|Publication number||USRE42096 E1|
|Application number||US 11/091,011|
|Publication date||Feb 1, 2011|
|Filing date||Mar 24, 2005|
|Priority date||Oct 21, 1998|
|Also published as||CA2348090A1, CA2348090C, DE69940673D1, EP1123087A1, EP1123087A4, EP1123087B1, EP1977736A1, US6322819, US6605300, US20010055613, US20030124188, US20040219213, USRE41148, WO2000023055A1, WO2000023055A9|
|Publication number||091011, 11091011, US RE42096 E1, US RE42096E1, US-E1-RE42096, USRE42096 E1, USRE42096E1|
|Inventors||Beth A. Burnside, Xiaodi Guo, Kimberly Fiske, Richard A. Couch, Rong-Kun Chang, Donald J. Treacy, Charlotte M. McGuiness, Edward M. Rudnic|
|Original Assignee||Shire LLC, USA|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (63), Non-Patent Citations (156), Referenced by (3), Classifications (25), Legal Events (6)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This invention pertains to a multiple dosage form delivery system comprising one or more amphetamine salts for administering the amphetamine salts to a recipient.
Traditionally, drug delivery systems have focused on constant/sustained drug output with the objective of minimizing peaks and valleys of drug concentrations in the body to optimize drug efficacy and to reduce adverse effects. A reduced dosing frequency and improved patient compliance can also be expected for the controlled/sustained release drug delivery systems, compared to immediate release preparations. However, for certain drugs, sustained release delivery is not suitable and is affected by the following factors:
First pass metabolism: Some drugs, such as β blockers, β-estradiol, and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre-systemic metabolism. Thus, a constant/sustained oral method of delivery would result in reduced oral bioavailability.
Biological tolerance: Continuous release drug plasma profiles are often accompanied by a decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal nitroglycerin.
Chronopharmacology and circadian rhythms: Circadian rhythms in certain physiological functions are well established. It has been recognized that many symptoms and onset of disease occur during specific time periods of the 24 hour day, e.g., asthma and angina pectoris attacks are most frequently in the morning hours (1,2).
Local therapeutic need: For the treatment of local disorders such as inflammatory bowel disease, the delivery of compounds to the site of inflammation with no loss due to absorption in the small intestine is highly desirable to achieve the therapeutic effect and to minimize side effects.
Gastric irritation or drug instability in gastric fluid: For compounds with gastric irritation or chemical instability in gastric fluid, the use of a sustained release preparation may exacerbate gastric irritation and chemical instability in gastric fluid.
Drug absorption differences in various gastrointestinal segments: In general, drug absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declining in the large intestine. Compensation for changing absorption characteristics in the gastrointestinal tract may be important for some drugs. For example, it is rational for a delivery system to pump out the drug much faster when the system reaches the distal segment of the intestine, to avoid the entombment of the drug in the feces.
Pulsed dose delivery systems, prepared as either single unit or multiple unit formulations, and which are capable of releasing the drug after a predetermined time, have been studied to address the aforementioned problematic areas for sustained release preparations. These same factors are also problematic in pulsed dose formulation development. For example, gastrointestinal transit times vary not only from patient to patient but also within patients as a result of food intake, stress, and illness; thus a single-unit pulsed-release system may give higher variability compared to a multiple unit system. Additionally, drug layering or core making for multiple unit systems is a time-consuming and hard-to-optimize process. Particularly challenging for formulation scientists has been overcoming two conflicting hurdles for pulsatile formulation development, i.e., lag time and rapid release.
Various enteric materials, e.g., cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and the EUDRAGIT® acrylic polymers, have been used as gastroresistant, enterosoluble coatings for single drug pulse release in the intestine (3). The enteric materials, which are soluble at higher pH values, are frequently used for colon-specific delivery systems. Due to their pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performance as well as inter- and intra-subject variability are major issues for using enteric coated systems as a time-controlled release of drugs.
A retarding swellable hydrophilic coating has been used for oral delayed release systems (4,5). It was demonstrated that lag time was linearly correlated with coating weight gain and drug release was pH independent.
Hydroxypropyl methylcellulose barriers with erodible and/or gellable characteristics formed using press coating technology for tablet dosage forms have been described to achieve time-programmed release of drugs (6). Barrier formulation variables, such as grade of hydroxypropyl methylcellulose, water-soluble and water-insoluble excipients, significantly altered the lag time and the release rate from the center cores.
Special grades of hydroxypropyl methylcellulose, e.g., METOLOSE® 60SH, 90SH (Shin-Etsu Ltd., Japan), and METHOCEL® F4M (Dow Chemical Company, USA), as a hydrophilic matrix material have been used to achieve bimodal drug release for several drugs, i.e., aspirin, ibuprofen, and adinazolam (7). Bimodal release is characterized by a rapid initial release, followed by a period of constant release, and finalized by a second rapid drug release.
Tablets or capsules coated with a hydrophobic wax-surfactant layer, made from an aqueous dispersion of carnauba wax, beeswax, polyoxyethylene sorbitan monooleate, and hydroxypropyl methylcellulose have been used for rapid drug release after a predetermined lag time. For example,. However, even though a two-hour lag time was achieved for the model drug theophylline at a higher coating level (60%), three hours were required for a complete release of theophylline after the lag time. (8)
A sustained-release drug delivery system is described in U.S. Pat. No. 4,871,549. When this system is placed into dissolution medium or the gastrointestinal tract, water influx and the volume expansion of the swelling agent cause the explosion of the water permeable membrane. The drug thus releases after a predetermined time period.
The OROS® push-pull system (Alza Company) has been developed for pulsatile delivery of water-soluble and water-insoluble drugs ( a specific site (e.g., colon) in the gastrointestinal tract (11). The drug formulation is contained within a water-insoluble capsule body and is sealed with a hydrogel plug. Upon oral administration, the capsule cap dissolves in the gastric juice and the hydrogel plug swells. At a controlled and predetermined time point, the swollen plug is ejected from the PULSINCAP® dosage form and the encapsulated drug is released. A pulsatile capsule system containing captopril with release after a nominal 5-hr period was found to perform reproducibly in dissolution and gamma scintigraphy studies. However, in the majority of subjects, no measurable amounts of the drug were observed in the blood, possibly due to instability of the drug in the distal intestine. (12)
ADDERAL® comprises a mixture of four amphetamine sulfate salts which, in combination is indicated for treatment of Attention Deficit of age. One disadvantage of current treatment is that a tablet form is commonly used which many young children have difficulty in swallowing. Another disadvantage of current treatments is that two separate doses are administered, one in the morning and one approximately 4-6 hours later, commonly away from home under other than parental supervision. This current form of treatment, therefore, requires a second treatment which is time-consuming, inconvenient and may be problematic for those children having difficulties in swallowing table t formulations.
Accordingly, in view of a need for successfully administering a multiple pulsed dose of amphetamine salts and mixtures thereof, the present invention provides an oral multiple pulsed dose delivery system for amphetamine salts and mixtures thereof.
In accordance with a preferred embodiment of the present invention, there is provided a pharmaceutical composition for delivering one or more pharmaceutically active amphetamine salts that includes:
In one embodiment, the immediate release and enteric release portions of the composition are present on the same core.
In another embodiment, the immediate release and enteric release components are present on different cores.
It is also contemplated that the composition may include a combination of the hereinabove referred to cores (one or more cores that include both components on the same core and one or more cores that include only one of the two components on the core).
The present invention provides a composition in which there is immediate release of drug and enteric release of drug wherein the enteric release is a pulsed release and wherein the drug includes one or more amphetamine salts and mixtures thereof.
The immediate release component releases the pharmaceutical agent in a pulsed dose upon oral administration of the delivery system.
The enteric release coating layer retards or delays the release of the pharmaceutical active or drug for a specified time period (“lag time”) until a predetermined time, at which time the release of the drug is rapid and complete, i.e., the entire dose is released within about 30-60 minutes under predetermined environmental conditions, i.e. a particular location within the gastrointestinal tract.
The delay or lag time will take into consideration factors such as transit times, food effects, inflammatory bowel disease, use of antacids or other medicaments which alter the pH of the GI tract.
In a preferred embodiment, the lag time period is only time-dependent, i.e., pH independent. The lag time is preferably within 4 to 6 hours after oral administration of the delivery system.
In one aspect, the present invention is directed to a composition that provides for enteric release of at least one pharmaceutically active amphetamine salt, including at least one pharmaceutically active amphetamine salt that is coated with an enteric coating wherein (1) the enteric release coating has a defined minimum thickness and/or (2) there is a protective layer between the at least one pharmaceutically active amphetamine salt and the enteric release coating and/or (3) there is a protective layer over the enteric release coating.
In attempting to provide for enteric release of an amphetamine salt, applicants found that use of an enteric release coating as generally practiced in the art did not provide effective enteric release.
Typical enteric coating levels did not meet the above requirements for the desired dosage profile of amphetamine salts. Using the typical amount of enteric coating (10-20 μ) resulted in undesired premature leakage of the drug from the delivery system into the upper gastrointestinal tract and thus no drug delivery at the desired location in the gastrointestinal tract after the appropriate lag time. Thus this coating did not meet the requirements for the drug release profile to provide full beneficial therapeutic activity at the desired time.
Surprisingly, applicants found that using a thicker application of enteric coating on the formulation allowed for the second pulsed dose to be released only and completely at the appropriate time in the desired predetermined area of the gastrointestinal tract, i.e., in the intestine.
Th is was surprising because an increase in thickness of about 5-10 μof enteric coatings above a minimum thickness of about 10-20 μtypically does not have a significant effect on release of d rug from within such coatings. Enteric coatings typically are pH dependent and will only dissolve/disperse when exposed to the appropriate environment. Typically, application of a thicker coating (greater than 20 μ) will only marginally increase the time for complete release at the appropriate environmental condition i.e., for a brief period of time (20 minutes). Using the typical coating, applicants could not achieve the desired result—rather, the coating leaked before the predetermined time in an inappropriate environment resulting in significant loss of the therapeutic agent.
Accordingly, in one aspect, the pulsed enteric release of the amphetamine salts is accomplished by employing a certain minimum thickness of the enteric coating .
In one embodiment of the invention, the pulsed dose delivery comprises a composition which comprises one or more pharmaceutically active amphetamine salts; an enteric coating over the one or more pharmaceutically active amphetamine salts, wherein the thickness of the enteric coating layer is at least 25 μ; a further layer of one or more pharmaceutically active amphetamine salts over the enteric coating layer; and an immediate release layer coating. The thicker enteric coating surprisingly provides the required delayed i m mediate release of the pharmaceutically active amphetamine salt at the desire d time in the desired area of the gastrointestinal tract.
In this aspect, the one or more pharmaceutically active amphetamine salts can be provided within or as a part of a core seed around which the enteric coating is applied. Alternatively, a core seed can be coated with one or more layers of one or more pharmaceutically active amphetamine salts.
It has further been discovered that a delayed immediate release drug delivery can also be accomplished by coating the drug first with a protective layer prior to applying the enteric coating.
Thus, in another embodiment, the pulsed enteric release is accomplished by employing a protective layer between the drug and the enteric coating. When using a protective coating, the enteric coating may be of an increased thickness or may be of lower thickness.
Thus, in another aspect, the object of the invention is met by providing a composition comprising one or more pharmaceutically active amphetamine salts; a protective layer coating over the one or more pharmaceutically active amphetamine salt layer(s), and an enteric coating layer over the protective coating layer; a further pharmaceutically active amphetamine salt layer and an immediate release layer coating. In a preferred embodiment of this aspect, the thickness of the enteric coating is at least 25 μ, and the protective layer comprises an immediate release coating.
With respect to this embodiment of the invention, the one or more pharmaceutically active amphetamine salts can be provided within or as a part of a core seed, during the core seed manufacturing process, around which the protective coating is applied. Alternatively, a core seed can be coated with one or more layers of one or more pharmaceutically active amphetamine salts.
In another embodiment, the pulsed enteric release is accomplished by employing a protective layer over the enteric coating.
Accordingly, in this embodiment of the present invention, there is provided a pulsed dose release drug delivery system comprising one or more pharmaceutically active amphetamine salts; an enteric coating layer over the pharmaceutically active amphetamine salt layer(s); and a protective layer over the enteric coating; a second pharmaceutically active amphetamine salt layer; and an immediate release layer coating.
In one aspect of this embodiment, the protective layer is comprised of one or more components, which includes an immediate release layer and a modifying layer. The modifying layer is preferably comprised of a semi water-permeable polymer. Applicants have surprisingly found that a semi-permeable polymer coating used in combination with an immediate release layer coating provided a delayed pulsed release drug delivery profile when layered over the enteric coating.
Thus, in this embodiment, the protective layer comprises a semi-permeable polymer and an immediate release coating layer. In a preferred embodiment, the modifying layer comprises a first layer of a semi-permeable polymer which is adjacent to the enteric coating layer and a second coating layer over the semi-permeable polymer coating layer comprising an immediate release polymer coating layer.
In one aspect of this embodiment, a semi-permeable polymer, which may comprise a low water-permeable pH-insensitive polymer, is layered onto the outer surface of the enteric layer, in order to obtain prolonged delayed release time. This semi-permeable polymer coating controls the erosion of the pH-sensitive enteric polymer in an alkaline pH environment in which a pH-sensitive polymer will dissolve rapidly. Another pH-sensitive layer may be applied onto the surface of a low water-permeability layer to further delay the release time.
In a still further aspect of the invention, in addition to a protective layer, the composition comprises an acid which is incorporated into the pharmaceutical active layer or coated onto the surface of the active layer to reduce the pH value of the environment around the enteric polymer layer. The acid layer may also be applied on the outer layer of the pH-sensitive enteric polymer layer, followed by a layer of low water-permeability polymer. The release of the active thus may be delayed and the dissolution rate may be increased in an alkaline environment.
In a further embodiment, the protective coating may be used both over the drug and over the enteric coating.
With respect to this embodiment of the invention, the one or more pharmaceutically active amphetamine salts can be provided within or as a part of a core seed, during the core seed manufacturing process, around which the enteric coating is applied. Alternatively, a core seed can be coated with one or more layers of one or more pharmaceutically active amphetamine salts.
The drug delivery system of the present invention as described herein preferably comprises one or a number of beads or beadlets in a dosage form, either capsule, tablet, sachet or other method of orally administering the beads.
The present invention comprises a core or starting seed, either prepared or commercially available product. The cores or starting seeds can be sugar spheres; spheres made from microcrystalline cellulose and any suitable drug crystals.
The materials that can be employed in making drug-containing pellets are any of those commonly used in pharmaceutics and should be selected on the basis of compatibility with the active drug and the physicochemical properties of the pellets. The additives except active drugs are chosen below as examples:
Binders such as cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer and the like.
Disintegration agents such as corn starch, pregelatinized starch, cross-linked carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE® XL), and any disintegration agents used in tablet preparations.
Filling agents such as lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
Surfactants such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate, PLURONIC® line (BASF), and the like.
Solubilizer such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid sodium bicarbonate and sodium carbonate and the like.
Stabilizers such as any antioxidation agents, buffers, acids, and the like, can also be utilized.
Methods of manufacturing the core include
a. Extrusion-Spheronization—Drug(s) and other additives are granulated by addition of a binder solution. The wet mass is passed through an extruder equipped with a certain size screen. The extrudates are spheronized in a marumerizer. The resulting pellets are dried and sieved for further applications.
b. High-Shear Granulation—Drug(s) and other additives are dry-mixed and then the mixture is wetted by addition of a binder solution in a high shear-granulator/mixer. The granules are kneaded after wetting by the combined actions of mixing and milling. The resulting granules or pellets are dried and sieved for further applications.
c. Solution or Suspension Layering—A drug solution or dispersion with or without a binder is sprayed onto starting seeds with a certain particle size in a fluid bed processor or other suitable equipment. The drug thus is coated on the surface of the starting seeds. The drug-loaded pellets are dried for further applications.
For purposes of the present invention, the core particles have a diameter in the range of about 500-1500 100-1500 microns; preferably 100-800 microns.
These particles can then be coated in a fluidized bed apparatus with an alternating sequence of coating layers.
The core may be coated directly with a layer or layers of at least one pharmaceutically active amphetamine salts and/or the pharmaceutically active amphetamine salt may be incorporated into the core material. Pharmaceutical active amphetamine salts contemplated to be within the scope of the present invention include amphetamine base, all chemical and chiral derivatives and salts thereof; methylphenidate, all chemical and chiral derivatives and salts thereof; phenylpropanolamine and its salts; and all other compounds indicated for the treatment of attention deficit hyperactivity disorder (ADHD).
A protective layer may be added on top of t he pharmaceutical active containing layer and also may be provided between active layers. A separation or protective layer may be added onto the surface of the active-loaded core, and then the enteric layer is coated thereupon. Another active layer may also be added to the enteric layer to deliver an initial dose.
A protective coating layer may be applied immediately outside the core, either a drug-containing core or a drug-layered core, by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. Suitable materials for the protective layer include cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose aqueous dispersions (AQUACOAT®, SURELEASE®), EUDRAGIT® RL 30D, OPADRY® and the like. The suggested coating levels are from 1 to 6%, preferably 2-4% (w/w).
The enteric coating layer is applied onto the cores with or without seal coating by conventional coating techniques, such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. All commercially available pH-sensitive polymers are included. The pharmaceutical active is not released in the acidic stomach environment of approximately below pH 4.5, but not limited to this value. The pharmaceutical active should become available when the pH-sensitive layer dissolves at the greater pH; after a certain delayed time; or after the unit passes through the stomach. The preferred delay time is in the range of two to six hours.
Enteric polymers include cellulose acetate phthalate, Cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, materials known under the trade name EUDRAGIT® L12.5, L100, or EUDRAGIT® S12.5, S100 or similar compounds used to obtain enteric coatings. Aqueous colloidal polymer dispersions or re-dispersions can be also applied, e.g. EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).
The enteric polymers used in this invention can be modified by mixing with other known coating products that are not pH sensitive. Examples of such coating products include the neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride, sold currently under the trade names EUDRAGIT® and EUDRAGIT® RL; a neutral ester dispersion without any functional groups, sold under the trade names EUDRAGIT® NE30D and EUDRAGIT® NE30; and other pH independent coating products.
The modifying component of the protective layer used over the enteric coating can include a water penetration barrier layer (semipermeable polymer) which can be successively coated after the enteric coating to reduce the water penetration rate through the enteric coating layer and thus increase the lag time of the drug release. Sustained-release coatings commonly known to one skilled in the art can be used for this purpose by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. For example, the following materials can be used, but not limited to: Cellulose acetate, Cellulose acetate butyrate, Cellulose acetate propionate, Ethyl cellulose, Fatty acids and their esters, Waxes, zein, and aqueous polymer dispersions such as EUDRAGIT® RS and RL 30D, EUDRAGIT® NE 30D, AQUACOAT®, SURELEASE®, cellulose acetate latex. The combination of above polymers and hydrophilic polymers such as Hydroxyethyl cellulose, Hydroxypropyl cellulose (KLUCEL®, Hercules Corp.), Hydroxypropyl methylcellulose (METHOCEL®, Dow Chemical Corp.), Polyvinylpyrrolidone can also be used.
An overcoating layer can further optionally be applied to the composition of the present invention. OPADRY®, OPADRY II® (Colorcon) and corresponding color and colorless grades from Colorcon can be used to protect the pellets from being tacky and provide colors to the product. The suggested levels of protective or color coating are from 1 to 6%, preferably 2-3% (w/w).
Many ingredients can be incorporated into the overcoating formula, for example to provide a quicker immediate release, such as plasticizers; acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate, dibutylsebacate, triacetin, polyethylene glycols, propylene glycol and the others; lubricants: talc, colloidal silica dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, and the like.
The composition, preferably in beadlet form, can be incorporated into hard gelatin capsules, either with additional excipients, or alone. Typical excipients to be added to a capsule formulation include, but are not limited to: fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler. In addition, there can be flow aids such as fumed silicon dioxide, silica gel, magnesium stearate, calcium stearate or any other material imparting flow to powders. A lubricant can further be added if necessary by using polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or calcium stearate.
The composition may also be incorporated into a tablet, in particular by incorporation into a tablet matrix, which rapidly disperses the particles after ingestion. In order to incorporate these particles into such a tablet, a filler/binder must be added to a table that can accept the particles, but will not allow their destruction during the tableting process. Materials that are suitable for this purpose include, but are not limited to, microcrystalline cellulose (A VICEL®), soy polysaccharide (EMCOSOY®), pre-gelatinized starches (STARCH® 1500, NATIONAL® 1551), and polyethylene glycols (CARBOWAX®). The materials should be present in the range of 5-75% (w/w), with a preferred range of 25-50% (w/w).
In addition, disintegrants are added in order to disperse the beads once the tablet is ingested. Suitable disintegrants include, but are not limited to: cross-linked sodium carboxymethyl cellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), and cross-linked polyvinylpolypyrrolidone (Plasone-XL). These materials should be present in the rate of 3-15% (w/w), with a preferred range of 5-10% (w/w).
Lubricants are also added to assure proper tableting, and these can include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behanate, and hydrogenated vegetable oil. These lubricants should be present in amounts from 0.1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).
Tablets are formed, for example, as follows. The particles are introduced into a blender along with AVICEL®, disintegrants and lubricant, mixed for a set number of minutes to provide a homogeneous blend which is then put in the hopper of a tablet press with which tablets are compressed. The compression force used is adequate to form a tablet; however, not sufficient to fracture the beads or coatings.
It will be appreciated that the multiple dosage form of the present invention can deliver rapid and complete dosages of pharmaceutically active amphetamine salts to achieve the desired levels of the drug in a recipient over the course of about 8 hours with a single oral administration.
In so doing, the levels of drug in blood plasma of the pharmaceutically active amphetamine salts will reach a peak fairly rapidly after about 2 hours, and after about 4 hours a second pulse dose is released, wherein a second fairly rapid additive increase of plasma drug levels occurs which slowly decreases over the course of the next 12 hours.
The following examples are presented to illustrate and do not limit the invention.
Immediate release formulation
The following formulation was used to layer the drug onto sugar spheres. Nonpareil seeds (30/35 mesh, Paulaur Corp., NJ), 6.8 kg were put into a FLM-15 fluid bed processor with a 9″ Wurster column and fluidized at 60° C. The suspension of mixed amphetamine salts (MAS) with 1% HPMC E5 Premium (Dow Chemical) as a binder was sprayed onto the seed under suitable conditions. Almost no agglomeration and no fines were observed with a yield of at least 98%. The drug-loaded cores were used to test enteric coatings and sustained release coatings.
mixed amphetamine salts
METHOCEL ® E5 Premium
*removed during processing
The drug release profile of the drug-loaded pellets of this example is shown in FIG. 3.
The following formulation was used to coat the mixed amphetamine salts loaded (MASL) pellets from Example 1 with the EUDRAGIT® L 30D-55 (Rohm Pharma, Germany) coating dispersion. 2 kg of MASL pellets were loaded into a fluid bed processor with a reduced Wurster column equipped with a precision coater(MP 2/3, Niro Inc.) . The coating dispersion was prepared by dispersing Triethyl citrate, Talc and EUDRAGIT® L 30D-55 into water and mixing for at least 30 minutes. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized MASL pellets. The spraying was continued until the targeted coating level was achieved(20μ) . The coated pellets were dried at 30-35° C. for 5 minutes before stopping the process. The enteric coated PPA MASL pellets were tested at different pH buffers by a USP paddle method. The drug content was analyzed using HPLC. The results showed that the enteric coating delayed the drug release from the coated pellets until after exposure to pH 6 or higher. (Reference # AR98I25-4)
EUDRAGIT ® L 30D-55
*removed during processing
The drug release profile of the coated pellets of this example is shown in FIG. 4.
The following formulation was used to coat the MASL pellets from Example 1 with the EUDRAGIT® 4110D (Rohm Pharma, Germany) coating dispersion. MASL pellets (2 kg) were loaded in a fluid bed processor with a reduced Wurster column (GPGC-15 Glatt). The coating dispersion was prepared by dispersing Triethyl citrate, Talc and EUDRAGIT® 4110D into water and mixing for at least 30 minutes. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized MASL pellets. The spraying was continued until the targeted coating level was achieved. The coated pellets were dried at 30-35° C. for 5 minutes before stopping the process. The enteric coated MASL pellets were tested u sing a USP paddle method at different pH buffers. The drug content was analyzed using HPLC. The enteric coating delayed the drug release for several hours from the coated pellets until the pH value reached 6.8 or higher. (Reference # AR98I25-3)
EUDRAGIT ® 4110D
*removed during processing
The drug release profile of coated pellets of this example is shown in FIG. 5.
The following formulation was selected to coat the enteric coated MASL pellets. Coated MASL pellets from Example 2 or coated MASL pellets from Example 3 (2 kg of either) were loaded into a fluid bed processor with a reduced Wurster column (GPGC-1 5, Glatt). The coating dispersion was prepared by mixing SURELEASE® (Colorcon) and water for at least 15 minutes prior to spraying. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized pellets. The spraying was continued until the targeted coating level was achieved. The coated pellets were coated with a thin layer of OPADRY® white (Colorcon) (2%) to prevent the tackiness of the coated pellets during storage. The coated pellets were then dried at 35-40° C. for 10 minutes before discharging from the bed. The drug dissolution from both coated pellets was performed using a USP paddle method at different pH buffers. The drug content was analyzed using HPLC. The 8% SURELEASE® coating slightly sustained the drug release from EUDRAGIT® L 30D-55 coated pellets at pH 7.5 buffer, while the SURELEASE® coating delayed the drug release up to 2 hours after the buffer switched from pH 1 to pH 7.5. (Reference ## AR98I25-1)
Amount, kg (%)
Enteric coated MASL pellets
OPADRY ® white
*removed during processing
The drug release profile of the coated pellets from this example is shown in FIG. 6.
1. B.Lemmer, “Circadian Rhythms and Drug Delivery”, J. Controlled Release, 16, 63-74 (1991)
2. B. Lemmer, “Why are so many Biological Systems Periodic?” in Pulsatile Drug Delivery: Current Applications and Future Trends, R Gumy, HE Junginger and NA Peppas, eds. (Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, Germany 1993) pp.11-24
3. X. Xu and PI Lee, “Programmable Drug Delivery from an Erodible Association Polymer System”, Pharm. Res. 10(8), 1144-1152 (1993)
4. A. Gazzaniga, ME Sangalli, and F Giodano, “Oral Chonotropic Drug Delivery Systems: Achievement of Time and/or Site Specificity”, Eur J Pharm. Biopharm., 40(4), 246-250 (1994)
5. A Gazzaniga, C Busetti, L Moro, ME Sangalli and F Giordano, “Time Dependent Oral Delivery Systems for Colon Targeting”, S. T.P. Pharma Sciences5(1), 83-88 (1996)
6. U Conte, L Maggi, ML Torre, P Giunchedi and A Lamanna, “Press-coated Tablets for Time programmed Release of Drugs”, Biomaterials, 14(13), 1017-1023 (1993)
7. AC Shah International Patent Application W098/00044
8. PS Walia, P Jo Mayer Stout and R Turton, “Preliminary Evaluation of an Aqueous Wax Emulsion for Controlled Release Coating”, Pharm Dev Tech, 3(1), 103-113 (1998)
9. F Theeuwes, “OROS® Osmotic System Development”, Drug Dev Ind Pharm9(7), 1331-1357 (1983)
10. F Theeuwes, “Triggered, Pulsed and Programmed Drug Delivery” in Novel Drug Delivery and its Therapeutic Application, LF Prescott and WS Nimmos. eds. (Wiley, New York, 1989) pp. 323-340
11. M McNeil, A Rashid and H Stevens, “International Patent App W090/09168
12. IR Wilding, SS Davis, M Bakhshaee, HNE Stevens, RA Sparrow and J Brennan, “Gastrointestinal Transit and Systemic Absorption of Captopril from a Pulsed Release Formulation”, Pharm Res 9(5), 654-657 (1992)
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US2099402||Jan 17, 1934||Nov 16, 1937||Pratt Food Company||Pill or tablet|
|US2738303||Jul 18, 1952||Mar 13, 1956||Smith Kline French Lab||Sympathomimetic preparation|
|US2881113 *||Jan 29, 1957||Apr 7, 1959||Ortho Pharma Corp||Therapeutically active compositions containing amphetamines|
|US3048526||Aug 4, 1958||Aug 7, 1962||Wander Company||Medicinal tablet|
|US3066075 *||Jul 25, 1960||Nov 27, 1962||G W Carnrick Co||Compositions comprising amphetamine and carboxymethyl cellulose in chemically combined form|
|US3365365||Aug 9, 1965||Jan 23, 1968||Hoffmann La Roche||Repeat action pharmaceutical compositions in the form of discrete beadlets|
|US3979349||May 1, 1974||Sep 7, 1976||Rohm Gmbh||Dispersions of water-soluble polymers and methods for making and using the same|
|US4049791||Jan 26, 1976||Sep 20, 1977||Delco Chemical Company, Inc.||Prolonged acting appetite suppressant and anti-obesity compositions containing amphetamine adipate, dextroamphetamine adipate, amphetamine sulfate and dextroamphetamine sulfate as the active agents|
|US4723958||May 23, 1986||Feb 9, 1988||Merck & Co., Inc.||Pulsatile drug delivery system|
|US4728512||Mar 4, 1986||Mar 1, 1988||American Home Products Corporation||Formulations providing three distinct releases|
|US4794001||Sep 24, 1987||Dec 27, 1988||American Home Products Corporation||Formulations providing three distinct releases|
|US4871549||Jul 10, 1986||Oct 3, 1989||Fujisawa Pharmaceutical Co., Ltd.||Time-controlled explosion systems and processes for preparing the same|
|US4891230||Nov 16, 1987||Jan 2, 1990||Elan Corporation Plc||Diltiazem formulation|
|US4894240||Nov 16, 1987||Jan 16, 1990||Elan Corporation Plc||Controlled absorption diltiazem formulation for once-daily administration|
|US4902516||Apr 6, 1988||Feb 20, 1990||Chemie Holding Aktiengesellschaft||Binder-free granules with delayed release of the active compound|
|US4917899||Nov 16, 1987||Apr 17, 1990||Elan Corporation Plc||Controlled absorption diltiazem formulation|
|US5002776||Nov 18, 1988||Mar 26, 1991||Elan Corporation, Plc||Controlled absorption diltiazem formulations|
|US5011692||Dec 23, 1986||Apr 30, 1991||Sumitomo Pharmaceuticals Company, Limited||Sustained pulsewise release pharmaceutical preparation|
|US5011694||Aug 1, 1989||Apr 30, 1991||Rohm Gmbh||Pharmaceutical dosage unit forms with delayed release|
|US5051262||Nov 18, 1986||Sep 24, 1991||Elan Corp., P.L.C.||Processes for the preparation of delayed action and programmed release pharmaceutical forms and medicaments obtained thereby|
|US5093200||Sep 30, 1988||Mar 3, 1992||Eisai Co., Ltd.||Multilayer sustained release granule|
|US5137733||Jun 28, 1991||Aug 11, 1992||Tanabe Seiyaku Co., Ltd.||Controlled release pharmaceutical preparation|
|US5156850||Aug 31, 1990||Oct 20, 1992||Alza Corporation||Dosage form for time-varying patterns of drug delivery|
|US5202159||Dec 31, 1990||Apr 13, 1993||Standard Chemical & Pharmaceutical Corp., Ltd.||Preparation method of microdispersed tablet formulation of spray-dried sodium diclofenac enteric-coated microcapsules|
|US5226902||Jul 30, 1991||Jul 13, 1993||University Of Utah||Pulsatile drug delivery device using stimuli sensitive hydrogel|
|US5229131||Oct 7, 1991||Jul 20, 1993||University Of Michigan||Pulsatile drug delivery system|
|US5260068||May 4, 1992||Nov 9, 1993||Anda Sr Pharmaceuticals Inc.||Multiparticulate pulsatile drug delivery system|
|US5260069||Nov 27, 1992||Nov 9, 1993||Anda Sr Pharmaceuticals Inc.||Pulsatile particles drug delivery system|
|US5275819||Apr 26, 1991||Jan 4, 1994||Amer Particle Technologies Inc.||Drug loaded pollen grains with an outer coating for pulsed delivery|
|US5308348||May 5, 1993||May 3, 1994||Alza Corporation||Delivery devices with pulsatile effect|
|US5328697 *||Feb 10, 1992||Jul 12, 1994||Mallinckrodt Veterinary, Inc.||Compositions and processes for the sustained release of drugs|
|US5364620||Jul 28, 1992||Nov 15, 1994||Elan Corporation, Plc||Controlled absorption diltiazem formulation for once daily administration|
|US5378474||Feb 22, 1993||Jan 3, 1995||F. H. Faulding & Co. Limited||Sustained release pharmaceutical composition|
|US5395628||Apr 13, 1992||Mar 7, 1995||Tanabe Seiyaku Co., Ltd.||Controlled release succinic acid microcapsules coated with aqueous acrylics|
|US5407686||Jan 29, 1992||Apr 18, 1995||Sidmak Laboratories, Inc.||Sustained release composition for oral administration of active ingredient|
|US5422121||Aug 16, 1993||Jun 6, 1995||Rohm Gmbh||Oral dosage unit form|
|US5474786||Oct 6, 1994||Dec 12, 1995||Ortho Pharmaceutical Corporation||Multilayered controlled release pharmaceutical dosage form|
|US5496561||Aug 24, 1994||Mar 5, 1996||Ss Pharmaceutical Co., Ltd.||Controlled release-initiation and controlled release-rate pharmaceutical composition|
|US5616345||Nov 4, 1994||Apr 1, 1997||Elan Corporation Plc||Controlled absorption diltiazen formulation for once-daily administration|
|US5773031 *||Feb 27, 1996||Jun 30, 1998||L. Perrigo Company||Acetaminophen sustained-release formulation|
|US5837284 *||Jul 14, 1997||Nov 17, 1998||Mehta; Atul M.||Delivery of multiple doses of medications|
|US5840329||May 15, 1997||Nov 24, 1998||Bioadvances Llc||Pulsatile drug delivery system|
|US6005027 *||Aug 16, 1996||Dec 21, 1999||Witco Corporation||Stable silane compositions on silica carrier|
|US6475493||Aug 30, 2000||Nov 5, 2002||Norstrum Pharmaceuticals, Inc.||Controlled release pellet formulation|
|US6605300 *||Oct 20, 1999||Aug 12, 2003||Shire Laboratories, Inc.||Oral pulsed dose drug delivery system|
|US6749867||Nov 21, 2001||Jun 15, 2004||Joseph R. Robinson||Delivery system for omeprazole and its salts|
|US6764696||Mar 18, 2003||Jul 20, 2004||Cima Labs Inc.||Effervescent drug delivery system for oral administration|
|US20040059002||Jan 29, 2003||Mar 25, 2004||Shire Laboratories, Inc.||Sustained release delivery of amphetamine salts|
|AU109438A||Title not available|
|EP0640337A2||Aug 25, 1994||Mar 1, 1995||Ss Pharmaceutical Co., Ltd.||Controlled release-initiation and controlled release-rate pharmaceutical composition|
|JPH0761922A||Title not available|
|JPH1081634A||Title not available|
|JPH03148215A||Title not available|
|JPH09249557A||Title not available|
|JPH09267035A||Title not available|
|JPS5982311A||Title not available|
|WO1987000044A1||Jun 18, 1986||Jan 15, 1987||The Upjohn Company||Therapeutic formulations with bimodal release characteristics|
|WO1990009168A1||Feb 15, 1990||Aug 23, 1990||National Research Development Corporation||Dispensing device|
|WO1997003673A1||Jul 15, 1996||Feb 6, 1997||Medeva Europe Limited||Sustained-release formulation of d-threo-methylphenidate|
|WO1998014168A2||Sep 16, 1997||Apr 9, 1998||Alza Corporation||Dosage form providing a sustained and ascending drug release|
|WO1999003471A1||Jun 9, 1998||Jan 28, 1999||Mehta, Atul, M.||Improved delivery of multiple doses of medications|
|WO2000025752A1||Nov 1, 1999||May 11, 2000||Church, Marla, J.||Multiparticulate modified release composition|
|WO2000035450A1||Dec 17, 1999||Jun 22, 2000||Euro-Celtique S.A.||Controlled/modified release oral methylphenidate formulations|
|1||Adderall XR Package Inset, Sep. (2004).|
|2||Agyilirah GA and Bauker SB, Polymers for Enteric Coating Applications, Polymers for Controlled Drug Delivery (Peter J. Tarcha ed. 1991) 39-66.|
|3||American Chemical Society, Polymer Preprints, pp. 633-634, vol. 34, No. 1, Mar. 1993.|
|4||Angrist et al., Early Pharmacokinetics and Clinical Effects of Oral D-Amphetamine in Normal Subjects, Biol. Psychiatry 1987, 22: 1357-1368.|
|5||Ansel, et al., Rate Controlled Dosage Forms and Drug Delivery Systems, Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th Ed. (1995), 213-222.|
|6||Answer and Counterclaims in Shire Laboratories, Inc. v. Andrx, LLC, in the United States District Court for the Southern District of Florida, Miami Division, Case No. 07-22201-CIV-Cooke/Brown, Aug. 31, 2007.|
|7||Answering Expert Report of Dr. Alexander Klibanov, Apr. 25, 2005.|
|8||Answering Expert Report of Robert Langer, Apr. 25, 2005.|
|9||Barr Laboratories Inc.'s Objections and Responses to Shire Laboratories Inc.'s Second Set of Interrogatories (Nos. 8-11), dated Feb. 18, 2004.|
|10||Barr Laboratories' Memorandum In Support of its Motion to Amend its Pleadings and exhibits thereto, dated Sep. 10, 2004.|
|11||Barr Laboratories' Memorandum in Support of its Motion to Compel Production, dated Sep. 13, 2004.|
|12||Barr Laboratories' Objections and Responses to Plaintiff Shire Laboratories Inc.'s Fifth Set of Interrogatories (No. 17), dated Sep. 3, 2004.|
|13||Barr Laboratories' Objections and Responses to Plaintoff Shire Laboratories Inc.'s Fourth Set of Interrogatories (Nos. 15-16), dated Jul. 9, 2004.|
|14||Barr Laboratories' Supplemetal Objections and Responses to Plaintiff Shire Laboratories Inc.'s Third Set of Interrogatories (Nos. 12-14 Redacted), dated Aug. 27, 2004.|
|15||Bauer, et al., Cellulose Acetate Phthalate (CAP) and Trimellitate (CAT), Coated Pharmaceutical Dosage Forms (1998), 102-104.|
|16||Bodmeier et al., The Influence of Buffer Species and Strength on Diltiazem HCl Release from Beads Coated with the Aqueous Catinoc Polymer Dispensions, Eudragit RS, RL 30D, Pharmaceutical Research vol. 13, No. 1, 1996, 52-56.|
|17||Brauer et al., Acute Tolerance to Subjective but not Cardiovascular Effects of d-Amphetamine in normal, Healthy Men, Journal of Clinical Psychopharmacology, 1996; 16(1):73-76.|
|18||Brown et al., Behavior and Motor Activity Response in Hyperactive Children and Plasma Amphetamine Levels Following a Sustained Release Preparation, Journal of the American Academy of Child Psychiatry, 19:225-239, 1980.|
|19||Brown et al., Plasma Levels of d-Amphetamine in Hyperactive Children, Psychopharmacology 62, 133-140, 1979.|
|20||Burns et al., A study of Enteric-coated Liquid-filled Hard Gelatin Capsules with Biphasic Release Characteristics, International Journal of Pharmaceutics 110 (1994) 291-296.|
|21||Burnside Deposition Transcript, Feb. 2, 2005.|
|22||Burnside Deposition Transcript, Feb. 3, 2005.|
|23||C. Lin et al., Biovailability of d-pseudoephedrine and Azatadine from a Repeat Action Tablet Formulation, J Int Med Res (1982), 122-125.|
|24||C. Lin et al., Comparative Biovailability of d-pseudoephedrine from a Conventional d-pseudoephedrine Sulfate Tablet and from a Repeat Action Tablet, J Int Med Res (1982) 10, 126-128.|
|25||Chan, Materials Used for Effective Sustained-Release Products, Proceedings of the International Symposium held on 29th to 31st of Jan. 1987 (The Bombay College of Pharmacy 1988), 69-84.|
|26||Chan, New Polymers for Controlled Release Products, Controlled Release Dosage Forms Proceedings of the International Symposium held on 29th to 31st of Jan. 1987 (The Bombay College of Pharmacy 1988) 59-67.|
|27||Chang Deposition Transcript, Jan. 20, 2005.|
|28||Chang Deposition Transcript, Sep. 8, 2004.|
|29||Chang et al., Preparation and Evaluation of Shellac Pseudolatex as an Aqueous Enteric Coating Systems for Pellets, International Journal of Pharmaceuticals, 60 (1990) 171-173, 1990.|
|30||Charles S.L. Chlao amd Joseph R. Robinson, Sustained-Release Drug Delivery Systems, Remington: The Science and Practice of Pharmacy, Tenth Edition (1995) 1660-1675.|
|31||Cody et al., Amphetamine Enantiomer Excretion Profile Following Administration of Adderall, Journal of Analytical Toxicology, vol. 2, Oct. 2003, 485-492.|
|32||Complaint for Declaratory Judgment, Impax Laboratories Inc. v. Shire International Laboratories, Inc. (Civ. Action No. 05772) and Exhibits attached thereto, dated Nov. 9, 2005.|
|33||Conte, et al., "Press-coated tablets for time-programmed release of drugs," Biomaterials, 14(13):1017-1023 (1993).|
|34||Couch Deposition Transcript, Sep. 8, 2004.|
|35||Daynes, Treatment of Noctural Enuresis with Enteric-Coated Amphetamine, The Practitioner, No. 1037, vol. 173, Nov. 1954.|
|36||Defendant Sandoz, Inc.'s Answers and Objections to Plaintiff Shire LLC's Interrogatories (No. 1-9), in the United States District Court for the District of Colorado, Case No. 07-CV-001197-EWN-CBS, Jun. 18, 2007.|
|37||Defendant Sandoz, Inc.'s Answers and Objections to Plaintiff Shire LLC's Second Set of Interrogatories (No. 10-19), in the United States District Court for the District of Colorado, Case No. 07-CV-001197-EWN-CBS, Nov. 20, 2007.|
|38||Defendant Sandoz, Inc.'s Answers and Objections to Plaintiff Shire LLC's Second Set of Interrogatories (No. 20-25) and Supplement to Answers to Interrogatories 8 and 9, in the United States District Court for the District of Colorado, Case No. 07-CV-001197-EWN-CBS, Dec. 10, 2007.|
|39||Deposition transcript of Honorable Gerald J. Mossinghoff and exhibits thereto, dated Jun. 8, 2005.|
|40||Edward Stempel, Prolonged Drug Action, HUSA's Pharmaceutical Dispensing, Sixth Edition, 1966, 464, 481-485.|
|41||Expert Report of Arthur J. Steiner in Shire LLC v. Colony Pharmaceuticals, Inc., in the United States District Court for the District of Maryland, case No. 1:07-cv-00718, Dec. 20, 2007.|
|42||Expert Report of Dr. Joseph R. Robinson and exhibits thereto, Feb. 28, 2005.|
|43||Expert Report of the Honorable Gerald J. Mossinghoff and exhibits thereto, Mar. 16, 2005.|
|44||Fiske Deposition Transcript, Sep. 17, 2004.|
|45||Freedom of Information Request Results for—Dexadrine (SmithKline Beecham): May 20, 1976 Disclosable Approval Information.|
|46||Fukumori, Coating of Multiparticulates Using Polymeric Dispersions, Multiparticulate Oral Drug Delivery (Swarbrick and Selassie eds. 1994), 79-110.|
|47||Garnett et al., Pharmacokinitic Evaluation of Twice-Daily Extended-Release Carbamazepine (CBZ) and Four-Times-Daily Immediate-Release CBZ in Patients with Epilepsy, Epilepsia 39(3):274-279, 1998.|
|48||Gazzaniga, et al., "Oral Chronotopic Drug Delivery Systems: Achievement of Time and/or Site Specificity," Eur. J. Pharm. Biopharma 40(3):246-250 (1994).|
|49||Gazzaniga, et al., "Time-dependent oral delivery systems for colon targeting," S.T.P. Pharma Sciences, 5(1):83-88 (1995).|
|50||Ghebre-Sellassie et ., "Evaluation of acrylic-based modified-release film coatings," International Journal of Pharmaceutics, 1987;37:211-218.|
|51||Goodhart et al., An Evaluation of Aqueous Film-Forming Dispersions for Controlled Release, Pharmaceutical Technology, Apr. 1984.|
|52||Greenhill et al., A Pharmacokinetic/Pharmacodynamic Study Comparing a Single Morning Dose of Adderall to Twice-Daily Dosing in Children with ADHD. J. Am. Acad. Adolesc. Psychiatry, 42:10, Oct. 2003.|
|53||Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations (1997).|
|54||Guidance for Industry: Food-Effext Bioavailability and Fed Bioequivalence Studies (2002).|
|55||Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage Forms (1997).|
|56||Guo Deposition Transcript, Jan. 24, 2005.|
|57||Guo Deposition Transcript, Jul. 26, 2004.|
|58||Hall HS and Pondell RE, Controlled Release Technologies: Method, Theory, and Applications, pp. 133-154 (Agis F. Kydonieus ed. 1980).|
|59||Handbook of Pharmaceutical Excipients: Ethylcellulose, Polymethacrylates, (4th ed. (2003), 237-240, 462-468.|
|60||Handbook of Pharmaceutical Excipients: Plymethacrylates, (2nd ed. 1994), 361-366.|
|61||Hans-Martin Klein & Rolf W. Gunther, Double Contrast Small Bowell Follow-Through with an Acid-Resistant Effervescent Agent, Investigative Radiology vol. 28, Jul. 1993.|
|62||Harrington Deposition Transcript, Jul. 27, 2005.|
|63||Harris et al., Aqueous Polymeric Coating for Modified-Release Pellets, Aqueous Polymeric Coating for Pharmaceutical Dosage Forms (McGinity ed., 1989).|
|64||Hawley's Condensed Chemical Dictionary 13th Ed. 1997, 584, 981.|
|65||Holt, Bioequivalence Studies of Ketoprofen: Product formulation, Pharmacokinetics, Deconvolution, and In Vitro-In Vivo correlations, Thesis submitted to Oregon State University, Aug. (1997).|
|66||Husson et al., Influence of Size Polydispersity on Drug Release from Coated Pellets, International Journal of Pharmaceutics, 86 (1992) 113-121, 1992.|
|67||Impax Laboratories Inc.'s First Amended Answer and Affirmative Defenses, dated May 2, 2005.|
|68||Impax Laboratories, Inc.'s First Supplemental Responses to Shire Laboratories Inc.'s First Set of Interrogatories (Nos. 11-12).|
|69||Impax Laboratories, Inc.'s Memorandum in Support of the Motion to Amend its Answer dated Feb. 25, 2005 and exhibits thereto.|
|70||Impax Laboratories, Inc.'s Reply Memorandum in Support of the Motion to Amend its Answer dated Mar. 18, 2005 and exhibit thereto.|
|71||Interview Summary U.S. Appl. No. 11/091,010 filed date Dec. 22, 2008.|
|72||Ishibashi et al., Design and Evaluatin of a New Capsule-type Dosage Form for Colon-Targeted Delivery of Drugs, International Journal of Pharmaceutics 168, (1998) 31-40, 1998.|
|73||J. Sjogren, Controlled release oral formulation technology, Rate Control in Drug Therapy, (1985) 38-47.|
|74||Jarowski, The Pharmaceutical Pilot Plant, Pharmaceutical Dosage Forms: Tablets, vol. 3, 2nd Ed. (1990), 303-367.|
|75||Judgment and Order of Permanent Injunction in Shire LLC v. Teva Pharmaceutical Industries Ltd. in the United States District Court for the Eastern District of Pennsylvania, Civil Action No. 06-952-SD, Mar. 6, 2008.|
|76||Judgment and Order of Permanent Injuunction in Shire Laboratories, Inc. v. Andrx Pharmaceuticals, LLC, in the United States District Court for the Southern District of Florida, Miami Division, Case No. 07-22201-CIV-Cooke/Brown, Nov. 19, 2007.|
|77||Kao et al., Lag Time Method to Delay Drug Release to Various Sites in the Gastrointestinal Tract, Journal of Controlled Release 44(1997) 263-270.|
|78||Kennerly S. Patrick & John S. Markowitz, Pharmacology of Methylphenidate, Amphetamine Enantiomers and Pemoline in Attention-Deficit Hyperactivity Disorder, Human Psychopharmacology, vol. 12, 527-546 (1997).|
|79||Kiriyama et al., The Bioavailability of Oral Dosage Forms of a New HIV-1 Protease Inhibitor, KNI-272, in Beagle Dogs, Biopharmaceutics & Drug Disposition, vol. 17 125-234 (1996).|
|80||Klaus Lehmann, Coating of Multiparticulates Using Polymeric Solutions, Multiparticulate Oral Drug Delivery (Swarbrick and Sellassie ed., 1994).|
|81||Krowczynski & Brozyna, Extended-Release Dosage Forms, pp. 123-131 (1987).|
|82||Leon Lachman, Herbert A. Lieberman, Joseph L. Kanig, The Theory and Practice of Industrial Pharmacy, Second Edition (1976) 371-373.|
|83||Leopold & Eikeler, Eudragit E as Coating Material for the pH-Controlled Drug Release in the Topical Treatment of Inflammatory Bowel Disease (IBD), Journal of Drug Targeting, 1998, vol. 6, No. 2, pp. 85-94.|
|84||Lin & Cheng, In-vitro Dissolution Behaviour of Spansule-type Micropellets Prpared by Pan Coating Method, Pharm. Ind. 51 No. 5 (1989).|
|85||Liu et al., Comparative Release of Phenylprepanolamine ECl from Long-Acting Appetite Suppressant Product: Acutrim vs. Dexatrim, Drug Development and Industrial Pharmacy, 10(10), 1639-1661 (1984).|
|86||Marcotte et al., Kinetics of Protein Diffusion from a Poly(D,L-Lactide) Reservoir System, Journal of Pharmaceutical Sciences vol. 79, No. 5, May 1990.|
|87||Mathir et al., In vitro characterization of a controlled-release chlorpheniramine maleate delivery system prepared by the air-suspension technique, J. Microencapsulation, vol. 14, No. 6,743-751 (1997).|
|88||McGough et al., Pharmacokinetics of SL1381 (Adderall XR), an Extended-Release Formulation of Adderall, Journal of the American Academy of Child & Adolescent Psychiatry, vol. 42, No. 6, Jun. 2003.|
|89||McGraw-Hill Dictionary of Scientific and Technical Terms, 5th Ed. (1994), 97, 972.|
|90||McGuiness Deposition Transcript, Aug. 6, 2004.|
|91||Mehta et al., Evaluation of Fluid-bed Processes for Enteric Coating Systems, Pharmaceutical Technology, Apr. 1986.|
|92||Moller, Dissolution Testing of Delayed Release Preparations, Proceedings of the International Symposium held on 29th to 31st of Jan. 1987 (The Bombay College of Pharmacy 1988), 85-11.|
|93||Notice of Allowance in U.S. Appl. No. 11/091,011 dated Jul. 20, 2007.|
|94||Notice of Allowance U.S. Appl. No. 11/091,010 filed dated Dec. 22, 2008.|
|95||Opening Expert Report of Dr. Michael Mayersohn and exhibits thereto, Mar. 12, 2005.|
|96||Opening Expert Report of Dr. Walter Chambliss and exhibits thereto, Mar. 15, 2005.|
|97||Order and Memorandum Denying Colony's Motion for Partial Summary Judgment of Noninfringement of the '819 and '300 Patents in Shire LLC v. Colony Pharmaceuticals, Inc., in the United States District Court for the District of Maryland, Case No. CCB-07-718, Jan. 2, 2008.|
|98||Ozturk et al., "Kinetics of Release from Enteric-Coated Tablets," Pharmacutical Research 1988;5:550-565.|
|99||PDR Drug Information for Ritalin LA Capsules, Apr. (2004).|
|100||Pelham et al., A Comparison of Morning-Only and Morning/Late Afternoon Adderall to Morning-Only, Twice-Daily, and Three Times-Daily Methylphenidate in Children with Attention-Deficit/Hyperactivity Disorder, Pediatrics, vol. 104, No. 6, Dec. 1999.|
|101||Petition to Withdraw Application from Issue Pursuant to 37 CFR 1.313(c)(2) dated Oct. 16, 2007.|
|102||Physicians' Desk Reference: Adderall, 51st Ed. (1997).|
|103||Physicians' Desk Reference: Adderall, 56th Ed. (2002).|
|104||Physicians' Desk Reference: Dexedrine 56th Ed. (2002).|
|105||Physicians' Desk Reference: Ritalin, 56th Ed. (2002).|
|106||Plaintiff Shire LLC's Responses to Interrogatories No. 1-13 in Shire LLC v. Colony Pharmaceuticals, Inc., in the United States District Court for the District of Maryland, Case No. 1:07-cv-00718-CCB, Jun. 6, 2007.|
|107||Plaintiffs Shire Laboratories, Inc.'s and Shire LLC's Reply to Defendant Andrx Pharmaceuticals, LLC's Counterclaims, in the United States District Court for the Southern District of Florida, Miami Division, Case No. 07-22201-CIV-Cooke/Brown, Sep. 24, 2007.|
|108||Pozzi, et al, The Time Clock system: a new oral dosage form for fast and complete release of drug after a predetermined lag time,: Journal of Controlled Release, 31:99-108 (1994).|
|109||Prescribing Information: Dexedrine, brand of dextroamphetamine sulfate (2001).|
|110||R. Bianchini & C. Vecchio, Oral Controlled Release Optimization of Pellets Prepared by Extrusion-Spheronization Processing, IL Farmaco 44(6), 645-654, 1989.|
|111||Rambali, et al., Using experimental design to optimize the process parameters in fluidized bed granulation on a semi-full scale, International Journal of Pharmaceutics 220 (2001) 149-160.|
|112||Remington: The Science and Practice of Pharmacy, Basic Pharmacokinetics, 16th Ed. (1980), 693.|
|113||Remington: The Science and Practice of Pharmacy, Elutriation, 20th Ed. (2000), 690.|
|114||Remington's Pharmaceutical Sciences, Fifteenth Edition (1975) 1624-1625.|
|115||Rong-Kun Chang and Joseph R. Robinson, Sustained Drug Release from Tablets and Particles Through Coating, Pharmaceutical Dosage Forms: Tablets (Marcel Dekker, Inc. 1990), 199-302.|
|116||Rong-Kun Chang, A Comparison of Rheological and Enteric Properties among Organic Solutions, Ammonium Salt Aqueous Solutions, and Latex Systems of Some Enteric Polymers, Pharmaceutical Technology, Oct. 1990.|
|117||Rosen et al., Absorption and Excretion of Radioactively Tagged Dextroamphetamine Sulfate from a Sustained-Release Preparation, Jama, vol. 194, No. 11, Dec. 13, 1965, 145-147.|
|118||Rosen, et al., Absorption and Excretion of Radioactively Tagged Dextroamphetamine Sulfate From a Sustained-Release Preparation, Journal of the American Medical Association, Dec. 13, 1965, vol. 194, No. 11, 1203-1205.|
|119||Rudnic Deposition Transcript, Jul. 28, 2004.|
|120||Schaffer Deposition Transcript, Aug. 17, 2005.|
|121||Scheiffele, et al., Studies Comparing Kollicoat MAE 30 D with Commercial Cellulose Derivatives for Enteric Coating on Caffiene Cores, Drug Development and Industrial Pharmacy, 24(9), 807-818 (1998), 807-818.|
|122||Second Amended Complaint for Patent Infringement and Declaratory Relief in Shire Laboratories, Inc. v. Andrx Pharmaceuticals, LLC, in the United States District Court for the Southern District of Florida, Miami Division, Case No. 07-22201-CIV-Cooke/Brown, Nov. 15, 2007.|
|123||Serajuddin, et al., Selection of Solid Dosage Form Composition through Drug-Excipient Compatibility Testing, Journal of Pharmaceutical Sciences vol. 88, No. 7, Jul. 1999, 696-704.|
|124||Shargel;. Pharmacokinetics of Oral Absorption, Applied Biopharmaceutics & Pharmacokinetics. 5th Ed. (2005), 164-166.|
|125||Sheen et al., Aqueous Film Coating Studies of Sustained Release Nicotinic Acid Pellets: An In-Vitro Evaluation, Drug Development and Industrial Pharmacy, 18(8), 851-860 (1992).|
|126||Shire Laboartories Inc.'s Opposition to Barr Laboratories' Motion to Amend Its Answers and Counterclaims, Sep. 15, 2004.|
|127||Slattum, et al., Comparison of Methods for the Assessment of Central Nervous System Stimulant Response after Dextroamphetamine Administration to Healthy Male Volunteers, J. Clin Pharmacol 1996; 36: 1039-1050.|
|128||Sprowls' American Pharmacy: An Introduction to Pharmaceutical Techniques and Dosage Forms, 7th Ed. (1974), 387-388.|
|129||Sriamornsak, et al., Development of sustained release theophylline pellets coated with calcium pectinate, Journal of Controlled Release 47 (1997) 221-232.|
|130||Stevens, et al., Controlled, Multidose, Pharmacokinetic Evaluation of Two Extended-Release Carbamazepine Formulations (Carbatrol and Tegretol-XR), Journal of Pharmaceutical Sciences vol. 87, No. 12, Dec. 1998, 1531-1534.|
|131||Supplemental Expert Report of Harry G. Brittain, PhD, FRSC in Shire LLC v. Colony Pharmaceuticals, Inc., in the United States District Court for the District of Maryland, Case No. 1:07-cv-00718, Feb. 15,2008.|
|132||Teva Notice letter: Feb. 21, 2005.|
|133||Teva Notice letter: Jun. 1, 2005.|
|134||The Merck Index: Amphetamine, 12th Ed., 620.|
|135||The Merck Index: Amphetamine, 13th Ed., (2001), 97, 1089.|
|136||The United States Pharmacopeia 23, National Formulary 18 (1995) pp. 1791-1799.|
|137||The United States Pharmacopeia 26, National Formulary 21 (2003) pp. 2157-2165.|
|138||The United States Pharmacopeia 27, National Formulary 22 (2004) pp. 2302-2312.|
|139||Transcrip of Richard A. Couch 30(b)(6) Deposition in Shire LLC vs. Sandoz Inc. in the United States District Court for the District of Colorado, Dec. 14, 2007.|
|140||Transcript of Beth A. Burnside Deposition in Shire LLC v. Colony Pharmaceuticals, Inc., in the United States District Court for the District of Maryland, Case No. 1:07-cv-00718-CCB, Nov. 9, 2007.|
|141||Transcript of Beth A. Burnside Deposition in Shire LLC vs. Sandoz Inc. in the United States District Court for the District of Colorado, Case No. 07-CV-001197-EWN-CBS, Nov. 30, 2007.|
|142||Transcript of Kimberly Fiske Farrand Deposition in Shire, LLC v. Sandoz, Inc. in the United States District Court of Colorado, Dec. 4, 2007.|
|143||Transcript of Richard A. Couch Deposition in Shire LLC v. Colony Pharmaceuticals, Inc., in the United States District Court for the District of Maryland, Case No. 1:07-cv-00718-CCB, Nov. 15, 2007.|
|144||Transcript of richard Rong-Kun Chang in Shire LLC v. Colony Pharmaceuticals, Inc., in the United States District Court for the District of Maryland, Case No. 1:07-cv-00718-CCB, Nov. 20, 2007.|
|145||Treacy Deposition Transcript, Aug. 31, 2004.|
|146||Treatise on Controlled Drug Delivery, pp. 185-199 (Agis Kydonieus ed. 1992).|
|147||Tulloch, et al., SL1381 (Adderall XR), a Two-component, Extended-Release Formulation of Mixed Amphetamine Salts: Bioavailability of Three Test formulations and Comparison of Fasted, Fed, and Sprinkled Administration, PHARMACOTHERAPY vol. 22, No. 11. (2002), 1405-1415.|
|148||US 6,034,101, 3/2000, Gupta et al. (withdrawn)|
|149||Vasilevska, et al., Preparation and Dissolution Characteristics of Controlled Release Diltiazem Pellets, Drug Development and Industrial Pharmacy, 18(15), 1649-1661 (1992).|
|150||Walia et al., "Preliminary Evaluation of an Aqueous Wax Emulsion for Controlled-Release Coating," Pharmaceutical Development and Technology, 3(1):103-113-(1998).|
|151||Watano, et al., Evaluation of Aqueous Enteric Coated Granules Prepared by Moisture Control Method in Tumbling Fluidized Bed Process, Chem. Pharm. Bull. 42(3) 663-667 (1994).|
|152||Wesdyk, et al., Factors affecting differences in film thickness of beads coated in fluidized bed units, International Journal of Pharmaceutics, 93 101-109, (1993).|
|153||Wigal, et al., Evaluation of Individual Subjects in the Analog Classroom Setting; II. Effects of dose of amphetamine (Adderall), Psychopharmacology Bulletin, vol. 34, No. 4, pp. 833-838, 1998.|
|154||Wilding, et al., "Gastrointestinal Transit and Systemic Absorption of Captopril from a Pulsed-Release Formulation," Pharmaceutical Research, 9(5):654-657 (1992).|
|155||Wouessidjewe, Aqueous polymethacrylate Dispersions as Coating Materials for Sustained and Enteric Release Systems, S.T.P. Pharma Sciences 7(6) 469-475 (1997).|
|156||Xin Xu and Ping I. Lee, "Programmable Drug Delivery from an Erodible Association Polymer System," Pharmaceutical Research, 10(8):1144-1152 (1993).|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US9545399||Jul 1, 2016||Jan 17, 2017||Tris Pharma, Inc.||Methylphenidate extended release chewable tablet|
|US9675703||Jul 1, 2016||Jun 13, 2017||Tris Pharma, Inc||Modified release formulations containing drug - ion exchange resin complexes|
|US9675704||Jul 1, 2016||Jun 13, 2017||Tris Pharma, Inc.||Modified release formulations containing drug-ion exchange resin complexes|
|U.S. Classification||424/494, 424/472, 424/480|
|International Classification||A61K9/16, A61K9/28, A61K31/137, A61K9/48, A61P25/28, A61K9/50, A61K47/26, A61K9/52, A61K9/26, A61K9/54, A61K9/32, A61K9/58, A61K9/22, A61K47/38|
|Cooperative Classification||A61K9/5047, A61K9/5078, A61K31/137, A61K9/5026|
|European Classification||A61K31/137, A61K9/50K2, A61K9/50H6F2B, A61K9/50H6B|
|Dec 19, 2005||AS||Assignment|
Owner name: SHIRE LABORATORIES, INC., MARYLAND
Free format text: RELEASE OF SECURITY INTEREST UNDER THE AMENDED AND RESTATED CREDIT AGREEMENT;ASSIGNOR:DLJ CAPITAL FUNDING, INC. AS ADMINISTRATIVE AGENT;REEL/FRAME:016914/0056
Effective date: 20040910
|Dec 18, 2006||AS||Assignment|
Owner name: SHIRE LLC, KENTUCKY
Free format text: MERGER;ASSIGNOR:SHIRE LABORATORIES, INC.;REEL/FRAME:018648/0711
Effective date: 20061215
|Sep 13, 2011||CC||Certificate of correction|
|Mar 14, 2013||FPAY||Fee payment|
Year of fee payment: 12
|Nov 10, 2015||IPR||Aia trial proceeding filed before the patent and appeal board: inter partes review|
Free format text: TRIAL NO: IPR2015-02009
Opponent name: AMERIGEN PHARMACEUTICALS LIMITED
Effective date: 20151001
|Jun 28, 2016||IPR||Aia trial proceeding filed before the patent and appeal board: inter partes review|
Free format text: TRIAL NO: IPR2016-01033
Opponent name: MYLAN PHARMACEUTICALS INC.,MYLAN INC. AND MYLAN N.
Effective date: 20160512