MXPA99011699A - Pharmaceutical composition for combination of piperidinoalkanol-decongestant - Google Patents

Abstract

The present invention provides a pharmaceutical composition in the form of a bilayer tablet comprising:(a) a first discrete zone made with Formulation (A) which comprises a therapeutically effective decongestant amount of a sympathomimetic drug, or a pharmaceutically acceptable salt thereof, in an amount of about 18%to about 39%by weight of Formulation (A), and a first carrier base material, the first carrier base material comprising a mixture of:(i) carnauba wax in an amount of about 59%to about 81%by weight of Formulation (A);and (ii) a suitable antiadherent in an amount of about 0.25%to about 2.00%by weight of Formulation (A);wherein said first carrier base material provides a sustained release of the sympathomimetic drug;and (b) a second discrete zone made with Formulation (B) which comprises a therapeutically effective antihistaminic amount of a piperidinoalkanol, or a pharmaceutically acceptable salt thereof, in an amount of about 15%to about 30%by weight of Formulation (B) and a second carrier base material, the second carrier base comprisisng a mixture of:(i) a cellulose diluent in an amount of about 27%to about 73%by weight of Formulation (B);(ii) pregelatinized starch in an amount of about 15%to about 30%by weight of Formulation (B);(iii) a suitable disintegrant in an amount of about 0.25%to about 6.00%by weight of Formulation (B);and (iv) a suitable lubricant in an amount of about 0.25%to about 2.00%by weight of Formulation (B);wherein said second carrier base material provides an immediate release of the piperidinoalkanol or the pharmaceutically acceptable salt thereof.

Description

PHARMACEUTICAL COMPOSITION FOR COMBINATION OF PIPERIDINOALCANOL-DECONGESCENTER BACKGROUND OF THE INVENTION It has been established that various piperidinoalkanol compounds are useful as antihistaminics, antiallergenic agents and bronchodilators as described in U.S. Patent Nos. 3,878,217, 4,254, 129 4,285,957. Several examples of formulations of these various piperidinoalkanol compounds are described below. J. Domet and D. Shah describe in the U.S. Patent. No. 4,929,605, a pharmaceutical composition in solid unit dosage form, comprising, a therapeutically effective amount of a piperidinoalkanol compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable nonionic or cationic surfactant in an amount from about 0.1% to about 6% by weight of the composition, and a pharmaceutically acceptable carbonate salt in an amount from about 2% to about 50% by weight of the composition. N. Webb and G. Hammer describe in U.S. Patent No. 4,996,061 a pharmaceutical composition in the form of a multiple compression tablet comprising a discrete zone made of a formulation which provides a sustained release of an effective therapeutically decongestant amount of a sympathomimetic drog and a discrete zone made of a different formulation which provides immediate release of a therapeutically effective antihistamine amount of a piperidinoalkanol and, optionally, a therapeutically effective decongestant amount of a sympathomimetic drug. H. Schock et al. Disclose in U.S. Patent No. 4,999,226 a multilayer tablet containing a layer of ibuprofen, an antihistamine layer of piperidinoalkanol, and a layer or layers containing conventional pharmaceutical excipients that are sandwiched between the layer of ibuprofen and piperidinoalkanol and serves to separate them physically. It was described by Schock et al, that attempts to formulate a two-layer tablet failed as a result of chemical degradation of piperidinoalkanol in the presence of ibuprofen, in addition, attempts to retard this degradation regime using antioxidants also failed. T. Ortyl et al. Disclose in International Application No. WO 96/26726, published September 6, 1996, a pharmaceutical composition in solid unit dosage form comprising a piperidinoalkanol compound and at least one inert ingredient. A number of products are currently available for the treatment of the symptoms associated with diseases such as the common cold, seasonal rhinitis, sinus headaches, sinusitis, etc., which contain multiple therapeutic agents. Many of these products contain an antihistamine in combination with a sympathomimetic decongestant. Such products in combination are convenient for the patient since they allow the patient to obtain relief from numerous symptoms without taking multiple medications.

An attempt was made to formulate a multiple compression tablet containing the sympathomimetic drug, pseudoephedrine hydrochloride and sustained release form with the piperidinoalkanol, 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] - 1 hydrochloride. hydroxybutyl] -a, to dimethylbenzeneacetic acid, in the form of immediate release using a formulation similar to that described by N. Webb and G. Hammer in the Patent of E. U., No. 4,996,061. However, this formulation failed as a result of an unexpected and unacceptable breakage and unacceptable physical force of the tablets in the final compression. In addition, an attempt was made to prepare a simple compression tablet where beds of sustained liberation of pseudoephedrine hydrochloride and an immediate release form of 4- [4- [4- (hydroxydiphenylmethyl) -1 piperidinyl] hydrochloride were combined. -1-Hydroxybutyl] -a, α-dimethylbenzeneacetic acid, in a single-layer tablet. However, this formulation also failed because some of the samples collected during the compression of tablets tested for uniformity of content did not meet the requirements of the United States Pharmacopeia (USP). An objective of the present invention is to provide a pharmaceutical composition in oral dosage form as a bilayer tablet which provides immediate release of a piperidinoalkanol compound and sustained release of a sympathomimetic drug exhibiting acceptable bioavailability of each compound. A further object of the invention is to provide a pharmaceutical composition in the form of a high integrity bilayer tablet consisting of an immediate release form of a piperidinoalkanol compound and a sustained release form of a sympathomimetic drug, such that the tablet resists rupture in behavior, have acceptable physical strength and provide uniformity of acceptable content that meets the requirements of the USP. A further objective of the present invention is to provide a bilayer tablet exhibiting a dissolution profile of piperidinoalkanol which is similar to that of 60 mg ALLEGRA® capsules. and a dissolving profile of the sympathomimetic drug that is slower than that of the SU DAFET® tablets of 120 mg. A novel pharmaceutical composition in the form of a bilayer tablet has now been found which provides efficient and immediate absorption, and bioavailability of a piperidinoalkanol, such as 4- [4- [4- (hydroxydiphenylmethyl) -hydrochloride) - 1-piperidinyl] -1-hydroxybutyl] -a, α-dimethylbenzeneacetic acid, and efficient sustained release and bioavailability of a sympathomimetic drug, such as pseudoephedrine hydrochloride after oral administration thereof. In addition, the novel bilayer tablet of the present invention exhibits uniformity of acceptable content under USP requirements, resists fracture in behavior and has acceptable physical strength. In addition, the novel bilayer tablet of the present invention provides a dissolution profile of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -, a-dimethylbenzeneacetic acid hydrochloride, which is similar to that for the 60 ml ALLEGRA® capsules. and a dissolution profile for pseudoephedrine hydrochloride which is slower than that of SU DAFET 1 HORAS® tablets of 120 mg.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a pharmaceutical composition in the form of a bilayer tablet comprising, (a) a first discrete zone made with Formulation (A) which comprises, an amount of decongestant therapeutically effective of a sympathomimetic drug, or a pharmaceutically acceptable salt thereof, in an amount of about 18% about 39% by weight of Formulation (A), and a first carrier base material, the first carrier base material comprising a mixture of; (i) carnauba wax in an amount of about 59% about 81% by weight of Formulation (A); and (ii) a suitable antiadherent in an amount of about 0.25% to about 2.00% by weight of Formulation (A); wherein said first carrier base material provides a sustained release of the sympathomimetic drug; and (b) a second discrete zone made with Formulation (B) 1 which comprises an antihistamine amount therapeutically effective of a piperidinoalkane or a pharmaceutically acceptable salt thereof, in an amount of about 15% to about 30% by weight of the Formulation (B) and its second carrier base material, the second carrier base comprising a mixture of; (i) a cellulose diluent in an amount of about 27% to about 73% by weight of the Formulation (B); (ii) pregelatinized starch in an amount from about 15% to about 30% by weight of the Formulation (B); (iii) a suitable disintegrant in an amount of about 0.25% to about 6.00% by weight of the Formulation (B); and (iv) a suitable lubricant in an amount of about 0.25% to about 2.00% by weight of the Formulation (B); wherein said second carrier base material provides an immediate release of the piperidinoalkanol or the pharmaceutically acceptable salt thereof. The present invention further provides a pharmaceutical composition in the form of a bilayer tablet comprising, (a) a first discrete zone made with Formulation (A) which comprises, a therapeutically effective decongestant amount of a sympathomimetic drug, or a salt of the same pharmaceutically acceptable, in an amount of about 18% to about 39% by weight of Formulation (A), and a first carrier base material, the first carrier base material comprising a mixture of; (i) Carnauba wax in an amount of about 59% to about 81% by weight of Formulaci (A); and (ii) a suitable antiadherent in an amount of about 0.25% to about 2.00% in pe of Formulation (A); wherein said first carrier base material provides for sustained release of the sympathomimetic drug; and (b) a second discrete zone made with Formulation (B) the cu comprises an amount of therapeutically effective antihistamine a piperidinoalkanol of the Formula; wherein X is a number ranging from about to about 5, and individual optical isomers thereof, in an amount of about 15% to about 30% by weight of Formulation (B) and a second carrier material, the second carrier base comprising a mixture of; (i) a cellulose diluent in an amount from about 27% to about 73% by weight of the Formulation (B); (ii) pregelatinized starch in an amount from about 15% to about 30% by weight of Formulation (B); (iii) a suitable disintegrant in an amount from about 0.25% to about 6.00% by weight of the Formulation (B); and (iv) a suitable lubricant in an amount from about 0.25% to about 2.00% by weight of the Formulation (B); wherein said second carrier base material provides an immediate release of the piperidinoalkanol or the pharmaceutically acceptable salt thereof. further, the present invention provides a pharmaceutical composition in the form of a bilayer tablet comprising, (a) a first discrete zone made with Formulation (A) which comprises, a therapeutically effective decongestant amount of a sympathomimetic drug, or a salt of the same pharmaceutically acceptable, in an amount from about 25% to about 33% by weight of Formulation (A), and a first carrier base material, the first carrier base material comprising a mixture of; (i) Carnauba wax in an amount of about 66 to about 74% by weight of Formulation (A); and (i) a suitable antiadherent in an amount from about 0.50% to about 1.50% weight of the Formulation (A); wherein said first carrier base material provides a sustained release of the sympathomimetic drug; and (b) a second discrete zone made with Formulation (B) which comprises a therapeutically effective antihistamine amount of a piperidinoalkanol of the Formula; wherein X is a number ranging from about to about 5, and individual optical isomers thereof, in an amount from about 15% to about 24% by weight of Formulation (B) and a second carrier base material, the second carrier base comprising a mixture of; (i) a cellulose diurent in an amount of about 43% to about 67% by weight of Formulation (B); (ii) pregelatinized starch in an amount from about 15% to about 24% by weight of Formulation (B); (iii) a suitable disintegrant in an amount from about 3.20% to about 4.80% by weight of the Formulation (B); and (iv) a suitable lubricant in an amount of about 0. 50% to about 1 .00% by weight of the Formulation (B); wherein said second carrier base material provides an immediate release of the piperidinoalkanol or the pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the terms "piperidinoalkanol compounds" and "piperidinoalkanol compounds and their pharmaceutically acceptable salts" refer to those compounds described by Formulas (I), (II), and (III) which are described in the Patents of E. U. , Nos. 3,878,217, 4,254, 129 and 4,285,957 descriptions of each patent being incorporated herein by reference. The piperidinoalkanol compounds of Formula (I) are those corresponding to the formula; where R. is hydrogen or hydroxy; R2 is hydrogen; or R. and R2 taken together form a second bond between the carbon atoms which support R1 and R2; n is a positive complete integer from 1 to 3; Z e thienyl, phenyl or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the unsubstituted phenyl ring ortho, meta or para positions and are selected from the group consisting of a halogen atom, a straight chain or branched alkyl lower from 1 to 4 carbon atoms, a lower alkoxy group of up to 4 carbon atoms, a dialkyl (lower) amino group, or a saturated monocyclic heterocyclic ring selected from the group consisting of pyrolidine, piperidino, morpholino, or N-alkyl (lower) piperizine, or pharmaceutically acceptable acid addition salt thereof. The piperidinoalkanol compounds of Formula (II) are those corresponding to the formula; Formula (II) wherein R-represents hydrogen or hydroxy; R2 represents hydrogen; or Ri and R2 taken together form a second bond between the carbon atoms bearing R. and R2; m is an integer from 1 to 5; R3 is -CH3, or -CH2OH; each A and B is hydrogen or hydroxy, with the provisos that at least one of A or B is hydrogen and one of A or B is different from hydrogen when R3 is -CH3; and pharmaceutically acceptable salts and individual optical isomers thereof. The piperidinoalkanol compounds of the Formula (I I I) are those corresponding to the formula; Formula (III) where R. represents hydrogen or hydroxy; R2 represents hydrogen; or Ri and R2 taken together form a second bond between the carbon atoms bearing R. and R2; m is an integer from 1 to 5; R4 is -CO2H, or -CO2alkyl wherein the alkyl portion has from 1 to 6 carbon atoms and is straight or branched; each of A and B is hydrogen or hydroxy; with the conditions that at least one of A or B is hydrogen; and pharmaceutically acceptable salts and individual optical isomers thereof. More specifically, 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzene acetic acid hydrochloride of the formula (Illa); Formula (Illa) wherein X is a number ranging from about zero to about 5, and the individual optical isomers thereof, is a preferred piperidinoalkanol compound. The compound of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, α-dimethylbenzeneacetic acid hydrochloride wherein X is zero or one in the formula (I 1 la) it is the most preferred piperidinoalkanol compound.

In addition, the free base of the 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a-, a-dimethylbenzeneacetic acid of the formula (11): Formula (lllb) wherein X is a number ranging from about zero to about 5, and the individual optical isomers thereof, is also a preferred piperidinoalkanol compound. Included within the scope of the present invention are the pseudomorphs and polymorphs of the hydrated and anhydrous free base of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzeneacetic acid which it can be prepared as described in International Publication No. WO 95/31437 published November 23, 1995. The free base of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] - a, a-dimethyl benzeneacetic is prepared rapidly using techniques and procedures well known to one of ordinary skill in the art. For example, the hydrochloride salt of 4- [4- [4- (hydroxydiphenylmethyl)] -l -piperidiniloj-l-hydroxybutyl-a-dimethylbenzeneacetic acid is dissolved in methanol and treated with one equivalent of aqueous sodium bicarbonate. After stirring for about 5 to 30 minutes, the white solid is collected by filtration, rinsed with water and air dried to give the free base dihydrate of 4- [4- [4- (h id roxid ifeni lmethyl) -1-piperidi ni lo] - 1-h idroxybutyl] -a, a-di methyl benzene acetic. Illustrative examples of straight or branched alkyl groups having from 1 to 4 carbon atoms alluded to herein are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Illustrative examples of straight or branched alkyl groups having from 1 to 6 carbon atoms alluded to herein are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl, n- hexyl and cyclohexyl. Illustrative examples of lower alkoxy groups of 1 to 4 carbon atoms alluded to herein are methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, sec-butoxy and t-butoxy. The terms "halo" and "halogen" or "halide" refer to a fluorine, chlorine, bromine or iodine atom. The term "pharmaceutically acceptable salt" refers to those salts of formulas (I), (II), (III) and (IIIa) that are not substantially toxic in the dosage administered to achieve the desired effect and do not independently possess pharmacological activity meaningful Salts included within the scope of this term are pharmaceutically acceptable acid addition salts of a suitable inorganic or organic acid. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric and phosphoric acids. Suitable organic acids include carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymalonic, dihydroxymalonic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic, sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid and β-hydroxyethane sulfonic acid. In addition, pharmaceutically acceptable salts include those salts of formulas (I), (II), (III) and (III) formed with inorganic and organic bases, such as those of alkali metals, eg, sodium, potassium and lithium, ferrous alkali metals, for example, calcium and magnesium, light metals of group I IA, for example aluminum, organic amines, for example primary, secondary or tertiary amines, such as cyclohexylamine, ethylamine, pyridine, methylaminoethanol and piperazine. The salts are prepared by conventional means known to one of ordinary skill in the art as, for example, treating a compound of the formulas (I), (II), (III) or (I l la) with an appropriate acid or base . Such salts can exist in either a substantially hydrated or anhydrous form. Preferred acid addition salts are those prepared from hydrochloric acid, sulfuric acid and tartaric acid. The term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes geometric isomers (cis / trans), and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers). The term "chiral center" refers to a carbon atom to which four different groups are attached. The term "enantiomer", "enantiomer" or "optical isomer" refers to a molecule that can not be superimposed on its mirror image and hence optically active where the optical isomer or enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction. The term "racemic mixture" or "racemic modification" refers to a mixture of equal parts of antimers that is optically inactive. As used herein, the prefixes "(+)" and "(-)" are used to designate the sign of rotation of the plane of light polarized by the compound, with (+) which means that the compound is dextrorotatory and (-) ) which means that the compound is levorotatory. The term "enantiomeric enrichment" refers to the increase in the amount of an antimer compared to its corresponding opposite enantiomer. A convenient method of expression of enantiomeric enrichment achieved is the concept of "enantiomeric excess" or "ee", which is expressed by the following equation; ee = E1 - E2 X 100 E1 - E2 in which E1 is the amount of the first enantiomer and E2 is the amount of the corresponding second enantiomer. For example, where the initial ratio of two enantiomers in a reaction is 50:50 (a racemic mixture) and the reaction produces enantiomeric enrichment with a final ratio of 90: 10, then the ee with respect to the first enantiomer is 80% .

Several sympathomimetic drugs, such as pseudoephedrine, phenylephrine and phenylpropanolamine, are recognized by those skilled in the art as affective therapeutic agents in the relief of nasal congestion and are commonly administered concomitantly with antihistamines for relief of nasal congestion associated with allergic rhinitis. These sympathomimetic drugs are generally effective when administered orally in unit dosage form in a four-times-a-day dosing schedule wherein the unit dosage form provides immediate release of the active medicament. For example, the recommended dosage for pseudoephedrine hydrochloride in adults is 60 mg. every 6 hours (q.i.d.). In addition, unit dosage forms containing sympathomimetic drugs can be formulated to provide sustained release of the active drug to allow the effective daily dose to be administered in a less frequent dosing schedule. For example, the recommended dosage for pseudoephedrine hydrochloride in a sustained release formulation may be 120 mg. 2 times a day (b.i.d.). As used herein, the term "sympathomimetic drug" refers to those sympathomimetic agents that are therapeutically effective in providing relief of nasal congestion in a patient suffering from this. These agents include, but are not limited to, pseudoephedrine, phenylephrine, and phenylpropanolamine. As is well recognized and appreciated by those skilled in the art, these sympathomimetic drugs can be used according to the present invention as free amines or as pharmaceutically acceptable salts thereof. A therapeutically effective decongestant amount of a sympathomimetic drug is that amount which produces the desired decongestant therapeutic response by oral administration and can be readily determined by one skilled in the art through the use of conventional techniques and observing the results obtained under analogous circumstances. To determine the therapeutically effective amount or dose of decongestant, a number of factors are considered by the attending physician, including, but not limited to: the mammalian species; its size, age and general health; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the selected dosage regimen; the use of concomitant medication; and other relevant circumstances. A therapeutically effective amount of decongestant of a sympathomimetic drug will vary from about 1 mg. to approximately 200 mg. The preferred amounts will vary from about 5 mg. up to about 150 mg. , about 120 mg being most preferred. administered twice per day. It is understood that a therapeutically effective decongestant amount of a sympathomimetic drug is present in Formulation (A). The carrier material of the Formulation (A) provides a sustained or prolonged release of the active medicament while the carrier material of the Formulation (B) provides an immediate release of the active medicament. As used herein the term "sustained release" refers to a property of the pharmaceutical composition wherein the absorption and bioavailability of the active drug is maintained in a time-release pattern such that therapeutically effective decongestant amounts of the sympathomimetic drug are maintained. They are bioavailable over an extended period of time. As used herein the term "immediate release" refers to a property of the pharmaceutical composition wherein the entire dose of active drug becomes bioavailable without substantial delay. A unit dose is that amount of the pharmaceutical composition which is administered individually to a patient. further, it is appreciated by one of ordinary skill in the art that the pharmaceutical compositions of the present invention are useful as antihistamines, anti-allergenic agents, bronchodilators, and in the treatment of urticaria. As used herein, the term "patient" refers to a warm-blooded animal, such as a mammal, that needs an antihistamine, an anti-allergenic agent, a bronchodilator or requires treatment against urticaria. It is understood that humans, mice, rats and dogs are included within the term "patient". As used herein, the term "cellulose diluent" includes microcrystalline cellulose, Avicel PH 101, Avicel PH 102, Avicel PH301, Avicel PH302, Avicel PH200, Avicel PH 12, Avicel PH 13, Avicel PH 103, Avicel PH 105 and similar ones. The preferred cellulose diluent is microcrystalline cellulose, Avicel PH 101 01 and Avicel PH 1 02, and the most preferred cellulose diluent is a combination of Avicel PH 1 01 and Avicel PH102. It is especially preferred that the mixture of Avicel PH 101 and Avicel PH 102 comprises approximately 12% Avicel PH 101 and approximately 88% Avicel PH102. As used herein, the term "suitable anti-adherent" includes stearic acid, cetyl alcohol, stearyl alcohol, paraffin, white wax, glycerin, lanolin, talc, mineral oil and the like. The preferred suitable non-stick is stearic acid. As used herein, the term "suitable disintegrant" includes sodium croscarmellose, crospovidone, alginic acid, sodium alginate, DVB methacrylic acid, interlaced PVP, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, starch pregelatinized and the like. The preferred suitable disintegrant is croscarmellose sodium. As used herein, the term "suitable glidant" includes silicon dioxide, talc and the like. The preferred suitable glidant is silicon dioxide. The term "micronization" refers to the process of increasing the particle surface area of the piperidinoalkanol compounds or their pharmaceutically acceptable salts to more than about 1.0 m2 / g. The micronization of the piperidinoalkanol compounds of the formulas (I) to (11) is carried out rapidly by someone of ordinary skill in the art, for example, as described by T.

Ortyl et al. In WO 96/26726 published September 6, 199β. The piperidinoalkanol compounds of formulas (I) to (11) when micronized have a particle surface area of greater than about 1.0 m2 / g. The preferred particle surface area when micronized is about 2 to 10 m2 / g, the most preferred particle surface area when micronized is about 2.0 to 5 m2 / g and the most preferred particle surface area especially of the piperidinoalkanol compounds of formulas (I) to (ll lb) when micronized is approximately 2.2 m2 / g. The piperidinoalkanol compounds of formulas (I) to (11) which are not subjected to micronization have a particle surface area of less than about 1.0 m2 / g. A quantity of therapeutically effective antihistaminic of a piperidinoalkanol compound of the formulas (I) to (IIIb) is that amount which produces the desired therapeutic response (ie, antihistaminic, anti-allergenic, bronchodilator effect, or reduction or elimination of urticaria) by oral administration according to a single or multiple dosage regimen. An amount of therapeutically effective antihistamine of a piperidinoalkanol compound of the formulas (I) to (1) may vary in a wide range from about 0.1 mg. up to about 240 mg. The amount of therapeutically preferred antihistamine of a piperidinoalkanol compound of the formulas (I) to (11b) will vary from about 20 mg. to approximately 70 mg. the most preferred being about 60 mg. administered twice a day. The amount of therapeutically effective antihistamine can be determined quickly by the attending physician, as one skilled in the art, by the use of known techniques and by observing the results obtained under analogous circumstances as described above for sympathomimetic drugs. It is understood that a therapeutically effective antihistamine amount of a piperidinoalkanol compound of formulas (I) to (ll lb) is present in Formulation (B) of the pharmaceutical composition of the present invention. This Formulation (B) provides immediate release of the active drug. In a preferred embodiment of the present invention with respect to the piperidinoalkanol in Formulation (B), about 60 mg is preferred. of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinium] -1-hydroxybutyl] -a, α-dimethylbenzeneacetic acid hydrochloride. In a preferred embodiment of the present invention with respect to the sympathomimetic drug in Formulation (A), about 120 mg is preferred. of pseudoephedrine hydrochloride. As used herein a layer tablet is a tablet that is made of two or more distinct layers or discrete granulation zones compressed together with individual layers that overlap one another. Layered tablets have the appearance of a sandwich because the edges of each layer or area are exposed. Such conventional layer tablets are generally prepared by compressing a granulation over a previously compressed granulation. The operation can be repeated to produce multilayer tablets of more than two layers. In a preferred embodiment of the present invention, the tablet consists of two layers wherein one layer is made from Formulation (A) and the other layer is made from Formulation (B) resulting in a bilayer tablet. Formulation (A) and Formulation (B) of the pharmaceutical compositions of the present invention may optionally contain one or more other pharmaceutically acceptable excipients. These excipients are therapeutically inert ingredients such as are well known and appreciated in the art. As used herein the term "inert ingredient" refers to those therapeutically inert ingredients that are well known in the art of pharmaceutical science which can be used alone or in various combinations, and include, for example, binders, diluents, lubricants, glidants, sweetening agents, disintegrants, coloring agents, flavoring agents, anti-oxidants, solubilizing agents, coating agents and the like, as described in The United States Pharmacopeia, XXI I, 1990, (1989 The United States Pharmacopeial Convention, Inc.), pages 1857-1859, which is incorporated herein by reference. For example, the following inert ingredients can be used alone or in various combinations; binders such as gelatin, polyvinyl pyrrolidone (PVP), pregelatinized starch, povidone; diluents such as calcium carbonate, lactose, starch, microcrystalline cellulose, and the like; lubricants such as magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, hydrogenated vegetable oil and the like; glidants such as silicon dioxide, talc and the like; disintegrants such as alginic acid, DVB methacrylic acid, interlaced PVP, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, starch sodium glycolate, starch, pregelatinized starch and the like; sweetening agents; coloring agents; flavoring agents; antioxidants; and the similar ones. Preferred compositions of the present invention are those in which a cellulose diluent, pregelatinized starch, croscarmellose sodium, and magnesium stearate are present with 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] hydrochloride] - 1-hydroxybutyl] -a, α-dimethylbenzeneacetic acid in the immediate release layer of Formulation (B), and where carnauba wax, stearic acid and colloidal silicon dioxide with pseudoephedrine hydrochloride are present in the sustained release layer of Formulation (A). Preferred amounts of 4- [4- [4- (hydroxyethyl ifenyl) ethyl] - 1 -piperidyl ni] - 1 -hydroxybutyl] -, a-dimethyl benzene acetic acid, cellulose diluent , pregelatinized starch, sodium croscarmellose and magnesium stearate in Formulation (B) are combined in amounts from about 15% to about 30%, from about 27% to about 73%, from about 15% to about 30%, of about 0.25% to about 6.00% and from about 0.25% to about 2.00%, respectively, by weight of the composition, more preferably from about 16% to about 24%, from about 43% to about 67, from about 15% to about 24%, from about 3.20% to about 4.80% and from about 0.50% to about 1.00%, respectively, by weight of the composition, and most preferably being especially approximate a. 17.09%, approximately 61.67%, approximately 17.09%, approximately 3.42% and approximately 0.75%, respectively. The preferred amounts of pseudoephedrine hydrochloride, carnauba wax, stearic acid flakes and colloidal silicon dioxide in Formulation (A) are combined in amounts from about 18% to about 39%, from about 59% to about 81%, of about 0.25% to about 2.00% and from about 0.00% to about 3.00%, respectively, by weight of the composition, more preferably from about 25% to about 33%, from about 66% to about 74%, of about 0.50 % to about 1.50%, and from about 0.00% to about 0.75%, respectively, by weight of the composition, and most especially being about 28.17%, about 70.42%, about 1.15% and about 0.25%, respectively. The piperidinoalkanol compounds of Formulas (I) to (IIIb) are readily prepared by one of ordinary skill in the art, for example, using the techniques and procedures described in US Patent Nos. 3,878,217, 4,254, 129 and 4,285,957, which are incorporated herein by reference, and International Application Number PCT / US93 / 02103 published October 28, 1993, WO 93/21 156, International Application Number PCT / US94 / 05982, published January 5, 1995, WO 95/00480 and International Application Number WO 95/31437, published November 23, 1995. The components of the pharmaceutical composition according to the present invention are combined in a bilayer tablet for oral administration in accordance with normal practice and procedures well known to one of ordinary skill in the art using conventional formulation and manufacturing techniques such as those described in the following examples. The following examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. Reagents and starting materials are available to one of ordinary skill in the art. As used in this, the following terms have the indicated meanings: "rsd" refers to percent of relative standard deviation; "kg" refers to kilograms; "g" refers to grams; "mg" refers to milligrams; "μg" refers to micrograms; "m2 / g" refers to square meters per gram and is used as a measurement of particle surface area; "mmol" refers to millimoles; "L" refers to liters; "mL" refers to milliliters; "μL" refers to microliters; "cm" refers to centimeters; "M" refers to molar; "mM" refers to millimolar; "μM" refers to micromolar; "nM" refers to nanomolar; "eq" refers to equivalents; "N" refers to normal; "ppm" refers to parts per million; "° C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "kPa" refers to kilopascals; "kg / cm2" refers to kilograms per square centimeter; "bp" refers to boiling point; "mp" refers to melting point; "dec" refers to decomposition; "HPLC" refers to high performance liquid chromatography; "RPM" refers to revolutions per minute; "hr" refers to hours; "min" refers to minutes; "Kp" refers to a thousand kilograms and "sec" refers to seconds.

EXAMPLE 1 Table 1. Composition of the Bicapa Tablet Component Weight Mg / tablet Immediate Release Layer Piperidinpalcanol 60.0 Microcrystalline Cellulose (Avicel PH 101) 26.00 Pregelatinized Starch 60.00 Microcrystalline Cellulose (Avicel PH 102) 190.5 Croscarmellose Sodium 12.00 Magnesium Stearate 2,633 Water, purified2 (60.00) Total Weight of Layer 351 .1 Cloak of Sustained Release Sympathomimetic Drug; 120.0 Carnauba Wax 300.0 Stearic Acid Scales 4.899 Colloidal Silicon Dioxide 1 .065 Total Weight of the Layer 426.0 Total Weight of the Tablet Core 777.1 Aqueous Coating Suspension OPADRY® YS-1 -7006 23.31 Water, purified2 (170.9) Weight Total Coated Tablet 800.4 4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, α-dimethylbepceneacetic acid hydrochloride. Removed during the process. The amount of water may vary during processing if necessary to achieve the desired granulation characteristics. Pseudoephedrine Hydrochloride.

Pilot Scale Process Used to Manufacture Bicapa Tablets The manufacture of the bilayer tablets at pilot scale is summarized as follows. The pseudoephedrine HCl granulate is manufactured by adding pseudoephedrine HCl to a molten mixture of carnauba wax and stearic acid with mixing. The liquid wax mixture is then poured into trays in sheets and allowed to solidify as the wax cools. The solidified wax is then ground and mixed with the colloidal silicon dioxide in an in-bin mixer. The granulation of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α-dimethylbenzeneacetic acid hydrochloride is manufactured using a high intensity granulator. The granulate is dried in a fluid bed dryer and milled. The components of the final mix are added and mixed in an in-bin mixer. The bilayer tablets are compressed in a bilayer tablet press with the compressed pseudoephedrine HCl granulate as the first layer and the final mixture of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- hydrochloride. hydroxybutyl] -a, a-dimethyl benzeneacetic compressed as the second layer or top layer. The compressed tablets are then film coated with a clear coating on an Accela-Cota. The total process time required to manufacture film coated tablets is approximately 33 hours for a pilot scale lot of 130,000 tablets.

Granulation of Pseudoephedrine HCl The amounts of components used to make the pseudoephedrine HCl granulate (batch size of 80 kg) are listed in Table 2. Carnauba wax melts while mixing continuously at approximately 85-90 ° C in a stainless steel tank with a 378.5 liter Hamilton hot water jacket. The water temperature of the jacket is set at approximately 100 ° C. After all the carnauba wax is melted, stearic acid flakes are added and allowed to melt. The pseudoephedrine HCl is sieved through a 30 mesh screen using a Stokes Oscillating Granulator. The screened pseudoephedrine HCl is added slowly to the molten wax while continuously stirring with a Lightnin propellant type mixer. The temperature of the melt is maintained at about 90 ° C during the addition of HCl of pseudoephedrine. Once all the pseudoephedrine HCl is added to the molten wax, the temperature is raised to 92 ° C and mixed continuously for 10 minutes. The approximate process time for manufacturing the suspension of pseudoephedrine / liquid wax HCl is 5 hours. The suspension of pseudoephedrine HCl / liquid wax is then dispensed in stainless steel trays to a thickness of approximately 6.35 mm and maintained at room temperature until they solidify and cool to the touch, approximately 2 hours. The HCl matrix of pseudoephedrine wax is stored in fiber drums with polyethylene coating at room temperature for a minimum of 12 hours before milling to ensure that the wax matrix is adequately cooled. The solidified wax is milled with the blades forward, at 2,500 rpm, through a Fitzmill equipped with a sieve with perforated holes # 0065. The ground granulated HCl of ground pseudoephedrine is added to an In-Bin Blending Tote of 200 liters. The required amount of colloidal silicon dioxide is screened through a 20 mesh manual screen and added to the 200 liter Tote. The components of the tote bin are mixed for 70 revolutions (counts) at 18 rpm using an In-Bin Blender CMS. The final mixture is stored in fiber drums with polyethylene coating until it is needed for compression. The approximate time of the process for the steps of grinding and mixing is one hour.

Granulation of Acid Hydrochloride 4-f4-β4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutylol-aa-dimethylbenzeneacetic acid v Final Blend Table 3 lists the ingredients and amounts used in the manufacture of the hydrochloride acid granulate. [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, -dimethylbenzene acetic acid and the final mixture. The granulation of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzene acetic acid hydrochloride is prepared using a 300 liter Fielder PMA high cut granulator / mixer. The hydrochloride of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzene acetic acid, croscarmellose sodium, pregelatinized starch and microcrystalline cellulose (Avicel PH 101) are added to the Fielder bowl and dry mix for 5 minutes with the propeller set at 1 10 RPM without grinding. The purified water is then added to the dry mix at a rate of 5.7 kg / min with the speed of the propeller set at 1 10 RPM the chopper (for milling) at 3,600 RPM. The granulate is mixed for 30 seconds after the addition of water has been completed. The granulate is divided into approximately equal halves and dry as two sub-batches in a Glatt Fluid Bed Dryer GPCG 30. The inlet air temperature is maintained at 80 ° C and the dew point is set at 9 ° C. of process air is set at 1.050 m3 / h initially and gradually reduced over the drying time to 55 m3 / hr. The granulate is dried to a moisture content of 2-3 as determined by a Computrac package at 125 ° C. The end product temperature is about 65 ° C and the drying time is about 160 minutes of total drying time. The final moisture content of the dry granulate is approximately 2.5%. Each sub-lot of hydrochloride granules of 4- [4- [4 (ethyl idroxydiphenyl ethyl) -1-piperid i nor 1] -hydroxybutyl] a] -dimethylbenzene acetic acid is ground separately through a screen with perforated hole 1532-0050 using a Fitzmill package set at medium speed with the blades in the forward position. Both sub-lots of granules are mixed together for 3 minutes in a Patterson Kell V-Blender of 0.142 cubic meters. The ground mixes are stored in fiber drums with polyethylene coating until they are needed for final mixing. The approximate process time through the grinding and mixing step for the hydrochloride granulate of 4- [4- [4- (h id roxid phenyl methyl) -1-piperidinyl] -1-hydroxybutyl] -a, α-dimethylbenzeneacetic acid is 8 hours. The formulation for the final mixture of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -, a-dimethylbenzene acetic acid hydrochloride is listed in Table 3. The final mixture of the Hydrochloride of 4- [4- [4- (4-hydroxyl if eni I methyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetic acid is manufactured using a 200 liter In-Bin Blending Tote. The microcrystalline cellulose (Avicel PH102), croscarmellose sodium (Ac-Di-Sol) and the granulate of the hydrochloride of the acid 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a - Acetic dimethylbenzene ground from before are loaded in the Bin Tote. The components are mixed for 140 revolutions (counted) at 18 rpm. The magnesium stearate is screened through a 30 mesh manual screen and added to the 200 liter Bin and mixed for 70 counts at 18 rpm. The final mixture is stored in fiber drums coated with polyethylene until it is needed for compression. The approximate time of process for the final mixing process is 0.5 hours.

Bilayer Tablet Compression The bilayer tablet batch is manufactured using a 35 Station Manesty BB4 Bi-Layer Rotary Tablet Press. The tablets are compressed using a standard concave tool in the form of a 0.7937 cm x 1,905 cm capsule. The batch size of tablets is 180, 000 tablets manufactured from the final mixture of 76.7 kg of phenylenedipine HCl granulate and 63.2 kg of 4- [4- [4- (hydroxydiphenylmethyl) -l-piperidinyl] -1-hydroxybutyl] -hydrochloride] -a, -dimethylbenzene acetic acid. The average press speed is approximately 640 tablets per minute. The total compression time is approximately 5 hours. The pseudoephedrine HCl granulate is compressed in the first layer at a target weight of 426 mg per tablet. The average hardness of the target tablet (Key Hardness Tester, tablet tested across the width) for the pseudoephedrine HCl layer is approximately 8 kp. The second layer consisting of the final mixture of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a-, a-dimethylbenzeneacetic acid hydrochloride is added to the first layer for a weight Total tablet target of 777.1 mg (which is equivalent to 351.1 mg / tablet of the final mixture of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a- hydrochloride -dimethylbenzeneacetic). The bilayer tablet is compressed to a target hardness of approximately 20 kp (Key Hardness Tester, tablet tested across the length).

Coating The compressed bilayer tablets are coated in a 121.92 cm Accela-Cota (101.0 kg of uncoated tablets, approximately 130,000 tablets) using a two-gun spray system at a speed of 10.5 rpm. The tablets are coated using a clear coating solution ai 12% w / w OPADRY® YS-1-7006 which contains hydroxypropyl cellulose and polyethylene glycol. The coating suspension is filtered through a 60 mesh filter before use. The tablets are coated with 25.25 kg of coating solution. The tablets are coated at an outlet air temperature of about 41 ° C with a range of 39.6-41.9 ° C. The inlet air temperature generally fluctuates from 55 to 62 ° C and a rate of air flow is used. 48.23-51 .07 cubic minute supply. The flow rate of the coating solution is started at approximately 230 g / min. and is periodically increased to achieve a final spray rate of approximately 390 g / min. S uses an atomizing air pressure of 3.51 kg / m2 during spraying of the coating solution. The total coating process time is approximately 1.5 hours.

Table 2. Pilot Scale Formulation of HCl granules of pseudoephedrine.

Table 3. Pilot Scale Formulation of the Final Blend of Piperidinoalkanol1. 1 Hydrochloride of 4- [4- [4- (idroxydiphenylmethyl) -1-piperidinyl] -1 hydroxylbutyl] -a, a-dimethylbenzeneacetic acid). 2 The water is removed during the process and does not appear in the final product. The amount of water can be varied to achieve adequate granulation.

Commercial Scale Process Used to Manufacture Bicapa Tablets The manufacture of the bilayer tablets on a commercial scale is summarized as follows. The granulation of HCl of pseudoephedrine is made by adding pseudoephedrine HCl to fused carnauba wax with mixing. The liquid wax mixture is pumped through a droplet-forming stainless steel tube (Rotoform® unit) onto a rotating chilled stainless steel band. The solidified droplets of wax (pellets are discharged from the end of the rotating band.) The pellets are then ground and mixed with the colloidal silicon dioxide in an in-bin mixer. The granulation of 4- [4- [4- (hydroxydiphenylmethyl ) - 1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzeneacetic acid is manufactured using a high intensity granulator.The granulate is dried in a fluid bed dryer and milled.The components of the final mixture are added and mixed in an in-bin blender The bilayer tablets are compressed in a two-layer tablet press with the compressed pseudoephedrine HCl granulate as the first layer and the final mixture of 4- [4- [4- (hydroxydiphenylmethyl) hydrochloride - 1-piperidinyl] -1- hydroxybutyl] -a, a-dimethylbenzeneacetic tablet as the second layer or top layer The compressed tablets are then film coated with a clear coating on an Accela-Cota. Total required for manufacturing film-coated tablets is approximately 50 hours for a commercial scale lot of 1, 374,000 tablets.

Granulation of Pseudoephedrine HCl The amounts of components used to make the pseudoephedrine HCl granulate (batch size of 600 kg) are listed in Table 4. Carnauba wax melts while mixing continuously at approximately 85-90 ° C in a stainless steel tank with 1, 135.5 liter shirt. The water temperature of the jacket is set at approximately 120 ° C. After all the carnauba wax is melted, stearic acid flakes are added and allowed to melt. The pseudoephedrine HCl is sieved through a 30 mesh screen using a Stokes Oscillating Granulator (Model 43-6). The screened pseudoephedrine HCl is slowly added to the molten wax while continuously mixing with a propellant type mixer (Sew-Eurodrive mixer). The temperature of the melt is maintained at about 92 ° C during the addition of HCl of pseudoephedrine. Once all the HCl of screened pseudoephedrine is added to the melted wax, the temperature is raised to 95 ° C and mixed continuously for a minimum of 20 minutes and mixing is continued until the solidification step of the wax is completed and the temperature is maintained at 95 ° C during the solidification step. The approximate process time for manufacturing the pseudoephedrine / liquid wax HCl suspension is 6 hours. The suspension of pseudoephedrine / liquid wax HCl is pumped using a positive displacement pump with hot water jacket (Wauakasha Model 6) through stainless steel lines with hot water jacket (1 10 ° C) of 0.9525 cm ( internal diameter) to a stainless steel tube that forms droplets (Sandvik Rotoform® 3,000, Model LV). A 20 mesh screen is placed in line with the liquid wax suspension feed to protect the Rotoform®. The Rotoform® has a 2.0 mm hull caliber, 8.0 mm helmet spacing, triangular deviated hull geometry and a 6.0 mm bar slot width. The Rotoform® is heated with hot water of 1 10 ° C through the fixed cylindrical stator body which has a depression of 2.54 cm so that the liquid wax flows through your entire body. The rotating Rotoform® unit is placed on the Sanvik rotating stainless steel cooled strip such that droplets of liquid wax fall on the moving belt. The Sanvik stainless steel chilled band is used for the wax cooling process (solidification). The band is cooled with water sprayed from the bottom side of the band. The chilled stainless steel band is 81.28 cm wide and has a cooling zone of 7.32 m in length. The front pulley in the belt is heated to 65 ° C. The Rotoform® unit is placed approximately 2 mm above the moving belt. A Rotoform® speed and band speed of 21.35 meters / minute are used together with a cooling water temperature of 15 ° C. The pseudoephedrine / liquid wax HCl suspension is pumped at a rate of approximately 5 kg / min. about the band The solidified wax droplets (pellets) of approximately 5 mm in diameter are discharged at the end of the rotating belt at a temperature of about 20 ° C. The solidified wax pellets are milled with the blades forward at 3,000 rpm. through a Fitzpatric DAS06 mill equipped with a perforated holes screen 0065. The approximate process time for the wax solidification and milling step is 3 hours. The granulate of HCl of pseudoephedrine is loaded in an In-Bin Blending Tote (Gallay) of 1800 liters. The colloidal silicon dioxide is sieved through a 20 mesh manual screen and added to the 1800 liter Tote. The contents of the bin are mixed for 140 revolutions (counts) at 14 rpm using a CMS In-Bin Blender. The final mix is stored in the bin tote until it is needed for tablet compression. The approximate process time for the mixing step of pseudoephedrine HCl granulate is one hour.

Granulation of Acid Hydrochloride 4-r4-r4- (hydroxydiphenylmethyl) -1-piperidin-1-lol-1-hydroxybutylol-a, -dimethylbenzeneacetic acid and Final Blend Table 5 lists the ingredients and amounts used in the manufacture of the hydrochloride granulate of 4- [4- [4- (hydroxydifen i Im ethyl) -1-pyridinyl] -1-hydroxybutyl] a, a-dimethylbenzene acetic acid and the final mixture. The granulation of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, -dimethylbenzene acetic acid hydrochloride is prepared using a Fielder PMA 800 high cut granulator / mixer liters. 4- [4- [4- (Hydroxy-phenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a-, a-dimethylbenzene acetic acid hydrochloride, sodium croscarmellose, pregelatinized starch and microcrystalline cellulose (Avicel PH 101) are added to the Fielder's bowl and mixed dry for 5 minutes with the propeller set at 1 16 RPM without grinding. The purified water is then added to the dry mix at a rate of 15 kg / min with the speed of the propeller set at 1 16 RPM the chopper (for milling) at 1, 800 RPM. After the water is added, the granulate is mixed for a total of 6 minutes from the beginning of the addition of water. The chopper speed is increased to 2,800 RPM with the impeller fixed at 1 16 RPM and the granulate mixes an additional 60 seconds and is then discharged from the granulator to the fluid bed dryer product bowl. The granulate is dried in a Glatt Fluid Bed Dryer GPCG 300. The inlet air temperature is maintained at 80 ° C and the dew point is set at 9 ° C. The process air flow is set at 3,800 m3 / h initially and is gradually reduced over the drying time to 290 m3 / hr. The granulate is dried to a moisture content of 2-4 as determined by a Computrac package at 1 15 ° C. The end product temperature is about 66 ° C and the drying time is about 100 minutes of total drying time. The final moisture content of the dry granulate is approximately 3.0%. The dry granule of the hydrochloride of 4- [4- [4 (hydroxyl ifenylmethyl) -1-piperidyl or 1-hydroxybutyl] o] -a, a-dimethylbenzene acetic acid is milled through a screen with perforated holes 1532 0050 using a Fitzmill package set at half speed with the blades in the forward position. The granulate is milled in an In Bin Blending Tote (Gallay) of 1800 liters. The approximate processing time through the grinding step for the hydrochloride granulate of 4- [4- [4- (hydroxydiphenylmethyl) -1-pipepdynyl] -1 hydroxybutyl] -a, a-dimethylbenzeneacetic acid is 5 hours . The formulation for the final mixture of 4- [4 [4- (hydroxydifenylmethyl) -1-pyridinyl] -1-hydroxybutyl] a] -dimethylbenzene acetic acid hydrochloride is listed in Table 4 The microcrystalline cellulose (Avicel PH102) and croscarmeUose sodium (Ac-Di-Sol) are loaded into the bin containing the hydrochloride of the acid 4- [4- [4 (hydroxydiphenylmethyl) -1-piperidinyl] -1 -hydroxybutyl] -a, acetic acid-dimethylbenzene. The contents are mixed for 140 revolutions (counted) at 14 rpm using an In-Bin Blender CMS. Magnesium stearate is screened through a 30 mesh manual screen and added to 1800 liter Tote Bin and the contents mixed for 70 counts at 1 rpm using an In-Bin Blender CMS. The final mixture is stored in e Tote Bin until it is needed for tablet compression. The approximate process time of the final mixture of the hydrochloride of 4- [4 [4- (hydroxydifen I-methylo) -1-pipe-ridin i l-1-hydroxybutyl] a, a-dimethylbenzene acetic acid is 1 hour.

Bilayer Tablet Compression The bilayer tablet batch is manufactured using a 51 Station Hat Bi-Layer Rotary Tablet Press, Model HT-HX51 LD-U. The tablets are compressed using standard concave tool in the form of a capsule of 0.7937 cm x 1 .905 cm. The batch size of tablets is 1, 374.00 tablets manufactured from 585.3 kg of HCl d-pseudoephedrine granulate and 482.4 kg of final mixture of hydrochloride of 4- [4 [4- (h id roxid if enyl methyl lo) - 1 -pipe ridin i lo] -1 -hidroxibuti lo] -a, α-dimethylbenzene acetic acid. The average press speed is approximately 1200 tablets per minute. The total compression time is approximately 19 hours. Both the pseudoephedrine HCl granulate and the final mixture of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, -d-methylbenzeneacetic acid hydrochloride are fed to the press from Tote Bins used for mixing using a Gallay cube drop station. The pseudoephedrine HCl granulate is compressed in the first layer at a target weight of 426 mg per tablet. The powder feeder for the granulation of pseudoephedrine HCl is operated at 75%. The target thickness for the pseudoephedrine HCl layer is 0.41 1 cm with an average tablet hardness (Key Hardness Tester, tablet tested across the width) of 8 kp. The second layer consisting of the final mixture of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a-, -dimethylbenzene-acetic acid hydrochloride is added to the first layer for a total tablet weight of 777.1 mg (which is equivalent to 351.1 mg / tablet of the final mixture of 4- [4- [4- (h id roxid ifeni I meti lo) - 1 -pipe ridin it] - 1-hydroxybutyl] -, a-dimethylbenzeneacetic). The powder feeder for the mixture of 4- [4- [4- (hydroxydiphenylmethyl) -1-pipepdynyl] -1-hydroxybutyl] -a-, a-dimethylbenzene-acetic acid hydrochloride is 100% operated. The bilayer tablet is compressed to an objective thickness of 0.6096 cm with an average hardness of approximately 20 kp (Key Hardness Tester, tablet tested across the length).

Coating The compressed bilayer tablets are coated in an Accela-Cota of 121.92 cm as 10 sub-lots of approximately 106.8 kg. of coated tablets (approximately 137,400 tablets) using a three-gun spray system at a rate of 1 1 RPM. The tablets are coated using a coating solution at 12% w / w of clear coat OPADRY® YS-1 -7006 which contains hydroxypropyl cellulose and polyethylene glycol. The tablets are coated with 26.70 kg. of coating solution. The tablets are coated at an outlet air temperature of about 41 ° C with a range of 39.0-41.0 ° C. The inlet air temperature generally fluctuates from 55 to 62 ° C and a flow rate of Supply air of 48.23-51.07 cubic meters per minute. The flow rate of the coating solution is started at approximately 250 g / min. and it increases periodically until reaching a final spray rate of about 375-400 g / min. An atomizing air pressure of 4.22 kg / cm2 is used during the spraying of the coating solution. The total coating process time is approximately 1.5 hours per sub-batch coating. The processing time for 10 sub-lots is 15 hours.

Table 4. Commercial Scale Formulation of Wax Granules of Pseudoephedrine HCl.

Table 5. Commercial Scale Formulation of the Final Piperidinoalkanol Mixture1. 4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -, -dimethylbenzeneacetic acid hydrochloride). 2 The water is removed during the process and does not appear in the final product. The amount of water can be varied to achieve adequate granulation.

Method for Determining Uniformity of Content Uniformity of content is determined by someone of ordinary skill in the art using known techniques and procedures. Someone with ordinary skill in the art, for example, can use an HPLC method, which employs a strong base cation exchange column Alltech Adsorbosphere XL SCX, 5 μm (50 mm × 4.6 mm DI) serially run by a ZORBAX SB-Phenyl reverse phase column, 5μm (250 mm x 4.6 mm ID). A mobile phase consisting of 65:35 v / v methanol: buffer (0.050 M sodium acetate and 0.075 M 1-octansulfonic acid, sodium salt, pH = 4.60 by adjustment with acetic acid) is pumped through the column to a flow rate of 1.5 mL / min. The column temperature is maintained at 35 ° C. Standards and samples are injected to the column using an injection volume of 20 μL followed by UV detection at 215 nm. Ten samples of individual tablets are prepared as follows. One tablet is placed in a 100 mL volumetric flask and 60.0 mL of methanol are added. The bottle is covered and stirred for 60 minutes in a mechanical stirrer placed at high speed. After the period of agitation, the bottle is placed in a Uitrasonic-Heating Bath and ultrasound is applied at 40 ° C for 60 minutes. During the 60 minute ultrasound application period, the bottle is shaken vigorously manually every 15 minutes to help break up the tablets. After the initial 60 minute ultrasound application period, 35 mL of the buffer is added to the vial (0.050 M sodium acetate and 0.075 M 1-octane sulfonic acid, sodium salt, pH = 4.60 by acetic acid adjustment), mixed , they are then placed in a Uitrasonic-Heating Bath for a second time and ultrasound is applied at 40 ° C for 60 minutes. During the second period of 60 minute ultrasound application, the vial is shaken vigorously manually to help break the tablets. After the second period of ultrasound application the bottles are removed from the ultrasound apparatus and allowed to cool to room temperature. After reaching room temperature, the bottle is shaken / mixed, then most of the floating excipients are decanted into a waste container. Approximately 6-8 mL of the remaining sample solution is filtered in a small flask using a 0.45 μm Whatman GD / X filter., giving a Sample Solution I. Using a volumetric pipette, 40 mL of Sample Solution I is pipetted into a 50 mL volumetric flask, diluted to volume with mobile phase to give Sample Solution II, and injected into the HPLC system. The peak areas for pseudoephedrine and 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzeneacetic acid are determined and the percent label affirmation is calculated for each active.

Table 6. Uniformity of Content of Bilayered Tablet Uncoated in Process; Uniformity of Hydrochloride content of 4-r4-r4- (h id roxid ifenilm ethyl) - 1 -piperidinilol-1-hydroxybutylol-a, a -dimethylbenzene acetic acid, n = 10.

Table 7. Uniformity of Unpainted Bilayer Tablet Content in Process; Uniformity of Content of the Pseudoephedrine Hydrochloride. n = 10 Tables 6 and 7 provide the content uniformity for 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzeneacetic acid hydrochloride and d-pseudoephedrine hydrochloride respectively. The good uniformity of content ensures that each tablet contains the amount of drog substance intended with small variation between tablets of a batch. In order to establish good uniformity of content, the United States Pharmacopeia 23, The United States Pharmacopeial Convention, Inc., Rockville, MD, page 1838, establishes a deviation of less than equal to 6% and all individual tablets must fall within from 85.0% to 115.0% of the label claim for a sample of 10 tablets. As disclosed above, the present invention provides a pharmaceutical composition which exhibits good uniformity of content wherein the largest variation observed for 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- hydrochloride. hydroxybutyl] -a, α-dimethylbenzeneacetic acid was 3.5% RSD in the 1 hour sample and for pseudoephedrine hydrochloride it was 3.7% RSD in the 3 hour sample.

Dissolution Method The dissolution profiles are determined by one of ordinary skill in the art using known techniques and procedures. For example, the dissolution test is performed in 900 mL of 0.001 N HCl (pH = 3.00) maintained at 37 ° C using the USP palette method (Aparat 2, see for example Remington's Pharmaceutical Sciences, Mac Publishing Company, (1990) , Eighth Edition, Pages 595-596) with a rotation speed of 50 RPM. Aliquots of each dissolution test solution are collected and filtered through 45 μm polyethylene sampling filters at the sampling intervals of 15, 30, 45, 60, 180, 300, 420 and 720 minutes. Each aliquot of the solution d sample of collected solution is analyzed using a Socratic procedure H PLC using a strong bastion cation exchange column Whatman Partisil 10 SCX (250 mm x 4.6 mm DI). A mobile phase consisting of 45:55 v / v of acetonitrile: buffer (sodium phosphate 0.05 M, pH = 2.00 ± 0.05) is pumped through the column at a flow rate of 1.0 mL / min. The temperature of the column is maintained at room temperature. Standard samples are injected to the column using an injection volume of 10 μL followed by UV detection at 210 nm. The peak areas for pseudoephedrine and the acid 4- [4- [4- (h id roxid if eni I meti it) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzeneacetic acid are determined and the percent of Label assertion released in each time interval is calculated for each asset.

Table 8. Uncoated Bilayer Tablet Dissolution Profile for the Dissolution of Acid Hydrochloride 4-r4-r4- (Hydroxydiphenylmethyl) -1-piperidine i lo] - 1 -hydroxybutyli, -a, a-di meti I benzeneacetic Table 9. Dissolution Profile of Uncoated Bilayer Tablet for Pseudoephedrine Hydrochloride Continue Table 9 Table 10. SUDAFED 12 HORAS® Tablet Dissolution: Percent of Release of Label Claim Table 11 Solution of ALLEGRA® Capsules in 1 mm of Medium HCl; Percent of Release of Label Affirmation Tables 8 and 9 provide the dissolution profiles for the Hydrochloride of 4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a-, a-dimethylbenzeneacetic acid and pseudoephedrine hydrochloride respectively. Tables 10 and 11 provide the dissolution profiles for SUDAFED 12 HORAS® tablets and ALLEGRA capsules respectively.

Claims (17)

REIVI N DICACIONES

1 . A pharmaceutical composition in the form of a bilayer tablet comprising, (a) a first discrete zone made with Formulation (A) which comprises, a therapeutically effective amount of decongestant of a sympathomimetic drug, or a pharmaceutically acceptable salt thereof, in an amount of about 18% to about 39% by weight of Formulation (A), and a first carrier base material, the first carrier base material comprising a mixture of; (i) carnauba wax in an amount from about 59% to about 81% by weight of Formulation (A); and (ii) a suitable antiadherent in an amount from about 0.25% to about 2.00% by weight of the Formulation (A); wherein said first carrier base material provides a sustained release of the sympathomimetic drug; and (b) a second discrete zone made with Formulation (B) which comprises an amount of therapeutically effective antihistamine of a piperidinoalkanol, or a pharmaceutically acceptable salt thereof, in an amount of about 15% to about 30% by weight of the Formulation (B) and a second carrier base material, the second carrier base comprising a mixture of; (i) a cellulose diluent in an amount from about 27% to about 73% by weight of

Formulation (B); (ii) pregelatinized starch in an amount from about 15% to about 30% by weight of

Formulation (B); (iii) a suitable disintegrant in an amount from about 0.25% to about 6.00% by weight of Formulation (B); and (iv) a suitable lubricant in an amount of approximately 0. 25% to approximately 2.00% by weight of the Formulació

(B); wherein said second carrier base material provides an immediate release of the piperidinoalkanol or pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition of claim 1 wherein piperidinoalkanol is of the Formula: wherein X is a number ranging from about ca to about 5, and individual optic isomers thereof. 3. A pharmaceutical composition in the form of a bicap tablet comprising: (a) a first discrete zone made with Formulation (A) which comprises, a therapeutically effective decongestant amount of a sympathomimetic drug, or a salt thereof acceptable pharmaceutically, in an amount of about 25% to about 33% by weight d Formulation (A), and a first carrier base material, the first carrier base material comprising a mixture of; (i) carnauba wax in an amount from about 66% to about 74% by weight of Formulació (A); and (ii) a suitable antiadherent in an amount of about 0.50% to about 1.50% by weight of Formulation (A); wherein said first carrier base material provides a sustained release of the sympathomimetic drug; and (b) a second discrete zone made with Formulation (B) which comprises a therapeutically effective antihistamine amount of a piperidinoalkanol of the Formula: wherein X is a number ranging from about zero to about 5, and isomers of the same individual optics, in an amount from about 15 to about 24% by weight of the Formulation (B) and its second carrier base material, the second carrier base comprising a mixture of; (i) a cellulose diluent in an amount from about 43% to about 67% by weight of the Formulation (B); (I) pregelatinized starch in an amount from about 15% to about 24% by weight of Formulation (B); (iii) a suitable disintegrant in an amount of about 3.20% to about 4.80% by weight of Formulation (B); and (iv) a suitable lubricant in an amount of about 0.50% to about 1.00% by weight of the Formula (B); wherein said second carrier base material provides an immediate release of the piperidinoalkanol or pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition according to claim 1 wherein a suitable glidant is included in the first base material of the Formulation (A) in an amount of 0.00% about 3.00% by weight of the Formulation (A).

5. A pharmaceutical composition according to claim 1 wherein a suitable glidant is included in the first base material of the Formulation (A) in an amount of 0.00% about 0.75% by weight of the Formulation (A).

6. A pharmaceutical composition according to claim 5 wherein the suitable glidant is colloidal silicon dioxide.

7. A pharmaceutical composition according to any of claim 3 or claim 6 wherein the sympathomimetic drug and pseudoephedrine hydrochloride.

8. A pharmaceutical composition according to claim 7 wherein the suitable anti-adherent of Formulation (A) is stearic acid, and in Formulation (B), the suitable croscarmellose sodium disintegrant and the suitable lubricant is magnesium stearate.

9. A pharmaceutical composition according to claim 8 wherein the pseudoephedrine hydrochloride, carnauba wax, stearic acid and colloidal silicon dioxide of Formulation (A) are combined in amounts of approximately 28.1%, approximately 70.42% approximately 1.15% and approximately 0.25%, respectively, and weight of the composition, of the Formulation (A), and the piperidinoalkanol cellulose diluent, pregelatinized starch, croscarmellose of sodium and magnesium stearate of the Formulation (B) are combined in amounts of approximately 17.09%, approximately 61.67% approximately 17.09%, approximately 3.42% and approximately 0.75%, respectively, by weight of the composition of the Formulació (B).

10. The pharmaceutical composition according to claim 9 wherein the piperidinoalkanol is the hydrochloride of 4- [4- [4 (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, α-dimethylbenzene acetic acid.

11. The pharmaceutical composition according to claim 10 wherein the cellulose diluent comprises a combination d Avicel PH101 and Avicel PH102.

12. The pharmaceutical composition according to claim 11 wherein the combination of Avicel PH 101 and Avicel PH 102 comprises approximately 12% of Avicel PH 101 and approximately 88% of Avicel PH 102.

13. The pharmaceutical composition according to claim 1. Wherein the hydrochloride of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, admethylbenzeneacetic acid is present in an amount of about 60 mg and the hydrochloride d-pseudoephedrine is present in an amount of approximately 12 mg.

14. A pharmaceutical composition according to the claim 13 wherein the bilayer tablet is coated with a suitable coating agent.

15. A pharmaceutical composition according to the claim 14 wherein the bilayer tablet is coated with OPADRY® YS-1 -7006.

16. A pharmaceutical composition according to the claim Wherein OPADRY® YS-1 -7006 is present in an amount of about 2.9% by weight of the composition.

17. A pharmaceutical composition according to claim 13 wherein the bilayer tablet has a hardness of about 15 kp to about 25 kp. SUMMARY The present invention provides a pharmaceutical composition in the form of a bilayer tablet comprising: (a) a first discrete zone made with Formulation (A) which comprises a therapeutically effective decongestant amount of a sympathomimetic drug, or a salt thereof; same pharmaceutically acceptable, in an amount of about 18% to about 39% by weight of the Formulation (A), and a first carrier base material, the first carrier base material comprising a mixture of: (i) carnauba wax in an amount of about 59% to about 81% by weight of the Formulation (A); and (ii) a suitable antiadherent in an amount of about 0.25% to about 2.00% by weight of the Formulation (A); wherein said first carrier base material provides a sustained release of the sympathomimetic drug; and (b) a second discrete zone made with Formulation (B) which comprises an amount of therapeutically effective antihistamine of a piperidinoalkanol, or a pharmaceutically acceptable salt thereof, in an amount of about 15% to about 30% by weight of Formulation (B) and a second carrier base material, the second carrier base comprising a mixture of: (i) a cellulose diluent in an amount of about 27% to about 73% by weight of Formulation (B); (ii) pregelatinized starch in an amount from about 15% to about 30% by weight of the Formulation (B); (iii) a suitable disintegrant in an amount of about 0.25% to about 6.00% by weight of the Formulation (B); and (iv) a suitable lubricant in an amount of about 0.25% to about 2.00% by weight of the Formulation (B); wherein said second carrier base material provides an immediate release of the piperidinoalkanol or the pharmaceutically acceptable salt thereof.