WO2007098446A2 - Méthode pour minimiser la variation dans des formes de dosage - Google Patents

Méthode pour minimiser la variation dans des formes de dosage Download PDF

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Publication number
WO2007098446A2
WO2007098446A2 PCT/US2007/062436 US2007062436W WO2007098446A2 WO 2007098446 A2 WO2007098446 A2 WO 2007098446A2 US 2007062436 W US2007062436 W US 2007062436W WO 2007098446 A2 WO2007098446 A2 WO 2007098446A2
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WO
WIPO (PCT)
Prior art keywords
composition
tablet
variation
fill
batch
Prior art date
Application number
PCT/US2007/062436
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English (en)
Other versions
WO2007098446A3 (fr
Inventor
Lawrence Solomon
Original Assignee
Accu-Break Pharmaceuticals, 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 Accu-Break Pharmaceuticals, Inc. filed Critical Accu-Break Pharmaceuticals, Inc.
Publication of WO2007098446A2 publication Critical patent/WO2007098446A2/fr
Publication of WO2007098446A3 publication Critical patent/WO2007098446A3/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

Definitions

  • the invention is directed to novel dosage forms and novel methods of manufacture of dosage forms containing one or more active ingredients, principally pharmaceuticals.
  • L-lhyroxine and other drugs such as those in the classes of narcotics, hypoglycemic agents, and vasoactive drugs, for which physicians closely regulate blood levels or their effects.
  • these drugs are especially preferred to be given in a dose that is as precise as possible.
  • the current invention is directed to a method of manufacturing a composition, e.g., a dosage form, such as a pharmaceutical product or drug product, in a manner that diminishes both the variation of mass and/or the amount or content of active drug(s) in these dosage forms in comparison to techniques currently known in the art.
  • a composition e.g., a dosage form, such as a pharmaceutical product or drug product
  • the subject invention also concerns a composition produced by the subject method.
  • the novel composition e.g., a dosage form made in accordance with the subject method is advantageously adapted for increased dosing accuracy of active ingredients contained therein.
  • the subject invention is especially concerned with a method for diminishing the variation within a "lot " ' of dosage forms; or between the average amount of drug per dosage form present in different lots of dosage forms produced according to the same formula, and with dosage forms that accomplish this improvement in the art.
  • the subject invention includes but is not limited to a method of producing a composition comprised of material also herein called "fill material.”
  • Fill material is material which is, or is intended to be, dispensed or placed, (i.e., "filled") into ⁇ receptacle to make a desired composition.
  • Fill material may for example be solid (e.g., a powder or granulation for placement into a die to form a compressed tablet), a liquid (e.g., a mixture, a solution, or melted wax or polymeric solution filling into a mold), or a gas (e.g., an gas anesthetic for dispensing into a compressed- gas container),
  • ' ihe receptacle may be such as a tablet die, a capsule, a glass container such as an ampoule, a vial, a bottle, a mold, a canister, and the like.
  • receptacle is non-limiting. Generally the receptacle will provide a shape or form to a solid composition or a liquid or gas that solidifies and will contain a liquid or gas composition that remains a liquid or a gas.
  • a dosage form may be produced using one or more of the above three embodiments (or other related embodiments as may be apparent from the disclosures herein).
  • the method of embodiment (1) above, as applied to the manufacture of a 500 mg pharmaceutical tablet can, for example, comprise the following steps: a) dispensing 250 mg fill material from a batch of a granulation (the fill material) into a tablet die (a "receptacle"), followed by dispensing a second 250 mg of the same batch of granulation into the tablet die.
  • the subject method can comprise the steps of (a) providing a batch of fill material, (b) partially filling the receptacle with the fill material and (c) completing the filling of the receptacle with the fill material.
  • the sequential filling of a tablet die per this example of the invention is most conveniently done during high-speed production by dividing the batch into a plurality of hoppers, but no limitation to this technique is intended.
  • 'lhe subject method further comprises the embodiment wherein a plurality of batches are produced according to the same formula (or substantially similar formulae) and are used as separate partial fills into the receptacle Io produce the tinal dosage form.
  • Another embodiment of the subject method considered as the invention includes making according to the same formula (or substantially similar formulae) a first and a second sub- batch of fill material and mixing the sub-batches to form a new batch of fill material.
  • This new batch of fill material can be dispensed one time into the receptacle to form the final composition, or, according to (1) above, it can be dispensed a plurality of times as portions of the final composition.
  • the subject invention advantageously provides a method of minimizing variation between or within production lots of units of a composition.
  • the method comprises, generally, the steps of providing a plurality of subportions of said composition or unit and forming the composition or unit as a whole from said subportions.
  • the preferred composition made by the subject method is a pharmaceutical product.
  • ⁇ more preferred composition made according to the subject method is a pharmaceutical tablet or fill for a pharmaceutical capsule,
  • Certain preferred pharmaceutical tablets of the subject invention arc -substantially homogeneous yet are stratified, having been produced in a layered fashion,
  • An example is a tablet comprising two layers, each derived from substantially compositional Iy identical (though with each layer potentially containing slightly or substantially different quantities of material) granulations introduced separately and sequentially into the same tablet die.
  • Another preferred embodiment of the subject invention involves a tablet comprising three or more compositionally substantially identical layers, produced by a method wherein each of the three or more layers is introduced separately into the same die.
  • a pharmaceutical capsule that is filled more than once with a substantially compositionally identical mixture or powder.
  • Another embodiment of the invention comprises a capsule that contains a pharmaceutical tablet produced by a method of the invention.
  • the subject invention provides its benetit(s) in part because of the statistical phenomenon of reversion to the mean (also called regression to the mean).
  • the current art for such products as single-agent products or fixed dose combinations consists of creating a substantially homogeneous tablet or fill to be used in a capsule by one fill of powder, paniculate, granulation, pellets, or the like, comprising a drug or drugs. Variation of the quantity of fill is acknowledged as the usual situation by persons of ordinary skill in the art. Assuming substantially homogeneous distribution of drug(s) within said powder (or fill, etc,)- the variation of drug(s) contained in the final dosage form will reflect the variation of quantity or weight of material containing or comprising that drug used in dosage form production.
  • the subject invention concerns a novel method of manufacture, and product of that method, preferably wherein the method leads to less variation between dosage forms, or lots of dosage forms, than conventional methods.
  • the subject method can be applied so that the variation of the actual value for a measured parameter from a theoretical or expected value for that parameter is lessened for each lot or batch of product, as compared to the variation of the actual values from theoretical values of each lot or balch of conventionally manufactured product.
  • Dosage forms of most of the embodiments of the subject invention are created in a manner more complex than has heretofore been described or taught for homogeneous products.
  • many preferred embodiments of the subject invention comprise creation of the tablet in layers. Layers have generally been taught to be different from each other within a tablet or capsule fill, except as has been disclosed in WO 2005/1 12900.
  • two successive fills from the same batch of a granulation are placed into a die and a tablet comprising those fills is compressed.
  • compositionatly substantially identical fills could be utilized to form the tablet.
  • all fi lls could be identical, all fills could contain an active ingredient, or one or more fills could contain inactive ingredient.
  • Immediate release or controlled release granulations or drug products can be made using the method of the subject invention. Controlled release coatings may be applied after tablet compression.
  • ⁇ pharmaceutical liquid disposed in an ampoule also typically is placed in the ampoule in a single fit! step.
  • the method of the invention involves filling an ampoule more than once, with two or more fills used to provide a final volume that technically would have been feasible to create with one fill.
  • Variations of the methods of the subjeel invention include, in one embodiment, a batch of precursor materials (such as a granulation for tablets and capsules, or solution for liquid drug products) created and placed into a plurality of hoppers or appropriate container.
  • Dosage form creation per these embodiments involves both or more than two such "fills.”'
  • This counterintuitive approach in fact has a benefit not heretofore recognized: diminished variation between individual dosage forms within a production lot.
  • the different "fills " ' are deliberately created from batches that are separately produced according to the same formula or similar formulae. This also counterintuitive approach produces diminished variation between the average amount of drug per dosage form found between different production lots.
  • ⁇ preferred embodiment of the above methods involves utilizing material, especially but not limited to active drugs, from different production lots, fhis could be useful in any of the above embodiments, and can further minimize unwanted variation.
  • Batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.
  • Component means any ingredient intended for use in the manufacture of a drtig product, including those that may not appear in such drug product.
  • Drug product means a finished dosage form, for example, tablet, capsule, solution, etc., that contains an active drug ingredaria generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo.
  • In-process material means any materia! fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product.
  • Lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uni form character and quality within specified limits.
  • lot refers to the latter part of the above definition when it applies to either a drug dosage form or to an amount of a raw material used in formulations, such as an active pharmaceutical ingredient or excipient; i.e., to a raw material or to a drug product but not to a composition such as a granulation that has been prepared and is portioned out for use in a dosage form.
  • Strength means: (i) The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or
  • the subject method tends to provide less variation in drug product, rhis improved variation may involve the difference of the actual measured value with a production run (lot) from a theoretical value for the range, number, or frequency of certain measured parameters.
  • One object of the invention is to diminish the amount of variation between one Sot and a different lot produced according to the same formula and intended to have identical characteristics, including the average amount of drug per dosage form in each lot.
  • a first layer is utilized from a first granulation batch, and a second layer is added onto the first layer in the die.
  • This second layer comes from a different granulation batch produced from an identical formula as said first layer.
  • a third layer, and then a fourth or fifth layer, etc. may be added, as the tabletti ⁇ g equipment permits, with all layers preferably being derived from different granulation batches but identical formulations.
  • an inactive layer may be utilized, either as an outer layer or as in interior, interposed layer.
  • the different batches may further utilize different lots of ingredients, especially different lots of the active ingredient(s). This will tend to further minimize the effect on the final dosage form of any variation in the purity of the active ingredient.
  • a benefit of this invention is that a batch such as a granulation batch has certain variation, so that the average amount of active ingredient(s) tends to vary from the desired amount.
  • Standards are set by the USP and IiP in this regard, but any variation is undesirable.
  • the errors in each batch will tend to cancel each other out, tending to improve (diminish) the variation of the average amount of drug per dosage form from the predicted, desired amount.
  • one cause of variation involves different purities of active drug, utilizing di fferent lots of active drug will tend to improve (diminish) unwanted variation of the average amount of drug per dosage form from the predicted, desired amount.
  • This aspect of the invention which relates to tablets, may apply to all known tableting processes, including wet or dry blends or granulations (with the limitation as it applies to wet granulations as mentioned above), pelleti/ation, or the like, and various methods of production, such as slugging. direct compression, or roller compaction, without limitation, as are known in the art. Further, there is no limitation of this technique to tablets. Similar techniques may be utilized to fill capsules with capsule fill material a plurality of times from separately-produced batches that utilize the same formula. Similar techniques may be utilized to 1111 a canister, ampoule, or other container with a gas or a liquid a plurality of times.
  • Another embodiment of the invention involves the mixing of different sub-batches of granulation, whether applied to stratified or layered tablets as described herein, or to tablets or other dosage forms manufactured by conventional processes. For example, it is known to make relatively small batches of wet granulated material and then to combine them to allow adequate quantities of tablets to be produced in one production run. However, it has not been taught until the invention to mix separately made sub-batches together to reduce variation of a single lot or batch of a granulation. 1 hus. an embodiment of the invention involving tablets is the use of a plurality of dry granulations made from substantially similar or identical formulae to be mixed together, thus decreasing any variation or error of average drug content introduced by one granulation, again by the regression to the mean phenomenon. Dosage forms other than tablets may equally usefully utiiize this same technique, such as gases, solutions and other liquids, and capsule fill.
  • novel dosage forms such as tablets and novel methods ol manufacture of both novel and conventional dosage forms represent embodiments of the invention.
  • Differeni fills of the same granulation entering a tablet die sequentially diminish variation of weight on a tablet-to-tablet basis, assuming substantial fy homogeneous dispersion of the active ingrcdient(s) throughout the fill material.
  • the subject method advantageously provides diminished variation of the active mgredie ⁇ t(s) on a tablet-to-tablet basis as well. This will be the case should the quantity of fill material be independent from one layer to the next. In other words, the inevitable errors that occur when filling powder or other material into a tablet die will balance each other out, so that measurements of tablet weight/drug content, such as standard deviation, are diminished.
  • tablet layer presses generally have a second Jill which is dependent on a fu st or preceding fill, which therefore tends to correct or compensate for an error occurring in the first or preceding fill.
  • i f the quantity of a first fill into the die is less than predicted, there will be more space in the die for the second fill. If this second fill is of identical fill material to the first, then the tablet will be closer to predicted weight and active drug content than if the second fill were independent of the volume/weight of the first fill.
  • a preferred embodiment of ' the subject method can be carried out as follows: step (a) introduce into a die or mold two successive layers that are substantially identical, derived from the same batch, and contain a drug; step (b) introduce an inactive layer lacking drug in contact with the second layer of step (a); and step (c) repeat step (a) contact the inactive layer of step (b) with the first layer of step (c).
  • step (a) introduce into a die or mold two successive layers that are substantially identical, derived from the same batch, and contain a drug
  • step (b) introduce an inactive layer lacking drug in contact with the second layer of step (a)
  • step (c) repeat step (a) contact the inactive layer of step (b) with the first layer of step (c).
  • the result is a novel tablet that, assuming adequate dimensions of the inactive middle layer, may be broken through said middle layer to produce two '"tablettes" without breaking through the material entering in either step (a) or step (c).
  • the first tablette consists of all of the fill from
  • the second tablette consists of all of the fill from step (c) plus a part of the fill from step (b).
  • Each "tablette " thus formed comprises a first, “active” part that contains drug and second, “inactive” part formed from a fill lacking a drug.
  • Each tablette thus represents a dosage form.
  • This dosage form embodies the invention, as it consists of two substantially Identical layers, and thus demonstrates diminished tabletle-to-tablettc (dosage form to dosage form) variation.
  • tablets may be created utilizing both of the above techniques, i.e.. minimization of variation Irons batch-to-batch and tablet-to-tablet.
  • a mixture of two batches of a dry granulation may be sequentially added to a layered tablet.
  • a five layered tablet may be created.
  • the bottom and top (first and fifth) layers may be identical and from the same granulation batch; the second and fourth layer may be identical, from a different granulation batch, but of the same formula as the first and fifth layers, and the third (middle) layer may be inactive.
  • Capsules are typically filled once with a compact that is generally not considered to be a tablet, although special cases exist in which capsules comprise a plurality of tablets (as in Dilacor XROD) or a tablet plus other fill (as in Lotrel®).
  • a capsule lacking a tab ⁇ et is filled a plurality of times, either ( ⁇ ) with di fferent fills from the same granulation batch or other filling material, thus diminishing variation of capsule content within a production run. or (B) from separately made batches according to the same formula, thus diminishing variation between the average amount of active drug found in different lots (production runs) of capsules thus produced.
  • dosage forms that are able to be created by repeated additions of a partial dose to create a larger dosage form represent embodiments of the subject invention as well, both with regard to the principles of reduced variation of the material being provided in a final dosage lo ⁇ n, e.g., being compressed into a tablet, as well as reduced variation in the filling of a tabiet die, as described herein.
  • Another example involves solutions and mixtures.
  • dosage forms such as solutions, mixtures, and aerosols may be improved by lhe processes described herein, but the dosage forms thereby produced will not be inherently distinguishable from conventionally produced dosage forms.
  • pha ⁇ naceuiicals are suitable for the techniques and dosage forms of the invention.
  • drugs for which dosing precision is of greatest importance are drugs for which dosing precision is of greatest importance, as well as dosage forms that are frequently subdivided.
  • Warfarin sodium is an example of a drug that fits both of the above criteria.
  • ⁇ benzodiazepine such as alprazolam is another example.
  • liquids that are applied to plants may be improved with regard to content uniformity or lot to lot uniformity.
  • powders such as fertilizers have one or more active ingredients, and the accuracy of the concentration of the active ingredient(s) will be improved by utilizing more than one lot to produce the material that is packaged or utilized at one time, again by reversion to mean phenomena.
  • the techniques of the subject invention may be utilized in creation of injectable material, for example, the same techniques may be utilized earlier in the manufacturing process to diminish variation of intermediate substances.
  • the invention is not limited to any therapeutic class of pharmaceutical agent.
  • the cardiovascular, psychiatric, neurologic, oncologic, endocrinoiogic, analgesic, and antiinflammatory classes are of especial interest.
  • the invention is not limited to homogeneous tablets.
  • the invention may comprise novel tablets as are described in WO 2005/1 12898 in which an active drug is separated in a tablet from a different active drug via a preferably substantially inactive segment or layer. Due to the broad nature of the applicability of the subject invention, no limitation should be inferred except as specified herein.
  • the invention involves production methods and solid dosage forms. Substances such as liquids and gases, in which mixing occurs, cannot be readily differentiated from conventionally manufactured dosage forms, however. Also comprising the subject invention are the product specifications from implementing the methods of the invention. For example, consider a production run of amlodipine besylate plus suitable excipients, as are qualitatively disclosed in the Norvasc ® Package Insert (see Physicians Desk Reference. 2006 Ed.. which is incorporated by reference). Currently, Pfizer, Inc., the manufacturer of Norvasc®, has established certain specifications for within-lot ("content uniformity * ') and between- lot variations.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des formes de dosage et des méthodes de fabrication de formes de dosage qui contiennent un ou plusieurs principes actifs, principalement les médicaments qui ont, entre autres, moins de variation de comprimé à comprimé.
PCT/US2007/062436 2006-02-21 2007-02-20 Méthode pour minimiser la variation dans des formes de dosage WO2007098446A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US77550306P 2006-02-21 2006-02-21
US60/775,503 2006-02-21

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WO2007098446A2 true WO2007098446A2 (fr) 2007-08-30
WO2007098446A3 WO2007098446A3 (fr) 2007-12-13

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030185885A1 (en) * 2001-08-10 2003-10-02 Franz G. Andrew Non-granulated levothyroxine pharmaceutical compositions
US20040048931A1 (en) * 2002-07-12 2004-03-11 Craig Heacock Modafinil pharmaceutical compositions
US20050181042A1 (en) * 2002-02-15 2005-08-18 Bengt Herslof Composition for oral or rectal administration
WO2005112900A1 (fr) * 2004-05-21 2005-12-01 Accu-Break Technologies, Inc. Tablettes pharmaceutiques comprenant au moins deux segments unitaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030185885A1 (en) * 2001-08-10 2003-10-02 Franz G. Andrew Non-granulated levothyroxine pharmaceutical compositions
US20050181042A1 (en) * 2002-02-15 2005-08-18 Bengt Herslof Composition for oral or rectal administration
US20040048931A1 (en) * 2002-07-12 2004-03-11 Craig Heacock Modafinil pharmaceutical compositions
WO2005112900A1 (fr) * 2004-05-21 2005-12-01 Accu-Break Technologies, Inc. Tablettes pharmaceutiques comprenant au moins deux segments unitaires

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