WO2008020990A1 - Nouveau mélange d'excipients compressible direct - Google Patents

Nouveau mélange d'excipients compressible direct Download PDF

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Publication number
WO2008020990A1
WO2008020990A1 PCT/US2007/017039 US2007017039W WO2008020990A1 WO 2008020990 A1 WO2008020990 A1 WO 2008020990A1 US 2007017039 W US2007017039 W US 2007017039W WO 2008020990 A1 WO2008020990 A1 WO 2008020990A1
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WO
WIPO (PCT)
Prior art keywords
blend
tablet
active pharmaceutical
pharmaceutical ingredient
percent
Prior art date
Application number
PCT/US2007/017039
Other languages
English (en)
Inventor
James Farina
Harry G. Brittain
Original Assignee
Mallinckrodt Baker, Inc.
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 Mallinckrodt Baker, Inc. filed Critical Mallinckrodt Baker, Inc.
Publication of WO2008020990A1 publication Critical patent/WO2008020990A1/fr

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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
    • A61K9/2095—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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • API is the tablet, which may be obtained through the compression of. appropriately formulated powders.
  • Conventional compressible mixtures are typically obtained by the blending of an API and suitable excipient materials. These excipients may include diluents or fillers, binders or adhesives, disintegrants, glidants or flow promoters, colors, flavors and mixtures thereof. These materials may simply be blended, or may be granulated in either the dry or wet state. Once mixing is complete, a lubricating excipient is added and the material compressed into tablets.
  • a tablet should be free of defects, have the strength to withstand mechanical shocks, and have the chemical and physical stability to maintain its physical attributes overtime.
  • the tablet must be able to release the API in a predictable and reproducible manner, and have a suitable chemical stability over time so as not to allow alteration of the API. Undesirable changes in either chemical or physical stability can result in unacceptable changes in the bioavailability of the API.
  • This product would then be mixed with an API and optionally with a lubricant, then compressed into tablets.
  • the physical properties of the universal excipient blend such as particle size and flowability, would be optimized in the product so as to maximize its processability.
  • Such a universal excipient blend would alleviate the need to conduct extensive drug formulation investigational studies, since the qualities of the excipient blend would be such that after the compression step, one would obtain pharmaceutically acceptable tablets for virtually any API.
  • the components in this universal excipient blend would be chosen so as to maximize the formulatability of APIs without adversely affecting its safety and efficacy profiles.
  • a method for making a pharmaceutically acceptable tablet comprises mixing a pre-mixed excipient blend with an active pharmaceutical ingredient to form an active pharmaceutical ingredient blend, and tableting the active pharmaceutical ingredient blend to form a pharmaceutically acceptable tablet.
  • the pre-mixed excipient blend includes at least one diluent, at least one binder and at least one disintegrant.
  • the pre-mixed excipient blend has a particle size of about 80 to 150 micrometers.
  • a pharmaceutically acceptable tablet is provided.
  • the tablet is produced by mixing a pre-mixed excipient blend with an active pharmaceutical ingredient to form an active pharmaceutical ingredient blend, and tableting the active pharmaceutical ingredient blend to form a pharmaceutically acceptable tablet.
  • the pre-mixed excipient blend includes at least one diluent, at least one binder and at least one disintegrant.
  • the pre-mixed excipient blend has a particle size of 80 to 150 micrometers.
  • Figure 1 is a flowchart illustrating a conventional method for formulating the excipient components utilized in a pharmaceutical tablet.
  • Fig. 2 is a flowchart illustrating a method for formulating a pharmaceutical tablet utilizing the universal excipient blends of the present invention.
  • the present invention relates to the use of universal excipient mixtures to make pharmaceutical tablets using direct compression tableting machines.
  • the universal excipient blends of the present invention provide a simplified method of formulation as compared to the traditional methods of tablet formulation. Conventional formulators typically utilize trial and error to develop different types of excipient blends for direct compression.
  • the conventional method for formulating the excipient components in a pharmaceutical tablet is illustrated in Figure 1. In the conventional formulation development approach, a significant amount of time is expended deducing which excipiets are advantageously included in the final formulation.
  • the excipients are pre-selected as a universal excipient blend and the entire formulation development is reduced to a series of blending steps.
  • the btend components include at least one diluent, at least one binder, and at least one disintegrant. At least one lubricant may optionally be added prior to tablet pressing.
  • the universal composition of the present invention is a pre-mixed, blended or granulated mixture that contains the necessary excipient materials, except for the optional lubricant, required to produce a pharmaceutically acceptable tablet.
  • the process of tablet production consists of mixing the composition with an API, optionally blending with at least one lubricant, and compressing the resulting blend into tablets.
  • these blends will allow for the formulation of a wide range of APIs for direct compression, thereby facilitating development of a solid dosage delivery device.
  • These universal blends of the present invention may further include optional components, for example glidants, colors, flavoring agents and mixtures thereof, as are well known in the art.
  • Powdered substances are generally unsuitable for use as direct compression ingredients as they do not exhibit the degree of powder flow necessary for use in high-speed instruments, or do not produce acceptably robust tablets after being compacted.
  • Some powdered substances can be transformed into a directly compressible form through the use of a wet granulation process, wherein the powder is wetted and then converted into a mass that can be screened, dried, and milled to the desired particle size.
  • the powders can be dry granulated, either by being compressed into slugs or being compressed into sheets, after which these compacts can be milled to the desired particle size.
  • the universal excipient blend comprises at least one filler or diluent, at least one binder, and at least one disintegrant. These materials, as well as any other optional excipients such as glidants, colors, or flavoring agents, are blended to yield a composition that is in the range of 80 to 150 micrometers, as measured by analytical sieving.
  • the blended excipient mixture is a product that owing to the choice of input material particle size is characterized by good flowability.
  • the excipient blend exhibits a flowability index that exceeds 70.
  • Excipient blends that meet the particle size and flowability criteria ensure that after an API is added to the excipient blend, and optionally a lubricant, the resulting formulation can be directly compressed into pharmaceutically acceptable tablets.
  • the universal excipient blend is produced by mixing the components, and then processing using either the wet or dry granulation techniques that are well known to those skilled in the art.
  • One route to produce a dry granulated excipient blend is by slugging process, where the excipient blend is pre-compressed into large tablets that are subsequently broken up into granulated particles having the desired mean particle size of 80 to 150 micrometers.
  • the dry granulated excipient granulate can be obtained by subjecting the blended ingredients to roller compaction where the excipient blend is pre-compressed into sheets that are subsequently broken up into granulated particles having the desired mean particle size of 80 to 150 micrometers.
  • the granulated excipient blend may be produced through a wet granulation process, where the component powders are blended, and then wetted to the appropriate consistency with a granulating fluid. The wetted mass is then extruded through a screen, dried to the appropriate water content, milled to the desired particle size, and optionally sieved into the desired mean particle size of 80 to 150 micrometers.
  • the universal excipient blend may be mixed with at least one API at levels ranging from about 5 to 50 percent by weight. Depending on the specific conditions and API, this mixture may be directly compressed into tablets, or the mixture may be blended with a lubricant at a level of about 0.5 to 2.0 percent by weight and this final mixture compressed into tablets.
  • the filler or diluent in the universal excipient blend includes dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, lactose or mixtures thereof, in the range of about 60 to 90 percent by weight, with about 80 percent preferred.
  • These fillers or diluents may be obtained either in powdered or granulated form, but must have a mean particle size suitable for tablet formulation, as is well known in the art.
  • Suitable binder in the universal excipient blend may include a cellulose derivative or a starch derivative, and will be present in the excipient granulate in the range of about 5 to 20 percent by weight, with about 6 percent preferred. These materials may be obtained either in powdered or granulated form.
  • Suitable disintegrants for use in the universal excipient blend may include sodium starch glycolate, polyvinylpyrrolidone or mixtures thereof, and will be present in the excipient granulate in the range of about 5 to 20 percent by weight, with about 6 percent preferred.
  • Example 1 Preparation of microcrystalline cellulose- hydroxypropyl methylcellulose - sodium starch glycolate (MCC-HPMC-SSG) powder blend:
  • V-blender 90 g of microcrystalline cellulose (EMCOCEL 90M) were blended with 10 g of hydroxypropyl methylcellulose for 1 hour. The resulting mixture was further blended for 1 hour in the "V- blender” with 9.9 g of sodium starch glycolate.
  • Table 1 lists the powder properties of the MCC-HPMC-SSG powder blend determined using a Hosokawa Micrometer Corporation Powder Tester PT-S.
  • the angle of spatula is the average of angle of spatula before and after impact.
  • Example 2 Powder properties of a mixture of 30% lbuprofen in MCC-HPMC-SSG powder blend: 280 g of MCC-HPMC-SSG blend prepared according to Example 1 was mixed with 120 g lbuprofen in a "V- blender" for 3 hours. Table 2 lists the powder properties of the 30% Ibuprofen/MCC-HPMC-SSG mixture determined using a Hosokawa Micrometer Corporation Powder Tester PT-S.
  • Example 3 Preparation of Placebo tablets from the MCC-HPMC-SSG powder blend: Two kilograms of MCC-HPMC-SSG powder blend were prepared by scaling up the procedure described in Example 1. The resulted powder blend was further mixed with 15 g of Magnesium Stearate. Tablets were pressed out from this final powder mixture. Table 3 lists tablets' properties.
  • MCC-HPMC-SSG powder blend Two kilograms of MCC-HPMC-SSG powder blend were prepared according to Example 1 and mixed with lbuprofen and, 19.5 g of Magnesium Stearate. The final content of lbuprofen in the mixture was 21%.
  • Table 4 lists same of the properties of the lbuprofen tablets obtained.
  • Example 5 Preparation of Acetaminophen tablets using the MCC-HPMC-SSG powder blend: MCC-HPMC-SSG powder blend prepared according to Example 1 was mixed with acetaminophen. Tablets were pressed at various compression forces. Tables 5, 6, 7 and 8 list the composition of the resulting tablets and their properties. [0029] Table 5
  • microcrystalline cellulose EMCOCEL 50M
  • sodium starch glycolate 9.0 g
  • HPMC hydroxypropyl methylcellulose
  • the resulted paste was extruded through the orifices of a screen.
  • the "spaghetti"-like strings were dried overnight in the air followed by oven-drying at 100 degrees
  • the dried strings were passed through a 40 mesh granulator.
  • the resulted granules had a mean particle size of 107 micrometers.
  • the angle of spatula is the average of angle of spatula before and after impact.
  • Example 8 Preparation of Placebo tablets from the DCP-HPMC-SSG powder blend: Two kilograms of DCP-HPMC-SSG powder blend were prepared by scaling up the procedure described in Example 7. The resulted powder blend was further mixed with 15 g of Magnesium Stearate. Tablets were pressed out from this final powder mixture. Table 11 lists the properties of the tablets.
  • Table 12 lists some characteristics of these tablets.
  • lactose monohydrate were blended with sodium starch glycolate (7.5 g) and Starch (7.5 g) in a "V-blender" for 3 hours.
  • sodium starch glycolate 7.5 g
  • Starch 7.5 g
  • To the Lactose-SSG-Starch blend were added 6.0 grams of hydroxypropyl methylcellulose (HPMC) in hot water (70 mL).
  • HPMC hydroxypropyl methylcellulose
  • the resulted paste was extruded through the orifices of a screen.
  • the "spaghettF-like strings were dried overnight in the air. The moisture content of the strings after the drying steps was approximately 3%.
  • the dried strings were passed through a 40 mesh granulator.
  • the resulting granules have a mean particle size of 119.33 micrometers.
  • excipient blend may be formulated to produce a particular type of tablet, a tablet having particular physical characteristics, or for a tablet incorporating a particular class of API, as are all well known in the art.
  • the excipient blend may be formulated to produce a tablet having an increased granular strength. Therefore, it is not intended that the scope of the invention be limited to the specific embodiments described. Rather, it is intended that the appended claims and their equivalents determine the scope of the invention.

Abstract

L'invention concerne un procédé servant à fabriquer un comprimé pharmaceutique ment acceptable à l'aide d'un mélange d'excipients prémélangés. Un mélange d'excipients prémélangés, universel, est mélangé avec un ingrédient pharmaceutique actif pour former un mélange d'ingrédients pharmaceutiques actifs. Le mélange résultant est ensuite comprimé pour former un comprimé pharmaceutiquement acceptable. Le mélange d'excipients prémélangés comprend au moins un diluant, un liant et un désintégrant. Le mélange d'excipients prémélangés a une dimension de particule d'environ 80 à 150 micromètres.
PCT/US2007/017039 2006-08-09 2007-07-30 Nouveau mélange d'excipients compressible direct WO2008020990A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82182706P 2006-08-09 2006-08-09
US60/821,827 2006-08-09

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WO2008020990A1 true WO2008020990A1 (fr) 2008-02-21

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009048557A1 (fr) * 2007-10-10 2009-04-16 Mallinckrodt Baker, Inc. Excipient à base de cellulose microcristalline granulaire à fonctionnalité élevée directement compressible, son procédé de fabrication et son utilisation
WO2010059534A2 (fr) * 2008-11-19 2010-05-27 Mallinckrodt Baker, Inc. Excipient à base de cellulose microcristalline granulaire directement compressible, procédé de fabrication et utilisation de cet excipient
WO2011074961A1 (fr) 2009-12-18 2011-06-23 Frieslandcampina Nederland Holding B.V. Composition d'excipient de comprimé co-traité, sa préparation et son utilisation
JP2012509326A (ja) * 2008-11-20 2012-04-19 アバントール パフォーマンス マテリアルズ， インコーポレイテッド 直接圧縮可能で高機能性な顆粒状のリン酸水素カルシウムベースの共に処理された賦形剤
US11040012B2 (en) * 2014-07-30 2021-06-22 Merck Patent Gmbh Pulverulent, directly compressible polyvinyl alcohol grades
WO2023012162A1 (fr) 2021-08-03 2023-02-09 Dfe Pharma Gmbh & Co. Kg. Procédé de préparation de granulés d'excipients co-traités
WO2023025672A1 (fr) 2021-08-25 2023-03-02 Basf Se Composition auxiliaire de compression directe

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006345A (en) * 1985-02-16 1991-04-09 Basf Aktiengesellschaft Direct tableting auxiliary
US5840769A (en) * 1996-07-16 1998-11-24 Basf Aktiengesellschaft Direct tabletting aids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006345A (en) * 1985-02-16 1991-04-09 Basf Aktiengesellschaft Direct tableting auxiliary
US5840769A (en) * 1996-07-16 1998-11-24 Basf Aktiengesellschaft Direct tabletting aids

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009048557A1 (fr) * 2007-10-10 2009-04-16 Mallinckrodt Baker, Inc. Excipient à base de cellulose microcristalline granulaire à fonctionnalité élevée directement compressible, son procédé de fabrication et son utilisation
WO2010059534A2 (fr) * 2008-11-19 2010-05-27 Mallinckrodt Baker, Inc. Excipient à base de cellulose microcristalline granulaire directement compressible, procédé de fabrication et utilisation de cet excipient
WO2010059534A3 (fr) * 2008-11-19 2011-01-20 Avantor Performance Materials, Inc. Excipient à base de cellulose microcristalline granulaire directement compressible, procédé de fabrication et utilisation de cet excipient
JP2012509326A (ja) * 2008-11-20 2012-04-19 アバントール パフォーマンス マテリアルズ， インコーポレイテッド 直接圧縮可能で高機能性な顆粒状のリン酸水素カルシウムベースの共に処理された賦形剤
WO2011074961A1 (fr) 2009-12-18 2011-06-23 Frieslandcampina Nederland Holding B.V. Composition d'excipient de comprimé co-traité, sa préparation et son utilisation
US10071059B2 (en) 2009-12-18 2018-09-11 Frieslandcampina Nederland Holding B.V. Co-processed tablet excipient composition its preparation and use
US11040012B2 (en) * 2014-07-30 2021-06-22 Merck Patent Gmbh Pulverulent, directly compressible polyvinyl alcohol grades
WO2023012162A1 (fr) 2021-08-03 2023-02-09 Dfe Pharma Gmbh & Co. Kg. Procédé de préparation de granulés d'excipients co-traités
WO2023025672A1 (fr) 2021-08-25 2023-03-02 Basf Se Composition auxiliaire de compression directe

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