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(11) Patent Number: KE 130
(45) Date of grant: 16/07/2001
(12) PATENT
 
(51) Int.C1.6:A 61K 31/455, 31/65
(21)  Application Number: 1997/ 000109
(22) Filing Date: 06/05/1997
(86) PCT data:
PCT/GB97/01222 06/05/1997
W098/50045    12/11/1998
 
(73) Owner: NORBROOK LABORATORIES LIMITED of , STATION WORKS, CAMLOUGH ROAD NEWRY 13115 6.1P, United Kingdom
(72) Inventor: PATTERSON, Alan; ORR, Neil
(74) Agent/address for correspondence: Kaplan & Stratton Advocates, P.O. Box 40111-00100, Nairobi
 
(54) Title: IMPROVEMENTS IN OR RELATING TO LONG-ACTING ANTIMICROBIALS
(57) Abstract: A method for producing m improved veterinary product comprising bringing a selected long-acting antimicrobial formulation into intimate admixture with a predetermined amount of an anti-inflammatory agent and preparing the admixture for parenteral administration.
 
Improvements in or Relating to Long-Acting Antimicrobials
This invention relates to administration of antimicrobials primarily in the field of veterinary medicine. The desirability of minimizing administration activities in veterinary medicine is particularly acute for several reasons. Obviously the subject of treatment in veterinary medicine cannot be counseled nor cooperate in the treatment process. Therefore in addition to therapeutic considerations there arise disadvantages including the labour involved in catching and handling the animal and the stress it suffers arising from the treatment. One way of addressing these difficulties is to provide long-acting formulations so that-each separate act of administration has a longer effect before a further treatment is called for.
Long acting or single treatment antimicrobials have been available for some time now in veterinary medicine. The long acting basis of such products can result from a combination of both the inherent nature of the drug or drug form used and the formulation in which it is administered. Their benefits over conventional repeat treatment products may include: reduced stress to the sick animal, in that it does not have to be caught and restrained on a daily basis in order to receive treatment, reduced work load for the farmer/veterinarian again because there are no repeat treatments and increased efficacy in treating clinical conditions in that drug levels are continuously present over a prolonged period.
However one of the problems with long acting formulations of antimicrobials is that they may cause irritation at the site of administration and also that high levels of antimicrobial can be found at the sites of administration for a long time.
A further difficulty with long acting or single treatment products can be that they may not give as high blood levels immediately following administration as do the repeat treatment products. Whilst this may not affect the overall level of efficacy of the product it may result in a slower initial rate of recovery which can in some cases lead to the increased rate of long term damage to affected tissues and organs. An alternative explanation for the cause of tissue/organ damage is that it results as a consequence of the animals own inflammatory response to infection. As well as causing damage to tissue this inflammatory process may also reduce the diffusion of antimicrobial to the site of infection/inflammation. One means of preventing this from happening is to administer an
/0 anti-inflammatory drug. Such a drug on its own will reduce the inflammatory response but will not reduce the incidence of bacterial infection and so it is also necessary to'' administer an antimicrobial. One such product containing both an anti-inflammatory drug and an antimicrobial is commercially available, namely, Finabiotic, Schering-Plough Animal Health, however, use of this product requires daily treatments in order to be effective.
Accordingly it is an object of the present invention to obviate or mitigate the aforesaid disadvantages by providing a long-acting or single treatment formulation which has both antimicrobial and anti-inflammatory effect.
According to this invention there is provided a veterinary product comprising an antimicrobial and an anti-inflammatory agent in intimate admixture wherein the antimicrobial is selected from the group consisting of long-acting antimicrobials or depot antimicrobial formulations.
The product is preferably provided as a single dosage in a pharmaceutically permissible "ready for use" container such as a multi-use vial or as a disposable syringe, or in packaging (e.g. blister packaging) containing a selected number of discrete dosage formulations for a prescribed period of treatment, each formulation being contained in a multi-use vial or in an ampoule or disposable dispensing device adapted for parenteral use or any other suitable physiologically acceptable carrier or vehicle.
Further according to the present invention there is provided a method of producing an improved veterinary product comprising bringing a selected amount of a long acting antimicrobial into intimate admixture with a predetermined amount of an anti-inflammatory agent and preparing the admixture for parenteral administration. Preferably the amounts of antimicrobial and anti - inflammatory agent are calculated to provide dosage amounts for a single treatment.
Advantageously this invention provides a veterinary product which on administration produces reduced irritation at the site of administration and reduced levels of antimicrobial found at the sites of administration over a period of time.
The invention will now be further described by way of reference to the following examples:
EXAMPLE 1 Comparison of a long-acting antimicrobial formulation with a formulation comprising a long-acting antimicrobial and an anti-inflammatory drug.
A trial was conducted to compare the efficacy of a long-acting antimicrobial formulation to a formulation comprising a long-acting antimicrobial and an anti-inflammatory drug. The active constituents of the two formulations are detailed in Table 1 below:
Table 1: Active constituents of formulations used in trial.
Active ingredients
Control article 300mg/m1 oxytetracycline in a long-
acting formulation
Test article    300mg/m1 oxytetracycline in a long-
acting formulation containing
20mg/m1 flunixin

The comparative efficacy of the formulations was tested using a controlled disease model of pneumonia in cattle. The object of the study was to evaluate whether the addition of anti-inflammatory drug imparted benefit to the test animals.

Sixteen cattle were inoculated over two consecutive days with cultures containing an isolate of Pasteurella haemolytica, serotype Al from a field case of bovine respiratory disease. This organism is one of the most common bacteria associated with respiratory disease in cattle. At 48 hours after initial inoculation, fourteen animals satisfied the requirements for selection for treatment (pyrexia >103.0°F and obvious signs of respiratory disease). These animals were randomly allocated to two groups, seven animals per group, One group received a single administration of the test article (antimicrobial and anti-inflammatory), the other group receiving treatment with the control article (antimicrobial alone). Both products were administered at the same dose rate of 1m1 per 10kg bodyweight on a single occasion. The study animals were maintained in their original pre-treatment pens and hence the animals from both groups were commingled in the same accommodation. The animals were closely monitored over the following days for response to treatment. This included detailed clinical examination at set time points by a veterinary surgeon blinded to the allocation to treatment groups. Body temperature, respiratory rate and the presence of clinical signs such as hyperpnoea (increased respiratory
effort), dullness and respiratory sounds on auscultation using a stethoscope were recorded. An increase in body temperature and respiratory rate would indicate a developing respiratory disease, as would the recording of dullness, hyperpnoea and respiratory sounds. Using a pre-determined semi-quantitative weighted scoring system, the values for these five parameters were combined to give an overall score
for each animal at each time point. The values were then summated to give a mean value per group per time point. The mean body temperature and total clinical score per group at time points considered to be representative of both short term and long term clinical efficacy are presented in Tables 2 and 3 below. The data was analyzed using the Student t-test (paired and unpaired).
 
Table 2: Body temperature (°F)


Time point       Test Article
(antimicrobials + anti-inflammatory)    Control Article (antimicrobials alone)
Pre-inoculation        102.2       102.1

Pre-treatment
    104.2    104.1
Post treatment      
       
3 hours     101.9    103.8

6 hours        101.8       103.2

9 hours        102.1       103.7

-12 hours        102.3       103.9

72 hours        102.4       103.1

96 hours        102.5       103.5

144 hours        102.1       103.1





At the 3, 6, 9 and 96 hour post treatment time points, the values for the antimicrobial alone group were statistically significantly higher than the pre-inoculation value (paired t-test). At none of the above post treatment time points were the values for the combination product statistically significantly higher than the pre-inoculation values, indeed, at the 6 hour time point the values were significantly lower than the baseline values. Also, at the 3, 6, 9, 12 and 96 hour time points, the values for the test article group were statistically significantly lower than the values for the control article (unpaired t-test).

Table 3: Total Clinical Score
Time-point    Test Article (antimicrobial + anti-inflammatory)       Control Article (antimicrobial alone)
Pre-inoculation        0.6       0.86

Pre-treatment   
    23.3       22.7
Post treatment      
       
3 hours        14.4       22.7

6 hours        13.3       19.4

9 hours        15.4       19.4

12 hours        16.7       21.6

72 hours   
    7.1       13.9
96 hours        4.9       14.9

144 hours        4.3       10.9













At only the last of the above post treatment time points (144 hours) were the values for the test group
(antimicrobial alone) significantly lower than those immediately prior to the onset of treatment (paired t-test). However, at all of the above post treatment time points, with the exception of the 12 hour time point, the values for the combination product were statistically significantly lower than the values immediately prior to treatment. Also, at the 3, 6, 96 and 144 hour time points, the values for the test article group were statistically significantly lower than the values for the control article (unpaired t-test),
40 the values at 72 hours being just outside statistically significance (P=0.06).
From this data, generated in a controlled acute disease model, it is clearly apparent that the combination of the long acting antimicrobial and anti-inflammatory drug had a significantly greater short term and long term therapeutic efficacy than the long acting antimicrobial alone.
 
EXAMPLE 2 Determination of the levels of antimicrobial in tissue.
A further trial was conducted using the formulations detailed in Table 1 to determine the levels of antimicrobial in tissue. One half of the animals received treatment with the control article at a dose rate of 1 ml per 10 kg bodyweight and the other half received the test article at the same dose rate i.e., 1 ml per 10 kg bodyweight. At 21 and 28 days following treatment, the muscle from the injection sites (of animals from both treatments) Whitt} received a dose volume in each case of 15 ml was removed for determination of the level of antimicrobial. The results are presented below as follows:
Table 4
                                     Oxytetracycline concentration (g/g)
at site of administration
    21 days    28 days
Control article    4.33    0.67
Test article    0.038   <0.025

As can be clearly seen from the results the levels of 30 antimicrobials were considerably lower in the group treated with the test article.
EXAMPLE 3 Determination of the degree of irritation following injection.

In a further study animals were again treated with the test and control articles of Table 1 at a dose rate of 1 ml per 10 kg bodyweight, in this case to determine the degree of irritation following injection. As well as receiving the control article, flunixin was administered as a separate formulation to the control group at a dose rate of 2 mg/kg bodyweight (the same dose as administered in the test article). Tissue irritation was assessed by means of the determination of the levels of the enzyme aspartate aminotransferase (AST). This enzyme is released when body tissues are damaged and so its level in plasma increases.
The results of the trial are presented below as follows:
Table

                                                      AST Levels (u/l) After Administration:
                                                     0 hours    6 hours    24 hours    48 hours    96 hours
Control article flunixin at
2 mg/kg    46    81    100    83    51
Test article    39    54    67    54    44

Clearly, it can be seen in Example 3 that the formulation of the present invention (the formulation containing the long acting antimicrobial in admixture with the anti-inflammatory drug) produced less irritation and/or tissue damage than did the long acting antimicrobial and anti-inflammatory when injected as separate products.
In the present invention the combination into one formulation of a long-acting or single treatment antimicrobial with an anti-inflammatory drug is completely novel and provides a single product which will be highly effective in the treatment of bacterial infections and associated anti-inflammatory reactions. The combination offers advantages by way of a more rapid and complete treatment of infection than delivery of either of the two individual components separately.
It should be noted that there are various possible combinations of a long-acting or single treatment antimicrobial with anti-inflammatory agent for use in veterinary medicine. In this invention the antimicrobial drug could usefully be a tetracycline, e.g., oxytetracycline, a cephalosporin, or a penicillin, e.g., ampicillin, amoxycillin, penicillin m or the like or a macrolide, e.g., erythromycin, tylosin, tilmicosin or the like or an aminoglycoside, e.g., dihydrostreptomycin or the like, or a sulphonamide or a diaminopyrimidine e.g., trimethoprim, alone or in combination. Other antimicrobials may also be usefully employed where they can exist in long-acting or single treatment formulations. The anti-inflammatory drug could usefully be flunixin, nimesulide, phenylbutazone, ketoprofen, piroxicam, dexamethasone, flumethasone, betamethasone or other drug possessing anti-inflammatory capabilities.
It will be understood by those in this art that the invention is not restricted to the particular embodiment described above, and variants based on alternative antimicrobials/anti-inflammatory agents are within the scope of the invention which is to be defined by the claims appended hereto.
 
CLAIMS
1. A method for producing an improved veterinary product comprising bringing a selected long.-acting antimicrobial formulation into intimate admixture with a predetermined amount of an anti-inflammatory agent and preparing the admixture for parenteral administration.
2.  A method according to claim 1 wherein the amounts of 10 antimicrobial and anti-inflammatory agent are calculated to provide an appropriate dosage for a single treatment.
3. A veterinary product produced by the process of claims 1 or 2 comprising an antimicrobial and anti-inflammatory 15 agent, in intimate admixture.
4. A veterinary product according to claim 3 wherein the antimicrobial is selected from the group consisting of tetracyclines such as oxytetracycline, cephalosporins, penicillins such as ampicillin, amoxycillin, penicillin G or the like, macrolides such as erythromycin, tylosin, tilmicosin or the like or aminoglycosides such as dihydrostreptomycin or the like or a guinolone or the like, or a sulphonamide or a diaminopyrimidine e.g., trimethoprim or the like, either alone or in combination.
5.  A veterinary product according to claim 4 wherein the anti-inflammatory agent is selected from the group consisting of indolines such as indomethacin, salicylates such as aspirin, oxicams such as piroxicam, acetic acid such as diclofenac, fenamates such as tolfenamic acid, propionic acids such as ketoprofen, para amino phenol derivatives such as acctaminophen, pyrazoles such as phenylbutazone, sulphonanilides such as nimesulide, or other drugs possessing anti-inflammatory or anti-pyretic capabilities.
 
6. A veterinary product comprising a long-acting antimicrobial, flunixin and a physiologically acceptable vehicle or carrier.
5 7. A veterinary product according to claim 6 comprising oxytetracycline, flunixin and a physiologically acceptable vehicle or carrier.
8. A veterinary product according to claim 7 comprising 10 300mg/m1 oxytetracycline, 20mg/m1 flunixin and a physiologically acceptable vehicle or carrier.

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