AU628671B2

AU628671B2 - Non-aqueous micellar solutions of various drugs

Info

Publication number: AU628671B2
Application number: AU64533/90A
Authority: AU
Inventors: Michael John Crooks
Original assignee: Individual
Current assignee: Individual
Priority date: 1989-10-12
Filing date: 1990-10-12
Publication date: 1992-09-17
Anticipated expiration: 2010-10-12
Also published as: AU6453390A

Description

0 861w FORM COMPLETE SPECIFICATION

(ORIGINAL)

For Official qJse Short Title: Int. Cl: Application Number: Lodged: Complete specification Lodged: Accepted% Lapsed: Publisiied: Priority: Related Art: 'TO BE COMPLETED BY APPLICANT Name of Applicant: BAN.S_1 AD-EN-T-ER-P R+&-L-TD- 29 Colwell Crescent Chatswood NSW 2067 ~I ,ci o*hddress of Applicant: -Actual Inventor: 4ddress for Service: MICHAEL JOHN CROOKS Barker, Blenkinship Associates PO Box 34 CHATSWOOD NSW 2067 Complete Specification for the invention entitled: NON-AQUEOUS MICELLAR SOLUIONS OF VARIOUS DRUGS The following statement is a full description of this inventi,'n, including the best method of performing it known to 'me: REpI ItT OF RECEIPT 1 790 1 1/: t ps. 1, 2- NON-AQUEOUS MICELLAR SOLUTIONS OF VARIOUS DRUGS The present invention relates to non-aqueous micellar solutions of anthelmintics and insect growth regulators used to enhance animal health and to a method for preparation of such solutions.

Many anthelmintics such as the Benzimidazole carbamates (BZs) Pnenothiazine or Closantel and Insect Growth Regulators (IGR's) such as Diflubenzuron are highly waterinsoluble compounds with a water solubility typically less than 1 ppm. The literature states that BZ's are only soluble in concentrated acids and IGR's are only soluble in 15 toxic solvents such as dimethylformamide or dioxane.

Closantel is only soluble in concentrated alkali.

iS mo U i ::2o20 4 I* 55 ',25 Because of the low solubility of these compounds they are generally administered in animal health in the forLn of suspensions; that is a pnysical dispersion of fine particles of the compound (usually 10-50 um) in an aqueous base (in the case of BZ's) or an aqueous or oily base (in the case of IGR's). Up until now the route of administration of the BZ's has been oral in sheep, horses, goats, cats and dogs and oral or intraruminal injection in cattle. In all cases the absocbtion of the BZ's is poor, it may be as low as in monogastric species, and only up to 50% in ruminants where the rumen aids in the absorbtion process. The ii ii 0~ -3achievement of peak plasma levels however is slow and variable from animal to animal. Anthelmintic activity is related to plasma concentration of the BZ and thus the higher the plasma level peak the greater the activity. In practice oral suspensions are given at a much higher dosage than is necessary to achieve reasonable plasma levels and the majority of the dose is excreted in the faeces unaDsoroed. In the case of some BZ's such as fenbendazole and albendazole, some of the metabolites have anthelmintic activity. A metabolite of fenbendazole is oxfendazole which is sold commercially. In the case of mebendazole only the parent compound has anthelmintic activity.

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0 0* *0 0 *0 15 00wo 04 0 1 **2 i 0 '0 0 0 •B 00 S, In monogastric species such as the dog the BZ's are the drug of choice for some worms such as hydutids but the absorbtion is so poor that dosage with an oral suspension has to be given over a five day period to achieve reasonable blood levels.

Insect growth regulators such as Diflubenzuron are being used experimentally as a spray on cattle and sheep with the aim that a residual of drug will be deposited in the animal and inhibit the maturation of insect parasites such as blowfly, lice and ticks. To achieve Lhis the drug must be absorbed across the skin and achieve skin and plasma levels.

The current formulations are suspensions generally in an

I

-4aqueous or oil base often with a carrier substance such as kaolin. The IGR is poorly absorbed from these products.

It is an object of the present invention to overcome one or more of the abovementioned disadvantages associated with existing non-water soluble Anthelmintics and Insect Growth Regulators wnen such products are applied to animals or at least to provide the market with a choice.

The present invention discloses a non-aqueous micellar solution of one or more non-water soluble Anthelmintics and/or Insect Growth Regulators in polyethoxylated castor oil and one or more co-solvents chosen from a group *15 comprising Dimethyl Sulpnoxide (DMSO), N-Methyl Pyrollidone (NMIP), Tetraglycol (TG) and Propylene Glycol (PG).

Tne present invention additionally discloses a metnod of preparing a stable non-aqueous micellar solution containing 20 one or more active ingredients in the nature of a non-water 9 9 soluble Anthelmintics or non-water soluble Insect Growth Regulators comprised of the steps of a) dissolving or dispersing the active or actives in an anhyurous solvent or solvents cnosen from the group comprising Dimethyl Sulphoxide, N-Methyl Pyrolidone,Tetraglycol and Propylene glycol; 11 49 t '9 I ti ii

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II, b) adding a surfactant in the nacure of Polyethoxylated Castor Oil or another polyethoxylated fat to the resulting mixture; c) stirring the resulting mixture whilst using ultrasonics and/or elevated temperature in order to disperse the active in the solvent/surfactant mixture whilst ensuring that tne temperature does not exceed that at which the stability of the active may be compromised; d) continuing to stir tne resulting mixture until a clear product results. The advantages of the present invention are well illustrated by the following discussion and example using carbamates and in particular Benzimidazole carbamates as an example of broad-spectrum anthelmintic drugs. By inhibiting tubulin polymerization and depending on the selective affinity and toxicity of carbamates towards different tubulins, carbamates can have anthelmintic, antifungal of even anticancer activity. Without limiting the scope of the present invention, further discussion will illustrate their anthelmintic activity.

Their almost insoluble nature in water, typically less than j.UO% W/v presents the major problem in their use.

t I t I I! 1 I I 4 Consequenty. their absorption in humans and animals is very poor and highly variable.

In order to achieve the desired anthelmintic effect, large dosages of the compounds are used resulting in a high cost of treatment. As an example the bio-availability of Mebendazole ranges from as low as 1% in dogs to 33% in pigs.

Known formulations of the compounds are in tablets, aqueous suspension, oil dispersion or suppositories.

It is known to increase the solubility of poorly water,soluble drugs by dissolving them in micelles of an aquous ,solution of surfactant. However, there is a limit to the '94t increase in solubility achievable by this method, dependant on the water-solubility of the drug, on the capacity of the micelles and on the desired consistency of tho end product.

Carbamates, when administered in suspension, are absorbed o~ t4 with fat in the gastrointestinal tract int-o lymph giving a low blood level prolonged over a sustained period. In addition the method of administration of an almost water- '4 insoluble drug itself presents problems in different species. As an example, it is difficult to drench cattle and thus the normal form of administration of a drug is by injection into tne rumen. This can be difficult 4o administer and causes trauma to the animal.

i/v Ii# -7- Car'bamates and in particular Benzimidazole carbamates are used and can be used in large dosage form because of their almost inert nature, i.e. they have low incidence of side effects giving high safety margins in dosage.

It is oovious that not withstanding the high safety margins a lower but eftective dosage is always preferred.

It has surprisingly been discovered that poorly-watersoluble drugs can have their bio-availability increased by dispersion of the drug in a non-aqueous mixture of a surfactant and a co-solvent with beating. The resultant product is free-flowing and completely miscible with water.

A concentration of 5% drug compound is easily achieved and with some drugs an even higher concentration is possible.

In this more water-soluble form the drug can be absorbed by passive diffusion into the liver. This achieves higher ttttU liver levels and consequently higher blood levels. There is potential for increased drug activity at lower dosage rates against for example liver flukes and hydatid cysts.

In addition this more water-soluble form of the drug could, allow transport of the drug across the skin and so permit administration in a pour-on formulation. Pour-on formulations are useful in treating parasites in cattle.

The fact that drugs prepared in accordance with the present 8- invention give a clear and water-soluble solution facilitates administration of the drugs by intra-muscular and/or subcutaneous injection at a diversity of sites on an animal.

The following example illustrates the present invention.

Example Albendazole (5g) in fine powder form is dispersed with vigorous stirring in 10g of DMSO (co-solvent). 85g of polyethoxylated castor oil (surfactant) is added and the S' mixture heated with stirring until a clear product results.

1,5 The resulting product is allowed to air cool.

r II Anthelmintics and Insect Growth Regulators may be applied to animals in the nature of dogs, sheep, cattle etc. either topically, orally or by subcutaneous or intramuscular 0 injection, Dependfng upon the active being utilised and tne method of application which is preferred different solvents or combinations of solvents may be utilised from the group comprising Dimothyl Sulphoxide, N-Methyl Pyrollidone, Tetraglycol and Propylene Glycol. The l m25 surfaccant Polyetnoxylated Castor Oil has been found to be most appropriate. It is desirable in order that the resulting product be of the desired viscosity that the ratio 1 *i 9 4, I I 44 154 4 4 44i 4 I

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(2 4 444 '2 .I

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of ethylene oxide to castor oil in the surfactant be between 20:1 and 60:1.

The solvent dimethyl sulphoxide is principally only of interest in relation to actives which are to be applied topically whereas N-Methyl Pyrollidone is usually the principal co- solvent utilised where the active is to be applied orally or by injection. With injectable products it is conventional wisdom to use multiple solvent systems to minimise the possioility of unwanted side-reactions or sideeftects in tne animal which could result from the use of single solvents due to the greater concentration of such solvent wnen used alone rather than in combination with other solventa. The ratio of surfactant to solvent is largely oetermined by thne affinity of tne particular active involved for the micelles in che solution and for example wnere a topical solution of Mebenzadole is being prepared using DMSO solvent and Polyethoxylated Castor Oil the ratios of Polyetnoxylated Castor Oil to co-solvent to active are 17/2/1 whereas where active ingredients such as Diflubenzuron is being utilised wnether for oral injection or topical use the optimal ratio of Polyethoxylated Castor Oil Surfactant to co-solvent to active is approximately 10/30/1, <7

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Kj~ Table 1A hereafter sets out a number of actives along with appropriate proportions of co-solvent/s and surfactgnt for, various applications.

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4. a TABLE IA OPTIMAL RATIOS OF ACTIVE TO CO-SOLVENT AND POLYETHOXYLATED CASTOR OIL AND HEATING TEMPERATURES REQUIRED

ACTIVE

4UTE oral) topical) injectable) OPTIMAL RATIO OF ACTIVE TO

TOTAL

MIXTJRL:

BY WEIGHT

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1 (Possible range of Active Content by weight) (0-10%) OPTIMAL RATIO OF CO-SOLVENT(S) TO TOTAL

MIXTURE

BY WEIGHT AMP 20, TG 10, PG DMSO 2 OPTIMAL RATIO OF POLY- ETHOXfLATED CASTOR OIL TO TOTAL

MIXIURE

BY WEIGHT (Possible range by weight) AiEATIN fEMP.

Room T.

LUXABENDAZOLE

M{EBERDAZDLE)

ALSENAZOLE!

FETBEDAZOLE/)

OKFENDAZOLE

KEBEKDAZOLE! ALB~fDAZOLE IFENfBENDAZOLEI)

OXFENDAZOLE)

FLUBEKDAZOLE

CLUSANfEt PffN0KJIAZIAE

DIFLUBENZU&ON

Of/Ti

T

(Ij-40%) (40-85%) 900 Of/T/I 0/T/I

OJTJI

(0-10%) NlMP 15 TG 15, aMP 20, 1?q NMP 10 TG 10, 500 250 (20-70%) Room T.

(20-70) Room T.

(l0-70) Room T.

O/1 NIP 8 0/TfI NMP 20, TG 10 PG 10 k -12- In all instances however the bio-availability of the active ingredient is greatly enhanced by incorporation of same into the non-aqueous micellar solution as will be observed from Cne test results set out hereafter.

TEST RESULTS In order to compare the effectiveness of a micellar preparation in accordance with the present invention containing the active anthelmintic ingredient Mebendazole the presently available commercial formulation utilising the samo active ingredient called "Telmin"TM an experiment was t"".«.devised involving sheep and tne mo!,itoring of faecal egg 4 S* count depression following treatment. The Mebendazole *4 *5 formulation in accordance with the present invention will t, hereinafter be referred to as "Nutrex".

*0*44 Tne experiment was performed in accordance with the following parameters: 4 4 32 :young lambs of mixed sex and varying between 2-8 months of age were inlecced with 1900 L3, of a BZ susceptible strain of Haemonchus contortus. Infection was by intra- Mruminal injection.

Vaecal egg counts were carried out 28 days after infection, following which sheep were allotted to groups using a method i of restricted randomisation, based on tho faecal egg counts.

anhyarous solvent or solvents chosen from the group comprising Dimethyl Sulphoxide, N-Methyl Pyrollidone, Tetraglycol and Propylene Glycol; S. ./2 -13- Treatments were then carried out at 0.85, 1.0625 and 1.328 mg/kg of mebeindazole as Telmin and 0.55, 0.6875 and 0.86 mg/kg of mebendazole as Nutrex. The dose rate was developed from an earlier experiment in which an estimate of the lowest limit of activity was sought. All treatments were administered by intra-ruminal injection.

Seven days after treatment faecal egg counts were carried out and the group mean total egg counts compared. An untreated control group was included to allow adjustment of the egg counts in treated animals.

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RESULTS

44 ,'15 Results of treatment are set out in Table 1 which shows that ce efficacy range of Telmin was from 3-90% and for Nutrex 50-86%.

In order to compare the formulations more precisely all 1,20 faecal egg counts were subjected to logarithmic transformation and the efficacy of treatment calculated.

Tne procedure also facilitated the calculation of the dose rate required for 25, 50, 75 and 100% efficacy (using linear regression analysis). The values obtained from transformed i 2 data are set out in Table II. The calculated values are included in Table III.

1 1 L r I C -I i %gj li -14- TABLE I F;8.eoai. E. CounL (egjs/g of Iaeois>, bei-ore and aftor Treatine C G~rp/N'o, Ios C AdI .CntLs -2 1.8 19 avg 3-8 7 a 9 avg I It I I *Lt t' u 1 Icl t I I. I tI A I tr S1 s 31 7-8 17 avg 211 1 12 2 1 22 avg 13 20 32 avg I 2 C) 24 8350 12250 7000 2400 7500 o t40o3 efficaoy 118 8250 12200 5500 2050 700CJ 4296 oeiso~.y 4'.9 1.5300 12000 1650 300 99 eftloacy U0,0 8550 3700 11.0 ri 0 7/500 8188 Z1 3025 incroase 12.2 2050 12250 83,50 5800 '7113 429:3 oJfV~ouy 51317 3000 20000 4500 2000 8825 Z' 7073 X OrUCi o ao y 77.0 1446 0 10400 1000 7550 0$ot 56.59 oieiouay Illso 14600 2950 *1 545 3900 200 690 2000 3300 600 10900 938 771 018 C 000 .050 ?250 200 4,0 600 350 1420) 2850 310 3508r 1.2843 9790 4039 25900 7268 3512 1537 3088 2502 3907 878 527 J.954 2093 263 1186 561.9 3732 3468 1010 34e:57 1.178 527 1758 834 823 The following statement is a full description of this inventiqn, including the best method of performing it known to me: REPRINT OF RECEIPT E"C)1 7601. 1 2/ 10 /9 0 hf rel Ir- I L :i ~myU~ nrrraruytrWCoM~-""~L~i"'i"~';~~ ~'cI-r U~1Li'~:li; i

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TAV3LX 2 EFFICACY ANALYSIS Log Trans -orin all Data and E,,:3tiiate fEIfioay GxP)e GxPost 16 439 6999 2. 595 2745 3 5804 2926 6160 145IV 6182 27 6 5804 95,1 Efficacy 6.75 53.5 4.6 76.3 90.2 83 .6 it 6 4~r 4 t t* I 4( SU M MARY 0 Sing/ kg 1.0625 1.328 E iMio 0y 6,8 49. G 900, 2 Nt tcrx 0 55mg/kg 0.8875 0.6 Efficaoy 53.5 76.3 83.8 ,r 9 u 04W4 0 TABLE III Daba From Doset espono Regression Analysis Calou ).ated Efficacy (X) 715 100 Telmin 0.8 1.17 1125) 1.30 Dose Rate (mrg/kg) Nut rex 01 0.40 O 75?1 0.5,4

N/T%

12.5 ,8o s 60.0 78.0

'N

j where the rumen aids in the absorbtion process. The f -16- INTERPRETATION OF RESULTS Using the regression equations Y (Log. efficacy) -0.99 2.2999 X (dose rate) for Telmin and Y (Log. efficacy) 1.4197 0.6075 X (dose rate) for Nutrex tne dose rates required to achieve efficacies of 75% and 100% were calculated and are set out in table III. It can oe seen that at the lowest efficacy value Nutrex achieves the result with only 12.5% of the amount of 6 mebendazole delivered by the Telmin formulation, but that at 100% efficacy the value has risen to 73% of that of Telmin.

o e *9 .5 Various Anthelmintics and insect growth regulators have been formulated in accordance with the methods and co-solvents described in this invention and a table of such actives giving the preferred method of administration as well as the t t approximate proportions of active, co-solvent and S0 Polyetnoxylated Castor Oil as well as the appropriate neating temperature is set out in Table IA hereof as aforementioned.

It will be appreciated from Table IA that each active listed in column 1 has a different affinity for the micelles created in the solvent/surfactant mix and consequently differing proportions of actives may be contained in the resulting mixture. The choice of solvent is to some extent i t LI -17dictated 'by the intended route of administration of the mixture either oral, topical or injectable). For e.:ample it can be seen that DMSO is only appropriate where topical administration is required whereas other solvents or mixtures of solvents are appropriate for either injectable, topical or indeed all three types of application. It will be noted that the table gives an optimal ratio of active to solvent co Polyetnoxylated Castor Oil for each active based upon weight as well as a range of feasible percentages which could be achieved in respect of the active and the .o surfactant (again by weight) depending upon the concentration of active which would be required in any particular application. The percentage of the final mixture which is comprised by surfactant may well be dictated by the required percentage of active as if a relatively high concentration of active is required then a relatively high proportion of surfactant will be required in order that the micelles can accommodate the active.

It will be noted that a number of the actives can be incorporated into a clear micellised solution at room temperature whereas others require elevated temperature. As an alternative to elevating the temperature agitation by ultrasonic means can be utilised in order to disperse the active in tte solvent/surfactant mixture. In practice it is often not necessary to resort to ultrasonic agitation as the temperatures required in most instances are not excessive.

"I patclrapiato.Tepretaeo h ia ixtue -18- In cases wnere ultrasonic agitation is utilised a small elevation in temperature is also desirable but naturally the temperature must be kept below that which would result in any degredation of the active being incorporated into the mixture.

It is envisaged that other surfactants apart from Polyethoxylated Castor Oil may be utilised as a surfactant )0 in accordance with the method disclosed in this invention ,,and for example sorbitan esters such as Tweens and Grills 0 could be utilised or indeed other polyethoxylated fats.

a B eeoe 1 i I,,r r* 14 I Ir I I 14 41C

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Claims

2. A method of preparing a stable non-aqueous solution containing one or more actives in the nature of a non- watersoluble Antheirnintics or non-wa ter soluble insect growth regulator.~ omprised of the steps of: a) dissolving or dispersing the active or actives in, an anhydrous solvent or solvents chosen from the group 4;4comprising Dimethyl Sulphoxide, N-Methyl Pyrollidonet Tetraglycol and Propylene Glycol; b) adding a surfactant in the nature of Polyethoxylated A4 4 Castor Oil or another polyethoxylated fat to the resulting mixture; c) stirring the resulting mixture whilst using ultrasonics and/or elevated temperature -in oir' to disperse the active or actives in the Si T j4 J.LIC- XcZllL LL~dL ULJJ5b j2Lupeiru in auuuruanue wli n e present- solvent/ sur factant mixture whilst ensuring that the temperature does not exceed that at which the stability of the active may be compromised; d) continuing to stir the resulting mixture until a clear product results.
3. A non-aqueous micellar solution containing Luxabendazole for administration to animals either orally, topically or by injection containing between 0- Luxabendazole by weight, between 10-40% by weight Polyethoxyjlated Castor Oil as surfactant; the balance of the mixture substantially comprising a solvent f or i.3.d from one or more of thle solvents N~-Methyl IPyroilidone, Tetraglycol and Propylene Glycol.
4. A non-aqueous micellar solution containing '4 Luxabendazole as set out in the previous claim when U prepared in accordance with the method disclosed in claim 2 hereof. A non-aqueous micollar solution containing Mebendazole, Albendazole, Eenbendazole or Oxfendazole for topical to animals containing between Mebendazole, Albende-ole, LFenbendazole or Oxfondazole by weight, between 40-85% by weight Polyethoxylated 44 -21- Castor Oil as surfactant; the balance of the mixture substantially comprising the solvent DMSO. K I- r 41 It 4 4 n 4 0 r4 44* ,'1'5 449' I* t iaO
6. A non-aqueous micellar solution containing Mebendazole, Albendazole, Fenbendazole or Oxfendazole as set out in the previous claim when prepared in accordance with the method disclosed in claim 2 nereof.
7. A non-aqueous micellar solution containing Mebendazole, Albendazole, Fenbendazole or Oxfendazole as set out in claim 5 when prepared in accordance with the method diiclosed in claim 2 hereod and wherein the beat of the mixture during the stirting step is between 80 and degrees Celsius.
8. A non-aqueous micellar solution containing Mebondazole, Albendazole, Fenbendazole or Oxfendazole for administration to animas either orally, topically or by injection containing between I-5% Mebendazole, Albendazole, Fenbendazole or Oxfendazole by weight, between 2J-50% by weight olyethoxylated Castor Oil as surfactant; the balance of the mixture substantially comprising a solvent fortned from one or more of the solvents N-Me:hyl Pyrollidone and Tetraglycol.
9. A non-aqueous micellar solution containing Mebendazole, Albendazole, Fenbandazole or Oxfendazole as set out in i: -22- the previous claim when prepared in accordance with the method disclosed in claim 2 hereof. A non-aqueous micellar solution containing Mebendazole, Albendazole, Fenbendazole or Oxfendazole as set out in claim 8 when prepared in accordance with the method disclosed in claim 2 nereof and wherein the heat which is supplied during the stirring step is between 45 and 55 degrees Celsius.
11. A non-aqueous micellar solution containing F1ubendazole ,t for administration to animals eitner orally, topically ,I or by injection containing between t-5% Flubendazoli by ::5weight, between 10-50% by weight Polyethoxylated Castor Oil as surfactant; the balance of the mixture substantially comprising a solvent formed from one or more of the solvents N-Methyl Pyrollidone, Tetraglycol *934 and Propylene Glycol. IC t I
12. A non-aqueous micellar solution containing Flubendazole as set out in the previous claim when prepared in accordance with the method disclosed in claim 2 hereof.
13. A non-aqueous micellar solution containing Closantel for administration to animals either orally, ttpically or by injection containing between 1-8% Closantel by weighb, between 10-70% by weight Polyethoxylated Castor C ~vt4~ d 4 I: -23- Oil as surfactant; the balance of the mixture substantially comprising the solvent N-Methyl Pyrollidone.
14. A non-aqueous micellar solution containing Closantel as set out in the previous claim when prepared in accordance with the method disclosed in claim 2 hereof.
15. A non-aqueous micellar solution containing so on Phenothiazine for administration to animals either 0 Sorally or by injection containing between 1-10% 4 '4 Phenothiazine by weight, between 20-70% by weight Polyetnoxylated Castor Oil as sucfactant; the balance of the mixture substantially comprising the solvent N- Methyl Pytollidone. ct S16. A non-aqueous micellar solution containing Phonothiazino as set out in the previous claim when prepared in accordance wito the method disclosed in I claim 2 toreof.
17. A non-aqueous micollar solution containing Diflubanzuron for administration to animals eithaer orally, topically or by injection containing between h Diflubeanzuron by weight, between 10-70% by weight Polyethoxylated Castor Oil as surfactant; the balance of the mixture substantially comprising a solvent ~I L <z W C10 M MI 4M z 4 C W zt W W z -40 t W W M W W W o P W W c W CO rQ t 4 0 t4 4 H 41 Z 14 44 Z 44 440 r U C C-4 b e Bc~L g24 b 0 r 14 U W~hl W c~ H d I zC jZ40 rCx. eO Pc t 4, 11.~ -24- formed from ono or more of the solvents N-Methyl Pyrollidone, Tetraglycol and Propylene Glycol.
18. A non-aqueous micellar solution containing Diflubenzuron as set out in the previous claim when prepared in accordance with the method disclosed in claim 2 hereof,
19. *I 9 4 t 15 5*4 r% 4 4 *t 4 I B4Pl A non-aqueous micellar solution of one or more non- watecooluble Anthelmintics and/or insect growth regulators in accordance with any one of claims 3-18 breof wherein the surfactant is not Polyethoxylated Castor Oil but another suitable polyethoxylated fat or sorbitan aster, such- as 'l t wioeesn ov Guis- :od i:hi 4th day of~ Octobar, 1990. BANSTSkAD-ENTR CS-M M k~s\k Cw)'r' V-0 rA4"1S