WO2007050631A2 - Forme posologique a enrobage actif - Google Patents

Forme posologique a enrobage actif Download PDF

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Publication number
WO2007050631A2
WO2007050631A2 PCT/US2006/041524 US2006041524W WO2007050631A2 WO 2007050631 A2 WO2007050631 A2 WO 2007050631A2 US 2006041524 W US2006041524 W US 2006041524W WO 2007050631 A2 WO2007050631 A2 WO 2007050631A2
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WIPO (PCT)
Prior art keywords
dosage form
active ingredient
amount
tablet
weight
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Application number
PCT/US2006/041524
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English (en)
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WO2007050631A3 (fr
Inventor
Derek Moe
Manuel A. Vega Zepeda
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Cima Labs Inc.
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Publication of WO2007050631A2 publication Critical patent/WO2007050631A2/fr
Publication of WO2007050631A3 publication Critical patent/WO2007050631A3/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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

Definitions

  • Orally dissolvable dosage forms are produced in many forms.
  • certain drugs and/or applications may provide unique challenges.
  • Chewable tablets for example, often provide inadequate taste-masking of bad tasting active ingredients.
  • Chewable tablets may also be incompatible with time-released agents, as chewing or compressive forces used to manufacture the dosage form often results in rupture of the agents, resulting in alteration of the intended drug delivery and/or exposing the patient to a bad-tasting ingredient.
  • Non-chewable dosage forms have also been tried.
  • Such dosage forms include, for example, freeze-dried rapidly dissolvable tablets, and oral dosage forms including microparticles and effervescents which rapidly disintegrate in the mouth and provide adequate taste-masking, such as produced by Cima. See Wehling et al . , U.S. Pat. No. 5,178,878. While these dosage forms are effective, the dosage , forms often break or crumble during production, storage, transport and consumer usage. In addition, these products generally require special packaging, such as blister packs, which results in added expense for manufacture and storage .
  • Other dosage forms are also known which are more robust, including a non-direct compression filler, which has a friability of about 2% or less as measured by the U. S. P. method and a hardness of greater than about 15 Newtons . These can be produced and packaged using traditional equipment and can be packaged in multi-tablet bottles .
  • Coated APAP particles intended to provide taste masking produced using a number of traditional techniques which are commercially available were considered. These included APAP granules manufactured using a microencapsulation technique, high shear granulation and traditional fluidized bed coating technology and all proved inadequate in this delivery format. Some proved sticky. Some prevented obtaining a low enough friability or provided too long an in mouth disintegration/dissolution time. Some proved difficult to blend, or capped when tableted and some provided inadequate taste masking, even though these same materials had proven useful in other formats.
  • the present invention is directed to rapidly dissolvable/disintegrable dosage forms including a coated active which is either a dual spray dried coated active ingredient (also herein referred to as "co-spray dried") or another such coated active with like properties, the dosage form being adapted for direct oral dosing.
  • a coated active which is either a dual spray dried coated active ingredient (also herein referred to as "co-spray dried") or another such coated active with like properties, the dosage form being adapted for direct oral dosing.
  • co-spray dried particles of active and a taste masking material succeeded where other coated forms did not .
  • a co-spray dried active reduces the level of stickiness, and produces good disintegration, friability, taste-masking and blend density allowing for the production of tablets of desirable properties. Stickiness is visually measured by the amount of material that "sticks" on the die, press, or sides of the punch. An undesirable amount of stickiness results in stripes on the dosage forms, or capping or breaking of the dosage forms.
  • the "dosage form adapted for direct oral dosing" or more simply the “dosage form(s)" of the invention are defined as dosage forms (tablets, capsule, caplets, films, and the like) adapted to rapidly dissolve/disintegrate in the mouth, before being swallowed. After the dosage form dissolves and/or disintegrates in the mouth, the resulting solution, slurry or suspension is swallowed such that the coated active ingredient can enter the digestive tract down stream of the mouth. Once the coating dissolves, is breached, or the active ingredient in some way migrates across the coating, the active can enter the blood stream via the stomach and/or intestines.
  • the coating provides some measure of taste masking sufficient to allow the dosage form to dwell in the mouth for a time that is sufficient to allow the dosage form to dissolve/disintegrate in the mouth before the active particles are swallowed, without exposing the patient to a taste that is sufficiently bad to discourage use of the dosage form.
  • the dosage form has a friability of about 2% or less, more preferably 1.5% or less when tested according to the U. S Pharmacopoeia No. 23, 1995, Chap. 1216 entitled “Tablet Friability.” In the context of friability, this is what is contemplated by the phrase “by U. S. P.” or words to that effect.
  • the dosage form will preferably have a hardness of about 50 Newtons or more, and more preferably greater than about 60 Newtons, and most preferably greater than about 75 Newtons. In yet another embodiment, where the size of the dosage form is less than 0.5 inches in any one dimension, the dosage form will preferably have a hardness of about 35 Newtons or greater, more preferably about 50 Newtons or greater and even more preferably, 60 Newtons or more. Hardness will generally not exceed 250 Newtons in either case.
  • a rapidly dissolvable/disintegrable oral tablet adapted for direct oral dosing having a friability of about 2% or less when measured by U. S. P. and a hardness of about 35 Newtons or more, more preferably about 40 Newtons or more, even more preferably about 45 Newtons or more; even more preferably about 50 Newtons or more, and even more preferably about 60 Newtons or more and which includes at least some nondirect compression sugar and a coated active produced by co-spray drying.
  • the dosage forms have co-spray dried particles having one or more of the following properties, a bulk density of about 0.1 to about 0.90 g/cm 3 , and/or a desirable porosity, and/or a particle size distribution of not more than 1% retained on a 600 micron screen, not more than 5% by weight retained on a 250 micron screen and not more than 50% through a 75 micron screen.
  • a rapidly dissolvable/disintegrable oral tablet having a size of about 1/2 inch or greater in at least one dimension, including at least one coated active ingredient which is provided by co-spray drying in a dosage of about 50 mg or more of the active, having a friability of about 1.5% or less when measured by U. S. P., and having a hardness of about 60 Newtons to about 250 Newtons.
  • an orally dissolvable/disintegrable dosage form adapted for direct oral dosing, said dosage form comprising a therapeutically effective amount of at least one coated active ingredient formed by co-spray drying an active ingredient and a coating, wherein said coated active ingredient has at least one of a bulk density of about 0.1 to about 0.90 g/cm 3 , a desirable porosity and/or has a particle size distribution of at least about 75% by weight between 30 and 200 mesh (74-590 microns) .
  • the dosage form also preferably comprises at least one filler in an amount about 5% to about 95% by weight of said tablet, and at f *- ' KAafitft wherein said tablet has a friability of about 2% or less; and a hardness of between about 60 Newtons to about 250 Newtons and will disintegrate/dissolve in a patient's mouth within about 60 seconds.
  • an orally dissolvable/disintegrable tablet adapted for direct oral dosing, said tablet comprising a therapeutically effective amount of at least one coated active ingredient formed by Co-spray drying acetaminophen and a coating material, wherein said coated active ingredient has a bulk density of about 0.2 to about 0.75 g/cm 3 , has a desirable porosity, and/or has a particle size distribution of not more than 1% retained on a 600 micron screen, not more than 5% retained on a 250 micron screen and not more than 50% through a 75 micron screen or 75% by weight between 30 and 200 mesh; and at least one filler in an amount about 5% to about 95% by weight of said tablet, wherein said tablet has a friability of about 1.5% or less; and a hardness of between about 60 Newtons to about 250 Newtons which will disintegrate/dissolve in a patient's mouth within about 60 seconds.
  • the dosage forms are tablets and
  • the . dosage form, caplet, or tablet may be stored in "bulk", e.g. drums, bulk bins, hoppers, and/or packaged in conventional openable and reclosable multi-tablet bottles, or other similar packaging.
  • bulk e.g. drums, bulk bins, hoppers, and/or packaged in conventional openable and reclosable multi-tablet bottles, or other similar packaging.
  • Methods of making these dosage forms are also contemplated. DETAILED DESCRIPTION
  • Rapid dissolve (able) and/or disintegrate (able) means that the rapidly water soluble ingredients within the dosage form will dissolve and or disintegrate sufficiently to allow ingestion as a solution, suspension or slurry in 60 seconds or less, preferably 40 seconds or less, and most preferably 30 seconds or less. Most preferably, the solution, s ⁇ speT ⁇ si ⁇ 5i ⁇ or sTurry will be considered non-gritty (of course at least the coated active remains even when the water-soluble ingredients have dissolved) .
  • a dosage form in accordance with the invention can be considered “dissolvable” or “disintegrable” or both depends upon at least the nature of the dosage form, the load of coated active, the size of the dosage form and the other materials used.
  • “Dissolving” in accordance with the present invention is a process similar to melting in one's mouth and depends upon a number of factors, including, the degree of water solubility of the ingredients in question and how much of the dosage form is composed of rapidly water-soluble ingredients. This involves the nature of the material (its inherent solubility in water at 25 degrees C. (in a glass) or 37 degrees C.
  • the dosage form includes at least one co-spray dried, coated active ingredient and may also include, without limitation, uncoated actives, actives which while coated have not been coated in accordance with the invention or do not have the properties of coated actives in accordance with the invention as described herein (collectively included within the terms “uncoated”, “non-coated” or “not coated” unless the context suggests otherwise) , as well as other ingredients or excipients including fillers (including both nondirect “ ⁇ " C ⁇ mp'r'es's ⁇ b'h 'su'gafs and direct compression sugars), lubricants, glidants, taste masking agents, wicking agents (disintegrants both effervescent and non-effervescent) , binders, binder- disintegrants, pH adjusting substances, flavors, sweeteners, colorings, preservatives, additional coatings and the like.
  • fillers including both nondirect " ⁇ " C ⁇ mp'r'es's ⁇ b'h
  • dosage forms in accordance with the invention can be made by any method, including, without limitation, those methods of making dosage forms as described in Khankari et al. , U.S. Patent No. 6,024,981. That patent is hereby incorporated by reference.
  • dosage forms which are in the form of tablets or caplets in accordance with the present invention can be produced by direct compression, compression molding and like techniques. Direct compression is a process where all of the materials are fed into a high-speed multi-tablet press (or a like commercial scale device when dosage forms other than tablets are being produced) as a dry mixture and then compressed into tablets, caplets or materials that can be filled into a capsule is preferred.
  • Direct compression can be accomplished using materials that are "directly compressible” (generally materials that have been engineered, often from nondirectly compressible materials, such that they can flow and/or compress sufficiently to allow them to be used in practical, commercial scale direct compression methods).
  • Wet or dry granulated materials are in many cases direct compression materials, although, depending upon the technique used, the results of such granulation techniques, the resulting granulate, may or may not remain directly compressible.
  • Materials which would not be considered directly compressible - nondirect compression fillers - may also be used to the extent that the resulting dosage forms have the desired properties of the invention. Likewise, whatever techniques used must still provide dosage forms in accordance with the present invention.
  • Active ingredients in accordance with the present invention preferably include materials capable of being spray-dried, capable of being co-spray-dried, or which are otherwise useful in the present invention.
  • Such active without limitation, systematically distributable pharmaceutical ingredients, vitamins, minerals, dietary supplements, as well as nonsystemically distributable drugs.
  • a combination or mixture of any of the foregoing is also contemplated by the present invention.
  • Pharmaceutical ingredients may include, without limitation, antacids, analgesics, anti inflammatories, antibiotics, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, antiflatuents, antimigraine agents, antispaspodics, sedatives, antihyperactives, antivirals, antihypertensive, tranquilizers, decongestants, beta blockers and combinations thereof as well as salts of any of the foregoing.
  • pharmaceutical ingredient (s) and “active agents” are the drugs and pharmaceutical active ingredients described in Mantelle U.S. Patent No. 5,234,957 includes 18 through 21. That text is hereby incorporated by reference.
  • the active ingredients are acetaminophen and hydrocodone.
  • the acetaminophen is a coated active ingredient in accordance with the invention and the hydrocodone is not .
  • Also particularly preferred active ingredients are fentanyl, codeine, clarithromycin, erythromycin, azithromycin, amoxicillin, fexofenadine, oxycodone, ibuprofen, phenitol, acyclovir, famciclovir, DOPA, L-DOPA, and tramadol, as well as their salts.
  • the amount of active ingredient used can vary greatly and can depend upon, among other things, the active, the condition it is intended to treat, the size and type of the patient, the question of whether or not it is a rapid or controlled release dosage form, the size and nature of the dosage form, and whether or not more than one active is to be delivered from a single or multiple dosage forms.
  • the total amount of active ingredient for any individual dosage form is provided in an amount of about 0.01 milligrams to about 2 grams, more preferably about 0.1 milligrams to about 1 gram, even more preferably about 0.1 to about 800 milligrams by ⁇ ⁇ We * igntT ⁇ nd mo v 's"t 'preferred is about 50 to about 800 milligrams by weight.
  • Non-coated active (a term which generally includes coated actives that are not coated in accordance with the invention) may be used in addition to the at least one coated active ingredient (a term limited to active particles produced in accordance with the present invention e.g. co-spray dried particles) . While any amount of coated and non-coated actives as described herein are possible, so long as there is at least some coated active in accordance with the present invention, in one embodiment, the amount of any coated active ingredient (s) in accordance with the invention should be equal to, or greater than the amount of any non-coated active ingredient .
  • Example 1 describes one preferred composition in accordance with the present invention.
  • the amount of co-spray dried active containing particles used in any dosage form in accordance with the present invention will generally range from between about 5% and about 95% by weight of the dosage form, more preferably between about 15% and about 85% by weight of the dosage form, and most preferably between about 30% and about 70% by weight of the dosage form.
  • the amount of non-coated active used in combination with a coated active in any dosage form in accordance with the present invention will generally range from between about 0.05% and 30% by weight of the dosage form, more preferably between about 0.1% and about 20% by weight of the dosage form, and by weight of the dosage form, and most preferably between about 0.3% and about 10% by weight of the dosage form.
  • the coated active has a bulk density of about 0.10 g/cm 3 to about 0.90 g/cm 3 , and more preferably about 0.30 g/cm 3 to about 0.75 g/cm 3 bulk density
  • the bulk density is g/ctn 3 to about 0 - 75 g/cm consult3 3/ and more preferably about 0.30 g/cm 3 to about 0.70 g/cm 3 .
  • the co-spray dried active will preferably have a desirable porosity which results from being spray dried, or co-spray dried with the coating. In one embodiment, the coated active will have a porosity of ⁇ 50% of that of the Faulding acetaminophen Batch No. 60718130. (See Example 2)
  • the coated active have a particle size distribution (sieving analysis) of not more than 1% retained on a 600 micron screen, not more than 5% retained on a 250 micron screen and not more than 50% through a 75 micron screen. Of course, overs and unders could be discarded. (See Certificate of Analysis at Example 2) In another embodiment, it is preferred that the coated active have a particle size distribution (sieving analysis) of not more than 2% retained on a 600- micron screen, not more than 7% retained on a 250 micron screen and not more than 25% through a 75 micron screen. Again, overs and unders could be discarded. In still another embodiment, it is preferred that at least about 75% of the coated active used, by weight, falls between 30 and a 200 mesh size.
  • Acetaminophen granules were manufactured using a micro encapsulation technology.
  • the Acetaminophen granules were manufactured using a high shear granulation technology, (manufactured in-house) 3
  • the Acetaminophen granules were manufactured using a coating technology from Ethypharm, Lot No. 020910-51.
  • 4 The Acetaminophen granules were manufactured using a fluid bed top spray granulation technology, (manufactured in-house) [0027] Different materials were used — in different ways.
  • the material of Example 2 was a co-spray dried material in accordance with the present invention (identified in Table 1 as "spray dry”) and was found effective.
  • 1029-DLG-059 (particle size: 30 mesh 4.4%, 40 mesh 3.0%, 60 mesh 6.3%, 80 mesh 8.3%, 120 mesh 17.3%, 200 mesh 40.3%, pan 20.3%); Lot No. 1029-DLG-077 (particle size: 30 mesh 5.2%, 40 mesh 4.1%, 60 mesh 9.0%, 80 mesh 10.4%, 120 mesh 31.6%, 200 mesh 33.0%, pan 6.6%); Lot No. 1029-DLG-078 (particle size: 30 mesh 2.2%, 40 mesh 0.9%, 60 mesh 9.6%, 80 mesh 13.0%, 120 mesh 34.8%, 200 mesh 34.9%, pan 4.5%); Lot No.
  • 1029-DLG-082 particle size: 30 mesh 4.0%, 40 mesh 2.5%, 60 mesh 5.2%, 80 mesh 5.3%, 120 mesh 12.6%, "* * ⁇ IO'bHttsMnWs"58 1 Ir 11 PaIi 24.5%); Lot No. (particle size: 30 mesh 0.0%, 40 mesh 0.6%, 60 mesh 7.3%, 80 mesh 46.4%, 120 mesh 23.0%, 200 mesh 22.2%, pan 0.2%); and Lot No. 1029-DLG-109 (particle size: 30 mesh 0.6%, 40 mesh 0.2%, 60 mesh 23.5%, 80 mesh 49.9%, 120 mesh 21.1%, 200 mesh 4.1%, pan 0.6%).
  • coating of the active is accomplished through a co-spray dried process.
  • the active or at least that portion to be coated in accordance with the present invention, and the coating material, are mixed, dissolved, suspended or the like and spray dried together.
  • the relative proportion of active ingredient and coating material by weight can range from between about 49:1 and about 1:19, more preferably from between about 19:1 and about 1:9, even more preferably, between about 9:1 and about 1:1.
  • Spray drying is a well-known method of powder agglomeration used to produce pharmaceutical products.
  • Preferred attributes of spray dried materials are that they often are generally spherical, have a relatively higher surface area compared to fused agglomerates, and have a relatively low density.
  • Spray-dried products are generally made by dissolving, dispersing or suspending a drug in a volatile solvent to form a drug solution, dispersion or suspension (collectively dry solution unless context suggests otherwise) combining at least one pore forming or film forming agent with the drug solution to form an emulsion, suspension, or second solution, and removing at least a portion of the volatile solvent and pore forming or film forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug.
  • both the active and the coating materials are dissolved, suspended or dispersed in the solvent or carrier.
  • the temperature of the inlet and outlet ports of the drying chamber, as well as the flow rates of the feed solution, atomization gas, and drying gas, can be controlled to produce the desired products.
  • Conventional techniques used in pharmacy are contemplated including the spray drying methods described in U.S. Pat. Nos. 6,869,550, 6,025,034, and 5,853,698, which are hereby incorporated by reference.
  • the coating materials which may be used in coating and/or co-spray drying, should assist in taste masking — making sure that the unpleasant taste of the active is minimized during that period of time that the dosage form is in the mouth before being swallowed. It is not a material that must provide complete taste-masking alone. Flavors, sweeteners, effervescent disintegration agents and the like may be used as well.
  • the coatings may be rapid release or controlled release. Rapid release means that once the coated active has been swallowed, the coating permits the active to dissolve or otherwise be released.
  • Controlled release includes sustained release dosage forms which release their content over a prolonged period of time. This could be a period of as little as six hours and as much as 24 hours, or even longer. Release can be smooth, in pulses or in any other specifically controlled way. Controlled release also includes enteric coatings - coatings that will release their contents when the dosage form enters the intestines. While couched primarily in terms of tablets, this applies to capsules and other dosage forms as well .
  • Coating materials may include natural or synthetic polymer including acrylic polymers, modified celluloses, and the like.
  • the coating materials are pH dependant materials that become soluble at a pH of 6.0-6.5 or below such as EUDRAGIT, from Rohn & GmbH, Chemische Fabrik, Kirschenallee, D-64293 Darmstadt, Germany, a group of acrylic polymers including for example, without limitation EUDRAGIT ElOO, modified celluloses such as ethyl cellulose, methyl cellulose, hydroxypropylcellulose, sodium carboxy methyl cellulose, hydroxyethylcellulose, polyoxymer, and/or hydroxypropylmethylcellulose .
  • the result is a material with a relatively tight particle size distribution, an advantageous average particle size, enhanced porosity and yet it is taste masked. It is believed that the coating materials tend to migrate to the exterior forming a coating or shell, or at least providing sufficient taste masking by reducing the exposed surface area of the active ingredient.
  • the porosity of the resulting co-spray dried coated active particles are believed, again without being limited to any particular theory, to be at least more porous at the center, that portion more rich in the active ingredient, and generally less porous at the level of the coating.
  • taste masking can be measured by placing a dosage form in the mouth and retaining it in the mouth until it dissolves/disintegrates in the mouth to the point where it would be swallowed. It may be swallowed or spit-out at that point. If the taste does not force one to spit out or swallow the dosage form prematurely, taste masking is adequate.
  • Any other technique which can produce coated active with properties which match those produced by co-spray drying may also be used.
  • One such way may be spray-drying an active ingredient followed by coating wherein the active ingredient is substantially coated. These are considered co-spray dried coated actives in accordance with the invention.
  • the preferred amount of coating is about 1% to about 300% weight gain of the dosage form, and more preferably about 5% to about 200% weight gain of the dosage form.
  • the rate limiting step in production is the speed at which the tablets can be individually handled and placed in a protective, usually specially designed, blister-style package.
  • the tablets are too fragile to withstand the forces involved in being dumped into the bulk-hopper of a packager or into some other form of intermediate or long-term storage vessel.
  • the dosage forms preferably have a friability of about 2% or less, more preferably 1.5% or less when tested accwM'nfT to tie" latest U. S Pharmacopoeia No. 24, 2006,
  • the dosage form will preferably have a hardness of about 50 Newtons or more, and more preferably greater than about 60 Newtons, and most preferably greater than about 75 Newtons. In yet another embodiment, where the size of the dosage form is less than 0.5 inches in any one dimension, the dosage form will preferably have a hardness of about 35 Newtons or greater, more preferably about 60 Newtons or greater. Hardness will generally not exceed 250 Newtons in either case.
  • a rapidly dissolvable/disintegrable oral tablet adapted for direct oral dosing having a friability of about 2% or less when measured by U. S. P.
  • the dosage forms have co-spray dried particles having one or more of the following properties, a bulk density of about 0.90 g/cm 3 or less, a desirable porosity, and/or a particle size distribution of not more than 1% retained on a 600 micron screen, not more than 5% by weight retained on a 250 micron screen and not more than 50% through a 75 micron screen
  • a spray dried coating or co-spray dried active reduces the level of stickiness, and produces good disintegration, friability, taste-masking and blend density allowing for the production of tablets of desirable properties.
  • a rapidly dissolvable/disintegrable oral tablet having a size of about 1/2 inch or greater in at least one f "' 1 T / ft It «u iflf K /' »4 1 H IR p U-
  • the dosage forms in accordance with the present invention can be placed in conventional openable and recloseable multi-tablet bottles or other similar packaging. That is to say that in accordance with the present invention, it is possible to provide more than a single dose in the lumen of a single, reopenable and reclosable package. Not only are such packages considerably less expensive over the cost of the number of tablets provided, but they are also far more efficient in terms of processing.
  • two-sided foil and other relatively soft, pliant envelope-type packages may be used in combination with the dosage forms in accordance with the present invention. It is not possible to use such packages, or even less protective blister-packs, with some of the relatively friable orally-disintegrable tablets of the prior art. [ ⁇ ohr ⁇ n • " " addition, in accordance with the present invention, conventional feeders can be used to feed the dosage forms into any type of packaging equipment .
  • the dosage form of the present invention generally also include at least one excipient.
  • Any conventional excipient may be used so long as it meets the overall objectives of the present invention, including taste masking and when formulated into an oral dosage form in accordance with the present invention, hardness, friability and rapid dissolvability/disintegrability in the mouth.
  • Excipients in accordance with the present invention may include fillers such as sugars, binders, effervescent or non-effervescent disintegration agents, coloring agents, flavoring agents, lubricants, wicking agents, and the like.
  • Binders can be anything known to be used as binders. Some binders that may be useful in the present invention include acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, sugars, invert sugars, and the like. Binders can be used in conventional amounts and preferably in an amount of up to 60 percent by weight and more preferably about 10 to about 40 percent by weight of the total dosage form.
  • Effervescent disintegration agents useful in the present invention can be anything known to be used as an effervescent disintegration, such as described in Wehling et al. , U.S. Patent No. 5,178,878 cols. 5-7, incorporated by reference herein and attached as part of this provisional application.
  • the acid sources or acid for the effervescent agent may be any which are safe for human consumption and may generally include food acids, acid anhydrides and acid salts.
  • Food acids include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acids etc.
  • Acid anhydrides and acid of the above described acids may also be used.
  • Acid salts may include sodium, dihydrogen phosphate, disodium dihydrogen pyrophosphate, acid citrate salts and sodium acid sulfite.
  • Carbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate and amorphous calcium carbonate .
  • the effervescent disintegration agent (s) of the present invention is not always based upon a reaction which forms carbon dioxide. Reactants which evolve oxygen or other gasses which are pediatrically safe are also considered within the scope.
  • the effervescent agent includes two mutually reactive components, such as an acid source and a carbonate source, it is preferred that both components react completely. Therefore, an equivalent ratio of components which provides for equal equivalents is preferred. For example, if the acid used is diprotic, then either twice the amount of a mono-reactive carbonate base, or an equal amount of a di-reactive base should be used for complete neutralization to be realized. However, in other embodiments of the present invention, the amount of either acid or carbonate source may exceed the amount of the other component .
  • the amount of effervescent disintegration agent of the present invention useful for the formation of tablets according to the present invention should range from about 2 to about 50% by weight of the final composition, and preferably between about 5 and about 40% by weight thereof.
  • Non-effervescent disintegrants or wicking agents can be anything known to be used as non-effervescent disintegrants.
  • Sbme"Son-eifervescent disintegrants that may be useful in the present invention include microcrystalline cellulose, (AVICEL PH 200, AVICEL PH 113, AVICEL PH 101), AC-Di-SoI (Croscaramellose Sodium) and PVP-XL (a crosslinked polyvinylpyrrolidone) ; starches and modified starches; polymers; hydroxyalkyl cellulose such as hydroxymethylcellulose, hydroxypropylcellulose, and hydroxyopropylmethylcellulose, sodium starch glycolate as well as compounds such as carbopol; sweeteners; clays, such as bentonite; alginates; gums such as agar, Arabic, xanthan, guar, locust bean, karaya, pecitin and tragacanth.
  • Non-effervescent disintegrants may be used in conventional amounts and preferably in an amount of about 30 percent by weight and more preferably between about 2 and about 25 percent by weight of the dosage form.
  • Coloring agents can be anything known to be used as a coloring agent.
  • Coloring agents useful in the present invention may include titanium dioxide, and dyes suitable for food such as those known as F.D.&C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta- carotene, annatto, carmine, turmeric, paprika, etc. Coloring may be used in conventional amounts, and preferably in an amount ranging from about 0.05% to about 3.5% by weight, and more preferably 0.1% to 2.0% by weight of the total dosage form.
  • Flavoring agents can be anything known to be used as flavoring agents. Flavoring agents that may be useful in the present invention may include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.
  • synthetic flavor oils and flavoring aromatics and/or natural oils extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.
  • flavoring agents are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, PE cherry, plum, pine-apple, apricot and so forth. Flavoring agents may be used in conventional amounts, and preferably in an amount ranging from about 0.1% to about 3.0% by weight of the total dosage form.
  • Lubricants can be anything known to be used as a lubricant.
  • Lubricants that may be useful in the present invention may include intrinsic or extrinsic lubricants.
  • Intrinsic lubricants may include magnesium, calcium, zinc salts of stearic acid, hydrogenated and partially hydrogenated vegetable oils, animal fats, polyethylene glycol, polyoxyethylene monostearate, talc, light mineral oils, sodium benzoate, sodium lauryl sulphate, magnesium oxide and the like.
  • Lubricants may be used in conventional amounts, and preferably in an amount of up to 5.0% by weight and more preferably between about 0.5% and about 4.0% by weight, and most preferably between about 1.25% and 3.0% by weight of the total dosage form.
  • Lubricants may also include those ingredients described in Wehling et al., U.S. Patent No. 5,178,878, cols. 8-9, incorporated herein by reference.
  • the dosage forms include at least some nondirect compression sugar ("sugar” is a term which includes sugar, aldoses, ketoses, sugar alcohols and other mono and disaccharides) .
  • nondirect compression sugars include, without limitation, dextrose, mannitol, sorbitol, lactose and sucrose.
  • these sugars generally exist as either a direct compression sugar, i.e., a sugar which has been modified to increase its compressibility and/or flow, or a nondirect compression sugar which does not have sufficient flowability and/or compressibility to allow it to be used in high speed processing and multi-tablet presses without some sort of augmentation such as, without limitation, a glidant to increase flow, granulation to increase flow and/or compressibility and the like.
  • a direct compression sugar i.e., a sugar which has been modified to increase its compressibility and/or flow
  • a nondirect compression sugar which does not have sufficient flowability and/or compressibility to allow it to be used in high speed processing and multi-tablet presses without some sort of augmentation such as, without limitation, a glidant to increase flow, granulation to increase flow and/or compressibility and the like.
  • techniques like granulation can also be used to convert something which initially has sufficient flow * a ⁇ i ⁇ OdfnpYessiblTity to be considered a direct
  • Nondirect compression sugars and direct compression sugars may both be used or either may be used individually, however, in one embodiment, it is preferred that there be at least some nondirect compression sugar present and the resulting dosage form has the performance properties of hardness, friability, dissolution/disintegration organoleptic properties (grittiness and mouth feel) and taste masking described herein.
  • the amount of total sugar used can range from about 5 to about 95% by weight of the dosage form. More preferably, the amount of sugar will range from about 15 to about 85% by weight and even more preferably between about 15 and 50% by weight. This is exclusive of other fillers, excipients and the actives used.
  • the amount of nondirect compression sugar used if in a mixture with direct compression sugars, can range from about 5 to about 100% of the sugars . More preferably the amount of nondirect compression filler can range from about 30% to about 100% and more preferably 50% or more by weight of the sugars used.
  • cPotff" s -" >M "Ait ⁇ ugK the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.
  • EXAMPLE 1 Formulation for tableting by direct compression
  • Citric Acid USP/EP/JP 15 .60
  • Hydrocodone Bitartrate is a Schedule II as a Bulk
  • APAP Paracetamol powder
  • Faulding lot No. 60717860, which is similar to the material described in Example 2, and is a co-spray dried material coated with ethylcellulose like that described in, Example 2.
  • the weighing and blending process was completed with the material transferred to the V-blender by hand.
  • Sodium bicarbonate, citric acid, colloidal silicon dioxide and paracetamol powder were passed through the russell sieve with a 18 mesh screen.
  • Mannitol 60, crospovidone, sucralose, mint flavor and microcrystalline cellulose were passed through the comil with a 0.024" screen.
  • APAP Paracetamol powder
  • V-blender The content of the V-blender was blended for a total of 30 minutes (pre-lubrication blend time) .
  • the magnesium stearate was transferred through sweco and added to the V-blender.
  • the batch was then blended for 5 minutes.
  • the blend was discharged into double lined polyethylene bags in HDPE drums .
  • the batch was then run in the Manesty Beta Press, it was set up with 16 stations of 5/8" plain flat-faced punches.
  • the press was set to run at a speed of 37 rpm with pre-compression.
  • the tablet weight was set to 1300 mg and the hardness was set to an average of 90 N.
  • the thickness was measured and recorded on the batch record control charts.
  • the tablets were manufactured according to the batch record and observed for signs of capping, chipping, or picking.
  • the actual average tablet weight was 1300 mg and the average hardness was 94 N.
  • the average thickness of the tablets was 0.225 inches.
  • the tablets were collected in bulk drums.

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Abstract

L'invention concerne des formes posologiq ues pouvant se dissoudre/se désagréger par voie orale, qui sont conçues pour administration directe par voie orale et qui comprennent au moins un ingrédient enrobé actif obtenu par séchage par pulvérisation d'un ingrédient actif et d'un enrobage. Ces formes posologiques sont plus dures que celles, courantes, qui peuvent se dissoudre et se désagréger par voie orale, et leur intérêt réside dans leurs coûts de fabrication et de stockage.
PCT/US2006/041524 2005-10-25 2006-10-24 Forme posologique a enrobage actif WO2007050631A2 (fr)

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US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
CN102885791A (zh) * 2012-09-24 2013-01-23 浙江万马药业有限公司 一种制备盐酸非索非那定口腔崩解片的方法
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
CN106511286A (zh) * 2016-10-27 2017-03-22 四川省百草生物药业有限公司 一种高稳定性的泛昔洛韦片及其制备方法
US20170172950A1 (en) * 2013-11-13 2017-06-22 National Defense Education And Research Foundation New hepatotoxicity-free pharmaceutical composition containing acetaminophen drugs
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
JP2018158928A (ja) * 2018-05-25 2018-10-11 ▲財▼▲団▼法人国防教育研究基金会Ｎａｔｉｏｎａｌ Ｄｅｆｅｎｓｅ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ 肝臓に対する副作用がない、新しいアセトアミノフェン複合組成
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

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WO2000051568A1 (fr) * 1999-03-01 2000-09-08 Ethypharm Comprime orodispersible presentant une faible friabilite et son procede de preparation
WO2001089484A2 (fr) * 2000-05-22 2001-11-29 Verion, Inc. Procede pour augmenter la compressibilite de matieres pulverulentes a faible pouvoir de liaison

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US4952402A (en) * 1984-10-30 1990-08-28 Elan Corporation, P.L.C. Controlled release powder and process for its preparation
US4631284A (en) * 1984-11-19 1986-12-23 Mallinckrodt, Inc. Acetaminophen compositions containing low doses of chlorpheniramine maleate, method for preparing same and tablets formed therefrom
US4710519A (en) * 1985-09-30 1987-12-01 Basf Corporation Process for preparing spray dried acetaminophen powder and the powder prepared thereby
US4904477A (en) * 1987-07-08 1990-02-27 American Home Products Corporation Spray dried ibuprofen compositions
WO2000051568A1 (fr) * 1999-03-01 2000-09-08 Ethypharm Comprime orodispersible presentant une faible friabilite et son procede de preparation
WO2001089484A2 (fr) * 2000-05-22 2001-11-29 Verion, Inc. Procede pour augmenter la compressibilite de matieres pulverulentes a faible pouvoir de liaison

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8309613B2 (en) 2003-08-28 2012-11-13 Abbvie Inc. Solid pharmaceutical dosage form
US8333990B2 (en) 2003-08-28 2012-12-18 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8399015B2 (en) 2003-08-28 2013-03-19 Abbvie Inc. Solid pharmaceutical dosage form
US8691878B2 (en) 2003-08-28 2014-04-08 Abbvie Inc. Solid pharmaceutical dosage form
CN102885791A (zh) * 2012-09-24 2013-01-23 浙江万马药业有限公司 一种制备盐酸非索非那定口腔崩解片的方法
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US20170172950A1 (en) * 2013-11-13 2017-06-22 National Defense Education And Research Foundation New hepatotoxicity-free pharmaceutical composition containing acetaminophen drugs
US10420737B2 (en) * 2013-11-13 2019-09-24 National Defense Education And Research Foundation Hepatotoxicity-free pharmaceutical composition containing acetaminophen drugs
US11534416B2 (en) 2013-11-13 2022-12-27 National Defense Education And Research Foundation Hepatotoxicity-free pharmaceutical composition containing acetaminophen drugs
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
CN106511286A (zh) * 2016-10-27 2017-03-22 四川省百草生物药业有限公司 一种高稳定性的泛昔洛韦片及其制备方法
CN106511286B (zh) * 2016-10-27 2019-12-20 四川省百草生物药业有限公司 一种高稳定性的泛昔洛韦片及其制备方法
JP2018158928A (ja) * 2018-05-25 2018-10-11 ▲財▼▲団▼法人国防教育研究基金会Ｎａｔｉｏｎａｌ Ｄｅｆｅｎｓｅ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ 肝臓に対する副作用がない、新しいアセトアミノフェン複合組成

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