WO1991015211A1

WO1991015211A1 - Veterinary compositions

Info

Publication number: WO1991015211A1
Application number: PCT/GB1991/000486
Authority: WO
Inventors: Dennis Frank Sharman
Original assignee: Dennis Frank Sharman
Priority date: 1990-03-30
Filing date: 1991-03-28
Publication date: 1991-10-17
Also published as: GB2242359A; GB9007250D0; GB9106694D0

Abstract

A medicament useful in producing a tranquillizing effect in pigs comprises a first compound which is metoclopramide, or a physiologically acceptable salt thereof, and a second compound which is midazolam or a physiologically acceptable salt thereof.

Description

VETERINARY COMPOSITIONS This invention relates to the chemical control of animal behaviour, particularly in the pig.

Pigs are one of the most potentially dangerous farm animals and the problem of controlling their behaviour is of long standing. Following the introduction of the neuroleptic drugs into human medicine it was found that certain of these drugs were suitable for controlling the behaviour of some domestic animal species. However, it is common for unwanted side effects to occur in the pig and, of this extensive group of drugs, only azaperone is recommended for use in pigs. Nevertheless, this compound does not always provide the adequate short-term control of behaviour required for veterinary examination and treatment since, for example, the pig will sometimes get up and move away even after administration of the drug.

There is therefore a long standing requirement for a medicament suitable for the control of pigs during veterinary examination and treatment. I have now found that such a medicament is provided by the use in conjunction of two pharmaceuticals well known in a different context.

Accordingly the present invention comprises the use for the manufacture of a medicament for use in producing a tranquillizing effect in the pig of a first compound which is metoclopramide or a physiologically acceptable salt thereof, and a second compound which is midazolam or a physiologically acceptable salt thereof. A large number of drugs acting on the central nervous system has been studied in the pig and these studies have included the use of metoclopramide (Fry and Sharman, Biochemistry and Neurology, Eds. Bradford and Marsden, Academic Press, London, 1976, pp 57-69 and Ely, Rumble and Sharman, British Journal of Pharmacology, 1978, 62, 392-393 P) . However, although metoclopramide produced cataleptic behaviour in some pigs, in others it produced a different effect, in particular undesirable activity such as stereotyped snout-rubbing. Metoclopramide used alone is^" not therefore suitable for producing a tranquillizing effect in pigs. Other investigations on the mode of action of metoclopramide in animals have utilized the guinea pig. Thus, Rodriguez del Camino and Sharman, Proceedings of the British Pharmacological Society, 1981, 7_ . 767-768 P and 1984, 81_, 22 P report the use of metoclopramide, at much higher dosage levels than were used in the pig, in conjunction with a variety of compounds acting on the central nervous system, such as apomorphine, atropine, diazepam and uscimol. Although these compounds, when used at appropriate dosage levels, were found to block the undesirable side effects which metoclopramide also produces in the guinea pig, none of them is suited to use in the manufacture of a sedative for pigs such as is described hereinbefore.

U.S. Patent 4,316,897 describes a method for reducing a high prolactin concentration induced by administration of a neuroleptic, including metoclopramide, which utilizes one of various benzodiazepines, but not midazolam. However, this patent makes no reference to any veterinary use of the invention, apart from the use of rats in animal tests which were carried out as a preliminary to clinical tests in humans. Moreover, midazolam is of particular value in tranquillizing pigs as compared with any of the benzodiazepines described in that patent.

The medicament produced according to the present invention has particular advantages in that it provides a tranquillizing effect in the pig which is sufficiently effective to enable veterinary examination and treatment to be carried out but is not long acting so that the pig recovers rapidly, with the onset of the effect usually occurring within about 10 minutes and with the pig usually being on its feet within about 30 minutes and soon reverting to its normal state, for example within 1 hour of administration of the medicament. A short residence time for the medicament in the pig is also desirable in relation to the eventual consumption of the pig meat by humans. Metoclopramide has the structure 4-amino-5-chloro-N- [2-(diethylamino)ethyl]-2-methoxybenzamide, whilst midazolam has the structure 8-chloro-6-(2-f1uorophenyl)-l-methyl-4H-imadazo- [1 ,5-a][l ,4]benzodiazepine, these structures being illustrated in The Merck Index, 1983, Tenth Edition, Windholz (Ed), Merck & Co. Inc., U.S.A.

The compounds may each be used as a physiologically acceptable salt formed with an inorganic or organic acid so that, for example, metoclopramide may be used as the mono- or di- hydrochloride, and midazolam as the hydrochloride or aleate (the mono-salt in each case).

The two compounds used in a medicament produced according to the present invention are most conveniently formulated together in the -medicament although the present invention does extend to a medicament, for example a kit or pack, comprising the first and second compounds as individual components for separate, simultaneous or sequential use, the second compound usually being administered before the first compound when the two are given separately. In view of the potential danger in handling pigs, however, a single administration of a composition comprising both compounds has very considerable advantages and it is believed that such compositions containing the first and second compounds are novel .

The present invention thus includes a pharmaceutical composition comprising a first compound which is metoclopramide or a physiologically acceptable salt thereof, and a second compound which is midazolam or a physiologically acceptable salt thereof, together with a physiologically acceptable diluent or carrier. Although such a composition can take various forms, the usual mode of administration of the compounds will be by injection, generally intramuscularly, and a liquid composition containing a diluent which is sterile and pyrogen free is therefore preferred. This will also be true should the two compounds be formulated separately. The diluent may comprise water and/or an organic solvent and may take the form of a solution, suspension or emulsion. In many cases it may be possible to produce an aqueous solution. It will be appreciated that a liquid composition containing both compounds may either be provided as such to the veterinarian or may be produced by him prior to administration, for example from separate liquid compositions containing the individual compounds, from the individual solid compounds or from a solid mixture of the compounds. Such separate liquid compositions may in turn either be provided as such to the veterinarian or may be produced prior to administration from the individual solid compounds. The separate first and second compounds may be presented to the veterinarian in the form of a kit or pack as referred to previously. All such modes of procedure fall within the present invention. Where desired, a medicament produced according to the present invention, for example a composition as described hereinbefore, may contain other compounds, for example other active components or additives such as preservatives.

As regards the dosages of the first and second compounds to be used, it may be stated by way of guidance that dosages in the range of 1 to 10 mg/kg for metoclopramide, for example 1.5 to 4.5 mg/kg, and in the range of 0.1 to 1.5 or 2 mg/kg for midazolam, for example 0.2 or 0.3 to 0.8 or 1 mg/kg are often suitable. These and other dosage figures and the figures for ratios of the first and second compounds which are given herein all relate to the free base parent compounds. When salts are used the dose of the salt will be such as to provide similar amounts of the parent compound. Where desired, however, dosages above and below these ranges may be used and when selecting a dosage for each of the compounds it is preferred to use a weight/weight proportion of first compound:second compound in the range of 2.5:1 to 25:1, for example 5:1 to 15:1 and especially about 10:1. If desired, the compositions may be formulated in unit dosage form, i.e. comprising a standard dose or a multiple or sub-multiple thereof. A suitable unit dosage form applicable to many pigs, weighing between about 30 and about 50 kilograms, may conveniently consist of 60 to 140 mg of metoclopramide, and of one quarter to one twentieth, for example one tenth, by weight of midazolam. A preferred unit dosage is 100 mg of metoclopramide and 10 mg of midazolam.

The present invention also includes a method of tranquillizing pigs which comprises administering to a pig in amounts which together are effective in producing a tranquillizing effect a first compound which is metoclopramide or a physiologically acceptable salt thereof, and a second compound which is midazolam or a physiologically acceptable salt thereof. The invention is illustrated by the following Examples.

EXAMPLES Example 1

Preparation of composition containing metoclopramide and midazolam A solution of metoclopramide or its monohydrochloride onohydrate ( 5% w/v) in sterile, pyrogen-free water is thoroughly mixed with an equal volume of a solution of midazolam or its monohydrochloride (0.5% w/v) in sterile, pyrogen-free water to provide a composition suitable for injection containing. a ratio of metoclopramide:midazolam of about 10:1 w/w (depending on whether the free base or the salt is used in each case).

A suitable unit dosage for many pigs will consist of 4 to 5 ml of such a composition. Alternatively the concentrations can be increased in order to reduce the volume of a unit dosage, for example to 2 to 3 ml. Example 2 The treatment of pigs with metoclopramide and midazolam

In each of the treatments described below the pigs used were Large White x Landrace pigs of both sexes (except where indicated) weighing between 30 and 60 kg. Pigs for use in a treatment were randomly selected from a large group of 25 animals and allowed 2 hours to adjust to their new surroundings before the onset of treatment.

For (a) and (b) the composition administered was prepared essentially as described in Example 1 but with the concentrations and/or volumes of the two solutions being varied as appropriate. Thus, solutions of metoclopramide hydrochloride and midazolam were prepared separately in sterile, pyrogen-free water immediately before use, the two solutions were then mixed in the same syringe and the solution was administered.

The concentrations were adjusted so that a total volume of 4 ml was administered to each animal. Administration was by deep intramuscular injection at the base of the right ear while the pig was restrained by the snout. (a) This treatment was directed particularly to a study of the level of sedation which could be achieved.

Four pigs were injected with metoclopramide (3.3 mg/kg), three of them in combination with midazolam (0.1, 0.25 and 0.4 mg/kg respectively). Four further pigs were injected with midazolam (0.25 mg/kg) alone or in combination with metoclopramide (1.5, 3.3 and 4.5 mg/kg respectively). For comparative purposes two other pigs received azaperone (Suicalm) at a dose of 4 mg/kg and two more pigs acted as controls, being given 5 ml of physiological saline solution by intramuscular injection. This high dose of azaperone was administered to female pigs, only, as reconmmended by the manufacturers. The sedation induced by the drugs was assessed semi- quantitatively by a method based on that described by Marsboom and Symoens, Netherlands Journal of Veterinary Science, 1968, 1, 124-131. The behaviour of each animal was scored by the observer according to the following scale:

Score Level of Sedation Criterion

0 No sedation Behaviour unchanged

0.5 Detectable sedation Not as responsive as normal

1.0 Slight sedation No response when approached

2.0 Moderate sedation Easily handled

3.0 Marked sedation Little responses to auditory, visual or tactile stimuli

4.0 Pronounced sedation No responses to such stimuli

The animals were assessed at five minute intervals for the first 30 or 40 minutes after receiving the injection and then at 10 or 20 minute intervals. Any behavioural changes, such as paradoxical behaviour, were noted if and when they occurred.

The results are illustrated by the Figure which shows the levels of sedation produced by metoclopramide alone (3.3 mg/kg) (plot A) and in combination with midazolam (0.25 mg/kg) (plot B) as compared with that induced by azaperone (4 mg/kg) (plot C). The combination of metoclopramide (3.3 mg/ g) and midazolam (0.1 mg/kg) (plot B) gave a response that was about half as intense as that resulting from the administration of metoclopramide (3.3 mg/kg) and midazolam (0.25 mg/kg) but the duration of both responses was similar. Increasing the dose of midazolam to 0.4 mg/kg did not increase the intensity or duration of the effect above that obtained with metoclopramide (3.3 mg/kg) and midazolam (0.25 mg/kg). It can be seen from the Figure that the sedation resulting from the administration of metoclopramide (3.3 mg/kg) together with midazolam (0.25 mg/kg) (plot B) is more intense than that caused by azaperone (4 mg/kg) (plot C) and that it lasts for only half as long. Midazolam (0.25 mg/kg) administered alone caused sedation at a score of 1 which lasted for 30 minutes and had worn off after 50 minutes. Increasing the dose of metoclopramide used with midazolam (0.25 mg/kg) to 4.5 mg/kg did not appear to increase the sedation whereas when the dose of metoclopramide was reduced to 1.5 mg/kg the sedation only reached a score of 3. The pig that received metoclopramide (3.3 mg/kg) alone showed pronounced snout-rubbing and chewing behaviour between 10 and 20 minutes after the administration of the drug. No adverse behaviour was observed in any of the other pigs.

(b) This treatment was directed particularly to an evaluation of various physiological responses in the pig.

The treatment described in part (a) indicated that a dosage level of metoclopramide (3.3 mg/kg) together with midazolam (0.25 mg/kg) was effective so that this regimen was used subsequently.

Two pigs at a time were placed in a pen and left for 1.5 hours to settle down. The observer then entered the pen and waited for 30 minutes before making control observations on the following physiological parameters:

1. Position (sitting, standing, recumbency, etc.).

2. Respiration rate.

3. Heart rate.

4. Rectal temperature. 5. Response to a pin-prick on the digit or lip.

6. Muscle tone.

7. Response to handclap.

8. Eye: a. palpebral reflex. b. corneal reflex. c. position of eye.

9. Any other physiological processes that took place. The pigs were then injected intramuscularly as described in part (a) with metoclopramide (3.3 mg/kg) together with midazolam (0.25 mg/kg) and the physiological parameters observed at 5 minute intervals for 40 minutes, and then at 10 minute intervals for up to 80 minutes. Observations were made on a total of four pigs. The sedative effects of the treatment were similar to that shown in the accompanying Figure. Two of the pigs were very excitable before the treatment and sternal recumbency appeared in these two animals only after 10 minutes whereas this position is usually taken up by the pigs after 5 minutes. Lateral recumbency was observed after 20 minutes in the excitable pigs and after 15 minutes in the other two animals. All of the animals were standing 35 minutes after injection and after 1 hour showed no visible signs of sedation. It was found that there was a 30% increase in the respiration rate during the period that the pigs were sedated..

No statistically significant changes in the heart rate or body temperature were observed, the largest change in temperature being 0.7°C. The cornea! reflex was present throughout the period of sedation and the eyes remained in a normal position. In three animals the palpebral reflex was absent for a short period, i.e. it was only observed in one test, at 20-25 minutes after treatment. Responses to a pin-prick on the digit or lip or to noise were almost completely absent during the period of maximum sedation. The attention response to a handclap was greatly reduced.

Muscle tone, assessed on a semi-quantitative scale of 0-4, was reduced from a normal value of 4 to 0-2 during the first 20 minutes after the injection, after which it returned to normal by 1 hour. All four pigs drank from the drinker and defecated after they had regained a standing posture (approximately 40 minutes after injection). A short period of squealing occurred with two of the pigs at 50-55 minutes after treatment. No other signs of excitement were observed and no excessive salivation was seen. The stockman observed no abnormal behaviour in these animals after their return to their home pen.

(c) This treatment was directed particularly to an investigation of the ease of veterinary examination and the taking of blood* samples.

The weight of the pigs was estimated visually and an intramuscular injection of midazolam (0.25 mg/kg) was given which was followed, 5 minutes later, by an intramuscular injection of metoclopramide (3.3 mg/kg), the commercially available solutions being used. Observations were reported as time permitted since most of these animals were also being investigated for another purpose.

Five pigs were treated with midazolam followed by metoclopramide. Approximately 20 minutes after the initial injection the animals could be examined including, in one case, a rectal examination, and could be given an intravenous injection or a blood sample could be taken without difficulty. In two of the pigs there was some reaction to the introduction of the needle, although the animals remained lying on their backs. One animal was allowed to recover and appeared normal after 50 minutes. In a later test this pig was given metoclopramide (3.3 mg/kg) alone and less sedation was observed but 15 minutes after the administration of the drug an intravenous injection could be administered without restraining the animal. A similar response was obtained with another pig.

One pig was given midazolam alone (0.25 mg/kg). The animal showed atoxia but was not effectively sedated and resisted being restrained for an intravenous injection.

Claims

1. The use for the manufacture of a medicament for use in producing a tranquillizing effect in the pig of a first compound which is metoclopramide or a physiologically acceptable salt thereof, and a second compound which is midazolam or a physiologically acceptable salt thereof.

2. The use according to Claim 1, in which the weight/weight proportion of first compound/second compound is in the range of 2.5:1 to 25:1 in terms of the free base.

3. The use according to Claim 2, in which the proportion is in the range of 5:1 to 15:1.

4. A pharmaceutical composition comprising a first compound which is metoclopramide or a physiologically acceptable salt thereof, and a second compound which is midazolam or a physiologically- acceptable salt thereof, together with a physiologically acceptable diluent or carrier.

5. A pharmaceutical composition according to Claim 4, in which the weight/weight proportion of first compound/second compound is in the range of 2.5:1 to 25:1 in terms of the free base.

6. A pharmaceutical composition according to Claim 5, in which the proportion is in the range of 5:1 to 15:1.

7. A pharmaceutical composition according to Claim 4, 5 or 6, in injectable form.

8. A composition comprising a first compound which is metoclopramide or a physiologically acceptable salt thereof, and a second compound which is midazolam or a physiologically acceptable salt thereof, for use in therapy.

9. A pharmaceutical composition for use in producing a tranquillizing effect in the pig which comprises a first compound which is metoclopramide or a physiologically acceptable salt thereof and a second compound which is midazolam or a physiologically acceptable salt thereof.

10. A method for the treatment of a pig to produce a tranquillizing effect therein which comprises administering thereto amounts which together are effective in producing such an effect a first compound which is metoclopramide or a physiologically acceptable salt thereof and a second compound which is midazolam or a physiologically effective salt thereof.