WO2008079102A1 - Composition de loxoprofène à libération modifiée - Google Patents

Composition de loxoprofène à libération modifiée Download PDF

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Publication number
WO2008079102A1
WO2008079102A1 PCT/US2006/017938 US2006017938W WO2008079102A1 WO 2008079102 A1 WO2008079102 A1 WO 2008079102A1 US 2006017938 W US2006017938 W US 2006017938W WO 2008079102 A1 WO2008079102 A1 WO 2008079102A1
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WO
WIPO (PCT)
Prior art keywords
composition
loxoprofen
release
component
active ingredient
Prior art date
Application number
PCT/US2006/017938
Other languages
English (en)
Inventor
John G. Devane
Paul Stark
Niall M. M. Fanning
Gurvinder Singh Rekhi
Gary Liversidge
Scott Jenkins
Original Assignee
Elan Corporation, Plc
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 claimed from US11/372,857 external-priority patent/US20060240105A1/en
Application filed by Elan Corporation, Plc filed Critical Elan Corporation, Plc
Priority to JP2008551241A priority Critical patent/JP2009514989A/ja
Priority to US11/568,925 priority patent/US20090297602A1/en
Publication of WO2008079102A1 publication Critical patent/WO2008079102A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the present invention relates to novel compositions and dosage forms for the treatment of pain and inflammation.
  • the present invention relates to novel compositions and dosage forms for the delivery of loxoprofen, or a salt or derivative thereof, and to methods of treatment using the same.
  • Loxoprofen is a phenylpropionic acid-type non-steroidal, anti-inflammatory drug (NSAID) prodrug. When orally administered, it is metabolized in the body (primarily in the liver and kidneys) into a trans-OH form, which exhibits potent anti-inflammatory activities. Loxoprofen is rapidily absorbed into the digestive tract localizing in the region of inflammation and serving as an anti-inflammatory analgesic for the management of pain and inflammation associated with skeletal muscle and joint disorders or resulting from operative procedures. Loxoprofen is particularly effective in the treatment of pain and inflammation resulting from chronic arthritis, rheumatism, lumbago, and trauma.
  • NSAID anti-inflammatory drug
  • Loxoprofen appears as a white or slightly yellowish white crystalline powder.
  • the chemical name of loxoprofen, also referred to as loxoprofen sodium, is monosodium 2-[4- (2-oxocyclopentylmethyl) phenyl] propanoate dehydrate.
  • the empirical formula of loxoprofen is Ci 5 H 17 NaO 3 ⁇ H 2 O and its molecular weight is 304.31.
  • the structural formula of loxoprofen is shown below:
  • Loxoprofen is described, for example, in U.S. Pat. No. 6,248,350 for "External Formulation Containing Loxoprofen” which describes an anti-inflammatory analgesic patch containing loxoprofen and which is incorporated herein by reference in its entirety.
  • Conventional loxoprofen tablets such as LOXONIN ® (marketed by Sankyo Co. Ltd. of Japan) are administered orally three times a day for the treatment of pain and inflammation.
  • Loxoprofen is of high therapeutic value for the treatment of pain and inflammation associated with skeletal muscle and joint disorders or resulting from operative procedures.
  • loxoprofen requires oral administration three times daily, strict patient compliance is a critical factor in the efficacy of loxoprofen.
  • such frequent administration often requires the attention of health care workers and contributes to the high costs associated with treatments involving loxoprofen.
  • loxoprofen compositions which overcome these and other problems associated with the use of conventional forms of loxoprofen for the treatment of pain and inflammation.
  • modified release drug formulations The objective of many modified release drug formulations is to produce a substantially constant release of the drug compound. Indeed, it is often a specific object of these formulations to minimize the variation in plasma concentration levels associated with conventional frequent dosage regimes. Another objective of modified release drug formulations is to hasten the onset of action by minimizing to time from the administration of the drug to the achievement of a therapeutically effective plasma concentration. A further objective of modified release drug formulations is to maintain a therapeutically effective plasma concentration throughout the dosing interval. The achievement of two or all three of these objectives in conventional drug formulations, however, is problematic.
  • modified release compositions or formulations which combine the benefits of at least two different release profiles to achieve a resultant plasma profile that minimizes variations in plasma concentration levels and/or provides rapid onset of action and/or maintains a therapeutically effective plasma concentration throughout the dosing interval is desirable.
  • modified release compositions or formulations which substantially mimic the release of frequent IR dosage regimes while reducing the need for frequent dosing is desirable.
  • a typical example of a drug which may produce tolerance in patients is rnethylphenidate.
  • Methylphenidate or ⁇ -phenyl-2-piperidine acetic acid methyl ester, is a stimulant affecting the central nervous and respiratory systems and is primarily used in the treatment of attention deficit hyperactivity disorder (ADHD).
  • ADHD attention deficit hyperactivity disorder
  • GIT gastrointestinal tract
  • drug effects persist for 3-6 hours after oral administration of conventional IR tablets or up to about 8 hours after oral administration of extended release formulations.
  • the total dosage is typically in the range of 5-30 mg per day, in exceptional cases rising to 60 mg/day.
  • methylphenidate is given twice daily, typically with one dose given before breakfast and a second dose given before lunch. The last daily dose is preferably given several hours before retiring.
  • Adverse effects associated with methylphenidate treatment include insomnia and the development of patient tolerance.
  • WO 98/14168 (Alza Corp.) teaches a dosage form and a method of administering methylphenidate in a sustained and constantly ascending rate.
  • the dosage form disclosed comprises a plurality of beads comprising a hydrogel matrix with increasing amounts of the active ingredient therein, coated with varying amounts of a release rate controlling material. Appropriate combinations of the active ingredient dose and the number and thickness coating layers can be selected to give an ascending release profile in which the plasma concentration of the active ingredient continually increases over a given period of time.
  • An object of WO 98/14168 is to release a dosage form at a constantly ascending rate specifically to avoid uneven blood levels (characterized by peaks and troughs) associated with conventional treatments using immediate release dosage formulations. As a result, this formulation does not deliver the active ingredient in either a pulsatile or a bimodal manner.
  • WO 97/03672 discloses that methylphenidate exhibits a therapeutic effect when administered in the form of a racemic mixture or in the form of a single isomer (such as the RR d-threo enantiomer).
  • WO 97/03763 discloses a sustained release formulation containing d-threo methylphenidate (dtmp). This disclosure teaches the use of a composition comprising a coating through which the dtmp passes in order to attain sustained release and achieve serum levels (of the active ingredient) of at least 50% cmax over a period of at least 8 hours. As above, this formulation does not deliver the active ingredient in either a pulsatile or a bimodal manner.
  • Giunchedi et al. Int. J. Pharm (1991) 77:177-181 discloses the use of a hydrophilic matrix multiple-unit formulation for the pulsed release of ketoprofen.
  • Giunchedi et al. teach that ketoprofen is rapidly eliminated from the blood after dosing (plasma half-life 1-3 hours) and consecutive pulses of drug may be more beneficial than constant release for some treatments.
  • the multiple-unit formulation disclosed comprises four identical hydrophilic matrix tablets placed in a gelatin capsule. Although the in vivo studies show two peaks in the plasma profile there is no well defined wash out period and the variation between the peak and trough plasma levels is small.
  • the three layer tablet is made up of a first layer containing the active ingredient, a barrier layer (the second layer) of semi-permeable material which is interposed between the first layer and a third layer containing an additional amount of active ingredient.
  • the barrier layer and the third layer are housed in an impermeable casing.
  • the first layer dissolves upon contact with a dissolving fluid while the third layer is only available after dissolution or rupture of the barrier layer. In such a tablet the first portion of active ingredient must be released instantly.
  • This approach also requires the provision of a semi-permeable layer between the first and third layers in order to control the relative rates of delivery of the two portions of active ingredient. Additionally, rupture of the semi-permeable layer leads to uncontrolled dumping of the second portion of the active ingredient which may not be desirable.
  • U.S. Pat. No. 5,158,777 discloses a formulation comprising captopril within an enteric or delayed release coated pH stable core combined with additional captopril which is available for immediate release following administration.
  • chelating agents such as disodium edetate or surfactants such as polysorbate 80 are used either alone or in combination with a buffering agent.
  • the compositions have an amount of captopril available for immediate release following oral administration and an additional amount of pH stabilized captopril available for release in the colon.
  • U.S. Pat. Nos. 4,728,512, 4,794,001 and 4,904,476 relate to preparations providing three distinct releases.
  • the preparation contains three groups of spheroids containing an active medicinal substance: the first group of spheroids is uncoated and rapidly disintegrates upon ingestion to release an initial dose of medicinal substance; the second group of spheroids is coated with a pH sensitive coat to provide a second dose; and the third group of spheroids is coated with a pH independent coat to provide to third dose.
  • the preparation is designed to provide repeated release of medicinal substances which are extensively metabolized presystemically or have relatively short elimination half-lives.
  • U.S. Pat. No. 5,837,284 discloses a methylphenidate dosage form having immediate release and delayed release particles.
  • the delayed release is provided by the use of ammonio methacrylate pH independent polymers combined with certain fillers.
  • the present invention relates to compositions comprising a population of loxoprofen-containing particles, wherein the particles comprise a modified release coating, a modified release matrix material, or both, such that the composition delivers the loxoprofen, or a salt or derivative thereof, to a subject in a pulsatile or continuous manner following oral delivery of the composition to the subject.
  • loxoprofen includes the specific compound described above as well as all pharmaceutically acceptable salts and derivatives thereof.
  • the present invention also relates to dosage forms comprising such compositions and methods for the treatment of pain and/or inflammation comprising the step of providing such dosage forms.
  • FIG. 1 Simulation of plasma concentrations obtained following dosing various percentages of CR (modified release) and IR (immediate release) loxoprofen.
  • the effectiveness of pharmaceutical compounds in the prevention and treatment of disease states depends on a variety of factors including the rate and duration of delivery of the compound from the dosage form to the patient.
  • the combination of delivery rate and duration exhibited by a given dosage form in a patient can be described as its in vivo release profile and, depending on the pharmaceutical compound administered, will be associated with a concentration and duration of the pharmaceutical compound in the blood plasma, referred to as a plasma profile.
  • a plasma profile concentration and duration of the pharmaceutical compound in the blood plasma
  • the release profiles of dosage forms may exhibit different rates and durations of release and may be continuous or pulsatile.
  • Continuous release profiles include release profiles in which a quantity of one or more pharmaceutical compounds is released continuously throughout the dosing interval at either a constant or variable rate.
  • Pulsatile release profiles include release profiles in which at least two discrete quantities of one or more pharmaceutical compounds are released at different rates and/or over different time frames. For any given pharmaceutical compound or combination of such compounds, the release profile for a given dosage form gives rise to an associated plasma profile in a patient.
  • the release profile of the dosage form as a whole is a combination of the individual release profiles and may be described generally as "multimodal.”
  • the release profile of a two- component dosage form in which each component has a different release profile may described as "bimodal," and the release profile of a three-component dosage form in which each component has a different release profile may described as "trimodal.”
  • the associated plasma profile in a patient may exhibit constant or variable blood plasma concentration levels of the pharmaceutical compounds over the duration of action and may be continuous or pulsatile.
  • Continuous plasma profiles include plasma profiles of all rates and duration which exhibit a single plasma concentration maximum.
  • Pulsatile plasma profiles include plasma profiles in which at least two higher blood plasma concentration levels of pharmaceutical compound are separated by a lower blood plasma concentration level and may be described generally as “multimodal.” Pulsatile plasma profiles exhibiting two peaks may be described as “bimodal” and plasma profiles exhibiting more than three peaks may be described as “trimodal.” Depending on, at least in part, the pharmacokinetics of the pharmaceutical compounds included in the dosage form as well as the release profiles of the individual components of the dosage form, a multimodal release profile may result in either a continuous or a pulsatile plasma profile upon administration to a patient.
  • the present invention provides a multiparticulate modified release composition which delivers loxoprofen in a pulsatile manner.
  • the present invention provides a multiparticulate modified release composition containing loxoprofen which produces a plasma profile substantially similar to the plasma profile produced by the administration of three IR dosage forms given sequentially.
  • the present invention provides a multiparticulate modified release composition which substantially mimics the pharmacological and therapeutic effects produced by the administration of three IR dosage forms of loxoprofen given sequentially.
  • the present invention provides a multiparticulate modified release composition which delivers loxoprofen in a continuous manner.
  • the present invention provides a multiparticulate modified release composition in which a first portion of loxoprofen is released immediately upon administration and one or more subsequent portions of loxoprofen are released after an initial time delay.
  • the present invention provides a multiparticulate modified release composition which provides rapid onset of action and a therapeutically effective plasma concentration level of loxoprofen for about 12 to about 24 hours.
  • the present invention provides solid oral dosage forms for once-daily or twice-daily administration comprising the multiparticulate modified release composition of the present invention.
  • the present invention provides a method for the treatment of pain and/or inflammation comprising the step of providing the solid oral dosage form of the present invention.
  • a pharmaceutical composition having a first component comprising active ingredient-containing particles, and at least one subsequent component comprising active ingredient-containing particles, each subsequent component having a rate and/or duration of release different from the first component wherein at least one of said components comprises loxoprofen-containing particles.
  • the loxoprofen-containing particles may be coated with a modified release coating.
  • the loxoprofen-containing particles may comprise a modified release matrix material.
  • the composition delivers loxoprofen in a pulsatile manner.
  • the first component provides an immediate release of loxoprofen and the one or more subsequent components provide a modified release of loxoprofen.
  • the immediate release component serves to hasten the onset of action by minimizing the time from administration to a therapeutically effective plasma concentration level, and the one or more subsequent components serve to minimize the variation in plasma concentration levels and/or maintain a therapeutically effective plasma concentration throughout the dosing interval.
  • the modified release coating and/or the modified release matrix material cause a lag time between the release of the active ingredient from the first population of active ingredient-containing particles and the release of the active ingredient from subsequent populations of active ingredient-containing particles.
  • the modified release coating and/or the modified release matrix material causes a lag time between the release of the active ingredient from the different populations of active ingredient-containing particles.
  • the duration of these lag times may be varied by altering the composition and/or the amount of the modified release coating and/or altering the composition and/or amount of modified release matrix material utilized.
  • the duration of the lag time can be designed to mimic a desired plasma profile.
  • the modified release composition of the present invention is particularly useful for administering a loxoprofen which is normally administered three times daily.
  • the composition delivers the loxoprofen in a trimodal manner. Upon administration, such a composition produces a plasma profile which substantially mimics that obtained by the sequential administration of three IR doses of loxoprofen in accordance with a typical treatment regimen.
  • the composition can be designed to produce a plasma profile that minimizes or eliminates the variations in plasma concentration levels associated with the administration of two or more IR dosage forms given sequentially.
  • the composition may be provided with an immediate release component to hasten the onset of action by minimizing the time from administration to a therapeutically effective plasma concentration level, and at least one modified release component to maintain a therapeutically effective plasma concentration level throughout the dosing interval.
  • pill refers to a state of matter which is characterized by the presence of discrete particles, pellets, beads or granules irrespective of their size, shape or morphology.
  • multiparticulate as used herein means a plurality of discrete or aggregated particles, pellets, beads, granules, or mixtures thereof, irrespective of their size, shape or morphology.
  • modified release as used herein includes a release which is not immediate and includes controlled release, extended release, sustained release and delayed release.
  • time delay refers to the period of time between the administration of a dosage form comprising the composition of the invention and the release of the active ingredient from a particular component thereof.
  • lag time refers to the time between the release of the active ingredient from one component of the composition and the release of the active ingredient from another component of the composition.
  • electrode refers to formulations which may be worn away, diminished, or deteriorated by the action of substances within the body.
  • diffusion controlled refers to formulations which may spread as the result of their spontaneous movement, for example, from a region of higher to one of lower concentration.
  • osmotic controlled refers to formulations which may spread as the result of their movement through a semi-permeable membrane into a solution of higher concentration that tends to equalize the concentrations of the formulation on the two sides of the membrane.
  • the active ingredients in each component may be the same or different.
  • the composition may comprise components comprising only loxoprofen as the active ingredient.
  • the composition may comprise a first component comprising loxoprofen and at least one subsequent component comprising an active ingredient other than loxoprofen suitable for coadministration with loxoprofen, or a first component containing an active ingredient other than loxoprofen and at least one subsequent component comprising loxoprofen.
  • two or more active ingredients may be incorporated into the same component when the active ingredients are compatible with each other.
  • An active ingredient present in one component of the composition may be accompanied by, for example, an enhancer compound or a sensitizer compound in another component of the composition, in order to modify the bioavailability or therapeutic effect thereof.
  • Enhancers refers to a compound which is capable of enhancing the absorption and/or bioavailability of an active ingredient by promoting net transport across the GIT in an animal, such as a human.
  • Enhancers include but are not limited to medium chain fatty acids; salts, esters, ethers and derivatives thereof, including glycerides and triglycerides; non-ionic surfactants such as those that can be prepared by reacting ethylene oxide with a fatty acid, a fatty alcohol, an alkylphenol or a sorbitan or glycerol fatty acid ester; cytochrome P450 inhibitors, P-glycoprotein inhibitors and the like; and mixtures of two or more of these agents.
  • the proportion of loxoprofen contained in each component may be the same or different depending on the desired dosing regime.
  • the loxoprofen present in the first component and in subsequent components may be any amount sufficient to produce a therapeutically effective plasma concentration level.
  • the loxoprofen when applicable, may be present either in the form of one substantially optically pure stereoisomer or as a mixture, racemic or otherwise, of two or more stereoisomers.
  • the loxoprofen is preferably present in the composition in an amount of from about 0.1 to about 500 mg, preferably in the amount of from about 1 to about 100 mg.
  • the loxoprofen is preferably present in the first component in an amount of from about 0.5 to about 60 mg; more preferably the loxoprofen, is present in the first component in an amount of from about 2.5 to about 30 mg.
  • the loxoprofen is present in subsequent components in an amount within similar ranges to those described for the first component.
  • the time release characteristics for the delivery of the loxoprofen from each of the components may be varied by modifying the composition of each component, including modifying any of the excipients and/or coatings which may be present.
  • the release of the loxoprofen may be controlled by changing the composition and/or the amount of the modified release coating on the particles, if such a coating is present. If more than one modified release component is present, the modified release coating for each of these components may be the same or different.
  • release of the active ingredient may be controlled by the choice and amount of modified release matrix material utilized.
  • the modified release coating may be present, in each component, in any amount that is sufficient to yield the desired delay time for each particular component.
  • the modified release coating may be preset, in each component, in any amount that is sufficient to yield the desired time lag between components.
  • the lag time and/or time delay for the release of the loxoprofen from each component may also be varied by modifying the composition of each of the components, including modifying any excipients and coatings which may be present.
  • the first component may be an immediate release component wherein the loxoprofen is released immediately upon administration.
  • the first component may be, for example, a time-delayed immediate release component in which the loxoprofen is released substantially in its entirety immediately after a time delay.
  • the second and subsequent component may be, for example, a time-delayed immediate release component as just described or, alternatively, a time-delayed sustained release or extended release component in which the loxoprofen is released in a controlled fashion over an extended period of time.
  • the exact nature of the plasma concentration curve will be influenced by the combination of all of these factors just described.
  • the lag time between the delivery (and thus also the onset of action) of the loxoprofen in each component may be controlled by varying the composition and coating (if present) of each of the components.
  • numerous release and plasma profiles may be obtained.
  • the duration of the lag time between the release of the loxoprofen from each component and the nature of the release of the loxoprofen from each component i.e.
  • the plasma profile may be continuous (i.e., having a single maximum) or pulsatile in which the peaks in the plasma profile may be well separated and clearly defined (e.g. when the lag time is long) or superimposed to a degree (e.g. when the lag time is short).
  • the plasma profile produced from the administration of a single dosage unit comprising the composition of the present invention is advantageous when it is desirable to deliver two or more pulses of active ingredient without the need for administration of two or more dosage units. Additionally, in the case of treating pain and/or inflammation, it is particularly useful to have such a multimodal plasma profile.
  • a typical loxoprofen treatment regime consists of the administration of two or three doses of an immediate release dosage formulation given four hours apart. This type of regime has been found to be therapeutically effective and is widely used.
  • coating materials suitable for use in the practice of the present invention include but are not limited to polymer coating materials, such as cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymers such as those sold under the trademark Eudragit ® RS and RL, poly acrylic acid and poly acrylate and methacrylate copolymers such as those sold under the trademark Eudragit ® S and L, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin,
  • polyvinylpyrrolidone mol. wt. ⁇ 10k-360k
  • anionic and cationic hydrogels polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (mol. wt. ⁇ 30k-300k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox ® polyethylene oxides (mol. wt.
  • AquaKeep ® acrylate polymers diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate (e.g. Explotab ® ; Edward Mandell C. Ltd.); hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides (e.g.
  • Polyox ® Union Carbide
  • Eudragit ® Rohm and Haas
  • other acrylic acid derivatives other acrylic acid derivatives
  • sorbitan esters natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and blends thereof.
  • excipients such as plasticisers, lubricants, solvents and the like may be added to the coating.
  • Suitable plasticisers include for example acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triis
  • modified release component comprises a modified release matrix material
  • any suitable modified release matrix material or suitable combination of modified release matrix materials may be used. Such materials are known to those skilled in the art.
  • modified release matrix material includes hydrophilic polymers, hydrophobic polymers and mixtures thereof which are capable of modifying the release of a loxoprofen dispersed therein in vitro or in vivo.
  • Modified release matrix materials suitable for the practice of the present invention include but are not limited to microcrystalline cellulose, sodium carboxymethylcellulose, hydoxyalkylcelluloses such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyethylene oxide, alkylcelluloses such as methylcellulose and ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acteate, cellulose acetate butyrate, cellulose acteate phthalate, cellulose acteate trimellitate, polyvinylacetate phthalate, polyalkylmethacrylates, polyvinyl acetate and mixture thereof.
  • a modified release composition according to the present invention may be incorporated into any suitable dosage form which facilitates release of the active ingredient in a pulsatile manner.
  • the dosage form comprises a blend of different populations of active ingredient-containing particles which make up the immediate release and the modified release components, the blend being filled into suitable capsules, such as hard or soft gelatin capsules.
  • the different individual populations of active ingredient-containing particles may be compressed (optionally with additional excipients) into mini-tablets which may be subsequently filled into capsules in the appropriate proportions.
  • Another suitable dosage form is that of a multilayer tablet. In this instance the first component of the modified release composition may be compressed into one layer, with the second component being subsequently added as a second layer of the multilayer tablet.
  • the populations of loxoprofen-containing particles making up the composition of the invention may further be included in rapidly dissolving dosage forms such as an effervescent dosage form or a fast-melt dosage form.
  • the composition comprises at least two loxoprofen components: a first loxoprofen component and one or more subsequent loxoprofen components.
  • the first loxoprofen component of the composition may exhibit a variety of release profiles including profiles in which substantially all of the loxoprofen contained in the first component is released rapidly upon administration of the dosage form, released rapidly but after a time delay (delayed release), or released slowly over time.
  • the loxoprofen contained in the first component is released rapidly upon administration to a patient.
  • released rapidly includes release profiles in which at least about 80% of the active ingredient of a component is released within about an hour after administration
  • delayed release includes release profiles in which the active ingredient of a component is released (rapidly or slowly) after a time delay
  • controlled release and extended release include release profiles in which at least about 80% of the active ingredient contained in a component is released slowly.
  • the second loxoprofen component of such embodiment may also exhibit a variety of release profiles including an immediate release profile, a delayed release profile or a controlled release profile.
  • the second loxoprofen component exhibits a delayed release profile in which the loxoprofen of the component is released after a time delay.
  • the second loxoprofen component exhibits a controlled release profile in which the loxoprofen of the component is released over a period of about 12 to about 24 hours after administration.
  • the loxoprofen in the first and second components are released over different time periods.
  • the loxoprofen in the first component is released rapidly and the loxoprofen in the second component is released within a period of about 12 hours after administration.
  • the loxoprofen in the first component is released rapidly and the loxoprofen in the second component is released within a period of about 24 hours after administration.
  • the loxoprofen in the first component is released rapidly and the loxoprofen in the second component is released over a period of about 12 hours after administration.
  • the loxoprofen in the first loxoprofen component is released rapidly and the loxoprofen in the second loxoprofen component is released over a period of about 24 hours after administration.
  • the loxoprofen in the first loxoprofen component is released rapidly and the loxoprofen in the second loxoprofen component is released over a period of at least about 12 hours after administration.
  • the loxoprofen in the first loxoprofen component is released rapidly and the loxoprofen in the second loxoprofen component is released over a period of at least about 24 hours after administration.
  • the plasma profile produced by the administration of dosage forms of the present invention which comprise an immediate release loxoprofen component and at least one modified release loxoprofen component can be substantially similar to the plasma profile produced by the administration of two or more IR dosage forms given sequentially, or to the plasma profile produced by the administration of separate IR and modified release dosage forms. Accordingly, the dosage forms of the present invention can be particularly useful for administering loxoprofen where the maintenance of pharmacokinetic parameters may be desired but is problematic.
  • the composition and the solid oral dosage forms containing the composition release the loxoprofen such that substantially all of the loxoprofen contained in the first component is released prior to release of the loxoprofen from the at least one second component.
  • the first component comprises an IR component
  • release of the loxoprofen from subsequent components may be delayed until substantially all of the loxoprofen contained in the first component has been released, and further delayed until at least a portion the loxoprofen released from the first component has been cleared from the patient's system.
  • release of the loxoprofen from subsequent components of the composition is substantially, if not completely, delayed for a period of at least about two hours after administration of the composition.
  • the release of loxoprofen from subsequent components of the composition is substantially, if not completely, delayed for a period of at least about four hours, preferably about four hours, after administration of the composition.
  • the present invention also includes various types of modified release systems by which loxoprofen may be delivered in either a pulsatile or continuous manner.
  • modified release systems by which loxoprofen may be delivered in either a pulsatile or continuous manner.
  • These systems include but are not limited to: films with loxoprofen in a polymer matrix (monolithic devices); loxoprofen contained by the polymer (reservoir devices); polymeric colloidal particles or microencapsulates (microparticles, microspheres or nanoparticles) in the form of reservoir and matrix devices; loxoprofen contained by a polymer containing a hydrophilic and/or leachable additive e.g., a second polymer, surfactant or plasticizer, etc.
  • a hydrophilic and/or leachable additive e.g., a second polymer, surfactant or plasticizer, etc.
  • loxoprofen release may be osmotically controlled (both reservoir and matrix devices); enteric coatings (ionizable and dissolve at a suitable pH); (soluble) polymers with (covalently) attached pendant drug molecules; and devices where release rate is controlled dynamically: e.g., the osmotic pump.
  • the delivery mechanism of the present invention can control the rate of release of loxoprofen. While some mechanisms will release loxoprofen at a constant rate, others will vary as a function of time depending on factors such as changing concentration gradients or additive leaching leading to porosity, etc.
  • Polymers used in sustained release coatings are necessarily biocompatible, and ideally biodegradable.
  • examples of both naturally occurring polymers such as Aquacoat ® (FMC Corporation, Food & Pharmaceutical Products Division, Philadelphia, USA) (ethylcellulose mechanically spheronised to sub-micron sized, aqueous based, pseudo-latex dispersions), and also synthetic polymers such as the Eudragit ® (Rohm Pharma, Rothstadt.) range of poly(acrylate, methacrylate) copolymers are known in the art.
  • a typical approach to modified release is to encapsulate or contain the drug entirely (e.g., as a core), within a polymer film or coat (i.e., microcapsules or spray/pan coated cores).
  • the active agent is in a saturated suspension, then the driving force for release is kept constant until the device is no longer saturated.
  • the release-rate kinetics may be desorption controlled, and a function of the square root of time. Transport properties of coated tablets, may be enhanced compared to free-polymer films, due to the enclosed nature of the tablet core (permeant) which may enable the internal build-up of an osmotic pressure which will then act to force the permeant out of the tablet.
  • Coated salt tablets shaped as disks, were found to swell in de-ionized water and change shape to an oblate spheroid as a result of the build-up of internal hydrostatic pressure: the change in shape providing a means to measure the force generated.
  • the osmotic force decreased with increasing levels of PEG content.
  • the lower PEG levels allowed water to be imbibed through the hydrated polymer, while the porosity resulting from the coating dissolving at higher levels of PEG content (20 to 40%) allow the pressure to be relieved by the flow of KCl.
  • Monolithic (matrix) devices are commonly used for controlling the release of drugs. This is possibly because they are relatively easy to fabricate compared to reservoir devices, and the danger of an accidental high dosage that could result from the rupture of the membrane of a reservoir device is not present.
  • the active agent is present as a dispersion within the polymer matrix, and they are typically formed by the compression of a polymer/drug mixture or by dissolution or melting.
  • the dosage release properties of monolithic devices may be dependent upon the solubility of the drug in the polymer matrix or, in the case of porous matrixes, the solubility in the sink solution within the particle's pore network, and also the tortuosity of the network (to a greater extent than the permeability of the film), dependent on whether the drug is dispersed in the polymer or dissolved in the polymer.
  • the drug will be released by a solution-diffusion mechanism (in the absence of pores).
  • the release mechanism will be complicated by the presence of cavities formed near the surface of the device as the drug is lost: such cavities fill with fluid from the environment increasing the rate of release of the drug.
  • plasticizer e.g., a poly( ethylene glycol)
  • a surfactant i.e., an ingredient which increases effectiveness
  • adjuvant i.e., an ingredient which increases effectiveness
  • matrix devices and reservoir devices
  • plasticizers may be fugitive, and simply serve to aid film formation and, hence, decrease permeability - a property normally more desirable in polymer paint coatings.
  • leaching of PEG increased the permeability of (ethyl cellulose) films linearly as a function of PEG loading by increasing the porosity, however, the films retained their barrier properties, not permitting the transport of electrolyte.
  • surfactant may increase the drug release rate by three possible mechanisms: (i) increased solubilization, (ii) improved 'wettability' to the dissolution media, and (iii) pore formation as a result of surfactant leaching.
  • improved wetting of the tablet led to only a partial improvement in drug release (implying that the release was diffusion, rather than dissolution, controlled), although the effect was greater for Eudragit ® RS than Eudragit ® RL, while the greatest influence on release was by those surfactants that were more soluble due to the formation of disruptions in the matrix allowing the dissolution medium access to within the matrix.
  • Composite devices consisting of a polymer/drug matrix coated in a polymer containing no drug also exist. Such a device was constructed from aqueous Eudragit ® lattices, and was found to provide a continuous release by diffusion of the drug from the core through the shell. Similarly, a polymer core containing the drug has been produced and coated with a shell that was eroded by gastric fluid. The rate of release of the drug was found to be relatively linear (a function of the rate limiting diffusion process through the shell) and inversely proportional to the shell thickness, whereas the release from the core alone was found to decrease with time.
  • Hollow microspheres were formed by preparing a solution of ethanol/dichloromethane containing the drug and polymer. On pouring into water, an emulsion is formed containing the dispersed polymer/drug/solvent particles, by a coacervation-type process from which the ethanol rapidly diffused precipitating polymer at the surface of the droplet to give a hard- shelled particle enclosing the drug dissolved in the dichloromethane. A gas phase of dichloromethane was then generated within the particle which, after diffusing through the shell, was observed to bubble to the surface of the aqueous phase.
  • the hollow sphere at reduced pressure, then filled with water which could be removed by a period of drying. No drug was found in the water.
  • Highly porous matrix-type microspheres have also been described.
  • the matrix-type microspheres were prepared by dissolving the drug and polymer in ethanol. On addition to water, the ethanol diffused from the emulsion droplets to leave a highly porous particle.
  • a suggested use of the microspheres was as floating drug delivery devices for use in the stomach.
  • a means of attaching a range of drugs such as analgesics and antidepressants, etc., by means of an ester linkage to poly(acrylate) ester latex particles prepared by aqueous emulsion polymerization has been developed. These lattices, when passed through an ion exchange resin such that the polymer end groups were converted to their strong acid form, could self-catalyze the release of the drug by hydrolysis of the ester link.
  • Drugs have been attached to polymers, and also monomers have been synthesized with a pendent drug attached. Dosage forms have been prepared in which the drug is bound to a biocompatible polymer by a labile chemical bond e.g., polyanhydrides prepared from a substituted anhydride (itself prepared by reacting an acid chloride with the drug: methacryloyl chloride and the sodium salt of methoxy benzoic acid) were used to form a matrix with a second polymer (Eudragit ® RL) which released the drug on hydrolysis in gastric fluid.
  • polyanhydrides prepared from a substituted anhydride (itself prepared by reacting an acid chloride with the drug: methacryloyl chloride and the sodium salt of methoxy benzoic acid) were used to form a matrix with a second polymer (Eudragit ® RL) which released the drug on hydrolysis in gastric fluid.
  • Enteric coatings consist of pH sensitive polymers. Typically the polymers are carboxylated and interact very little with water at low pH, while at high pH the polymers ionize causing swelling or dissolving of the polymer. Coatings can therefore be designed to remain intact in the acidic environment of the stomach, protecting either the drug from this environment or the stomach from the drug, but to dissolve in the more alkaline environment of the intestine.
  • the osmotic pump is similar to a reservoir device but contains an osmotic agent (e.g., the active agent in salt form) which acts to imbibe water from the surrounding medium via a semi-permeable membrane.
  • an osmotic agent e.g., the active agent in salt form
  • Such a device called an elementary osmotic pump, has been described.
  • Pressure is generated within the device which forces the active agent out of the device via an orifice of a size designed to minimize solute diffusion, while preventing the build-up of a hydrostatic pressure head which can have the effect of decreasing the osmotic pressure and changing the dimensions of the device.
  • the internal volume of the device remains constant, and there is an excess of solid or saturated solution in the device, then the release rate remains constant delivering a volume equal to the volume of solvent uptake.
  • Monolithic devices have been prepared using polyelectrolyte gels which swell when, for example, an external electrical stimulus is applied causing a change in pH.
  • the release may be modulated by changes in the applied current to produce a constant or pulsatile release profile.
  • hydrogels find use in a number of biomedical applications such as, for example, soft contact lenses, and various soft implants, and the like.
  • a method for treating a patient suffering from pain and/or inflammation comprising the step of administering a therapeutically effective amount of the loxoprofen composition of the present invention in solid oral dosage form.
  • Advantages of the method of the present invention include a reduction in the dosing frequency required by conventional multiple IR dosage regimes while still maintaining the benefits derived from a pulsatile plasma profile or eliminating or minimizing the variations in plasma concentration levels. This reduced dosing frequency is advantageous in terms of patient compliance and the reduction in dosage frequency made possible by the method of the present invention would contribute to controlling health care costs by reducing the amount of time spent by health care workers on the administration of drugs.
  • purified water refers to water that has been purified by passing it through a water filtration system. It is to be understood that the examples are for illustrative purposes only, and should not be interpreted as restricting the spirit and breadth of the invention as defined by the scope of the claims that follow.
  • a multiparticulate modified release composition according to the present invention comprising an immediate release component and a modified release component containing loxoprofen is prepared as follows.
  • a solution of loxoprofen is prepared according to any of the formulations given in Table 1.
  • the loxoprofen solution is then coated onto nonpareil seeds to a level of approximately 16.9% solids weight gain using, for example, a Glatt GPCG3 (Glatt, Protech Ltd., Leicester, UK) fluid bed coating apparatus to form the IR particles of the immediate release component.
  • Glatt GPCG3 Glatt, Protech Ltd., Leicester, UK
  • Loxoprofen containing delayed release particles are prepared by coating immediate release particles prepared according to Example 1 (a) above with a modified release coating solution as detailed in Table 2.
  • the immediate release particles are coated to varying levels up to approximately to 30% weight gain using, for example, a fluid bed apparatus.
  • Talc is simultaneously applied during coating for formulations in column (i), (iv) and (vi).
  • the immediate and delayed release particles prepared according to Example l(a) and (b) above are encapsulated in size 2 hard gelatin capsules to an overall 20 mg dosage strength using, for example, a Bosch GKF 4000S encapsulation apparatus.
  • the overall dosage strength of 20 mg loxoprofen was made up of 10 mg from the immediate release component and 10 mg from the modified release component.
  • Multiparticulate modified release loxoprofen compositions according to the present invention having an immediate release component and a modified release component having a modified release matrix material are prepared according to the formulations shown in Table 5(a) and (b).
  • IR component 100 mg is encapsulated with 100 mg of modified release (MR) component to give a 20 mg dosage strength product
  • Figure 1 is a graphical representation of a simulation of plasma concentrations obtained following dosing various percentages of modified release (CR) and immediate release (IR) loxoprofen.
  • CR modified release
  • IR immediate release
  • the pulsatile system can minimize the variation in plasma concentration levels exhibited by administration of immediate-release dosage forms resulting in more consistent blood levels and improved efficacy.
  • the pulsatile release formulation also minimize GI irritation by decreasing incidences of locally high concentrations of the NSAID.
  • Loxoprofen is currently administered three times daily.
  • the modified release formulation can be administered twice a day thus improving patient compliance.

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Abstract

L'invention concerne une composition à libération modifiée comprenant du loxoprofène ou un de ses sels ou dérivés qui lors de son utilisation délivre le médicament de manière pulsatile ou continue pour le traitement de la douleur et/ou de l'inflammation. La composition peut comprendre un premier composant de loxoprofène et un autre composant de loxoprofène, le premier composant de loxoprofène comprenant un composant à libération immédiate et l'autre composant de loxoprofène comprenant un composant à libération modifiée.
PCT/US2006/017938 1998-11-02 2006-05-09 Composition de loxoprofène à libération modifiée WO2008079102A1 (fr)

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JP2008551241A JP2009514989A (ja) 2005-05-10 2006-05-09 改変放出ロキソプロフェン組成物
US11/568,925 US20090297602A1 (en) 1998-11-02 2006-05-09 Modified Release Loxoprofen Compositions

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US11/372,857 US20060240105A1 (en) 1998-11-02 2006-03-10 Multiparticulate modified release composition
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010103367A1 (fr) * 2009-03-09 2010-09-16 Council Of Scientific & Industrial Research Composition à libération pulsatile d'un agent thérapeutique
US9283192B2 (en) 2010-03-05 2016-03-15 University Of Strathclyde Delayed prolonged drug delivery
US9474719B2 (en) 2010-03-05 2016-10-25 University Of Strathclyde Pulsatile drug release
US9974752B2 (en) 2014-10-31 2018-05-22 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US10137091B2 (en) 2010-03-05 2018-11-27 University Of Strathclyde Immediate/delayed drug delivery
US10722473B2 (en) 2018-11-19 2020-07-28 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4904476A (en) * 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
US6599529B1 (en) * 1997-09-11 2003-07-29 Nycomed Danmark A/S Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (NSAIDs)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4904476A (en) * 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
US6599529B1 (en) * 1997-09-11 2003-07-29 Nycomed Danmark A/S Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (NSAIDs)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010103367A1 (fr) * 2009-03-09 2010-09-16 Council Of Scientific & Industrial Research Composition à libération pulsatile d'un agent thérapeutique
US10137091B2 (en) 2010-03-05 2018-11-27 University Of Strathclyde Immediate/delayed drug delivery
US9283192B2 (en) 2010-03-05 2016-03-15 University Of Strathclyde Delayed prolonged drug delivery
US9474719B2 (en) 2010-03-05 2016-10-25 University Of Strathclyde Pulsatile drug release
US11065205B2 (en) 2010-03-05 2021-07-20 Drug Delivery International Limited Immediate/delayed drug delivery
US10449159B2 (en) 2014-10-31 2019-10-22 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10292939B2 (en) 2014-10-31 2019-05-21 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10292938B2 (en) 2014-10-31 2019-05-21 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10111839B2 (en) 2014-10-31 2018-10-30 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US10500162B2 (en) 2014-10-31 2019-12-10 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10507186B2 (en) 2014-10-31 2019-12-17 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10512612B2 (en) 2014-10-31 2019-12-24 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10512613B2 (en) 2014-10-31 2019-12-24 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10568841B2 (en) 2014-10-31 2020-02-25 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10688060B2 (en) 2014-10-31 2020-06-23 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US9974752B2 (en) 2014-10-31 2018-05-22 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US11896722B2 (en) 2014-10-31 2024-02-13 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10722473B2 (en) 2018-11-19 2020-07-28 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder

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