications and equivalents as may be included within = the scope=20 of the invention as defined by the appended claims. Thus, the following = examples=20 which include preferred embodiments will serve to illustrate the = practice of=20 this invention, it being understood that the particulars shown are by = way of=20 example and for purposes of illustrative discussion of preferred = embodiments of=20 the present invention only and are presented in the cause of providing = what is=20 believed to be the most useful and readily understood description of = formulation=20 procedures as well as of the principles and conceptual aspects of the = invention.=20

In the following examples and comparative examples, tradenames = and/or=20 trademarks will be used to indicate components of compositions instead = of the=20 chemical names, according to the following key:

1.=20 NIPAGIN.TM.--ethylparaben, 4-hydroxybenzoic acid ethyl ester

2.=20 NAPASOL.TM.--propylparaben, 4-hydroxybenzoic acid propyl ester =

3.=20 CARBOPOL.TM. 940--carbomer, carboxyvinyl polymer, carboxypolymethylene=20

4. LUTROL .TM. F-127--poloxamer 407, polyethylenepolypropylene = glycols=20

5. METHOCEL K 15M--Hydroxypropyl methylcellulose

6.=20 TRANSCUTOL.TM.--ethoxy di-glycol

7. DRAGOSAN.TM. W/O--a mixture = of=20 sorbitan isostearate, hydrogenated castor oil, ceresin, beeswax and = mineral oil=20

8. VESTAN.TM. 50--mineral oil

9. MYGLOIL.TM.=20 812--caprylic/capric acids

10. DRAGOXAT.TM. EH--octyldodecyl = octanoate=20

COMPARATIVE EXAMPLE 1

a) The objective of the present = study was=20 to compare several acyclovir gels and one w/o cream that were formulated = in our=20 laboratory with 5% ZOVIRAX (o/w) cream (Burroughs-Wellcome, North = Carolina), in=20 their ability to deliver the drug transdermally. The gels and the w/o = cream were=20 physically acceptable as topical preparations and could challenge the = present=20 patents, if they would deliver the drug effectively. That was, = basically, the=20 goal of the present study.

b) The formulations were prepared and = sent to=20 an independent laboratory for transdermal assessment in two separated=20 experiments. The first experiment was performed with formulations = designated=20 AGD2110, AGD2210, AGD21T10, AGD22T10 and a commercial ZOVIRAX cream = (D8289). All=20 these formulations were radiolabeled under gentle heating with 0.04 mCi = of=20 tritiated acyclovir per 5g of the gel. The second experiment was = conducted with=20 formulations designated AGD37, AGD38A, ZOVIRAX and ACD03. All = preparations were=20 tested for acyclovir permeation through hairless rat skin in a diffusion = cell=20 system. The permeated acyclovir was analyzed in the first experiment by=20 measuring the radioactivity (in dpm/mg), and in the second experiment by = HPLC.=20 Only product ACD03, from which a 5 g specimen was taken and radiolabeled = (without heating), was analyzed by the two methods.

c. = Formulations:=20

______________________________________ Conc., %=20 ______________________________________ AGD 21A 22A 21A-3 22A-3 = Ingredients=20 (2110) (2210) (21T10) (22T10) 37 38A = ______________________________________=20 Acyclovir mic.** 5 5 5 5 5.3* 5.3* Purified Water 60 66.6 55 61.6 35 = 45.3=20 Propyl. Glycol 25 -- 20 -- 39.5 38 Nipagin 0.2 0.2 0.2 0.2 0.2 0.1 = Nipasol -- --=20 -- -- 0.0 0.0 Glycerine 6.6 6.6 6.6 6.6 -- -- Cyclodextrine 1.6 -- 1.6 = -- -- --=20 Carbopol 940 0.8 0.8 0.8 0.8 -- -- Lutrol F-127 -- -- -- -- 20 -- Pot. = oleate=20 40% -- -- -- -- -- 7 Methocel-K 15M -- -- -- -- -- 1.5 citric acid 20% = -- -- --=20 -- -- 2.7 NaOH 20% 0.8 0.8 0.8 0.8 -- -- Transcutol -- -- 10 10 -- -- = Alcohol=20 (ethanol) -- 20 -- 15 -- -- ______________________________________ = Ingredients=20 ACD 03 ______________________________________ Phase A: Dragosan w/o 8 = Vestan-50=20 6 Mygloil-812 10 Dragoxat EH 4 Nipasol 0.0 Phase B: Acyclovir mic. 0.5 = Purified=20 water 63 MgSO.sub.4.7H.sub.2 O 0.7 Propyl. glycol 3 Nipagin 0.1 Phase C: = Acyclovir mic 4.7 ______________________________________ *A correction = was made=20 in accordance to the material's assay. **Resfar R51209-021

d)=20 Manufacturing Procedure:

Formulations containing glycerine were = prepared=20 by dispersing acyclovir in the glycerine, and mixing this paste with an = aqueous=20 solution of the other ingredients. Small portions of acyclovir (16%) = were=20 dissolved in the aqueous solution by using an appropriate amount of = sodium=20 hydroxide. The last step was an addition of carbopol and mixing until an = homogeneous gel was obtained.

Formulation AGD37 and AGD38A were = prepared=20 by dispersing the acyclovir in propylene glycol (and potassium oleate as = in=20 AGD38A). Then, the aqueous solution containing the preservative was = added and=20 mixed followed by a subsequent addition of the gelling agent. The pH was = adjusted, if necessary, to 7-8.

The w/o cream (ACD03) was = prepared as=20 follows:

1. Phase A was heated while stirring at 80.degree. C.=20

2. Phase B was prepared by dissolving nipagin and magnesium = sulphate in=20 the 80.degree. C. preheated water. While stirring, propylene glycol and = the=20 small portion of acyclovir were added and dissolved.

3. At = 80.degree. C.=20 phase B was emulsified in phase A.

4. On cooling to 50.degree. = C., the=20 acyclovir (phase C) was added, mixed and the cream was homogenized. =

e)=20 In-vitro Skin Permeability of Acyclovir:

Diffusion cells: The=20 permeability of hairless rat skin to acyclovir was measured in vitro = using=20 diffusion cells. The diffusion area was 2.54 cm.sup.2, and the donor = compartment=20 volume was 8 ml. The solutions in the donor side were stirred by = externally=20 driven, teflon-coated magnetic bars. Half of the cells were immersed in = a=20 37.degree. C.-water bath for the whole experiment. In the first = experiment, 6=20 diffusion cells were used for each formulation, while in the second = experiment=20 only 3 were employed.

Skin preparation: Full-thickness hairless = rat (5-6=20 wks nude rats, Hyfac Credo, Orleans, France) skin was excised from the = fresh=20 carcasses of animals (abdominal side only) sacrificed with chloroform.=20 Subcutaneous fat was removed with a scalpel and the skin was mounted in=20 diffusion cells. The abdominal skin of each animal was placed with the = stratum=20 corneum facing up, and five donor chambers were attached by adhering = their edges=20 using cyanoacrylate glue. The excess skin was trimmed off and the = receiver=20 chamber, defined as the side facing the dermis, was conncected and = filled with=20 purified water.

Permeation: After 4 hours of the skin hydration=20 performed at 37.degree. C. in a water bath, the water was removed from = the=20 cells. Cream or gel specimens (100-200 mg) were accurately weighed on = the skin=20 in the donor compartments, and phosphate buffer (0.05M, pH=3D7.4) = containing=20 penicillin/streptomycin (Sigma. 10 ml sol./1 liter) was filled in the = received=20 sides. Cells used for the radiolabeled preparations were filled with = purified=20 water containing penicillin/streptomycin and 0.5% human serum albumin = (Sigma).=20 Samples (2 ml) were withdrawn from the receiver solution at = predetermined time=20 intervals and the cells were replenished to 8 ml with a fresh solution. = The=20 careful addition of solution into the receiver compartment took place in = order=20 to avoid air trapping beneath the dermis.

f) Calculations: =

As=20 the result of large-volume sampling from the receiver solution and = replacing=20 with equal volumes, the solution was constantly diluted. Taking this = into=20 account, cumulative drug permeation (Q.sub.t) was calculated from the = following=20 equation: ##EQU1## where C.sub.t is the drug concentration of the = receiver=20 solution at each sampling time point, C.sub.i is the drug concentration = of the=20 i-th sample, V.sub.r and V.sub.s are the volumes of the receiver = solution (ml)=20 and the sample (2 ml), respectively. Data was expressed as the = cumulative=20 acyclovir permeation per unit of skin surface area, Q.sub.t /S (S=3D2.54 = cm.sup.2).

g) Analytical Techniques:

Analysis of = tritium-labeled=20 acyclovir: Specific activity and consistency of the radiolabeled drug in = formulations were first checked by serial sampling (200 mg.times.5) and=20 measurement of radioactivity in a liquid scintillation counter. Each one = of the=20 samples taken from the receiver chambers were divided into two specimens = of=20 about 1 ml which were accurately weighed in the scintillation vials. = Then, vials=20 were filled with scintillation liquid and radioactivity in dpm was = counted.=20

Acyclovir concentration (mg/g solution) in the receiver chamber = at each=20 sampling point (C.sub.t) was calculated as follows: ##EQU2## where: = A.sub.1 and=20 A.sub.2 are the counts (in dpm) of each 1-ml specimen, and W.sub.1 and = W.sub.2=20 are the weights in g of the specimens. The specific activity (SPA) of = the active=20 principal is expressed as the dpm counts of 1 mg of acyclovir in a = homogeneous=20 formulation. Tables I(a-f) present the calculation of the specific = activity=20 values of radiolabeled formulation.

HPLC analysis of acylovir: = 40 .mu.l=20 of phosphoric acid were added into vials containing the 2-ml samples, = and the=20 mixtures were vortexed. Aliquots of 20 .mu.l from each vial were = injected into=20 the HPLC system (Waters Model 501, Milford, Mass., U.S.A.), which was = equipped=20 with a prepared C.sub.18 column (Lichrospher 60 RP-select B, 5 .mu.m,=20 125.times.4mm). The detection of acyclovir was carried out at 254 nm = with Waters=20 484 variable wavelength detector. Data was recorded on a Waters 740 Data = Module=20 single-channel integrator. The samples were chromatographed using an = isocratic=20 mobile phase consisting of a phosphate buffer (0.05M Na.sub.2 HPO.sub.4, = pH=3D2.5=20 adjusted with phosphoric acid). A flow rate of 1.3 ml/min was used. The = data was=20 analyzed using an eight-point calibration curve which was run for every = series=20 of chromatographed samples. Plots of the calibration curves [peak area = versus=20 drug concentration] over the range 1-40 .mu.g/ml were linear = (r=3D0.998). The=20 lower limit of detection was 10 ng per injection.

h) Results:=20

Tables 2-6 represent the results of the first experiment. It is = clear=20 from this data that ZOVIRAX cream was superior to these gel = formulations. After=20 50 hours, all gels released to the receiver solution very low amounts of = acyclovir (10-40 .mu.g/cm.sup.2, while ZOVIRAX delivered 510 = .mu.g/cm.sup.2).=20 ZOVIRAX cream, however, demonstrated an unusual nonlinear permeation = profile,=20 that was repeated and confirmed further on Tables 6 (Radioactivity) and = 8 (HPLC=20 analysis).

Table 2 shows the permeation profile of the=20 acyclovir-containing w/o cream. As mentioned above, this work was done=20 separately from the other radiolabeled formulations. A difference = between the=20 results of the in vitro test obtained from ZOVIRAX and the w/o cream was = noted=20 after 24 hours. It should be noted that results from the radiolabeled = ZOVIRAX=20 cream were achieved about 3 months prior to the labeled w/o cream. = Furthermore,=20 the methods of dispersing the tritium-labeled acyclovir in the two cream = products were different, and might have determined if tritiated = acyclovir did=20 reflect the "cold" drug release.

Since it was not clear if the=20 radioactivity method was reliable enough, an HPLC method was also = carried out.=20 Tables 8 and 9 present the significant difference between the ZOVIRAX = cream and=20 the w/o cream in delivering acyclovir, and reflect the inaccuracy of the = radiolabeling techniques. According to the data achieved by the HPLC = method,=20 ZOVIRAX o/w cream is superior as a topical drug delivery system to the = w/o=20 cream, but is comparable to the gel formulation AGD38A and even inferior = (see=20 Tables 8, 11 and 12).

As already mentioned and as it is shown in = Tables=20 8 and 11, the permeation profile of the acyclovir demonstrated by = ZOVIRAX cream=20 was found to be nonlinear--an unusual and undesired phenomenon. Usually, = it=20 takes 4 to 6 hours for many drugs to reach a steady state flux after the = onset=20 of the system application on the surface of the skin. This lag-time is = actually=20 the time needed for drug to diffuse across the stratum corneum barrier. = When the=20 delivery sysem is removed (i.e., wiping or washing), appreciate amount = of drug=20 molecules may remain in the stratum corneum and cause a reservoir effect = for=20 many hours after the medication. With regard to the ZOVIRAX cream, the = steady=20 state flux is not reached and the reservoir effect may not exist, if the = cream=20 is incidently wiped. Therefore, skin application of ZOVIRAX cream might = not be=20 as good as the proposed gel AGD38A, which demonstrated higher in vitro = acyclovir=20 permeation after a short lag-time with a constant drug delivery rate. =

i)=20 Conclusion:

1. The incorporation of potassium oleate in gel = formulation=20 AGD38A, significantly affected the skin permeability to acyclovir. =

2.=20 ZOVIRAX cream, which was used as a reference product in these = experiments,=20 proved to deliver the drug transdermally much better than all = formulations=20 tested except the oleate-containing gel. The oleate-containing gel = (AGD38A)=20 demonstrated a constant flux of acyclovir and an enhanced skin = penetration.=20

EXAMPLES 2-8

The following preferred compositions are = prepared=20 according to the present invention.=20

______________________________________ Ingredient 2 3 4 5 6 7 8=20 ______________________________________ Acyclovir 5.0 5.0 5.0 5.0 5.0 5.0 = 5.0=20 Sodium Oleate 3.0 3.0 3.0 3.0 5.0 10.0 30.0 Methocel K 1.5 1.5 1.5 1.5 = 1.5 1.5=20 1.5 Nipagin 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Nipasol 0.05 0.05 0.05 0.05 0.05 = 0.05=20 0.05 Glycerine 40.0 -- -- -- -- -- -- Propylene glycol -- 40.0 -- -- = 39.0 37.0=20 28.0 polyethylene- -- -- 40.0 -- -- -- -- glycol 400 Citric acid sol./ = 100 100=20 100 100 100 100 100 Purified water ad. = ______________________________________=20

TABLE 1 ______________________________________ WEIGHT Specific = Activity=20 SpA of acyclovir DPM (mg) (DPM/mg) (DPM/mg)=20 ______________________________________ (a) Specific activity of gel = Preoaration=20 No AGD2110 965374 119.2 8099 161980 1032035 133.5 7731 154620 952399 = 122.2 7794=20 155880 897689 106.9 8397 167940 1069639 136.0 7865 157300 Mean =3D 7977 = dpm/mg=20 Avg.: 159544 S.D.: 5457 (b) Specific activity of gel preparation No = AGD21T10=20 909327 107.7 8443 168860 971167 114.2 8504 170080 985210 123.5 7977 = 159540=20 1122679 139.5 8048 160960 919056 110.8 8295 165900 Mean =3D 8253 dpm/mg = Avg.:=20 165068 S.D.: 4680 (c) Specific activity of gel preparation No AGD2210 = 1024660=20 118.6 7967 159356 892433 119.6 7461 149236 943178 128.1 7362 147256 = 931417 115.0=20 8099 161985 925356 116.7 7929 158587 Mean =3D 7764 dpm/mg Avg.: 155284 = S.D.: 6584=20 (d) Specific activity of gel preparation No AGD22T10 1056319 125.2 8437 = 168741=20 964027 104.1 9260 185211 1178337 139.2 8465 169301 980326 107.5 9119 = 182386=20 1003463 113.3 8856 177133 Mean =3D 8828 dpm/mg Avg.: 176554 S.D.: 7465 = (e)=20 Specific activity of ZOVIRAX cream #D8289 1421278 114.5 13286 265725 = 1650828=20 127.7 12927 258547 1861945 144.7 12867 257352 1515519 111.2 13628 272575 = 1418427=20 105.8 13406 268133 Mean =3D 13223 dpm/mg Avg.: 264466 S.D.: 6450 (f) = Specific=20 activity of cream preparation No ACD03 2593503 210.3 12332 246648 = 2280941 220.6=20 10340 206794 1317710 160.9 8189 163792 1327891 181.6 7312 146243 1404385 = 175.9=20 7984 159680 Mean =3D 9231 dpm/mg Avg.: 184631 S.D.: 41436=20 ______________________________________

TABLE 2=20 ______________________________________ Cumulative permeated acyclovir = Gel=20 preparation - AGD2110 Time Q.sub.t Q.sub.t /S (h) (.mu.g) = (.mu.g/cm.sup.2) S.D=20 (n =3D 6) ______________________________________ 1.5 0.000 0.0 0.0 3 = 2.794 1.1 0.3=20 5.5 5.588 2.2 0.7 6.5 5.664 2.2 0.7 8 6.350 2.5 0.8 10 6.858 2.7 0.8 12 = 7.366=20 2.9 1.0 24 35.560 14.0 4.0 29 43.180 17.0 5.2 34 55.880 22.0 7.0 49 = 95.504 37.6=20 11.0 ______________________________________ Flux: 0.77 .+-. 0.2 = .mu.g/cm.sup.2=20 /h Lag time: 4.3 h

TABLE 3 = ______________________________________=20 Cumulative permeated acyclovir Gel preparation - AGD2210 Time Q.sub.t = Q.sub.t /S=20 (h) (.mu.g) (.mu.g/cm.sup.2) S.D (n =3D 6) = ______________________________________=20 1.5 0.000 0.0 0.0 3 5.715 2.2 0.8 6 5.690 2.2 0.8 8 8.306 3.3 1.2 10 = 10.668 4.2=20 1.5 22 21.844 8.6 3.0 24 25.146 9.9 4.0 27 29.710 11.7 4.0 34 38.862 = 15.3 5.0 46=20 55.880 22.0 8.0 ______________________________________ Flux: 0.47 .+-. = 0.2=20 .mu.g/cm.sup.2 /h Lag time: 1 h

TABLE 4=20 ______________________________________ Cumulative permeated acyclovir = Gel=20 preparation - AGD21T10 Time Q.sub.t Q.sub.t /S (h) (.mu.g) = (.mu.g/cm.sup.2) S.D=20 (n =3D 6) ______________________________________ 1.5 0.000 0.0 0.0 3 = 1.270 0.5 0.3=20 5.5 2.286 0.9 0.6 6.5 2.794 1.1 0.6 8 3.505 1.4 1.0 10 4.166 1.6 0.0 12 = 4.826=20 1.9 0.4 24 12.192 4.8 0.9 29 18.542 7.3 0.5 34 20.320 8.0 0.5 49 29.972 = 11.8 2.2=20 ______________________________________ Flux: 0.25 .+-. 0.05 = .mu.g/cm.sup.2 /h=20 Lag time: 2.4 h

TABLE 5 ______________________________________=20 Cumulative permeated acyclovir Gel preparation - GD22T10 Time Q.sub.t = Q.sub.t /S=20 (h) (.mu.g) (.mu.g/cm.sup.2) S.D (n =3D 6) = ______________________________________=20 1.5 0.000 0.0 0.0 3 2.794 1.1 0.5 5.5 5.944 2.3 1.4 6.5 5.588 2.2 1.0 8 = 5.385=20 2.1 1.4 10 7.010 2.7 0.3 12 8.636 3.9 2.5 24 26.162 10.3 3.4 29 34.798 = 13.7 3.8=20 34 39.116 15.4 4.2 49 61.468 24.2 7.0 = ______________________________________=20 Flux: 0.51 .+-. 0.2 .mu.g/cm.sup.2 /h Lag time: 2.7 h

TABLE 6=20 ______________________________________ Cumulative permeated acyclovir = ZOVIRAX=20 cream - #D8289 Time Q.sub.t Q.sub.t /S (h) (.mu.g) (.mu.g/cm.sup.2) S.D = (n =3D 6)=20 ______________________________________ 1.5 0.000 0.0 0.0 3 5.080 2.0 1.0 = 5=20 38.100 15.0 6.0 6.5 48.260 19.0 6.0 8 58.420 23.0 7.0 9 68.420 27.0 9.0 = 10=20 76.200 30.0 10.0 12 93.980 37.0 15.0 24 100.500 75.0 30.0 30 406.400 = 160.0 50.0=20 36 635.000 250.0 80.0 48 1295.400 510.0 170.0=20 ______________________________________ Flux: 9.4 .+-. 3 .mu.g/cm.sup.2 = /h Lag=20 time: 6 h

TABLE 7 ______________________________________ = Cumulative=20 permeated acyclovir Cream (w/o) - ACD03 Time Q.sub.t Q.sub.t /S (h) (mg) = (.mu.g/cm.sup.2) S.D (n =3D 3) ______________________________________ = 1.25 0.001=20 0.42 0.40 3.25 0.011 4.26 4.67 15.50 0.118 46.44 27.59 19.33 0.167 66.02 = 35.60=20 23.16 0.211 83.20 45.23 41.00 0.486 191.52 92.76=20 ______________________________________

TABLE 8=20 ______________________________________ Cumulative permeated acyclovir = (Results=20 acc. to HPLC analysis) Cream (o/w) - ZOVIRA Time Q.sub.t Q.sub.t /S (h) = (mg)=20 (.mu.g/cm.sup.2) S.D (n =3D 3) ______________________________________ 2 = 3.16 1.24=20 0.10 4 4.53 1.78 0.53 16 40.09 15.78 13.82 20 60.47 23.81 15.32 24 = 166.68 65.62=20 3.80 ______________________________________

TABLE 9=20 ______________________________________ Cumulative permeated acyclovir = (Results=20 acc. to HPLC analysis) Cream (w/o) preparation - ACD03 Time Q.sub.t = Q.sub.t /S=20 (h) (mg) (.mu.g/cm.sup.2) S.D (n =3D 3) = ______________________________________ 2=20 3.29 1.29 0.27 4 5.22 2.05 0.68 16 6.90 2.71 0.25 20 7.17 2.82 0.19 24 = 9.27 3.65=20 0.66 ______________________________________

TABLE 10=20 ______________________________________ Cumulative permeated acyclovir = (Results=20 acc. to HPLC analysis) Gel preparation - AGD37 Time Q.sub.t Q.sub.t /S = (h) (mg)=20 (.mu.g/cm.sup.2) S.D (n =3D 3) ______________________________________ 2 = 3.07 1.21=20 0.12 4 4.50 1.77 0.65 16 4.89 1.93 1.42 20 4.10 1.61 1.56 24 9.00 3.54 = 4.89=20 ______________________________________

TABLE 11=20 ______________________________________ Cumulative permeated acyclovir = (Results=20 acc. to HPLC analysis) Gel preparation - AGD38A Time Q.sub.t Q.sub.t /S = (h) (mg)=20 (.mu.g/cm.sup.2) S.D (n =3D 3) ______________________________________ 2 = 4.47 1.76=20 0.37 4 8.28 3.26 1.55 16 113.75 44.78 23.48 20 139.50 54.92 30.48 24 = 190.41=20 74.96 37.92 ______________________________________

TABLE 12=20 ______________________________________ Cumulative PERCENT of permeated = acyclovir=20 Time (h) ZOVIRAX (o/w) ACD03 (w/o) AGD38A (gel)=20 ______________________________________ 2 0.036 0.048 0.060 4 0.054 0.080 = 0.111=20 16 0.526 0.104 1.520 20 0.768 0.108 1.870 24 1.906 0.136 2.550=20 ______________________________________

Further formulation work = and in=20 vitro biological evaluation was carried out, the results of which = highlight the=20 properties of the presently claimed gel composition, and support the = advantages=20 of the invention.

In general, all formulation experiments were = performed=20 as described in Example 1 hereinabove (for gel preparations). In several = preparations, a modification was made in the manufacturing procedure. = Instead of=20 using sodium oleate as the raw material, an equivalent oleic acid was = added and=20 converted "in-process" to sodium oleate by a stochiometric amount of = sodium=20 hydroxide (see formulations AGD-57, 58, 65).

The in vitro = percutaneous=20 absorption/penetration of acyclovir from the gel or cream vehicles was = carried=20 out using Franz diffusion cell system (1.767 cm.sup.2 diffusion area, = Crown=20 Bioscientific, Inc., New Jersey, U.S.A.). Skin was excised from the = abdominal=20 side of nude mice (CD-1) purchased from Weitzmann Institute, Israel. In = some=20 experiments, hairless guinea pigs were used (males, IAF/HA-HO, Charles = River,=20 Va. U.S.A.).

The invention will now be described in connection = with=20 certain preferred embodiments with reference to the following = illustrative=20 figures so that it may be more fully understood.

With specific = reference=20 now to the figures in detail, it is stressed that the particulars shown = are by=20 way of example and for purposes of illustrative discussion of the = preferred=20 embodiments of the present invention only, and are presented in the = cause of=20 providing what is believed to be the most useful and readily understood=20 description of the principles and conceptual aspects of the invention. = In this=20 regard, no attempt is made to show structural details of the invention = in more=20 detail than is necessary for a fundamental understanding of the = invention, the=20 description taken with the drawings making apparent to those skilled in = the art=20 how the several forms of the invention may be embodied in practice . =

IN=20 THE DRAWINGS

FIG. 1 is a graph of the influence of different = levels of=20 oleic acid on acyclovir penetration across guinea pig's skin; =

FIG. 2 is=20 a graph of percutaneous permeation of acyclovir in nude mice after = application=20 of 2 gels prepared with sodium oleate and ZOVIRAX commercial cream; =

FIG.=20 3 is a graph of the influence of various sources of oleic acid/oleate in = gel=20 preparations;

FIG. 4 is a graph of the influence of two sources = of oleic=20 acid/oleate in gel preparations;

FIG. 5 is a graph of a = comparison=20 between gel RDAG-5 and ZOVIRAX commerical cream in their drug delivery=20 (permeation across skin) profiles; and

FIG. 6 is a graph of a = comparison=20 between gel AGD-65 (more Methocel K) and ZOVIRAX commercial cream in = their drug=20 delivery (permeation across skin) profiles.

The following = further=20 comparative example is to be read in conjunction with said = aforementioned=20 drawings.

COMPARATIVE EXAMPLE 9

The following further=20 formulations were manufactured and examined:=20

_________________________________________________________________= _________=20 Percentage in Formulation AGD-42 AGD- AGD- AGD- AGD- AGD- AGD- = Ingredient=20 (RDAG-2) 46 47 49 AGD-52* 53 57 AGD-58* 65 RDAG-4 RDAG-5=20 _________________________________________________________________________= _=20 Acyclovir 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Sodium oleate 5.0 = -- -- --=20 5.0 10.0 -- -- -- 5.0 -- Oleic acid** -- 3.0 -- 1.0 -- -- 4.4 4.4 4.4 -- = 4.4=20 Methocel K-15M 1.5 1.5 1.5 1.5 1.5 1.5 1.9 1.9 2.5 1.9 1.9 Nipagin 0.1 = 0.1 0.1=20 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Nipasol 0.02 0.02 0.02 0.02 0.02 0.02 = 0.02 0.02=20 0.02 0.02 0.02 Propylene glycol 38.0 40.0 40.0 40.0 50.0 50.0 so.0 50.0 = 50.0=20 50.0 50.0 NaOH 10 N sol. -- 0.67 1.4 1.1 -- -- 0.64 0.64 0.64 -- 0.64 = Citric=20 acid 20% 3.2 3.7 3.9 3.4 3.2 4.4 3.0 3.0 2.9 3.2 3.0 solution Water, up = to 100%=20 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%=20 _________________________________________________________________________= _ pH of=20 gel preparations ranged between 7.3-7.7. *AGD52 was similar to RDAG4, = except=20 that Methocel had been increased to 1.9%. AGD58 was similar to RDAG5, = except=20 that a different source of oleic acid was used. **The source of oleic = acid was=20 Oleofina, except AGD58 (Mallinkrodt), AGD6 and RDAG5 (Unichem). =

A.=20 Influence of the Oleic Acid and Its Concentration on Alcyclovir = Permeated=20 Amounts

Formulations AGD-46, 49 and 47 were examined together = and=20 compared in two sets of in vitro permeation experiments, using guinea = pigs.=20 AGD-46 contained 3% oleic acid; AGD-49 contained 1% oleic acid; while = AGD-47=20 contained no oleic acid but all other ingredients were identical (pH = values were=20 7.54, 7.58 and 7.4, respectively). FIG. 1 shows the obtained penetration = pattens, indicating the significance of oleic acid/sodium oleate as the=20 penetration enhancer in the gel vehicle. Preparation with 3% oleic acid=20 demonstrated higher permeated levels of acyclovir as compared with the=20 preparation with 1% oleic acid. Almost no permeation was observed with = the=20 vehicle that did not contain oleic acid/oleate at all.

B. Use of = Sodium=20 Oleate as the Starting Raw Material in the Formulation Procedure =

FIG. 2=20 shows the penetration patterns of two gel formulations containing 5% and = 10%=20 sodium oleate, as compared with the marketed product, ZOVIRAX cream. It = has been=20 proven again that the gel vehicle of the present invention is superior = over the=20 commercial cream. The results demonstrated that the rise in oleate level = from 5%=20 to 10% did not concomitantly increase the percutaneous permeation, but = even=20 somewhat decreased the penetration. The decrease in the amount permeated = can be=20 explained only if we can understand the mechanism by which oleic acid = enhances=20 the penetration of acyclovir. It is assumed that "oleic acid selectively = perturbs the inherent lipid structure of the stratum corneum, reducing = the=20 transition temperatures and cooperativity associated with their phase=20 properties: [Pharm. Res., Vol. 7, pp. 621-627 (1990)]. The enhanced = transport of=20 drug molecules through these interfacial "defects" may require water. = Therefore,=20 increase in oleate in the gel vehicle may exceed the critical = micellization=20 concentration (CMC), resulting in less water availability in the = interfacial=20 regions of the stratum corneum. It should be noted that, although up to = 30% of=20 oleate can be formulated in practice very easily, the appearance and = cosmetic=20 properties of the gel vehicle are different from formulae containing = less than=20 10% oleate.

C. Comparison between Formulations Containing 4.4% = of Oleic=20 Acid from Various Sources (Influence of the Material's Quality) =

Four=20 sources of oleic acid were examined: Mallinckrodt, Oleofina, Unichem and = Riedel-de-Haan (RDH-sod. oleate). All formulations tested were prepared = with=20 1.9% Methocel, a change that was made to improve the consistency of the = gel.=20 FIG. 3 shows the patterns of three formulations that were tested = simultaneously.=20 From the results, Formula AGD-58, with oleic acid obtained from = Mallinkrodt, had=20 the best performance, while AGD-57 (Oleofina) had a slightly decreased = flux.=20 Formula RDAG-4 (Oleate-RDH) exhibited a poor pattern, with no more = penetration=20 after 17 hours. FIG. 4 presents the comparison between the fourth source = of=20 oleic acid--Unichem--and the already examined RDH-oleate. Here again, = the=20 differences are clear and significant, and yet all the formulations have = better=20 penetration than the Zovirax cream.

D. The Validity of Results = with=20 Formulation RDAG-5 (Batch Manufactured for the Pre-Clinical Study), = Influence of=20 Methocel Addition, and Comparison with the ZOVIRAX Commerical Cream=20

Formulation of batch RDAG-5 (corresponding to AGD-58) was = reexamined in=20 the diffusion cell system (n=3D6), and results overlapped those obtained = previously. FIG. 5 presents these results as compared simultaneously = with=20 ZOVIRAX cream. As can be seen, the cumulative permeated amounts of = acyclovir=20 were four times higher in the gel preparation than in the commercial = cream. FIG.=20 6 presents a comparison between a gel that contained 2.5% Methocel = (instead of=20 1.9% in RDAG-5) and ZOVIRAX commercial cream. The results are not = significantly=20 different from those obtained previously (FIG. 5), indicating that = Methocel does=20 not affect the mechanism of penetration at this range of concentrations. =

COMPARATIVE EXAMPLE 10

In-Vivo Preventive Testing of = Acyclovir=20 Gel (Formula RDAG-5) in the Topical Treatment of Experimental Cutaneous = Herpes=20 Simplex Virus Type 1 (HSV-1) Infection

In a double-blind study, = the=20 efficacy of a drug-containing gel according to the present invention = (batch=20 RDAG-5) and ZOVIRAX commercial cream was evaluated as compared to a=20 non-treatment control. A guinea pig model was selected for the cutaneous = HSV-1,=20 because the model mimics the human herpes simplex labialis infection = [Hubler, et=20 al, J. Invest. Dermatol., Vol. 62, pp. 92-95 (1974)]. Forty-eight = animals (young=20 male D. Hartly guinea pig, CRL:(HA)BR strain, Charles River, Va., U.S.) = were=20 assigned to the experiment. The virus was inoculated intradermally on = three=20 locations on the back of each animal. The area into which the virus was = to be=20 inoculated was divided into three squares with a marking pen. In the = middle of=20 each area, about 20 microliters of HSV at a concentration of 106 PFU/ml = was=20 applied by 10 injections close to each other. In order to assign the = location of=20 the various treatments on each animal and to overcome any gradient = effect, a=20 latin-square design was used.

Treatment was started 2-3 hours = after=20 inoculation and consisted of three daily applications of the topical=20 preparations (about 50 mg) for a period of three days (9 treatments). = Animals=20 were inspected once daily and the lesions (or inoculated sites) were = scored in=20 the following manner:

______________________________________ = Score=20 Description ______________________________________ 0.0 No signs detected = 0.5=20 Erythema and slight edema at the site 1.0 Erythema and one or two small = vesicles=20 2.0 Erythema and numerous small vesicles 2.5 Numerous medium-sized = vesicles 3.0=20 Numerous large vesicles ______________________________________ =

In=20 addition, the number of vesicles for each site was counted and recorded. =

Results

Table 13 shows the mean and standard deviations = of the=20 scores, observed at day 2 and day 3 from inoculation. Table 14 presents = the mean=20 vesicle quantities at days 2 and 3, and Table 15 shows the combination = of the=20 two parameters, providing a more comprehensive picture of the diseased = state.=20 The results clearly demonstrate the significant superiority of the gel = over the=20 commercial cream and the non-treated control.

TABLE 13=20 ______________________________________ Mean Score Number at Each = Infection Site=20 Day 2 Day 3 ______________________________________ Control 2.063 (.+-. = 0.727)=20 1.896 (.+-. 0.928) Zovirax 2.052 (.+-. 0.604) 1.833 (.+-. 0.853) ACV Gel = 2.188=20 (.+-. 0.727) 0.677 (.+-. 0.696) ______________________________________ = ACV =3D=20 acyclovir

TABLE 14 ______________________________________ Mean = Count of=20 Vesicles at Each Infection Site Day 2 Day 3=20 ______________________________________ Control 6.167 (.+-. 3.218) 5.833 = (.+-.=20 3.328) Zovirax 5.979 (.+-. 2.957) 5.000 (.+-. 3.149) ACV Gel 5.188 (.+-. = 3.057)=20 0.854 (.+-. 2.073) ______________________________________ ACV =3D = acyclovir=20

TABLE 15 ______________________________________ Mean of Combined = Parameters (Score X Vesicles at Each Infection Site Day 2 Day 3=20 ______________________________________ Control 14.479 (.+-. 8.151) = 13.583 (.+-.=20 8.118) Zovirax 13.406 (.+-. 7.163) 11.302 (.+-. 7.963) ACV Gel 12.333 = (.+-.=20 7.563) 1.708 (.+-. 4.382) ______________________________________ ACV =3D = acyclovir=20

The gel of the present invention greatly enhances the delivery = of the=20 drug to the target site, namely, deep in skin tissues. this finding = influences=20 the efficacious administration of acyclovir for other herpes and = non-herpes=20 associated diseases. These include:

a) Post-herpetic neuralgia, = which is=20 a common cause of chronic neuropathic pain and progression of rash in = the=20 elderly population.

b) Vulvar vestibulitis in many women, who = experience=20 severe pain on vestibular touch or vaginal entry, without apparent = cause. Since=20 Friedrich [J. Reproductive Medicine, Vol. 33, pp. 514-518 (1988)] = discovered=20 that oral acyclovir has a therapeutic effect on vulvar vestibulitis, an=20 efficient topical application, such as with the gel of the invention, = provides=20 more beneficial local therapy with reduced dosage and minimized adverse=20 reactions.

c) Recurrent genital herpes.

It will be = evident to=20 those skilled in the art that the invention is not limited to the = details of the=20 foregoing illustrative examples and that the present invention may be = embodied=20 in other specific forms without departing from the essential attributes = thereof,=20 and it is therefore desired that the present embodiments and examples be = considered in all respects as illustrative and not restrictive, = reference being=20 made to the appended claims, rather than to the foregoing description, = and all=20 changes which come within the meaning and range of equivalency of the = claims are=20 therefore intended to be embraced therein.

* * * * *

=20

=20

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Current U.S. = Class:	514/263.38 ; = 424/677;=20 514/944; 514/946; 514/947
Current International = Class:=20	A61K = 31/52 (20060101); A61K=20 31/519 (20060101); A61K 47/12 (20060101); A61K=20 031/52 ()
Field of Search: =	514/49,50,256,261,944,946 424/677=20