WO1989006955A1 - Process for manufacturing veterinary products being suitable particularly for treatment of mastitis and the product thus obtained - Google Patents

Abstract

The subject of the present invention is a process for manufacturing veterinary products suitable first of all 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 by cold process and one or two emulsifier/emulsifiers of low HLB-value (3-8) in a quantity of 1 to 6 v/v % each, in a given case one emulsifier of high HLB-value (8-18), 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 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 of 0.5 to 10 v/v %, made by cold process and one or two emulsifier/emulsifiers of low HLB-value (3-8) in a quantity of 1 to 6 v/v % each, in a given case one emulsifier of high HLB-value (8-18), 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.

Description

PROCESS FOR MANUFACTURING VETERINARY PRODUCT S 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 mastitis and the product itself .

B ackground art

It is well known that mastitis - according to scientific literature available up to now - is a polyfactorial /polyethio logical / illness , that' s why no prevention and treatment resp. with general effectiveness is possible . Mastitis affects in most case s cows with big 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 los s 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 to 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 c ow, caused by mastitits. The yearly loss caused by this disease in European countries is estimated as follows :

France : FRF 5 thousand m illion; United Kingdom: GBP 35 millions ; G DR : DDM 1 70 millions ; GF R : 450 millions .

Garget generally decreases the total milk production by 11 % in each country. The damages are listed below:

- milk yield falls by 10 to 20 %;

- the quality of milk is worsening;

- treatment costs are considerably high ; - after treatment the milk has to be destroyed as long as the active ingredients are off the organism which takes in most cases 3 to 7 days;

- 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 ;

- period of milk production becomes shorter;

- there is a great hazard for healthy animals to get infected ;

- human being might be affected, too. The frequency and appearance of gargets are highly influenced by the prevailing conditions of animal keeping, feeding and hygiene and also by the breeder of animals himself. This means that the appearance and severity of garget varies a lot with diaries and individuals - depending on the conditions mentioned. The pathogens causing infection /bacteria, fungi, viruses, etc. / reach the lacteal tracks of the udder in most cases in a galactogen way and the parenchyme of the udder resp. bringing on disease of varying severity, depending on their patho genetics and resistance of the organism or udder respectively. Local medical treatment is generally applied in case of disease manifesting itself by clinical symptoms . Both the Hungarian and foreign preparations known so far contain some potent antibiotics or combinations of antibiotics and sulfonamyde . Should such preparation be applied a waiting time of 3 to 7 days from the last treatment - or more - is necessary, subject to the sort of preparation, to have milk being fit for human consumption from the diseased udder or uddersection resp.

The invention has the aim to provide a process to produce veterinary preparations eliminating the above mentioned disadvantage , for treatment of mastitis and the product thus obtained.

We have recognized that preparations containing soft propolis as active ingredient - namely udder infusion, emulsion and ointment - guarantee at least the same result in prevention and treatment of the disease as preparations containing antibiotics and sulfonamyde resp. , eliminating, however, the disadvantage referred to above .

In order to produce such preparations we had to find out the special emulsifiers 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 had to make allowance s for the natural emulsifiers of milk and also for the capacity conditions of the o/v emulsifier owing to the reduced fat content of the infected milk.

Disclosure of invention

In order to achieve the task according to the foregoings we had to solve optimally two emulsifiers of low HLB value /3 to 8/ and type v/o on water bath, 1-6 v/v % each, in ointment-emulsion /e . g . white vaseline - liquid paraffin/ b asic material of ideally selected proportion. For practical purposes we apply two emulsifiers ; lanalcolum /2 v/v %/ and alcohol cetylstearylicus /1-2 v/v %/ are the most advantageous ones. On the edge surface of the phases the two emulsifiers consitute a stable dense film. The above basic material emulsifyer system is sufficient for emulsification of the soft propolis active ingredient of thin sour cream substance , rather of hydrophilous character of 0,5 - 10 v/v %.

Regarding that the udder infusion of 2 decilitres meets 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 v/v % - and of high HLB values /8 to 18 / with emulsifier of type o/v, optimally with sorboxetene derivative /Polysorbate 20/ t hus emulsifying it in the above basic material containing emulsifier or a pair of emulsifiers of type v/o. The received system containing complex emulsifier is to be introduced from the disposable plastic appliance into the diseased uddersection where it meets the milk and becomes activated.

Influenced by the o/v emulsifier /sorboxetene derivative [Polysorbat 20]/ and the complicated, mixed phosphatide-albumin complex - being present in the milk in a minimal surplus - as an emulsifier of type o/v, further 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 proportion have considerably bee n 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 phosphatide albumin complex/ can also be taken into consideration. The presence of Polysorbate 20 - in a capacity of an o/v emulsifier - is seemingly "unnecessary" to emulsifying liquid propolis-extract, to stabilizing the system, i. e. to formulating the udder infusion. However, on meeting the milk it will play an essential part, becoming activated at that time. Only an insignificant quantity of liquid paraffin /0 to 2 v/v %/ separates from the viscous or thin ointment-like emulsion resp. under special storage conditions - at extreme temperature intervals - if aerosil is added to the preparation.

The main point of the invention-based preparation is consequently that its active ingredient is soft propolis of 0,5 -10 v/v %

/made by cold extraction/, further it contains one or tw o emulsifier /emulsifiers / with quantity of 1 -6 v/v % each, of low HLB-value /3 in a given case one emulsifier of high HLB-value /8-18/, further one or more additives selected - for practical purposes - from among the following ones: the usual basic materials of ointment and emulsion resp., auxiliary materials which influence viscosity and are after-lubricant, inert hydrophilous solvents and pH-regulators.

Best mode of 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 resp. of acute, subacute and chronic mastitis of cattle

The following substances have been used for making udder infusion: Standard propolis concentrate /soft propolis/ 15,0 g

Polyoxaethen 400 30,0 g

Lanalcolum 15,0 g

Alc. cetylstearylic 7,5 g

Vaselin album 227,5 g Polysorbatum 24,0 g

Paraffinum liquid um 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 mentioned below have been used:

Standard propolis concentrate /soft propolis/ 45,0 g

Lanalcolum 15,0 g

Alcohol cetylstearylic 7,5 g Vaselin album 227,5 g

Polysorbatum 24, 0 g

Paraffinum liquidum 431 , 0 g

The total weight of the components used in both cases: 750,0 g .

Lanalcolum, alcohol cetylstearylic. and vaselin album have been melted on water bath, at stirring to be followed by a three-hour-sterilization at 140 ºC and stirring - under aseptic conditions - until cooling. Homogenization was effected after 24 hours. Polysorbat was emulsified in the gained basic ointment - still under aseptic conditions - then propolis added in parts and liquid paraffin in more parts - at intensive stirring - also sterilized at 140 ºC for 3 hours which was followed by homogenization. The viscous emulsion has at stirring been introduced - by weighing into the container compartment of the disposable plastic syringe and shut off by a piston. After capping packing of the individual units took place. The plastic syringe has been cleaned and sterilized under aseptic conditions suitable for storage of medical preparations .

Example 2 Emulsion ointment of soft propolis content

Soft propolis 10 g

Propyleneglycol 20 g

Lanalcolum 50 g

Ale. cetylstearyl 30 g Vaselin album 640 g

P araffinum liquidum 200 g

01. ricini 50 g

Example 3 Standard propolis concentrate /soft propolis / 15 g

Lanalcolum 25 g

Vaselin album 265 g

Polysorbatum 24 g Paraffinum liquidum 421 g

Example 4

Standard propolis concentrate /soft propolis / 1 5 g

Alcohol cetylstearylic 25 g

Vaselin album 265 g P olysorbatum 24 g

Paraffinum liquidum 421 g

Method of preparing

Soft propolis 0,5-10 /optimally 6/ v/v % was mixed with an indifferent solvent of hydrophilous character /propyleneglycol - polioxaeten 400/ , for practical purposes with propylenglycol .

In the mixture of vaselin album and liquid paraffin of 5-30 /for practical purposes 20/ v/v % one or two emulsifier /s / - soluble in hydrocarbons - of low HLB-value /3-8/ was /were / solved on 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 have been used, for example lanalcolum and ale. cetylstearyl. in a proportion of 5: 3 v/v %. This basic ointment has been stirred until cooling, the day. after homogenized and the homogeneous mixture of soft propolis and propyleneglycol emulsified in it in small parts . The preparations made according to the invention /udder infusion, ointment and similar ones / have numerous advantage s 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 bactericide , viricide and fungicide on 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 analgetic effect;

- after use of the preparations the milk produced from the treated udder has no more germicidal substance content after 6 hours, thus the value of milk does not drop.

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 disease; - the treatment has to be effected with craftsmanship /lege artis /;

- a proper period of treatment is necessary /till the symptoms cease to exist and even longer resp. /.

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 production level and the results have been compared with those of preparations with antibiotics content, used previously.

The results obtained are as follows: All experimental milk-farms used the preparation uniformly, in case of peracute, acute, subacute and chronic mastitits declaring itself at any stage of the 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: %

E. coli 18,9

Str. uberis 13,9

Str. dysgalactiae 12,8

Str. agalactiae 2,1

St aph. aureus 7,5

Staph. albus 4,3

Corynebact. pyogenes 7,5

Klebsiella 4,8

Coliform bact. 4,3

Bac. subtilis 3,2

Pseud, aeruginosa 1,6

Bac. cereus 1,1

Bac. negativium 0,5

Gemmiparous fungi 4,8

100,0%

According to the scattered bacteriological results of the other milk -farms similar pathogens could be found at incidences of garget.

- On 32 occasions the preparation was used for inflammatory symptoms observed in one udder-section /pains, the skin of the udder got red, 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 change 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 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 manife sted 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 4 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 udder-section 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 intramammal 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, wheyey. 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 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 5th 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, parenteral therapy has also been applied in the above cases. Generally speaking 80 % of the case s recovered , 20 % 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 o f the udder infusion 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 udder-section, for 3 to 7 days after the treatment /it is of invaluable significance 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 .

Claims

Claims

1. Process for manufacturing veterinary products suitable first of all for the treatment of Mastitis, char acterized in that the active ingredient is soft propolis of 0,5 to 10 v/v % /made by cold process/ and one or two emulsifier / /emulsifiers of low HLB-value /3-8/ in a quantity of 1 to 6 v/v % each, in a given case one emulsifier of high HLB-value /8-18/, 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 - is /are mixed together.

2. A veterinary preparation suitable first of all for the treatment of Mastitis, especially in the form of udder infusion, ointment, emulsion and the like, charact erized by containing as active ingredient soft propolis of 0,5 to 10 v/v% /made by cold process/ and one or two emulsifier/emulsifiers of low HLB-value /3-8/ in a quantity of 1 to 6 v/v % each, in a given case one emulsifier of high HLB-value /8-18/, 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.