WO2004087095A2

WO2004087095A2 - Osmotic controlled release device containing zafirlukast and an h1-antagonist

Info

Publication number: WO2004087095A2
Application number: PCT/CR2004/000004
Authority: WO
Inventors: Juan A. Vergez; Joaquina Faour; Marcelo F. Befumo
Original assignee: Osmotica Costa Rica, Sociedad Anonima
Priority date: 2003-03-31
Filing date: 2004-03-30
Publication date: 2004-10-14
Also published as: WO2004087095A3

Abstract

The invention relates to a controlled release device, e.g. an osmotic device, which releases zafirlukast in a controlled manner and which releases a H1 antagonist in a rapid and/or immediate manner. A wide range of antihistamine H1 antagonists, particularly loratadine, can be used in the inventive device. Specific embodiments of the invention comprise osmotic devices which release zafirlukast and a H1 antagonist in a controlled manner from the nucleus over an extended period of time. The aforementioned devices can be used for the treatment of allergic reactions, inflammation and asthma.

Description

OSMOTE DEVICE CONTAINING ZAFIRLUKAST AND A

ANTAGONIST Hl

INVENTORS

Juan A. Vergez, Joaquina Faour, and Marcelo Befumo.

FIELD OF THE INVENTION The present invention pertains to an osmotic device containing zafirlukast. More particularly, it belongs to an osmotic tablet device that provides a controlled release of zafirlukast and an Hl antagonist, according to particularly advantageous release profiles, for the treatment of asthma, inflammation and allergic reactions.

BACKGROUND OF THE INVENTION

Asthma is a chronic inflammatory disease of the respiratory tract that is characterized by obstruction of these pathways, which is at least partially reversible with or without medication, and by a bronchial sensitivity greater than a variety of stimuli. Asthma is generally associated with allergy, perennial and seasonal rhinitis and rhinosinusitis, and atopy is the predominant identifiable factor in the development of asthma. Patients with allergic rhinitis may report increased asthma symptoms during pollen time. Inflammation plays a very important role in the pathogenesis of both allergic rhinitis and asthma. Asthma is an inflammatory disorder of the airways that involves the production and activity of endogenous inflammatory mediators known as leukotrienes. The administration of a leukotriene antagonist to a patient with asthma produces a therapeutic benefit by inhibiting the action of leukotrienes in the receptors of the smooth muscles of the respiratory tract.

Zafirlukast is a selective, potent and long-lasting leukotriene receptor antagonist that shows mild anti-inflammatory properties and bronchodilator effects. Zafirlukast has been effective in controlling persistent asthma symptoms in adults and children over 5 years. It is believed that leukotrienes contribute to allergic rhinitis. Zafirlukast selectively inhibits types of leukotrienes D ₄ (LTD), and E (LTE). Zafirlukast is commercially available in immediate-release tablets coated by a film by AstraZeneca under the trademark Accolate ^® . The tablets are available in doses of 10 and 20 mg.

Antihistamines such as histamine Hl receptor antagonists (hereinafter "Hl antagonists" or "antihistamines") are the mainstay of pharmacotherapy for allergic rhinitis. The Hl receptor antagonist blocks histamine-induced symptoms such as rhinorrhea, pruritus and sneezing. Allergic rhinitis is one of the most common allergic diseases in the United States. Its beginning is common is childhood, adolescence and early adulthood. Allergic rhinitis can contribute to other conditions, such as sleep disorders, fatigue and learning problems. Allergic rhinitis usually coexists with other allergic disorders such as asthma. Some patients with allergic rhinitis reported increases in asthmatic symptoms during pollen season.

Rhinitis and asthma involve the same respiratory mucosa and allergic reactions in the nasal mucosa can increase the hypersensitivity of the lower respiratory tract in asthma, therefore, the treatment of upper respiratory tract symptoms is a part of the management of Potentially beneficial asthma. Rhinitis treatment can improve asthma. Non-sedating oral antihistamines and the combination of antihistamines and decongestants may improve the consequences of asthma in some patients.

Loratadine is a non-sedating oral Hi blocker that is sold in the form of tablets under the trademark Claritin ^® and Claritin Reditabs ^® by Shering. Dahlen et al. (J. Allergy Clin. Immunol., (2002 May), 109 (5), 789-93) evaluated loratadine (10 mg twice daily) and zafirlukast (80 mg twice daily) in a double-blind study , crossed, alone and in combination, in 16 non-smoking patients with mild asthma, with bronchoconstriction induced by previously documented exercise and hypersensitivity of the airways to histamine. The study confirmed the beneficial effect of a leukotriene receptor antagonist on exercise-induced bronchoconstriction but showed no evidence that the Hl receptor antagonist alone or together with zafirlukast (cysteinyl-leukotriene receptor antagonist 1), offer a protective effect. . Roquet et al. (Am. J. Respir. Crit. Care Med., (1997 Jun.), 155 (6), 1856-63) evaluated the contribution of histamine and leukotrienes in airway obstruction induced by allergens in asthmatics. Twelve subjects with allergic asthma underwent identical allergen bronchoprovocations four times. In the control session, all subjects showed early and late asthmatic reactions. The influence of a week of pretreatment randomized with the leukotriene receptor antagonist, zafirlukast (Accolate) (80 mg twice daily), and with antihistamine loratadine (10 mg twice daily) and the combination of both antagonists. The results indicate that leukotrienes and histamine together mediate most of the early and late allergic reactions that follow asthmatic exposure to allergens. Roquet et al. suggest that the combination of leukotriene receptor antagonists and antihistamines could represent a new strategy for the treatment of airway obstruction in asthma.

PCT International Publication WO 97/28797 granted to Merck & Co, discloses the administration of loratadine with a selective leukotriene antagonist, including zafirlukast, for the treatment of asthma, allergy and inflammation.

US Pat. Nos. 6,248,308, No. 6,384,038, No. 6,509,353, and No. 6,436,924 disclose methods of treatment and prevention of asthma symptoms in a human which include administration to humans of norastemizol, cetirizine, azelastine or a non-sedating antihistamine (fexofenadine, mizolastine, astemizole, levocabastine) and a leukotriene inhibitor, for example zafirlukast, montelukast or pranlukast.

Acrivastine is classified as an alkylamine antihistamine. Acrivastine provides symptomatic relief in reactions that depend totally or partially on the release of histamine. A competitive histamine Hl antagonist sold in capsules under the trademark Semprex of Glaxo Wellcome Group of Companies. The capsules contain 8 mg of acrivastine and are administered 3 times per day. The peak plasma concentration (C _max ) of acrivastine is approximately 150 ng / ml, at 1.5 hours (T _max ) after the administration of 8 mg acrivastine. The plasma half-life is 1.5 hours. Such a short half-life results in the need for multiple doses or higher doses to obtain the desired therapeutic effect, which may lead to the occurrence of unwanted side effects. Mizolastin binds to the Hl histamine receptor. U.S. Patent No. 6,165,507 issued to Chariot et al. discloses a pharmaceutical sustained release formulation containing mizolastine for oral administration which has a release profile such that it is possible to obtain a lower plasma peak without decreasing bioavailability.

Osmotic devices and other tablet formulations are known for their ability to provide a controlled release of a large amount of drugs. Such devices and formulations are disclosed in US Patent No. 4,014,334 issued to Theeuwes et al., U.S. Patent No. 4,576,604 issued to Guittard et al., Argentine Patent No. 234,493, U.S. Patent No. 4,673,405 to Guittard et al., U.S. Patent No. 5,558,879 to Chen and col., U.S. Patent No. 4,810,502 issued to Yesterday et al., U.S. Patent No. 4,801,461 issued to Hamel et al., U.S. Patent No. 5,681,584 issued to Savastano et al., U.S. Patent No. 3,845 .770, U.S. Patent No. 4,008,719 issued to Theeuwes et al., U.S. Patent No. 4,058,122 issued to Theeuwes et al., U.S. Patent No. 4,116,241 issued to Theeuwes et al., U.S. Patent No. 4,160 .452 granted to Theeuwes, US Patent No. 4,256,108 granted to Theeuwes, and Argentine Patent No. 199,301, the entire description of which is incorporated herein by reference. Osmotic dual-release devices are known for concurrent or sequential administration of two or more drugs in a single dosage form. Other appropriate references concerning the preparation of osmotic devices are U.S. Patent No. 6,004,582 issued to Faour et al., U.S. Patent No. 6,352,721 issued to Faour, U.S. Patent No. 6,491,949 issued to Faour et al., US Patent Application No. US2002 / 0099361 granted to Faour, PCT International Application No. PCT / CR02 / 00006 granted to Vergez et al., Whose entire description is incorporated herein by reference.

It would be an improvement in the art to provide controlled release dosage forms that reduce the dosage frequency of zafirlukast, produce a desired release rate or a desired release profile for the combination of zafirlukast with an Hl antagonist, increase treatment compliance , provide a lower plasma concentration peak, and may result in the reduction of unwanted side effects caused by high plasma concentration peaks.

To date, the prior art does not reveal an oral dual-release dosage form that provides specific formulations and release profiles for the combination of zafirlukast and Hl antagonists for the treatment of asthma, inflammation and allergic reactions claimed herein.

SUMMARY OF THE INVENTION The present invention reveals an improvement on the dosage forms with zafirlukast and the currently available Hl antagonist. The immediate objective of the invention is that the osmotic tablet device provided by zafirlukast and an antagonist is available Hl, with particularly advantageous release profiles, for the treatment of asthma, inflammation and allergic reactions, of a daily intake.

Another object of the invention is to provide a single dosage form for oral administration of zafirlukast in a controlled manner for an extended period of time and a release of the Hl antagonist in the form of immediate or rapid release for the treatment of asthma, inflammation and allergic reactions. .

Another object of the invention is to provide a single dosage form for oral administration of zafirlukast and an Hl antagonist in a controlled manner for an extended period of time for the treatment of asthma, inflammation and allergic reactions. An embodiment of the invention provides an osmotic device comprising: a core comprising a therapeutically effective amount of zafirlukast, which is released in a controlled manner for a period of at least about 18-24 hours; a membrane surrounding the core and one or more passages through the semipermeable membrane; a water soluble coating containing an Hl antagonist that surrounds the membrane for the release of the total Hl antagonist rapidly over a period of less than about 120 minutes when the device is exposed to an aqueous environment of use.

Another embodiment of the invention provides an osmotic device comprising: a core comprising a therapeutically effective amount of zafirlukast and an Hl antagonist; a membrane surrounding the core and one or more passages through the semipermeable membrane; where zafirlukast and the antagonist Hl are released in a controlled manner for a period of at least about 12-24. Specific embodiments of the osmotic device include those where: 1) the osmotic device further comprises an inert water-soluble coating interposed between the semipermeable membrane and the drug-containing coating; 2) the osmotic device further comprises one or more coatings surrounding the core, where the coatings are selected from the group consisting of inert water soluble or water erodible coating, and immediate, rapid or delayed release coating; 3) zafirlukast is released in a controlled or sustained manner for a period of about 20-24 hours after exposure to an aqueous environment; 4) antihistamine Hl is released for a period of about 5-120, or 15-120, or 5-60 minutes after exposure to an aqueous environment; 5) the osmotic device has a zafirlukast dissolution profile and a dissolution profile of the Hl antagonist as described herein; 6) Antihistamine Hl is released for a period of about 12-24, or 16-24, or 20-24 hours after exposure to an aqueous environment.

In some embodiments, the Hl antagonist is selected from the group consisting of acrivastine, astemizole, azelastine, cetirizine, ebastine, epinastine, fexofenadine, loratadine, desloratadine, mizolastine, norastemizole, promethazine and terfenadine.

In another embodiment, the outer coating is applied by dew rather than compression. The outer coating is thinner when applied by spray rather than compression and therefore a smaller osmotic device is formed.

Another aspect of the invention provides a method for treating asthma, inflammation and allergic reactions. The method comprises the step of administering a dual release dosage form comprising zafirlukast and an Hl antagonist, where zafirlukast is released in a controlled and / or sustained manner and the Hl antagonist is released immediately or rapidly.

The target therapeutic levels of the Hl antagonist are in the range of about 2 ng to about 700 ng per ml of plasma.

The white therapeutic levels of zafirlukast are generally in the range of about 0.01 ug per mi to about 10 ug per mi of plasma. Other features, advantages and embodiments of the invention will be apparent to those skilled in the art with the description that follows and the accompanying examples.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are part of the present specification and are included to more fully demonstrate certain aspects of the invention. The invention can be better understood by referring to one or more of these drawings in combination with the detailed description of the specific embodiments presented herein.

FIG. 1 shows in vitro dissolution profiles of zafirlukast released from the exemplary formulation of Example 1. FIG. 2 shows the plasma profile of zafirlukast obtained with the osmotic device in tablets of Example 1 compared to the plasma profile of zafirlukast obtained with an immediate release formulation.

DETAILED DESCRIPTION OF THE INVENTION The invention provides the administration of zafirlukast and Hl antagonists as free base, free, racemic acid, optically pure, diastereomeric forms and / or pharmaceutically acceptable salts. Appropriate Hl antagonist antihistamines include, for example, the first and second generation of antihistamines, diphenhydramine, chlorpheniramine, bronpheniramine, tripolidine, promethacin, hydroxyzine, pinlamine, dimenhydrinate, acrivastine, azelastin, cetirizine, ebastine, epinastineadine, fendinadine, phenyleadine, phenyleadine, phenyleadine, phenyleadine, phenyleadine, phenyleadine, phenyleadine, phenatin , mizolastine, norastemizol and promethazine.

As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds where the therapeutic compound is modified by making acid salts or base thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, organic or mineral acid salts of zafirlukast or the Hl antagonist. Pharmaceutically acceptable salts include conventional non-toxic salts, for example non-toxic organic or inorganic acids. For example, said conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like; and the prepared salts of organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palamic, maleic, hydroximaléic, phenylacetic, glutamic, benzoic, salicylic, sulfanyl, 2-acetoxybenzoic , fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and others known to those with common knowledge in the pharmaceutical sciences. Lists of appropriate salts are found in Remington's Pharmaceutical Sciences, 18th Ed. (Alfonso R. Gennaro, ed .; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19 ^th Ed. (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, ^3rd Ed (Arthur H. Kibbe, ed .; Amer Pharmaceutical Assoc . , 1999).; the Pharmaceutical Codex: Principies and Practice of Pharmaceutics 12 ^th Ed. (Walter Lund ed .; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds .; McGraw Hill, 1992), whose entire description is incorporated herein by reference.

The phrase "pharmaceutically acceptable" is used herein to designate those compounds, materials, compositions, and / or dosage forms that, within the scope of medical judgment, are appropriate for use in the tissues of humans and animals without excessive toxicity. , irritation, allergic response, or other commensurate problem or complication in a reasonable risk / benefit ratio.

As used herein, the term "controlled release" refers to a dosage form that provides for the release of a drug for an extended period of time. The drug is generally released approximately according to a predetermined manner for an extended period of time. Examples of specific embodiments include those where a substantially constant amount of drug is released for an extended period of time. As used herein, the term "sustained release" refers to the dosage form that the drug releases for an extended period of time and successfully maintains substantially constant levels of drug in the blood or white tissue for approximately a predetermined period. of time.

Figure 1 shows an in vitro release profile of zafirlukast for the osmotic tablet device described in Example 1. The release profile of the osmotic device of the invention will vary from that shown in Figure 1 according to the materials used to form the core and the semipermeable membrane that covers the core. For example, the release profile may be influenced by the material used to form the semipermeable membrane surrounding the core, by the material used to form any coating on the semipermeable membrane, by the excipients present in the core, or by the presence or absence of an osmoagent in the nucleus. Depending on the particular combination of ingredients used to prepare the dosage form of the invention, immediate and / or rapid release of the Hl antagonist can be provided.

The zafirlukast release profile of the formulation of Example 1, exposed to an aqueous environment, is generally described as follows and as shown in FIG. one:

The loratadine release profile of the formulation of Example 1, exposed to an aqueous environment, is generally described as follows:

In standard dissolution tests, the above values may vary depending on the conditions used. Furthermore, the values may have an absolute standard deviation (STD) of ± 10%, ± 5% or ± 3% at each given time point. For example, the amounts released within two hours could be 25 ± 5% (maximum) and 5 ± 5% (minimum). In this way, each value in the above tables should be considered to include the standard deviation as described here.

The relative bioavailability of the osmotic devices in tablets of Example 1 was evaluated in a pharmacokinetic study with a two-period, single-dose, randomized, randomized design, with a separation period of one week, using Accolate ^® (zafirlukast immediate release) as a control product, as described in Example 8. Comparative data of the plasma profile obtained with the osmotic devices in tablets compared to the plasma profile obtained with the immediate release formulation is described in the following table:

#Note: the data of the second peak in parentheses.

The data show absolute differences in the values of Cmax and Tmax obtained. The ANO VA for the ratio of the AUCinf of the osmotic devices in tablets of Example 1 / the immediate release formulation show that there are no significant differences between the formulations in relation to the extent of drug absorption. The relative bioavailability of the osmotic devices in tablets of Example 1 is 96.58% compared to that of the treatment with the immediate release formulation. The average residence time (TRM) of the drug is about 17.9 hours, covering a range of 15 hours to 21 hours for osmotic devices in tablets of Example 1. This value is significantly higher than the residence time average of about 10.8 hours, covering a range of 8 to 13 hours, observed for the immediate release formulation administered twice a day.

FIG. 2 shows the zafirlukast plasma profile of the osmotic devices in tablets of Example 1 (mean ± SD, n = 12 runs) (administration of a single tablet) compared to the zafirlukast plasma profile of the zafirlukast immediate release formulation (two tablets administered with an approximate interval of 12 hours). The osmotic device of Example 1 provides therapeutically effective levels of zafirlukast between a period of about 2 to about 30 hours after administration. Therapeutic concentration levels of zafirlukast in plasma cover a range of about 10 to about 800 ng / ml, usually about 30 to about 500 ng / ml. The average Cmax was about 208 ng of zafirlukast per ml of plasma, after about 8 to 15 hours of administration, and about 482 ng per ml of plasma after about 1 to 4 hours (for the first peak) of the administration of the osmotic device of Example 1 and the immediate release formulation of zafirlukast respectively. Accordingly, the osmotic device of the invention will provide therapeutically effective concentrations of zafirlukast for a period substantially longer than a form of immediate release. This is because the release of the drug is distributed for a longer period of time, reducing Cmax and increasing Tmax compared to the immediate release dosage form. According to an embodiment of the invention, the osmotic device provides a therapeutically effective plasma concentration of zafirlukast for a period of at least 18 hours, at least 20 hours, at least 24 hours, or at least 30 hours. All tablet formulations of the invention will provide therapeutically effective levels of zafirlukast and an Hl antagonist for at least a predetermined period of time. The tablets of the invention will generally provide therapeutically effective amounts of zafirlukast for a period of not less than 18 hours and no more than 30 hours, no less than 20 hours and no more than 28 hours, no less than 18 hours and no more than 24 hours, or not less than 22 hours and no more than 24 hours.

The controlled release core generally begins to release zafirlukast within about 0.5-3 hours or 0.5-2 hours after administration or within less than 1 hour after administration.

The quick-release coating will release the entire Hl antagonist within 3 hours after administration and at least 65% of the Hl antagonist within about 40 minutes after administration. Approximately all loratadine is released from the formulation of Example 1 in less than 20 minutes, or in about 15 minutes.

The quick and / or immediate release composition is a water soluble and / or erodible composition that generally comprises an inert and non-toxic material that is at least partially, and in general, substantial and completely soluble and / or erodible in the environment of use. The composition comprises a synthetic or natural material that, through selective dissolution and / or erosion, provides the release of an active agent. The choice of appropriate materials for the composition will depend on the desired amount of drug released by the composition. Examples of materials are disclosed in US Patents No. 4,576,604 issued to Guittard et al. and No. 4,673,405 granted to Guittard et al., and No. 6,004,582 granted to Faour et al. and in the text Pharmaceutical Dosage Forms: Tablets Volume I, 2 "Edition. (A. Lieberman ed. 1989, Marcel Dekker, Inc.), whose relevant parts are incorporated herein by reference. In some embodiments, the composition may be soluble in saliva, gastric juices or acidic fluids.

Appropriate materials for preparing the composition of the invention soluble or water erodible are, by way of example and without being limiting, water-soluble polysaccharide gums such as carrageenan, fucoidane, ghatti gum, tragacanth, arabinogalactan, pectin, and xanthan; salts of water-soluble polysaccharide gums such as sodium alginate, sodium tragacanth, and sodium gum gum; water-soluble hydroxyalkylcellulose where the alkyl group is linear or branched from 1 to 7 carbons such as hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose; water soluble synthetic celluloses forming foils such as methyl cellulose and hydroxyalkyl methyl cellulose cellulose derivatives such as a member selected from the group consisting of hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, and hydroxybutyl methyl cellulose; croscarmellose sodium; other cellulose polymers such as sodium carboxymethyl cellulose; and other materials known to those with common knowledge in the art. Other materials that can be used for this purpose include poly (vinyl pyrrolidone), polyvinyl alcohol, polyethylene oxide, a mixture of gelatin and polyvinyl pyrrolidone, gelatin, glucose, saccharides, povidone, copovidone, copolymer of poly (vinyl pyrrolidone) -poly (vinü acetate). The composition may comprise other pharmaceutical excipients that may or may not alter the manner in which the composition behaves when exposed to an aqueous environment. The artisan with common knowledge in the art will recognize that the aforementioned materials include film-forming polymers.

Other materials that can be used in the composition include hydroxypropyl cellulose, microcrystalline cellulose (MCC, Avicel ™ from FMC Corp.), poly (ethylene vinyl acetate) copolymer (60:40) (EVAC from Aldrich Chemical Co.), 2-hydroxyethyl methacrylate (HEMA), MMA, terpolymers of HEMA: MMA: MA synthesized in the presence of N, N'- bis (methacryloxyethyloxycarbonylamine) -azobenzene, azopolymers, and calcium pectinate.

In some embodiments, the quick release composition will be insoluble in the fluid of a first environment of use, such as gastric juices, acidic fluids or polar liquids, and will be soluble and / or erodible in the fluid of the second environment of use, such as intestinal juices, substantially pH neutral or basic fluids, or apolar fluids. In this case, the dosage form will provide a delayed and rapid release of the drug, that is, a Rapid release of the drug occurs after an initial period of delay has passed. A wide variety of polymeric materials with known to possess these different solubility properties and can be included in the composition. These polymeric materials include, by way of example and without limitation, cellulose acetate phthalate (CAP), cellulose acetate trimelllet (CAT), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate (HP), poly copolymer (methacrylate ethylacrylate) (1: 1) (MA-EA), copolymer of poly (methacrylate methylmethacrylate) (1: 1) (MA-MMA), copolymer of poly (methacrylate methylmethacrylate) (1: 2), Eudragit ™ L- 30-D (MA-EA, 1: 1), Eudragit ™ L-100-55 (MA-EA, 1: 1), hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric ™ (PVAP), Aquateric ™ (CAP), AQOAT ™ (HPMCAS), polyvinyl pyrrolidone-acetate acetate copolymer, such as the material provided by BASF under its trademark Kollidon VA64, povidone, provided by BASF under its trademark Kollidon K 30, hydroxypropyl methylcellulose, provided by Dow under its Methocel E-15 trademark, and combinations thereof. The composition may also comprise dissolution aids, stability modifiers and bioabsorption improvers.

An embodiment of the invention includes a multilayer osmotic device comprising a core, a membrane surrounding the core and having a passage therein, and a composition surrounding the membrane containing an H1 antagonist. The core comprises zafirlukast. The membrane can be permeable, impermeable, porous or semipermeable. The membrane may comprise one or more passages and / or pores. In this embodiment, the composition containing the H1 antagonist is generally an immediate and / or rapid release composition. The osmotic device may comprise additional layers interposed or around the layers mentioned above.

Such osmotic devices may be made in accordance with U.S. Patent No. 4,014,334 issued to Theeuwes et al., U.S. Patent No. 4,576,604 issued to Guittard et al., Argentine Patent No. 234,493, U.S. Patents No. 4,673 .405 granted to Guittard et al., No. 5,558,879 granted to Chen et al., No. 4,810,502 granted to Ayer et al., No. 4,801,461 granted to Hamel et al., No. 5,681,584 granted to Savastano et al., No. 3,845,770, No. 4,008,719 granted to Theeuwes et al., No. 4,058,122 granted to Theeuwes et al., No. 4,116,241 granted to Theeuwes et al., No. 4,160,452 granted to Theeuwes, No. 4,256,108 granted to Theeuwes, Argentine Patent No. 199,301, and other patents and scientific literature concerning the preparation of osmotic devices, the entire description of which is incorporated herein by reference, and other formulations of osmotic devices known to those with common knowledge in the art. Other appropriate references concerning the preparation of osmotic devices, the entire description of which is incorporated herein by reference, are U.S. Patent No. 6,004,582 issued to Faour et al., U.S. Patent No. 6,352,721 issued to Faour, U.S. Patents No. 6,491,949 granted to Faour et al., US Patent Application Publication No. US2002 / 0099361 granted to Faour, and PCT International Application No. PCT / CR02 / 00006 granted to Vergez et al. Osmotic devices such as those described by Faour et al. (US 6,004,582) are particularly advantageous for the release of two different drugs from a single osmotic tablet device. Faour et al. reveal osmotic device formulations comprising a core containing controlled release drug combined with a rapid release coating. Controlled release formulations containing the pharmaceutical formulation of the invention can be made in accordance with Biorelated Polymers and Gels: Controlled Relay and Applications in Biomedical Engineering (ed. Temo Okano; 1998); Encyclopedia of Controlled Drug Delivery (ed. Edith Mathiowitz; 1999); Future Strategies for Drug Delivery with Particulate Systems (ed. JE Diederichs; 1998); Controlled Relay Series (ed. JM Anderson; 1987); Controlled Drug Delivery Series (Ed. SD Bruck; 1983); Controlled Relay of Drugs Series (ed. M. Rosoff; 1989); Controlled Relay Technology: Pharmaceutical Applications (ACS Symposium Series No. 348) (eds. PI Lee and WR Good; 1987); Extended Relay Dosage Forms (ed. L. Krowczynski; 1987); Handbook of Pharmaceutical Controlled Relay Technology (ed. DL Wise; 2000); Intelligent Materials for Controlled Relay (ed. SM Dinh; 1999); Multicomponent Transport in Polymer Systems for Controlled Relay (Polymer Science and Engineering Monograph Series) (ed. A. Polishchuk; 1997); Pharmaceutical Technology: Controlled Drug Relay (ed. M. Rubenstein; 1987); Polymers for Controlled Drug Delivery (ed. PJ Tarcha; 1991); Tailored Polymeric Materials for Controlled Deliverv Systems (ACS Symposium Series No. 709) (ed. I. McCulloch; 1998); Oral Colon- Specific Drug Delivery (ed. DR Friend, 1992); and other publications known to those with common knowledge in art, whose entire description is incorporated here by reference.

A coating, cover, shell, membrane, sheet or wall (these terms can be used interchangeably) that surround the core of the controlled release dosage form can be permeable, impermeable or semipermeable. The term "permeable" is used to name a wall that is permeable to the passage of fluid and drug. The term "waterproof" is used to name a wall that does not allow the passage of the fluid or the drug unless a passage or pore is formed in the wall. The term "semipermeable" is used to name a wall that is permeable to the passage of fluid but impermeable to the passage of the drug. A dosage form of the invention can have any of these types of walls.

A semipermeable membrane is formed of a material that is substantially permeable to the passage of fluid from the environment of use to the core and substantially impermeable to the passage of the active agent of the core. Many common materials that form a semipermeable wall known to those with common knowledge in the art of pharmaceutical sciences are appropriate for this purpose. Such materials are, for example, cellulose esters, cellulose ethers, cellulose ether ether, cellulose diesters, cellulose triesters, cellulose acylate, diacrylate cellulose, triaclate cellulose, cellulose acetate, diacetate cellulose, triacetate cellulose, acetate cellulose propionate, cellulose acetate butyrate and ethyl cellulose. The preferred material for the semipermeable membrane is cellulose acetate commercially available from Eastman Chemical Products. The semipermeable membrane may also contain a flow enhancing agent which increases the volume of fluid in the core, such as sugar, mannitol, sucrose, sorbitol, sodium chloride, potassium chloride, polyethylene glycol (average molecular weight 380-3700) , propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose and mixtures thereof. A preferred flow improver is PEG 400. The semipermeable membrane may also contain plasticizers. Plasticizers suitable for the manufacture of the semipermeable membrane include sebacate, dibutyl sebacate, adipate, azelate, enzoate, citrate, triethyl citrate, tributyl citrate, glycerol tributyrate, acetyltributyl citrate, acetyltriethyl citrate, stearate, isoethyl acetolate, acetyl citrate, monoglorate, acetyl citrate, acetyl citrate, acetyl citrate, acetyl citrate, acetyl citrate, acetyl citrate, acetyl citrate, acetyl citrate, acetyl citrate, acetyl citrate Olive, sesame and rapeseed oil, and the like. A preferred plasticizer is triacetin. It has been found that a semipermeable membrane comprising cellulose acetate (CA) and poly (ethylene glycol) (PEG), in particular PEG 400, it works well when used in combination with other materials required in the osmotic device in question. This particular combination of CA and PEG provides a semipermeable membrane that gives the osmotic device a good controlled release profile for the active agent in the nucleus and retains its chemical and physical integrity in the environment of use. The radius of AC: PEG is generally between 50-99% by weight of CA: about 50-1% by weight of PEG, and about 95% by weight of CA: about 5% by weight of PEG. The radius may vary to alter the permeability and ultimately the release profile of the osmotic device. Other materials may include a member selected from the group of cellulose acylates such as cell acetate, cellulose diacetate, cellulose triacetate and combinations thereof. Many suitable polymers include those disclosed in Argentine Patent No. 199,301, US Patent No. 6,004,582 and the references cited herein, the entire description of which is incorporated herein by reference.

Representative materials include a member selected from the group of cellulose acylate, cellulose diacylate, cellulose triaclate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono, di and tricellulose alkanolates, mono, di and tricellulose aroylates, and Similar. Examples of polymers include cellulose acetate having a DS up to 1 and an acetyl content of up to 21%; cellulose acetate having an acetyl content of 32 to 39.8%; cellulose diacetate having a DS of 1 to 2 and an acetyl content of 21 to 35%; cellulose triacetate containing a DS of 2 to 3 and an acetyl content of 35 to 44.8%; and the like More specific cellulosic polymers include cellulose propionate having a DS of 1.8 and a propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; butyrate cellulose acetate having a DS of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%; a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triaclate having a DS of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisucinate, cellulose triclanoate; cellulose diacylate having a DS of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentate, and the like. Additional semipermeable polymers include dimethyl acetaldehyde acetate, ethyl carbamate cellulose acetate, cellulose acetate phthalate for use in low pH environments, cellulose acetate methylcarbamate, cellulose acetate dimethyl aminoacetate, semipermeable polyamides, semipermeable polyurethanes, semipermeable sulfonated polysters, selectively cross semipermeable polymers formed by coprecipitation of a polyanion and a polycation as disclosed in US Pat. Nos. 3,173,876, No. 3,276 No. 3.54., 005, No. 3,541,006, and No. 3,546,142; semipermeable polymers as disclosed by Loeb and Sourirajan in US Patent No. 3,133,132; cross-linked polystyrene derivatives; cross-linked poly (sodium styrene sulfonate), cross-linked poly (vinylbenzyltrimethyl ammonium chloride), semipermeable polymers showing a fluid permeability of 10 ^"5 to 10 ^-1 (cc.mil/cm ² .hr.atm) expressed as the difference in atmospheres of the hydrostatic or osmotic pressure in the semipermeable wall These and other polymers are disclosed in US Patents No. 3,845,770, No. 3,916,899, No. 4,765,989 and No. 4,160,020; and in Handbook of Common Polymers (Scott, JR and Roff, WJ, eds .; 1971; CRC Press, Cleveland, Ohio).

The osmotic device of the invention comprises at least one passage (pore, hole or opening) that communicates the exterior of the semipermeable wall with the core of the device. The passage can be formed according to any of the known methods with which passages are formed in a membrane. These methods include, for example, 1) piercing a hole through the semipermeable membrane with a wick or laser; 2) include a water-soluble material in the composition that forms the semipermeable membrane so that the pore is formed when the osmotic device is in the aqueous environment of use; 3) drill a hole through the semipermeable membrane; 4) use a tablet punch with a pin to drill a hole through the semipermeable sheet; 5) form a rupture in the membrane during use and after exposure of the osmotic device to the aqueous environment. The passage can pass through the membrane and through one or more of the sheets that cover the membrane, or that are between the membrane and the core. The passage (s) may have the desired shape. In some embodiments, the passage is laser perforated and has the shape of an oval, an ellipse, a groove, a slit, a cross or a circle.

Methods for forming passages in the membrane of osmotic devices are disclosed in U.S. Patents No. 4,088,864 issued to Theeuwes et al., No. 4,016,880 issued to Theeuwes et al., No. 3,916,899 issued to Theeuwes et al., No. 4,285,987 granted to Yesterday et al., No. 4,783,337 granted to Wong et al., No. 5,558,879 granted to Chen et al., No. 4,801,461 granted to Hamel et al., and No. 3,845,770 granted to Theeuwes et al., as well as in scientific literature publications whose complete contents are incorporated herein by reference.

In one embodiment of the present invention the tablet core comprises zafirlukast, at least one pharmaceutically acceptable excipient and optionally one or more materials. Other osmotic devices of the invention can be performed with zafirlukast and an Hl antagonist in the nucleus. Generally, tablet formulations will comprise about 0.1-99.9% by weight of zafirlukast in the core of the uncoated tablet. Acceptable ranges may vary according to the desired therapeutic response, the size of the tablet, the amount and type of excipients used in the core of the device and the amount of zafirlukast and antagonist Hl used.

Osmotically effective solutes, osmotic agents or osmoagents are added to the osmotic device. These osmoagents can help both in the suspension and in the dissolution of the active agent in the nucleus. Examples of osmoagents include organic and inorganic compounds such as salts, acids, bases, chelating agents, sodium chloride, lithium chloride, magnesium chloride, magnesium sulfate, lithium sulfate, potassium chloride, sodium sulphite, calcium bicarbonate , sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, alpha-d-lactose monohydrate, glucose, combinations thereof and other similar or equivalent materials that are widely known in the art. Osmoagents can also be added to the core of the osmotic device to control the release of the active agent. US Patent No. 4,077,407 issued to Theeuwes et al., Whose entire description is incorporated herein by reference, discloses appropriate osmoagents.

The osmotic devices of the invention can also include a displacement composition in the core. Such devices are formed with the inclusion of an inflatable material in the displacement composition. After exposure and immersion in water of the inflatable material, the composition that is displaced swells, forcing, therefore, the composition containing drug, for example composition containing zafirlukast, out of the dosage form and entering The environment of use. These types of osmotic devices are well known and are revealed in many of the references cited here. The tablets of the invention may also comprise an absorbent, antioxidant, buffer, colorant, flavoring, sweetener, non-stick, binder, capsule and tablet diluent, direct compression excipient, disintegrant, slider, lubricant, opaque and / or tablet polisher or capsules As used herein, the term "absorbent" refers to an agent capable of maintaining other molecules on its surface by physical or chemical means (chemoabsorption). Such compounds include, by way of example and without limitation, powdered and activated charcoal and other materials known to those with common knowledge in the art.

As used herein, the term "antioxidant" refers to an agent that inhibits oxidation and is therefore used to prevent the deterioration of preparations by oxidative process. Such compounds include, by way of example and without limitation, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formyl sulfoxylate and sodium metabisulfite and other materials known to those with common knowledge in the art.

As used herein, the term "buffer agent" refers to a compound used to resist pH change when there is dilution or addition of acids or alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and anhydrous and dehydrated sodium citrate and other materials known to those with common knowledge in the art.

As used herein, the term "sweetening agent" refers to a compound used to impart sweet taste to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, sodium saccharin, sorbitol and sucrose and other materials known to those with common knowledge in the art. As used herein, the term "non-stick" refers to agents that prevent the adhesion of the ingredients of the formulation to the punches and molds in a tablet making machine during the production process. Such compounds include, by way of example and without limitation, magnesium stearate, talc, calcium stearate, glycerylbehenate, PEG, hydrogenated vegetable oil, mineral oil, stearic acid and other materials known to those with common knowledge in the art. As used herein, the term "binder" refers to a substance used to cause adhesion of the dust particles in the granulation of the tablet. Such compounds include, by way of example and without limitation, acacia, alginic acid, sodium carboxymethyl cellulose, poly (vinyl pyrrolidone), compressible sugar (for example NuTab), ethyl cellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch and other materials known to those with common knowledge in art.

When necessary, binders can also be included in tablets. Examples of binders include acacia, tragacanth, gelatin, starch, cellulose materials such as methylcellulose and sodium carboxymethylcellulose, alginic acids and salts thereof, polyethylene glycol, guar gum, polysaccharides, bentonites, sugars, invert sugars, Poxámeros68 (PLURONIC ™, PLURONIC68, PLURONIC68 PLURONIC ™ F127), collagen, albumin, gelatin, non-aqueous cellulosic solvents, combinations thereof and the like. Other binders include, for example, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, combinations thereof and other materials known to those with common knowledge in the art.

As used herein, the term "tablet or capsule diluent" or "filler" refers to inert substances used as filler material to create the desired filler mass, fluidity properties and compression characteristics in tablet preparation. and capsules. Such compounds include, by way of example and without limitation, calcium dibasic phosphate, kaolin, lactose, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, and starch and other materials known to those with knowledge common in art.

As used herein, the term "direct compression excipient" refers to a compound used in the compression of tablet formulations. Such compounds include, by way of example and without limitation, calcium dibasic phosphate (for example Ditab) and other materials known to those with common knowledge in the art.

As used herein, the term "slider" refers to agents used in capsule and tablet formulations to promote the fluidity of granulation. These compounds include, by way of example and without limitation, colloidal silica, corn starch, talcum, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel and other materials known to those with common knowledge in the art. As used herein, the term "lubricant" designates substances that are used in tablet formulations to reduce friction during tablet compression. These compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate and other materials known to those with common knowledge in the art.

As used herein, the term "opaque tablet / capsule" refers to a compound used to coat a tablet or capsule with an opaque coating. It can be used in isolation or in combination with a dye. These compounds include, by way of example and without limitation, titanium dioxide, talc and other materials known to those with common knowledge in the art.

As used herein, the term "tablet polishing agent" refers to a compound used to provide coated tablets with an attractive gloss. These compounds include, by way of example and without being limiting, carnauba wax, white wax, and other materials known to those with common knowledge in the art. As used herein, the term "tablet disintegrant" refers to a compound used in solid dosage forms to promote the breakdown of solid mass into small particles that are more easily dispersible or dissolved. Examples of disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, and pre-gelatinized and modified starches thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. Avicel), calcium carboxymethylcellulose, potassium polacriline cellulose (eg Amberlite), alginates, sodium starch glycolate, gums such as agar, guar, carob, karaya, pectin, tragacanth; Crospovidone and other materials known to those with common knowledge in the art.

As used herein, the term "dye" refers to a compound used to color solid pharmaceutical compositions (for example, tablets). These compounds include, by way of example and without limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, ferric oxide, red, other FD&C dyes and other natural dyes such as grapefruit extract, red beet powder, beta carotene, bijol, carmine, turmeric, paprika, and other materials known to those with common knowledge in art The amount of coloring agent used may vary as desired. As used herein, the term "flavoring" refers to a compound used to give a flavor and, sometimes, a pleasant aroma, to a pharmaceutical preparation. Examples of flavoring agents include synthetic flavoring and aromatic flavoring oils and / or natural oils, plant extracts, leaves, flowers, fruits and other combinations thereof. These may also include cinnamon oil, pyrol oil, peppermint oils, clove oil, bay oil, aniseed oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, oil of bitter almonds and cassia oil. Other useful flavors include vanilla, citrus oils, including lemon, orange, grape, lime and grape juice, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, damask, and so on. Flavors that have proven to be particularly useful include commercially available orange, grape, cherry and chewing gum and mixtures thereof. The amount of flavoring may depend on a number of factors, including the desired organoleptic effect. The flavors will be present in the amount desired by those with common knowledge in art. Particularly preferred flavors are grape and cherry and citrus flavors such as orange.

The tablets may also employ one or more known surface active agents or co-solvents that improve wetting or disintegration of the tablet core or layers. The plasticizers can also be included in the tablets to modify the properties and characteristics of the polymers used in the layers or core of the tablets. As used herein, the term "plasticizer" includes all compounds capable of plasticizing or softening a polymer or binder used in the invention. The plasticizer should be able to lower the mixing temperature or the glass transition temperature (softening point temperature) of the polymer or binder. Plasticizers, such as low molecular weight PEG, generally extend the average molecular weight of the polymer in which they have been included, thus lowering their glass transition temperature or softening point temperature. Plasticizers also generally reduce the viscosity of a polymer. It is possible that the plasticizer endows the osmotic device of the invention with certain advantageous physical properties.

Plasticizers useful in the invention may include, by way of example and without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls. ester plasticizers, glycol ethers, polypropylene glycol, multiblock polymers, single block polymers, low molecular weight polyethylene glycol, citrate ester plasticizers, triacetin, propylene glycol and glycerin. These plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrenglycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other polyethylene glycol compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethylene ether, ethylene glycol monoethylene ether, ethylene glycol monoethylene ether sorbitol, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetyltributyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and aflyl glycolate. All these plasticizers are commercially available from suppliers such as Aldrich or Sigma Chemical Co. It has also been contemplated and it is within the scope of the invention that a combination of plasticizers be used in the present formulation. PEG-based plasticizers are commercially available or can be obtained through a variety of methods, such as those described in Poly (ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (JM Harris, Ed .; Plenum Press, NY), whose content It is incorporated here as a reference. The tablets of the invention may also include oils, for example, fixed oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil; fatty acids, such as oleic acid, stearic acid and isotearic acid; and esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. They can also be mixed with alcohols such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol; with glycerol ketals, such as 2,2-dimethyl-l, 3-dioxolane-4-methanol; with ethers, such as polyethylene glycol 450, with petroleum hydrocarbons, such as mineral oil and petroleum jelly; with water, or with other mixtures thereof; with or without the addition of a pharmaceutically appropriate surfactant, suspending agent or emulsion agent. Soaps and synthetic detergents can be used as surfactants and as vehicles for detergent compositions. Suitable soaps include alkali metal, ammonium and triethanolamine salts of fatty acids. Suitable detergents include cationic detergents, such as, for example, dimethyl dialkyl ammonium halides, alkyl pyridine halides, and alkylamine acetates; anionic detergents, such as, for example, alkyl, aryl and olefinic sulphonates, alkyl, olefinic and monoglyceric sulfates, and sulphoccinates; non-ionic detergents, such as fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-b / oc £ -polyoxypropylene copolymers; and amphoteric detergents, such as, for example, quaternary ammonium salts of alkyl β-aminopropionates and 2-alkylimidazolines; and mixtures thereof.

Many other components, not mentioned above, can be added to the present formulation for the optimization of the desired release profile of the active agent, including, by way of example and without limitation, glycerylmonostearate, nylon, cellulose acetate butyrate, d, 1-polylactic acid, 1,6-hexanediamine, diethylenetriamine, starches, starch derivatives, acetylated monoglycerides, gelatin coacervates, poly (styrene-maleic acid) copolymer, glycerol, castor wax, stearyl alcohol, glycerol palmostearate, polyethylene , polyvinyl acetate, polyvinyl chloride, butylene glycol 1,3-dimethacrylate, ethylene glycol dimethacrylate and methacrylate hydrogels.

It should be understood that the compounds employed in the art of a pharmaceutical formulation generally serve a variety of functions or purposes. Thus, if a compound mentioned here is cited only once or is used to define more than one term, its purpose or function should not be limited solely to the purpose or function mentioned.

Those with common knowledge in the art will appreciate that the particular amounts of zafirlukast and the Hl antagonist used in the dosage form will vary according to, among other things, the desired pharmacokinetic, pharmacological, therapeutic and / or pharmacodynamic performance in a mammal to which It was administered. The dosage form of the invention can assume any figure or form known in the art of pharmaceutical sciences. The device of the invention can be a pill, sphere, tablet, bar, plate, revolution paraboloid, revolution ellipsoid or the like. The dosage form may also include marks, cuts, gaps, letters and / or numbers on its surface for decoration, identification, and / or other purposes. A composition comprises an H1 antagonist that can be applied on a layer by understanding or dew. Spray coating is thinner and lighter than compression coating, and an osmotic device that includes spray as a coating is, therefore, smaller than a similar device with compression coating. Even more, the use of a drug coating by water-soluble and / or erodible spray allows the loading of larger amounts of drug than those used in a drug coating by water-soluble and / or erodible compression. A smaller osmotic device usually results in an increased confidence in the patient to take the osmotic device and therefore it is advantageous.

The solid dosage forms of the invention can be coated with a final coating, as is generally done in the art, to provide gloss, color, taste and other desired aesthetic characteristics. Appropriate materials for preparing the final layer are well known in the art and are found in the revelations of many of the references cited herein and incorporated by reference.

The present invention is particularly suitable for use in the treatment or prevention of allergic inflammations or disorders, such as asthma or its symptoms.

The following examples should not be considered exhaustive, but merely illustrative of some of the many embodiments contemplated in the present invention. The methods described herein can be followed for the preparation of osmotic devices according to the invention.

EXAMPLE 1 The following procedure is used to prepare osmotic devices in tablets containing zafirlukast (20, 40, 80 and 160 mg) in the nucleus. The osmotic device in tablets contains the following ingredients in the amounts indicated:

* Indicates liquids used in the manufacture of tablets. The liquids, for the most part, are absent in the final tablet.

The core composition is prepared by placing zafirlukast, sodium chloride, microcrystalline cellulose, PEO (polyethylene oxide, Polyox WSR 205 NF), HPMC (hydroxypropyl methylcellulose 2208, Methocel K 4M), and povidone in a high performance mixer and mixing for 5 minutes The granulation process begins with the gradual addition to the mixer of a granulating solution containing polyethylene glycol 400 and purified water, mixing continuously to obtain a wet mixture. Then, the wet mixture is granulated and dried at 40-50 ° C for 20 minutes in a fluid bed to remove water. Then, the dried granules are screened in a USP mesh of 30 to reduce their size. Then, the sieved granules are mixed with colloidal silicon dioxide and magnesium stearate, previously sieved in a 60 mesh, in a V mixer for 5 minutes. The final mixture is compressed to obtain the cores. A composition for coating the cores is prepared as follows: cellulose acetate and polyethylene glycol 400 are added to acetone and mixed to form a polymer solution. This solution is sprayed on the tablets in a perforated pan to obtain the cores coated by a semipermeable membrane. A 0.5 mm hole is drilled through the coating to provide osmotic devices in tablets containing zafirlukast.

EXAMPLE 2

The following procedure is used to prepare osmotic devices in tablets containing zafirlukast (20, 40, 80 and 160 mg) in the osmotic nucleus and loratadine (5, 10 and 20 mg) in the outer coating that contains the osmotic device drug. The osmotic device in tablets contains the following ingredients in the amounts indicated:

The osmotic devices in tablets manufactured as described in example 1 are coated with a composition containing loratadine prepared as follows: loratadine, HPMC 2910, crospovidone, colloidal silicon dioxide and polyethylene glycol 6000 are added to the purified water to form the suspension of coating. This suspension is sprayed on the tablets in a perforated pan to obtain the drug-coated tablets.

A final coating comprising Opadry in purified water is applied on the film-coated tablets to obtain the osmotic devices in tablets.

EXAMPLE 3

The following procedure is used to prepare multilayered osmotic devices in tablets containing zafirlukast (20, 40, 80 and 160 mg) in the osmotic nucleus and loratadine (5, 10 and 20 mg) in the outer coating containing drug of the osmotic device. The multilayered osmotic device in tablets contains the following ingredients in the indicated amounts:

The osmotic devices in tablets manufactured as described in Example 1 are coated with a second composition prepared as follows: copolividone, titanium dioxide and talc are added to the purified water to form the coating suspension B. This suspension is sprayed on the tablets in a perforated pan to obtain the osmotic devices in tablets coated with the B coating.

A third composition for coating the coated osmotic devices is prepared as follows: loratadine, HPMC 2910, crospovidone, carbon dioxide are added Colloidal silicon and polyethylene glycol 6000 to purified water to form the coating suspension C. This suspension is sprayed onto the tablets in a perforated pail to obtain the drug-coated tablets.

A final coating comprising Opadry in purified water is applied on the tablets to obtain the multilayer osmotic devices in tablets.

EXAMPLE 4

The following procedure is used to prepare osmotic devices in tablets containing zafirlukast (20 and 40 mg) and acrivastine (12 and 24 mg) in the osmotic nucleus of the osmotic device. The osmotic device in tablets contain the following ingredients in the amounts indicated:

First, the core composition is prepared by placing zafirlukast, acrivastine, sodium chloride, microcrystalline cellulose, PEO (polyethylene oxide, Polyox WSR 205 NF), HPMC (hydroxypropylmethylcellulose 2208, Methocel K 4M), and povidone in a high mixer yield and mix for 5 minutes. The granulation process begins with the gradual addition to the mixer of a granulating solution containing polyethylene glycol 400 and purified water, mixing continuously to obtain a wet mixture. Then, the wet mixture is granulated and dried at 0-50 ° C for 20 minutes in a fluid bed to remove water. Then, the dried granules are screened in a USP mesh of 30 to reduce the size. Then, the sieved granules are mixed with colloidal silicon dioxide and magnesium stearate, previously sieved in a 60 mesh, in a V mixer for 5 minutes. The final mixture is compressed to obtain the cores.

A first composition covering the cores is prepared as follows: cellulose acetate and polyethylene glycol 400 are added to the acetone and mixed to form a polymer solution. This solution is sprayed on the tablets in a perforated pan to obtain the cores coated by a semipermeable membrane. A 0.5 mm hole is drilled through the coating to provide perforated cores.

EXAMPLE 5

The following procedure is used to prepare osmotic devices in tablets containing zafirlukast (20 and 40 mg) and mizolastine (10 and 20 mg) in the osmotic nucleus of the osmotic device. The osmotic device in tablets contains the following ingredients in the amounts indicated:

First, the core composition is prepared by placing zafírlukast, mizolastine, sodium chloride, microcrystalline cellulose, PEO (polyethylene oxide, Polyox WSR 205 NF), HPMC (hydroxypropyl methylcellulose 2208, Methocel K 4M), and povidone in a high performance mixer and mix for 5 minutes. The granulation process begins with the gradual addition to the mixer of a granulating solution containing polyethylene glycol 400 and purified water, mixing continuously to obtain a wet mixture. Then, the wet mixture is granulated and dried at 40-50 ° C for 20 minutes in a fluid bed to remove water. Then, the dried granules are screened in a USP mesh of 30 to reduce the size. Then, the sieved granules are mixed with colloidal silicon dioxide and magnesium stearate, previously sieved in a 60 mesh, in a V mixer for 5 minutes. The final mixture is compressed to obtain the cores.

EXAMPLE 6

The following procedure is used to prepare osmotic devices in tablets containing zafirlukast (20 and 40 mg) and acrivastine (12 and 24 mg) in separate layers in the core of the osmotic device. The osmotic device in tablets contains the following ingredients in the amounts indicated:

The zafirlukast composition is prepared by mixing zafirlukast, sodium chloride, microcrystalline cellulose, PEO (polyethylene oxide, Polyox WSR 205 NF), HPMC (hydroxypropylmethylcellulose 2208, Methocel K 4M), and povidone in a high performance mixer and mixing for 5 minutes The granulation process begins with the gradual addition to the mixer of a granulating solution containing polyethylene glycol 400, Cremophor EL (polyoxyethylated castor oil) and purified water, mixing continuously to obtain a wet mixture. Then, the wet mixture is granulated and dried at 40-50 ° C for 20 minutes in a fluid bed to remove water. Then, the dried granules are screened in a USP mesh of 30 to reduce their size. Then, the sieved granules are mixed with colloidal silicon dioxide and magnesium stearate, previously sieved in a 60 mesh, in a V mixer for 5 minutes. The acrivastine composition is prepared by mixing acrivastine, sodium chloride, PEO (polyethylene oxide, Polyox WSR 205 NF), povidone and microcrystalline cellulose. The mixture is moistened with a mixture of polyethylene glycol 400 and purified water. The wet mixture is granulated and dried at 40-50 ° C for 20 minutes in a fluid bed to remove water. Then, the dried granules are screened in a USP mesh of 30 to reduce their size. Then, the sieved granules are mixed with colloidal silicon dioxide and magnesium stearate, previously sieved in a 60 mesh, in a V mixer for 5 minutes. The stacked core is prepared as follows: first the zafirlukast composition is added to a set of punches, and it is rammed. The acrivastine composition is then added on top of the rammed zafirlukast composition and both layers are compressed using punches to form bilayer cores.

A first composition for coating the bilayer cores is prepared as follows: cellulose acetate and polyethylene glycol 400 are added to the acetone and mixed to form a polymer solution. This solution is sprayed on the tablets in a perforated pan to obtain the cores coated by a semipermeable membrane. A 0.5 mm hole is drilled through the coating on each face of the coated core. A final coating comprising Opadry in purified water is applied over the perforated coated cores to obtain the osmotic devices in tablets.

EXAMPLE 7

The following procedure is used to prepare osmotic devices in tablets containing zafirlukast (20 and 40 mg) and mizolastine (10 and 20 mg) in separate layers in the core of the osmotic device. The osmotic device in tablets contains the following ingredients in the amounts indicated:

The zafirlukast composition is prepared by mixing zafirlukast, sodium chloride, microcrystalline cellulose, PEO (polyethylene oxide, Polyox WSR 205 NF), HPMC (hydroxypropylmethylcellulose 2208, Methocel K 4M), and povidone in a high performance mixer and mixing for 5 minutes The granulation process begins with the gradual addition to the mixer of a granulating solution containing polyethylene glycol 400, Cremophor EL (polyoxyethylated castor oil) and purified water, continuously mixing to obtain a wet mixture. Then, the wet mixture is granulated and dried at 40-50 ° C for 20 minutes in a fluid bed to remove water. Then, the dried granules are screened in a USP mesh of 30 to reduce their size. Then, the sieved granules are mixed with colloidal silicon dioxide and magnesium stearate, previously sieved in a 60 mesh, in a V mixer for 5 minutes. The mizolastine composition is prepared by mixing acrivastine, sodium chloride, PEO (polyethylene oxide, Polyox WSR 205 NF), povidone and microcrystalline cellulose. The mixture is moistened with a mixture of polyethylene glycol 400 and purified water. The wet mixture is granulated and dried at 40-50 ° C for 20 minutes in a fluid bed to remove water. Then, the dried granules are screened in a USP mesh of 30 to reduce their size. Then, the sieved granules are mixed with colloidal silicon dioxide and magnesium stearate, previously sieved in a 60 mesh, in a V mixer for 5 minutes. The stacked core is prepared as follows: first the zafirlukast composition is added to a set of punches, and it is rammed. The mizolastin composition is then added on top of the rammed záfirlukast composition and both layers are compressed using punches to form bilayer cores. A first composition for coating the bilayer cores is prepared as follows: cellulose acetate and polyethylene glycol 400 are added to the acetone and mixed to form a polymer solution. This solution is sprayed on the tablets in a perforated pan to obtain the cores coated by a semipermeable membrane. A 0.5 mm hole is drilled through the coating on each face of the coated core. A final coating comprising Opadry in purified water is applied over the perforated coated cores to obtain the osmotic devices in tablets.

EXAMPLE 8

The following general method was used to administer the osmotic device of the invention to healthy volunteers and to evaluate the performance of the osmotic device of the invention with that of a zafirlukast immediate release formulation. The relative bioavailability of the osmotic device was evaluated in a pharmacokinetic study with a two-period, single-dose, cross-randomized design, with a one-week wash period, using Accolate ^® (zafirlukast immediate release) as a control product. Twelve healthy hospitalized volunteers (non-smokers, between 21 and 50 years of age) were randomly separated into two groups of equal size. The first group of six subjects received the formulation of Example 1 (80 mg zafirlukast) and the second group received the control formulation (80 mg zafirlukast in two doses per day) under fasting conditions during the first period. After the washing period, the first group received the control formulation and the second group received the formulation of Example 1 during the second period. Blood samples were taken periodically from zero hour to 48 hours after administration, and plasma aliquots were immediately obtained and frozen at -20 ° C for further analysis by HPLC (high pressure liquid chromatography) to determine the Zafirlukast content. The following pharmacokinetic parameters were calculated from the plasma concentration curve of each formulation and each subject: areas under the curve from 0 to 48 hours (ABCo-t) and extrapolated to infinite time (ABCo-in _f ), maximum concentration of zafirlukast in plasma (C _max ), and time in which maximum concentration is reached (T _max ). Safety was assessed with physical exams, determination of vital signs and recording of adverse events. Statistical comparisons were made using the Variance Analysis technique (ANOVA) after the log transformation for the cross design. In addition, the geometric means and the 90% confidence intervals for the ratios of the _0-t ABC and the ABCo-inf of the formulation of Example 1 over the control were calculated for each parameter, in order to assess the relative bioavailability.

The foregoing is a detailed description of particular embodiments of the invention. It is recognized that it can move away from the disclosed embodiments within the scope of the invention and that obvious modifications will occur to persons with knowledge in the art. Those with knowledge in this art, in the light of the present description, will appreciate that many changes can be made in the specific embodiments disclosed herein and still obtain a similar or similar result, without departing from the spirit and scope of the invention. All the embodiments described and claimed herein can be performed and executed without undue experimentation in the light of the present description.

Claims

1. A controlled release device comprising:

(a) a core comprising a therapeutically effective amount of zafirlukast, which is released in a controlled manner for a period of at least about 18 to 24 hours;

(b) a membrane surrounding the core and one or more passages through the semipermeable membrane;

(c) a water soluble coating containing an Hl antagonist that surrounds the membrane for the release of the total Hl antagonist rapidly over a period of less than about 120 minutes when the device is exposed to an aqueous environment of use.

2. The controlled release device of claim 1, characterized in that at least 75% of the Hl antagonist is released within about 120 minutes and at least about 60% of zafirlukast is released within about 24 hours after Exposure of the device to an aqueous environment.

3. The controlled release device of claim 1, characterized in that the controlled release device further comprises one or more coatings interposed between the membrane and the drug-containing coating.

4. The controlled release device of claim 3, characterized in that one or more coatings are selected from the group consisting of: water soluble inert coating, water erodible inert coating, immediate release coating, quick release coating and release coating delayed

5. The controlled release device of claim 3, characterized in that the coating is an inert water soluble coating.

6. The controlled release device of claim 5, characterized in that the water-soluble drug-containing coating is sprayed on the water-soluble inert coating.

7. The controlled release device of claim 1, characterized in that the Hl antagonist is selected from the group consisting of: acrivastine, astemizole, azelastine, cetirizine, ebastine, epinastine, fexofenadine, loratadine, mizolastine, norastemizol, promethazine and terfenadine.

8. The controlled release device of claim 1, characterized in that the device provides a zafirlukast dissolution profile approximately as shown below when exposed to an aqueous environment:

9. The controlled release device of claim 1 or 8, characterized in that the device provides an approximately Hl antagonist dissolution profile as shown below when exposed to an aqueous environment:

10. An osmotic device comprises: (a) a core comprising a therapeutically effective amount of zafirlukast, which is released in a controlled manner for a period of at least about 18 to 24 hours;

(b) a semipermeable membrane that surrounds the core and one or more passages through the semipermeable membrane;

(c) a water soluble inert coating that surrounds the semipermeable membrane and seals the passage; Y

(d) a water soluble coating containing an Hl antagonist surrounding the water soluble inert coating for the total release of the Hl antagonist rapidly for a period of less than about 120 minutes.

11. The osmotic device of claim 10, characterized in that it contains about 20 to 160 mg of zafirlukast and about 2.5 to 180 mg of Hl antagonist.

12. The osmotic device of claim 10, characterized in that it contains about 20 to 160 mg of zafirlukast and about 10 to 20 mg of loratadine

13. The osmotic device of claim 12, characterized in that the device provides a zafirlukast dissolution profile approximately as shown below when exposed to an aqueous environment:

14. The osmotic device of claim 12 or 13, characterized in that the device provides an approximately Hl antagonist dissolution profile as shown below when exposed to an aqueous environment:

15. The osmotic device of claim 12, characterized in that: the core comprises an osmoagent, an osmopolymer, a diluent and a binder; the semipermeable membrane comprises cellulose ester and a plasticizer; the water soluble inert coating comprises a water soluble polymer, an opaquent and a filler; and the water soluble coating containing the H1 antagonist further comprises a film-forming polymer and a disintegrant.

16. The osmotic device of claim 15, characterized in that: the osmoagent is selected from the group consisting of sodium chloride, salt, mannitol, acid, sugar, base, calcium salt, and lactose; the osmopolymer is selected from the group consisting of hydroxypropyl methylcellulose and polyethylene oxide; The diluent is selected from the group consisting of microcrystalline cellulose, lactose, sucrose, mannitol, cellulose, starch, sorbitol, dibasic calcium phosphate, and calcium carbonate; The binder is selected from the group consisting of poly (vinyl pyrrolidone), povidone, sodium carboxymethylcellulose, alginic acid, polyethylene glycol, guar gum, polysaccharides, bentonite clay, sugar, poloxamer, collagen, albumin, gelatin, poly (propylene glycol), and oxide of polyethylene; the cellulose ester is selected from the group consisting of cellulose acetate, cellulose acylate, cellulose fatty acid ester, and cellulose acetate phthalate; the plasticizer is independently selected at each occurrence of the group consisting of polyethylene glycol, low molecular weight polymer, citrate ester, triacetin, propylene glycol, glycerin, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, and dibutyl sebacate; The water-soluble polymer is independently selected at each occurrence of the group consisting of hydroxypropyl methylcellulose, polyvinylpyrrolidone - (vinyl acetate) copolymer, polyvinylpyrrolidone, methyl methacrylate, calcium pectinate, poly (ethylene vinyl acetate ), hydroxylalkyl alkyl cellulose, polyvinyl alcohol, polyethylene oxide, a mixture of gelatin and polyvinyl pyrrolidone, gelatin, glucose, saccharides, povidone, copovidone, and polysaccharide gum; the opaquent is selected from the group consisting of titanium dioxide and talc; the load is selected from the group consisting of talc and starch; the film-forming polymer is selected from the group consisting of hydroxypropyl methylcellulose, and poly (vinyl pyrrolidone); and the disintegrant is selected from the group consisting of: crospovidone, bentonite clay, microcrystalline cellulose, starch, carboxymethyl cellulose, alginate, sodium starch glycolate, and gum.

17. A method of treating asthma, inflammation and allergic reactions comprising the steps of administering a controlled release device according to any one of claims 1 to 9.

18. A method of treating asthma, inflammation and allergic reactions comprising the step of administering an osmotic device according to any of claims 10 thereto.

19. A controlled release device comprising:

(a) a nucleus comprising a therapeutically effective amount of zafirlukast and an Hl antagonist; (b) a membrane surrounding the core and one or more passages through the semipermeable membrane; where zafirlukast and the Hl antagonist are released in a controlled manner for a period of at least about 12 to 24 hours.

20. The controlled release device of claim 19, characterized in that the Hl antagonist is selected from the group consisting of acrivastine and mizolastine.

21. The controlled release device of claim 19, characterized in that the Hl antagonist is acrivastine.

22. The controlled release device of claim 19, characterized in that the Hl antagonist is mizolastin.