FIELD OF THE INVENTION

This invention is in the field of pharmaceutical dosage forms. The invention provides a pharmaceutical composition in solid unit dosage form prepared by a wet granulation process comprising (a) a therapeutically effective amount of an active piperidinoalkanol compound or a pharmaceutically acceptable salt, thereof and the individual optical isomers thereof, (b) not more than one functional excipient mixed with the therapeutically active compound. This mixture of the active compound and a single functional excipient may be wet granulated with a binding agent in an aqueous or non-aqueous solvent. The wet granulation may then be screened and dried. The dry granulation may be screened and blended with other excipients which comprise of at least one disintegrant and other excipients such as lubricants, surfactants etc

BACKGROUND OF THE INVENTION

It has been established that various piperidinoalkanol compounds are useful as antihistamines, antiallergy agents and bronchodialators as disclosed in US Patent Nos. 3,878,217; 4,254,129 and 4,285,957. Included within the scope of these, which are commercially defined piperidinoalkanols is (±)-4-[l -hydroxy -4- [4 (hydroxydiphenylmethyl) -1 -piperidinyl ]- butyl ]- α, α-dimethyl benzeneacetic acid hydrochloride which is commercially available as Fexofenadine and formulated as a pharmaceutical composition in solid unit dosage form for the treatment of patients with symptoms of seasonal allergic rhinitis. In US patent No. 4,929,605, J. Domet and D. Shah describe 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 6.0% 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 US patent No. 4,996,061, a pharmaceutical composition in the form of a multiple - compression tablet comprising a discrete zone made from a formulation that provides sustained release of a therapeutically effective decongestant amount of a sympathomimetic drug and a discrete zone made from a different formulation that provides immediate release of a therapeutically effective antihistaminic amount of a piperidinoalkanol and optionally, a therapeutically effective decongestant amount of a sympathomimetic drug.

In general, these piperidinoalkanol derivatives are only minimally soluble in water and therefore the use of therapeutically inactive ingredients in a pharmaceutical composition containing one or more of these compounds are very important in providing for their efficient and immediate absorption and bioavailability after oral administration.

A novel pharmaceutical composition is now provided that allows an efficient and immediate absorption and bioavailability of these compounds after oral administration thereof.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition in solid unit dosage form, prepared by wet granulation process. This process comprises, (a) a therapeutically effective amount of a piperidinoalkanol compound or a pharmaceutically acceptable salt thereof, and the individual optical isomers thereof, (b) at least one functional excipient preferably a diluent. This mixture is mixed with a solution of a binding agent; the wet granulation is screened, the wet granulation is dried, the granulation is screened, and the dry granulation is blended with at least one disintegrant. In addition, the present invention provides combining the above blended dry granulation with a lubricant. The present invention further provides pressing the above final mixture into a tablet. The final tablets were film coated by using a suitable film forming material.

DESCRIPTION OF THE INVENTION

The reference product of Fexofenadine manufactured by Aventis Inc; (earlier Hoechst Marion Roussel, Inc.), commercially known as Allegra® and Allegra-D®, have been formulated using a composition and process as disclosed US 5,855,912 and US 5,738,872. Fexofenadine immediate release tablet composition has been prepared by first blending the drug, one or more diluents and one or more disintegrants,, followed by aqueous wet granulation using a binder solution, drying and sizing into granules. Later, additional extragranular ingredients like disintegrants and lubricants are blended with the granules and compressed into tablets. As claimed in the patents, the binders include gelatin, polyvinypyrrolidone (PVP), pregelatinized starch, povidone, cellulose derivatives including methyl cellulose, carboxymethyl cellulose, hydroxypropyl methycellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose and the like; diluents were calcium carbonate-, lactose, starch, microcrystalline cellulose, and the like; lubricants include magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, hydrogenated vegetable oil and the like. Silicon dioxide, talc and the like were listed as glidants. Disintegrants were considered from alginic acid, methacrylic acid DVB, crosslinked PVP, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch and the like; croscarmellose sodium, starch, pregelatinized starch and sodium starch glycolate were preferred disintegrants.

A suitable combination of inert ingredients in the reference tablet composition of Fexofenadine comprise microcrystalline cellulose, pregelatinized starch, gelatin, magnesium stearate, calcium carbonate and sodium starch glycolate, in amounts of from about 20% to about 85% , 5% to about 50%, 1% to about 15% , 0.05% to about 3%, 5% to about 50% and 1% to about 15% respectively. A preferred combination of inert ingredients is microcrystalline cellulose, pregelatinized starch, calcium carbonate, magnesium stearate and sodium starch glycolate in amounts of from about 20% to about 85%, 5% to about 50%, 5% to about 50% , 0.05% to about 3% and 1% to about 15%. Another preferred combination of inert ingredients comprises: microcrystalline cellulose, pregelatinized starch, magnesium stearate, and croscarmellose sodium in amounts of from about 20% to about 85%, 5% to about 50%, 0.05% to about 3%, 1% to about 10%. The most preferred combination of inert ingredients is croscarmellose sodium, microcrystalline cellulose, lactose, pregelatinized starch and gelatin, in amounts of from about 1% to about 10%, 20% to about 85%, 20% to about 85%, 1% to about 30% and 1% to about 15%, respectively. The most especially preferred combination of inert ingredients is croscarmellose sodium, microcrystalline cellulose, lactose, pregelatinized starch, gelatin and magnesium stearate, in amounts of from about 1% to about 10%, 20% to about 85%, 20% to about 85%, 1% to about 30%, 1% to about 15% and 0.05% to about 3% respectively.

For the purposes of clarity, a "functional excipient" is defined as a single excipient or mixture of excipients, which have similar functions. For example, the use of lactose or calcium carbonate or a mixture of lactose and calcium carbonate falls within the scope of the definition here as even in a mixture of lactose and microcrystalline cellulose both excipients per se individually have similar function namely a diluent and hence the mixture also serves the same function. In contrast a mixture of lactose / calcium carbonate with croscarmellose sodium / pregelled starch is not a "functional excipient" as in this case the lactose / calcium carbonate is a diluent whereas the croscarmellose sodium / pregelled starch is a disintegrant thus possessing different functionalities.

Surprisingly, the present inventors have found that it is possible to formulate a Fexofenadine solid dosage form by blending together a mixture of a therapeutically active ingredient (Fexofenadine) and just one functional excipient (diluent) before wet granulation with a binder solution. Thus in the present invention, no disintegrant of any kind is used in the pre granulation blend. It is ideally known that a blend prior to granulation usually contains more than one excipient serving different functionalities. For example, a disintegrant is included so that the tablet may disintegrate and release the active principle when consumed by the subject. Another important observation made in case of the present invention, is that a Fexofenadine tablet dosage form prepared by using the active component and just one ftøictipπal excipjefltj prβfprøbly a diluent or mixture of diluents and devoid of other functional excipients at the pre-granμtøjjpn, stage, results in a formulation that has an in-vitro dissolution profile similar to AllegraR, or |q ttøθ }n- vitro release profile of the Fexofenadine immediate release layer in Allegra-DR. The composijion comprises blending the drug and an excipient (diluent or mixture of diluents) uniformly together, the Wend devoid of any other functional excipient, followed by wet granulation using a suitable binder solution. The granules are dried and sifted to obtain desired size, blended with extragranula| inert excipients like disintegrants, lubricants and glidants, and compressed into tablet. Unlike the reference composition and process, no intragranular disintegrant was incorporated, . The drug was suitably milled to obtain d (0.9) less than 35 microns, if required, preferably fpf the immediate release layer in case of fexofenadine alone or of the combination product of fexofenadine and pseudoephedrine. The tablets so obtained are intended to be equivalent of Allegra® and Allegra-Dφ, and match in in-vitro dissolutions and biopharmaceutical profiles, for the Fexofenadine therapeutically active moiety. The process described is only intended for illustration and it is possible for a person skilled in the art to suitably modify the process to achieve the same end result as described in this invention. This invention encompasses all such modifications.

The desired functional excipient (preferably a diluent or a mixture of diluents) is blended together with the piperidinoalkanol compound utilizing techniques and procedures well known to one of the ordinary skill in the art. Preferred ingredient comprises lactose (20-80%) as diluent. After wet granulation with a binder solution other excipients such as disintegrants and lubricants are added extragranularly. The characteristic feature of the present invention is the presence of only one functional excipient (diluent or mixture of diluents) along with the active component prior to granulation. The invention is illustrated using a set of examples below and they do not in any way limit the scope of the invention to only those examples.

Example - 1

180 mg tablet for oral administration

Blend 180 g of fexofenadine hydrochloride and 320 g of lactose monohydrate. Prepare binder solution by using 17 g Povidone K-30 in 107 g purified water. To the above powder blend add this binder solution and mix. Dry the resulting wet granulation. Screen the dried granulation through a 16-mesh screen.

Transfer the granulation to a blender and add 42 g microcrystalline cellulose (Avicel pH 102), 38 g sodium starch glycolate, 6 g of talc, 3 g of colloidal silicon dioxide (Aerosil 200) and 18 g of Pregelatinised starch (starch 1500) to the blender. Blend these components. Add 6 g of Stearic acid and blend. Compress the finished granulation into tablets. Table 1 provides the composition of each tablet in percent by weight.

To coat the compressed tablets with a white aqueous coating, prepare an aqueous suspension comprised of 18 g Opadry Y- 1-7000, a coating ready mix from Colorcon containing hydroxy propyl methyl cellulose, titanium dioxide and a plasticizer, in 180 gm of purified water. Place the tablets in a coating pan and coat the tablets using the above white aqueous coating solution to achieve about a 3% weight gain. This procedure provides a tablet with a total weight of about 648 mg. Table - 1

Composition of 180 mg tablets

Ingredients Amount mg/tablet Composition % weight

Fexofenadine hydrochloride 180 28.60

Lactose monohydrate 320 50.80

Povidone K-30 17 2.70

Microcrystalline cellulose (Avicel 42 6.70 PH 102)

Sodium starch glycolate 38 6.00

Talc 6 0.95

Colloidal silicon dioxide (Aerosil 3 0.48 200)

Pregelatinised starch (Starch 1500) 18 2.90

Stearic acid 6 0.95

Opadry Y-l-7000 18 3.00

Example - 2

180 mg tablet for oral administration

Mix 18O g of fexofenadine hydrochloride and 301 g of lactose monohydrate in a blender Prepare binder solution by using 17 g Povidone K-30 and 19 g of polysorbate - 80 in 97 g purified water. Add this binder to the above dry mix and granulate. Dry the resulting wet granulation. Screen the dried granulation through 16 mesh screen. Transfer the granulation to a blender. Add 42 g microcrystalline cellulose (Avicel PH 102), 38 g of sodium starch glycolate, 6 g of talc and 3 g of colloidal silicon dioxide (Aerosil 200) to the blender. Blend these components. Add 6 g of stearic acid and blend. Compress the finished granulation into tablets. Table 2 provides the composition of each tablet in percent by weight. To coat the compressed tablets, a white aqueous coating using 18 g of Opadry Y- 1-7000 of Colorcon was used which contained hydroxy propyl methyl cellulose, titanium dioxide and plasticizer and about 180 g of purified water used. Place the tablets into a coating pan and coat the tablets using the white aqueous coating solution to achieve about a 3% weight gain. This procedure provides a tablet with a total weight of 648 mg. Table - 2 Composition of 180 mg tablets Ingredients Amount mg/tablet Composition % weight Fexofenadine hydrochloride 180 28.57 Lactose monohydrate 301 47.77 Povidone K-30 17 2.70 Polysorbate - 80 19 3.00 Microcrystalline cellulose (Avicel 42 6.67 PH 102) Sodium starch glycolate 38 6.03 Talc 6 0.95 Colloidal silicon dioxide (Aerosil 3 0.48 200) Pregelatinised starch (Starch 1500) 18 2.86 Stearic acid 6 0.95 Opadry Y- 1-7000 18 3.00 Example - 3

ISO mg tablet for oral administration

Combine 126.Og fexofenadine hydrochloride and 321 g of lactose monohydrate. Prepare binder solution by using 17 g Povidone K-30 in 107 g purified water. Add 54.Og of fexofenadine hydrochloride in above binder solution and stirred well to form a slurry. Add this binder slurry into the blender containing the above dry mix and granulate. Dry the resulting wet granulation. Screen the dried granulation through 20 mesh screen. Transfer the granulation to a blender. Add 42 g microcrystalline cellulose (Avicel PH 102), 37 g of sodium starch glycolate, 6 g of talc and 3 g of colloidal silicon dioxide (Aerosil 200) to the blender. Blend these components. Add 6 g of stearic acid and blend. Compress the finished granulation into tablets. Table 3 provides the composition of each tablet in percent by weight.

To coat the compressed tablets with a white aqueous coating, 18 g of Opadry Y- 1-7000 of Colorcon which contains hydroxy propyl methyl cellulose, titanium dioxide and plasticizer and about 180 g of purified water was used. Place the tablets into a coating pan and coat the tablets using the white aqueous coating solution to achieve about a 3% weight gain. This procedure provides a tablet with a total weight of 630 g. Table - 3 Composition of 180 mg tablets Ingredients Amount mg/tablet Composition % weight Fexofenadine hydrochloride 180 29.40 Lactose monohydrate 321 52.46 Povidone K-30 17 2.78 Microcrystalline cellulose (Avicel 42 6.86 PH 102) Sodium starch glycolate 37 6.05 Talc 6 0.98 Colloidal silicon dioxide (Aerosil 3 0.49 200) Stearic acid 6 0.98 Opadry Y-I -7000 18 3.00

Example - 4

60 mg tablet for oral administration

Combine 60 g of fexofenadine hydrochloride and 229 g of lactose monohydrate. Prepare binder solution by using 9 g of Povidone K-30 in 60 g of purified water. To the above powder blend add this binder solution and mix. Dry the resulting wet granulation. Screen the dried granulation through 16 mesh.

Transfer the granulation to a blender and add 30 g of microcrystalline cellulose (Avicel PH 102), 28 g of sodium starch glycolate, 4.5 g of talc, 13 g of pregelatinised starch (starch 1500) and 2 g of colloidal silicon dioxide (Aerosil 200) to the blender. Blend these components. Add 4.5 g of stearic acid and blend. Compress the finished granulation into tablets. Table 4 provides the composition of each tablet in percent by weight.

To coat the compressed tablets with a white aqueous coating solution with 12 g of Opadry Y-I- 7000, a coating ready mix from Colorcon was used containing hydroxy propyl methyl cellulose, titanium dioxide and a plasticizer, in 120 g of purified water. Place the tablets in a coating pan and coat the tablets using the above white aqueous coating solution to achieve about a 3% weight gain. This procedure provides a tablet with a total weight of about 392 mg. Table - 4 Composition of 60 mg tablets Ingredients Am t mg/tablet Composition % weight Fexofenadine hydrochloride 60 15.79 Lactose monohydrate 229 60.26 Povidone K-30 9 2.37 Microcrystalline cellulose (Avicel PH 30 7.89 102) Sodium starch glycolate 28 7.37 Talc 4.5 1.18 Colloidal silicon dioxide (Aerosil 200) 2 0.53 Pregelatinised starch (starch 1500) 13 3.42 Stearic acid 4.5 1.18 Opadry Y-l-7000 12 3.00

Example - 5

60 mg tablet for oral administration

Combine 60 g of fexofenadine hydrochloride (micronised) and 208.5g of lactose anhydrous. Prepare binder solution by using 9.0 g of povidone K-30 in 60 g of purified water. To the above powder blend add this binder solution and mix. Dry the resulting wet granulation. Screen the dried granules through 16 mesh.

Transfer the granulation to a blender and add 30 g of microcrystalline cellulose (Avicel PH 102), 58.5 g of sodium starch glycolate, 4.5 g talc, 13 g of pregelatinised starch (Starch 1500) and 2 g of colloidal silicon dioxide (Aerosil 200) to the blender. Blend these components. Add 4.5 g of stearic acid and blend. Compress the finished granulation into tablets. Table 5 provides the composition of each tablet in percent by weight.

Coat the compressed tablets with a white aqueous coating solution with 12 g of Opadry Y- 1-7000, a coating ready mix from Colorcon containing hydroxy propyl methyl cellulose, titanium dioxide and a plasticizer, in 120 g of purified water. Place the tablets in a coating pan and coat the tablets using the above white aqueous coating solution to achieve about a 3% weight gain. This procedure provides a tablet with a total weight of about 402 mg. Table - 5 Composition of 60 mg tablets Ingredients Amount mg/tablet Composition % weight Fexofenadine hydrochloride (micronised) 60 15.38 Lactose anhydrous 208.5 53.46 Povidone K-30 9 2.31 Microcrystalline cellulose (Avicel PH 30 7.69 102) Sodium starch glycolate 58.5 15.00 Talc 4.5 1.15 Colloidal silicon dioxide (Aerosil 2 0.51 200) Pregelatinised starch (starch 1500) 13 3.33 Stearic acid 4.5 1.15 Opadry Y- 1-7000 12 3.00

Example - 6

60 mg tablet for oral administration

Blend 60 g of fexofenadine hydrochloride (micronised) with 119.5 g of lactose monohydrate. Prepare binder solution by using 9 g of Povidone K-30 in 60 g of purified water. To the above powder blend add this binder solution and mix. Dry the resulting wet granulation. Screen the dried granules through 20 mesh.

Transfer the granulation to a blender and add 70 g Prosolv HD 90, 60 g of croscarmellose sodium, 50 g of pregelatinised starch (Starch 1500), and 5 g of talc and 2 g of colloidal silicon dioxide (Aerosil 200). Blend these components. Add 4.5 g of stearic acid and blend. Compress the finished granulation into tablets. Table 6 provides the composition of each tablet in percent by weight. Coat the compressed tablets with a white aqueous coating solution of 12 g of Opadry Y-I -7000, a coating ready mix from Colorcon containing hydroxy propyl methyl cellulose, titanium dioxide and a plasticizer, in 12O g of purified water. Place the tablets in a coating pan and coat the tablets using the above white aqueous coating solution to achieve about a 3% weight gain. This procedure provides a tablet with a total weight of about 392 mg.

Table - 6 Composition of 60 mg tablets Ingredients Amount mg/tablet Composition % weight Fexofenadine hydrochloride (micronised) 60 15.79 Lactose monohydrate 119.5 31.45 Povidone K-30 9 2.37 Prosolv HD 90 70 18.42 Croscarmellose sodium (Ac-di-sol) 60 15.79 Pregelatinised starch (starch 1500) 50 13.16 Talc 5 1.32 Colloidal silicon dioxide (Aerosil 200) 2 0.51 Stearic acid 4.5 1.15 Opadry Y- 1-7000 12 3.00

The in-vitro dissolution profiles for the representative examples comparing them against AllegraR or Allegra-DR are given in Figures 1 to 4.