MXPA99009783A - Composition and methods using an eutomer - Google Patents

Abstract

Method for improving health, survival and muscle growth rate of animals, while reducing carcass fat and improving feed efficiency by administering an optically pure eutomer of an adrenergic beta-2 agonist. The invention is also directed to food compositions comprising the adrenergic beta-2 agonists.

Description

COMPOSITION AND METHODS USING AN EUTOMER BACKGROUND OF THE INVENTION Many biologically active molecules exist as enantiomers. Although structurally identical enantiomers may have different effects on biological systems: one isomer may have specific therapeutic activity while the other isomer may not have therapeutic activity or may have completely different activity forms of biological activity.

The form in which the beta-2 adrenergic agonist drugs are currently used therapeutically in mammals are as racemic mixtures of two isomers (for example, R- and S-albuterol, R- and S-salmeterol, R- and S-terbutaline ). An R-isomer of a racemic compound is structurally identical to the S-isomer and the isomers differ only in that one isomer is an image in the mirror of the other. Molecules with two chiral centers have four isomers, for example, RR-formoterol, SS-formoterol, RS-formoterol and SR-formoterol. The therapeutically active isomers (the eutomers) of the beta-2 agonists are the R- or RR-isomers, while REF .: 31772 that the S- or SS-isomers usually do not possess therapeutic activity (distomeres). An exception is salmeterol, where both isomers have beta-2 adrenergic agonist activity and thus either of the two isomers of salmeterol can be considered as a eutomer. A therapeutic action of beta-2 agonist drugs is to activate beta-2 adrenergic receptors and with this initiate cellular responses, the best known in the relaxation of bronchial smooth muscles. Beta-adrenergic agonist drugs also have metabolic effects and increase growth or development, and such effects may reside in any of the isomers. It has been shown that the beta-agonist eutomer causes improved muscle development, whereas a decrease in body fat has been established. The pharmacological effects and toxicity of beta-adrenergic agonists vary, depending on the animal species and which drug is studied. It has now been found that the therapeutically effective S-isomer of albuterol is approximately equitoxic to the R-isomer. It has now been found that the S-isomers of albuterol and salmeterol are metabolized significantly slower than the R-isomers, causing a prolonged presence of residual S-albuterol and S-salmeterol, respectively, to exist in the body. The most commonly used therapeutic indication for beta-agonists in man is to treat bronchial spasms in asthmatic individuals. Beta-agonist adrenergic drugs have also been shown to inhibit premature contractions (tocolysis) of the uterus of pregnant women. Potentially dangerous side effects of albuterol in humans, include, but are not limited to, bronchial hyperreactivity, increased intraocular pressure, uterine hyperreactivity (stimulation of uterine contractions) and teratogenic effects of the drug to the fetus.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a method for improving health and muscle development in animals, especially domestic animals, including fish, by administering the optically pure eutomer of albuterol, terbutaline, clenbuterol, salmeterol, fenoterol and / or formoterol or other drugs beta-2 agonists, while eliminating the side effects caused by the drug's dyssite and decreasing total drug residues in the animal's body. The method has proven to be particularly useful in animals that have shown a propensity to health disorders, in which the health status and survival rate are improved by the eutomers of beta-2 agonists, and in animals that have a proportion of muscle development that needs to be improved, and in cases where improved feeding efficiency is sought. In cases of chickens, pigs, sheep, cows and fish and all other animals that enter the food chain, there is a risk of side effects induced by drugs, in other animals, usually of a higher order, that eat the meat of those animals that have been sacrificed. The very long biological half-lives of the albuterol and salmeterol dysmomers can be found in domestic animals, including fish from farms, and consequently, the body or channel of such animals to which these drugs have been administered contain significant tissue concentrations of the S -albuterol and S-salmeterol, for example, after sacrificing them. R-albuterol and R-salmeterol, on the other hand, were found to have shorter biological half-lives, and consequently less drug residue is found in the bodies of the slaughtered animals that have been administered the R- pure isomer of those compounds. Since the R-isomers of beta-agonists such as albuterol, clenbuterol and terbutaline have not been shown to possess such side effects as bronchial hyperresponsiveness, increased intraocular pressure, increased uterine contractility or teratogenic activity, the R-isomer is significantly less toxic than the racemate of the compound. Thus, the administration to animals of appropriate doses of the optically pure eutomers will not cause harm to the animal, will not leave drug residues of the dystomers in the body thereof, and will not cause damage, induced by the distomer, to others. animals usually of a higher order, such as humans who eat the slaughtered animals. The present method provides an effective and safe way to treat animals, such as birds, including chickens and turkeys, mammals, including horses, cows, pigs and sheep, and farmed fish without causing side effects on the animal or mammal that eats the animal, or in the unborn progeny of the mammal that eats the animal, the purpose of such treatment is to improve health, the survival rate and / or the rate of development. The present invention also relates to nutritional or nutritional supplements of animal animals, such as warm-blooded animals, which contain one or more of the optically pure eutomers discussed above. In one embodiment, the nutritional supplement is a protein-containing food, fortified with one or more optically pure eutomers of an adrenergic beta-agonist.

DETAILED DESCRIPTION OF THE INVENTION The R-isomers of albuterol and other beta-adrenergic agonists have not been found to improve survival and muscle development in animals, including farmed fish. The S-isomers of albuterol and other beta-adrenergic agonists have been found to be promoters of serious side effects and dystores have not been found to occur in the body of slaughtered animals, including farmed fish, after administration of the racemates to the animals. The present invention relies on the activity of the eutomers of albuterol, terbutaline, clenbuterol, salmeterol, fenoterol and formoterol to provide improved health and increased body weight in domestic animals, including farmed fish, while minimizing or simultaneously eliminating the side effects that are caused by the beta-agonist dissenter in said animal, in mammals such as the people eating the slaughtered animal and in the unborn progeny of a pregnant mammal that eats the slaughtered animal. The risk for the side effects that reside in the distomer, for example, bronchial and uterine hyperresponsiveness induced by the distomer of said beta-agonist, are minimized by using the optically pure eutomer instead of the racemic mixture. As an example, bronchial hyperreactivity and cough induced by S-albuterol in horses is avoided by using the optically pure eutomer. In the present method, an optically pure eutomer of albuterol, terbutaline, clenbuterol, salmeterol, fenoterol or formoterol substantially free of their corresponding dystomomers, can be administered alone, or in combination with at least one other drug in adjunct treatment, to animals in whom the relief of disorders to health or the development of increased body weight is desired. As examples of the R-isomer of albuterol, as used herein, reference is made to the R (+) - optically pure isomer of a? - [(tert-butylamino) -methyl] -4-hydroxy-m-xylene- aa '-diol, and any biologically acceptable salt or ester thereof, the R-isomer of clenbuterol refers to the optically pure R (+) isomer of the alcohol 4-amino-a- [(tert-butylamino) methyl] -3 , 5-dichlorobenzyl, and any biologically acceptable salt or ester thereof, the R-isomer of salmeterol refers to the optically pure R (+) - isomer of 4-hydroxy-a- [[[6- (phenylbutoxy) -hexyl] ] amino] methyl] -m-xylene-a, a'-diol and any biologically acceptable salt or ester thereof, and the R-isomer of terbutaline refers to the optically pure R (+) - isomer of 1- (3 , 5-dihydroxyphenyl) -2- (tert-butylamino) ethanol, and any biologically acceptable salt or ester thereof. The terms "optically pure" or "substantially free of the S-enantiomer" as used herein, means that the composition contains at least 85% by weight of the R-isomer of a beta-agonist and 15% by weight or less of the S-isomer; preferably, the optically pure drug consists of at least 99% of the eutomer. Optically pure beta adrenergic agonists are readily obtainable by methods known to those of skill in the art, for example, by synthesis from an optically pure intermediate or resolution of the racemic compound in its isomers. In the present method, the optically pure eutomer of albuterol, clenbuterol, salmeterol or terbutaline is administered to an animal, in which improved health, improved survival, improved muscle development rate and / or improved feeding efficiency are sought. . For example, R-albuterol is administered to an animal to correct or ameliorate a health disorder, such as for example metabolic disorders or to accelerate the rate of muscle development, or prophylactically to improve health status or rate of development muscle of the animal. In the present method, the optically active R-isomer of albuterol, terbutaline, salmeterol or formoterol can be administered by inhalation, parenterally, subcutaneously, intravenously, intramuscularly or another type of injection or infusion, orally, topically, rectally or via an implanted reservoir containing the drug. The form in which the drug will be administered (for example, inhalant, powder, granulate, tablet, capsule, solution, emulsion, etc.) will depend on the route by which it is administered. The preferred route of administration is the oral route, with the eutomer of the beta-2 agonist mixed in the animal feed. The amount of the drug to be administered will depend on an individual basis, and will be based on the pharmacological potency of the drug, in the route of administration, and at least in part in consideration of the size of the animal, the severity of the symptoms that go to be treated and the results sought. In general, sufficient amounts of optically pure eutomer will be administered to improve health, survival, muscle development and / or feeding efficiency. The effective dose (amount administered at a time) and the number of administrations per day will depend on the pharmacokinetic property of the drug and the metabolism of the drug in the body of the specific animal species.

For example, about 10 to 3000 micrograms of the optically pure R (-) -alomer of albuterol or terbutaline can be administered by various forms of inhalation devices, 0.01 to 200 milligrams can be administered by the oral route (eg, as powders, granulates or liquids) 1 to 4 times per day, and may be a suitable dose in most animals to produce the desired effect. The doses of R-salmeterol and R-clenbuterol may be lower and the dosage may also be less frequent than what is the case with R-albuterol and R-terbutaline. Doses of drug may be higher or lower and administration may take place more or less frequently than indicated above, as determined by the person skilled in the art. Drugs can also be mixed in foods, which can be made available to animals at d l ib. The animals can also be administered with a long-acting drug that is substituted with a short-acting drug for the period of time before sacrificing it. In the method of the present invention, the optically pure eutomer of the beta-2 agonist will be prepared as a dry powder or a granulate and added to the animal's feed, such as by mixing. The drug can be premixed into the food according to any of the methods known to those of skill in the art, or it can be mixed or incorporated into the food at the time of feeding. In the method of the present invention, the optically pure R-isomer of albuterol, clenbuterol, salmeterol or terbutaline or the RR-isomer of formoterol or fenoterol, can be administered together with one or more other compounds. For example, various antibacterial agents, growth factors, hormones, etc. can be administered. with or between doses of the eutomeric beta-agonist. Compounds that improve or prolong the therapeutic effect of R-albuterol, R-salmeterol or R-terbutaline, for example, compounds that inhibit the metabolic degradation of the compound (such as acetaminophen), can also be co-administered with the beta-agonist eutomerically, the two (or more) drugs (the optically pure active beta-agonist isomer, together with the other drug (s)) can be administered in a composition or as separate identities. For example, these can be administered in a simple capsule, tablet, granulate, powder, or liquid, mist, aerosol, injection, etc., or as individual drug formulations. The components included in the particular formulation, in addition to the optically pure R-isomer or the isomers and another drug or drugs, are determined primarily by the manner in which the composition is to be administered. For example, a composition to be administered in liquid form may include, in addition to the drugs, a liquid carrier, an emulsifying agent, a flavoring agent, an antibacterial or a bacteriostatic agent and / or a coloring agent. A formulation that is to be administered in powder form or as a granulate may include a filler (eg, lactose), a binder (eg, carboxymethylcellulose, gum arabic, gelatin), an adjuvant, a flavoring agent and / or a coloring agent. In general, according to the method of the present invention, the optically pure eutomers of albuterol, clenbuterol, salmeterol, formoterol or terbutaline, alone or in combination with one another and / or with other drugs, are administered to animals, farmed fish , periodically or continuously as necessary to improve health, survival or muscle development (weight gain) and to reduce body fat or to improve feeding efficiency. The food composition of the present invention is not particularly limited, and will depend on the identity of the animal consuming the food. In general, the food composition is a protein-containing food, having mixed therein one or more of the optically pure eutomers of the present invention. The food composition may contain fat, sugars, vitamins or other nutritionally valuable ingredients. The present composition, feed and method provide effective treatment, while eliminating the unwanted side effects induced by the distomer in the racemic albuterol, clenbuterol, salmeterol, terbutaline, fenoterol or formoterol, in the animal to which the drug is administered. , and in other animals usually of a higher order that eat the animal after it has been slaughtered. These side effects include bronchial hyperresponsiveness, increased uterine contractility, increased intraocular pressure, effects on the central nervous system such as tremors, weakness and fading, and cardiovascular effects, in addition, the teratogenic effects associated with racemic albuterol are considered to be located in the distomer of the drug Thus, by administering the optically pure eutomer of albuterol, clenbuterol, salmeterol, fenoterol, terbutaline or formoterol, the side effects of the corresponding dystreomer, which may be of long duration, have been avoided. Those skilled in the art will recognize, or be able to evaluate using no more than routine experimentation, many equivalents to the specific embodiments of the present invention. Such equivalents include the active isomers of other drugs with beta-2 adrenergic agonist properties, such as for example hexoprenaline, isoprenaline, riniterol, isoetharine, metaproterenol, reproterenol, cyanterol, procaterol, carbuterol, tulobuterol, pibuterol, mabuterol, bitolterol and bambuterol. Also included are the eutomers of the beta-2 agonists under development, such as broxaterol, ethanterol, imoxiterol, namiterol, picumeterol, RP 58802, RU 42173 and ZK 90055. Those skilled in the art will realize that there are many pharmaceutically acceptable salt forms. of the drugs of the invention, such as for example sulfate, fumarate, hydrobromide, dihydrochloride, methanesulfonate, hydroxynaphthoate, hydrochloride, or where appropriate, one or another of the hydrated forms thereof, see Merck Index lia. edition (1989) paragraphs 9089, 209, 3927, 4628, 8223, 5053, 5853, 5836, 8142, 2347, 7765, 1840, 9720, 7461, 1317, 4159 and 963 and references cited therein, and AM. Rev. Resp. Dis. 1988, 137: (4; 2/2) 32, the description of which is incorporated by reference herein. Those skilled in the art will realize that the eutomers of beta-adrenergic agonists can improve muscle development and decrease body fat in both humans and other mammals, and this indication for eutomers of beta-agonists in humans is included in the present invention.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A method for feeding animals, characterized in that it comprises administering to them an effective amount of an optically pure eutomer of a beta-2 adrenergic agonist, while minimizing or eliminating the side effects that reside in the corresponding distomer.

2. The method according to claim 1, characterized in that the animal is selected from the group consisting of birds, cows, pigs, horses, sheep and farmed fish.

3. The method according to claim 1, characterized in that the eutomer of a beta-adrenergic agonist is selected from the group consisting of R-albuterol, R-clenbuterol, R-salmeterol, S-Salmoterol, R-terbutaline, -RR-formoterol and RR-fenoterol.

4. A method for inducing muscle weight gain of animals in need thereof, characterized in that the method comprises administering to them an effective amount of an optically pure eutomer of a beta-2 adrenergic agonist, while minimizing or eliminating the collateral effects that reside in the corresponding distomer.

5. The method according to claim 4, characterized in that the animal is selected from the group consisting of birds, cows, pigs, horses, sheep and farmed fish.

6. The method according to claim 5, characterized in that the eutomer of a beta-2 adrenergic agonist is selected from the group consisting of R-albuterol, R-clenbuterol, R-salmeterol, S-salmeterol, R-terbutaline, RR-formoterol and RR-fenoterol.

7. A food composition, characterized in that it comprises mixing with food materials containing protein, an optically pure eutomer of a beta-2 adrenergic agonist.

8. The food composition according to claim 7, characterized in that the eutomer of a beta-2 adrenergic agonist is selected from the group consisting of R-albuterol, R-clenbuterol, R-salmeterol, S-salmeterol, R-terbutaline, RR- formoterol and RR-fenoterol.

9. A method for improving muscle development and decreasing body fat in humans, characterized in that the method comprises administering to them an effective amount of an optically pure eutomer of a beta-2 adrenergic agonist, while minimizing or eliminating side effects that reside in the corresponding distomer.

10. The method according to claim 9, characterized in that the eutomer of a beta-2 adrenergic agonist is selected from the group consisting of R-albuterol, R-clenbuterol, R-salmeterol, S-salmeterol, R-terbutaline, RR-formoterol and RR-fenoterol.