Transmucosal administration of drug compositions for treating and preventing disorders in animals
Abstract
A composition comprising meloxicam, or a pharmaceutically acceptable salt, solvate, or ester thereof, and an aqueous solution of ethanol, wherein the composition has a pH greater than 8 and less than 9, for use in a method of treating pain, inflammation and / or fever in a non-human animal, where the non-human animal is a dog, a cat, a horse, a cow, a pig, a sheep or poultry, the method comprising: administering the composition by spraying the oral mucosa of the non-human animal that needs it, thereby providing transmucosal absorption of a pharmaceutically effective amount of meloxicam, or of a pharmaceutically acceptable salt, solvate or ester thereof, to the animal's systemic circulatory system.

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7 claims: 1 independent, 6 dependent
- 1REIVINDICACIONES 1. Una composición que comprende meloxicam, o una de sus sales, solvatos, o ésteres farmacéuticamente aceptables, y una solución acuosa de etanol, donde la composición tiene un pH mayor de 8 y menor de 9, para uso en 5 un método para tratar el dolor, la inflamación y/o la fiebre en un animal no humano, donde el animal no humano es un perro, un gato, un caballo, una vaca, un cerdo, una oveja o aves de corral, comprendiendo el método:administrar la composición pulverizando la mucosa oral del animal no humano que la necesita, proporcionando de este modo la absorción transmucosal de una cantidad farmacéuticamente eficaz del meloxicam, o de una de sus 10 sales, solvatos o ésteres farmacéuticamente aceptables, al sistema circulatorio sistémico del animal.
- 2La composición para usar de acuerdo con la reivindicación 1, donde dicha pulverización comprende pulverizar en la mucosa oral, mucosa gingival, mucosa lingual, mucosa palatina, mucosa faríngea, mucosa sublingual o combinaciones de las mismas de un animal no humano.
- 3La composición para usar de acuerdo con la reivindicación 2, donde dicha pulverización comprende pulverizar en la mucosa bucal.
- 4La composición para usar de acuerdo con la reivindicación 1, donde el meloxicam tiene una concentración de entre 20 aproximadamente 0,01 y aproximadamente 10 por ciento en peso de la composición total.
- 5La composición para usar de acuerdo con la reivindicación 1, donde dicho método comprende además administrar al menos un agente terapéutico adicional. 25 6. La composición para usar de acuerdo con la reivindicación 1, donde dicho animal no humano está anestesiado.
- 7La composición para usar de acuerdo con la reivindicación 1, donde dicha pulverización es de la mucosa oral del animal dos o más veces. 30 8. Uso de una composición que comprende meloxicam, o una de sus sales, solvatos o ésteres farmacéuticamente aceptables, y una solución acuosa de etanol para la fabricación de un medicamento para uso en un método de tratamiento del dolor, la inflamación y/o la fiebre en un animal no humano, donde el animal no humano es un perro, un gato, un caballo, una vaca, un cerdo, una oveja o aves de corral y el método es tal como se expone en una cualquiera de las reivindicaciones 1 a 7.
- 9Una composición para uso de acuerdo con una cualquiera de las reivindicaciones 1 a 7, donde la composición está contenida en un recipiente pulverizador, que es un recipiente para pulverización en aerosol cerrado herméticamente o un recipiente para pulverización mediante bomba, con una válvula dosificadora adecuada para liberar desde dicho recipiente una cantidad predeterminada de dicha composición.
Independent claims7
461 paragraphs, as filed
Transmucosal administration of drug compositions to treat and prevent disorders in animals
Field of the Invention
In one embodiment, the present invention relates to the transmucosal administration of pharmaceutical compositions in an animal for use in the treatment or prevention of diseases. In particular, embodiments of the invention encompass compositions comprising meloxicam for use in the treatment of pain, fever and / or inflammation in a non-human animal, by transmucosal administration of a prophylactic or therapeutically effective amount to an animal in need of spraying. the one or more active ingredients in the oral cavity of the animal. The non-human animal is a dog, cats, horse, cows, pigs, sheep, or poultry.
Background of the invention
Pharmaceutical compounds originally developed for human use have also been used in veterinary medicine. However, the efficacy of human drugs in non-human animals is unpredictable due to metabolic differences between humans and the various non-human animal species. Even for individuals belonging to the same species, the effectiveness of a specific drug can vary greatly. For example, H1 receptor antagonists such as clemastine have been used as antihistamines for humans and animals. However, it has been found that doses that are effective in humans are ineffective in canine and equine subjects due to poor oral bioavailability and rapid elimination of clemastine (see Hanson et al., Veterinary Dermatology 2004, 15, pages 152 -158; and Torneke et al., J. Vet. Pharmacol. Therap. 26, pages 151-157, 2003). Only therapeutic levels of plasma clemastine were obtained in canine and equine subjects by intravenous administration using relatively high doses (compared to humans), which significantly limit the usefulness of clemastine for veterinary applications.
It is known that certain biologically active compounds are better absorbed through the oral mucosa than through other routes of administration, such as through the stomach or intestine. However, formulations suitable for such administration through the oral mucosa have their own problems. For example, the biologically active compound must be compatible with the rest of the components of the composition such as propellants, solvents, etc. Many of these formulations have been proposed. For example, the US document
No. 4,689,233 to Dvorsky et al., Describes a soft gelatin capsule for the administration of the nifedipine anticoronary drug dissolved in a mixture of polyether alcohols. US 4,755,389 to Jones et al. Describes a chewable hard gelatin capsule containing nifedipine. A chewable gelatin capsule containing a solution or dispersion of a drug is described in US 4,935,243 to Borkan et al. The document
US 4,919,919 to Aouda et al., And US 5,370,862 to Klokkers-Bethke, describe a nitroglycerin spray for administration to the oral mucosa comprising nitroglycerin, ethanol, and other components. A spray dosing pump administered orally in Cholcha is described in US.
5,186,925. Aerosol compositions containing a hydrocarbon propellant and a drug for administration to a mucosal surface are described in UK 2,082,457 of Su, US 3,155,574 of Silson et al., US 5,011,678 of Wang et al., And in Parnell in US 5,128,132. It should be noted that these references describe the bioavailability of solutions by inhalation and not through the membranes to which they are administered.
Transmucosal absorption through oral mucosal surfaces allows the permeation of pharmaceutical compounds such as nutrients or drugs directly into the bloodstream and then into the cells in a period of time that comprises a few minutes. Inside the oral cavity, numerous mucosal surfaces can be used to administer the pharmaceutical compounds, including but not limited to: (i) sublingual surfaces, that is, the mucosal membranes that line the base of the mouth, (ii) buccal surfaces, that is, the mucosal membranes that line the cheeks, (iii) lingual surfaces, that is, the superficial membranes of the tongue, (iv) palatine surfaces, that is, the membranes that line the palate of the mouth, (v) pharyngeal surfaces, that is, the membranes of the pharynx, (vi) gingival mucosa, that is, the gums, and the (vi) gingival groove, that is, the cavity formed between the teeth and gums. Conventional oral administration of a drug by ingestion is often not easily carried out for various reasons such as the difficulty that an owner may have to force his animal to swallow a tablet or liquid, the inability to manipulate an animal to which He dislikes the taste of the medication and he resists being treated, and medical ailments that make it difficult for animals to ingest oral formulations. In animals, these limitations are often exacerbated because the animal does not realize that the treatment is aimed at improving the physical ailment of the animal.
Animal owners and veterinarians know equally well that oral administration of a drug to an animal has associated disadvantages (for example, difficulty in stimulating swallowing, the animal spitting the pill, or failing to receive the proper dosage). In addition, conventional oral administration of drugs to animals has disadvantages, such as first-pass hepatic metabolism and enzymatic degradation inside the gastrointestinal tract, which prevent the administration of certain types of drugs, especially peptides and proteins. Although intravenous administration can overcome these inconveniences, invasiveness in the animal,
difficulties for the owner of the animal, as well as the increase in increased costs and the risk of infection, make intravenous administration a less viable alternative.
The oral mucosa offers an attractive route of transmucosal administration for systemic administration of the drug to animals. For example, an oral spray that has an aerosol pump can directly deliver a drug to the bloodstream. When sprayed in the mouth, the microdimensioned droplets are absorbed immediately through the mucosal lining to the capillaries, which are located near the surface of the lining in the mouth. This procedure can provide the definitive absorption of the drug in a short period of time without producing any extra stress to the organs.
Film administration systems are also known for use on mucosal surfaces. These types of systems, which are insoluble in water and usually in the form of laminated, extruded or composite films, are described in US Pat. Nos. 4,517,173; 4,572,832; 4,713,243; 4,900,554; and 5,137,729. US Patent No. 4,517,173 describes and claims a membrane-adhering film consisting of at least three layers, including a pharmaceutical layer, a very water-soluble layer, and an intermediate layer. The pharmaceutical layer includes the drug and a cellulose derivative selected from hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose. The very low water soluble layer is prepared by combining one or more cellulose derivatives with a very water soluble fatty acid, and the intermediate layer is made of cellulose derivatives. US Patent No. 4,572,832 refers to a soft film for oral administration, prepared by the combined use of a water soluble protein, a polyol, and a polyhydric alcohol such as cellulose and polysaccharides, and also teaches the use of coloring or flavoring agents. US Patent No. 4,713,243 describes a mono or multilayer bioadhesive thin film prepared from 40-95% water soluble hydroxypropyl cellulose. 5-60% water insoluble ethylene oxide, 0-10% water insoluble ethyl cellulose, propyl cellulose, polyethylene, or polypropylene, and a medicine. The films are layered with three layers and include a bioadhesive layer, a deposit layer, and a protective outer layer not soluble in water. US Patent No. 4,900,554 teaches a soft adhesive film applicable to the oral mucosa containing a systemic drug and comprising a mixture of a non-water soluble vinyl acetate homopolymer, an acrylic acid polymer, and a cellulose derivative. Finally, US Patent No. 5,137,729 describes a device for use in the oral cavity having an adhesive layer that includes a mixture of an acrylic acid polymer, a water insoluble cellulose derivative, and a pharmaceutical preparation, and a support layer insoluble or poorly soluble in water. The adhesive layer contains the pharmaceutical compound and, after application to the mucosal surface, releases the drug.
It has recently been shown that oral administration of the active ingredients can result in the absorption of the active ingredients through the oral mucosa. For example, United States patents with numbers 5,869,082, 5,955,098; 6,110,486; and 6,676,931, describe the administration of active ingredients using a spray or capsule for oral spray. In addition, U.S. applications published with numbers 2005/0025717, 2005/0025716, 2005/0025715, 2005/0025714, 2005/0025713, 2005/0025712, 2005/0002867, 2004/0265239, 2004/0141923, 2004/0136915, 2004 / 0136914, 2004/0136913, 2004/0120896, 2004/0120895, 2004/0062716, 2003/0211047, 2003/0190286, 2003/0185761, 2003/0095927, 2003/0095926, 2003/0095925, 2003/0082107, 2003/0077229, 2003/0077228, 2003/0077227, and 2003/0039680, describe aerosol buccal sprayers or capsules that use polar and non-polar solvents, which provide biologically active principles for absorption through the oral mucosa.
However, the bioavailability of drugs administered by an aerosol or spray, for example, to the respiratory system, can depend significantly on the specific formulation used, and even, aerosol formulations that provide satisfactory bioavailability of the drug may have undesirable side effects. such as irritation of mucosal tissue.
Summary of the Invention
The invention is as defined in the claims. The active substance used in the invention is meloxicam or a pharmaceutically acceptable salt, solvate or ester thereof.
Brief description of the drawings
Figure 1 shows the average plasma concentrations of meloxicam when administered using two different dosage forms (oral suspension and transmucosal oral mist (hereinafter, "TMOM ™")) at the same dosage (~ 0 , 2 mg / kg). The oral suspension was administered to the dog orally and swallowed. The mist was sprayed into the oral cavity of the dogs.
Figure 2 shows a comparison of the pharmacokinetic parameters for administration of meloxicam by oral suspension and administration using TMOM ™ to dogs at a dosage of approximately 0.2 mg / kg. The ABC represents the area under the curve or the total amount of drug exposure to the animal after administration by the two different dosage forms. Cmax represents the maximum plasma concentration of meloxicam measured in ng / ml when administered by dosage forms. The Tmax denotes the
time it takes to reach the maximum meloxicam plasma concentration achieved after administration of both dosage forms. The t © is the distribution or elimination rate of meloxicam calculated when administered by both dosage forms.
5 Figure 3 shows the results of the bioequivalence test in dogs between meloxicam administered by TMOM ™ and the administration of an oral suspension (~ 0.2 mg / kg).
Figure 4 shows the levels in cephalic and jugular blood plasma of meloxicam in anesthetized dogs, administered by TMOM ™.
10 Figure 5 shows blood plasma concentrations of meloxicam for two different TMOM ™ formulations of meloxicam in anesthetized and awake dogs.
Figure 6 shows a comparison of blood plasma carprofen levels in dogs, administered by oval tablet, TMOM ™, or injected.
Figure 7 shows pharmacokinetic parameters and bioequivalence data after administration of carprofen to dogs by oval tablets, TMOM ™ and subcutaneous injection.
twenty Figure 8 shows the levels in cephalic and jugular blood plasma of carprofen in anesthetized dogs, administered by TMOM ™.
Figure 9 shows the blood plasma levels of carprofen administered by TMOM ™ in anesthetized and awake dogs.
25 Figure 10 shows the average plasma concentrations of clemastine fumarate when administered using two different dosage forms (normal swallowing tablets and TMOM ™) at the same dosage (1 mg / kg) and both administered orally to cats.
30 Figure 11 shows a comparison of the pharmacokinetic parameters for administration of clemastine by tablet and administration using TMOM ™ to cats at a dosage of approximately 1 mg / kg.
Figure 12 shows the average plasma concentrations of clemastine fumarate when administered
35 using two different dosage forms (normal swallowing tablets and TMOM ™) at the same dosage (0.1 mg / kg) and both administered orally to horses. The tablets were crumbled and administered by nasogastric tube as a nasogastric tube and TMOM ™ was administered to the oral oral mucosa. The plasma concentration of clemastine fumarate is shown on a logarithmic scale. After dosing with the tablets, it was only possible to measure clemastine fumarate at three time points
40 in which plasma concentrations achieved detectable levels such that the curve is plotted only for a short period of time.
Figure 13 shows the pharmacokinetic parameters after administration of clemastine fumarate to horses by TMOM ™ and oral nasogastric tube.
Four. Five Figure 14 shows the average plasma concentrations of clemastine fumarate in dogs after administration of TMOM ™ and tablet formulations at ~ 1.0 mg / kg.
Figure 15 shows a comparison of the pharmacokinetic parameters for the tablet and TMOM ™ when 50 clemastine fumarate was administered to dogs at a dosage of 1 mg / kg.
Figure 16 shows the levels in cephalic and jugular blood plasma of clemastine in anesthetized dogs, administered by TMOM ™.
55 Figure 17 shows the blood plasma levels of carprofen administered by TMOM ™ in anesthetized and awake dogs.
Figure 18 shows a graphical representation of the percentage of PK / PD inhibition against IgE-IDT for atopic dogs, to which clemastine fumarate was administered by TMOM ™.
60 Figure 19 shows the levels in cephalic and jugular blood plasma of diphenhydramine hydrochloride in dogs, administered by TMOM ™.
Figure 20 shows the pharmacokinetic parameters after administration of diphenhydramine hydrochloride to 65 dogs, administered by TMOM ™.
Figure 21 shows the average plasma concentrations of zolpidem tartrate when administered to dogs using two different dosage forms (TMOM ™ and tablet) at the same dosage (~ 0.5 mg / kg).
Figure 22 shows the average plasma concentrations of zolpidem tartrate when administered to 5 cats using two different dosage forms (TMOM ™ and tablet) at the same dosage (~ 0.5 mg / kg) and both administered orally.
Figure 23 shows a comparison of the pharmacokinetic parameters for the administration of zolpidem tartrate to dogs by oral suspension and administration using TMOM ™ for a dosage of about 0.5 mg / kg.
Figure 24 shows a comparison of the pharmacokinetic parameters for oral suspension and TMOM ™ when zolpidem tartrate was administered to cats at a dosage of approximately 0.6 mg / kg.
fifteen Figure 25 shows average plasma concentrations of propofol after intravenous administration at ~ 6.0 mg / kg and administration by TMOM ™ at ~ 30.0 mg / kg.
Figure 26 shows the pharmacokinetic parameters after administration of propofol to dogs by intravenous administration and TMOM ™
twenty Figure 27 shows the average levels of milbemycin in blood plasma in dogs, administered by TMOM ™ and an oral chewable tablet.
Figure 28 shows the pharmacokinetic parameters (corrected for dosing) after administration of 25 milbemycin oxime to dogs by tablet and TMOM ™
Figure 29 shows the mean plasma concentration curves for enrofloxacin in felines, administered by tablets and TMOM ™.
30 Figure 30 is a diagram of the pharmacokinetic parameters after administration of enrofloxacin to cats using tablets and TMOM ™.
Figure 31 is a diagram of concentrations of enrofloxacin in jugular and cephalic plasma in felines after administration by TMOM ™. 35 Figure 32 is an acceptance diagram of TMOM ™ administration in dogs of various vehicles.
Figure 33 is a diagram of the severity of reactions to TMOM ™ administration in dogs of various vehicles. 40 Figure 34 is a diagram of acceptance of TMOM ™ administration in felines of various vehicles.
Figure 35 is a diagram of the severity of reactions to TMOM ™ administration in dogs of various vehicles.
Four. Five Figure 36 is an acceptance diagram of the administration of TMOM ™ in dogs of various meloxicam formulations.
Figure 37 is an acceptance diagram of the administration of TMOM ™ in dogs of various formulations 50 of meloxicam.
Figure 38 is a diagram of the severity of reactions to TMOM ™ administration in dogs of various meloxicam formulations.
55 Figure 39 is a diagram of the severity of reactions to TMOM ™ administration in dogs of various meloxicam formulations.
Figure 40 is a diagram of the severity of reactions to TMOM ™ administration in felines of various vehicles. by number of doses and formulation.
60 Figure 41 is a diagram of the severity of reactions to TMOM ™ administration in felines of various vehicles. by number of doses and formulation.
Figure 42 is a diagram of the severity of reactions to TMOM ™ administration in dogs of various formulations of meloxicam by number of doses and formulation.
Figure 43 is a diagram of the severity of reactions to TMOM ™ administration in dogs of various meloxicam formulations. by number of doses and formulation.
Figure 44 is a response diagram to TMOM ™ administration in dogs and cats.
Figure 45 is a graphical representation showing the average plasma clemastine concentration in dogs that were given increasing dosages from 0.25 to 1 mg / kg by TMOM ™ administrations.
Detailed description of the invention
A. General
The compositions of the present invention are to be administered to any membrane of the mucosal surface of the oral mucosa, including the lingual surfaces, sublingual surfaces, buccal surfaces, palatine surfaces, and pharyngeal surfaces, preferably buccal or gingival surfaces. In other embodiments, the compositions of the present invention can also be administered to more than one membrane of the oral mucosa, for example, the lingual and sublingual surfaces or the lingual, sublingual and buccal surfaces, etc. In other additional embodiments, the compositions of the present invention can be administered to the area of the oral cavity of an animal between the teeth and the cheeks, thereby allowing the compositions of the present invention to come into contact with at least the oral mucosa and gingival.
Administration of the compositions of the present invention is to be carried out using a sprayer, such as an aerosol or pump sprayer.
The compositions of the present invention are suitable for transmucosal administration, preferably to the oral mucosa and more preferably for administration to the oral mucosa or other oral mucosal surfaces.
The transmucosal administration methods of the embodiments described herein provide a simple, safe and very potent method of administration for administering drugs to animals. Compositions administered transmucosally to the oral mucosa of an animal are easier to administer than, for example a pill, the amount of drug needed can be reduced, and, in turn, reduce adverse effects, while providing a maximum dose response. Additionally, the compositions and methods of the invention can provide a shorter time frame necessary to achieve maximum plasma concentration and greater bioavailability.
The present invention is described herein using some definitions, which are defined below and throughout the application.
B. Definitions
As indicated herein and unless otherwise indicated, the term "active principle of the invention" and "active principle" refers to an active principle selected from the group consisting of a non-steroidal anti-inflammatory drug, an antiparasitic agent, an antihistamine, a cardiovascular agent, a hormone, an immunosuppressive agent, a nutraceutical, a vitamin, a mineral, a sedative / tranquilizer / behavior modifying agent, an antiemetic, and an antibiotic, or pharmaceutically acceptable salts, solvates or derivatives (eg, esters) thereof. The active substance used in the invention is meloxicam, or a pharmaceutically acceptable salt, solvate or ester thereof.
As indicated herein and unless otherwise indicated, the term "non-steroidal anti-inflammatory agent" refers to a non-steroidal compound that reduces inflammation or inflammatory responses in an animal, for example, COX inhibitors. -1 and COX-2.
As indicated herein and unless otherwise indicated, persons normally skilled in the art will understand the term "approximately" and will vary to some extent in the context in which the term is used. If there are uses of the term that are not clear to people normally skilled in the art given the context in which they are used, "approximately" will mean up to about 10% of the specific term or amount.
As indicated herein and unless otherwise indicated, the term "alkanoyl esters" refers to a monovalent group of formula -C (O) -alkoxy. Preferably, the hydrocarbon chain of an alkoxy group is 1 to 8 carbon atoms in length.
As indicated herein and unless otherwise indicated, the term "alkoxy group" refers to a group -O-alkyl, where alkyl is as defined below. An alkoxy group may be unsubstituted or substituted with one or two suitable substituents. Preferably, the alkyl chain of an alkoxy group has 1
at 8 carbon atoms in length. and an alkoxy group having 1 to 8 carbon atoms is referred to herein as "(C1-C8) alkoxy"
The term "alkyl group" means a saturated, monovalent, unbranched (ie, linear) or branched hydrocarbon chain, for example, a saturated hydrocarbon chain (ie, a chain of hydrogen substituted carbon atoms) having 1 to 18 carbons in length (referred to herein as "(C1-C18 alkyl"), a hydrocarbon chain (C1-C8), or a hydrocarbon chain (C1-C6). The alkyl groups of the present invention may be unsubstituted or optionally substituted with one or two suitable substituents. Examples of alkyl groups include, but are not limited to, (C1-C6) alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl -1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl -1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2 -ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as and octyl.
The term "hydrocarbon group" can be used interchangeably with the term "alkyl group" when the "hydrocarbon group" is a saturated hydrocarbon. However, the term "hydrocarbon group" also includes monovalent unsaturated hydrocarbons, for example, alkenyl and alkynyl groups. Suitable hydrocarbon groups thus include, for example, monovalent groups selected from alkyl (CrC8), alkenyl (C2-C8), and alkynyl (C2-C8), optionally substituted with one or two suitable substituents. Preferably, the hydrocarbon chain of a hydrocarbon group is 1 to 6 carbon atoms in length. referred to herein as "(C1-6 hydrocarbon)". Examples of hydrocarbon groups include, but are not limited to the alkyl groups described above, and, in addition, unsaturated hydrocarbons such as vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-ethynyl, 1-propynyl, 2-propynyl, etc.
Similarly, the term "hydrocarbon" refers to a molecule comprising carbon and hydrogen. The hydrocarbons of the present invention may be optionally substituted. Suitable hydrocarbons of the present invention have 4 or more carbon atoms, preferably 4 to 18 carbon atoms.
As indicated herein and unless otherwise indicated, the term "additional therapeutic agent (s) refers to a second (or third, etc.) drug (and / or a pharmaceutically acceptable salt, solvate or ester thereof) added in addition to the active ingredient and may include agents to enhance drug absorption or combinations that include, but are not limited to, permeation enhancers or bioadhesive agents.
As indicated herein and unless otherwise indicated, the term "animal" refers to any non-human animal, including mammals, birds, reptiles, marsupials, amphibians, and fish. In a preferred embodiment, the term "animal" includes domesticated animals, such as a cow, horse, sheep, pig, goat, chicken, turkey, quail, duck, goose, cat, dog, mouse, rat, rabbit, or guinea pig, and is preferably a dog, cat, or horse. The term "animal" also includes non-domesticated wild animals and exotic captive animals, for example, "pets" and untamed animals that are housed in zoos or other captive environments.
As indicated herein and unless otherwise indicated, the terms "bioadhesive agents" and "bioadhesive polymers" refer to any agent that can adhere to a biological surface, preferably the oral mucosa and more preferably the mucosa buccal, to increase the time in which a drug is in contact with the oral mucosa, and therefore, increase its absorption.
As indicated herein and unless otherwise indicated, the term "oral mucosa" refers to the oral mucosal membranes that line the cheeks.
As indicated herein and unless otherwise indicated, the term "transmucosal oral administration" includes any method of administering an active ingredient in the oral cavity of an animal in which a substantial portion of the active ingredient penetrates into the animal's bloodstream by diffusion or movement through the mucous membranes of the oral cavity. By "substantial portion" is meant that at least 20% of the active substance of the administered dose penetrates the animal's bloodstream through movement through the mucous membranes of the oral cavity. Preferably, at least 50%, more preferably, at least 80% penetrates the animal's bloodstream by movement through the mucous membranes of the oral cavity.
As indicated herein and unless otherwise indicated, the term "transmucosal oral haze" includes formulation forms intended to be administered to an animal by a transmucosal oral administration method in which the formulation is administered in the form of droplets that come into contact with the oral mucosa of the animal. The droplets can have any size or size distribution, and include very thin droplets capable of being suspended in the air (eg, aerosols), or thicker droplets of the type provided by conventional spray devices, including pump sprayers, sprayers in spray, etc.
As indicated herein and unless otherwise indicated, the term "effective amount" means
an amount of an active ingredient, or a pharmaceutically acceptable salt thereof, that is sufficient to provide the desired local or systemic effect and behavior at a reasonable benefit / risk ratio relative to any medical treatment. Specifically, the term "effective amount" means an amount of an active substance,
or a pharmaceutically acceptable salt, solvate or ester thereof, which is sufficient to mitigate, improve, substantially reduce, or cause the cessation of at least one adverse effect associated with the disease or condition being treated, or at least one discernible symptom. of the ailment, disease, or disease that should be treated by the compositions according to the invention. "Therapeutically effective" also refers to an amount of the active ingredient that results in an improvement of at least one measurable physical parameter, not necessarily discernible, by the animal. In another additional embodiment, the term "therapeutically effective" refers to an amount of active ingredient sufficient to inhibit the progression of at least one adverse effect, both physically (for example, stabilization of a discernible symptom), physiologically (for example, stabilization of a physical parameter), or both. In another additional embodiment, the term "therapeutically effective" refers to an amount of active ingredient that results in a delayed onset of a disease or condition. The amount of active ingredient that constitutes a "therapeutically effective amount" will vary depending on the pathology, condition, disorder, or disease to be treated or avoided, the severity of the condition, and the age and body weight of the animal being treated. will try, but a person skilled in the art can determine it routinely taking into account their own knowledge and this disclosure,
Meloxicam is a non-steroidal anti-inflammatory agent; The term "therapeutically effective" with respect to the amount of non-steroidal anti-inflammatory agent refers to an amount of non-steroidal anti-inflammatory agent capable of causing an improvement in at least one adverse effect associated with pain, inflammation, and / or fever in an animal or at least a discernible improvement of one of its symptoms.
As used herein, the term "substantially reduce" refers to the ability of an active ingredient or composition of the invention to reduce at least one adverse effect, for example, as described below. In a preferred embodiment, substantially reduces refers to the ability of an active ingredient or composition of the invention to reduce or prevent all adverse effects associated with the disease or condition.
Meloxicam is a non-steroidal anti-inflammatory drug; An adverse effect includes, but is not limited to, pain, inflammation, fever, and combinations thereof.
As used herein, the terms "flavoring agent" and "masking agent" refer to any agent that improves the palatability or acceptability of an agent or composition in an animal. Such agents may improve the taste, smell, or both, such that an animal more readily accepts the treatment according to the invention.
As indicated herein and unless otherwise indicated, the term "non-polar solvent" includes, but is not limited to, esters (C2-C6) of fatty acids (C2-C24), hydrocarbons (C7 -C18), alkanoyl esters (C2-C6), and triglycerides of the corresponding acids.
As indicated herein and unless otherwise indicated, the term "transmucosal administration" refers to the administration of the active substance of the invention to a mucous membrane, thus allowing the diffusion of the active substance through the mucous membrane.
As indicated herein and unless otherwise indicated, the term "oral mucosa" refers to any mucosal surface that is found in the oral cavity or that can be achieved by administration to the oral cavity, including but not limited to: (i) lingual surfaces, that is, the superficial membranes of the tongue, (ii) sublingual surfaces, that is, the mucous membranes that line the base of the mouth, (iii) buccal surfaces, that is, the mucosal membranes that line the cheeks, (iv) palatine surfaces, that is, the membranes that line the palate of the mouth, (v) pharyngeal surfaces, that is, the mucous membranes that line the pharynx, (vi) gingival surfaces, that is, the mucous membranes of the gums, and the (vi) gingival groove, that is, the cavity formed between the teeth and the gums. When the animal is a fish, the term "oral mucosa" includes any of the mucous membranes of the fish's gills.
As indicated herein and unless otherwise indicated, the term "penetration enhancer (s)" refers to any substance (s) used to increase the flow of drugs through the oral mucosa.
As used herein, the term "pharmaceutical agent" includes, but is not limited to, any agent, compound or mixture thereof that induces a physiological, metabolic, phenotypic, or other change in the animal regardless of The molecular composition and may include, but is not necessarily limited to, small organic molecules, biological molecules, nutrients, vitamins, metabolites, foods, vaccines, proteins, lipids, and carbohydrates.
As indicated herein and unless otherwise indicated, the term "pharmaceutically
acceptable "means approved or approved by a federal or state government regulatory agency or cited in the United States Pharmacopoeia or other pharmacopoeia generally recognized for use in animals. The term" vehicle "refers to a diluent, an adjuvant, excipient , or vehicle with which the active ingredient of the invention is administered. Such pharmaceutical vehicles may be liquids, such as water or an alcoholic aqueous solution (for example, aqueous ethanol) and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, oil mineral, sesame oil, and the like. Pharmaceutical vehicles may also include, for example, saline, aqueous alcohol solution, or water. When administered to an animal, the active ingredients of the invention and pharmaceutically acceptable carriers are preferably sterile. The aqueous ethanol solution is a preferred vehicle, since the agents of the invention are administered transmucosally. The present compositions, if desired, may also contain minor amounts of wetting or emulsifying agents, and / or pH buffering agents.
As indicated herein and unless otherwise indicated, the term "polar solvent" includes, but is not limited to, low molecular weight polyethylene glycols (PEG) of Mw 400-1000 (preferably 400-600) , mono and low molecular weight polyols (C2-C8) and straight or branched chain hydrocarbon alcohols (C7-C18). Glycerin may also be present, and water can also be used in the sprayers. A preferred polar solvent is an aqueous ethanol solution.
As indicated herein and unless otherwise indicated, the term "non-polar solvent" includes, but is not limited to a linear or branched C7-C18 hydrocarbon, fatty acid esters, triglycerides, or migliol
As indicated herein and unless otherwise indicated, the term "transmucosal" refers to the diffusion of the active substance of the invention through a mucous membrane, preferably the oral mucosa and more preferably the oral mucosa. .
As indicated herein and unless otherwise indicated, the terms "ABC", "Tmax", Cmax "and" t © "have their conventional meanings. Therefore," ABC "represents the area under the curve or the total amount of exposure of the active substance to the animal after administration The term "Cmax" represents the maximum plasma concentration of the active ingredient measured in the indicated units, after administration to the animal. The term "Tmax" denotes the time it takes for the active ingredient to reach the maximum plasma concentration in the animal after administration. The t © is the distribution or elimination rate of meloxicam calculated after administration. Absorption t © is the calculated absorption half of the active substance.
C. Compositions of the invention
The invention is as defined in the claims. The active substance used in the invention is meloxicam or a pharmaceutically acceptable salt, solvate or ester thereof.
Formulations suitable for transmucosal administration include those described in WO 2005/030167, WO 2005/032520; WO 2005/032518; WO 2005/032519; and in WO 2005/032517.
The active principle or principles of the compositions of the various embodiments of the present invention may have a concentration in the range of about 0.01 to about 10% by weight of the composition. In other embodiments, the concentration of the active ingredient may be about 0.05% by weight, 0.10% by weight, 0.5% by weight, 1.0% by weight, 1.5% by weight, 2, 0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% by weight, 5.0% by weight, 5.5 % by weight, 6.0% by weight, 6.5% by weight, 7.0% by weight, 7.5% by weight, 8.0% by weight, 8.5% by weight, 9.0% by weight, and 9.5% by weight, including all values and subintervals between them.
The invention uses the non-steroidal anti-inflammatory agent meloxicam, (4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) or a salt, solvate or ester thereof. Various meloxicam salts that can also be used in the compositions according to the invention are also described in European Patent Documents No. EP 0 002 482 B1, United States Patent 4,233,299, and PCT Publication No. WO 99 / 49867.
The active principle, as well as any active or therapeutic principle present in the compositions according to the invention, may be present in its free base form (i.e., pure or not associated) or in the form of a pharmaceutically acceptable salt. Depending on the nature of the active ingredient, suitable pharmaceutical salts may include, but are not limited to, hydrochloride, hydrobromide, iodhydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, carbonate, bicarbonate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tanate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, sucrate, format, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e. 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)), or the like, or one of their combinations. Additionally or alternatively, the active ingredient may be present in the form of a sodium salt, potassium salt, ammonium salt, meglumine salt, TRIS salt salt with a basic amino acid, or the like, or one of its combinations .
The invention also includes active ingredient compositions together with one or more pharmaceutically acceptable carriers, adjuvants, or non-toxic carriers, referred to as carriers as a whole, with no intention of limiting. Pharmaceutically acceptable compositions and carriers are formulated for transmucosal administration, preferably to the oral mucosa and more preferably to the oral mucosa.
The compositions comprise at least one active ingredient and are suitable for transmucosal administration to the oral mucosa and more preferably to the oral mucosa. In illustrative embodiments of the invention, novel methods of transmucosal administration of at least one active ingredient and optionally additional therapeutic agents are described, and methods for using them are taught. The active substance is meloxicam or a pharmaceutically acceptable salt, solvate or ester thereof.
The compositions of the various embodiments of the present invention may also include solubilizing agents, preferably the solubilizing agents listed in the FDA Inactive Ingredients Guide. Examples of solubilizing agents include, but are not limited to polyvinyl alcohol (PVA), polyoxyethylene sorbitan fatty acid esters such as Polysorbate 80 or Tween 80, and polyols such as glycerin.
Compositions of the various embodiments of the present invention may also include preservatives to inhibit or prevent microbial activity. Examples of suitable preservatives include, but are not limited to Purite®, benzyl alcohol, and sodium benzoate. When ethanol is used in a sufficient amount as the polar solvent, ethanol can also serve as a preservative.
In general, the absorption rate of an active substance may increase depending on the mode of administration (for example, transmucosal administration versus conventional oral swallowed or swallowed). In some described methods of compositions for transmucosal administration comprising active ingredients, efforts have been made to control the size and size range of the particles of the pharmaceutical compositions of the invention. The active ingredient formulations suitable for transmucosal administration are to be administered to the oral mucosa using a sprayer.
The advantages of transmucosal administration of the active ingredient compositions of various embodiments of the invention, as compared to conventional oral or intravenous formulations include, but are not limited to.
a: (1) smaller size of the dosage form; (2) smaller doses of drug required to obtain the same pharmacological effect; (3) increased bioavailability; (4) substantially similar pharmacokinetic profiles of the compositions administered both with food and on an empty stomach; (5) improved pharmacokinetic profiles; (6) ease of administration for the administrator (professional or layman); (7) the compositions can be used together with other active ingredients; (8) reduced stress or discomfort for the animal patient; (9) greater exposure of the administered dose versus conventional oral intake swallowed or swallowed; (10) ability to administer to an unconscious animal; and (11) ease of administration against oral nasogastric tube or ball gun, particularly in large animals.
Transmucosal administration of the compositions of the active ingredient of the invention preferably have a higher bioavailability, require smaller doses, and have a shorter time to reach the maximum concentration in plasma after administration compared to the previous formulations of the conventional active ingredient ( for example, conventional oral administration). In an illustrative embodiment, greater bioavailability due to transmucosal administration of the active ingredient compositions of the invention may allow a smaller dose size to achieve the same therapeutic or prophylactic effect. This is particularly significant for populations of animals such as pets that may require repeated treatment or treatment of a herd or entire population. In another illustrative embodiment of the invention, transmucosal administration of the active ingredient compositions provides enhanced bioavailability so that the dose of the active ingredient can be reduced, resulting in a potential decrease in the risk of toxicity associated with said active ingredients. It has been surprisingly discovered in the invention that the methods of transmucosal administration of the active ingredient compositions may allow therapeutic and prophylactic levels with a desirable dose lower than conventional methods of administration.
Methods of transmucosal administration of active ingredient compositions having a desirable pharmacokinetic profile when administered to animals are also described. The desirable pharmacokinetic profile of the active ingredient compositions preferably includes, but is not limited to: (1) the Tmax of an active ingredient, when tested in the plasma of an animal after transmucosal administration, is preferably less than the Tmax for a conventional form (ie, a pill) of the same active ingredient, administered at the same dosage; (2) The Cmax of an active ingredient, when tested in the plasma of an animal after transmucosal administration, is preferably greater than Tmax for a conventional form (i.e., a pill) of the same active ingredient, administered thereto. dosage; and / or (3) that the ABC of an active ingredient, when tested in the plasma of an animal after transmucosal administration, is preferably greater than the ABC for a conventional form (i.e., a pill) of the same active ingredient, administered at the same dosage.
The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured after
the initial transmucosal administration of a dose of the active substance. The compositions can be formulated in the manner described below and using the methods known to those skilled in the art.
A transmucosal composition of a preferred active ingredient of the invention may present in the comparative pharmacokinetic assay with a non-transmucosal formulation of the same active ingredient, administered at the same dosage; a Tmax of no more than approximately 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 30%, no more than 25%, no more than 20 %, not greater than 15%, or not greater than 10%, of the Tmax presented by the non-transmucosal formulation of the same active ingredient. The range of Tmax values of a transmucosal composition of the active ingredient of the invention may present in the comparative pharmacokinetic assay with a non-transmucosal formulation of the same active ingredient, administered at the same dosage, may be 10% -90% of the Tmax presented by the non-transmucosal formulation of the same active ingredient, including all subintervals between them (for example, 10% -80%, 20% -90%, 50% -70%, etc.).
A transmucosal composition of a preferred active ingredient of the invention may also present in the comparative pharmacokinetic assay with a non-transmucosal formulation of the same active ingredient, administered at the same dosage, a Cmax that is at least about 10%, at least about 20% , at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, about 500%, or about 1000% higher than the Cmax presented by the non-transmucosal formulation of the same active ingredient. The range of Cmax values of a transmucosal composition of the active ingredient of the invention may present in the comparative pharmacokinetic assay with a non-transmucosal formulation of the same active ingredient, administered at the same dosage, may be 10% -90% of the presented Cmax. by the non-transmucosal formulation of the same active ingredient, including all subintervals between them (for example, 10% -80%, 20% -90%, 50% -70%, etc.).
A transmucosal composition of a preferred active ingredient of the invention may also present in the comparative pharmacokinetic assay with a non-transmucosal formulation of the same active ingredient, administered at the same dosage, an ABC that is at least about 10%, at least about 20% , at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, about 500%, or about 1000% higher than the ABC presented by the non-transmucosal formulation of the same active ingredient. The range of ABC values of a transmucosal composition of the active ingredient of the invention may also present in the comparative pharmacokinetic assay with a non-transmucosal formulation of the same active ingredient, administered at the same dosage, may be 10% -1000% of the presented ABC by the non-transmucosal formulation of the same active ingredient, including all subintervals between them (for example, 20% to approximately 1000%, 50% to approximately 500%, 500 % to about 1000%, etc.).
Any form of transmucosal composition that provides the desired pharmacokinetic profile is suitable for administration to the oral mucosa according to the present methods. Exemplary dosage forms of the transmucosal formulations that provide such profiles are liquid dispersions, aerosols, pump sprayers, or mists of an active ingredient composition. The transmucosal composition of the invention is preferably a dosage form of liquid mist, although any pharmaceutically acceptable dosage form can be used for transmucosal administration to the oral mucosa of an animal.
The active ingredient compositions of the invention can be administered transmucosally together with an additional therapeutic agent, for example, one or more additional drugs, penetration enhancers, bioadhesive agents, flavoring agents, masking agents, or the like, as further described herein.
Transmucosal administration of the compositions of the non-steroidal anti-inflammatory agent meloxicam of the invention are useful in the methods of treatment or prevention of pain, inflammation, and / or fever, as further described herein.
D. Administration and therapeutic / prophylactic compositions
Due to the greater potential bioavailability and the lower potential dose or other advantage resulting from the transmucosal administration of the compositions of the invention, the compositions are advantageously useful in veterinary medicine.
The compositions, comprising one or more active ingredients of the invention, are administered transmucosally to the oral mucosa, and more preferably to the buccal or gingival mucosa. The compositions of the invention can be administered by any convenient route, for example, by absorption through epithelial or mucocutaneous coatings (for example, the oral mucosa or the oral mucosa) and can be administered together with an additional therapeutic agent. It is known that various administration systems can be used to administer an active ingredient of the invention. The preferred mode of administration may be left to the discretion of the
specialist, and may depend in part on the specific type of medical ailments of interest. In most cases, administration will result in the release of the active ingredients of the invention in the bloodstream.
The methods of transmucosal administration of a composition comprising active ingredients of the invention can be tested in vitro and / or in vivo, to determine the desired therapeutic or prophylactic activity. For example, in vitro assays can be used to determine if administration of a specific principle of the invention is preferred.
or a combination of active ingredients of the invention. It can also be demonstrated that the active ingredients of the invention are effective and safe using laboratory animal model systems. In vitro and in vivo assays are known in the art.
The compositions will contain a therapeutically or prophylactically effective amount of an active ingredient of the invention, optionally more than one active ingredient of the invention (or its salts, solvates, or derivatives), preferably in purified form, together with a suitable amount of a vehicle. Pharmaceutically acceptable in order to provide the form for transmucosal administration to the animal.
The compositions to be used in the methods of the invention can take the form suitable for the use of administering a drug transmucosally by spraying to the oral mucosa, preferably the oral mucosa of an animal. In one embodiment, the pharmaceutically acceptable carrier is a transmucosal oral spray (see, for example, U.S. Patent No. 6,676,931). Other examples of suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by EW Martin.
In an illustrative embodiment, the active ingredients of the invention are formulated according to routine procedures as a pharmaceutical composition adapted for transmucosal administration to the oral mucosa of an animal. Usually, the compositions of the invention for transmucosal administration are sterile isotonic aqueous alcoholic solutions with buffer. Optionally, the compositions may also include a flavoring agent. In general, the ingredients are supplied both separately and mixed together in a unit dosage form, for example, as an aerosol spray or a pump spray indicating the amount of the active ingredient. Optional flavoring agents include, for example, natural or synthetic animal flavoring agents or aroma enhancers, agents that improve palatability or odor of compositions for an animal, and preservatives, to provide a pharmaceutically palatable preparation. For example, flavorings that can be used include, but are not limited to, liver, chicken, veal, or bacon flavorings. In some cases, the compositions of the invention may be formulated to comprise species-specific agents such as: liver, veal, chicken, cheese, or honey for dogs; fish, tuna, sardine or cod liver oil for cats; apple, apple / caramel, clove or honey for horses; eggnog, anise, alfalfa or maple for cattle; Lemon cream or banana cream for reptiles, chocolate or peanut butter for ferrets; carrot, celery or lettuce for rabbits; and tutti-frutti, pina colada or tangerine for birds.
The compositions of the various embodiments of the present invention may also include sweeteners to improve the palatability of the compositions. Examples of suitable sweeteners include, but are not limited to sucralose (commercially available as Splenda®), sucrose, neotame, and acesulfame K.
The amount of an active ingredient of the invention that will be effective in the treatment of a particular disorder, disease, or condition described herein can often depend on the nature of the disorder, disease, or condition, and can be determined by techniques. standardized clinics. In addition, in vitro or in vivo assays can optionally be used to help identify the optimal dosage ranges. The precise dose to be used in the compositions may also depend on the route of administration and the severity of the disease, disorder, or condition and the animal being treated, and should be decided according to the criteria of the specialist and the specific circumstances of each animal.
The dosage amounts described herein refer to the total amounts administered; that is, if more than one agent of the invention is administered, the preferred dosages correspond to the total amount of each agent administered. Oral compositions normally contain about 10% to about 95% of the active ingredient by weight.
i. Sprayers spray
In an illustrative embodiment, the invention encompasses the transmucosal administration of a composition of the invention to the oral mucosa using an aerosol dosage spray. Aerosol dosing sprayers comprise one or more active ingredients in the form of a suspension, emulsion, or solution and can be used for transmucosal administration of the active ingredients. A specific application comprises pharmaceutical suspensions for the transmucosal administration of an active ingredient in a particulate form.
A specific embodiment encompasses a measured dose aerosol sprayer that conventionally consists of a pressurized container having a fixed volume measuring valve for measuring individual doses of a
suspension of medication contained in the container to be administered to the oral mucosa. For example, for the convenience of veterinary use, a spray for aerosol dosing may contain a measured dose that will allow precise application of a therapeutically or prophylactically effective amount of an active ingredient for each type of animal, for example, a dog, cat, or horse In addition, dosages can be measured for a specific size of an individual animal. For example, measured doses can be prepared for large dogs (greater than about 50 pounds; 22.5 kg) or small (less than about 25 pounds; 11.25 kg). In order to ensure the transmucosal administration of a precise dose of active ingredient, it is essential that the suspension be dispersed consistently and homogeneously and that the behavior of the valve be reproducible and effective throughout the life of the container. The suspension conventionally comprises active ingredient particles dispersed in a liquefied gas, which during use acts as a propellant. By pressing the actuator of the measuring valve stem, the propellant fraction of the measured dose is rapidly vaporized, in order to aerosolize the suspended particulate active ingredient, which is then administered to the oral mucosa.
To administer a transmucosal oral mist, the corner of the animal's lips (for example, of the dog, of the cat,
or the horse) will grab and remove from the gums by opening the oral space. The mist will normally be directed in a caudal manner and towards the gingival and / or buccal mucosal surfaces. The nebulizer head will be completely depressed, ensuring that the mist does not escape from the mouth. If the dose is greater than about 300 to about 500 microliters, the dose can be distributed between both sides of the mouth.
Traditionally, chlorofluorocarbons such as CFC-11, CFC-12, and CFC-114 have been employed as propellants in metered dose inhalers. A particulate medicament intended for transmucosal administration may have a particle size with an average aerodynamic diameter of about 0.05 mm to about 11 mm. Particles that are between about 0.05 mm and about 11 mm may have a high surface energy and may therefore be difficult to initially disperse in the propellant, and, once dispersed, may have a tendency to aggregate undesirably and quickly, eventually leading to irreversible aggregation of the particles. In the case of using a CFC as a propellant, this problem has been solved by the addition of a surfactant soluble in the CFC in order to coat the drug particles and to avoid aggregation by steric hindrance. It is also believed that the presence of surfactant is an aid to the behavior of the valve. In practice, the drug particles are homogenized in the liquid propellant with the inclusion of a soluble surfactant in the propellant, for example, such as lecithin, oleic acid, or sorbitan trioleate. The resulting suspension volume is then dispensed in individual metered dose inhalers and a propellant with a high vapor pressure is added.
The alternative propellants, which share some physical properties similar to those of the CFC propellants used previously and which have been suggested for use in metered dose inhalers, are hydrofluoroalkanes, notably HFA-134a and HFA-227. The propellant is normally material without freon, preferably a linear or branched (C3-C8) hydrocarbon. The propellant must be substantially non-aqueous and can produce a pressure in the aerosol dosing container such that, with normal expected use, sufficient pressure is produced to expel the solvent from the container when the valve is activated, but not it is an excessive pressure such that it damages the seals of the container or the valve.
In a particular embodiment, the aerosol spray compositions of the invention, for the transmucosal administration of a pharmacologically active principle soluble in a pharmacologically acceptable non-polar solvent comprises in% by weight of total composition: a pharmaceutically acceptable propellant from about 5 to about 80%, a non-polar solvent from about 19 to about 85%, an active ingredient from about 0.05 to about 50%, further comprising suitably, by weight of the total composition, an optional flavoring or odor enhancer from about 0.01 to about 10% (when present). In one embodiment, the composition comprises: (a) a propellant from about 10 to about 70%, a non-polar solvent from about 25 to about 89.9%, active ingredient from about 0.01 to about 40%, and an agent or optional flavoring agents or odor enhancers from about 0.01 to about 8% (when present). or (b) a propellant from about 20 to about 70%, a non-polar solvent from about 25 to about 74.75%, active ingredient from about 0.25 to about 35%, and an optional flavoring or odor enhancer agent from about 0.02 to about 7.5% (when present).
Another specific embodiment of the invention comprises a polar composition for aerosol spraying for the transmucosal administration of a pharmacologically active principle soluble in a pharmacologically acceptable polar solvent, which can also be administered in the form of an aerosol driven by a propellant. In this case, the composition comprises a% by weight of total composition: aqueous polar solvent from about 10 to about 99%, active ingredient from about 0.1 to about 25%, further comprising suitably, by weight of the total composition , an optional flavoring or odor enhancer from about 0.01 to about 10% (when present) and a propellant from about 2 to about 10%. In another embodiment, the composition comprises (in% by weight of the total composition): (1) an aqueous polar solvent from about 20 to about 99%, active ingredient from about 0.01 to
about 15%, an optional flavoring or flavoring agent or agents from about 0.1 to about 5% (when present), and a propellant from about 2 to about 5%, or (2) an aqueous polar solvent from about 25 to about 99%, active ingredient from about 0.2 to about 25%, an optional flavoring or flavoring agent or agents from about 0.02 to about 2.5% (when present), and a propellant from about 2 to about 4%.
Another particular embodiment of the invention encompasses a tightly sealed aerosol spray container containing a composition of the non-polar or polar aerosol spray formulation, and a measurement valve suitable for releasing a predetermined amount of said composition from said container.
Non-polar or polar solvents must dissolve the active substance and be miscible with the propellant, (ie, the solvent and the propellant must form a single phase at a temperature between about 0 and about 40 ° C and at a pressure range between about 1 and approximately 3 atm (101 kPa 303 kPa).
The polar and non-polar aerosol spray compositions of the invention are intended to be administered from a tightly sealed pressurized container. Unlike a pump sprayer, which allows air to enter the container after each activation, the aerosol container of the invention closes tightly at the time of manufacture. The contents of the container are released by activation of a measuring valve, which does not allow the entry of atmospheric gases with each activation. Such containers are commercially available.
ii. Pump sprayers,
Another embodiment of the invention encompasses a pump dosing spray container containing a composition for transmucosal administration for the pump spray formulation, and a suitable measuring valve for releasing a predetermined amount of said composition from said container.
In a particular embodiment, the composition for the pump sprayer of the present invention, (i.e. propellant-free composition), for transmucosal administration of an active ingredient, wherein said active ingredient that is soluble in a pharmacologically acceptable non-polar solvent It comprises in% by weight of total composition: an aqueous non-polar solvent from about 30 to about 99.69%, active ingredient from about 0.005 to about 55%, and additionally suitably, an optional flavoring agent or agents from about 0.1 to about 10% (when present ).
Another specific embodiment encompasses a polar pump spray composition of the present invention, (i.e. propellant-free composition), for transmucosal administration of a pharmacologically active principle soluble in a pharmacologically acceptable polar solvent comprising in% by weight of composition total: a pharmaceutically acceptable propellant from about 30 to about 99.69%, active ingredient from about 0.001 to about 60%, additionally suitably comprising, by weight of the total composition, an optional flavoring agent or agents from about 0.1 to about 10% (when present). Preferably, the composition comprises: (a) an aqueous polar solvent from about 37 to about 98.8%, active ingredient from about 0.005 to about 55%, an optional flavoring agent from about 0.5 to about 8% (when present ). or (b) an aqueous polar solvent from about 60.9 to about 98.8%, active ingredient from about 0.01 to about 40%, an optional flavoring agent from about 0.75 to about 7.5% (when it is I presented).
In another embodiment, the composition comprises: (a) an aqueous polar solvent from about 70 to about 99%, an active ingredient from about 0.01 to about 1.0%, or (b) an aqueous polar solvent from about 80 to about 99%, and an active ingredient from about 0.1 to about 0.5%, In another additional embodiment, the polar solvent of the composition comprises 7.5 to 20% ethanol, preferably 7.5 to 15% ethanol in water
iii. Dosage and compositions
The dosage amounts described herein refer to the total amounts administered; that is, if more than one agent of the invention is administered, the preferred dosages correspond to the total amount of each agent administered. Oral compositions normally contain about 10% to about 95% of the active ingredient by weight.
Anti-inflammatory agents
The invention provides the treatment or prophylaxis by transmucosal administration to the oral mucosa of an animal in need thereof, of a therapeutically or prophylactically effective amount of a composition comprising a
non-steroidal anti-inflammatory agent of the invention. Non-steroidal anti-inflammatory people are meloxicam or one of its pharmaceutically acceptable salts, solvates or esters.
Suitable dosage ranges for transmucosal administration to the oral mucosa are generally from about 0.001 milligrams to about 200 milligrams of a non-steroidal anti-inflammatory agent of the invention per kilogram of body weight. In specific preferred embodiments of the invention, the oral dose of a non-steroidal anti-inflammatory agent is from about 0.005 milligrams to about 100 milligrams per kilogram of body weight, more preferably from about 0.01 milligrams to about 50 milligrams per kilogram of weight. body, more preferably from about 0.03 milligrams to about 20 milligrams per kilogram of body weight, and even more preferably from about 0.05 milligrams to about 5 milligrams per kilogram of body weight, In the most preferred embodiment, the oral dose is about 0.1 milligrams of a non-steroidal anti-inflammatory agent of the invention per kilogram of body weight.
The compositions according to the invention can be used in animals to treat arthritis, to treat acute inflammation, in post-surgery situations, in the treatment of colic, or in any situation where pain relief is desired. In addition, the non-steroidal anti-inflammatory agent compositions according to the invention, comprising meloxicam, which is one of the known selective COX-2 inhibitors in humans, can be used to treat diseases, conditions, or disorders in animals where the Selective COX-2 inhibition would be desirable and / or therapeutically effective.
The transmucosal compositions of the various embodiments of the invention can also be administered with a pump, (for example, the propellant-free composition). For transmucosal administration of a pharmacologically antiparasitic compound soluble in a pharmacologically acceptable polar solvent comprising in% by weight of the total composition: approximately 30-99.69% aqueous polar solvent, approximately 0.001-60% active compound, comprising additionally suitably, by weight of the total composition: about 0.1-10% flavoring agent. Preferably, the composition comprises: approximately 37-98.58% polar solvent. about 0.005-55% active compound, about 0.5-8% flavoring agent; about 60.9-97.06% of the most suitable polar solvent, about 0.01-40% of active compound, about 0.75-7.5% of flavoring agent.
In one embodiment, administration of a transmucosal composition can be provided in a single application to the animal. That is, the expected dose is applied, for example, by applying a single spray comprising the expected volume and concentration of the active ingredient to the oral mucosa. of the animal, thus providing the appropriate amount of the active ingredient suitable for treating the animal. In another embodiment, larger animals that require larger doses of active ingredient can be treated by repeated applications (ie, multiple sprays each with a defined spray volume of a composition having a defined concentration of an active ingredient). Repeated application to the oral mucosa of an animal can be carried out in a short period of time (that is, each additional spray is carried out immediately after the previous spray), or each application can be separated in time ( that is, minutes or hours) from the previous spraying, depending on the expected release profile of the active ingredient in the animal.
E: Combined treatment
In certain embodiments of the present invention, the active ingredients of the invention can be used in a combination treatment with at least one additional therapeutic agent. The active ingredient of the invention and the additional therapeutic agent can act additively or, more preferably, synergistically. In a preferred embodiment, a composition comprising an active ingredient of the invention is administered simultaneously with the administration of another therapeutic agent, which forms part of the same composition as the active ingredient of the invention or is a different composition. In another embodiment, a composition comprising an active ingredient of the invention is administered before or after administration of an additional therapeutic agent. Furthermore, the additional therapeutic agent may be an active ingredient of the invention. Therefore, a combined treatment according to the present invention may include combinations of two or more (eg, two, three, four or more) active ingredients. For example, the combined treatment may include two or more antihistamines, and an antihistamine and an antiemetic agent, etc.
In another embodiment, the compositions of the invention encompass the administration of an active ingredient of the invention with a second therapeutic agent. Non-limiting examples of the second therapeutic agent include a muscle antispasmodic agent, an antispasmodic agent, a bone resorption inhibitor, a contractile smooth muscle agent, a calcium absorption enhancer, a muscle relaxant, or a mixture thereof. .
In another embodiment, the second therapeutic agent is an agent to treat urinary incontinence. Suitable agents for treating urinary incontinence for transmucosal administration include, but are not limited to, darifenacin, vamicamide, detrol, ditropan, imipramine, and mixtures thereof.
In another embodiment, the second therapeutic agent is an antidiarrheal agent. Antidiarrheal agents suitable for transmucosal administration include, but are not limited to, ondansetron, palnosetron, tropisetron, attapulgite, atropine, bismuth, diphenoxylate, loperamide, and mixtures thereof.
In another embodiment, the second therapeutic agent is an agent to treat nausea and / or vomiting. Suitable agents for treating nausea and / or vomiting for transmucosal administration include, but are not limited to, alosetron, dolasetron, granisetron, meclizine, metoclopramide, ondansetron, palnosetron, procoperazine, promethazine, trimethobenzamiode, tropisetron, and mixtures of the same.
In another embodiment, the second therapeutic agent is an opioid. Opioids suitable for transmucosal administration include, but are not limited to, alfentanil, butorphanol, codeine, dezocine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, propoxyphene, pentaccinaphene tramadol, and mixtures thereof.
In another embodiment, the second therapeutic agent is an antibacterial agent. Antibacterial agents suitable for transmucosal administration include, but are not limited to, aminoglycoside, azol, cephalosporin, chlorhexidine, GAR-936, metronidazole, pazufloaxacin, penem, penicillin, rifapentene, sulfabenzamide, sulfacetamide, sulfathiazine, tichlorochinazolothiochloxacin, titholphocinate, thickepoxin, telol their mixtures
In another embodiment, the second therapeutic agent is an agent to treat a fungal infection. Suitable agents for treating fungal infections for transmucosal administration include, but are not limited to, voriconazole, griseofulvin, and mixtures thereof.
In another embodiment, the second therapeutic agent is a sedative. Sedatives suitable for transmucosal administration include, but are not limited to, dexmedetomidine, eszopiclone, indiplon, zolpidem, and zaleplon.
In another embodiment, the active ingredient is an antihistamine, an immunosuppressant, an antiemetic, an antibiotic, or an antiparasitic agent administered in combination with a steroid. Non-limiting examples of such combinations include an antihistamine such as clemastine or a diphenhydramine administered in combination with a steroid such as prednisone; an immunosuppressant such as cyclosporine in combination with a steroid such as prednisone; an antiemetic such as ondansetron in combination with a steroid such as prednisone; an antibiotic such as enrofloxacin in combination with a steroid such as prednisone; and an antiparasitic agent such as nitenpiram, ivermectin or milbemycin in combination with a steroid such as prednisone. Different steroids of prednisone are also contemplated. Additionally, the term "combination" may include physical combinations of the active principle or principles with the second therapeutic agent (for example, a steroid) in a dosage form, as well as the administration of the active principle or principles and the second therapeutic agent in forms separate dosing (for example, administration of the active ingredient by TMOM ™ followed or preceded by the administration of the second therapeutic agent in any dosage form). Alternatively, the active principle or principles and a second therapeutic agent can be administered essentially simultaneously.
i. Bioadhesive agents
Optionally, in some embodiments, the compositions of the invention may comprise a bioadhesive agent in addition to the active ingredient. The bioadhesive agents of the various embodiments of the invention allow the adherence of an active ingredient to a biological substrate, preferably the oral mucosa, more preferably the oral mucosa, to maintain a continuous contact of the non-steroidal anti-inflammatory agent with the site of the administration. This process is called mucoadhesion when the substrate is mucosal tissue (see, for example, Chang et al., J. Pharm. Sci. (1985) 74, 4, pp 399-405).
In one embodiment, the bioadhesive agents of the invention comprise at least one surface stabilizer (for example, a cationic surface stabilizer), which is described in more detail below. Bioadhesive agents of various embodiments of the invention result in bioadhesion or additional bioadhesion of transmucosal compositions to biological surfaces, such as the oral mucosa or the oral mucosa. The term bioadhesion includes any attractive interaction between two biological surfaces or between a biological and a synthetic surface. In the case of bioadhesive agents, the term bioadhesion is used to describe adhesion between the transmucosal compositions of the invention and a biological substrate (i.e., oral mucosa or oral mucosa) (see, for example, the United States patent United 6,428,814 on "Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers").
The mechanisms that may be responsible for bioadhesion phenomena include, but are not limited to, mechanical or physical interactions and chemical interactions. The first mentioned ones, the mechanical or physical mechanisms, imply the overlapping or physical interpenetration between a bioadhesive agent and the receiving tissue, which results in the wetting of the bioadhesive surface, the swelling of the bioadhesive polymer, the penetration of the bioadhesive agent into the cracks of the tissue surface, or the interpretation of bioadhesive composition chains with those of the oral mucosa or other related tissues. The second possible bioadhesion mechanism
It incorporates forces such as ionic attraction, dipole forces, van der Waals interactions, and hydrogen bonds. It is this second form of bioadhesion, or chemical, that is believed to be primarily responsible for the bioadhesive properties of the transmucosal compositions of the invention. However, physical and mechanical interactions can also play a role in the bioadhesion of such compositions.
Transmucosal compositions of various embodiments of the invention, further comprising a bioadhesive agent, are useful in any situation in which it is desirable to apply the compositions to a biological surface. The compositions may coat the target surface with a continuous and uniform film, which is normally invisible to the naked eye, but which allows penetration of the active ingredient.
Examples of bioadhesive agents include, but are not limited to, 23-lauryl ether, aprotinin, one of, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, lauric acid, lauric acid / propylene glycol, lysophospholine, lysophospholine , menthol, methoxysalicylate, methyl oleate, oleic acid, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium salts of EDTA, glycocholate, glycodeoxycholate, lauryl sulfate, salicylate, taurocholate, and taurodeoxycholate, sulfoxides, or various alkyl glycosides.
ii. Permeation Enhancers
Optionally, the compositions of various embodiments of the invention may comprise a permeation enhancer to increase the passage of the active ingredients through the oral mucosa. The term of permeation enhancers or penetration enhancers, or similar terms, are used to describe materials that enhance the permeation of a therapeutically or prophylactically effective amount of the active ingredient through the oral mucosa. Studies have suggested the feasibility of oral administration even of a rather large molecular weight pharmaceutical compound using a permeation enhancer (August and Rogers, Int. J. Pharm. (1989) 53, pp. 227-235). The flow of active ingredient through the oral mucosa can be increased by changing both the resistance (i.e., the diffusion coefficient) and the driving force (i.e., the diffusion gradient). The flow can be enhanced by the use of so-called permeation enhancers.
Preferred permeation enhancers for use in transmucosal delivery systems of various embodiments of the invention include, but are not limited to, agents that mess up the cell envelope, solvents, steroidal detergents, bile salts, chelants, surfactants, non-surfactants. , fatty acids, and mixtures thereof, with bile salt enhancers being more preferred.
Agents that disrupt the cell envelope are known in the art that are useful in topical pharmaceutical preparations and also function in the administration of the drug through the skin or mucosa. It is believed that these agents aid in dermal penetration by disrupting the lipid structure of the stratum corneum of cell envelopes. A list of such agents is described in European Patent Application No. 43,738. published on June 13, 1982. It is believed that any agent that disrupts the cell envelope can be used in various embodiments of the compositions and methods of the present invention.
Suitable solvents include water; diols, such as propylene glycol and glycerol; monoalcohols, such as ethanol, propanol, and higher alcohols; DMSO; dimethylformamide, N, N-dimethylacetamide; 2-pyrrolidone; N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-dodecylazacycloheptan-2-one, and other n-substituted alkyl-azacycloalkyl-2-ones (atones); and the like
Other permeation enhancers that can be used in various embodiments of the compositions and methods of the invention include DMSO or aqueous solutions of DMSO, as taught in US Patent No. 3,551,554 to Herschler, the US Pat. United States No. 3,711,602 to Herschler, and United States Patent No. 3,711,606 to Herschler, and the atonas (for example, n-substituted alkyl-azacycloalkyl-2-ones) as noted in U.S. Patent No. 4,557,943 to Cooper.
Permeation enhancers for use in combination with the various embodiments of the compositions and methods of the invention also include, but are not limited to, POLYSORBATE-80 sorbitol, and phosphatidylcholine.
F. Kits
Various embodiments of the invention also provide pharmaceutical packs or kits comprising one or more containers filled with one or more agents or compositions of the invention suitable for at least one transmucosal administration to the oral mucosa, for example, as a single aerosol spray on The oral mucosa of an animal. The containers and kits may contain more than one actuator for multiple administrations, adjustable actuators to allow dose adjustment or actuators of different shape and size to modulate particle spraying or mist size to allow administration of certain types and animal sizes Together with said container or containers, a notice may be optionally associated in the form indicated by the government agency that regulates the manufacture, use, or sale of pharmaceutical or biological products, where said notice notifies the approval or homologation by the agency of the manufacture, use, or sale for animal administration. In a particular embodiment, the kit contains more than one non-inflammatory agent.
Steroid of the invention. In another embodiment, the kit comprises a non-steroidal anti-inflammatory agent of the invention and an additional therapeutic agent, including, but not limited to, a bioadhesion promoter, a permeation enhancer, a flavoring or aroma masking agent, or one of your combinations
5 The invention is further defined by reference to the following examples, which are intended to be illustrative.
G. Examples
The present invention is not limited in scope by the specific embodiments described in the examples which
10 they are intended as illustrations of a few aspects of the invention and any embodiment that is functionally equivalent is within the scope of the present invention. Thus, various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art and are intended to be included in the appended claims.
fifteen Nonsteroidal anti-inflammatory agents
Compositions according to the invention have been prepared according to the teachings of one or more of US Pat. Nos. 5,869,082 5,955,098, 6,110,486, and 6,676,931, whose compositions have been prepared to contain meloxicam (0 , 5-1.0%), ethanol, polyethylene glycol 400, povidone, sodium chloride and water. Any of the
twenty The following experimental examples use other active ingredients and are not included in the scope of the claims.
Example 1: Meloxicam formulations
25 An example of a composition according to the invention is shown in Table 1 below:
Table 1: Composition of illustrative meloxicam
<dl><dt>Ingredients </dt><dd>Amount (mg / g) </dd></dl>
<dl><dt>Meloxicam, BP, </dt><dd> 4,67 </dd></dl>
<dl><dt>Boric Acid, NF </dt><dd> 0,77 </dd></dl>
<dl><dt>Potassium Chloride, USP </dt><dd> 0,93 </dd></dl>
<dl><dt>Poly (vinyl alcohol), USP </dt><dd> 5,00 </dd></dl>
<dl><dt>Ethyl alcohol, dehydrated, USP </dt><dd> 150,00 </dd></dl>
<dl><dt>Sodium Hydroxide, NF / FCC </dt><dd> 1,08 </dd></dl>
<dl><dt>Purified water, USP </dt><dd> 837.57 </dd></dl>
The formulation of Table 1 has a pH of approximately 8.4, and can be prepared by the following method:
30 Preparation of 0.93% meloxicam stock solution
In a 250 ml medium bottle, meloxicam, BP (0.93 g) in 94.00 g of purified water, USP and 4.95 g of a 1 M solution of sodium hydroxide. After dissolving the meloxicam completely, the pH should be approximately 11.5. 35 If a pH adjustment is not necessary, additional purified water is added to adjust the total weight of the solution to 100
g. If the pH is not in the range of 11.5 ± 0.2, 1 M sodium hydroxide is then added to adjust the pH to a value in this range, and additional purified water is added to provide a total weight of the 100 g solution.
40 Preparation of alkali borate buffer
Boric acid, NF (12.37 g) and 14.91 g of potassium chloride, USP were added to a 1000 ml volumetric flask with 750 ml of purified water. The solution was mixed well, and diluted to 1000 ml. The resulting solution (50 ml) was mixed with 8.6 ml of 0.2 M sodium hydroxide in a 200 ml volumetric flask, and diluted with more purified water to
Four. Five provide 200 ml of alkali borate buffer solution.
Preparation of the formulation of Table 1
Meloxicam stock solution (prepared as described above) was mixed with 10 g of alcohol
fifty 5% polyvinyl (aqueous solution) and mixed vigorously. Then, 20 g of the alkali borate buffer solution (prepared as described above) was added and mixed well. Finally, 15 g of dehydrated ethyl alcohol was added and the solution was mixed. The pH was then tested and adjusted, as necessary, with 0.2 M HCl HCl at a pH of 8.5 ± 0.2. Then, additional alkaline borate buffer was added to provide a 0.47% (w / w) solution of meloxicam.
Solubility of meloxicam Meloxicam is very poorly soluble, and its solubility is pH dependent. Table 2 below shows the solubility of meloxicam in various solutions, as shown below. Table 2: Solubility of meloxicam in various solvents
<dl><dt>Solvent </dt><dd>Solubility of meloxicam (p / v) </dd></dl>
<dl><dt>100% water </dt><dd> < 1 % </dd></dl>
<dl><dt>100% ethanol </dt><dd> < 1 % </dd></dl>
<dl><dt>100% Propylene Glycol </dt><dd> < 1 % </dd></dl>
<dl><dt>100% PEG-400 </dt><dd> < 1 % </dd></dl>
<dl><dt>Water: Ethanol 50:50 </dt><dd> < 1 % </dd></dl>
<dl><dt>Water: PEG-400 50:50 </dt><dd> < 1 % </dd></dl>
<dl><dt>EtOH: PEG-400 50:50 </dt><dd> < 1 % </dd></dl>
<dl><dt>Water: Proplenglicol 50:50 </dt><dd> < 1 % </dd></dl>
<dl><dt>Ethanol: Propylene Glycol 50:50 </dt><dd> < 1 % </dd></dl>
<dl><dt>5% povidone in water </dt><dd> < 1 % </dd></dl>
However, after the addition of very small amounts of a 1 M NaOH solution, the meloxicam completely dissolved.
The solubility of meloxicam in various different solvent systems was evaluated. Sufficient meloxicam was added to a mixture of 80% water / 15% EtOH / 5% Poloxamer 188 to obtain a final concentration of 1% meloxicam. Meloxicam does not dissolve completely, and the resulting mixture had a pH of approximately 5.8. NaOH solution (1 M) was added to the mixture to provide a pH of 10. It was observed that meloxicam dissolved. The solution was then acidified to a pH of 7 with 0.2 M HCl, after which it was observed that meloxicam precipitated. Additional 1 M NaOH was added, adjusting the pH to 8, and the meloxicam was re-dissolved and remained in solution.
enough meloxicam was added to 100% water or 85:15 water: ethanol to provide a 1% meloxicam solution. Then, in each case, 1 M NaOH was added to ensure the complete meloxicam solution. Each solution was then titrated with HCl (ac). For 100% aqueous solution, precipitation of meloxicam was observed when the pH dropped to a value of 7.2. After adjusting the pH to 10.1, the meloxicam was dissolved again. The pH was then reduced to a value of approximately 7.8, and no additional precipitation was observed. Similarly, for the 85:15 solvent system of water: ethanol, a precipitate formed when the initial apparent pH was reduced from 12 to 7.7 (by the addition of HCl).
A solution of 1% meloxicam was prepared in a 95: 5 solvent system of water: propylene glycol. Concentrated NaOH solution (10 M) was added to help meloxicam solution. However, meloxicam does not dissolve because the concentration of the NaOH solution is too high. It was determined that the solution having a pH value of less than 8 resulted in the precipitation of meloxicam. To ensure that meloxicam remains in solution, the pH needs should be greater than about 8.0. However, for the safety and palatability of the animal (for example, a can), the pH should be less than about 9.0.
Storage stability
Stability during storage is an important point to take into account when it is envisaged to administer compositions of the formulation by means of a spray-type device. For example, precipitation or decomposition of the active ingredient of the invention would result in the administration of less than the expected dose and / or would cause a clogging of the spraying device. Accordingly, the compositions of the present invention were evaluated to determine stability at 5 ° C. Meloxicam (0.5% w / w) was dissolved in each of the solvent systems shown below in Table 3.
Table 3: Storage stability of various meloxicam 5 solutions
<dl><dt>Matrix (p / p) </dt><dd>% of meloxicam Filtered out </dd></dl>
<dl><dt>100% water </dt><dd>0.5 No </dd></dl>
<dl><dt>100% water </dt><dd>0.5 Yes </dd></dl>
<dl><dt>100% water </dt><dd>0.75 No </dd></dl>
<dl><dt>100% water </dt><dd>0.75 Yes </dd></dl>
<dl><dt>95: 5 Water: Propylene Glycol </dt><dd>0.5 No </dd></dl>
<dl><dt>95: 5 Water: Propylene Glycol </dt><dd>0.5 Yes </dd></dl>
<dl><dt>95: 5 Water: Propylene Glycol </dt><dd>0.75 No </dd></dl>
<dl><dt>95: 5 Water: Propylene Glycol </dt><dd>0.75 Yes </dd></dl>
<dl><dt>95: 5 Water: EtOH </dt><dd>0.5 No </dd></dl>
<dl><dt>95: 5 Water: EtOH </dt><dd>0.5 Yes </dd></dl>
<dl><dt>95: 5 Water: EtOH </dt><dd>0.75 No </dd></dl>
<dl><dt>95: 5 Water: EtOH </dt><dd>0.75 Yes </dd></dl>
<dl><dt>Metacam® </dt><dd>0.5 No </dd></dl>
Each solution was divided into two aliquots, one of which was filtered, the other remained unfiltered. After 24 hours, each of the solutions in Table 3 was transparent and yellow, without precipitate. After 7 days, only the following solutions remained free of precipitate: 0.5% meloxicam in 95: 5 of water: EtOH, 0.5% meloxicam in
95: 5 water: propylene glycol, 0.75% meloxicam in 95: 5 water: propylene glycol, all filtered. After 16 and 19 days, only the following remained free of precipitate: 0.5% meloxicam in 95: 5 water: EtOH, filtered and with Metacam® (ie, the injectable meloxicam solution available from Boehringer-Ingelheim; each ml contains 5.0 mg of meloxicam, 15% alcohol, 10% glycofural (tetraglycol), 5% poloxamer 188, 0.6% NaCl, 0.5 glycine, 0.3% meglumine, rest of water). After 27 days, only Metacam® was free of precipitate.
Stability of meloxicam with various solubilizing agents
Storage of meloxicam with both PVA, Polysorbate 80, and glycerin indicated that the physical stability of the meloxicam solution was greater with PVA than with Polysorbate 80 or glycerin.
Spray characteristics
It was found that aqueous meloxicam solutions comprising PVA as a solubilizing agent provide relatively bad spray characteristics by "sight" observations of the spray model. Ethanol was added to these aqueous PVA / melxicam solutions at two levels: 7.5% and 15%. Tables 4 and 5 show the results of studies of spray characteristics. The term "<10 mm" refers to the percentage of particles that have a diameter of less than 10 mm. The terms "Dv (10)", "Dv (50)", and "Dv (90)" refer to particle sizes below which the indicated cumulative percentage of the population is produced. Therefore, "Dv (10)" indicates the particle size for which the cumulative 10% of the particle population is less than or equal to the quoted size. The term "ovality" is the Dmax / Dmin ratio where Dmax is the longest string in mm that can be represented in the spray model that crosses the COMw (that is, the center of mass of the spray model) in base units, and Dmin is the smallest radius that can be traced inside the spray model that crosses the COMw in base units. The closest ovality is 1.0, the most symmetrical form of the spray model. More symmetrical spray models are desired. The 0.5% PVA formulation has an ovality of 1.26, and accordingly, 0.25% PVA formulations have an ovality of 1.51, the spray model of the formulation of PVA at 0.50%.
Increasing levels of methanol improved the rheological characteristics of the composition by reducing the viscosity of the solution. In addition, higher levels of ethanol serve as an antimicrobial preservative. The formulation containing 15% ethanol provided a suitable "pen" spray.
Table 4: Characterization study of the meloxicam 0.5% spray with 0.5% PVA and 15% EtOH
<dl><dt>Sample ID </dt><dd><10 mm Dv (10) Dv (50) Dv (90) Duration Spray angle Ovality </dd></dl>
<dl><dt>11 </dt><dd> 1,59 % 23,09 45,53 102,73 1,75 27,9 1,343 </dd></dl>
<dl><dt>12 </dt><dd> 1,59 % 22,96 46,50 106,95 1,81 39,0 1,154 </dd></dl>
<dl><dt>21 </dt><dd> 1,64 % 23,18 49,14 108,73 1,74 42,5 1,211 </dd></dl>
<dl><dt>22 </dt><dd> 1,69 % 22,86 48,16 108,63 1,78 29,9 1,205 </dd></dl>
<dl><dt>31 </dt><dd> 1,52 % 23,45 47,92 104,45 1,69 31,2 1,186 </dd></dl>
<dl><dt>32 </dt><dd> 1,57 % 23,02 48,02 103,92 1,68 40,5 1,468 </dd></dl>
<dl><dt>Average </dt><dd> 1,60 % 23,09 47,55 105,90 1,74 35,17 1,26 </dd></dl>
<dl><dt>Std. Dev. </dt><dd> 0,06 % 0,21 1,30 2,55 0,05 6,22 0,12 </dd></dl>
<dl><dt>RSD </dt><dd> 3,7 0,9 2,7 2,4 2,9 17,7 9,5 </dd></dl>
Table 5: Characterization study of the meloxicam 0.5% spray with 0.25% PVA and 15% EtOH
<dl><dt>Sample ID </dt><dd><10 mm Dv (10) Dv (50) Dv (90) Duration Spray angle Ovality </dd></dl>
<dl><dt>Sample ID </dt><dd><10 mm Dv (10) Dv (50) Dv (90) Duration Spray angle Ovality </dd></dl>
<dl><dt>11 </dt><dd> 2,62 % 18,7 39,08 100,01 2,08 29,1 1,298 </dd></dl>
<dl><dt>12 </dt><dd> 2,46 % 19,38 39,41 96,70 1,96 29,6 1,426 </dd></dl>
<dl><dt>21 </dt><dd> 2,36 % 19,36 40,27 102,34 2,06 37,9 1,336 </dd></dl>
<dl><dt>22 </dt><dd> 2,33 % 19,58 39,98 96,13 1,91 44,0 1,818 </dd></dl>
<dl><dt>31 </dt><dd> 2,34 % 19,62 41,67 99,86 1,93 29,2 1,593 </dd></dl>
<dl><dt>32 </dt><dd> 2,41 % 19,22 40,80 98,49 1,94 31,2 1,611 </dd></dl>
<dl><dt>Average </dt><dd> 2,42 % 19,31 40,20 98,92 1,98 33,50 1,51 </dd></dl>
<dl><dt>Std. Dev. </dt><dd> 0,11 % 0,33 0,94 2,31 0,07 6,13 0,20 </dd></dl>
<dl><dt>RSD </dt><dd> 4,5 1,7 2,3 2,3 3,6 18,3 13,0 </dd></dl>
Stability of meloxicam formulations containing glycofural
Glycofural was used as a penetration enhancer for topical and intranasal formulations, and is a
5 component of the injectable Metacam® formulation. However, as shown in Tables 4-6, then meloxicam was less stable in formulations containing glycofurol than in formulations containing ethanol.
Table 6: Stability of 0.5% meloxicam with glycofurol
<dl><dt>Stability Condition * </dt><dd>Spray weight Spray Content SC / SW ratio % of what is indicated on the label Impurity B and C Other impurities </dd></dl>
<dl><dt>Initial </dt><dd>N / A Bulk 0.484%; RSD: 0.2% N / A 96.80% N / A Unknown 0.7% </dd></dl>
<dl><dt>25/60/2 db; n = 3</dt><dd>98.4 mg; RSD: 1.5% 0.461 mg; RSD: 1.1% 0.00468; RSD: 0.4% 92.10% <0.10% N / A </dd></dl>
<dl><dt>25/60/4 dAb; n = 3</dt><dd>100.2 mg; RSD: 2.5% 0.475 mg; RSD: 2.3% 0.00474; RSD: 0.5% 95.00% Imp. B: 0.18% N / A </dd></dl>
<dl><dt>25/60/8 dAb; n = 3</dt><dd>91.6 mg; RSD: 9.4% 0.472 mg; RSD: 9.0% 0.00466; RSD: 0.5% 85.40% Imp. B: 0.14% N / A </dd></dl>
<dl><dt>25/60/12 dAb; n = 3</dt><dd>99.8 mg; RSD: 2.5% 0.467 mg; RSD: 1.3% 0.00468; RSD: 1.0% 93.50% Tax B: 0.20% N / A </dd></dl>
<dl><dt>25/60/4 mo; n = 3</dt><dd>100.7 mg; RSD: 0.4% 0.473 mg; RSD: 1.1% 0.00469; RSD: 0.9% 94.50% Tax B: 0.27% N / A </dd></dl>
<dl><dt>25/60/4 mo, cycle **; n = 3</dt><dd>90.5 mg; RSD: 15.1% 0.418 mg; RSD: 14.9% 0.00462; RSD: 0.3% 83.60% Imp. B: 0.25% N / A </dd></dl>
<dl><dt>40/75/2 dAb; n = 3</dt><dd>96.1 mg; RSD: 2.5% 0.450 mg; RSD: 2.4% 0.00468; RSD: 0.3% 89.90% Tax B: 0.10% N / A </dd></dl>
<dl><dt>40/75/4 dAb; n = 3</dt><dd>86.0 mg; RSD: 12.8% 0.411 mg; RSD: 13.0% 0.00478; RSD: 0.3% 82.10% Tax B: 0.29% N / A </dd></dl>
<dl><dt>40/75/8 dAb; n = 3</dt><dd>84.9 mg; RSD: 10.1% 0.396 mg; RSD: 9.8% 0.00466; RSD: 0.4% 79.20% Tax B: 0.33% N / A </dd></dl>
<dl><dt>40/75/12 dAb; n = 3</dt><dd>86.0 mg; RSD: 9.5% 0.402 mg; RSD: 9.4% 0.00467; RSD: 0.4% 80.40% Tax B: 0.49% N / A </dd></dl>
<dl><dt>40/75/4 mo; n = 3</dt><dd>85.4 mg; RSD: 8.0% 0.411 mg; RSD: 8.1% 0.00481; RSD: 2.0% 82.20% Tax B: 0.67% N / A </dd></dl>
<dl><dt>* Accelerated stability conditions: ° C /% relative humidity / test interval ** samples cycled from 5 ° C / 16 h at 40 ° C / 8 h N / A means not detected </dt><dd /></dl>
Table 7: Stability of 0.5% meloxicam with 0.5% PVA and 7.5% EtOH
<dl><dt>Stability Condition * </dt><dd>Spray weight Spray Content SC / SW ratio % of what is indicated on the label Impurities B and C Other impurities </dd></dl>
<dl><dt>Initial </dt><dd>N / A Bulk 0.475%; RSD: 0.4% N / A 95.00% N / A Unknown 0.5% </dd></dl>
<dl><dt>25/60/2 dAb; n = 3</dt><dd>98.4 mg; RSD: 0.5% 0.467 mg; RSD: 0.7% 0.00475; RSD: 0.3% 93.40% <0.10% N / A </dd></dl>
<dl><dt>25/60/4 dAb; n = 3</dt><dd>98.6 mg; RSD: 1.5% 0.481 mg; RSD: 2.0% 0.00488; RSD: 0.5% 96.20% <0.10% N / A </dd></dl>
<dl><dt>25/60/8 dAb; n = 3</dt><dd>90.3 mg; RSD: 11.5% 0.436 mg; RSD: 11.9% 0.00483; RSD: 0.5% 87.20% <0.10% N / A </dd></dl>
<dl><dt>25/60/12 dAb; n = 3</dt><dd>90.5 mg; RSD: 11.3% 0.430 mg; RSD: 11.5% 0.00475; RSD: 0.4% 85.90% <0.10% N / A </dd></dl>
<dl><dt>25/60/4 mo; n = 3</dt><dd>96.7 mg; RSD: 2.4% 0.463 mg; RSD: 3.6% 0.00479; RSD: 1.8% 92.70% <0.10% N / A </dd></dl>
<dl><dt>25/60/4 mo, cycle **; n = 3</dt><dd>98.7 mg; RSD: 5.4% 0.466 mg; RSD: 5.0% 0.00472; RSD: 0.4% 93.10% <0.10% N / A </dd></dl>
<dl><dt>Stability Condition * </dt><dd>Spray weight Spray Content SC / SW ratio % of what is indicated on the label Impurity B and C Other impurities </dd></dl>
<dl><dt>40/75/2 dAb; n = 3</dt><dd>99.1 mg; RSD: 0.6% 0.476 mg; RSD: 0.3% 0.00480; RSD: 0.4% 95.30% <0.10% N / A </dd></dl>
<dl><dt>40/75/4 dAb; n = 3</dt><dd>92.8 mg; RSD: 11.9% 0.456 mg; RSD: 12.0% 0.00491; RSD: 0.9% 91.20% <0.10% N / A </dd></dl>
<dl><dt>40/75/8 dAb; n = 3</dt><dd>96.6 mg; RSD: 2.7% 0.462 mg; RSD: 2.3% 0.00478; RSD: 0.9% 92.50% <0.10% N / A </dd></dl>
<dl><dt>40/75/12 dAb; n = 3</dt><dd>97.3 mg; RSD: 1.2% 0.464 mg; RSD: 2.0% 0.00477; RSD: 1.1% 92.80% Imp. B: 0.18% N / A </dd></dl>
<dl><dt>40/75/4 mo; n = 3</dt><dd>98.1 mg; RSD: 1.7% 0.482 mg; RSD: 1.6% 0.00491; RSD: 0.6% 96.40% Tax B: 0.54% N / A </dd></dl>
<dl><dt>* Accelerated stability conditions: ° C /% relative humidity / test interval ** samples cycled from 5 ° C / 16 h at 40 ° C / 8 h N / A means not detected </dt><dd /></dl>
Table 8: Stability of 0.5% meloxicam with 0.5% PVA and 15% EtOH
<dl><dt>Stability Condition * </dt><dd>Spray weight Spray Content SC / SW ratio % of what is indicated on the label Impurity C Other impurities </dd></dl>
<dl><dt>Initial </dt><dd>N / A Bulk 0.470%; RSD: 0.4% N / A 94.00% N / A Unknown 0.5% </dd></dl>
<dl><dt>25/60/2 dAb; n = 3</dt><dd>98.5 mg; RSD: 0.5% 0.474 mg; RSD: 1.5% 0.00481; RSD: 0.2% 94.70% <0.10% N / A </dd></dl>
<dl><dt>25/60/4 dAb; n = 3</dt><dd>98.5 mg; RSD: 1.2% 0.485 mg; RSD: 1.5% 0.00492; RSD: 0.3% 97.00% <0.10% N / A </dd></dl>
<dl><dt>25/60/8 dAb; n = 3</dt><dd>90.7 mg; RSD: 8.4% 0.454 mg; RSD: 7.7% 0.00485; RSD: 0.7% 90.90% Imp. B: 0.14% N / A </dd></dl>
<dl><dt>25/60/12 dAb; n = 3</dt><dd>98.5 mg; RSD: 1.9% 0.481 mg; RSD: 1.1% 0.00488; RSD: 0.8% 96.20% <0.10% N / A </dd></dl>
<dl><dt>25/60/4 mo; n = 3</dt><dd>98.8 mg; RSD: 1.2% 0.493 mg; RSD: 2.6% 0.00499; RSD: 3.8% 98.50% <0.10% N / A </dd></dl>
<dl><dt>25/60/4 mo, cycle **; n = 3</dt><dd>98.1 mg; RSD: 4.6% 0.467 mg; RSD: 1.9% 0.00476; RSD: 1.0% 93.40% <0.10% N / A </dd></dl>
<dl><dt>40/75/2 dAb; n = 3</dt><dd>95.2 mg; RSD: 4.6% 0.459 mg; RSD: 4.4% 0.00482; RSD: 0.2% 91.80% <0.10% N / A </dd></dl>
<dl><dt>40/75/4 dAb; n = 3</dt><dd>98.5 mg; RSD: 1.1% 0.490 mg; RSD: 1.2% 0.00497; RSD: 0.2% 97.90% <0.10% N / A </dd></dl>
<dl><dt>40/75/8 dAb; n = 3</dt><dd>96.6 mg; RSD: 2.7% 0.468 mg; RSD: 3.3% 0.00484; RSD: 1.4% 93.70% <0.10% N / A </dd></dl>
<dl><dt>40/75/12 dAb; n = 3</dt><dd>97.4 mg; RSD: 3.0% 0.469 mg; RSD: 3.2% 0.00482; RSD: 0.9% 93.80% Imp. B: 0.12% N / A </dd></dl>
<dl><dt>40/75/4 mo; n = 3</dt><dd>100.5 mg; RSD: 0.6% 0.504 mg; RSD: 2.9% 0.00501; RSD: 2.9% 100.80% Tax B: 0.35% N / A </dd></dl>
<dl><dt>* Accelerated stability conditions: ° C /% relative humidity / test interval ** samples cycled from 5 ° C / 16 h at 40 ° C / 8 h N / A means not detected </dt><dd /></dl>
For the formulation with glycofurol, the initial concentration of meloxicam was 96.8% of what was indicated on the label, and
5 decreased to 82.2% at the time point at 4 months at 40 ° C / 75% RH In addition, an "B" impurity was identified. The impurity concentration "B" started at 0.1% at 2 weeks, and increased to 0.7% at 4 months. The formulation containing glycofurol showed an absence of chemical stability over time, especially under conditions of accelerated stability.
10 For the 7.5% ethanol formulation, the initial meloxicam concentration was 95.0% and was 96.4% after 4 months at 40 ° C / 75% RH Under the conditions of 40 ° C / 75% of HR, the impurity level "B" was less than 0.1
% over 8 weeks of trial. Observable levels of impurity "B" appeared at 12 weeks (0.2%) and increased to 0.4% at 4 months. This level of impurity formation "B" was lower than that observed for the formulation containing glycofurol.
For the 15% ethanol formulation, the initial meloxicam concentration was 94.0% and increased to 100.8% after 4 months at 40 ° C / 75% RH. The increase in meloxicam concentration may be due to evaporation of part of ethanol. Under the conditions of 40 ° C / 75% RH, the level of impurity "B" was less than 0.1% over 8 weeks of testing. Observable levels of impurity "B" appeared at 12 weeks (0.1%) and increased to 0.4% at 4 months. This level of impurity formation "B" was lower than that observed for the formulation containing glycofurol. and the formulation containing 7.5% ethanol.
The compositions of the present invention, as described above, were formed in a spray that was administered to dogs by the oral mucosa, between the lips and teeth of each animal at a target dose of approximately 0.2 mg / kg ( approximately 0.1 mg / lb) body weight.
An expert in veterinary techniques will recognize that the target dose may vary depending on the nature and severity of the condition being treated or prevented, the species of the animal being treated, the size of the animal being treated, etc.
In addition, various treatment protocols can be used. For example, the animal can be treated once, or repeatedly at intervals during a single day, or at intervals for an extended time depending on the nature of the treated condition, the size and condition of the treated animal, etc. For example, acute ailments can be treated for a short period with one or more administrations of the compositions according to the invention, while chronic ailments may require repeated administrations (eg, daily) of the compositions for an extended time.
Example 2: Study of absorption of meloxicam in dogs
A two-way cross-over experiment was conducted with six dogs comparing conventional oral administration of meloxicam (ie, an oral suspension of Metacam®) with transmucosal oral administration (i.e., a commercially available Metacam® injectable solution applied by transmucosal oral spray) of meloxicam. The target dose was 0.2 mg / kg meloxicam. The average dose of oral suspension was 0.20 mg / kg (0.19-0.21 mg / kg range), and the average dose for use in transmucosal oral administration was 0.20 mg / kg (range 0.19-0.21 mg / kg). Blood samples were obtained at 0, 5, 30 minutes and 1, 2, 4, 8, 12, 24, 48, and 72 hours after the dose.
Figure 1 shows that, after administration of meloxicam using TMOM ™, the absorption time, maximum plasma concentration, and total absorption are comparable or better compared to the administration profile obtained with the oral suspension. Therefore, TMOM ™ provides a simpler method of administration that effectively administers meloxicam as conventional oral dosage forms.
Figure 2 shows the pharmacokinetic parameters for oral suspension administration and administration using TMOM ™. The ABC represents the area under the curve or the total amount of drug exposure to the animal after administration by the two different dosage forms. Cmax represents the maximum plasma concentration of meloxicam measured in ng / ml when administered by dosage forms. Tmax denotes the time it takes to reach the maximum plasma concentration of meloxicam after administration of both dosage forms. The t © is the calculated elimination half-life (the time it takes to decrease plasma concentrations by 50%) of the active substance (in this case, meloxicam) when administered by both dosage forms. The absorption half-life is the amount of time it takes for the remaining half that remains at the absorption site until it is absorbed.
Figure 3 shows that meloxicam administered by TMOM ™ appears to be bioequivalent to meloxicam administered by oral suspension.
Example 3: Study of absorption of meloxicam in anesthetized dogs
The absorption of an anesthetized can was also carried out. The subjects that were anesthetized were dogs using minimal preanesthetics (isoflurane through an endotracheal tube). The possibility of inward escape and absorption by the gastrointestinal tract by obstructing the esophagus with a Foley catheter was avoided. Meloxicam was administered using a transmucosal oral mist, and after 30 minutes, the mouths of the dogs were washed to remove any residual oral mist formulation. Blood samples were taken 0, 5, 30 min, and 1, 2, 4, 8, 12, 24, and 72 hours after the dose. Samples of the jugular and cephalic vein were obtained 5, 30 min and 4, and 8 hours after the dose. The target dosage was 0.1 mg / kg (4.66 mg / ml of meloxicam in 15% ethanol, 0.5% polyvinyl alcohol, the pH was adjusted to 8.5 200 ml (0.09 mg ), dose range 0.08-0.15 mg / kg). The results are shown in Figures 4 and 5.
The transmucosal administration of meloxicam was clearly confirmed. Figure 4 shows that meloxicam absorption was transmucosal since gastrointestinal absorption was impossible. This result was confirmed by the higher levels of meloxicam in the jugular plasma (that is, the drainage route of the oral mucosa) compared to cephalic (systemic) levels at 30 min and at 4 h. In addition, the results show that transmucosal absorption can occur under anesthesia.
Additionally, up to approximately 90% of the dose in an awake animal was administered transmucosally. Figure 5 compares plasma meloxicam concentrations in anesthetized dogs and awake animals (from previous studies shown in Figure 1. Administration by TMOM ™ at 0.2 mg / kg-cephalic). After correction of the higher dose by TMOM ™ administered to the awake animal, the ABC for anesthetized animals is comparable (-92%) with the ABC for awake animals.
Example 4: Study of carpofreno in dogs
A three-way cross-experiment was conducted with six dogs comparing conventional oral administration of carprofen (Rimadyl® oval tablets, 25 mg; average dose 1.06 mg / lb (2.33 mg / kg) (0.93-1.14 mg / lb (2.04-2.51 mg / kg)), oral transmucosal administration of carprofen (Rimadyl solution for injection ®, 50 mg / ml, average dose 1.08 mg / lb (2.33 mg / kg) (0.96-1.14 mg / lb (2.04-2.51 mg / kg)), oral administration transmucosal carprofen (Rimadyl® injectable solution, 50 mg / ml, average dose 1.08 mg / lb (2.37 mg / kg) (0.96-1.16 mg / lb (2.11-2.55 mg / kg)). Blood samples were obtained at 0, 5, 30 minutes and 1, 2, 4, 8, 12, and 24 hours after the dose. The results are shown in Figures 6 and 7.
Transmucosal oral administration was more similar to the administration of oval tablets than subcutaneous injection (Figure 6). Administration by subcutaneous injection resulted in slower absorption and longer time for maximum concentrations (Tmax) than any administration by oval tablet or TMOM ™. Figure 7 shows that the ABC values of the three methods of administration were similar, and that the Cmax of the subcutaneous injection was approximately half that of both the oval tablet and the transmucosal oral administration. Transmucosal oral administration resulted in a slightly faster absorption of carprofen than that of the oval tablet - there was no delay and a shorter Tmax. The Cmax and ABC values for the oval tablet and oral transmucosal administration of carprofen were very similar.
Example 5: Study of absorption of carprofen in anesthetized dogs
The absorption of an anesthetized can was also carried out. The subjects that were anesthetized were dogs using minimal preanesthetics (isoflurane through an endotracheal tube). The possibility of inward escape and absorption by the gastrointestinal tract by obstructing the esophagus with a Foley catheter was avoided. Carprofen was administered using a transmucosal oral mist. Blood samples were taken 0, 5, 15, 30 min, and 1, 2, 4, 8, 12, and 24 hours after the dose. Samples of the jugular and cephalic vein were obtained 5, 15 and 30 and 1 and 2 hours after the dose. The target dose was 2.2 mg / kg (50 mg / ml of Rimadyl® injectable solution, 300 ml (15 mg), target dose range 1.9-2.5 mg / kg). The results are shown in Figures 8 and 9.
Figure 8 confirms the transmucosal administration of carprofen given that intestinal absorption was impossible, which was confirmed by higher levels of carprofen in the jugular plasma compared to cephalic levels at 30 min. Figure 9 shows the levels of carprofen in blood plasma in anesthetized and different dogs (from Figure 6-cephalic). The ABC for anesthetized animals was approximately 25% of that of awake animals.
Antihistamine agents
A composition according to the invention was prepared according to the teachings of one or more of the United States patents with US 5,869,082, 5,955,098, 6,110,486, and 6,676,931. This composition was formed in a spray that was administered to dogs, horses, and cats, through the oral mucosa, between the lips and teeth of each animal, at a target dose of approximately 0.1 mg / kg or approximately 1 mg / kg body weight
Example 6
A two-way cross-experiment was carried out with six animals (in each species: can, feline, equine) using clemastine tablets (Tavist®) and a composition for oral transmucosal clemastine administration (25 mg / ml clemastine fumarate , vehicle: 75% ethanol, 25% water). The daily dose for canine subjects was 1 mg / kg (oral administration both transmucosal and in tablets). The average dose per tablet was 0.96 mg / kg (0.95-0.97 mg / kg) and the average transmucosal oral administration dose was 0.97 mg / kg (0.91-1.06 mg / kg) administered in a spray volume of 400-650 ml using 4-7 pumps of the delivery device. The target dose for feline subjects was also 1 mg / kg for oral administration both transmucosal and in tablets. The average dose per tablet was 1.07 mg / kg (0.89-1.22 mg / kg) and the oral dose
Average transmucosal was 0.95 mg / kg (0.83-1.14 mg / kg) administered in a spray volume of 100-200 ml using 1-2 pumps of the delivery device. The target dose for equine subjects was 0.1 mg / kg for oral administration both transmucosal and in tablets. The average dose per tablet (through a tube to the stomach) was 0.1 mg / kg (0.10-0.11 mg / kg) and the average transmucosal oral administration dose was 0.1 mg / kg (0.09-0.11 mg / kg) administered in a spray volume of 1.4-1.7 ml using 14-17 pumps of the delivery device.
Blood samples were taken 5, 15, 30 min, 1, 2, 4, 7, 12, and 24 hours after the dose. Variable salivation (none to moderate, mild to severe) was observed in canine and feline subjects, respectively.
Figures 10 and 11 show a faster uptake of clemastine in feline subjects using transmucosal oral administration (shorter Tmax) compared to conventional oral administration. The lower ABC values for feline subjects appear to be an artifact of salivation observed for these subjects.
Figures 12 and 13 show the significantly better bioavailability of clemastine in equine subjects with oral transmucosal administration and faster drug uptake (shorter Tmax). It was difficult to compare the PK parameters of the approach with conventional oral administration (ie oral nasogastric tube) and transmucosal oral administration due to extremely poor bioavailability in equine subjects of clemastine in tablet form. However, t © with oral transmucosal administration is similar to that reported in the literature (2.8 hours with oral transmucosal administration versus 2.9 hours with oral nasogastric tube; Torneke et al., J. Vet. Pharmacol Therap. 26, pages 151-157, 2003).
Figures 14 and 15 show a significantly better relative bioavailability of clemastine (ABC) in canine subjects with a much higher peak (Cmax) achieved with transmucosal oral administration compared to conventional oral administration (i.e., by tablet).
The preparation for transmucosal oral spraying of the clemastine composition showed unexpectedly high plasma drug concentrations in dogs (see Figures 14 and 15) and horses (see Figures 12 and 13), compared to the administration of a similar dose ( on a mg / kg basis) through the form of an oral tablet to each type of animal. In cats, (see Figures 10 and 11), clemastine was well absorbed, although the metabolism of the drug in these species is different from that of other species, and consequently there was less difference in plasma concentrations between the preparation for transmucosal oral spray and oral tablets.
In dogs, for example, as can be seen in Figure 15, the total administration of the clemastine available in the bloodstream, represented by ABC, and the maximum concentration of clemastine, represented by Cmax, in the blood are both a order of magnitude greater for the route of administration of TMOM ™ than for the route of administration of the oral tablet. In addition, the maximum release of the antihistamine in the bloodstream occurs more quickly in approximately 10 minutes, as shown by the Tmax values, for the TMOM ™ administration route than for the oral tablet administration route.
Thus, the administration of TMOM ™ appears to provide substantially higher plasma clemastine levels in animals, particularly in dogs and horses, compared to conventional oral dosage forms (e.g., tablets), and provides significantly more convenient administration and Safe alternative to intravenous administration.
Example 7: Absorption study in anesthetized dogs
An absorption study was also carried out in anesthetized dogs. The subjects were anesthetized dogs using minimal preanesthetics (isoflurane through an endotracheal tube). The possibility of inward escape and absorption by the gastrointestinal tract by obstructing the esophagus with a Foley catheter was avoided. Clemastine was administered using TMOM ™. Blood samples were taken 0, 5, 15, 30 min, and 1, 2, 4, 8, 12 and 24 hours after the dose. Samples of the jugular and cephalic vein were obtained 5, 15 and 30 and 1 and 2 hours after the dose. The target dosage was 0.33 mg / kg (16.67 mg / ml clemastine in 75% ethanol, 25% water, 200 ml (3.3 mg), dose range 0.30-0.55 mg / kg)
Figures 16 and 17 show that clemastine was rapidly absorbed by anesthetized canine subjects through the transmucosal route. The similarity in exposure with varying doses (i.e., awake is 1.0 mg / kg and anesthetized is 0.46 mg / kg) indicated that saturation (eg, absorption, liver metabolism) may have occurred, possibly due for the purposes of the anesthetic.
Example 8: Transmucosal oral administration to atopic canine subjects
The efficacy of clemastine administered by transmucosal oral administration in a colony of allergic atopic canine subjects with spontaneous feeding (Maltese x Beagle dogs) was evaluated. Figure 18 shows the efficacy of clemastine administered at various dosages (0.125, 0.5 and 1 , 0 mg / kg) by TMOM ™ (16.67,
4.17 mg / ml clemastine fumarate, 75% ethanol and 25% water) against a skin reaction characterized by hives and rash caused by the release of histamine from mast cells. Transmucosal oral administration of clemastine provided approximately 40-70% inhibition of this reaction for up to 24 hours.
Example 9; Study of diphenhydramine in dogs
A study was conducted with three dogs to evaluate administration by TMOM ™ of diphenhydramine, using a commercially available injectable formulation (Benadryl, sterile pyrogen-free solution containing 50 mg of diphenhydramine hydrochloride / ml; 3 mg / kg dose target; 2.7 mg / kg average dose (2.5-2.9 mg / kg); 400 ml volume). Blood samples were taken 10, 30 min, and 1, 2, 4, 8, and 12 hours after the dose. and the samples at 10, 30 min and 4 h were taken by jugular and cephalic vein puncture. The results are shown in Figures 19 and 20. Significant concentrations of diphenhydramine were obtained, and jugular / cephalic differentials confirm the administration of diphenhydramine through the transmucosal route.
Cardiovascular agents,
Compositions according to the invention have been prepared according to the teachings of one or more of the
Us
U.S. Patents 5,869,082, 5,955,098, 6,110,486, and 6,676,931, such that the compositions contain: between about 0.1 milligrams to about 25 milligrams of digoxin per kilogram of body weight, and at Less a vehicle. Such compositions may be therapeutically and / or prophylactically effective for treating an abnormal // irregular heart rate, weakness, respiratory distress, reduced exercise tolerance, lethargy, syncope, hypoxia, pulmonary edema, ascites, and / or loss of consciousness, or similar, in animals, for example, dogs and cats. In most cases, the total dose of digoxin administered per animal is approximately 4 milligrams to approximately 25 milligrams per kilogram of body weight per day.
Hormones,
Compositions according to the invention have been prepared according to the teachings of one or more of the
Us
U.S. Patents 5,869,082, 5,955,098, 6,110,486, and 6,676,931, such that the compositions would contain: between about 0.01 milligrams to about 0.5 milligrams of levothyroxine per kilogram of body weight, and at least one vehicle. such that the composition is therapeutically and / or prophylactically effective for treating a decreased or non-existent production of thyroid hormones such as thyroxine in animals.
The recommended average dose rate of levothyroxine is approximately 0.2 mg / kg body weight, given once or twice daily for dogs, and between approximately 0.05 mg to approximately 0.2 mg per day for cats. The veterinarian normally adjusts the frequency of administration to the adequacy of blood levels of levothyroxine (T4) after 4-12 weeks. As the reduced or absent production of thyroid hormones is generally irreversible, treatment continues normally for the rest of the animal's life.
This composition is formed in a spray that is administered to dogs through the oral mucosa, between the lips and teeth of each animal at an appropriate target dose.
In another example, compositions according to the invention have been prepared according to the teachings of a
or more than US Pat. Nos. 5,869,082 5,955,098, 6,110,486, and 6,676,931, such that the compositions could contain: insulin (from naturally derived pig sources, from sources that they involve recombinant DNA techniques, or one of their combinations) and at least one carrier, such that the composition is therapeutically and / or prophylactically effective for treating decreased or non-existent insulin production in animals.
This composition is formed in a spray that is administered to dogs through the oral mucosa, between the lips and teeth of each animal at an appropriate target dose.
Immunosuppressive agents
Compositions according to the invention have been prepared according to the teachings of one or more of the
Us
U.S. Patents 5,869,082, 5,955,098, 6,110,486, and 6,676,931, such that the compositions would contain: between about 0.1 milligrams to about 1 milligram of cyclosporin A per kilogram of body weight, and At least one vehicle. such that the composition is therapeutically and / or prophylactically effective for treating an enhanced or overactive immune response in animals. The recommended average dose rate of cyclosporine is approximately 5 mg / kg body weight per day administered according to the following scheme. For atopic dermatitis, for example, the compositions of the invention will initially be administered daily until a satisfactory clinical improvement is observed. This will generally be the case after 4 to 8 weeks. Once the clinical signs of atopic dermatitis are
satisfactorily controlled, the compositions of the invention can be administered approximately every other day. If the signs are then controlled with this dosage, the compositions of the invention can then be administered approximately every 3 to 4 days. The veterinary surgeon will adjust the frequency of administration to the response. Treatment can be stopped when clinical signs are controlled. After the recurrence of clinical signs, treatment should be resumed with daily dosing, and in certain cases, repetition of the treatment cycle may be required.
This composition is formed in a spray that is administered to dogs through the oral mucosa, between the lips and teeth of each animal at an appropriate target dose. The methods and compositions can be used to systemically modulate the immune system, for example, during organ transplantation such as kidney transplantation and / or can be used to treat atopic dermatitis, immunomediated hemolytic anemia, discoid systemic lupus, keratoconjunctivitis sicca in animals such as a dog. Methods and compositions can also be used to treat German shepherd pannus.
Nutraceuticals, vitamins, and / or minerals
Compositions according to the invention have been prepared according to the teachings of one or more of the
Us
U.S. Patents 5,869,082, 5,955,098, 6,110,486, and 6,676,931, such that the compositions could contain lysine or a pharmaceutical salt thereof; and at least one vehicle. such that the composition is therapeutically and / or prophylactically effective in treating a decreased or non-existent production or dietary intake of lysine in animals.
This composition was formed in a spray that was administered to dogs, horses, and / or cats through the oral mucosa, between the lips and teeth of each animal at an appropriate target dose.
Sedatives / tranquilizers / behavior modifiers
Compositions according to the invention have been prepared according to the teachings of one or more of US Pat. Nos. 5,869,082 5,955,098, 6,120,486, and 6,676,931, such that the compositions contained: between approximately 0.05 milligrams to approximately 0.6 milligrams of zolpidem tartrate per kilogram of body weight, and at least one vehicle. Such compositions may be therapeutically and / or prophylactically effective for treating insomnia, stress, separation anxiety, and / or hyperactivity, or the like, in animals, for example, dogs and cats.
Example 10: Zolpidem,
A two-way cross-experiment was carried out with six animals (dogs and cats) in which subjects were given a zolpidem tablet or a transmucosal oral mist of a 2.5% zolpidem tartrate solution.
Tablets were administered to canine subjects (average dose of 0.55 mg / kg (0.40-0.63 mg / kg)) or a transmucosal oral mist (average dose of 0.55 mg / kg (0.42-0 , 62 mg / kg)). The administration of the transmucosal oral mist used a spray volume of 200-250 ml in 2-3 pumps of the spray dispenser. By comparison, the average dose in a human being is 0.08-0.17 mg / kg.
Tablets were administered to feline subjects (average dose of 0.74 mg / kg)) or a transmucosal oral mist (average dose of 0.72 mg / kg). The transmucosal oral mist used a spray volume of 100 ml in 1 pump of the spray dispenser.
Blood samples were taken for both subjects at 5, 15, 30 min, and 1, 2, 4 and 8 hours after the dose.
Figures 21 and 22 show the average plasma concentrations during the treatment time of dogs and cats, respectively, with the compositions of sleep adjuvant agents described above, compared to similar doses of orally administered tablet formulations. Figures 23 and 24 show comparisons of the pharmacokinetic parameters measured and / or calculated from this test in dogs and cats, respectively. The secondary peak in Figure 21 reflects oral gastrointestinal absorption. However, even if some oral gastrointestinal absorption occurs, transmucosal administration generally provides a faster increase in plasma levels compared to conventional oral administration methods. The data in Figure 21 shows that, after administration of zolpidem tartrate using TMOM ™, the absorption time and absorption half-life are significantly shorter (shorter), and the maximum plasma concentration is greater, compared to the administration profile observed with the tablet. The data in Figure 22 shows that, after administration of zolpidem tartrate using TMOM ™, the absorption time, maximum plasma concentration, and total absorption are comparable (in experimental error) when compared to the profile of administration observed with the tablet.
Figure 23 shows that transmucosal oral administration to canine subjects provides faster drug uptake (e.g., a shorter Tmax, a larger Cmax, and a shorter absorption half-life) in comparison.
to conventional oral administration with a tablet. In addition, oral transmucosal administration provides good absorption of zolpidem (for example, a larger ABC) compared to conventional oral methods.
5 Figures 23 and 24 show the rapid uptake of the drug in dogs and cats using oral transmucosal administration, with good pharmacokinetic / pharmacodynamic agreement. However, salivation of feline subjects can lead to reduced absorption (low ABC) using oral transmucosal administration. Likewise, the ABC and Cmax values obtained by jugular sampling may be greater than the values obtained by cephalic sampling (Figure 24, only).
10 One of the canine subjects vomited 12 minutes after the administration of zolpidem by TMOM ™. The plasma zolpidem levels in this animal remained consistent with the plasma zolpidem levels observed for the remaining dogs in the study that had not vomited. This indicates that substantially the entire dose of zolpidem was absorbed within 12 minutes of dosing. Additionally, this demonstrates a
fifteen advantage of transmucosal administration in animals over conventional oral dosage forms (ie tablets or oral suspension). Vomiting of an animal subject immediately after administration of a conventional oral dosage form would be expected to result in an underdosing of the animal (because the tablet or oral suspension could be removed from the animal's digestive tract before a significant absorption of the active substance). On the contrary, the dose of the active substance provided to the torrent
twenty The blood of the animal through transmucosal administration does not seem to be relatively affected by vomiting. Therefore, transmucosal administration provides a distinct advantage in veterinary medicine, where patients can resist or reject conventional oral dosage forms.
Example 11: Propofol
25 A two-way cross-experiment was conducted with six dogs with a target dose of 6.0 mg / kg of propofol administered by IV, and 30.0 mg / kg of propofol using a transmucosal oral administration. The average IV dose (Propoflo ™, 10 mg / ml) was 5.9 mg / kg (5.7-6.2 mg / kg), and the average dose of transmucosal oral administration (propofol, 950 mg / ml) was 31.3 mg / kg (28.6-34.2 mg / kg; 350-550 ml using 4 -6 pumps of the
30 spray device). Blood samples were obtained at 0, 2, 5, 15, 30 minutes and 1, 2, 4 and 6 hours after the dose.
The average plasma propofol concentrations are shown in Figure 25, and the pharmacokinetic parameters are provided in Figure 26. Propofol uptake using transmucosal oral administration was rapid,
35 although different from the administration of IV. more than 90% of the propofol administered transmucosally was absorbed in 2 hours. However, the rapid distribution of propofol provided a somewhat lower Cmax value compared to IV administration.
Antiparasitic agents
40 Illustrative formulations of antiparasitic agents are shown below
Nitenpiram
<dl><dt>Ingredient </dt><dd>Quantity Illustrative quantity Illustrative quantity </dd></dl>
<dl><dt>nitenpiram </dt><dd> 0,1-25 % 0,5-15 % 0,6-10 % </dd></dl>
<dl><dt>Ethanol </dt><dd> 40-99 % 60-97 % 70-97 % </dd></dl>
<dl><dt>Water </dt><dd> 0,01-5 % 0,1-4 % 0,2-2 % </dd></dl>
<dl><dt>Aromas </dt><dd> 0,05-10 % 0,1-5 % 0,1-2,5 % </dd></dl>
<dl><dt>Propeller </dt><dd> 0-20 % 0-5 % 0-4 % </dd></dl>
Ivermectin
<dl><dt>Ingredient </dt><dd>Quantity Illustrative quantity Illustrative quantity </dd></dl>
<dl><dt>Ivermectin </dt><dd> 0,01-10 % 0,1-5 % 0,2-3 % </dd></dl>
<dl><dt>Ethanol </dt><dd> 10-90 % 20-75 % 25-50 % </dd></dl>
<dl><dt>Propylene glycol </dt><dd> 1-90 % 5-80 % 10-75 % </dd></dl>
<dl><dt>Water </dt><dd> 0,01-5 % 0,14 % 0,2-2 % </dd></dl>
<dl><dt>Aromas </dt><dd> 0,05-10 % 0,1-5 % 0,1-2,5 % </dd></dl>
<dl><dt>Propeller </dt><dd> 0-10 % 0-5 % 0-4 % </dd></dl>
Biological data The concentration of the active substance in the formulation will vary to carry out the desired dose levels over a wide weight range of target animal patients. For example, they were administered to a dog of 120
pounds (54.5, kg) 1 to 3 sprays of the transmucosal oral mist that will be greater than the concentration needed to treat a 12-pound dog (5.45 kg ) with 1 to 3 sprays. The number of sprays per application will vary for the same reason.
The active substance may vary depending on the spectrum of target parasites in any product. With thousands of parasites that infect the target animal species, the active ingredient (s) may vary to obtain the desired medical result.
The area of the treated oral mucosal surface may vary and includes any surface in the oral cavity, including the buccal, gingival, lingual, or sublingual surfaces.
Example 12: Study of milbemycin in dogs
A randomized parallel design was carried out in twelve dogs to compare conventional oral administration (ie, tablets) of milbemycin with oral transmucosal administration. The tablets used were Interceptor® Flavor Tab®, 5.75 mg and 11.5 mg, which provide an average dose of 0.78 mg / kg (0.50-0.99 mg / kg); The formulation for transmucosal administration (14.3 mg / ml milbemycin (4.9%) DMSO 31.9%, ethanol 14.7%, 4.9% benzyl alcohol, Tween-20 2.45% , 2.45 mg / ml of BAC, 2.45 mg / ml of liver extract, 1.96% of cod liver oil ester, 17.2% of propylene glycol and 22.1% of water) provided a average dose (based on a post-dose analysis) of 0.28 mg / kg (0.24-0.34 mg / kg; 200-300 ml of spray volume using 2 -3 spray device pumps). Blood samples were obtained at 0, 5, 15, 30 minutes and 1, 2, 4 and 8 hours after the dose.
The results of this study are shown in Figures 27 and 28. Milbemycin uptake through oral transmucosal administration was very good. The bioavailability through oral transmucosal administration and using the conventional tablet was similar, but transmucosal administration showed less variable plasma concentrations.
Antibiotics
Example 13: Study of enrofloxacin in felines
A two-way cross-sectional study was conducted with six cats to compare conventional oral administration (ie, tablets, Baytril®) with transmucosal oral administration (Baytril® 100; 100 mg enrofloxacin, L-arginine base 200 mg, alcohol n-butyl 30 mg, benzyl alcohol (as a preservative) 20 mg and water for injection, cs). The target was 5 mg / kg enrofloxacin. The average tablet dose was 4.7 mg / kg and the average dose using TMOM ™ was 4.9 mg / kg (250-300 ml). Blood samples were obtained at 5, 30 minutes and 1, 2, 4, 8, 12 and 24 hours after the dose. The results are shown in Figures 29-31, which show that transmucosal administration provides enrofloxacin profiles similar to those provided by conventional administration, without essentially difference in the values of ABC, Cmax, Tmax ot ©. In addition, no delay was observed in the uptake of enrofloxacin with TMOM ™ and significant minutes were achieved in plasma concentrations. Consistently and significantly, higher plasma concentrations of the jugular compared to cephalic concentrations measured at the 5 minute time point confirm the transmucosal route of administration for enrofloxacin.
Example 14: Acceptability studies
The acceptability of oral transmucosal administration and various formulations for oral transmucosal administration in animal subjects was evaluated. The results are shown in Figures 32-44. As a whole, transmucosal oral administration seems to be easily tolerated by most subjects (see Figure 44).
Figures 32 and 33 show the acceptance and severity of the reaction in canine subjects of various vehicles, administered by TMOM ™. All vehicles tested were acceptable for most subjects, although formulations containing glycofurol were found to be slightly less acceptable.
Figures 34 and 35 show the acceptance and severity of the reaction in feline subjects of various vehicles, administered by TMOM ™. It was found that the formulation containing salmon flavoring was somewhat less acceptable than other formulations containing other flavoring agents, or without flavoring agents.
Figures 36-39 show that various formulations of meloxicam were easily accepted by canine subjects.
Figures 40-43 show the acceptance and severity of the reaction of canine and feline subjects to various vehicles and on a number of doses for administration by TMOM ™.
Figure 44 shows the percentage of satisfaction of dose administrations using administration by
TMOM ™ in canine and feline subjects. Administration using TMOM ™ was almost satisfactory in 99%, and more than 99% of administrations did not require assistance. Therefore, transmucosal administration is a simple and very effective method for administering active ingredients to animals.
5 Example 15: Administration of multiple doses using TMOM ™
Different doses of clemastine were administered to the dogs using multiple administrations using TMOM ™. Figure 45 shows that an increasing dose volume by TMOM ™ (by increasing number of sprays) of a formulation containing 13 mg / ml clemastine fumarate provided concentrations
10 increasing in plasma. Multiple doses administered to one part of both, or distributed between both sides of the mouth provide similar results.
45 sheets
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26 members in 7 offices
Priority claims21
| Document | Office | Kind | Date |
|---|---|---|---|
| 653964P | United States of America | – | |
| 65396405 | United States of America | P | |
| 661920P | United States of America | – | |
| 66192005 | United States of America | P | |
| 664181P | United States of America | – | |
| 66418105 | United States of America | P | |
| 664183P | United States of America | – | |
| 66418305 | United States of America | P | |
| 664938P | United States of America | – | |
| 66493805 | United States of America | P | |
| 664939P | United States of America | – | |
| 66493905 | United States of America | P | |
| 665525P | United States of America | – | |
| 66552505 | United States of America | P | |
| 669888P | United States of America | – | |
| 66988805 | United States of America | P | |
| 670651P | United States of America | – | |
| 67065105 | United States of America | P | |
| 693942P | United States of America | – | |
| 69394205 | United States of America | P | |
| 2006005575 | United States of America | W |
Members26
| Document | Office | Kind | |
|---|---|---|---|
| AU2006214166A1 | Australia | A1 | |
| CA2597956A1 | Canada | A1 | |
| CA2819963A1 | Canada | A1 | |
| WO2006089082A2 | World Intellectual Property Organization (WIPO) | A2 | |
| US2006239928A1 | United States of America | A1 | |
| WO2006089082A3 | World Intellectual Property Organization (WIPO) | A3 | |
| EP1848270A2 | European Patent Office (EPO) | A2 | |
| JP2008530233A | Japan | A | |
| AU2006214166B2 | Australia | B2 | |
| US8097614B2 | United States of America | B2 | |
| AU2012200031A1 | Australia | A1 | |
| EP1848270A4 | European Patent Office (EPO) | A4 | |
| US2012289470A1 | United States of America | A1 | |
| JP2013067643A | Japan | A | |
| CA2597956C | Canada | C | |
| AU2012200031B2 | Australia | B2 | |
| AU2013263787A1 | Australia | A1 | |
| AU2012200031B9 | Australia | B9 | |
| EP1848270B1 | European Patent Office (EPO) | B1 | |
| EP2767163A1 | European Patent Office (EPO) | A1 | |
| JP5577021B2 | Japan | B2 | |
| ES2490595T3This record | Spain | T3 | |
| US8940271B2 | United States of America | B2 | |
| JP5681693B2 | Japan | B2 | |
| US2015174060A1 | United States of America | A1 | |
| AU2013263787B2 | Australia | B2 |
Numbers
- Publication
- 2490595
- Application
- 6735301
Titles2
- Spanish
- Administración transmucosal de composiciones de fármacos para tratar y prevenir trastornos en animales
- English
- Transmucosal administration of drug compositions to treat and prevent disorders in animals
Classification
- CPC, 24
- A61K9/006
- A61K9/12
- A61K31/704
- A61K31/7048
- A61K38/13
- A61K31/352
- A61K31/44
- A61K31/4178
- A61P1/00
- A61P1/08
- A61P25/20
- A61P29/00
- A61P3/00
- A61P3/02
- A61P31/00
- A61P31/04
- A61P33/00
- A61P37/06
- A61P37/08
- A61P43/00
- A61P9/00
- A61M11/006
- A61D7/00
- A61M2250/00
- IPC, 8
- A61P29 00
- A01N25 00
- A61K9 00
- A61K9 12
- A61K31 4178
- A61K31 704
- A61K31 7048
- A61K38 13