FR2494115A1 - PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF BACTERIAL INFECTIONS IN ANIMALS, CONTAINING HALOGENO-6B PENICILLANIC SALT OR DERIVATIVE AND ONE OR MORE B-LACTAM ANTIBIOTICS - Google Patents

Abstract

THE INVENTION CONCERNS A PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF BACTERIAL INFECTIONS IN ANIMALS, CONTAINING A HALOGENO-63 PENICILLANAL SALT OR DERIVATIVE AND ONE OR MORE ANTIBIOTICS OF B-LACTAM TYPE; SUCH A PREPARATION IS PARTICULARLY SUITABLE FOR INTRAMAMMARY ADMINISTRATION TO COMBAT VERY EFFICIENTLY AGAINST MASTITE AND FOR A SIMILAR LOCAL TREATMENT OF CAVITIES.

Description

The present invention relates to a preparation

  pharmaceutical tion for the treatment of infections

  bacterial from animals, containing a salt or derivative ha-

  log6no-6 / penicillanic and one or more elactam antibiotics. More particularly, the invention relates to a pharmaceutical preparation which is well suited for intramammary use and for similar local treatment of cavities to fight against bacterial infections.

with the animals.

  Pharmaceutical preparations for intramammary administration are particularly intended for the treatment of mastitis. A lot of effort and money has gone into developing products for the treatment of mastitis, which is an inflammation of the udder caused by a bacterial infection, this disease being very important.

for milk production.

  The Applicant has discovered that a halo-6 acid ,? penicillanic administered as such or in the form of a salt or ester hydrolyzable in vivo penetrates into the breast tissue to cause a high concentration in the milk and / or in the acid serum

  halogeno-6p penicillanic ece which protects an anti

  -lactam-type biotic used for treatment

  infection and / or increases the effect of this

  biotic. Therefore the particularly advantageous pharmaceutical preparations of the invention consist of preparations against mastitis containing at least one or more antibiotics of the lactam type as such or in the form of prodrugs, and a 6-halo-penicillanic acid either as such or in the form of a salt or an ester hydrolyzable in vivo or a salt of such an ester. These preparations may also contain a salt of a halo-61penicillanic acid

  and a lactam-type antibiotic or a

  corresponding drug having a basic group. Among the lactam-type antibiotics suitable for such preparations, there may be mentioned: penicillin G and V, ampicillin, amoxycillin, epicillin, carbeni-

  cillin, cloxacillin, azlocillin, flucloxacil-

  line, ticarcillin, nafcillin, dicloxacillin, oxacillin, l. has methicillin, carfecillin,

  mecillinam, cephalothin, cephaloridine, cepha-

  loglycine, cephazoline, cephacetrile, cefoxi-

  tine, cephalexin, cephoxazole, cephalonium, or their prodrugs, and mixtures of one or more of these lactam-type antibiotics or their prodrugs, e.g. ampicillin / cloxacillin, amoxycillin / cloxacillin, ampicillin / flucloxacillin combinations , amoxycillin / flucloxacillin, ticarcillin / flucloxacillin and ampicillin / mecillinam or similar combinations containing prodrugs, this list is not exhaustive.

  A specific pharmaceutical preparation-

  importantly contains as an antibiotic benzyl-

  penicillin in the form of its ester / -diethylaminoethy-

  which bears the generic name of penhamate.

  It is known that penethamate-as such or for example in the form of its iodhydrate is very effective in the treatment of mastitis because it causes a rapid and high concentration of benzylpenicillin

in the udder.

  Also aminopenicillins, for

  example ampicillin, amoxycillin or their pro-

  drugs, are very effective in treating mastitis. -. *

  As is well known, some -

  penicillins, for example penicillin G and V and aminopenicillins, are very sensitive to / l-1actamases and therefore the combination of these antibiotics

  (or prodrugs) with a 6o-halo acid peni-

  cillanic in a preparation against mastitis is

  appropriate as a result of the protection of penicillin.

  In these preparations, it is possible to incorporate other antibiotics of the type / lactam, for example those mentioned above, in order to obtain a more antibacterial spectrum.

  broad and / or increased antibacterial activity

  and / or a synergistic effect. In one embodiment

  In particular, a salt of a 6-halo penicillanic acid with

  penetrhamate, pivampicillin or bacampicillin.

  Other antibiotics which may be present in the preparation against mastitis according to the invention are for example: tetracyclines such as tetracycline, oxytetracycline, chlortetracycline, and rolitetracycline; sulfonamides,

  for example sulfadiazine, sulfadoxine, sulfatroxa-

  zole, sulfadimidine, sulfathiazole; the trimetho-

  premium; aminoglucosidic aminocyclitols, for example streptomycin, dihydrostreptomycin, kanamycin, gentamycin, neomycin, framycetin, apramycin; aminocyclitols, for example spectinomycin; chloramphenicol; fusidic acid; lincomycin; macrolides, for example erythromycin, tylosin,

  spiramycin, oleandomycin; novobiocin; poly-

  hagfish, for example polymyxin B and E; and pleuro-

  mutilins, for example tiamulin, this enumeration

not limiting the invention.

  Suitably, and according to current practice, the preparation against mastitis may also contain, for example, a corticosteroid or agents

  analgesics or other similar active compounds.

  The composition of the invention intended for the treatment of mastitis is in the form of suspensions or solutions of the active components in a vehicle

2 24 941 15

  suitable which can be made of an aqueous or oily base

  leuse. The composition can be administered in a conventional manner for the treatment of mastitis, for example with an intramammary injector or in the form of an aerosol. In the preferred embodiment, the composition can be administered in the form of an aerosol foam. To obtain the maximum degree of stability, it is preferred as a vehicle to use non-aqueous media such as vegetable oils or paraffin oil. We can suitably add a thickening agent

  such as hydroxy-12 stearin or aluminum stearate.

  Also as thickening agents can be used

  beeswax, castor oil or peanut hydro-

  or a soft or hard paraffin. More like

  thickener can be used for example lactose.

  In addition, the composition used for the treatment of mastitis can suitably contain surface-active agents such as a Span, a Tween or a Cremophor. Conventionally these additives are used in amounts of at most 10% w / v of the composition while, suitably, the amount of detergent

varies between 0.1 and 8% w / v.

  Vegetable oil can advantageously be chosen from commercial oils whose fatty acids contain 8 to 10 carbon atoms. Commercial products with low viscosity such as "Viscoleo"

  which is a fractionated copra oil are particular-

useful.

  The quantity of agents with therapeutic activity

  may in all of the above mastitis preparations may appropriately vary between

0.5 and 40% w / v.

The invention also relates to

2494 115

  the choice of a unit dose of the compositions of the

  vention, this unit dose can be administered to obtain the desired results without effects

simultaneous secondary.

  Typically the unit dose according to the invention contains from 0.025 g to 2.5 g, preferably from 0.1 g to 1 g of active ingredients, for example g'-lactam antibiotic or antibiotics and the inhibitor

dep -lactamase.

  For the treatment of mastitis, one.

  appropriately administers the composition or associated composition of the invention with an injector

  (intramammary) containing for example 5 ml.

  The invention also relates to a method for treating animals which comprises administering an effective amount of the compositions of the invention

  has an animal with an infectious disease.

  During the lactation period when it is desirable for the duration of the treatment to be short, the composition is administered in an appropriate manner at a rate of 5 to 10 ml per quarter-with a base consisting mainly of vegetable oils to obtain a

  rapid excretion of active ingredients.

  During the dry period, the composition or associated composition may suitably be

  based on paraffin or vegetable oils with stéa-

  aluminum spleen and preferably contains other

  antimicrobial agents, for example streptomycin.

  The method may include administering the inventive compositions or associated compositions or administering such compositions with compositions containing other antibiotics. In the latter case, the two types of composition can be administered simultaneously or at intervals and with varying proportions between the active components in the compositions. In the treatment of mastitis, the infected quarter is treated with the intramammary composition every 12 or 24 hours during the lactation period until the infection stops, normally after 3 treatments, and in the dry period, the infected quarter is appropriately treated with one or more long-acting unit doses

  term, depending on the length of the dry period.

  The invention is illustrated by the examples

following nonlimiting.

Example i

  The following composition is prepared: Penethamate iodide 100 g Bromo6 potassium penicillanate 100 g Hydroxy-12 stearin known under the trade name of "Thixcin R" 20 g Modified copra oil, known under the trade names of "Miglyol 812 R" and "Neobee R" '780 g 1000 g The hydroxy-12 stearin is dissolved in copra oil at 70 ° C. and cooled to room temperature. The penethamate iodhydrate and potassium bromo-6 penicillanate are incorporated by stirring and then homogenized. We fill syringes with material

  suspension plastic obtained so that they

each hold 5 g of suspension.

Example 2

  The following composition is prepared according to

the procedure of Example 1.

  Penethamate iodide 100 g Iodo-6-potassium penicillanate 50 g Polysorbate 80 10 g -12-hydroxy stearin - --25 g Modified coconut oil. 812 g 1000 g Plastic syringes are filled with the suspension obtained for that each

  syringe contains 5 g of suspension.

Example 3

  The following composition is prepared: Penethamate iodide 20 g Potassium bromo6ipenicillanate 40 g Framycetin sulfate 20 g Aluminum monostearate 20 g 12-hydroxy stearin 10 g OJ Liquid paraffin 890 g 1000 g The aluminum monosterate and hydroxy-12 stearin in liquid paraffin at 130 C

  and cooled to 30 C. The iodine is incorporated by stirring

  penethamate hydrate, iodo-6 penicillanate

  potassium and framycetin sulfate and then homogenous

  neise. Plastic syringes are filled with the suspension obtained so that each syringe

contains 5 g of the suspension.

  EXAMPLE 4 The procedure of Example 1 is repeated to prepare a similar composition except that the penethamate iodide is replaced by an equivalent amount of the penhamillin salt of penicillanic acid. We are preparing 195 syringes from the

suspension obtained.

Example 5

  The following composition is prepared: Ampicillin 30 g Bromo-6? potassium penicillanate 30 g Hydroxy-12 stearin 20 g Polysorbate 80 20 g Modified copra oil 900g 1000 g The hydroxy-12 stearin and polysorbate 80 are dissolved in copra oil at 80OC and cooled to temperature ordinary. Ampicillin and potassium bromo-61 penicillanate are incorporated by stirring and then homogenized. Plastic syringes are filled with the suspension so that they each contain 5 g of suspension.

Example 6

  The following composition is prepared: Ampicillin sodium 40 g Bromo-6 sodium penicillanate 20 g Silicon dioxide 30 g Stearyl alcohol 20 g Peanut oil 890 g 1000 g Dissolve stearyl alcohol in peanut oil at 650C and cooled to room temperature. The dioxide is stirred in.

  silicon, ampicillin sodium and bromo-6th penicilla-

  sodium nate then homogenized. Syringes are filled with plastic syringes to

  that they each contain 5 g of suspension.

Example 7

  The following composition is prepared: Pivampicillin 100 g Bromo-6S sodium penicillanate 50 g Hydroxy-12 stearin 25 g Modified copra oil 825g 1000 g The hydroxy-12 stearin is dissolved in copra oil at 80 C and cooled at room temperature. Pivampicillin is stirred in

  and sodium bromo-6C penicillanate and then homogenized.

  Plastic syringes are filled with the suspension so that they each contain 5 g of suspension.

Example 8

  The following composition is prepared: Bacampicillin 40 g Bromo-6, potassium penicillanate 10 g Aluminum monostearate 20 g Hlydroxy-12 stearin 20 g Liquid paraffin 910 g 1000 g Dissolve aluminum monostearate and hydroxy-12 stearin in liquid paraffin at C and cooled to 30 C. Pivampicillin and potassium bromo-6 penicillanate are incorporated by stirring, then homogenized. Syringes are filled with plastic from the suspension so that they

  each contain 5 g of suspension.

  EXAMPLES 9 to 13 The procedure of the example is repeated to prepare a similar composition except that the penethamate iodide is replaced by a

  equivalent amount respectively of the salt of

  thamate of iodo-6 penicillanic acid, bacampicillin salt of bromo-6l penicillanic acid, bacampicillin salt of iodo6f penicillanic acid, pivampicillin salt of bromo-6p penicillaniqoe acid

  or pivampicillin salt of iodo-6f penicilla-

  fuck. Of course, various modifications can be made by those skilled in the art to the devices or methods which have just been described only by way of nonlimiting examples without departing from the scope of

the invention.

Claims (12)

  1. Pharmaceutical veterinary preparation for intramammary administration or a similar local treatment of cavities, characterized in that it comprises a halo-6G acid. penicillanic as such or in the form of a salt or ester hydrolyzable in vivo or of a salt of such an ester with one or more antibiotics of the fl lactam type as such or in the form of prodrugs, and optionally with other active ingredients and 0l with non-toxic vehicles and / or auxiliary agents acceptable in pharmacies.   2. Preparation according to claim l, characterized in that it is in the form of a unit dose containing 0.025 g to 2.5 g and preferably   0.1 to 1.0 g of active ingredients.   3. - Preparation according to one of claims   1 or 2, characterized in that it contains a salt of   alkali metal of a 6-halo penicillanic acid.   4. Preparation according to claim 1, characterized in that it contains penetrhamate hydroiodide.   5. Preparation according to one of the claims   1 or 2, characterized in that it contains a salt   a 6-halo penicillanic acid and an anti   biotic type, 3-lactam or a corresponding prodrug   laying containing a basic group.   6. Preparation according to claim 5, characterized in that it contains the penetamate salt of 6-bromo-penicillanic acid or of acid iodo-6 penicillanic.   7. Preparation according to claim 5,   characterized in that it contains bacampicil salt-   line or pivampicillin of bromo-6f penicilla-   or penicillanic acid iodo-6p.   8. Preparation according to claim 1, characterized in that it contains ampicillin as such or in the form of an alkali metal salt or in the form of a prodrug.   9. Preparation according to claim 1, characterized in that it contains pivampicillin or bacampicillin. 10. Preparation according to any one of   Claims 1 to 9, characterized in that it contains J $ 955% active ingredients.   11. Preparation according to any kind   of claims 1 to 10, characterized in that it   is in the form of a solution or a suspension of the active ingredients in an aqueous medium and in that it   is contained in an intramammary injector.   12. Preparation according to claim 1, charac-   terized in that the total amount of ingredients a c t i f s varies between 0.5 and 40% w / v.