AU629201B2 - Process for manufacturing veterinary products being suitable particularly for treatment of mastitis and the product thus obtained - Google Patents

Description

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To: THE COMMISSIONER OF PATENTS.

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OPI DATE 25/08/89 wc AOJP DATE 28/09/89 APPLN. ID 30516 89 PCT NUMBER PCT/HU89/00004 PCIr INTERNATIONAL APPLICATION PUBLISHMb UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/ 06955 A61K 9/06, 35/64 Al (43) International Publication Date: 10 August 1989 (10.08.89) (21) International Application Number: PCT/HU89/00004 (74) Agent: PATENT AND LAW OFFICE FOR INTER- NATIONAL AFFAIRS; P.O. Box 360, H-1369 Bu- (22) International Filing Date: 8 February 1989 (08.02,89) dapest (HU).

(31) Priority Application Number: 551/88 (81) Designated States: AT (Europeon patent), AU, BE (European patent), BG, BR, CH (European patent), DE (32) Priority Date: 8 February 1988 (08.02.88) (European patent), DK, FI, FR (European patent), GB (European patent), IT (European patent), LU (33) Priority Country: HU (European patent), NL (European patent), NO, RO, SE (European patent), SU, US.

(71) Applicant (for all designated States except US): UN- 1PHARMART [HU/HU]; Korong u, 29, H-1145 Bu- Published dapest Witi international search report.

(72) Inventors; and Inventors/Applicants (for US only) KOVACS, Frigyes [HU/HU]; Beke u. 6, H-3232 MAtrafilred LAM- MEL, Andrs [HU/HU]: Virag u, H-3214 Nagyrde KUBANYI, G6za [HU/HU]; Flresz u, 92/b, H- Lukacs u, 1, H-1023 Budapest (HU), (54)Title: PROCESS FOR MANUFACTURING VETERINARY PRODUCTS BEING SUITABLE PARTICULARLY FOR TREATMENT OF MASTITIS AND THE PRODUCT THUS OBTAINED (57) Abstract The subject of the present invention is a process for manufacturing veterinary products suitable first of ll for the treatment of Mastitis. The process is characterized in that the active ingredient is soft propolis of 0,5 to 10 v/v made b/ cold process and one or two emulsifier/emulsifierS of low HLB-value in a quantity of 1 to 6 v/v each, in a given case one emulsifier of high HLB-value further one or more additive/additives selected for practical purposes from among the following: the usual ointment or enulsion basic inaterials, auxiliary materials influencing viscosity and afterlubricants, inert hydrophilous solvents, pH regulators is/are mixed together A further subject of the present invention is a veterinary preparation suitable first of all for the treatment of Mastitis, especially in the form of udder infusion, ointment, emulsion and the like, The preparation is characterized by containing as active Ingredient soft propolis of0,5 to 10 v/v made by cold process and one or two emulsifier/emulsifiers of low HLB.value in a quantity of I to 6 v/v each, in a given case one emulsifier of high HLB-value further one or more additive/additives selected for practical purposes from among the following; the usual ointment or emulsion basic materials, auxiliary materials influencing viscosity and after-lubricants, inert hydrophilous solvents, pH regulators.

i S WO 89/06955 PCT/HU89/00004

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PROCESS FOR MANUFACTURING VETERINARY PRODUCTS BEING SUITABLE PARTICULARLY FOR TREATMENT OF MASTITIS AND THE PRODUCT THUS OBTAINED Technical field The subject of the invention is a process for manufacturing veterinary products e. g. udder infusion, ointment, emulsion, etc.

suitable particularly for treatment of rmastitis and the product itself.

Background art It is well known that mastitis according to scientific literature available up to now is a polyfactorial /polyethiological/ illness, that's why no prevention and treatment resp. with general effectiveness is possible.

Mastitis affects in most cases cows with bij, milk production which is easy to understand knowing the fact that production of 1 litre of milk requires 300 to 500 litres of blood to flow through the lactiferous gland. The new process is of great importance since mastitis according to the opinion of several authors causes more economic loss than all other infectious and parasitic diseases all together.

This statement is proved and confirmed by the data on loss.

The yearly loss in Hungary is estimated reach HUF 720 to 750 millions at present, the same in the USA amounts to US D 1294 millions which means a yearly loss of USD 150 to 300 per cow, caused by mastitits. The yearly loss caused by this disease in European countries is estimated as follows: France: FRF 5 thousand million; United Kingdom: GBP millions; GDR: DDM 170 millions; GFR: 450 millions.

Garget generally dec:reases the total milk production by 11 in each country.

2 The damages are listed below: milk yield falls by 10 to the quality of milk worsens; treatment costs are considerably high; after treatment the milk has to be destroyed where products from micro organisms or antibiotic treatment of microorganisms remain in the milk; the value of breeding animal degrades to that of beef-cattle; forced killing and death are more frequent; cows with garget have to be separated; puriod of milk production becomes shorter; there is a great hazard for healthy animals to get infected; human beings might be affected, too.

The frequency and appearance of garqets are highly influenced by the prevailing conditions of animal keeping, feeding and hygiene and also by the breeder of animals 1 5 himself. This means that the appearance and severity of garget varies a lot with dairies and individuals depending on the conditions mentioned. The pathogens causing infection such as bacteria, fungi, viruses, etc. reach the lacteal tracks of the udder in most cases via galactogen and the parenchyme of the udder respectively bringing on disease of varying severity, depending on their pathogenicity and resistance of the organism and or the udder respectively.

Local medical treatment is generally applied in case of disease manifesting itself lby clinical symptoms. Both the Hungarian and foreign preparations known so far contain some potent antibiotics or combinations of antibiotics and sulfonamide. Should Ssuch preparations be applied a waiting time of 3 to 7 days from the last treatment or S 25 more is necessary, subject to the sort of preparation, in order to obtain milk fit for human consumption from the diseased udder or udder-section. In that it is undesirable and possibly dangerous to consume milk from cows which have been treated by these agents since the agents themselves or metabolites therefrom are still present in the milk.

The aim of the invention is to provide a process for production of veterinary preparations eliminating the above mentioned disadvantages, for treatment of mastitis and the product thus obtained.

We have recognized that preparations containing soft propolis as active ingredient in an udder infusion, emulsion or ointment guarantees at least the same result i i 4 li i~Ltlll~- ~i 3 in prevention and treatment of the disease as preparations containing antibiotics or sulfonamide eliminating, however, the disadvantage referred to above.

In order to produce such preparations we had to find out the special emulsiiers enabling the manufacture of a stable preparation of proper quality and to work out a seemingly "passive emulsion system" which becomes activated when meeting the milk in the diseased udder-section, further we had to make allowances for the natural emulsifiers of milk and also for the capacity conditions of the o/w emulsifier owing to the reduced fat content of the infected milk.

The propolis used in the instant invention should be handled with care and therefore materials and additives selected for use with the instant invention should be selected so that the emulsion is stable and the active ingreCG.nt is released in a continuous and uniform way. This is due to the highly hydrophobic nature of propolis.

The presence of an o/w emulsifier having a high HLB value (9 to 16) is essential to the invention because this enables the active ingredient to be released. The HLB value refers to Hydrophilic Lipophilic Balance.

In the case of an infusion, in use the infusion encounters a large volume of milk in the udder.

In order that 'he active ingredient be released the o/w emulsion with a high HLB value interacts with the milk components to form a phase inversion at the interface where milk and infusion meets. This leads to a continuous and uniform release of the active ingredient.

At least one w/o emulsifier with a low HLB value is also present in the preparation. This 20 enables a film to be formed at the surface phase, Preferably two emulsifiers with low HLB values can be employed.

in a most preferred embodiment the invention is prepared by dissolving two w/o emulsifiers of low HLB value (ie. 3 to 8) in a water bath, 1-6 v/v each, in ointment-emulsion white vaseline -liquid paraffin) with basic material of ideally selected proportion. For practical purposes we apply two S 2 5 emulsifiers. These are alcohols lanal, consisting of wool fat mixed with cholesterol or other alcohols with at least 28% sterol calculated o)n the basis of the cholesterol, and alcohols cetylstearylicum So"" consisting of cetostearolum, cetostearylicum. The alcohols lanal at 2% v/v and the alcohol 0: cetylstearylicum at 1 to 2% v/v. On the edge surface of the phases the two emulsifiers constitute a stable dense film. The above basic material emulsifier system is sufficient for emulsification of the 3 0 soft propolis active Ingredient of thin sour cream substance, rather of hydrophilous character of 0,5 O. 0v/v%.

S S ooo 4 An udder infusion of 2 decilitres is sufficient for several litres of milk in the milk pelvis of both the milkers and non-milkers, on making udder infusion one has to mix the soft propolis of 1-6 v/v% (-optimally 3-4 and an emulsifier of high HLB value of o/vWtype, optimally with sorboxetene (polysorbate 20) derivative thus emulsifying it in the above basic material containing emulsifier or a pair of type o/w' emulsifiers. The preparation containing complex emulsifier is to be introduced from a disposable plastic appliance into the diseased udder-section where it meets the milk and becomes activated.

Influenced by the o/W emulsifier the complicated, mixed phosphatide-albumin 1 0 complex being present in the milk in a minimal surplus under the influence of the movement of the cow and that of the intensity of the biological motion of the udder a phase inversion takes place at udder-temperature and a release of a steady, good active ingredient is ensured from the basic material dispergated in this way. All this is definitely proved by clinical results. The selection of the applied emulsifiers and their 1 5 proportion have considerably been influenced by the fundamental realization according to which the fat content of the milk of a cow with garget does not reach the average value and in this case the capacity surplus of the biological emulsifier (mixed phosphatldealbumin complex) can also be taken into consideration.

The presence of Polysorbate 20 in a capacity of an o/ emulsifier is 20 seemingly "unnecessary" to emulsifying liquid propolis-extract, to stabllizing the system, I.e. to formulating the udder infusion. However, on meeting the milk i: will *le: play an essential part, becoming activated at that time.

Only an insignificant quantity of liquid paraffin (0 to 2 separates from the viscous or thin ointment-like emulsion under special storage conditions at 25 extreme temperature intervals if aerosil is added to the preparation, In a preferred embodiment the preparation of the invention is that its active ingredient is soft propolis of 0,5-10 further containing one or more emulsifiers and further one or more additives selected (for practical purposes) from among the following: the usual basic materials of ointment and emulsion restively, auxiliary materials which influence viscosity and are after-lubricant, inert hydrophilous solvents and pH-regulators.

Best mode for carrying out the invention The details of the invention are demonstrated with the following examples: Example 1 Udder infusion of propolis-content for treatment and prevention respectively of acute, subacute and chronic mastitis of cattle.

The following substances have been used for making udder infusion: Standard propolis concentrate (soft prop'.!s) 15,0 g Polyoxaethen 400 30,0 g Lanalcolum 15,0 g Cetylstearyl alcohol 7,5 g Petroleum Jelly 227,5 g 1 0 Polysorbatum 24,0 g Liquid Paraffin 431,0 g The components listed above yield udder infusion with a propolis content of 2 v/v%.

To yield an udder infusion with propolis content of 6 v/v the components 1 5 mentioned below have been used: Standards propolis concentrate (soft propolis) 45,0 g Lanalcolum 15,0 g Cetylstearyl alcohol 7,5 g Petroleum Jelly 227,5 g Polysorbatum 24,0 g Liquid Paraffin 431,0 g The total weight of the components used in both cases: 750,0 g.

Lanalcolum, cetylstearyl alcohol and petroleum Jelly were melted on a water bath, while being stirred followed by a three-hour.sterilization at 140°C and stirring 25 (under aseptic conditions) until cool. Homogenization was effected after 24 hours, Polysorbat was emulsified in the newly formed basic ointment (still under aseptic conditions) then propolis added In parts and liquid paraffin In more parts with Intensive stirring. Sterilized at 140°C for 3 hours was performed and followed by homogenizatfon. The viscous emulsion was introduced while stirring by weighing it into 3 0 the container compartment of a disposable plastic syringe and shut off by a piston. After capping packing of the individual units took place. The plastic syringe was cleaned and sterilized under aseptic conditions suitable for storage of medical preparations.

Example 2 Emulsion ointment of soft propolls content Soft propolis 10 g

S..

S

S

S.

S

S

S.

I I Propyleneglycol 20 g Lanalcolum 50 g Cetylstearyl Alcohol 30 g Petroleum Jelly 640 g Liquid Paraffin 200 g Castor Oil 50 g Example 3 Standard propolis concentrate (soft propolis) 15 g Lanalcolum 25 g 1 0 Petroleum Jelly 265 g Polysorbatum 24 g Liquid Paraffin 421 g Example 4 Standard propolis concentrate (soft propolis) 15 g 1 5 Cetylstearyl alcohol 25 g Petroleum Jelly 265 g Polysorbatum 24 g Liquid Paraffin 4;1 g Method of preparing S 20 Soft propolis 0,5-10 v/v% (optimally 6 v/v was mixed with an indifferent solvent of hydrophilous character (propyleneglycol polloxaeten 400) which is for "i practical purposes propyleneglycol.

S In the mixture of petroleum Jelly and liquid paraffin of 5-30 v/v% (for practical purposes 20 v/v one or two emulsifiers which are soluble in 2 5 hydrocarbons and of low HLB value were dissolved on a water bath, in a proportion of 2-6 v/v each. A pair of emulsifiers matching each other ideally and constituting a dense, homogeneous film can be used, for example lanalcolum and cetylstearyl alcohol in a proportion of 5:3 v/v This basic ointment is stirred until cool and the day after homogenized. The homogeneous mixture of soft propolis and propyleneglycol are then emulsified.

The preparations made according to the invention (udder infusion, ointment and similar) have numerous advantages as far as efficiency and economy is concerned compared to the preparations containing specific active ingredients used so far.

The advantages are as follows: the active ingredient content is bactericidal, viricidal and fungicidal or a quite wide scale; there is no food hygiene waiting time since the active ingredient is natural substance; the preparations have a significant antiphlogistic, local anaesthetic, epidermidalizationing and an analgesic effects; within 6 hours after use of the preparations the milk produced from the treated udder does not contain germicidal substances. Thus the value of milk does not drop.

1 0 Practical use of the preparations according to the invention have unambiguously proved advantages as described above, Of course, the usual basic principles on use for the treatment of mastitis have to be considered, namely: medical treatment is to be started at the earliest possible stage of the S 15 disease; S- the treatment has to be effected with craftsmanship; S- a proper period of treatment is necessary.

Under the consideration of the said principles we tested the efficaciousness of the preparations according to the invention in ten dairy-farms of different potentiality and 20 production level f',nd the results have been compared with those of preparations with antibiotics content, used previously.

iiia The results obtained are as follows: All experimental milk-farms used the preparation uniformly, in case of peracute, acute, subacute and chronic mastitis decla'dng Itself at any stage of the 25 lactation. One dairy-farm had data of a former survey on the pathogens of garget given in the percentage of the incidence, which are the following: WO 89/06955 PCT/HU89/00004 E. colt 18,9 Str. 'uberis 1319 Str. dysgalactiao, 12;8 Str. agalactiae 2l1 St aph. aureus Staph. albus 4,3 Corynebact. pyogenes Kieb siella 4l8 Colijorm bact. 4,3 Bac, subtilis 3l2 Pseud. aeruginosa 1 ,6 Bac, cereus11 Bac. negativium Gemmiparous fuagi 4,8 100 According to the scattered bacterioloic~al results of the other milk--farms similar pathogens could be fQuand at incidences of On 32 occasions the preparation was used for inflammatory symnptomns observed in one udder-section /Paans, the sk\in of the udder, got re4\, slight fever/; no visible change of the milk could be observed yet. All udders recovered without exception after one treatment.- On 14 occasions the recovery followed after 2 treatments without any lesion of the milk. On 15 occasions fluffiness and purulence were observed. in the milk, mainly in the first milk-jets. In these cases the treatment has been continued. The condition of the milk and udder got back to normal on 8 occasions after the third treatment, on 7 occasions after the fourth 'treatment and on 3 occasions not only purulent flocks were found, but also a chatnge in the consistence of the milk since. it become thinner and wheyish. Recovery took place on these occasions In 2 cases after the fifth treatment and In S8 5 PCT/HU89/00004 WO 89/06955 1 case after the sixth treatment. Treatments were applied at intervals of 24 hours. Although full recovery was observed after just as much treatments when udder infusion preparations of antibiotics content mainly import goods have previously been used in cases being similar to the described ones, however the milk had to be destroyed for 3-7 /or more/ days.

On 25 occasions garget was observed at a stage when change in the milk mainly that of the first milk-jets namely fluffiness, clots up to purulence manifested itself. Pain and redness in the udder-sections producing change in the consistence of milk have not manifested themselves expressly. Other general symptoms like slight fever and Lack of appetite were observed at 6 animals. The other animals with the exception of the 6 ones mentioned recovered after three to four treatments. Full recovery resulted at animals after five treatments, at one animal after six treatments, In case of one animal although treated the change of milk has got more severe; milk become a sort of whey and scarlet and had to be dried. The uddersection has become unsuitable to secretion of milk.

On applying the udder infusions of antibiotics content used previously the above cases recovered to an extent of 50 only when also antibiotics and electrolytes were parenterally applied beside the local intrmam mal treatment.

On 12 occasions the -preparation was applied for animals showing very severe general symptom s /high fever, myasthenia, proffus scour/. Garget affected more than one udder-section, acute clinical symptoms and serious change in milk were observed. Milk was definitely purulent, yellow-coloured, wheyV. On 6 occasions antibiotics, electrolytes and liver-protecting therapy were applied together with the udder infusion.

On the 5th day after the treatment 5 cows fully recovered, the general symptoms ceased to exist, the consistence of milk returned to normal. On a single occasion the half of the back part of the animal SWO 89/06955 PCT/HU89/00004 (0 become fully paralysed, a forced slaughtering had to be performed.

On four occasions when myasthenia has not been definite yet the udder therapy was applied two times daily, without any additional therapy. The condition of the udder came back to normal one the day, there were no more visible changes in milk on the 7th day.

On 2 occasions the parenteral therapy of antibiotics and electrolytes was started on the 3rd day after the treatment of the udder-sections since the general symptoms have not ceased to exist.

These symptoms came back to normal on the 7th day after their realization, and milk became normal on the 8th day.

On applying the udder infusions of antibiotics content used previously the additional, paronteral therapy has also been applied in the above cases. Generally speaking 80 of the cases recovered, died and had to be slaughtered respectively or sorted out owing to a final irreversible change of several udder-sections.

Summarizing the clinical experiences of application of the udder itfusion of propolis-content manufactured on the basis of the invention the following can be stated: It was proved for all users that the milk produced from the treated udder-section was suitable for industrial use at full price as early as 6 hours after the treatment of the udder. It means that there is no need to destroy the milk, produced from the treated uddersection, for 3 to 7 days after the treatment /it is of invaluable signlficance for the economy/; The efficaciousness of the preparation is the same /in certain cases even better than/ as that of the preparation of antibiotics content, available in Hungary as home or foreign-made products.

4 I

Claims (7)

1. A veterinary composition for the treatment of mastitis in cattle, in the form of an ;dder infusion, which comprises: 0.5 to 10% v/v soft propolis 1 to 6% v/v each of at least one w/o emulsifier having a low HLB value as hereinbefore defined, an o/w emulsifier of high HLB value and an Inert carrier or excipient

2. carrier The veterinay composition as claimed in Claim 1 wherein said inert or exciplent is a mixture of petroleum jelly and liquid paraffin, Ii 0 0 0 01 0 *0 I 0D 600 00 00 00 00

3. The veterinary composition as claimed in Claim 1 o, Claim 2 wherein said carrier or excplent comprises polyoxyethylene 400 and propylene glycol,

4. A method of treating a cow for mastitis w-ich comprises the step of administering to an udder section of said cow suffering from mastitis, a therapeutically effective amount of ths veterinary composition as claimed In Claim 1 In the form of an udder infusion, which craTprises: 0.5 to 10% v/v soft propolls 1 to 6% v/v each of at least one w/o emulsifier having a low HLB value as herelndfore defined, an o/vv emulsifier of high HLB value and an inert carrier of excipient. t .f 00o00 0 0 0000 00 0 0 0 I: V V 12 A process for preparing a veterinary composition in the form of an udder infusion containing 0.5 to 10% v/v soft propolis comprising the addition of sufficient soft propolis to an inert pharmaceutical carrier or excipient containing an o/w emulsifier having a high HLB value as hereinbefore defined and 1 to 6% v/v each of at least one w/o emulsifier having a low HLB value.

6. A process as claimed in Claim 5 wherein said pharmaceutical carrier or excipient comprises 1 to 6% v/v each of lanalcolum and cetylstearyl alcohol with the balance petroleum jelly, liquid paraffin and polysorbatum and wherein the following steps are carried out: s lting lanalcolum, cetylstearyl alcohol, petroleum jelly and liquid paraffin sterillslng the melt formed In step (a) cooling the sterilised melt and homogenising same to form a homogenised ointment base adding polysorbatum and soft propolls to the ointment base; and homogrqlsing the product formed In step SUNIPHARMA RT WATERMARK PATENT AND TRADE MARK! ATTORNEYS THE ATRIUM 290 2URWOOD ROAD HAWTHORN VICTORIA 3122 STRALIA AUSTRALIA 1 1 INTERNATIONAL SEARCH REPORT International Aeolicatlon No PC- HU 89 /00004 I. CLASIFICAION Off UUSJUCr MATTER (df sowoal cioahificagohti,, yboli; laly. indicate all) AcCordin to 6*fW-Uo-. Petafit Cltiodlceaee (10C) or Is bothl National Cutiaaficaton and IPC IPC A 61 K 9/06,35/64

11. FIILOS SEARCHED Minimrum' Oocurmwniaior, Seoarched~ ciaaawication system Clasetflcation Ilymbole Int,Cl. 4 A 61 K 9/00,35/00 Documnomatiar S.arched oter than Miuyltm ocumen~tation, to the ExteMi that such 0ocumeritI are Included In~ Ihe Fields Searched I AT III, OCUMNTS C01111111101111 TO 09 REUIVANT' Category~ Citallaof .1 tcumeftt,"1 wett Indication, Whafer ppfuwlle of the wre4vt ottsaoa8 Is Relevant to Claim Po,.i YIEP, Al, 0 109 993 (Z.M.S0SNQWSKI) 13 June 1(1,2) 1984 (13,06.84), see claim 1, points a-b, claim 11, examples XI-XX,XXVII-XXIX; page 115, lines 26-33; page 18, lines 1-20. Y;FE, A, 1 084 006 FOSSEZ) 14(12 January 1955 (14.01.55), see totality.(i2 Y~0sterreichische Apothe1ken-Zeitung, Volume 33,. (1,2) published, 1979, V.J, Brondegaard ""Harz" als H -lilmittel in der Volksmedizin", see pages

956-959; especially page 956, left column, last passage right column, line 2; page 957, ri'pht column, line 20 page 958, left cQolumn, line 1$i. AIAT, 1U 862 (A.JE'KO) 10 Mar'ch 1951 (1,2) ;(10,03.51), see claim, 1. A U, Al, 0 061 508 (R.SCHANZE) 06 October (1,211 11982 (06.10.82), see abstract; claims 1,8, 10,15; page 9, lines 15-22. Spcial catoo of etd dscumerts T" later document oubiliaped after the ti~rtuitieona filing 44te opridfimlltegnrlIinoo "at hc s"Ior ar data end fnst I" corit t lh the itoolication but Adecmn oiigtegnrlsa..1. r hc e ite to unersand the Uaitteipie or theery unelying the conside~red to bet ofParticular rolevance rvmo earlier documont 61A publisheda ohm "lot tww~all 'X ecifflen O 8et osticuar an~ace! te claimed Invention Rulng date cannet be C"6eldered "eatl W Ccaot, 6 considerted to *L docu"M wichI tney throe doubts on pri~rit cwom(ai or mnves an ittoitiv* els" thiCh Is tited It estabisah the pubict:804A of anothtw decunien of sa.ier vi.eIN c~ ile cilthd invenrtion Citation er Other asibciali rason (s specified) can~not*ord to Mnoblv 0 an lveNtivme atOO when the "0 4ecument fere is a deeoal disclosure, Wed. soahIlhent or decuwm is 60mbilfed wit1h ene or W4o thr such docy- Other moone WMut, Ouch Cem*4SUn"e bein ebyleg 10 pet"en skiled 1P* document oubAltow pisew to the leamierw~i@ flits do burt lt the am. lete thant the "w"tt dole climed "a d"WOuen wwfil~ber of the sw ak- ter muy IV._CEIMP1CATION____________ Date of the Actual Cofflos"" o SO he trtana Ieertt DUo4 at s oiii 4M flqthei Seeth Rs 08 March 1989 (08,03-8,9) $0 March 1989 (3O00389) Interryiltegnl Soorching Auerl Sw~areof Avwuolrad Mwca AUSTRIAN PATEN'T OFFICE Poft leCTf511@ sacondi ihept) t.jwvrs 11111) we nave recognizea trat preparations containing soft propolis as active ingredient in an udder infusion, emulsion or ointment guarantees a ,t least the same result ~T 4 -4 Intemational Aptlication No. 1l1. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHETH) 9004 Catogory CUsuort of Docutrwnt. witfl .ldcatioq, w9wru appropoate, of tr roievaft Deluges I elevani to Claim No A US, A, 3 950 554 (E.C.PRINCE) 13 April 1976 (1,2) (13.04.76), see claims 1,4. AIUS, A, 3 049 473 (E.P.BEATSON, J.CFLOYD) (1,2) 14 August 1962 (14.08.62), see colur~is 1-4. form PCTilSA/210 jestra sh~et) qj&wwy 1jf3 0 a Anhang zum internatio- nalen Recherchenbericht Uber die internationale Patentanmeldung Nr. In diesem Anhang Find die Nitglieder der Patentfamilien der im obengenannten interna- tionalen Recherchenbe- richt angefUhi-ten Patentdokumente ange- geben. Diese Angaben diee rur r Lrterrich- tung und erfoigen ohne Gew~hr. Annex to the International Search Report on Interna- tional Patent Application No. PCT/HU 89/00004 This Annex lists the patent family members relating to the patent documents cited in the above-mentioned Inter- national search report. The Austrian Patent Office is in no way liable for these par- ticulars which are merely given for the purpose of in- formation. Annexe au rapport df! recherche internationale relatif i la, demande de brevet international n". La prbsente annexe indique les membres de la famille de brevets relatifs au? docu- ments de brevets cit~s kians le rapport de recherche inter- nationalevis& ci-deszus. Les renseignements fournis sont donn~s i titre indicatif et n'engagent pas la responsa- bilit& de l'Office autrichieln des brevets. Im Recherchenbericht Datum der Mitglied(er) der Datum der angefUhrtes Patent- Ve-r~ffentlichung Patentfamilie Verdffentlichung dokument Publication Patent family Publication Patent document cited date member(s) date in searih report Date de Membre(s) de la 1)ate de Document de brevet cit6 publication famille de publication dans le rapport brevets de recherche 109 993 13/06/1984 AT-E- 40 647 15/02/1989 -Bi- 08/02/1989 F1R-A -1 084 006 14/01/1955 None AT-A 167 862 10/03/1951 None 061 508 06/10/1982 AT-E- 13 976 15!07/198S -Bi- 26/06/1985 US-A -3 950 554 13/04/1976 US-A-4 067 967 10/01/1978 US-A -3 049 4' 13 14/(.$/1962 None