FIELD OF THE INVENTION

The invention relates to the field of medicine, in particular to the field of veterinary medicine. The invention relates to a preparation for the reduction of both intra-operative and post-operative pain caused by castration of male piglets.

BACKGROUND INFORMATION

In swine production, male piglets are routinely surgically castrated when they are up to 7 days old. The aim is to avoid the characteristic boar taint, which reduces the value of pore as it is unpleasant to humans. The taint is caused by compounds that accumulate in the fat of sexually mature male pigs.

Castration causes pain in the concerned piglets. As of 2019, piglet castration will only be allowed under German animal welfare legislation if both intra-operative as well as postoperative pain is treated.

It is a requirement for a medication against pain during piglet castration, that it can be used by the farmer after prescription and guidance by the responsible veterinary surgeon. Moreover, the medication should not be a scheduled drug like most opioids, as the legal requirements for distribution and use would not be practical for farming conditions.

For the treatment of post-operative pain, Metacam is licensed in the EU (Ref. 1). However, Metacam is not approved to treat pain during the intervention (intra-operative pain). To date, no method to alleviate surgical pain during castration is established in routine farming practice. To achieve complete surgical tolerance, basically two methods are established in medicine in general: local anaesthesia and general anaesthesia. However, neither of these two methods is suitable for piglet castration under farming conditions. Local anaesthesia was tested in controlled studies but showed not to be of advantage to the piglets. General anaesthesia can legally only be used by veterinary surgeons, but not by the farmers and therefore, there is an unmet need for a treatment and/or a preparation to alleviate surgical pain in male animals during castration without the use of general (or local) anaesthesia. Immunocastration is possible. A licensed product in Europe is Imrovac (Ref. 2). With this approach, boar taint can be reduced. Moreover, it avoids pain of surgical castration. However, it has not reached widespread use in the pig industry, which favours surgical castration.

The problem underlying the present invention is to provide a medication to alleviate surgical pain during (and after) castration.

BRIEF SUMMARY OF THE INVENTION

Surprisingly, the solution to this problem is a treatment and /or medication combining meloxicam (e.g. as approved in the EU) and butorphanol. Meloxicam will reduce postoperative pain, whereas butorphanol will reduce pain during the surgical intervention. Butorphanol is currently not approved in pigs. The registered species are cats, dogs and horses (Ref. 3). In none of these species, butorphanol is approved to alleviate pain during soft tissue surgery or castration specifically. Butorphanol is a prescription only medicine, but it is not a scheduled drug. An acceptable daily intake (ADI) and a withdrawal period for edible tissues from horses is established in the EU (Ref. 4).

Although both meloxicam and butorphanol are used as medication against pain, it is surprising that this combination actually leads to pain relief during castration especially without general (or local) anaesthesia. In other species, it is described that opioids like butorphanol need to be combined with general analgesia or a neuroleptanalgesia, which is needed for surgical tolerance. (Ref. 5-8).

The advantage of this solution compared to the use of meloxicam alone is that intraoperative pain is controlled better according to some parameters indicative for pain. The advantage of the combined use of butorphanol and meloxicam in comparison to an opioid alone is that also post-operative pain, which is mainly inflammatory pain, is treated, as meloxicam has anti-inflammatory action. Butorphanol has the advantage over most other opioids that in many countries, it is not a scheduled drug, making prescription, storage and documentation much easier. Moreover, oral bioavailability in humans is low, which is relevant for the evaluation of potential residues in edible tissues. In contrast to general anaesthesia, piglets will remain conscious and will not have a recovery time. Therefore, the male piglets will not be disadvantaged to the non-castrated female piglets for example in the competition for access to milk, social ranking etc..

DETAILED DESCRIPTION OF THE INVENTION

Before describing the various aspects of the present invention it shall be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "a preparation" includes a plurality of such preparations reference to the "carrier" is a reference to one or more carriers and equivalents thereof known to those skilled in the art, and so forth. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All given ranges and values may vary by 1 to 5 % unless indicated otherwise or known otherwise by the person skilled in the art, therefore, the term "about" was omitted from the description. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies as reported in the publications which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

"Meloxicam" (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H- 1 ,2-benzothiazine-3- carboxamide- 1,1 -dioxide) is a non-steroidal-antiinflammatoriy drug NSAID of the oxicam family. These types of drugs inhibit the enzyme prostaglandine H2 synthase, also called cyclooxygenase or COX. Meloxicam has antiinflammatoric, antipyretic and analgetic properties.

(formula 1)

Meloxicam and its sodium and meglumine salts are described in EP0002482. The active ingredient alone has a low water solubility as shown in EP0945134 that also discloses the pH dependent solubility of meloxicam and its salts. There are many different application forms of meloxicam including a solution (EP 1299107), a suspension (EP 1066029), water- soluble granules (EP1558262), tablets made of either granules containing meloxicam (EP1942902) or of directly compressed powder mixtures (EP1385483 and GB2455875).

The term "butorphanol" (17-cyclobutylmethyl-morphinan-3,14-diol ) is well known in the art and means a mor hinan-type synthetic opioid analgesic.

(formula 2)

Butorphanol exhibits partial agonist and antagonist activity at the μ opioid receptor, as well as competitive antagonist activity and partial agonist activity at the κ opioid receptor. Stimulation of these receptors on central nervous system neurons causes an intracellular inhibition of adenylate cyclase, closing of influx membrane calcium channels, and opening of membrane potassium channels. This leads to hyperpolarization of the cell membrane potential and suppression of action potential transmission of ascending pain pathways. The advantage of butorphanol being merely a partial agonist and antagonist is that it has less abuse potential than many other opioids and is therefore not a scheduled drug. In consequence, it is a prescription only medicine (POM).

In a specific aspect of the present invention butorphanol is used in the form of butorphanol tartrate, preferably in a dose range between 0.05 to 0.6 mg/kg, preferably 0.2 mg/kg or less, more preferably 0.2 mg/kg.

The term "pharmaceutically acceptable excipient (or carrier or adjuvants)" for use with the pharmaceutical composition(s) according to the present invention include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. This is not a complete list possible pharmaceutically acceptable carriers, excipients and/or adjuvants, and one of ordinary skilled in the art would know other possibilities, which are replete in the art.

The term "patient" or "subject" means animals and embraces mammals such as primates including humans. The term "patient" or "subject" as used herein relates specifically to Suidae, especially to male pigs or male piglets, more specifically to male pigs or piglets, which are routinely castrated / subject to castration.

The term "castration" in male animals, such as mammals, preferably pigs or piglets means the following: Surgical removal of the testicles.

The term "pain" can be measured by behavioural or biochemical variables. In piglets these are for example defense movements during castration, quality of vocalisation, time spent at the mammary gland of the sow, activity , plasma Cortisol, catecholamine or ACTH levels. The term "intra-operative pain" means the following: Pain felt during the actual incision through the tissues at castration.

The term "post-operative pain" means the following: Pain arising after the end of the surgical intervention, which consists of inflammatory pain. The behavioural or biochemical variables may vary between "intra-operative pain" and "post-operative pain". The plasma Cortisol or ACTH levels are indicative for "postoperative pain". Reduction of pain reduces the plasma Cortisol or ACTH levels.

The quality of vocalization differs between presence and absence of "intra-operative pain" also referred to herein as "pain during castration".

The term "effective amount" as used herein means an amount sufficient to achieve a reduction of pain in piglets during castration.

The progress of the therapy can be monitored by diagnosis, for example, by clinical examination, analysis of behaviour and biochemical variables. These are for example: quality of vocalisation, time spent at the mammary gland of the sow, activity, plasma Cortisol or ACTH levels.

The catecholamine levels are indicative for stress and pain. Recent reports (Ref. 9 and 10) on opioids in general and butorphanol in particular disclose that catecholamine levels increase. Therefore, a decrease of this stress response caused by surgery can only be achieved by concomitant treatment e.g. with meloxicam.

The term "pharmaceutically acceptable derivative thereof means but is not limited to pharmaceutically acceptable salts, derivatives, metabolites or pro-drugs of a drug. Derivatives as used herein include but are not limited to, any hydrate forms, solvates, isomers, enantiomers, racemates, racemic conglomerate and the like of the compound of choice. Suitable pharmaceutically acceptable salts are well known in the art and may be formed with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malo- nic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hy- droxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

A pharmaceutical composition/ preparation / medicament according to the invention may contain, as the meloxicam salt, the meglumine, sodium, potassium or ammonium salt. The solubilisers used may be, for example poly ethylenegly cols (e.g. Macrogol 300), poly- oxyethylene-polyoxypropylene copolymers (e.g.poloxamer 188), glycofurol, arginine, lysine, castor oil, propyleneglycol, solketal, polysorbate, glycerol, sorbitol, mannitol, xylitol, polyvinylpyrrolidone, lecithin, cholesterol, 12-hydroxystearic acid-PEG660-ester, propyleneglycol monostearate, polyoxy-40-hydrogenated castor oil, polyoxyl-10-oleyl-ether, polyoxyl-20-cetostearylether and polyoxyl-40-stearate or a mixture of sorbitol, mannitol and xylitol, preferably polyethyleneglycols, polyoxyethylene-polyoxypropylene copolymers, glycofurol, polyvinylpyrrolidone, lecithin, cholesterol, 12-hydroxystearic acid- PEG660-esters, propyleneglycol monostearate, polyoxy-40-hydrogenated castor oil, poly- oxyl-10-oleyl-ether, polyoxyl-20-cetostearylether and polyoxyl-40-stearate. The preservatives used may be, for example, ethanol, benzoic acid and the sodium or potassium salts thereof, sorbic acid and the sodium or potassium salts thereof, chlorobutanol, benzyl alcohol, phenylethanol, methyl, ethyl, propyl or butyl-p-hydroxybenzoates, phenol, m-kresol, p-chloro-m-kresol or benzalkonium chloride.

The buffer system may be, for example, glycine, a mixture of glycine and HC1, a mixture of glycine and sodium hydroxide solution, and the sodium and potassium salts thereof, a mixture of potassium hydrogen phthalate and hydrochloric acid, a mixture of potassium hydrogen phthalate and sodium hydroxide solution or a mixture of glutamic acid and glu- tamate.

Other suitable excipients are citric acid, lecithin, gluconic acid, tartaric acid, phosphoric acid and EDTA or the alkali metal salts thereof, preferably tartaric acid and EDTA or the alkali metal salts thereof, particularly disodium EDTA.

The concentration of the solubilisers may be in the range from 20-200 mg/ml, preferably 30-150 mg/ml, preferably 40-130 mg/ml, more preferably 50-120 mg/ml, especially 70- 100 mg/ml.

The concentration of the preservative ethanol may be in the range from 100-200 mg/ml, preferably 120-180 mg/ml, more preferably about 150 mg/ml.

The concentration of the preservatives benzoic acid and the sodium or potassium salts thereof, sorbic acid and the sodium or potassium salts thereof, chlorobutanol, benzyl alcohol, phenylethanol, phenol, m-kresol and p-chloro-m-kresol may be in the range from 0.5- 50 mg/ml, preferably 1-10 mg/ml, more preferably 3-5 mg/ml.

The concentration of the preservatives benzalkonium chloride, phenylmercurynitrate and methyl-, ethyl-, propyl- or butyl-p-hydroxybenozates may be in the range from 0.01-4 mg/ml, preferably 0.02-3 mg/ml, more preferably 0.1-0.5 mg/ml.

The concentration of the buffer substances may be between 4 and 50 mg/ml, preferably between 5 and 20 mg/ml, more preferably between 8 and 10 mg/ml.

The concentration of the other excipients mentioned above, i.e. EDTA, citric acid, lecithin, gluconic acid, tartaric acid and phosphoric acid or the salts thereof may be in the range from 0.2-3 mg/ml, preferably 0.3-2.5 mg/ml, preferably 0.5-2 mg/ml, most preferably 0.6- 1.5 mg/ml, and in particular 0.7-1.0 mg/ml.

A suitable form of "administration" is for example parenteral administration, e.g. subcutaneous, intravenious or intramuscular injection (i.m.), preferably i.m.. A preparation containing butorphanol and meloxicam is preferably used as solution for injection, preferably i.m..

Preferred concentration ranges of meloxicam are 1-100 mg/ml or more preferred 1-30 mg/ml, especially 5 mg/ml.

A preferred concentration range of butorphanol is 1-30 mg/ml, especially 5 mg/ml.

A suitable dosage of the pharmaceutical composition according to the present invention is in the range of:

For meloxicam 0.1 to 1 mg/kg, especially 0.4 mg/kg once or twice at 24 h interval, preferably once.

For butorphanol: 0.05 to 0.6 mg/kg, especially 0.2 mg/kg or 0.4 mg/kg, preferably 0.2 mg/kg, once or twice after castration, preferably once.

The present invention concerns a pharmaceutical composition / preparation / medicament comprising (both) meloxicam or pharmaceutically acceptable salts thereof and butorphanol or pharmaceutically acceptable salts thereof (as the main and/or the sole active ingredients) and optionally a pharmaceutically acceptable excipient (or carrier), whereby said composition is preferably a liquid formulation, most preferably a solution for injection.

In a specific aspect of said pharmaceutical composition / preparation / medicament the concentration of meloxicam ranges between 1-30 mg/ml, preferably 1-5 mg/ml, most preferred the concentration of meloxicam is 5 mg/ml. In another specific aspect of said pharmaceutical composition / preparation / medicament the concentration of butorphanol ranges between 1-30 mg/ml, preferably 1-5 mg/ml, most preferred the concentration of butorphanol is 5 mg/ml.

The present invention further concerns a pharmaceutical composition / preparation / medicament according to the present invention for use as a medicament in an animal, preferably in a mammal, most preferably in a Suidae such as a pig or piglet. In a specific aspect the animal is a male animal.

The present invention furthermore concerns a pharmaceutical composition / preparation / medicament comprising meloxicam or a pharmaceutically acceptable salt thereof in combination with butorphanol (or a pharmaceutical composition / preparation / medicament comprising butorphanol or a pharmaceutically acceptable salt thereof) for use as a medicament in an animal, preferably in a mammal, most preferably in a Suidae such as a pig or piglet. In a specific aspect the animal is a male animal.

The present invention further concerns a pharmaceutical composition / preparation / medicament according to the present invention for use in a method of treating pain in a male animal during and preferably also after castration, preferably said animal is a mammal, most preferably a Suidae such as a pig or piglet.

The present invention further concerns a pharmaceutical composition / preparation / medicament comprising meloxicam or a pharmaceutically acceptable salt thereof in combination with butorphanol (or a pharmaceutical composition / preparation / medicament comprising butorphanol or a pharmaceutically acceptable salt thereof) for use in a method of treating pain in a male animal during and preferably also after castration, preferably said animal is a mammal, most preferably a Suidae such as a pig/ piglet, whereby said compositions are preferably liquid formulations, most preferably solutions for injection. In a specific aspect the male animal is treated at least once prior to castration, preferably 10 to 60 minutes before castration, more preferably 15 to 30 minutes before castration, most preferably 20 minutes before castration. In another specific aspect castration is performed without the use of general (or local) anaesthesia. In a further specific aspect the male animal is treated to reduce the pain during and after (surgical) castration. In a specific aspect no general (or local) anaesthesia is used. In another specific aspect the dose for meloxicam ranges between 0.1 to 1 mg/kg, preferably 0.4 mg/kg, and preferably the dose for butorphanol ranges between 0.05 to 0.6 mg/kg, preferably 0.2 mg/kg or 0.4 mg/kg, more preferably 0.2 mg/kg.

In a further specific aspect the dose for meloxicam ranges between 0.1 to 1 mg/kg, preferably 0.4 mg/kg, and preferably the dose for butorphanol ranges between 0.05 to 0.6 mg/kg, preferably 0.2 mg/kg or less, preferably 0.2 mg/kg.

In a further aspect the pharmaceutical composition(s) / preparation(s) / medicament(s) is (are) administered once or twice, preferably once. Preferably the second administration occurs after a 24 h interval.

In another aspect butorphanol is additionally administered (alone) once or twice after castration, preferably once, preferably at a dose of 0.05 to 0.6 mg/kg, most preferably at a dose of 0.2 mg/kg or 0.4 mg/kg, more preferably 0.2 mg/kg.

In a further aspect butorphanol is additionally administered (alone) once or twice after castration, preferably once, preferably at a dose of 0.05 to 0.6 mg/kg, most preferably at a dose of 0.2 mg/kg or less, preferably 0.2 mg/kg.

The present invention further concerns a method of treating pain in a male animal during and preferably also after castration comprising (a) administrating a therapeutically effective amount of the pharmaceutical composition / preparation / medicament (fixed dose combination) according to the present invention or (b) administrating a pharmaceutical composition / preparation / medicament comprising meloxicam or a pharmaceutically acceptable salt thereof in combination with butorphanol (a pharmaceutical composition / preparation / medicament comprising butorphanol) to a patient in need thereof, whereby said animal is preferably a mammal, most preferably a Suidae such as a pig or piglet, whereby said animal is preferably male, whereby preferably no general (or local) anaesthesia is used, whereby meloxicam and butorphanol are preferably administered 10 to 60 minutes before castration, more preferably 15 to 30 minutes before castration, most preferably 20 minutes before castration. In a specific aspect the dose for meloxicam ranges between 0.1 to 1 mg/kg, preferably 0.4 mg/kg, and preferably the dose for butorphanol ranges between 0.05 to 0.6 mg/kg, preferably 0.2 mg/kg or less, preferably 0.2 mg/kg. The present invention further concerns a kit consisting of a pharmaceutical composition / preparation / medicament according to the present invention (fixed dose combination and/ or one or both active ingredients meloxicam and butorphanol separately / in separate vials), an injection device (preferably designed to inject Suidae such as a pig or piglet) suitable for parenteral administration (subcutaneously, intraveniously or intramuscular), and optionally an instruction leaflet or information and/or direction for use.

The present invention further concerns a kit consisting of

(a) a pharmaceutical composition according to claims 1 to 3 or

(b) a pharmaceutical composition comprising meloxicam or a pharmaceutically acceptable salt thereof in combination with

a pharmaceutical composition comprising butorphanol or a pharmaceutically acceptable salt thereof,

(c) an injection device suitable for parenteral administration preferably designed to inject Suidae such as pigs or piglets, and

(d) optionally an instruction leaflet or information and/or

(e) direction for use.

EXAMPLES

The following examples serve to further illustrate the present invention; but the same should not be construed as a limitation of the scope of the invention disclosed herein.

EXAMPLE 1

A preparation containing butorphanol and meloxicam is used as solution for injection. Such preparation is injected intramuscularly to male piglets which are up to 7 days old before castration. Both butorphanol and meloxicam are used at a dosage of 0.4 mg/kg. The solution for injection contains butorphanol and meloxicam at equal concentration of 5 mg/ml. Therefore, 0.08 ml are administered per kg bodyweight of the piglet. After treatment, piglets are surgically castrated. Treated piglets show less pain reactions such as vocalization during castration or defense movements during castration than untreated castrated piglets and lower levels of certain stress indicators such as plasma Cortisol and catecholamines (especially adrenalin and noradrenalin) than untreated castrated piglets. EXAMPLE 2

A preparation containing meloxicam is administered in a dose of 0.4 mg/kg i.m. into the left neck to male piglets which are up to 7 days old.

Further, a preparation containing butorphanol tartrate is administered in a dose of 0.2 mg/kg i.m. into the right neck to male piglets which are up to 7 days old.

Surgical castration is performed 20 minutes after drug administration.

Treated piglets show less pain reactions such as vocalization during castration or defense movements during castration than untreated castrated piglets and lower levels of certain stress indicators such as plasma Cortisol and catecholamines (especially adrenalin and nor- adrenalin) than untreated castrated piglets.

REFERENCES:

1. Summary of Product Characteristics Metacam 5 mg/ml solution for injection for cattle and pigs, EMA

2. Summary of Product Characteristics Improvac, EMA

3. Summary of Product Characteristics Turbogesic, VMD

4. MRL summary report butorphanol, EMA

5. Shih et al, Veterinary Anaesthesia and Analgesia, 2008, 35, 69-79

6. Borer et al., Americam Journal of Veterinary Research, 2003, 64(1 1), 1429-1437

7. Caulkett et al., Canadian Veterinary Journal, 2003, 44, 565-570

8. Mathews et al., American Journal of Veterinary Research, 2001, 62(6), 882-888

9. Vaisanen et al, American Journal of Veterinary Research, 2002, 63 (7), 969-975

10. Chambrier, C.and Bouletreau, P., Annales francaises d'anesthesie et de reanimation, 1992, 11 (6), pp. 636-643