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WO2006008567A1 - Compositions pharmaceutiques a base de composes piperidinoalcanols - Google Patents

Compositions pharmaceutiques a base de composes piperidinoalcanols Download PDF

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Publication number
WO2006008567A1
WO2006008567A1 PCT/IB2004/002099 IB2004002099W WO2006008567A1 WO 2006008567 A1 WO2006008567 A1 WO 2006008567A1 IB 2004002099 W IB2004002099 W IB 2004002099W WO 2006008567 A1 WO2006008567 A1 WO 2006008567A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
dosage form
unit dosage
solid unit
form according
Prior art date
Application number
PCT/IB2004/002099
Other languages
English (en)
Inventor
Gour Mukherji
Jayadev Patil
Siddharth Mate
Original Assignee
Wockhardt Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wockhardt Limited filed Critical Wockhardt Limited
Priority to PCT/IB2004/002099 priority Critical patent/WO2006008567A1/fr
Publication of WO2006008567A1 publication Critical patent/WO2006008567A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat

Definitions

  • the 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • a "functional excipient” is defined as a single excipient or mixture of excipients, which have similar functions.
  • 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.
  • 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.
  • 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.
  • a disintegrant of any kind is used in the pre granulation blend.
  • a blend prior to granulation usually contains more than one excipient serving different functionalities.
  • a disintegrant is included so that the tablet may disintegrate and release the active principle when consumed by the subject.
  • a Fexofenadine tablet dosage form prepared by using the active component and just one ft ⁇ ictip ⁇ al excipjefltj pr ⁇ fpr ⁇ bly a diluent or mixture of diluents and devoid of other functional excipients at the pre-gran ⁇ t ⁇ jjpn, stage, results in a formulation that has an in-vitro dissolution profile similar to Allegra R , or
  • 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
  • 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-D ⁇ , 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.
  • lactose (20-80%) as diluent.
  • a binder solution 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.
  • 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.
  • Microcrystalline cellulose (Avicel 42 6.70
  • 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.
  • Microcrystalline cellulose (Avicel 42 6.67
  • Microcrystalline cellulose (Avicel 42 6.86
  • Example - 4 60 mg tablet for oral administration
  • 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.
  • 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
  • Example - 5 60 mg tablet for oral administration
  • Microcrystalline cellulose (Avicel PH 30 7.69
  • Example - 6 60 mg tablet for oral administration
  • Pregelatinised starch (starch 1500) 50 13.16

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition pharmaceutique en formes dosifiées unitaires solides, obtenue par la mise en oeuvre d'un procédé de granulation par voie humide. Cette composition contient : (a) une quantité thérapeutiquement efficace d'un composé pipéridinoalcanol ou d'un sel pharmaceutiquement acceptable ou d'isomères optiques individuels de celui-ci ; et (b) au moins un excipient fonctionnel (de préférence un diluant ou un mélange de diluants) mélangé à une solution d'agent liant. La granulation humide est d'abord criblée, puis séchée. La granulation sèche est ensuite criblée, puis mélangée à au moins un délitant.
PCT/IB2004/002099 2004-06-18 2004-06-18 Compositions pharmaceutiques a base de composes piperidinoalcanols WO2006008567A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2004/002099 WO2006008567A1 (fr) 2004-06-18 2004-06-18 Compositions pharmaceutiques a base de composes piperidinoalcanols

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2004/002099 WO2006008567A1 (fr) 2004-06-18 2004-06-18 Compositions pharmaceutiques a base de composes piperidinoalcanols

Publications (1)

Publication Number Publication Date
WO2006008567A1 true WO2006008567A1 (fr) 2006-01-26

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PCT/IB2004/002099 WO2006008567A1 (fr) 2004-06-18 2004-06-18 Compositions pharmaceutiques a base de composes piperidinoalcanols

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WO (1) WO2006008567A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4254129A (en) * 1979-04-10 1981-03-03 Richardson-Merrell Inc. Piperidine derivatives
US4929605A (en) * 1987-10-07 1990-05-29 Merrell Dow Pharmaceuticals Inc. Pharmaceutical composition for piperidinoalkanol derivatives
US4996061A (en) * 1987-10-07 1991-02-26 Merrell Dow Pharmaceuticals Inc. Pharmaceutical composition for piperidinoalkanol-decongestant combination

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4254129A (en) * 1979-04-10 1981-03-03 Richardson-Merrell Inc. Piperidine derivatives
US4929605A (en) * 1987-10-07 1990-05-29 Merrell Dow Pharmaceuticals Inc. Pharmaceutical composition for piperidinoalkanol derivatives
US4996061A (en) * 1987-10-07 1991-02-26 Merrell Dow Pharmaceuticals Inc. Pharmaceutical composition for piperidinoalkanol-decongestant combination

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