WO2009005803A1 - Comprimé de combinaison avec une couche extérieure pouvant être mâchée - Google Patents

Comprimé de combinaison avec une couche extérieure pouvant être mâchée Download PDF

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Publication number
WO2009005803A1
WO2009005803A1 PCT/US2008/008191 US2008008191W WO2009005803A1 WO 2009005803 A1 WO2009005803 A1 WO 2009005803A1 US 2008008191 W US2008008191 W US 2008008191W WO 2009005803 A1 WO2009005803 A1 WO 2009005803A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
therapeutic agent
niacin
effective amount
layer
Prior art date
Application number
PCT/US2008/008191
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English (en)
Inventor
Joseph Peter Habboushe
Original Assignee
Joseph Peter Habboushe
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
Priority to JP2010514861A priority Critical patent/JP2010532358A/ja
Priority to EP08768855A priority patent/EP2170051A1/fr
Priority to CA2690956A priority patent/CA2690956C/fr
Application filed by Joseph Peter Habboushe filed Critical Joseph Peter Habboushe
Publication of WO2009005803A1 publication Critical patent/WO2009005803A1/fr
Priority to US12/646,395 priority patent/US8404275B2/en
Priority to US13/720,723 priority patent/US8652520B2/en
Priority to US14/152,744 priority patent/US20140220124A1/en
Priority to US14/880,067 priority patent/US20160030354A1/en
Priority to US15/340,594 priority patent/US20170042821A1/en
Priority to US15/925,513 priority patent/US20190091155A1/en
Priority to US16/438,204 priority patent/US20200046644A1/en
Priority to US17/239,319 priority patent/US20220008342A1/en

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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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the combination tablet of the present invention relates to the technical fields of medicine, pharmacology and drug delivery. More specifically, the invention disclosed herein relates to developing formulations for co-administering in a patient, two or more therapeutic agents.
  • the goal of co-administering a secondary therapeutic agent with the primary therapeutic agent is to achieve an effective level of the secondary therapeutic agent at the relevant target site (i.e., cell type, tissue, organ, and the like) during the time period that the side effects caused by the primary therapeutic agent would have been demonstrable had the primary therapeutic been administered individually.
  • the relevant target site i.e., cell type, tissue, organ, and the like
  • the problem becomes more complex when the pharmacokinetic parameters of the primary and secondary therapeutic agents are incompatible.
  • Niacin also known as nicotinic acid was introduced in the 1950s as the first effective lipid-modifying compound. Niacin was found to inhibit the mobilization of free fatty acids from peripheral tissues, reduce hepatic synthesis of triglycerides and secretion of very low- density lipoprotein (VLDL). Niacin has been shown to significantly lower levels of total cholesterol, LDL cholesterol, and triglyceride while increasing HDL cholesterol by blocking hepatic uptake of apolipoprotein A- 1. Further, niacin is perhaps the only available therapeutic agent that significantly lowers lipoprotein (a) and provides the greatest HDL cholesterol-raising effects of all available therapeutic agents.
  • VLDL very low- density lipoprotein
  • niacin administration also results in patients experiencing several side effects that have limited its widespread use.
  • the immediate release form of niacin (niacin IR) stimulates prostaglandin-mediated flushing of the face and trunk over a period of days after beginning treatment.
  • the extended and sustained release forms also cause the flushing reaction, although not to as great an extent.
  • Patients experiencing the flushing side effect experience a diminution of symptoms over time and eventually develop a tolerance to the flushing, but not against the lipid-lowering effects (Zoltan Benyo et al, December 2005).
  • the level of discomfort is such that many patients stop therapy in the early period of treatment and never reach the tolerant stage.
  • the dosing of niacin IR was three times per day, a factor that also contributed to low patient compliance.
  • niacin SR a sustained release form of niacin, i.e., niacin SR.
  • the niacin SR which requires a period of at least 12 hours for complete absorption, has met with only modest success. It was observed that niacin SR, was significantly less effective in lowering than the IR form, (e.g., see Knopp et al, June 1985), and also was associated with an increased incidence of hepatotoxicity and gastrointestinal intolerance. More recently, an intermediate or extended release form of niacin, niacin ER has been developed that has an absorption rate in the 8-12 hour range. Niacin ER lowers the rate of flushing observed with niacin IR, and lowers the hepatotoxicity incidence seen with niacin SR.
  • NSAID non-steroidal anti-inflammation drug
  • Cyclooxygenase is an enzyme (EC 1.14.99.1) that is responsible for formation of important biological mediators collectively referred to as the prostanoids (including prostaglandins, prostacyclin and thromboxane).
  • the prostanoids including prostaglandins, prostacyclin and thromboxane.
  • NSAIDs include well-known compounds such as aspirin and ibuprofen.
  • the most relevant reaction catalyzed by COX is the conversion of the fatty acid arachidonic acid to prostaglandin, although other fatty acids are converted to additional prostanoids. It is noteworthy that prostaglandins are important cofactors in the niacin-mediated flushing effect.
  • COX-I COX-I
  • COX-2 COX-2
  • COX-3 COX-Ib
  • Different tissues express varying levels of COX-I and COX-2.
  • both enzymes act basically in the same fashion, selective inhibition can make a difference in terms of side-effects.
  • COX-I is considered a constitutive enzyme, being found in most mammalian cells. It is an inducible enzyme, becoming abundant in activated macrophages and other cells at sites of inflammation.
  • niacin IR The dosing regimen of niacin IR requires that it be taken three times per day, thereby requiring that a patient also take at least one NSAID tablet, tablet, caplet, capsule, and the like, with each niacin dose. It is clear that a patient would need a minimum of six tablets daily during the initial phase of niacin IR therapy; i.e., the period prior to tolerance development. The need to take at least six tablets is likely a major contributor to low compliance to niacin IR therapy.
  • One aspect of the invention is to provide a solid pharmaceutical composition comprising an effective dose of one or more NSAID and an effective dose of a niacin IR compound or composition.
  • An additional aspect of the invention is to regulate the release of the effective amounts of the one or more NSAID in relation to the niacin IR in order to significantly inhibit COX prior to the increase in niacin IR levels.
  • niacin IR-mediated prostaglandin mobilization will be impaired at the time that serum niacin levels start to increase.
  • the inhibition of either COX-I and/or COX-2 by the NSAID will maintain these enzymes in an inhibited state thereby diminishing the prostaglandin-mediated flush side effect.
  • the regulation of release of these therapeutic agents are achieved by the design of the pharmaceutical composition of the present invention.
  • the pharmaceutical composition of the present invention is a combination tablet contemplated as comprising two or more therapeutic compositions, each of which, independently, is formulated to enter the circulation by different routes of administration.
  • the combination tablet of the present invention is further applicable to instances where differential release kinetics are preferred.
  • the proximate release of a therapeutic agent across the buccal mucosa may be expected to provide more rapid release kinetics than another therapeutic agent that traverses the gastrointestinal mucosa, i.e., the enteral route.
  • the pharmaceutical composition is therefore formulated to provide (a) a rapidly absorbed therapeutic component that traverses the buccal mucosa lining the oral cavity and sublingual region; and (b) a slower release component that enters the circulation by traversing the mucosa of the gastrointestinal (GI) tract.
  • the more rapid release component i.e., that which traverses the buccal mucosa
  • the more slowly absorbed component i.e., traversing the GI tract mucosae
  • the pharmaceutical composition of the present invention may be prepared in different ways so that the rapid release and slower release forms are not commingled particulates, but each existing as at least one distinct layer within the solid pharmaceutical composition.
  • the COX inhibitor may be mixed with "rapid release” excipients and formed into a layer, while niacin is compounded into a distinct layer with “slower release” excipients.
  • the excipients selected for each layer will affect the rate of absorption of the therapeutic agent therein.
  • the combination tablet of the present invention may be applicable to any circumstance where a rapidly released therapeutic agent and a more slowly released therapeutic agent will be beneficial to a patient.
  • any therapeutic agent that can traverse the buccal mucosa can be formulated within the combination pill's rapid release component, and can be combined with a more slowly and enterically absorbed component comprising a therapeutic agent that is identical or distinct from that present in the rapidly released component.
  • FIG. 1 is a perspective view of the combination tablet with chewable outer layer before being chewed or masticated.
  • FIG. 2 is a side view of the combination tablet with chewable outer layer, after mastication has commenced.
  • FIG. 3 is a top view of the combination tablet with a liquid or powder or chewable outer layer enclosed by a thin outer "skin" that provides an easily rupturable barrier.
  • the skin is easily disrupted by minimal pressure generated during mastication.
  • the outer pulverizable layer is just below the skin and in this embodiment, is in the form of a liquid, a gel, a powder or other form that rapidly dissolves and is easily absorbed through mucous membranes; (same as 102 and 106); (same as 103 and 105)
  • This invention is a design of a combination tablet, which allows one (or more) medications within the tablet to be absorbed quickly, while an additional one (or more) medications in the tablet is absorbed slowly.
  • composition comprising;
  • a hard inner component comprising an effective amount of a first therapeutic agent, wherein the hard ingestible component releases the first therapeutic agent by dissolving in the gastrointestinal tract;
  • a pulverizable outer layer comprising an effective amount of a second therapeutic agent, wherein the pulverizable layer is dispersed in the oral cavity by masticating, thereby releasing the second therapeutic agent into the oral cavity where it enters the circulatory system by traversing the buccal mucosa;
  • the outer slow-release component (b) comprises one or more prostaglandin inhibitors as the second therapeutic agent.
  • prostaglandin inhibitor is any compound that impairs the functioning or action of one or more prostanoid compounds, including prostaglandins, prostacyclin and thromboxane. It is understood that this definition prostaglandin inhibitor is not limited to any single specific form of inhibition.
  • the prostaglandin inhibitor may slow or completely inhibit the synthesis of a prostanoids compound.
  • the prostaglandin inhibitor may accelerate the clearance or metabolic inactivation of one or more prostanoids.
  • the prostaglandin inhbitor may interfere with any prostanoid compound and its receptor or cellular targets, binding proteins, and the like. Therefore, compounds that are inhibitors of the enzymes cyclooxygenase-1 (COX-I) and cycloxygenase- 2 (COX-2), which are collectively known as NSAID, are included as inhibitors.
  • the compound laropiprant ((2-[(3R)-4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3- dihydro-lH-cyclopenta[b]indol-3-yl]acetic acid) is known to be a prostaglandin D2 receptor 1 antagonist, and accordingly, would be considered a prostaglandin inhibitor.
  • the COX- 1 receptors that have been implicated in the deleterious side effects of aspirin (GI ulcers and bleeding), this may allow for longer use or higher-dose use of the flush-blocking adjuvant.
  • the present invention described and claimed herein is directed to pharmaceutical compositions providing distinct release rates that are, in part, determined on whether the particular agent is absorbed through the buccal mucosa or the GI tract.
  • the rapidly absorbed therapeutic agent is a COX inhibitor that when absorbed in the proper time frame offsets the side effects of niacin IR therapy; specifically the flushing of the skin on the face and trunk.
  • an embodiment of the present invention suitable for preventing the flushing reaction comprises a pharmaceutical composition in the form of a combination tablet or other solid dosage form, wherein the combination of components comprises,
  • a hard inner component comprising an effective amount of a niacin, wherein the hard ingestible component releases the niacin by dissolving in the gastrointestinal tract;
  • a pulverizable outer layer comprising an effective amount of a prostaglandin inhibitor, wherein the pulverizable layer is dispersed in the oral cavity by masticating, thereby releasing the prostaglandin inhibitor into the oral cavity where it enters the circulatory system by traversing the buccal mucosa,
  • the rapid-release composition comprises a chewable layer that is absorbed through the buccal mucosa, and wherein (a) and (b) further comprise one or more pharmaceutically acceptable excipients, carriers or diluents.
  • niacin is unimportant as the combination tablet of the present invention is contemplated to be effective with either the immediate-, extended-, or sustained-release forms of niacin.
  • composition so described above are useful in treatment regimens directed to:
  • composition of the present invention can be expanded to other clinical applications, such as, e.g.,
  • (a) comprises a premedication for anesthesia such as a anticholinergic, for example atropine, and (b) comprises sedative, anesthetic or amnesiatic which is commonly given with such premedication.
  • a premedication for anesthesia such as a anticholinergic, for example atropine
  • b comprises sedative, anesthetic or amnesiatic which is commonly given with such premedication.
  • the use of the term hard in reference to the inner layer or core particle comprising a first therapeutic agent is used to connote that the inner layer and/or core particle is not pulverized by the force of masticating or chewing that effectively pulverizes the outer layer of the pharmaceutical composition of the present invention.
  • the inner layer or core particle as being ingestible it is meant that the inner layer is capable of being taken up and absorbed by one or more portions of the gastrointestinal tract.
  • the inner core portion of the combination tablet may be conventionally covered with one or more layers of coatings to permit a timed release of the active contained therein following ingestion by a subject.
  • the present invention contemplates a release profile of the ingested core particle of from 30 minutes to 24 hours.
  • the term pulverizable or easily pulverizable refers to a layer of a material that is ground or dispersed into small particles within the oral cavity by gentle pressure generated by chewing or masticating the layer to be ground.
  • pulverizable or easily pulverizable refers to a layer of a material that is ground or dispersed into small particles within the oral cavity by gentle pressure generated by chewing or masticating the layer to be ground.
  • masticating or chewing in the context of the present invention, is meant to signify that the pulverizing or grinding is being performed by a patient's or subject's teeth, or gums.
  • a specific embodiment of the combination pill may cause the first bite(s) to rupture or dislodge the outer layer thereby releasing it from the central core and can then be chewed.
  • the term intact does not require that the inner layer or core remain in one piece. Instead, it signifies that at least 50% of the inner layer or core particle is swallowed, but preferably that 75% of the inner core material is swallowed; even more preferably that approximately 75% to about 85% of the inner core material is swallowed, and most preferably, from about 85% to about 95% of the inner core material is swallowed, and most particularly, that greater than 95% of the inner core material is swallowed.
  • the buccal mucosa is meant to refer to the epithelium lining the oral cavity, including the sublingual region.
  • the buccal mucosa further includes the sub-epithelial tissue; i.e., the tissue and macromolecular layers that accumulate underneath the epithelium.
  • the subepithelial tissue includes, inter alia, connective tissue cells (fibroblasts, adipocytes, lymphocytes, and the like), extracellular matrix, basement membrane, smooth muscle, and vascular elements, etc.
  • the buccal mucosa is a highly vascular tissue, and therefore a desirable route of entry into the general circulation
  • Fig. 1 provides a sectional view through the combination tablet of the present invention.
  • the outer pulverizable layer (101) surrounds the inner core (103) that comprises the slowly absorbed therapeutic agent.
  • Additional embodiments of the combination tablet may have an optional intermediate layer (102) between the outer pulverizable layer (101) and the inner core that serves to protect the inner core (103).
  • the intermediate layer (102) may help protect the inner layer or core (103) from being unintentionally cracked or fragmented during the mastication of the outer layer ( 101 ) of the combination tablet.
  • the intermediate layer (102) may also slow absorption of inner core medication.
  • Fig. 2 illustrates an intermediate stage in the pulverizing and dissolution of the outer layer (104), which is depicted as somewhat intact but no longer adhering to the intermediate layer ( 106) and/or the inner core ( 105).
  • Fig. 3 provides a sectional view through an embodiment of the combination tablet.
  • the illustrated embodiment provides a modification of the previously illustrated embodiments in that the outer layer (202), i.e., the rapidly absorbed layer (202), is commercially provided in either a liquid, a gel or a pulverized form (i.e., powder, granules, fragments, and the like).
  • a very fragile outer coat (201) is applied and extends over the entire surface of the combination tablet.
  • the coating or skin may result from several layers or coats of e.g. a conventional flavored or non-flavored coating. This type of skin may be prepared from several types of compositions such as fragile dried layers of sugar.
  • the first embodiment has a chewable outer layer, such that it can be absorbed quickly.
  • This chewable layer may be adhered directly to the inner layer, or it may be such designed that when it is bitten lightly (e.g. with minimal force, such as the force needed to chew a banana), this outer chewable layer breaks off into many pieces within the mouth, and can be chewed and thus absorbed, leaving the hard inner layers in the mouth to be swallowed.
  • the chewable layer By making the chewable layer "crumble" in such a way, the patient will avoid biting hard through the hard inner layer of the tablet, which could be uncomfortable if the inner tablet is very hard, or could damage the integrity of the inner tablet, allowing it to be absorbed earlier than desired.
  • the outer chewable layer can be formulated, e.g., with a water soluble sugar and/or a sugar substitutes.
  • Suitable water-soluble sugars and/or sugar substitutes are glucose, maltose, sucrose, dextrose, fructose, sorbitol, mannitol or other types of natural or artificial sweeteners. Mixtures of various sugars or sugar substitutes are also suitable.
  • the chewable layer can also be formulated with, e.g., a gel forming agent.
  • suitable gel formers are xanthan gum, methylcelluloses such as sodium carboxymethylcellulose or hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, alginates, tragacanth or soluble starch. These substances are all commercially available and usually meet the purity requirements and quality regulations for pharmaceutical products. All such gel formers and coatings contemplated are GRAS.
  • wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, sweetening agents (including other nonnutritive sweeteners), tableting agents, stabilizers, antioxidants, cooling agents, and preservatives, can also be present.
  • a binding agent can also be present such as cellulose, cellulosic derivatives, polyvinyl pyrrolidone, starch, modified starch, and mixtures thereof, and, in particular, microcrystalline cellulose.
  • the compression coating can be prepared by, e.g., a Manesty Dry-Cota press, which consists of two side by side interconnected tablet presses where the core is made on one press then mechanically transferred to the next press for compression coating.
  • Each "press” has an independent powder feed mechanism so that core blend is loaded on one machine and coating blend on the other. Mechanical transfer arms rotate between the machines to remove cores from one press and transfer them to the coating press.
  • Other and more modern types of presses which may be used e.g. Elizabeth Hata HT- AP44-MSU-C, Killian RUD, Fette PT 4090
  • This configuration is more flexible, in that cores can be pan coated with a functional or cosmetic coating before compression coating.
  • any conventional, art- recognized manufacturing technique that permits the formulation of a chewable component over a solid dosage form will be readily appreciated by the skilled artisan and is contemplated by the present invention.
  • a similar embodiment would not only have an outer chewable layer, but also a thin shell outside of the chewable layer. This would be similar to the thin candy shell of an M&M candy. With this thin outer shell helping to hold the tablet together, the chewable layer can be designed to more easily crumble and dissolve than if there was no outer shell, e.g., by reducing the amount of binder or by reducing the compression to that which will minimally hold the chewable component together until the outer shell is applied.
  • the outer shell can be a sugar coating or a polymer coating such as hydroxypropylmethylcelluose or polyvinylalcohol or combinations thereof, for example.
  • Another embodiment contemplated by the present invention is an outer layer made from liquid, within a thin outer skin or shell. When the patient bites lightly on the tablet , this outer skin would fracture, allowing the liquid (or gel) of a fast-absorbing medication to release into the mouth and thus be absorbed quickly, starting at the mouth's mucous membranes.
  • this outer layer includes viscous liquids, gels, quick absorbable substances, powder within a breakable skin, substances that "melt" in the mouth (quickly absorb) and more.
  • the drug can be formulated with a water soluble excipient such as a sugar, sugar alcohol, polyethylene glycol (PEG), or polyethylene oxide.
  • a water soluble excipient such as a sugar, sugar alcohol, polyethylene glycol (PEG), or polyethylene oxide.
  • the preferred water-soluble excipients are the sugar alcohols including, but not limited to sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose, erythritol, and combinations thereof.
  • the preferred sugar is glucose.
  • Other suitable water-soluble excipients include gelatin, partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate and mixtures thereof.
  • a disint grating agent such as sodium starch "meltable" formulation can be readily determined by one of skill in the art.
  • the outer skin can be gelatin and the drug can be mixed with water or miscible solvents such as propylene glycol; PEG's and ethanol, or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive oil.
  • water or miscible solvents such as propylene glycol; PEG's and ethanol, or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive oil.
  • Another embodiment has an outer layer which rapidly dissolves when sucked on. When the inner layer is reached, the patient would swallow the tablet.
  • This embodiment can be designed such that the outer surface of the inner, hard layer has a texture that is easily recognized by the tongue, so that it is clear to the patient when the outer layer is fully dissolved, and thus when it is time to swallow the inner layer.
  • the outer drug can be formulated in a dissolvable matrix material.
  • the dissolvable matrix may include carbohydrates, fats, proteins, waxes (natural and synthetic), hydrocarbons, and other materials which safely and rapidly dissolve in the mouth.
  • the inner "slow absorb” or “extended release” layer contemplated by the present invention has any number of art-recognized constituencies.
  • the inner layer is designed similar to a standard tablet.
  • the inner layer is enteric coated, further slowing the release of the medication, hi still another embodiment the inner layer can be an extended release dosage form.
  • the coating can be, e.g., a material selected from the group consisting of one or more of the following: cellulose acetate phthalate, alginates, alkali-soluble acrylic resins, hydroxypropyl methylcellulose phthalate, methacrylate- methacrylic acid copolymers, polyvinyl acetate phthalate and styrol maleic acid copolymers.
  • the coating can also be multilayered; i.e. one or more coatings are contemplated to provide extended release kinetics which permit the inner tablet to release over a period of from 15 minutes to 24 hours or more.
  • the extended release dosage form can be formulated with the drug dispersed in a matrix or with an extended release coating.
  • Suitable materials form inclusion in an extended release matrix or coating can be, e.g., a cellulosic material, an acrylic polymer, or a combination thereof.
  • the contemplated inner layer can also be made of a substance which is softer and more pliable than a standard hard tablet, e.g. similar to a hard taffy. In this way, the patient could * not chip their teeth when biting the tablet, as the inner layer will absorb some of the shock of the bite without breaking or dissolving. It can then by swallowed to be absorbed in the GI system, after the outer layer was absorbed in the mouth.
  • the "taffy” can be prepared, e.g., with an admixture of a sugar melt having at least 40% sugar, such as fructose and a surface active agent.
  • a sugar melt having at least 40% sugar, such as fructose and a surface active agent.
  • sugar-based substances can readily prepare alternative formulations of sugar-based substances to achieve an inner core that absorbs the shock of the chewing force exerted by an individual in the normal course of taking a chewable medication.
  • niacin can be prepared as an extended release powder and dispersed throughout a chewable tablet containing the COX inhibitor. In these embodiments the whole tablet could be chewed without destroying the integrity of the extended release powder, which can be subsequently swallowed.
  • the extended release powder can be microspheres comprised of micronized niacin coated with a polymer such as poly (lactic-co-glycolic) acid (PLGA).
  • PLGA poly (lactic-co-glycolic) acid
  • the outer layer can be the adjuvant COX inhibitor, which can include medications such as aspirin, other NSAIDs such as naproxen sodium (sodium (2S)-2-(6-methoxynaphthalen-2-y])propanoate) and ibuprofen (2-[4-(2- methylpropyl)phenyl]propanoic acid) COX-2specific inhibitors such as colecoxib
  • Vitamins such as Vitamin C, and more, or any combination of the above.
  • the inner "slow release” or “extended release” layer can be niacin, or slow release niacin or other combination drugs such as statins, other cholesterol medications, other diabetes or hypertension medications, and the like.
  • niacin released from the core can have an in vitro dissolution profile, when measured in a type I dissolution apparatus (basket) according to U.S. Pharmacopeia XXII, at about 37 degrees C in deionized water at about 100 rpm, as follows (a) less than about 15% of the niacin is released after about 1 hour in the apparatus, (b) between about 15% and about 30% of the niacin is released after about 3 hours in the apparatus, (c) between about 30% and about 45% of the niacin is released after about 6 hours in the apparatus, (d) between about 40% and about 60% of the niacin is released after about 9 hours in the apparatus, (e) between about 50% and about 75% of the niacin is released after about 12 hours in the apparatus, and (f) at least about 75% of the niacin is released after about 20 hours in the apparatus.
  • antipsychotic medications may make sense to put in combination, as schizophrenics have been shown to have lower baseline flush response to niacin due to their low levels of arachidonic acid, making them particularly a good match for niacin medications, especially due to their high rates of obesity, bad cholesterol, and poor compliance (this combination tablet should greatly increase compliance due to requirements for less tablets per day).
  • Niacin is best started at a low dose and ramped up over time as tolerance to the flush is achieved.
  • the contemplated dosages are readily understood by the skilled physician based on the age, weight, sex and physiological characteristics of the patient.
  • the COX inhibitor e.g. aspirin
  • COX inhibitors have the side effect of ulcers and GI bleeds, which must be weighed against the beneficial effect of decreasing flush.
  • the first aspect is to pre-load the patient with COX inhibitor. Therefore, for several days before their first dose of niacin, the patient would first take COX inhibitor for several days.
  • the combination tablets should be taken on a full stomach, after food, as the fast-absorb layer will be mostly absorbed through mucous membranes, and the slow-absorb will be delayed due to recent food in the GI tract, helping to reach the desired gap in absorption of the two medications.
  • the patient may take a combination tablet that has lOOmg niacin and 325mg aspiring, while the week-two combination tablet will have 250mg niacin and still 325mg aspirin, and so forth.
  • the amount of COX inhibitor may be tapered.
  • the aspirin dose may be tapered.
  • the patient may be taking a combination tablet with lOOOmg niacin and 325mg aspirin, three times per day, then a tablet with lOOOmg niacin and 162mg aspirin, and then lOOOmg niacin and 81 mg aspirin, which may be the maintenance dose.
  • combination tablets contemplated by the present invention can be conventionally flavored with palatable flavorants known in the art.
  • the regimen should be made very simple, through posters or cards describing which tablets to take during which weeks. Patients could be encouraged to switch earlier to the next tablet if they feel the flush has decreased, or to delay switch if they still need time to develop tolerance. Also, tablet boxes can be employed to help with this compliance.
  • the first number of each tablet is the amount of niacin
  • second is the amount of aspirin.
  • Week l Aspirin only, 325mg, 3x/day
  • Week 7 1000mg/162mg 3x/day Week 8: and beyond 1000mg/81mg 3x/day
  • regimen is just one non- limiting illustration.
  • the regimen may be much simpler, i.e., may be a much simpler chart, for example starting with 325mg + 500mg, then going to 81mg + 500mg).
  • prostaglandin inhibitor is any compound that impairs the function of one or more prostanoid compounds, including prostaglandins, prostacyclin and thromboxane.
  • COX-2 specific inhibitor ideally an irreversible one. As it is the COX-I receptors that have been implicated in the deleterious side effects of aspirin (GI ulcers and bleeding), this may allow for longer use or higher-dose use of the flush-blocking adjuvant.
  • COX-2 specific inhibitor ideally an irreversible one.
  • COX-I receptors that have been implicated in the deleterious side effects of aspirin (GI ulcers and bleeding), this may allow for longer use or higher-dose use of the flush-blocking adjuvant.

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  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur une composition pharmaceutique sous la forme d'un comprimé de combinaison. Le comprimé comporte un composant à absorption rapide qui entre dans la circulation en traversant la muqueuse buccale, et un composant à absorption plus lente qui est avalé. L'agent thérapeutique dans la partie avalée est absorbé à travers la muqueuse gastrique. Les composants rapide et lent peuvent comporter des agents thérapeutiques identiques ou différents en fonction de l'application à un état médical spécifique. Un mode de réalisation du comprimé de combinaison comprend un inhibiteur de la prostaglandine dans le composant à absorption rapide afin d'atténuer les effets secondaires de la niacine à libération immédiate qui se trouve dans le composant à absorption lente. Ces compositions de combinaison augmenteront l'observance du patient grâce à la réduction du nombre de comprimés qu'un patient devra absorber de façon quotidienne.
PCT/US2008/008191 2007-07-01 2008-07-01 Comprimé de combinaison avec une couche extérieure pouvant être mâchée WO2009005803A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
JP2010514861A JP2010532358A (ja) 2007-07-01 2008-07-01 咀嚼可能外層を有する配合剤
EP08768855A EP2170051A1 (fr) 2007-07-01 2008-07-01 Comprimé de combinaison avec une couche extérieure pouvant être mâchée
CA2690956A CA2690956C (fr) 2007-07-01 2008-07-01 Comprime de combinaison avec une couche exterieure pouvant etre machee
US12/646,395 US8404275B2 (en) 2007-07-01 2009-12-23 Combination tablet with chewable outer layer
US13/720,723 US8652520B2 (en) 2007-07-01 2012-12-19 Combination tablet with chewable outer layer
US14/152,744 US20140220124A1 (en) 2007-07-01 2014-01-10 Combination tablet with chewable outer layer
US14/880,067 US20160030354A1 (en) 2007-07-01 2015-10-09 Combination tablet with chewable outer layer
US15/340,594 US20170042821A1 (en) 2007-07-01 2016-11-01 Combination tablet with chewable outer layer
US15/925,513 US20190091155A1 (en) 2007-07-01 2018-03-19 Combination tablet with chewable outer layer
US16/438,204 US20200046644A1 (en) 2007-07-01 2019-06-11 Combination Tablet With Chewable Outer Layer
US17/239,319 US20220008342A1 (en) 2007-07-01 2021-04-23 Combination tablet with chewable outer layer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94744007P 2007-07-01 2007-07-01
US60/947,440 2007-07-01

Related Child Applications (1)

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US12/646,395 Continuation-In-Part US8404275B2 (en) 2007-07-01 2009-12-23 Combination tablet with chewable outer layer

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WO2009005803A1 true WO2009005803A1 (fr) 2009-01-08

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US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
WO2014191396A1 (fr) * 2013-05-29 2014-12-04 Grünenthal GmbH Forme dosifiée inviolable à profil de libération bimodale
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US9226891B2 (en) 2011-10-28 2016-01-05 Vitalis Llc Anti-flush compositions
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
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
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US11052062B2 (en) 2004-10-08 2021-07-06 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form

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US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
US11052062B2 (en) 2004-10-08 2021-07-06 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US11229619B2 (en) 2004-10-08 2022-01-25 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10675278B2 (en) 2005-02-04 2020-06-09 Grünenthal GmbH Crush resistant delayed-release dosage forms
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
US8652520B2 (en) 2007-07-01 2014-02-18 Vitalis Llc Combination tablet with chewable outer layer
US8404275B2 (en) 2007-07-01 2013-03-26 Vitalis Llc Combination tablet with chewable outer layer
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US10493033B2 (en) 2009-07-22 2019-12-03 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
WO2011079239A2 (fr) * 2009-12-23 2011-06-30 Joseph Peter Habboushe Comprimé de combinaison avec couche externe croquable
WO2011079239A3 (fr) * 2009-12-23 2011-11-24 Joseph Peter Habboushe Comprimé de combinaison avec couche externe croquable
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10864164B2 (en) 2011-07-29 2020-12-15 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US20160143922A1 (en) * 2011-10-28 2016-05-26 Vitalis Llc Anti-flush compositions
US9226891B2 (en) 2011-10-28 2016-01-05 Vitalis Llc Anti-flush compositions
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
WO2014191396A1 (fr) * 2013-05-29 2014-12-04 Grünenthal GmbH Forme dosifiée inviolable à profil de libération bimodale
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
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
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10172797B2 (en) 2013-12-17 2019-01-08 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
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
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
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations

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EP2170051A1 (fr) 2010-04-07
CA2690956C (fr) 2017-01-03
JP2010532358A (ja) 2010-10-07
CA2690956A1 (fr) 2009-01-08

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