DE2819859A1 - ANIMAL TREATMENT AND INHALATION DEVICE FOR ANIMALS - Google Patents

Description

The present invention relates to the treatment of animals and to corresponding new preparations.

The present invention provides a possibility for the prophylactic or therapeutic treatment of allergic diseases in cattle, horses, pigs, cats and dogs, in which the cattle, horse or pig, cat or dog suffering from such a disease or could be affected by it, administered an active substance that has an effect similar to that of sodium cromoglycate.

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Compounds with a sodium cromoglycate-like effect can inhibit the release of pharmacological mediators caused by the in vivo combination of certain types of antibodies and specific antigens arise, e.g. through the combination reactive antibody with specific antigen (see example 27 of GB-PS 1 292 601 - passive cutaneous anaphylaxis test with Rats).

The active ingredients can be characterized by the following biological tests and their results.

The first step is the passive cutaneous anaphylaxis test used with rats. It does not show any substantial inhibition of the allergic phenomena when taken in a crowd of 20 mg / kg body weight is administered intraperitoneally (i.p.) or intravenously (i.v.), their effectiveness is generally too low. Various other biological tests can also be used to prove that the compound is shows its anti-allergic effect in inhibiting anaphylaxis mediators as e.g. an end organ antagonist, anti-cholinergic or represents adenyl cyclase stimulator. Therefore, tests can also be used to show whether the connection supports the Effect of histamine, serotonin and the slowly reacting anaphylaxis substance (SRSA) inhibited, i.e. whether the compound is an end organ antagonist for the mediators. Such attempts are well known; an example is the one to determine the serotonin effect applied contraction test with a

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Guinea pig ileum in the presence of methysergide. Is at If there is still activity in these systems, it is based on the action of histamine. Histamine can still be detected determine by the spectrofluorimetric analysis of Shore, Burkhalter and Cohn; see Journal of Pharmacology and Experimental Therapeutics, Bend 127, page 182. The inventive Active substances are not end-organ antagonists.

If the results of these tests show that the active ingredient is not an end organ antagonist, further tests can be used to determine whether it also shows no anticholinergic effect, e.g. by reversing the contraction attempt induced with acetylcholine with a guinea pig trachea. The active ingredients used according to the invention are also not anticholinergics.

Suitable groups of active ingredients are among the chromone-2-carboxylic acids and their derivatives, such as those disclosed in British Patents 1,368,243, 1,144,905 and 1,230,087 and in German Patent 2,553,688. Other active ingredients can be found under the xanthones, e.g. in Belgian patents 759 292 and 787 843 and Dutch patents 72 09622 and 7306958; the Compounds of Belgian patent 792,867; the azapurines, e.g. Belgian patent 776 683; the oxazoles, e.g., German Offenlegungsschrift 2,459,380; and the Plavonen, e.g. Belgian patent 823 875.

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The chromones and chromone-like compounds are preferred British patents 1,144,905 and 1,230,087 and German patent 2,553,688, in particular the compounds of formula I:

HOOCJJ Il Λ ^OX0 'κ π ii _cocn

in which X stands for a polymethylene chain having 3 to 7 carbon atoms which can be substituted by a group -OH; and the pharmaceutically acceptable derivatives of these compounds.

1,3-Bis- (2-carboxychromon-5-yloxy) -propan-2-ol or one of its pharmaceutically acceptable derivatives, for example a salt such as the disodium salt; the latter is commonly referred to as sodium cromoglycate or cromolyn sodium. Further preferred compounds are 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho- / 2 *, 3-b7-pyran-2-carboxylic acid and 6,7,8,9-tetrahydro -5-hydroxy-4-oxo-10-propyl-4H-naphtho / 2,3-b7-pyran-2-carboxylic acid and its pharmaceutically acceptable derivatives can be mentioned. Suitable pharmaceutically usable derivatives are, for example, salts, alkyl-C ^ g-esters, mono-alkyl -C ^ _-1 Q-amides, dialkyl-C _1-1Q -amides or an unsubstituted amide of the 2-carboxylic acid group .

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The preparations according to the invention are suitable for the treatment of Diseases, especially lung diseases, in which allergic reactions or immune reactions play a role, such as in certain respiratory and lung disorders. Particularly noteworthy are diseases which are caused by antigens and cause a shock reaction and slowly reacting anaphylaxis substance (SRS-A) is released. In horses, for example, respiratory disorders (broken wind), horse asthma (lung disease, accompanied by heavy breathing and heavy lifting and lowering of the flanks), chronic obstructive pulmonary disease), laminitis and sweat itch; and at Cattle, fog fever, hoarseness (husk), acute pulmonary emphysema, "farmer's lung" (bovine farmer's lung) as well Respiratory diseases caused - at least in part - by the bovine respiratory syncytic virus (RSB respiratory syncytial bovine virus). The latter disease is flu-like and accompanies it dyspnea, emphysema and foaming from the mouth. It leads to death within a few hours, if not immediately effective treatment begins. Respiratory disorders in cattle and horses are particularly common in humid climates, or when moldy hay is being fed or present.

* «" Heaves "

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The preparations according to the invention are suitable for cats and dogs

- especially its oral and external forms of application - / especially
'For the treatment of allergic diseases caused either by allergens that can be found in feed, feed additives, therapeutic preparations or in parasitic fungi caused by bacterial or fungal infections, or by inhaled antigens or. Contact antigens were caused. Symptoms that can be mentioned are: pruritis, which manifests itself in vigorous scratching, nibbling, licking or rubbing of the skin as well as in an exaggerated scratch reflex or skin twitching; self-inflicted lesions, which can vary in shape, size, and distribution across the body; other skin changes accompanied by general hyperemia, papular reaction, edematous areas, as well as edema of the head, vulva and extremities; and severe inflammatory changes that cause serum leakage and peeling skin on parts of the body. Lesions are mostly found on the hairless parts of the body, but their distribution depends on the cause and which part of the body comes into direct contact with the allergen. Inhaled antigens can cause "hay fever", asthma-like attacks, and conjunctivitis, especially in dogs. Allergic contact dermatitis also is especially common in dogs.

Gastrointestinal disorders and enteritis in young pigs and cattle can cause neo-natal diarrhea and fluid loss often lead to death. These disorders can be treated according to the invention (in particular by oral administration of the active ingredient), as well as diarrhea in somewhat older animals that are still suckled or have just been weaned. Highlighted

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Such diarrhea be fen by infections and / or viruses (such as rotavirus and coronavirus) and / or hypersensitivity to, for example, soybean meal, by endotoxins formed coil by certain pathogenic species of E., or by encountered in transmissible gastroenteritis virus.

The active ingredient can be administered in any suitable manner which either leads to a sufficient concentration of the active ingredient in the blood or acts directly on the organ affected by the disorder, for example on the respiratory tract, the digestive tract or the skin. If a disease of the respiratory tract is to be treated, the active ingredient can be brought directly into the respiratory tract by letting the animal inhale, for example, a very finely atomized solution or a powdered aerosol, either through its mouth or nose. A conventional atomizer can be used to generate the solution mist. Such an atomizer can for example consist of an air nozzle which blows an air jet over the open end of a tube, the other end of which protrudes into the solution to be atomized, and also have a surface on which the larger drops of the atomized solution are collected. The nebulizer can be operated with compressed air or compressed nitrogen or oxygen, or a hand-operated, mechanical or, preferably, an electric pump can be used.

The atomizer (s) are - preferably mounted in a device, one inhalation chamber that fits over the animal's mouth and nose having. This device is preferably cylindrical or bag-

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shaped and preferably made of a material, in particular a relatively stiff material, which has sufficient strength for veterinary practice, for example made of fiberglass or polypropylene. In addition, one or more openings or valves are preferably provided so that the animal can exhale relatively easily. Finally, means are preferably also provided to fasten the device over the nose and mouth of the animal, for example straps that are tied together behind the head and ears of the animal. To ensure that the solution mist cannot escape from the device but is completely inhaled, means can also be provided to seal the inhalation chamber on the head of the animal, e.g. a seal made of rubber or another flexible material around the head of the animal fits and, if necessary, can be tightened more, for example with the help of a drawstring. To generate powder aerosols, the active ingredient can be placed in a pressure vessel or the device described in British Patent 1,182,779 can be used. Atomized solutions or powder aerosols can then be delivered from the device in which they are generated to the animal's nose or mouth in the manner described above, or a flexible tube can be used which, if it is intended to be inhaled through the nose, is provided with fitting parts for insertion into one or both nostrils or, if inhalation is to be carried out through the mouth, with an attachment which prevents the tube from being compressed in the animal's mouth. In addition, the active ingredient can be administered intravenously, intramuscularly or, preferably, subcutaneously.

* "pressure pack"

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If desired, the active ingredient to be administered according to the invention can be mixed with one or more other compounds which are tolerated by the animal in the chosen mode of administration; For inhalation purposes, for example, water and coarse lactose or, in the case of aerosols, suitable propellants and surface-active agents are suitable. The active ingredient can also be mixed with a compound that prevents the release of SRS-A (slowly reacting anaphylaxis substance) or acts as an antagonist for SRS-A that has already been released. An example of such anti-SRS-A compounds is diethylcarbamazine. Such mixtures can be used in accordance with the process according to the invention. However, the active ingredient can also be administered shortly after or at the same time as the anti-SRS-A compound. If diethylcarbamazine is used, a dosage of about 15 to 25 mg, for example 20 mg, per kg of body weight of the animal is recommended. When administered orally, the active ingredient can be mixed with inert diluents such as talc, dextran, lactose, calcium phosphate, water and the like. The active ingredient can also be mixed with the animal's feed, for example with milk, or enriched with other substances that are to be administered to the animal orally. Suitable additives for the Wiitetoff are: trace elements such as copper, cobalt and / or manganese; one or more vitamins, such as vitamins A, D, B ^, Bp » Bg, B ^ ₂ and / or E (or other antioxidants); Antibiotics (which help prevent neonatal diarrhea ) such as broad spectrum antibiotics such as chlortetracycline hydrochloride, oxytetracycline, and nitrofurans; Absorption aids, for example certain amino acids and / or electrolytes; Immunoglobulins; or corticosteroids.

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Of the preparations suitable for oral administration, mention should be made of the flowable preparations which are entered, for example, as a swallow portion with the aid of a pistol, a bottle or some other device that allows precise dosing. These preparations can be made as wettable powders and dispersed or dissolved in water before use. Such powders generally contain the active ingredient, a colloid which gives the swallowable fraction a viscosity suitable for the pistol, and a surface-active agent which facilitates the dispersion and dissolution of the powder in water. The swallow portion can also be made in liquid form, but should then contain a preservative such as chloroform, glycerine or sodium benzoate. The active ingredient can also be offered in one of the following forms;

- as a tablet, the active ingredient, binding agent, humectant, contains a disintegration accelerator and lubricant;

- "as a capsule containing the active ingredient, binding agent, humectant and lubricant;

- as a pill or bolus containing the active ingredient and syrup or molasses;

- As a paste, the active ingredient, vegetable gum and preservative contains; or

- as an aerosol pack, the active ingredient, surface-active agent, Contains propellant and optionally water.

If desired, aerosol, ingestion , and paste preparations may contain a suitable flavoring agent to make them more readily accepted by the animals. Of course they should

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Preparations are in a form that allows the administration of the required Easier dose, e.g. as individual dosage units. Solids or pastes are preferred because they are special can be entered easily and securely.

The active ingredient can be administered orally to the animal in a conventional manner; Tablet, capsule, pill or bolus, for example, is best placed far back in the animal's mouth, shot or thrown, and a paste is carefully applied to tongue, teeth and the Lubricated inside of the mouth. Other modes of administration are also possible: liquids and pastes can e.g. be entered with a bottle or gun that delivers a precisely measured dose, and aerosol preparations can be supplied in containers that also dispense a measured dose. Such bottles, pistols and containers filled with a preparation containing the active ingredient are further objects of the present invention.

Oral treatment of gastrointestinal disorders is most appropriate in young calves and pigs, e.g. during the first 12 weeks and preferably during the first 21 days in the life of these animals. Preferably weigh this, on gastrointestinal Disturbances to be treated calves about 40 to 60 kg and can be animals intended for intensive fattening. In general these are bull calves.

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The required dosage of the active ingredient naturally depends on the selected active ingredient, the type and severity of the disease to be treated, the selected mode of administration and the size of the Animal. However, it has been found that with intravenous, intramuscular or subcutaneous injections, in general, a daily Active ingredient dose up to about 15 mg per kg of body weight of the animal is sufficient, e.g. a dose of about 5 to 15 mg / kg and preferably about 10 mg / kg. Intravenous injections preferably last at least 60 seconds. Should the active ingredient be inhaled For example, in the form of a finely atomized solution, the daily dose is generally up to 160 mg, preferably about 40 to 160 mg and in particular 40 to 80 mg per animal.

Oral administration is used to treat gastrointestinal disorders of the active ingredient preferred. In the case of piglets, the daily dose in this case is up to 1500 mg, preferably 10 to 500 mg and in particular 10 to 200 mg, while in the case of calves about 50 to 1000 mg, preferably 50 to 500 mg and in particular about Apply 100 mg per day. For cats and dogs, a daily dose of up to 250 mg is administered, preferably 25 to 250 mg Active ingredient per day.

The above dosages can be divided and entered 1 to 4 times, preferably 1 to 2 times per day.

If the method according to the invention is applied to cattle, pigs and horses, the animals show a greater increase in weight than untreated animals.

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The following examples illustrate the present invention.

Example 1: Chronic lung obstruction in horses Two horses sensitized to M.faeni were used. The M.faeni sensitization was carried out by atomizing a spore suspension in a Wright nebulizer, guiding the mist laden with spores through a rubber hose into a bucket attached to the horse's mouth and allowing the horse to breathe it normally into the respiratory tract.

Atomized disodium cromoglycate was inhaled by the horses using a mask that was attached and sealed to their mouths became. This mask consisted of a plastic bucket in which Side walls 4 atomizer units had been welded. These atomizers were md to the horse's nostrils placed about 8 to 10 cm from the bottom of the bucket. In the bottom of the bucket was a one-way valve that allows exhalation allowed. The nebulizer units were mounted so that they were in a horizontal position when in use. Every The unit was filled with 2 ecm of a 1 # aqueous disodium cromoglycate solution charged and operated with a Wright pump, the flow rate using a drain valve was reduced to 9 l / min.

In the initial trial, the horse was treated with a dose of 80 mg disodium cromoglycate each time for four days. Then it was sensitized with M. faeni at certain intervals after this treatment time, with clinical appearance, auscultation

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of the rib cage and changes in intra-thoracic pressure and arterial oxygen pressure served as the main indicators of response to the irritation.

The horse showed no reaction to the sensitization for up to 7 days, however, was no longer protected 4 weeks after the initial treatment.

In a second attempt, the 4-day treatment period with equal amounts of disodium cromoglycate protected the horse from M. faenl sensitization for 10 days, but was no longer effective after 17 days of follow-up treatment.

In the final experiments, the duration of protection of a single disodium cromoglycate treatment should be determined.

First attempt with a single dose of 80 mg disodium cromoglycate protection lasted 2 days, but was no longer detectable after 4 days of follow-up treatment. On the second try the protection provided by a single dose of 160 mg disodium cromoglycate could not survive a 4-day follow-up treatment.

A second horse was protected by the 4-day treatment with disodium cromoglycate described above for 10 days.

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Example 2

A diarrhea epidemic broke out in a farm for rearing calves, which affected 50% of the calves and - despite antibiotic treatment - led to the death of 10% of the calves.

10 calves were treated with 100 mg disodium cromoglycate per day for 21 days from birth (administered in one dose, dissolved in 100 ecm milk).

None of these calves developed diarrhea and there were no deaths.

Example 3

A litter of 6 piglets aged 3 weeks served as test animals. All animals have suffered from diarrhea since birth and had already been treated with antibiotics twice. Each treatment had lasted 3 days and resulted in the Diarrhea stopped for 1 to 2 days.

Three of these piglets were then treated for 3 days with 25 mg disodium cromoglycate each, dissolved as a single dose in 5 ecm of water, administered daily.

After just two treatments, the diarrhea stopped in those treated Piglets and was no longer detectable within the observation period (1 week).

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Example 4

Six dogs and one cat were used as experimental animals. During the duration of the experiment, the animals received a gelatin capsule every day, the 25 mg respectively. 100 mg of disodium cromoglycate as the active ingredient.

All animals were subjected to a daily clinical examination with a record of their skin condition.

Results

The response of each animal to the treatment is as follows summarized.

1. Cat - food allergy - beef General pruritis. Skin macroscopically normal; however, when feeding cooked beef, irritation occurred which led to self-inflicted skin damage.

i 1 x 25 mg disodium cromoglycate per day; Start of treatment 24 hours after the animal is on a beef diet had been set. All irritation caused by beef ceased in the next 24 hours. Treatment was Continued for 7 days, during which time the animal was in good health with no signs of skin irritation in spite of it continued to be fed beef. After the treatment was discontinued, the irritation reappeared.

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2. Dog Retriever Allergy

Severe pollen contact allergy that could not be combated with steroids despite the initial success of these
Therapy.

Treatment ^ 1 χ 100 mg disodium cromoglycate per day at the beginning, then increased to 1 χ 200 mg disodium cromoglycate per day. at
the lower dose showed no improvement. There was slight improvement seven days after the dose was increased to 200 mg disodium cromoglycate per day. However, skin thickening and hyperemia persisted and the animal continued to scratch itself very frequently.

3. Dog - German shepherd - food allergy - pork
The allergy had existed for at least 12 months; distinct
secondary changes and widespread staph infection of the skin.

^ ^x 1ÖÖ ^m S disodium cromoglycate per day. There was a slight improvement within the 7-day trial period
record.

4. Dog - terrier - food allergy - cow's milk

The allergy had previously been successfully treated with betamethasone treatment. ·.

Treatment ^ 1 χ 100 mg disodium cromoglycate per day. Steroid therapy was replaced by treatment with cromo glycate disodium for 4 days . The skin irritation reappeared, although not very severely.

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5. Dog - setter - food allergy - cow's milk

Allergy caused general skin irritation; additional pollen contact allergy with skin changes in places. The animal could not tolerate steroid therapy; this led to excessive thirst, strong urination and pseudo-affinity.

§Sii§ ⁿ älH2Si ^ ^x 100 mg disodium cromoglycate per day. The skin irritation on the back subsided within the 7-day trial.

6. Dog - Terrier - Food allergy - Mutton The allergy had been successfully treated with steroids.

Treatment: 1 χ 100 mg disodium cromoglycate per day. After the In the first 48 hours, the treatment results were quite good over the test period of 5 days.

7. " Dog - Labrador Retriever - Food allergy - Beef The allergic skin reaction was accompanied by a bacterial infection.

1 χ 100 mg disodium cromoglycate per day. As well as clinical allergic condition as well as bacterial infection responded very well to treatment.

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The attached drawing shows the disassembled parts a device that allows animals to inhale an atomized solution.

In this drawing, the base plate 1 is provided with two openings 2 into which the two atomizers 3 are fitted. the Atomizers 3 are connected to the compressed air supply 4. The base plate 1 is mounted on a frame 5 that holds the compressed air

I system

Supply ^ 4 bears. This frame 5 is provided with hinge brackets 7, via the corresponding hooks 8 on the inhalation chamber 9 fit. The inhalation chamber 9 has two exhalation valves 10, slots 11 for the head straps, and pressure pins 12 Inhalation chamber is pushed over elastic (rubber) seal 13 and connected to it by pressure pins 12; the elastic seal 13 is provided with a drawstring 14.

In use, the inhalation chamber 9 and the elastic Seal 13 is pushed onto the head of the animal, and the frame 5, which holds the atomizer 3 (which is made with an aqueous solution of the active ingredient have been filled), the base plate 1 and the compressed air supply 4 carries, is attached to the inhalation chamber with the help of the bracket 7 and hook 8. Then the atomizers put into operation, and the animal is allowed to inhale the atomized solution until it has the required amount Has absorbed the active ingredient.

- patent claims -

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Claims (1)

Patent claims: 1. Agents for the prophylactic or therapeutic treatment of diseases on an allergic basis, in particular in cattle, horses, pigs, cats or dogs, characterized in that it has an active ingredient with a similar effect like sodium cromoglycate includes: 2. Agent according to claim 1, characterized in that the active ingredient is a compound of the following formula I: HOOC OXD in which X is a polymethylene chain with 3 to 7 carbon atoms which can be substituted by a group -OH; or a pharmaceutically acceptable derivative of this compound . 3 «means according to claim 1 to 2, characterized in that that the active substance is sodium cromoglycate. 809845/1051 ORIGINAL INSPECTED N ^ .CHC REACHED .Z 4. Composition according to claim 1 to 3 » characterized in that it is present as a preparation for direct administration into the respiratory tract, the digestive tract or the skin. 5. Composition according to claim 4, characterized in that it is present for administration into the respiratory tract as a nebulizable solution or powder aerosol. 6. Inhalation device for animals, especially horses, cattle, pigs, cats or dogs, for administering the Agent according to Claims 1 to 5, characterized in that it comprises an inhalation chamber (9) which extends over the nose and mouth of the Animal fits and is provided with one or more internal atomizers (3). 7. Apparatus according to claim 6, characterized in that that it has one or more openings or valves (10), which allow the animal to exhale easily. 309845/1051