MXPA97003950A - Method of combination dosage comprising cetirizine and pseudoefedr - Google Patents

Abstract

The present invention relates to a dosage form containing cetirizine as an immediate release component and pseudoephedrine or a pharmaceutically acceptable salt thereof as a controlled release component. A part of the pseudoephedrine may also be incorporated as an immediate release component. The dosage form lacks alcohols having a molecular weight of less than 100 and reactive derivatives of the same.

Description

METHOD OF COMBINATION DOSAGE COMPRISING CE "IRIZINR AND PSEUDOEFEDRINA FIELD OF LR INVENTION 5 This invention relates to dosage forms comprising cetipzin and pseudoephedrm, which contain both a sustained release component and an immediate release component. BACKGROUND OF THE INVENTION The ce + nz na has the formula 0 and is a member of the group of compounds called acids *? - 114 - (d? Fen? Lme +? L Fs + os compounds are u + i them as anti-ialerHjenos, espasmolit cos and antihis-tamí nicos that «jeneralinen-re are not sedan-res. See the Pa + en-te < 1e United States 4,525,358 and The MercV Tndex, 17 »Fdicion, 1989, page 310, article 2013.

The pseudoetomer, as well as the pharmacologically acceptable cycid addition salts of the same, such as the hydrochloride and sulfate salts, is a sympathomimetic drug known to those skilled in the art as a therapeutic agent. sure to treat nasal congestion, usually orally and jointly with an anti-stainma for treatment of nasal congestion in the treatment of allergic rhinitis. Cetirizine and pseudoephedrna can be co-administered. The general program for administering the two drugs together includes a tablet of 10 mg of cetipzam per day, plus eight tablets of 30 mg of pseudoephedrine immediate release, divided into four doses throughout the day. However, it is well known that compliance of the patient with a program of administration of several daily doses may be affected by the inconvenience of having to remember the medicine in appropriately spaced numbers. Accordingly, it would be useful for patients to be able to use it as a pseudo diet as a unit dosage form, such as a tablet, for example, once or twice a day, to improve convenience and to ensure the best patient compliance. ; > BRIEF DESCRIPTION OF THE INVENTION In one aspect, this invention provides a solid dosage form comprising cetirizine and pseudo-ephedrine wherein at least a portion of said pseudoephedrine is contained in a nucleus comprising said pseudoephedrine, thereby release of said pseudoephedrine in the medium of use is sustained; wherein said cetipzam is contained in the form of an immediate release component in said dosage form; and wherein said dosage form substantially lacks alcohols having a molecular weight of less than 100 and reactive derivatives thereof. In a preferred embodiment, this invention provides a solid dosage form comprising cetipzin and pseudoephedrine, wherein at least one portion of said pseudoephedrine is contained in a core comprising said pse-doefedpne portion. said core being surrounded by a permeable membrane, whereby the release of said pse? dophedrine in a medium of use is sustained; where di ceti p zina is controlled in the form of an immediate release component of a dosage form; and wherein said dosage form substantially lacks alcohols having a molecular weight of less than 50 and reactive derivatives thereof. In a preferred embodiment, the dosage form is substantially free of alcohols having a molecular weight of less than 250 and reactive derivatives thereof. In a preferred embodiment, the dosage form is substantially free from alcohols having a molecular weight less than 500 and reactive derivatives thereof. In a still further preferred embodiment, the dosage form is substantially free from alcohols having a molecular weight of less than 1000 and reactive derivatives thereof. The invention further provides a method for making dual dosage forms containing cetinzma and pse? Doefedpna., which comprises coating a sustained release core with an appropriate form, comprising pse? doefedp na, with an immediate release layer comprising ce pzma and? n water soluble film forming polymer, said core and said layer substantially lacking. of immediate release of alcohols having a molecular weight less than 100 and reactive derivatives thereof. In a preferred embodiment, this invention provides a preferred method for manufacturing a solid dosage form containing cetipzin and pseudoephedrine, comprising the steps of coating a composition with a suitable form, comprising pseudoe fednna, with a membrane permeable membrane. coating said permeable membrane with an immediate release layer comprising cetipz na and a water soluble film polymer, said composition, said membrane and said layer substantially lacking, alcohols having a molecular weight of less than 100 and reactive derivatives thereof. The term "cet pzina", as used herein, is intended to include not only the free compound of formula (I), but also any pharmaceutically acceptable salt thereof. Acid addition salts are preferred, especially the dihydrochloride salt (also referred to herein as "hydrochloride"). The term "cetirizm" is also intended to encompass the individual enantiomers as well as the racernat. The term "pse? Doefedp na", as used herein, is intended to include the free base and also any pharmaceutically acceptable acid addition salt. For use in this invention, the sulfate and hydrochloride salts are referred to. The term "alcohols" is used generically to imply any compound having one or more hydroxyl groups (-0H) reactive with ipzma ce. Therefore, the term includes diols and polycides as well as oncoalcohols that are reactive with cetirizine under normal conditions of processing and storage. A "reactive derivative," as used herein, includes those materials that have alcohol (OH) groups that have been fused and that can react with cetipzma porstrans transplants. "With a suitable form" usually means round or more or less spherical, but it can also mean any other way in which cores of joined cornpr can be made. The invention provides a dosage form that contains both cetirizine and pse? Dophedrine. Cetir-Lzina as pse? Doefedpna ,. Cetirizm is contained in an immediate release component from which it begins to be released or is released substantially after ingestion (ie, after swallowing). In the dosage form, no mechanism has been tested to delay the release, which would otherwise take place after exposure of a means of use, such as the luminal fluid of the gastrointestinal tract (Gl). Generally, cetirizm should be released in at least 80% from the dosage form, within one hour of administration. The pseudoephedrine, on the other hand, is released in a sustained manner, at least about 75% of the drug contained in the dosage form being released over a period of 4 to 36 hours, preferably approximately 8 to about 24 hours, although the sustained release period may be adapted to have an immediate release component, as described further below. The term "approximately", as used above and elsewhere in this document, means at least 10% for each of the numerical limits. The sustained release pse? Dophedrine is contained in a core that can be manufactured in a variety of ways and embodiments to achieve sustained release. For example, pse? Dophdrin can be incorporated into a sustained release matrix that doses the pseudoephedrine for a period of 4 to 35 hours., thus constituting the matrix the nucleus. Alternatively, the pse? Doephedrin core may comprise an immediate release composition of pse? Dophedrine with a suitable shape and a membrane limiting the velocity surrounding it and imparting sustained release behavior to the core. In the dosage form of the final product (ie, the dosage form intended to be sold or administered) and during processing when manufacturing the dosage form, it is important to avoid contact of the oetirizm with alcohols having A molecular weight less than 100, since such contact could produce a reaction with ceti izma, normally of stagnation and, therefore, a damage to the dosage form by reaction with the active medicinal agent. Therefore, the dosage form must be substantially free of such reactive components at the time when the immediate release cetipzine component is introduced into the dosage form and thereafter. Alcohols and other reactive components can be used for processing, provided that they are removed to produce * or eliminate their presence before introducing cetirizine. If alcohols are not used during processing or are removed before introducing the cetipzma into the doping format, this is what is meant by the phrase "essentially without alcohols having a molecular weight less than ...". In the final dosage form, some level of alcohols that are reactive with cetirizm may be taken, the exact level depending on the particular alcohol. In general, for "substantially lacking" alcohol (s), the total amount of alcohol of molecular weight less than 100, either a single alcohol or a mixture, must be less than the amount needed to react with an alcohol. 5% of the cetipzine in the dosage form, preferably lower <; } ue the amount needed to react with 1% of the cetipzina. More preferably, it is preferred < The level of alcohol having a molecular weight less than 100, whether it is only alcohol or one alcohol, is less than the amount of alcohol needed to react with 0.5% of the cetirizm of the dosage form and still Thus, I preferred that the dosage form completely lack alcohols having a molecular weight of 100. Thus, the final dosage form, both the nucleus and the layer (s) e? tepor (s) , it has to be substantially free of low molecular weight alcohols and reactive derivatives of Los misinos. Such materials include monohulroxyl and polyhydric alcohols having a molecular weight or << Conventionally and frequently, if not universally, they are used as solvents in the techniques of the formulations and in compositions containing them as excipient carriers. Examples of such reactive alcohols include lower molecular weight alcohols such as methanol, ethanol. osipropanol and glycepna. As they are difficult to remove, high boiling alcohols such as glycerin may be problematic, and components are to be avoided altogether. Many plastificant.es are alcohols and, therefore, contact with cetirizine should be avoided if they have a low molecular weight. Many plastiforms are also esters, that is, materials that are reactive derivatives of alcohols, and the contact of La cetirizma with these materials should be avoided, since < The ester groups can undergo transestep f cation with ceti izma and therefore give rise to the dosage form. However, not all components containing alcoholic groups are reactive with cetipzin ba or normal processing and storage conditions (temperatures below 100 ° C), and such components are not "alcohols" for the purposes of this invention. Examples include cellulosic materials containing free hydroxyl groups, such as most commonly used nicrocrystalline celluloses as comprehensive excipients as well as cellulose ethers useful as a coating in the formulations described herein. Specific dosage forms contemplated for use in this invention include tablets, capsules and dosage forms comprising a plurality of particles, referred to herein as "multiparticulate or multiparticulate" dosage form for brevity. A single vector can have numerous formulation applications. For example, a particulate can be used in the form of a powder to fill a capsule shell or it can be used per se to mix foods, for example ice cream, to increase the appetite. Cetirizm can be incorporated in the dosage form as an "immediate release" component in a variety of ways. For example, it can be incorporated into an outer coating - for a tablet, the liquid is released in a substantial way immediately after ingestion. The coating may be a complete coating or may cover less of the surface of the dosage form, as described below. Such a coating may be applied analogously to each of the particles comprising a plural particle. If the dosage form is going to be a capsule, the cetizine may be contained in a single granule inside the capsule, from which it is released in an immediate and immediate manner once it has been dissolved. the ? i wrapped of the capsule. Alternatively, cetirizm may be contained in several smaller angles or may be present in particles of immediate release. In this type of capsule realization, the pseudo-ephedrine is generally present, for example, in the form of a slow release particle, with each particle comprising a central nucleus of incorporated pseudoephedrine. in a matrix or elbowed by a membrane limiting the speed. The term "compressed" refers to conventional macroscopic dosing as is known in the art and, as applied in this invention, indicates a unit dosage having a central core that releases pseudoeffined in a sustained manner, over a period of time. ? o < from 4 to 36 hours, preferably from about 8 to about 24 hours. As mentioned above, the nucleus can be a matrix that doses the pseudoephedrine. Alternatively, the pse-doped nucleus can be formed from a composition containing immediate release pse? Doephedrin, which is surrounded by a velocity-limiting membrane, permeable and water-soluble that provides sustained release of the pse? pseudoefedpna limiting the speed at which the pseudoefedpna diffuses in the medium of use. After the core to s? it is coated, on at least one part of its surface, with a layer comprising cetirizm and a water-soluble film-forming polymer that provides immediate release. The layer containing cet n-izi na < Immediate release preferably coats the entire surface of the core for convenience in the form of compression. The immediate release layer can also be made, if desired, to cover less than the area of the membrane, by conventional methods known in the art. For example, if the tablet has flat surfaces, the layer that contains cetipzma can only cover one or more, but not all, the surfaces. If the tablet is spherical, the layer containing cetipzin can coat a surface smaller than the entire layer of the sphere. A tablet dosage form is desirable as a prefabricated dosage form, easily purchased, which can be administered in most cases to patients who need and / or desire a medication containing both an antihistamine and a decongestant. onante. In the case of nuclei < They contain pseudoephedrine, which is passed through a limiting membrane, and the velocity, the membrane is "permeable." The permeability can be achieved by making a coating that completely surrounds the core and that has a pore size that allows the passage of water and pseutjoefedpna through the membrane. In this type of membrane, the water passes through the membrane, passes into the nucleus and dissolves the pseudoephedrine so that the pseudoephedrine is released on the other side of the membrane inside the GT tract at a desired speed, that is, at a speed that is reasonably constant, until you have substantially released all the pseudoe fedp na «. uring a period of 4 to 36 hours. This type of membrane is described, for example, in EP-A-0 357 369, incorporated herein by reference in its entirety. As an alternative, the membrane can be permeable only to water, but it has one or more openings such as a hole re «don« or a hole «otherwise, the form being not critical. The opening can be physically enhanced, for example, by drilling, on any part of the surface, to allow the release of pse? Doefedpna. This type of dosage is known in the art and is described in numerous United States patents, including 4,915,954; 4,915,953; 4,915,952; 4,847,093; and 4,810,502; Each of which is hereby incorporated by reference in its entirety. The term "form of" multiparticulation "or "Particulate product" is intended to encompass a dosage form comprising a multiplicity of particles that fully represent the intended useful therapeutic dose of cetipzin plus pseudoephedrine. The particles generally have a diameter of approximately 50 nm to approximately 0. 3 cm, with a preferred range of LOO μm to 1 nm. Each individual particle is essential in my nor compressed and each comprises a central core of sustained release pseudoephedrine, sustained release being achieved as described above. Each particulate may also be coated, in whole or in part, with an immediate release layer comprising cetipzin plus a water-soluble wicking polymer. In an alternative embodiment, a matrix containing a membrane-coated pseudoephedrine or non-membrane-coated pseudoephedrine, without immediate release coating with cetirizm, can be used to partially fill a capsule, and one or more granules of ceramide deliberation can be added thereto. tie as part of the capsule filling. A multiparticulate dosage form is desirable, since it allows personalization or adaptation according to the weight of the patient, simply by proportionally reducing the number of particles in the dosage form. Thus, for example, in order to fill a capsule, a weight of a particle may be used < adapted to a particular patient or to a group of patients who may need more or less cant < i of the measurement that is supplied in a prefabricated tablet. Capsules adapted for older or younger patients can simply be adjusted by adjusting, upward or downward as appropriate, the filling weight of the particulate core. If a single particle is reclbled or with a membrane, the individual particles are usually formed from a time when the membrane completely surrounds the central core of the pseudo-ephedrine and, in the medium of use, is permeable to both water and to the pseu «doefedp a. In one embodiment of the dosage form of the invention, all cetirizine is incorporated into a separate immediate release (ie, detached from the sustained release nucleus) coating surrounding the pseudoephedrine core of the dosage form, and all the pseudoephedrine is incorporated into the nucleus. This embodiment may be in the form of a macroscopic tablet or the "form of a particulate fragment used as a filling of the capsule." In an alternative embodiment, the entire cetirizm and f > Art of the pseudoe fed ri na are incorporated into the immediate release coating of the separated layer and the remainder of the pseudoe fedp na is incorporated into the sustained release core. This alternative embodiment provides some of the pseudoephedrine for immediate release along with the immediate release matrix also in the coating. The amount of cetirizm administered may vary with the size of the patient, as discussed above, but generally be in the range of about 5 to about 20 mg / day. The amount of pseudoephedra administered will generally vary between about 60 and about 240? Ng / day. "Up to about? 25%" of pse? Doefedpna, corresponding to 15-60 rng / day, may be incorporated into the layer with It has instant ce + irizma, which provides that amount for immediate release along with the cetirizma. However, it is preferred to incorporate "the peeudoefed in the nucleus. The fact that alcohols and their derivatives, such as esters, are harmful to formulations containing cetirizine is surprising considering the fact that esters, for example, glycerol esters of cetipzine, are difficult. to manufacture 5 by conventional methods of direct filtration. In view of the difficulty associated with direct staining, it is surprising that the reactivity of the matrix to alcohols is such that an extensive formation of esters was observed when processes are used to formulate solid LO formulations, such as as compressed, in which cetipzin is exposed to glycepne or other alcohols in one or more et ap ..

DETAILED DESCRIPTION OF THE INVENTION L5 In this invention, any dosage form useful for determining whether a particular alcohol is potentially harmful can be tested by the following procedure. The dosage form can be stored at 0 50 ° C for twelve weeks in a closed container (including the commercial container, if it can be closed) and then dissolved in water. After filtration, an aqueous sample can be injected into a liquid chromatograph and analyzed for the presence of ceti izine esters by reverse phase liquid chromatography (HPLC) using UV detection at 231 n. For the phase 1 system < " In reverse, a column "j? e has" a stationary hydrocarbon phase C-18, a type called column ÜDS C-18 Ultrasphere (registered trademark of Beckman Instruments, Tnc), using an isocratic mobile phase consisting of 60% water with a pH of 2.5 (pH adjusted by the addition of potassium hydrogen phosphate) and 40% acetonitrile. The flow rate is typically 1 ml / minute. Cetipzin esters normally elute after the cetirizm. Identification can be made by comparing "an unknown peak with a known pattern that elutes at the same time" retention. Confirmation can be made by mass spectrometry. The sustained release cores are manufactured from a matrix material in which the pseudo-infusion is dispersed or dispersed and which acts to remove the release of the pseudoephedrine to the medium of use, the Gl tract. When the pseudo-ephedrine is present in this type, the release of the drug takes place mainly from the surface of the matrix. Thus, the drug is released from the surface of the matrix after d melting therethrough or when the surface of the matrix erodes, exposing the drug. In some matrices, the two mechanisms can act simultaneously. These types of systems are well known in the art and are discussed extensively, for example, in "PCT / EB95 / 00264, published as UO 95/30422, incorporated herein by reference in its entirety. 19 A preferred embodiment of a matrix "core" has the fopna of a hydrophilic matrix, ie, a core containing pseudoephedrine and, as a matrix, a sufficient quantity of hydrophilic polymer to provide a useful degree of control over the matrix. pseudoephedrine solution. Hydrophilic polymers useful for forming the matrix include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), poly (ethylene oxide), poly (vinyl alcohol), xanthan gum, carborne, carrageenan and zooglan. A preferred material is HPMC. Similar hydrophilic polymers can also be used. In use, the hydrophilic material swells and finally dissolves in water. The pseudoephedrine is released both by injection from the matrix and by erosion of the matrix. The rate of dissolution of pseidophedrine from a hydrophilic matrix core can be controlled by the amount and molecular weight of the hydrophilic polymer employed. In general, using a greater amount of hydrophilic polymer decreases the rate of dissolution, as well as using a higher molecular weight polymer. Using polymer, the lower molecular weight increases the rate of dissolution. The isolution velocity is also controlled by the use of water-soluble additives such as sugars, salts or soluble polymers. Examples of these additives are sugars such as lactose, sucrose or mam tol, salts such as NaCl, KCl, NaHC? 3 and water soluble polymers such as poly (N-vmyl-2-pi rrolidmone) or polyvinylpyrrolidone, HMPC or HPC of ba or molecular weight or hypromellose. In general, increasing the fraction of soluble material in the formulation increases the rate of release. A hydrophilic matrix core typically comprises about 20 to 90% by weight "of? Se?" Doephedrine and from about 80% to 10% by weight of polymer. A nucleus of the pse? Dophedrine hydrogel matrix can be coated with an "immediate release" coating comprising cetirizine and a "fi lm-forming" polymer soluble in water. A preferred matrix composition for use as a core comprises, by weight, "from about 50% to about 80% pseudoephedrine, from about 15% to about 35%" of HPMC, "from 0 to about 35% lactose, from 0% to approximately 15% "of PVP, from 0% to about 20% microcrystalline cellulose and from about? 0.25% to about 2% magnesium stearate. Matrix systems, as a class, often present a non-constant release of the matrix from the matrix. This result may be a consequence of the "release mechanism" of the drug release and modifications may be made to the geometry of the dosage form to achieve the most constant release rate of the drug as detailed below. In a particular embodiment, a pseudoephedrine matrix core is to be covered with an impermeable coating and a hole can be made (eg, a circular hole or a rectangular opening) by which the contents of the tablet are exposed to the aqueous medium. of the Gl tract. This embodiment is in accordance with the indications presented in U.S. 4,792,448 of Renade, incorporated herein by reference. The opening typically has size such that the area of the exposed underlying pseudoephedrine composition constitutes less than about 40% of the surface area of the device, preferably less than about 15%. The nuc Leo enter-o can be coated with an immediate release layer comprising cetirizm and a water-soluble film-forming polymer. In another particular embodiment, a pseudoephedrine hydrogel matrix can be coated with an impermeable material and an opening for drug transport can be produced by piercing a hole through the coating. The hole can be made through the coating only or it can extend as a passageway into the core. The entire core can be coated with an immediate release layer comprising cetirizm and a water-soluble film-forming polymer. In another particular embodiment, a "hydrophilic matrix" core of pse? Doefedpna can be coated with a waterproof material and a passageway can be produced for triaging the drug by piercing a passageway through the tablet. whole. The entire core can be coated with an immediate release layer comprising cetirizm and a water-soluble film-forming polymer. In another particular embodiment, a matrix core and hydrogel of the pseudoephedrine can be coated with an impermeable material and one or more passageways can be produced for the transfer of drug by removing one or more strips from the impermeable coating or by cutting one or more layers. slots through the coating, preferably over the radial surface or coating of the tablet. The entire core can be coated with an immediate release layer comprising cetirizm and a water soluble film-forming polymer. In another particular embodiment, a hydrogel matrix core of pseudoephedrine can be cone-shaped and completely coated with a waterproof material. A passageway can then be produced for the transport of the drug by cutting the tip of the cone and the tip of the cone. whole cone can be coated with an immediate release layer <;, which comprises cetirizine and a water-soluble film-forming polymer. In another particular embodiment, a pseudoephedrine hydrogel matrix core can be given a sermesphere shape, it can be completely covered with an impermeable material and a through passageway can be produced for the transport of the drug by drilling A hole in the center of the plane of the serpent. Then, the entire core can be coated with an immediate release layer comprising cetLrizma and a water-soluble film-forming polymer.

In another particular embodiment, a pseudoephedrine hydrogel matrix core can be formed into a sernicilmdro form and completely covered with impermeable material. A passageway for transporting the drug can be produced by cutting a slot therethrough or by removing a strip of the impermeable coating along the length of the semicircle or along the center line of the flat face of the half-circle. The entire core can be coated with an immediate release layer comprising cetirizm and a water-insoluble film-forming polymer. Those skilled in the art will appreciate that geometric modifications can be produced equivalently to the embodiments described above by more than one procedure. For example, cutting or perforating to obtain a passageway for drug transport can be achieved by other operations such as by a technique that produces the desired partial invasion. The term "impermeable material" means a material that has sufficient thickness and impermeability for the pseudoephedrine so that no significant transport of the pseudoephedrine occurs through the material during the period of time desired for drug release ( that is, 4-36 hours). Such a coating can be obtained by selecting a coating material with a diffusion coefficient sufficiently low for the pseudoephedrine and applying it with sufficient thickness. The materials used to form the impervious coating of these implementations include substantially all materials in which the coefficient of the fusion of the pseudo-ephedrine is less than "approximately 1 -7 cm2 / s. It should be noted that the above diffusion coefficient can be extended enough for a matrix device, as discussed above. However, in a device of the type that is now under discussion, < It has a macroscopic opening, a material with this diffusion coefficient, and almost any membrane material "was not a liquid, as opposed to the pseudo-fedren contained, in contrast, as if it were impermeable because most of the transport It was done through the opening. Preferred coating materials include polymeric film-forming polymers and waxes. Particular preference is given to thermoplastic polymers such as polyethylene-co-acetate and vinyl), poly (vinyl chloride), ethyl-cellulose and cellulose acetate. These materials exhibit the desired low filtration rate with respect to the pseudoephedrine when they are applied as coatings with a thickness greater than about 100 μrn. When making cores comprising an immediate release pseudoephedrine composition surrounded by a velocity-limiting membrane, the types of membranes that may be employed are widely known in the art, for example, by the patents and publications mentioned above < What are the "documents EP 0 357 369, U.S. 4,047,093 and U.S. 4,915,953. The membranes can be manufactured from film-forming polymers more soluble in water, for example, from "polymers of the defines and vimiles, polymers" of organosilicon, polysulphones, polyarylates, polyurethanes, esters of "cellulose, ethers". of cellulose and the like. The polymers can be condensation polymers or addition polymers. Specific non-cellulosic polymers include poly (methyl methane), poly (butyl netacplate), polyethylene, copolymer of ethylene and vinyl acetate, polyidimethylsiloxane), polypropylene, polyvinyl chloride, polyvinyl alcohol), ethylene alcohol, villic and the like. For use in the manufacture of membranes for ro < In the case of tablet cores, cellulosic materials such as cellulose esters and ethers are preferred. The examples of cellulose esters and ethersThese include the mono-, di-, and t-cyclic esters in which the acyl group consists of two to four carbon atoms and lower alkyl ethers of cellulose in which the group having 1 to 4 atoms of carbon. Cellulose esters can also be mixed esters, such as cellulose acetate butyrate or a mixture of cellulose esters. It is possible to find the same variations in cellulose ethers and to include mixtures of cellulose esters and cellulose ethers. Other cellulose derivatives that can be used to make membranes useful in the present invention include the materials associated with reverse osmosis membranes and include cellulose nitrate, acetalde or dnnethyl cellulose, cellulose acetate ethane carbamate, cellulose acetate phthalate, acetate cellulose netil carbamate, cellulose acetate scinacinate, dimethyl acetate cellulose inoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate, cellulose acetate, cellulose acetate butyl cellulose acetate , cellulose acetate, p-toluene sulphonate, cellulose cyanoacetates, cellulose acetate tprnelitate and cellulose metacp. Cellulose esters can be formed by the acylation of cellulose with the corresponding anhydride of acyl or acyl halide. Several of the common cellulose esters are available in the market. The cellulose acetates 394-60, 398-10 and 400-25, "having acyl contents" of 39.4, 39.8 and 40%, can readily be obtained from Eastman ChenicaL Co., Kingsport, Tenn. This in the form of a compressed or multi-particulate tablet, the type of tablet core discussed now constitutes a reservoir system or moderated by rnernbrana. In this type of sustained release system, a reservoir of "pseudoephedrine surrounded by a limiting membrane «of the speed that allows the passage of pseudoephedrine and water. The pseudoephedrine traverses the membrane by mass transport mechanisms well known in the art including, but not limited to, the dissolution of the second membrane by diffusion through the membrane. As previously indicated for this invention, these dosage forms of individual storage systems can be large, as in the case of "a compartment containing a single large tank, or multiparticulate, as in the case of a capsule. which contains a plurality of "reservoir" particles, each individually coated by a membrane. The coating may be non-porous, yet permeable to the pseudoephedrine (for example, pse? Doephedrine may diffuse directly through the membrane), or it may be porous. The particular transport mechanism that acts to achieve sustained release is not considered critical. Membrane moderated cores can also be manufactured as "osmotic delivery" systems, that is, systems such as those previously described in which the velocity-limiting membrane surrounding the pseudoephedrine core is impermeable or poorly permeable to pse? , but n? and permeable to water. Then, the water can diffuse through the membrane and dissolve the pseudo-diaphragm from the nucleus which then passes to the outside of the tablet through one or more holes that have been punctured or that have been created in another way. The surface of the tablet, so that the hole exposes the inside of the nucleus «of pseudoephedrine. The size and shape of the hole are not critical and are usually of the order of 0.05 rnm to 2 rnm. The term "hole" is intended to encompass any exit passageway whatever its name (eg, hole, hole, perforation, slot, and the like). Sustained-release coatings more soluble in water may be employed, as is known in the art. , to fabpcaí the membrane that surrounds the core, special rn € >Polymeric coatings, such as any of the water-soluble coatings mentioned above. Cellulosic materials are preferred, as previously described. Particularly preferred materials include ethyl cellulose, cellulose acetate and cellulose acetate butyrate. The polymer can < to be applied as a solution in an organic solvent, such as an aqueous dispersion or latex. The coating operation can be carried out in conventional equipment such as a fluted bed coater, a Uur ter coater or a rotary perforator, If desired, the permeability of the membrane can be adjusted by mixing two. or more materials, a process particularly useful for adapting the porosity of the coating to the addition of a predetermined amount of water-soluble material finely "J? v? < 1t < do, such as sugars , water-soluble salts or polymers, to a solution or dispersion (eg, an aqueous layer) of the membrane-forming polymer to be used Other "useful pore-formers" include "dirnethylsulfone and nicotmamide. Dosage is ingested and passed to the aqueous medium of the GT tract, these water-soluble membrane additives exit the membrane from "pores" that facilitate the release of the drug. be added by the addition of a plasticizer, as is known in the art. These types of process are fully described in U.S. Patents 4,851,228, 4,687,660 and 3,538,214, "all of which are incorporated herein by reference. Auntjue alcohols are also known in the art as useful pore formers, including sorbitol, pentaephtriol, ma tol and other rnonools and aromatic and aliphatic polyols, including diols and triols, in this procedure the use of these types of alcohols should be avoided. as pore formers, since they tend to react with cetirizma by esterification. The "pore size" of the membrane is not considered particularly critical; rather, the overall coverage of the coating is considered more important. The optimal pore size depends on the individual core size. Generally, the pore size is less than 50 μm and the total pore area is less than 1% of the total area of the membrane surface. The optimum thickness of the membrane also varies depending on the size of the core, ie, whether the core is unitary and macroscopic (for example, for use in a unitary tablet) or inultiparticulated. For unitary macroscopic cores, the thickness of the membrane is generally 100-700 μm, with an optimum thickness, in most cases, of 200-500 μm. For nultiparticulates, membrane thicknesses generally range between 5 and 75 μm. The size of the pores of a membrane and its thickness can be determined by measuring ba or an electron microscope. The thickness of the membrane and the porosity can be modified to adapt a particular device and achieve the desired release characteristics. A preferred membrane is an asymmetric membrane of the type described in EP 0 357 369. As described herein, the asymmetric membrane is composed of two membrane regions or layers. A layer is a relatively thick and porous substructure. This substructure serves as support for the other part of the membrane, a thin layer dense "dense". The membrane can be manufactured from cellulose derivatives that form water soluble films such as the esters and cellulose tetras mentioned above. Mixed esters and ethers can be used. Many other materials may also be used, including any of those described in EP 0 357 369. The formulation used to make the membrane "must comprise at least about 60% to 90% by weight of a polymer. water insoluble film forrnador y, <equivalently, from about 40% to 10% "of a pore formers" reagent such as any of those mentioned above. For optimum results, the membrane formulation must contain from 55% to 75%, especially approximately 68% by weight of a water-insoluble film-forming polymer, the remainder being a formation reagent. of pores A particularly useful method for applying a membrane coating is to dissolve the coating polymer in a mixture of selected solvents so that the coating dries, a phase reversal occurs in the solution of the coating. applied coating and obtain a membrane with a porous structure. In the present invention, if the velocity-limiting membrane is to be an asymmetric membrane of the type described in EP 0 357 369, it is possible to pre-form the pores (as opposed to the formation of "pores" in the Gl tract). ) using one or more alcohols, usually volatile, as pore-forming ingredients, but it is important to remove all the alcohol before "applying the immediate release layer" or containing cetipzine. Thus, if a low molecular weight alcohol or a mixture thereof is used as a pore former when manufacturing membrane surrounded cores, the alcohol (s) < must be removed after completing the formation of the cores. The removal can be carried out in a conventional manner, for example, by placing the cores in a pressurized air oven, a vacuum oven or a fluidized bed for several hours, typically overnight. The alcohols used must also be low boiling point liquid liquids at room temperature, such as methanol and ethanol. Alcohols with higher boiling points which are liquefied at room temperature, such as glycerol, butanol and higher monoalcohols, and diols such as glycols of high molecular weight such as ethylene glycol and propylene glycol, are problematic and avoid yourself A tablet core according to the invention comprises "from about 60 to about 360 mg of pseudoephedrine, from about 70 to about 425 mg" of compressible excipients, from about 2 to about 17 mg "of binder and" from about 0.5 to about 4 rng of lubricant. A preferred dosage form contains 240 mg of pseudoephedrine (or 120 g if the dose is to be divided) in the form of the hydrochloride and a quantity of compressible excipient, binder and lubricant within the ranges indicated above. Generally, the greater the amount of pseudoephedrine hydrochloride used in the core, the greater- should be the amount of compressible excipient that is used. The proportions and amounts mentioned above are advantageous because they provide compressible tablet cores with good mechanical properties, including roughness and low "wear. By using quantities outside the above limits, the difficulties generally increase in order to make the formulation and / or scaling possible, including the low hardness of the tablet, the reliability and the coating. The term "compressible excipients" refers to materials generally known in the art to be used in formulations to improve the flowability and compression properties of a drug formulation. Preferred are materials such as cellulose microcrystals sold as ftvicels (registered trademark "by FMC Corporation, Philadelphia, Pa.). The aggluti are materials that generally act to keep the drug and other powdered ingredients together in a granulation, and conventionally known binders can also be used in this invention. Suitable binders include water soluble polymers such as hydroxy propyl cellulose (HPC), pol? (N- v il -2-pyrrolidone) (PVP) and hydroxypropyl proelim (HPMC). Advantageously, it is possible to acquire grades of microcrystalline cellulose which are pre-formulated containing binders such as HPMC. As the lubricant, magnesium stearate is preferred, although other lubricants, such as stearic acid and sadistical latent is also used. If the immediate release cetipzin component is made as a coating on the velocity-limiting membrane, the coating may contain from about 40 to about 85% by weight of cetiriz with respect to the weight of the product. coating, being the n rest (from 15 to 60% by weight): a water-soluble film-forming polymer such as hydroxypropyl hypromellose (HPMC) or a mixture of hydroxypropyl cellulose and hydroxypropylphenol, which can be manufactured or purchased under the registered trademark OPODRY, of Colorcon. The water soluble film forcing ingredient also "ue" to be a sugar. Can the coating optionally contain other ingredients such as titanium dioxide? another suitable pigment that does not contain htdroxyl groups. For compressed (macroscopic), this coating will typically comprise 2.5 to 20 mg of cetipzine and 4 to 50 mg of "polymer" form "dor" of films. In a preferred wet-granulation process for making tablets, first cores are formed from "tablets mixed with the pseudospredri a in the form of the hydrochloride salt with cellulose my crocrystalline (e.g., Avicel® PHL01) and a binder (e.g. Klucel® EXF, registered trademark of flqualon Company) in a V or? N P / K processor (Patterson-KeiLe). The resulting mixture is then granulated with water (about 9-13% by weight) to obtain a wet mass and dried to a final moisture content of less than 1% by weight, as determined by a moisture balance. The granules are then crushed and mixed with more icrocrystalline cellulose such as ñv? CelR PH 200. A lubricant can then be added, the whole mass mixed with a V mixer and then uncoated cores are formed with membrane by compression of the mixture. resulting in a press to manufacture tablets. The membrane coating solution can be formed by mixing ethylcellulose, or other suitable "membrane-forming material, plus a pore-forming component (eg, polyethylene glycol with a molecular weight greater than 3000" such as PEG 3350 sold by Union Carbi). "From Corporation under the trademark CARBOUAX) in a solvent mixture of acetone and water. The mixture is stirred until a solution is formed. Then, the tablet cores can be added to a coating container, the formalized membrane solution is sprayed and the coated cores can be dried on a dry tray tray. Next, an aqueous solution of the water-soluble film-forming agent (Opadry®) and cetirizine can be sprayed onto the dried membrane-coated cores to apply the cetirizine coating. At this time, the tablets are ready for therapeutic use. However, if desired, an outermost layer of an element can be added to mask the taste to the tablet or ultiparticulate. Such a layer can be added in an easy manner by simply coating an additional amount of film-forming polymer in a "one layer" form of full coverage over the layer containing cetirizine. If desired, opacifiers such as titanium dioxide may be added to the outermost coating.

Ultiparticulates can be manufactured for the description given above for tablets, wherein each niparticulate core is, essentially, a core of a minicomprimer matrix or a core surrounded by a membrane. A preferred method for manufacturing multiparticulate cores is the extrusion process. spheronization For this procedure, the pseudoephedrine is kneaded in the wet state with a binder, extruded through a perforated plate matrix and placed in a rotary die. The extrudate is ideally broken into pieces that are rounded to form spheres, spheroids or rounded rods in the rotating plate. An example "of this type of process and a composition involves the use" of water to wet-granulate a mixture comprising, as a matrix, from about 10 to 75% "of microcrystalline cellulose mixed with, equivalently, about 90 to 25% of pseudosphedrine in the form of the hydrochloride. Another preferred process for making matrix particles is the preparation of wax granules. In this process, a desired amount of pseudosphedrine is stirred with liquid wax to form a homogeneous mixture, cooled and then forced through a screen to form granules. Preferred matrix materials are waxy substances. Especially preferred are hydrogenated castor oil, carnauba wax and stearyl alcohol.

Another method referred to for making matrix particles includes the use of an organic solvent to assist in mixing the pseudoephedrine with the matrix material. This technique can be used if it is desired to use a matrix material with an inappropriate high melting point which, if the material were used in a molten state, could cause the decomposition of the drug or the matrix material, or it could produce a "Unacceptable melting viscosity, preventing mixing of the pseudoephedrine with the matrix material. The pseudoephedrine and the matrix material can be combined with a modest amount of solvent to form a paste and then forced through a screen to form granules from which the solvent is then removed. Alternatively, the pseudoephedrine and the matrix material may be combined with sufficient solvent to completely dissolve the matrix material and the resulting solution, which may contain solid drug particles, may be lyophilized to form the "dosage" form. particulate This technique is preferred when the matrix material is a high molecular weight synthetic polymer such as a cellulose ether or a cellulose ester. The solvents typically employed in the process include acetone, ethanol, isopropanol, ethyl acetate and mixtures of two or more of these. The dosage forms "according to the invention can be tested to measure the" release "rate of cefirizine and" of pseudoephedrine by the following procedure employing n USP Apparatus 2 as described in USP, Chapter < 711 > . The apparatus is arranged to operate at a paddle speed of 50 rpm, with one liter of water distilled at 37 ° C. The dosage form is added to the apparatus and the cetiriz is controlled by HPLC with UV detection to "determine the time at which the concentration of cetirizine reaches a stationary value. The typical times at which the concentration "of cetirizine is monitored with 15 minutes, 30 minutes, 45 minutes and 1 hour" after the addition, although different or additional times may also be used. The point at which the concentration of cetirizine "of immediate release reaches a steady value is the moment when a release of the order of 80% has been completed, typically it is less than one hour. The concentration of pseudoephedrine is similarly controlled at intervals of "two hours, starting at the time of the first two hours after adding the dosage form to Apparatus 2 USP, until the concentration has stabilized. The HPLC system used to control the aqueous medium USP can be the same reverse phase system for both the cet rizm and the pseudo-fedrin. The column is typically a C-18 CN column, "of the type available under the registered trademark ZORBAX of Mac-Mod. The mobile phase is maintained at 30 ° C and can be an isocratic combination of 1: 1 (V / V) water / methanol with the pH adjusted to 6.5 by the addition of sodium dihydrogen phosphate and sodium hydrogen, as appropriate, and leads to 5 mM in sodium salt of l-octanosulfomco acid. The detection can be carried out for both the cetiriz and the pseudoephedrine in a UV detector at 214 nm. Typical retention times are "3-4 minutes for pseudoephedrine and" 8-9 minutes for cetirizine, thus ensuring a reasonably good separation. The invention is further described and detailed in the following examples which should not be considered as limiting: EXAMPLE 1 This example illustrates that the use of common alcohol components can be problematic. A "pseudoephedrine" composition core of the composition was made by the following procedure. A wet granulation of ingredients 1-5 was prepared with a 50/50"solution of isopropyl alcohol and ethanol, ingredients 6-7. The addition of sufficient solvent and the mixture of the granulation resulted in a doughy paste which was subsequently crumbled and dried in an oven. Granulation -, it is dimensioned appropriately by crushing. An acceptably sized form of sodium chloride constituting 5.6% of said granulation was added. To this, 0.5% magnesium stearate was added to serve as an adjuvant to form tablets. The granulation was compressed to form cores of imides containing approximately 180 mg of pseudoephedrine using a conventional concave tool 13/32 on a conventional rotary tablet press.

COMPRESSED NUCLEI * OR «designates a volatile component, not present in the form of« two final fication. The membrane coating described in the table below was applied to the tablet cores in a perforated tablet coating container (Hi-Coater, HCT-30, Vector Corpo.). A batch of tablet cores of approximately B25 grams was coated by spraying the membrane solution at approximately 27 g / mm while maintaining an "exit" temperature of about 190C. After application of 30% (by weight) of the membrane and the coated cores were dried for approximately 12-16 hours at 50 ° C in dishes, in a pressurized air oven.

MEMBRANE COVERING 15 20 * Or «designate a volatile component, not present in the final dosage form. ' > G-, Subsequently, the dried membrane-coated cores were coated with the coat containing oet irizin HCL and which also included a "60 mg" dose of pseudoephedrine Lorhydrate shown in the following table. The drug layer was coated on about 900 grams of membrane-coated cores in a perforated tablet coating container (Hi-Ooater, HCT-3Q, Vector- Corp.). The drug solution was sprayed at approximately 9 g / inin while maintaining an exit temperature of 35-40 ° C. Sufficient "drug-like" layer was applied as the cores of tablets were coated with approximately 60 mg of "pseudoephedrine hydrochloride" and approximately 10 mg of cetirizine hydrochloride.

CETIRIZINE / PSEUDOEPHEDRINE COATING fifteen twenty * O designates a volatile component, not present in the form of ? K dosification f \ nal .. An additional layer was applied to these tablets to enrnascar-ar-the flavor by spraying «an aqueous solution of Opadry, transparent (YS-1-7006), at 5%, increasing the weight of the compressed or individual approximately 20 rng. The solution was sprayed at 5 g / rnin while "th" an outlet temperature of "O.

COATING TO MASK THE TASTE fifteen * O designates a volatile component, not present in the form "of «final dosage. These coated tablets were subjected to the following storage conditions as part of an accelerated stability study (note: "HR" means relative heat): 50 ° C / 20% RH, 40 ° C / 75% HR and 5 ° C. After "three weeks, ? r, «I determine the next degradation« of etirizine to the glycerol ester «of cetirizine (CEG).

EXAMPLE 2 This example demonstrates process and a preferred composition.

A "pseudoephedrine tablet" core of the composition "given below was prepared by the following procedure. First, 155 v 9 dl granulation was prepared by combining components 1, 2 and 3 (in the proportions shown) in a "double wrapped mixer" of 0.283 n3 equipped for wet granulation ("P-K Processor", Patterson -Kelly Corp., East Stroudeburg, PA, USA). The mixed components were granulated by the addition of water (component 4). After finishing the addition of water, the mixture was continued for 3 minutes and then the moist mass was dried in situ by applying vacuum at 60 ° C with agitation. When the "water content of the granulation had reached a level less than?% (Determined by a measurement of loss during drying), the dry granulation was passed through" a mill and divided into two equal parts for? post processing. Then a part of the dry granulation was combined with micro-crystalline cellulose (component 5) in the PK Processor, mixed "for 15 minutes, ground, mixed again for 15 minutes and then mixed with magnesium stearate (component 6) for 5 minutes to produce the final mixture, suitable for forming compressed tablets with a high speed press. The mixture was compressed into tablets using a concave round tablet with a nominal weight of 535 mg ca one day.

COMPRESSED NUCLEUS Weight Component (mg / tablet) 1. PseudoefeíJpna HCL. 240.00 2. Cellulose Mi croen st Li na, NF (Avicel PH 101) 67.48 3. Hydroxypropyl cellulose, NF (Klucel FXF) 10.82 4. Purified Water, USP * (31.80) . Microcpstal cellulose ina, NF (Avicel PH 200) 213.98 6. Magnesium stearate, NF 2.67 534.95 rng * Note: water is used in the processor-, but it is removed. Then, the tablet cores prepared above were coated with the solution shown below in a perforated vessel reefer ("HiCoater, HCT-60", Vector Corp.). A batch of 10 μl of cores was coated by spraying the coating solution at about 175 g / nm, maintaining the air outlet temperature at 35 ° C until the required coating weight was obtained. Subsequently, the cores were dried in an oven at 50 ° C for 16 hours.

MEMBRANE COATING SOLUTION Weight Component (mg / compprnido) Ethylcellulose Std. 100 Prom 59.84 Polyethylene glycol 3350 31.11 Purified Water (70.03) Acetone (748.53) 90. 94 ng The cores prepared above were further coated with cetipzma pulverizing with the solution shown below on the HiCoair using two spray guns at a rate of "application of the solution of 20 g / minutes per gun and at an exit temperature" of the air of 45 ° C. The application of the correct amount of drug to each tablet was verified by measuring the weight gain of a sample of 100 tablets and was confirmed by UV analysis. The cetipzin-coated tablets were further coated with the taste-masking coating by spraying them with a coating solution to mask the taste (also shown below) at an application rate of 60 g / mm using a spray gun and a spray temperature. Air output «of 45 ° C to produce the final product.

CETIRIZINE COATING SOLUTION Weight Component (mg / comppmido) Ce i i ina HCl 10.00 Opadry, Transparent (YS-5-19010) 10.30 Water P? R? ? ca "da (470.70) 29. 3 rng COATING TO MASK THE TASTE Component Weight (mg / comp) Opadry, White (YS-5-18011) 19.70 Purified Water (177.30) . 20 ng EXAMPLE 3 This example demonstrates a process and composition for making a tablet within the scope of the invention.

COMPRESSED NUCLEUS Component Weight (mg / oomppmido) Pseu «doefedpna HCL 240.00 Microcrystalline Cellulose, NF (Avicel PH 101) 67.48 Cellulose Mi cr ocp st aliña, NF: (Avicel PH 200) 213.98 Hydr-oxy? R-op? L-cellulose, NF (Klucel EXF) 10.82 Purified Water, USP * (31.80) Magnesium Stearate, NF 2.67 534. 95 rng MEMBRANE COATING SOLUTION The following membrane coating was used to coat tablet cores with an asymmetric membrane as defined and described in EP 0 357 369.

Component Weight (mg / cornppmido) Ethylcellulose Std. 100 Prem 59.84 Polyethylene glycol 3350 31.11 Purified water (70.03) Acetone (748.53) 90. 94 mg CETIRIZINE COATING Component Weight (rng / comppmido) Cetnzma HCl 10.00 Opadry, Transparent (YS-5-19010) 10.30 0 Purified Water (470.70) 29. 3 ng COATING TO MASK THE TASTE Component Weight (rng / conpressed) 0 Opadry, White (YS-5-18011) 19.70 Purified Water (181.80) ,20 rng > 5 Manufacturing process Pseudoephedrine HCl, rnicrocrist cellulose, and hydroxypropylcellulose were mixed in a P-K O processor of 0.0566 m3 for 15 minutes the mixture was triturated through a Fitz mill (using a d? mens? ona plate from 2AA and blades directed forward) and mixed for 15 minutes. The mixture was granulated in the wet state in the P-K process with 9% by weight of water. The granulation is dried in the P-K processor using a heating jacket temperature of 60 °, to a final water content of less than 1% for loss in drying. The dried granulation was triturated through a Fitz mill (using a 2 P sized plate and forward-facing blades) and mixed for 10 minutes in a "double-wrapped" 0.1415 3. Mixer. The microcrystalline cellulose was added and mixed. during 15 minutes. Magnesium stearate was added and mixed for 5 minutes. The granulation was compressed in a Kilian LX21 tablet press using a SRC 7/16"tool with a tablet hardness of 10 t-p The asymmetric membrane coating was applied to the tablets in a HCT-0 coating using a speedometer."spray rate of 140 g / min," was then dried for 16 hours in a Stokes hot-air dryer. The asymmetric membrane coated tablets were coated with cetinzine in a HCT-60 coating using a spray nozzle and a spray rate of 40 g / min. Then the final coating was applied to mask the taste using a spray rate of 40 g / min. The formulation did not form rnonoalcoholic esters of cetipzine since no monoalcohol reactive with cet ipzine was used in the formulation. No significant esters of cet i ri i na were formed with other excipients containing hydroxyl.

EXAMPLE 4 A pseudoephedrine tablet core was obtained from the composition given below by the following procedure. Approximately 56 kg of a wet granulation was prepared by first mixing ingredients 1-5 in a 0.1415 p > mixer. 3 for 20 minutes. Then it was triturated and mixed again for another 15 minutes. The mixture was transferred half in a Hobart mixer of 159.04 liters. The 50/50 solution of iopropyl alcohol and ethanol (approximately 7.7 kg) was added slowly over 15 minutes so that the mixture was thoroughly wetted and really appeared to be "saturated with moisture". The granulation was mixed for approximately 35 more minutes. The wet mass was dried on a tray in an air oven under pressure at 50 ° C for 12-16 hours. The dry granulation is triturated at a slow speed. The two pieces of crushed granulation were combined in a mixer - 0.1415 rn3 and mixed for 5 minutes. Pre-ground sodium chloride was added to the mixer to make up 5.6% of the mixture. It was mixed for 5 more minutes. To this, a 0.5% magnesium stearate was added and an additional 5 minutes mixed. The lubricated granulation was compressed into tablet cores that weighed approximately 600 rng using a conventional "7/16" concave back tool in a conventional rotary tablet pre-stretch.

COMPRESSED NUCLEUS * () designates a volatile component, not present in the final dosage form. The membrane coating described in the table below was applied to the tablet cores in a "perforated tablet coating container" (Hi-coater, HCT-30, Vector Corp.). tablets of approximately 1200 grams by spraying the membrane solution at approximately 30 g / rnin while maintaining an outlet temperature of approximately 24 ° C. Then 20% by weight of membrane was applied and the tablets were dried for a period of 16-24 hours at 50 ° C in trays in a pressurized air oven.

MEMBRANE COVERING THE fifteen * () «designates a volatile component, not present in the final dosage form. Subsequently, the tablets were coated with the coating "containing cetirizine HCl shown" in the ? < =; next table. The drug layer coated approximately 1100 grams "of membrane-coated tablets in a" perforated tablet coating "container (Hi- Coater, HCT-30, Vector Corp.). The drug solution was sprayed at about 5 g / min while maintaining an exit temperature of about 40 ° C. Sufficient drug was applied so that the compressed cores were coated with approximately 10 mg of cetirizine hydrochloride.

CETIRIZINE / PSEUDOEPHEDRINE COATING * () «Designates a volatile component, not present in the final dosage form. To these tablets an additional layer was applied to mask the taste by spraying a 5% aqueous solution of Opadry, transparent (YS-5-19010) increasing the weight of the individual tablet approximately 23 rng. The solution was sprayed at approximately 5"g / min while maintaining an exit temperature of approximately 40 ° C.

COATING TO MASK THE TASTE • * () designates a volatile component, not present in the form of «final dosage. These coated tablets were subjected to the following storage conditions as part of an accelerated stability study: 50 ° C, 40 ° C, 30 ° C and 5 ° C. The «ester degradation« of cetirizine PEG3350 was determined after of 12 weeks and 18 months as shown below in the table. tc¡ No of ctado

Claims (38)

NOVELTY OF THE INVENTION CLAIMS

1. A solid dosage form comprising cetipzma and pseudoephedrine in which at least a portion of icha pseudoefednna is contained in a core comprising said portion of pseudoephedrine, whereby the release of said pseudo-dopain in a medium of use is sustained; wherein said cetiriz is contained in "one-component" form of immediate release to said dosage form; and wherein said "dosage form" substantially lacks alcohols having a molecular weight less than 100 and reactive derivatives thereof.

2. A dosage form as defined in claim 1, wherein said cetmzine is in the form of a pharmaceutically acceptable salt.

3. A dosage form as defined in claim 2, wherein said salt is the dihydrochloride.

4. A dosage form as defined in claim 1 in the pse? Doephedrine said is in the form of a pharmaceutically acceptable salt.

5. A "dosage" form as defined in claim 4, wherein said salt is the sulfate or the hydrochloride.

6. A dosage form as defined in claim 1, wherein said "dosage form" essentially lacks alcohols having a molecular weight of less than 250 and "reactive derivatives" thereof.

7. A dosage form as defined in claim 6, wherein said dosage form lacks substantially alcohols having a molecular weight less than 500 and reactive derivatives thereof.

8. A dosage form as defined in claim 7, wherein said dosage form substantially lacks "alcohols having a molecular weight less than 1000 and reactive derivatives thereof.

9. A "dosage" form as defined in claim 1, wherein said pseudoephedrine is contained in said core.

10. A dosage form as defined in claim 1, wherein said core com- pounds "an immediate release composition containing pseudoephedrine surrounded by a limiting membrane" of the velocity.

11. A dosage form as defined in claim 1, wherein said core comprises a sustained release matrix containing pseudoephedrine.

12. A "dosage" form as defined in claim 11, wherein said matrix comprises a hydrophilic polymer.

13. A dosage form as defined in claim 1, in the form of a tablet.

14. A dosage form as defined in claim 1, in the form of a multiparticulate.

15- A "dosage" form as defined in claim 1, wherein said portion of pseudoephedrine is released to said means of use during a "period" of 4 to 36 hours.

16. A dosage form as defined in claim 15, wherein said period is "about 24 hours.

17. A "solid dosage" form comprising cetirizm and pse? Doephedrna, wherein at least a portion of said pse? Doefednna is contained in a nucleus surrounded by a permeable membrane, whereby the release of said part. «From pseidopefodrine to a means of use is sostem« da; wherein said cetipzin is contained as an immediate release component in "said" dosage form; and wherein said "dosage form" substantially lacks "alcohols having a molecular weight less than 100 and reactive derivatives thereof.

18. A dosage form as defined in the claim as defined in claim 17, wherein said cetipzma is in the form of a pharmaceutically acceptable salt.

19. A dosage form as defined in claim 18, wherein said salt is dichlor idrate.

20. A dosage form as defined in claim 17, wherein said pseudoephedrine is in the form of a pharmaceutically acceptable salt.

21. A dosage form as defined in claim 20, in the said salt is the sulfate or the hydrochloride.

22. A dosage form as defined in claim 17, wherein said form of ossification is substantially free of alcohols having a molecular weight of less than 250 and of reactive derivatives thereof.

23. A dosage form substantially lacks alcohols having a molecular weight less than 500 and reactive erivatives therein.

24. A "dosage" form as defined in claim 23, wherein said "dosage form" is essentially free from alcohols having a molecular weight of less than 1000 and "from" reactive derivatives thereof.

25. A dosage form as defined in claim 17, in the form of a tablet.

26. A dosage form as defined in claim 25, wherein said core comprises "from about 60 to about 360 ng of pseudoephedrine, from about 70 to about 425 mg of understandable excipients, from about 2 to about 17 mg of binder and "from approximately 0.5 to approximately 4 g of lubricant.

27. A dosage form as defined in claim 17, in the form of a multiparticulate.

28. A dosage form as defined in claim 17, wherein said permeable membrane is made from a cellulosic material.

29. A "dosage" form as defined in claim 17, wherein said portion of pseudoephedrine is released to said "use" medium for a period of from 4 to 36 hours.

30. A form of "dosage as defined" in claim 23, wherein said period is from about 8 to about 24 hours.

31. A process for manufacturing a solid dosage form comprising cetipzin and pse? Doefedpna, which comprises coating a sustained release core comprising pseudoephedrine, with an "immediate release" layer comprising cetmzine and a water soluble film forming polymer. , lacked substantially such a layer and said core of alcohols with a molecular weight of less than 100 and of reactive derivatives of the same reactants thereof.

32. A method as defined in claim 31, wherein said dosage form is a tablet.

33. A method as defined in claim 31, wherein said dosage form is a non-particulate form.

34. A process for manufacturing a solid dosage form containing cetipz and pse? Dophedrna, comprising the steps of coating a composition, with a suitable shape, comprising pseudoephedrine, with a permeable membrane, covering said membrane. permeable with an immediate release layer comprising "of cetipzin and a water-soluble film-forming polymer, substantially lacking said composition, said membrane and said layer" of alcohols with molecular weight less than 100 and derivatives reagents thereof.

35. A method as defined in claim 34, wherein said "dosage form" is a tablet.

36. A method as defined in claim 35, wherein said core comprises from about 60 to about 360 ng "of pseudoephedrine," from about 70 to about 425 mg "of understandable excipients, from about 2 to about 17 mg of binder and "from about 0.5 to about 4 mg of lubricant.

37. A method as defined in claim 34, wherein said "dosage form is an iced-up form.

38. A process as defined in claim 34, wherein said permeable membrane is made from a cellulosic material.