US20180333362A1 - Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems - Google Patents
Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems Download PDFInfo
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- US20180333362A1 US20180333362A1 US16/050,664 US201816050664A US2018333362A1 US 20180333362 A1 US20180333362 A1 US 20180333362A1 US 201816050664 A US201816050664 A US 201816050664A US 2018333362 A1 US2018333362 A1 US 2018333362A1
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- drug delivery
- population
- delivery device
- dosage forms
- api
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Definitions
- the present invention is directed to a drug delivery engine which provides an extended-pulsed pulsed or pulsed extended-pulsed controlled release delivery of active pharmaceutical ingredient(s) APIs, and more specifically to the superior and precise control of the release of API to the gastrointestinal tract and plasma whereby the shape, number, magnitude, position and chronological separation of the plasma concentration peaks (maxima), troughs (minima) and plateaus and their inter relations can be determined and controlled precisely.
- the present invention relates to a better once daily dosing of a medication in a unitary dosage form designed to mimic desirable in-vivo characteristics of multiple dosing per day regimen.
- the dosage forms can be formulated to initially provide extended release followed by one or more pulses of drug release or initially to provide one or more pulses of drug release followed by extended release. It may also be formulated to initially provide one or more pulses of drug release and optionally followed by an extended release and one or more pulses of drug release. The rate, extent and time of the pulses are controlled precisely.
- the dosage forms and methods of the present invention are particularly suitable for the administration of APIs, their bases, salts, metabolites, pro-drugs, racemates, enantiomers, optical isomers, related substances or a mixture thereof.
- a device that allows the delivery of pharmaceutically active ingredients their bases, salts, metabolites, pro-drugs, racemates, enantiomers, optical isomers, related substances or a mixture thereof in such a way that the shape, number, magnitude, position and timing of the plasma concentration peaks (maxima), troughs (minima) and plateaus and their inter relations can be controlled precisely such a device would have a positive value and represent an advancement in the science of controlled delivery technology.
- the present invention is directed to these, as well as other, significant outcome.
- the present invention provides, in embodiments, a therapeutic composition in a device for the oral administration of APIs, the device including: a first population of unit dosage forms comprising a core, wherein the core comprises a pharmaceutically acceptable bead and an API loaded coating, wherein the API loaded coating comprises an API and hydroxypropyl methyl cellulose and wherein the first population of unit dosage forms further comprises a pH-reactive coat, and a second population of unit dosage forms comprising a core, wherein the core comprises a pharmaceutically acceptable bead and an API loaded coating, wherein the API loaded coating comprises the API and hydroxypropyl methyl cellulose and wherein the second population of unit dosage forms comprises an extended release coat on the core and further comprises a pH-reactive coat on the extended release coat.
- the API can be duloxetine.
- the API can be present in the API loaded coating in both the first population and second population in an amount of 67%.
- the pharmaceutically acceptable bead comprises a non pareil bead.
- the present invention also provides, in embodiments, a therapeutic composition in a device for the oral administration of APIs, the device including: a first population of unit dosage forms comprising a core, wherein the core comprises an API and microcrystalline cellulose and wherein the first population of unit dosage forms further comprises a pH-reactive coat, and a second population of unit dosage forms comprising a core, wherein the core comprises an API and microcrystalline cellulose and wherein the second population of unit dosage forms comprises an extended release coat on the core and further comprises a pH-reactive coat on the extended release coat.
- the API can be rivastigmine.
- the API can be present in both the first population and second population in an amount of 3%.
- the microcrystalline cellulose is present in the core of the first and second population of unit dosage forms in an amount of 97%.
- the core for the first and second population of unit dosage forms is made by dissolving the API in water, granulating the API solution with the microcrystalline cellulose, extruding the granulated API-microcrystalline cellulose mixture to produce an extrudate, and forming core particles from the extrudate.
- the device may be designed to provide an initial release of aliquot amount of the API, followed by one or more pulsed and or an extended pulsed release delivery of additional aliquot amount of API at predetermined times resulting in one or more plasma concentration peaks and/or troughs. They may also be designed to provide extended pulsed release of aliquot amount of the API, followed by one or more pulsed delivery of additional aliquot amount of API at predetermined times resulting in one or more plasma concentration peaks and/or troughs. In another design, the device provides an extended pulsed release of aliquot amount of the API, resulting in one or more plasma concentration peaks and/or troughs and/plateaus.
- the device may yield a pulsed pulsed-extended release profile; an extended-pulsed release profile; a multi pulsed release profile; a delayed multi-pulsed release profile; a delayed extended-pulsed release profile; a delayed pulse on, pulse off and pulse on release profile; a pulse on, pulse off and pulse on release profile or a combination there of.
- the ratio of the plasma concentration values of any one peak (maxima) to any one trough (minima) or plateau is from about 25% to 400%. It is also preferred that the ratio of the plasma concentration values of a peak (maxima) to the next trough (minima) or plateau is from about 25% to 400%. It is further preferred that the ratio of the plasma concentration values of a trough (minima) or plateau to the next peak (maxima) is from about 25% to 400%.
- the coats on an individual basis are applied to yield a weight gain of up to 500% and surface area of up to 80 mg per cm 2 . In a further aspect of the embodiments it may be preferable to have a lag phase before the onset of release of API.
- the amount of doses, the separation of doses and the rate of input of API is used to control the release profile and the chronological separation of doses, maxima, minima or plateau in vivo.
- FIG. 1 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting pulsed pulsed-extended release profile.
- FIG. 2 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting extended-pulsed release profile.
- FIG. 3 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting multi pulsed release profile.
- FIG. 4 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting delayed multi-pulsed release profile.
- FIG. 5 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting another type of delayed multi-pulsed release profile.
- FIG. 6 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting delayed extended-pulsed release profile.
- FIG. 7 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting delayed pulse on, pulse off and pulse on release profile.
- the invention comprises a variety of therapeutic compositions contained within a device or housing such as a chamber or reservoir.
- a device or housing such as a chamber or reservoir.
- Each unit dosage form or population of composition contained within the housing can be made into a variety of different vehicles such as granules, beads, pellets, or tablets.
- Each vehicle in one aspect consists of a core containing the agent to be delivered, a disintegrant, and optionally a bases and an acid.
- the cores may be coated with the agent and or delayed release coat.
- the core may contain a polymeric material in a matrix.
- a variety of the different types of vehicles may be packed into a housing.
- the housing may also additionally comprise the agent to be release in powdered, crystalline or granule form.
- the vehicles as made into granules, beads, pellets or tablets can be further fabricated to be regular or irregular in shape and preferably have a diameter and thickness of up to about 40 mm, and preferably up to about 20 mm and most preferably up to about 13 mm.
- the polymer(s) for use in making the different vehicles of pharmaceutical formulations may be selected from any polymers which are soluble or insoluble in water and can retard the release especially those which can form hydrocolloids. They include naturally occurring or synthetic, anionic or nonionic, hydrophilic rubbers, starch derivatives, cellulose derivatives, polysaccharides, carbomer, proteins, and the like.
- acacia tragacanth, Xanthan gum, locust bean gum, guar-gum, karaya gum, pectin, alginic acid, polyethylene oxide, polyethylene glycol, propylene glycol alginate, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, carboxyvinyl polymer, sodium polyacrylate, alpha starch, sodium carboxymethyl starch, albumin, dextrin, dextran sulfate, agar, gelatin, casein, sodium casein, pullulan, polyvinyl alcohol, deacetylated chitosan, polyethyoxazoline, poloxamers, ethylcellulose, chitin, chitosan, cellulose esters, aminoalkyl methacrylate polymer, anionic polymers of methacrylic acid and methacrylates
- the super-disintegrant that may be formulated into the compositions of the invention may be selected from the group consisting of sodium starch glycolate, sodium croscarmellose, homopolymer of cross-linked N-vinyl-2-pyrrolidone, and alginic acid and the like and mixtures thereof.
- the delayed release coat for use in the compositions of the invention may be selected from shellac, polyvinyl acetate phthalate (PVAP), hydroxypropylmethyl-cellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), methacrylic acid copolymer, hydroxy propyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate, methacrylic acid/methacrylate polymer, methacrylic acid-methyl methacrylate copolymer, ethyl methacrylate-methylmethacrylate-chiorotrimethylammonium ethyl methacrylate copolymer, natural resin
- the bases for use in the compositions of the invention may be selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate.
- the acids for use in the compositions of the invention may be selected from citric acid, malic acid, adipic acid, tartaric acid and fumaric acid.
- compositions may be formulated into a variety of different vehicles such as for example granules, beads, pellets, or tablets which may also contain surfactants, excipients and mixtures thereof in amounts that are readily determined by one of skill in the art.
- vehicles such as for example granules, beads, pellets, or tablets which may also contain surfactants, excipients and mixtures thereof in amounts that are readily determined by one of skill in the art.
- the vehicle(s) of the invention may include a variety of active agents such as for example pharmaceuticals, chemicals, biologicals, pesticides, insecticides, algicides, fungicides, germicides and herbicides, their metabolites, pro-drugs, racemates, enantiomers, optical isomers, salts, bases, related substances or a mixture thereof.
- active agents such as for example pharmaceuticals, chemicals, biologicals, pesticides, insecticides, algicides, fungicides, germicides and herbicides, their metabolites, pro-drugs, racemates, enantiomers, optical isomers, salts, bases, related substances or a mixture thereof.
- the active agent comprises Acetaminophen/Codeine, Albuterol, Alendronate, Allopurinol, Alprazolam, Amtriptyline, Amlodipine, Amlodipine/Benazepril, Amoxicillin, Amoxicillin/Clavulanate, Amphetamine Mixed salts, acarbose, Atelolol, Atorvastatin, Azithromycin, Beclomethasone, Benazepril, Bisoprolol/HCTZ, Brimonidine, Calcitonin Salmon, Carbamazepine, Carisoprodol, Carvedilol, cefprozil, Cefuroxime, Clecoxib, Cephalexin, Cetinzine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clonazepam, Klondike, Clopidogrel, Clotrimazole/Betamethasone, Cyclobenza
- the active agent comprises one or more of the drugs used in HIV or AIDS treatment such as for example Abacavir, amprenavir, stavudine, zalcitabine, didanosine, delavirdine, efavirenz Hydroxyurea, indinavir, lamivudine, lopinavir, nelfinavir, nevirapine, ritonavir, Saquinavir, stavudine and zidovudine.
- the drugs used in HIV or AIDS treatment such as for example Abacavir, amprenavir, stavudine, zalcitabine, didanosine, delavirdine, efavirenz Hydroxyurea, indinavir, lamivudine, lopinavir, nelfinavir, nevirapine, ritonavir, Saquinavir, stavudine and zidovudine.
- the active agent comprises one or more proteins, peptides, hormones, prostaglandins, and anticancer agents.
- the unit dosage forms present in the controlled release delivery device in accordance with the present invention may be manufactured using conventional granulation, pelletization, tabletting and/or coating technologies.
- a homogeneous blend of the pharmaceutically active substance, disintegrant, and excipients are granulated, dried, milled, lubricated, blended and pressed into tablets or pellets.
- the homogeneous blend is granulated, extruded and dried.
- Other populations of vehicles are manufactured by powder/solution layering on non pareils or inert pharmaceutical spheres.
- a complete or partial coating may be applied on one or more of the vehicle populations by spraying, molding and/or dipping.
- the various population of vehicles in the form of granules, beads, pellets and tablets are assembled in no particular order within a housing such as a chamber chamber/reservoir.
- the housing that forms the chamber or reservoir for encapsulating the various vehicles comprising the different pharmaceutical formulations therein may additionally contain a non-toxic metal or metal alloy such as for example titanium, platinum and gold
- the housing may also contain non-toxic plastic, hard gelatin or hydroxypropyl methyl cellulose.
- the device of the invention is suitable for oral ingestion as well as via sublingual, intraocular, intramuscular, subcutaneous, anal and vaginal use as well as for implantation to a desired location within the body.
- the device of the present invention can be used for a variety of different applications including for human and veterinary use and agricultural use.
- the controlled release drug delivery system as taught in the preset invention provides a novel device in which a housing has incorporated therein a variety of different compositions in the form of pellets, granules, beads and tablets that each may provide a different dose, rate of input of a dose, chronological separation of doses, maxima, minima or plateau used for the unexpected and unobvious but precise delivery of similar, dissimilar or incompatible substances in a pulsatile manner in the environment of use.
- Oil components may also be used in the current invention. These include oils and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, metal salts of higher fatty acids, and the like.
- oils and fats include plant oils, e.g. cacao butter, palm oil, Japan wax (wood wax), coconut oil, etc.; animal oils, e.g. beef tallow, lard, horse fat, mutton tallow, etc.; hydrogenated oils of animal origin, e.g. hydrogenated fish oil, hydrogenated whale oil, hydrogenated beef tallow, etc.; hydrogenated oils of plant origin, e.g. hydrogenated rape seed oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated soybean oil, etc.; and the like.
- waxes include plant waxes, e.g. carnauba wax, candelilla wax, bayberry wax, auricurry wax, espalt wax, etc.; animal waxes, e.g. bees wax, breached bees wax, insect wax, spermaceti, shellac, lanolin, etc.; and the like. Of these preferred are carnauba wax, white beeswax and yellow beeswax. Paraffin, petrolatum, microcrystalline wax, and the like, are given as specific examples of hydrocarbons, with preferable hydrocarbons being paraffin and microcrystalline wax.
- higher fatty acids are caprilic acid, undecanoic acid, lauric acid, tridecanic acid, myristic acid, pentadecanoic acid, palmitic acid, malgaric acid, stearic acid, nonadecanic acid, arachic acid, heneicosanic acid, behenic acid, tricosanic acid, lignoceric acid, pentacosanic acid, cerotic acid, heptacosanic acid, montanic acid, nonacosanic acid, melissic acid, hentriacontanic acid, dotriacontanic acid, and the like.
- myristic acid palmitic acid, stearic acid, and behenic acid.
- higher alcohols are lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachyl alcohol, behenyl alcohol, camaubic alcohol, corianyl alcohol, ceryl alcohol, and myricyl alcohol.
- Particularly preferable alcohols are cetyl alcohol, stearyl alcohol, and the like.
- esters are fatty acid esters, e.g.
- lauric monoglyceride myristic monoglyceride, stearic monoglyceride, behenic monoglyceride, oleic monoglyceride, oleic stearic diglyceride, lauric diglyceride, myristic diglyceride, stearic diglyceride, lauric triglyceride, myristic triglyceride, stearic triglyceride, acetylstearic glyceride, hydoxystearic triglyceride, etc.; and the like.
- Glycerine fatty acid esters are more preferable.
- metal salts of higher fatty acid are calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, zinc palmitate, zinc myristate, magnesium myristate, and the like, with preferable higher fatty acid salts being calcium stearate and magnesium stearate.
- Polyethoxylated castor oil (cremaphor) is also useful.
- oil components and polymers can be used either singly or in combination of two or more. These are used in the following amounts, from about 1% to about 90% but preferably from about 1% to about 70%.
- the drug loaded cores used in this invention can be made using extrusion spheronization techniques or by layering of drugs on sugar spheres, microcrystalline cellulose spheres, non pareil seeds or any pharmaceutically acceptable microspheres which are less than 3 mm in diameter.
- Non drug loaded cores may be used in this invention to help provide homogeneity to ensure even distribution of the cores in the housing.
- Non drug loaded cores can be made using extrusion spheronization techniques. They can also be sugar spheres, microcrystalline cellulose spheres, non pareil seeds or any pharmaceutically acceptable microspheres which are less than 3 mm in diameter.
- the drug loaded or non-drug loaded cores that can be used range in size from about 1 micron to about 3000 microns in diameter and preferably from about 50 microns to about 1500 microns in diameter. From about 1% to about 100% and preferably from about 5% to about 100% of the drug loaded cores may be used in the housing. While from about 0% to about 90% and preferably from about 0% to about 70% of the non-drug loaded cores may be used in the housing.
- compositions such as diluents e.g., sugars, compression aids e.g., microcrystalline cellulose, surfactants e.g., sodium lauryl sulphate, surfactant micelles e.g., polyethoxylated castor oil (cremaphor), polymeric micelles e.g., amphiphilic block polymers (poloxamers), binders e.g., polyvinyl pyrolidone, glidants e.g., silicone dioxide, lubricants e.g., magnesium stearate etc. may be used in this invention.
- diluents e.g., sugars
- compression aids e.g., microcrystalline cellulose
- surfactants e.g., sodium lauryl sulphate
- surfactant micelles e.g., polyethoxylated castor oil (cremaphor)
- polymeric micelles e.g., amphiphilic block polymers
- the composite is prepared by embedding the drug loaded depots and optionally the non-drug loaded depots in the release retarding polymer material and compressing to shape. This is accomplished by wet granulation to form wet granules and subsequent compression of the granules after they have been dried and lubricated.
- the dosage form can also be prepared by direct compression of a lubricated homogeneous blend of the drug loaded cores and optionally non drug loaded cores.
- excipients may be added to aid in granulation or compression etc. Another method of manufacture is by melt granulation.
- the dosage form is a layered tablet made by compression in a layer press.
- One layer is the release retarding layer and the other is an immediate release layer.
- the release retarding layer is sandwiched between non release retarding layers.
- Each tablet population is manufactured by wet granulation or dry granulation of a homogeneous blend of d-threo-methylphenidate hydrochloride+pharmaceutical necessities with exception of magnesium stearate.
- the wet granules are dried and passed through a comill.
- the resulting milled granules are lubricated with magnesium stearate and compressed into a preselected shape to form one population.
- a delayed release coat of the type that is pH reactive specifically EUDAGRIT® L (anionic copolymer) is applied onto Tablet population designated Tablet II to give a coverage of 4 mg per cm 2 .
- a delayed release coat of the type that is pH reactive specifically EUDAGRIT® S (anionic copolymer) is applied onto Tablet population designated Tablet Ill to give a coverage of 6 mg per cm 2 .
- Coating application is done in a perforated side vented coating pan.
- one tablet each from the three populations of tablets are assembled in no particular order in the holding chamber/reservoir made of hard gelatin or hydroxypropyl methyl cellulose.
- Beads I (mg) Beads II (mg) Duloxetine hydrochloride 200 200 OPADRY ® II (pigmented PVA- 50 50 based film coating formulation) Sodium lauryl sulphate 50 50 Non pareil beads 1200 120
- duloxetine loaded bead population is manufactured by powder suspension layering of duloxetine hydrochloride unto non pareil beads in a fluid bed using top spray or bottom spray techniques.
- Duloxetine is suspended in OPADRY® II (pigmented PVA-based film coating formulation) aqueous suspension.
- a fluid set up for bottom spray is charged with non pareil beads.
- the duloxetine-OPADRY® II (pigmented PVA-based film coating formulation) suspension is sprayed unto the beads.
- a delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) is applied onto the duloxetine loaded beads I to give a coverage of 4 mg per cm2.
- An extended release coat specifically a 50:50 ethylcellulose:hydroxypropyl methyl cellulose coat is applied to duloxetine loaded beads II to obtain a 4% weight gain.
- the extended release coated duloxetine loaded beads II is further coated with a delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) to give a coverage of 4 mg per cm 2 .
- EUDRAGIT® L anionic copolymer
- Spheroids I (mg) Spheroids II (mg) Rivastigmine 12 12 Microcrystalline cellulose 388 388 PH 101 Water qs qs
- Each rivastigmine loaded bead population is manufactured by extrusion spheronization techniques. Rivastigmine is dissolved in water. Rivastigmine water solution is used to granulate microcrystalline cellulose in Hobart mixer. The wet granules are extruded in a Caleva extruder. The extrudate is charged into a Caleva spheroniser and spheronized to obtain rivastigmine loaded spheroids. The spheroids are dried to a loss of drying of less than 2%. A fluid set up for bottom spray is charged with spheroids!.
- a delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) is applied onto the rivastigmine loaded spheroids I to give a coverage of 4 mg per cm 2 .
- An extended release coat, specifically a 60:40 ethylcellulose:hydroxypropyl methyl cellulose coat is applied to rivastigmine loaded spheroids II to obtain a 4% weight gain.
- the extended release coated rivastigmine loaded beads II is further coated with a delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) to give a coverage of 4 mg per cm 2 .
- the two populations of beads are assembled in a ratio of 1:3 (rivastigmine coated spheroids I: rivastigmine coated spheroids II) in the holding chamber/reservoir made of hard gelatin or hydroxypropyl methyl cellulose.
- Tablet I (mg) Tablet II (mg) Risperidone 3 2 Hydroxypropyl methyl cellulose 12 — cross-linked N-vinyl-2-pyrrolidone — 2 Lactose 58 69 Sodium lauryl sulphate 5 5 Silicone dioxide 1 1 Microcrystalline cellulose 20 20 Magnesium stearate 1 1
- Each tablet population is manufactured by wet granulation or dry granulation of a homogeneous blend of risperidone+pharmaceutical necessities with exception of magnesium stearate.
- the wet granules are dried and passed through a comill.
- the resulting milled granules are lubricated with magnesium stearate and compressed into a preselected shape to form one population.
- a delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) is applied onto Tablet population designated Tablet II to give a coverage of 4 mg per cm 2 .
- 1 mg of risperidone is blended into OPADRY® II (pigmented PVA-based film coating formulation) 15% (wt/wt) suspension in water.
- This suspension is used to coat the tablet population designated Tablet I.
- the risperidone OPADRY® II (pigmented PVA-based film coating formulation) suspension is prepared sufficient to apply a weight gain of 3% to the tablet. Coating application is done in a perforated side vented coating pan. Finally, one tablet each from the two populations of tablets are assembled in no particular order in the holding chamber/reservoir made of hard gelatin or hydroxypropyl methyl cellulose.
- Tablet I (mg) Tablet II (mg) Duloxetine 40 20 Hydroxypropyl methyl cellulose 30 — cross-linked N-vinyl-2-pyrrolidone — 4 Lactose 76 96.4 Sodium lauryl sulphate 10 10 Silicone dioxide 2 2 Citric acid — 4 Tartaric acid — 8 Sodium bicarbonate — 13.6 Microcrystalline cellulose 40 40 Magnesium stearate 2 2
- Each tablet population is manufactured by direct compression of a homogeneous blend of duloxetine+pharmaceutical necessities which has been lubricated with magnesium stearate.
- a delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) is applied onto Tablet population designated Tablet I to give a coverage of 4 mg per cm 2 .
- Tablet population designated Tablet II is not coated.
- Coating application is done in a perforated side vented coating pan.
- one tablet each from the two populations of tablets are assembled in no particular order in the holding chamber/reservoir made of hard gelatin or hydroxypropyl methyl cellulose.
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Abstract
The disclosure is directed to drug delivery devices that provide for combinations of extended- and pulsed controlled release delivery of active pharmaceutical ingredient(s) APIs. The described drug delivery devices for oral administration of therapeutic compositions can include two or more populations of unit dosage forms including one or more API's in various combinations of pulsed and delayed/extended delivery formulations. The population of unit dosage forms are provided in a variety of different vehicles such as granules, beads, pellets, or tablets and can be contained within a drug delivery device of the present disclosure.
Description
- This application is a Continuation of U.S. Non-Provisional Patent Application entitled “Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems” having Ser. No. 11/315,868, filed on Dec. 23, 2005, which is herein incorporated by reference in its entirety.
- The present invention is directed to a drug delivery engine which provides an extended-pulsed pulsed or pulsed extended-pulsed controlled release delivery of active pharmaceutical ingredient(s) APIs, and more specifically to the superior and precise control of the release of API to the gastrointestinal tract and plasma whereby the shape, number, magnitude, position and chronological separation of the plasma concentration peaks (maxima), troughs (minima) and plateaus and their inter relations can be determined and controlled precisely. In particular, the present invention relates to a better once daily dosing of a medication in a unitary dosage form designed to mimic desirable in-vivo characteristics of multiple dosing per day regimen. The dosage forms can be formulated to initially provide extended release followed by one or more pulses of drug release or initially to provide one or more pulses of drug release followed by extended release. It may also be formulated to initially provide one or more pulses of drug release and optionally followed by an extended release and one or more pulses of drug release. The rate, extent and time of the pulses are controlled precisely. The dosage forms and methods of the present invention are particularly suitable for the administration of APIs, their bases, salts, metabolites, pro-drugs, racemates, enantiomers, optical isomers, related substances or a mixture thereof.
- The ability to precisely control the shape, number, magnitude, position and timing of the plasma concentration peaks (maxima), troughs (minima) and plateaus and their inter relations, provides for better tolerance, reduced abuse potential, reduced side effects, and improved treatment compliance. This approach to drug delivery is far more superior and represents a paradigm shift from the current practice whereby delivery systems are designed only with the intention to control bioavailability and maximum concentration of drug in plasma.
- It is well known in the art that extended release dosage forms are used to control the release of pharmaceutically active ingredients. These devices operate successfully for their intended use. However, these devices are often limited in their use to deliver pharmaceutical active ingredients in a pulsatile manner. These devices are also limited in their ability to mimic precisely the desirable in-vivo characteristics that multiple dosing per day regimen presents i.e., the ability to “switch on and switch off’, or provide pulsed or multiple peaks, troughs and plateau of drug concentration at predetermined time or time interval while still maintaining control on the rate and extent of drug input.
- It will be appreciated by those versed in the art, that if a device can be provided that allows the delivery of pharmaceutically active ingredients their bases, salts, metabolites, pro-drugs, racemates, enantiomers, optical isomers, related substances or a mixture thereof in such a way that the shape, number, magnitude, position and timing of the plasma concentration peaks (maxima), troughs (minima) and plateaus and their inter relations can be controlled precisely such a device would have a positive value and represent an advancement in the science of controlled delivery technology. The present invention is directed to these, as well as other, significant outcome.
- The present invention provides, in embodiments, a therapeutic composition in a device for the oral administration of APIs, the device including: a first population of unit dosage forms comprising a core, wherein the core comprises a pharmaceutically acceptable bead and an API loaded coating, wherein the API loaded coating comprises an API and hydroxypropyl methyl cellulose and wherein the first population of unit dosage forms further comprises a pH-reactive coat, and a second population of unit dosage forms comprising a core, wherein the core comprises a pharmaceutically acceptable bead and an API loaded coating, wherein the API loaded coating comprises the API and hydroxypropyl methyl cellulose and wherein the second population of unit dosage forms comprises an extended release coat on the core and further comprises a pH-reactive coat on the extended release coat.
- In examples of embodiments of the drug delivery device described immediately above the API can be duloxetine. In embodiments, the API can be present in the API loaded coating in both the first population and second population in an amount of 67%. In further embodiments, the pharmaceutically acceptable bead comprises a non pareil bead.
- The present invention also provides, in embodiments, a therapeutic composition in a device for the oral administration of APIs, the device including: a first population of unit dosage forms comprising a core, wherein the core comprises an API and microcrystalline cellulose and wherein the first population of unit dosage forms further comprises a pH-reactive coat, and a second population of unit dosage forms comprising a core, wherein the core comprises an API and microcrystalline cellulose and wherein the second population of unit dosage forms comprises an extended release coat on the core and further comprises a pH-reactive coat on the extended release coat.
- In further example embodiments of the drug delivery devices described immediately above, the API can be rivastigmine. In embodiments, the API can be present in both the first population and second population in an amount of 3%. In further embodiments, the microcrystalline cellulose is present in the core of the first and second population of unit dosage forms in an amount of 97%.
- In some embodiments of the drug delivery devices described above having a core comprising an API and microcrystalline cellulose, the core for the first and second population of unit dosage forms is made by dissolving the API in water, granulating the API solution with the microcrystalline cellulose, extruding the granulated API-microcrystalline cellulose mixture to produce an extrudate, and forming core particles from the extrudate.
- The device may be designed to provide an initial release of aliquot amount of the API, followed by one or more pulsed and or an extended pulsed release delivery of additional aliquot amount of API at predetermined times resulting in one or more plasma concentration peaks and/or troughs. They may also be designed to provide extended pulsed release of aliquot amount of the API, followed by one or more pulsed delivery of additional aliquot amount of API at predetermined times resulting in one or more plasma concentration peaks and/or troughs. In another design, the device provides an extended pulsed release of aliquot amount of the API, resulting in one or more plasma concentration peaks and/or troughs and/plateaus. In yet other designs, the device may yield a pulsed pulsed-extended release profile; an extended-pulsed release profile; a multi pulsed release profile; a delayed multi-pulsed release profile; a delayed extended-pulsed release profile; a delayed pulse on, pulse off and pulse on release profile; a pulse on, pulse off and pulse on release profile or a combination there of.
- In such embodiments, it is most preferred that the ratio of the plasma concentration values of any one peak (maxima) to any one trough (minima) or plateau is from about 25% to 400%. It is also preferred that the ratio of the plasma concentration values of a peak (maxima) to the next trough (minima) or plateau is from about 25% to 400%. It is further preferred that the ratio of the plasma concentration values of a trough (minima) or plateau to the next peak (maxima) is from about 25% to 400%. In the embodiments taught by this invention it is preferred that the coats on an individual basis are applied to yield a weight gain of up to 500% and surface area of up to 80 mg per cm2. In a further aspect of the embodiments it may be preferable to have a lag phase before the onset of release of API.
- In a preferred embodiment, the amount of doses, the separation of doses and the rate of input of API is used to control the release profile and the chronological separation of doses, maxima, minima or plateau in vivo.
- The various types of in vivo release profile and chronological separation of doses, maxima, minima or plateau will be further illustrated by the following in vivo schematics thereof, given by way of example only with reference to the accompanying drawings.
-
FIG. 1 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting pulsed pulsed-extended release profile. -
FIG. 2 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting extended-pulsed release profile. -
FIG. 3 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting multi pulsed release profile. -
FIG. 4 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting delayed multi-pulsed release profile. -
FIG. 5 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting another type of delayed multi-pulsed release profile. -
FIG. 6 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting delayed extended-pulsed release profile. -
FIG. 7 illustrates an in vivo time-concentration profile for a variation of certain preferred dosage forms in accordance with the invention depicting delayed pulse on, pulse off and pulse on release profile. - The invention comprises a variety of therapeutic compositions contained within a device or housing such as a chamber or reservoir. Each unit dosage form or population of composition contained within the housing can be made into a variety of different vehicles such as granules, beads, pellets, or tablets.
- Each vehicle in one aspect consists of a core containing the agent to be delivered, a disintegrant, and optionally a bases and an acid. The cores may be coated with the agent and or delayed release coat. The core may contain a polymeric material in a matrix. A variety of the different types of vehicles may be packed into a housing. The housing may also additionally comprise the agent to be release in powdered, crystalline or granule form.
- The vehicles as made into granules, beads, pellets or tablets can be further fabricated to be regular or irregular in shape and preferably have a diameter and thickness of up to about 40 mm, and preferably up to about 20 mm and most preferably up to about 13 mm.
- The polymer(s) for use in making the different vehicles of pharmaceutical formulations may be selected from any polymers which are soluble or insoluble in water and can retard the release especially those which can form hydrocolloids. They include naturally occurring or synthetic, anionic or nonionic, hydrophilic rubbers, starch derivatives, cellulose derivatives, polysaccharides, carbomer, proteins, and the like. Specific examples are acacia, tragacanth, Xanthan gum, locust bean gum, guar-gum, karaya gum, pectin, alginic acid, polyethylene oxide, polyethylene glycol, propylene glycol alginate, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, carboxyvinyl polymer, sodium polyacrylate, alpha starch, sodium carboxymethyl starch, albumin, dextrin, dextran sulfate, agar, gelatin, casein, sodium casein, pullulan, polyvinyl alcohol, deacetylated chitosan, polyethyoxazoline, poloxamers, ethylcellulose, chitin, chitosan, cellulose esters, aminoalkyl methacrylate polymer, anionic polymers of methacrylic acid and methacrylates, copolymers of acrylate and methacrylates with quaternary ammonium groups, ethylacrylate methylmethacrylate copolymers with a neutral ester group, polymethacrylates, surfactants, aliphatic polyesters, zein, polyvinyl acetate, polyvinyl chloride, cellulose esters, cellulose ethers, polyethylene oxide, carbomer, cyclodextrins, polyethelene glycol, dextran, polyvinylpyrrolidone, lactide/glycolide copolymers, poly(ortho esters), polyanhydrides, polyvinyl alcohol, alginates, polysaccharides, polyamides, polyvinyl chloride, polyethylene vinyl acetate, polvinyl pyrrolidone, polyurethanes, hydrogels, silicone polymers, polyacrylates, polymethacrylates, polyanhydrides, poly amino carbonates, deacetylated chitin, collagen, polyisobutylenes, gelucire, glyceryl behenate and the like.
- The super-disintegrant that may be formulated into the compositions of the invention may be selected from the group consisting of sodium starch glycolate, sodium croscarmellose, homopolymer of cross-linked N-vinyl-2-pyrrolidone, and alginic acid and the like and mixtures thereof.
- The delayed release coat for use in the compositions of the invention may be selected from shellac, polyvinyl acetate phthalate (PVAP), hydroxypropylmethyl-cellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), methacrylic acid copolymer, hydroxy propyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate, methacrylic acid/methacrylate polymer, methacrylic acid-methyl methacrylate copolymer, ethyl methacrylate-methylmethacrylate-chiorotrimethylammonium ethyl methacrylate copolymer, natural resins, Sandarac, copal collophorium and the like and mixtures thereof.
- The bases for use in the compositions of the invention may be selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate.
- The acids for use in the compositions of the invention may be selected from citric acid, malic acid, adipic acid, tartaric acid and fumaric acid.
- Each composition may be formulated into a variety of different vehicles such as for example granules, beads, pellets, or tablets which may also contain surfactants, excipients and mixtures thereof in amounts that are readily determined by one of skill in the art.
- The vehicle(s) of the invention may include a variety of active agents such as for example pharmaceuticals, chemicals, biologicals, pesticides, insecticides, algicides, fungicides, germicides and herbicides, their metabolites, pro-drugs, racemates, enantiomers, optical isomers, salts, bases, related substances or a mixture thereof.
- In one preferred aspect, the active agent comprises Acetaminophen/Codeine, Albuterol, Alendronate, Allopurinol, Alprazolam, Amtriptyline, Amlodipine, Amlodipine/Benazepril, Amoxicillin, Amoxicillin/Clavulanate, Amphetamine Mixed salts, acarbose, Atelolol, Atorvastatin, Azithromycin, Beclomethasone, Benazepril, Bisoprolol/HCTZ, Brimonidine, Calcitonin Salmon, Carbamazepine, Carisoprodol, Carvedilol, cefprozil, Cefuroxime, Clecoxib, Cephalexin, Cetinzine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clonazepam, Klondike, Clopidogrel, Clotrimazole/Betamethasone, Cyclobenzaprine, Diazepam, Misoprostol, Digoxin, Divalproex, Donepezil, Doxazosin, Enalapril, Erythromycin, Estradiol, Ethinyl Estradiol/Norethindrone, Famotidine, Felodipine, Fexofenadine, Fexofenadine/Pseudoephedrine, Fluoxetine, Fluticasone Propionate, Fluvastatin, Fluvoxamine maleate, Fosinopril, Furosemide, Gemfibrozil, Glimepiride, Glyburide, Guaifenesin/Phenylpropanolamine, Granisetron HCl, Hydrochlorothiazide, Hydrocodone w/APAP, Ibuprofen, Ipratropium, Ipratropium/Albuterol, Irbesartan, Isosorbide Mononitrate, Lansoprazole, Latanoprost, Levofloxacin, Levonorgestrel/Ethinyl Estradiol, Levothyroxine, Lisinopril, Lisinopril/HCTZ, Loratadine, Loratidine/Pseudoephedrine, Lorazepam, Losartan, Losartan/HCTZ, Lovastatin, Methylprednisolone, Methylphenidate or its optical isomers, Metoprolol, mightol Mometasone, Montelukast, Mupirocin, Naproxen, Nitrofurantoin, Nizatidine, Olanzapine, Oxaprozin, Oxycodone, Oxycodone/APAP, Paroxetine, Penicillin VK, Phenytoin, Potassium, Chloride, Pramipexole HCl, Pravastatin, Predinisone, Promethazine, Propoxyphene N/APAP, Propranolol, Quinapril, Raloxifene, Ramipril, Ranitidine, repaglinide, Risperidone, Rofecoxib, Salmeterol, Sertraline, Sildenafil Citrate, Simvastatin, Sumatriptan, Tamoxifen, Tamsulosin, Tamazepam, Terazosin, Terbinafine, Tobramycin/Dexamethasone, Tolterodine, Tranylcypromine sulfte, Trazodone, triamterene/HCTZ, Troglitazone, Valsartin, Venlafaxin, Warfarin, Zafirlukast and Zolpidem.
- In a further embodiment the active agent comprises one or more of the drugs used in HIV or AIDS treatment such as for example Abacavir, amprenavir, stavudine, zalcitabine, didanosine, delavirdine, efavirenz Hydroxyurea, indinavir, lamivudine, lopinavir, nelfinavir, nevirapine, ritonavir, Saquinavir, stavudine and zidovudine.
- In yet another embodiment, the active agent comprises one or more proteins, peptides, hormones, prostaglandins, and anticancer agents.
- The unit dosage forms present in the controlled release delivery device in accordance with the present invention may be manufactured using conventional granulation, pelletization, tabletting and/or coating technologies. As an example, a homogeneous blend of the pharmaceutically active substance, disintegrant, and excipients are granulated, dried, milled, lubricated, blended and pressed into tablets or pellets. Alternatively, the homogeneous blend is granulated, extruded and dried. Other populations of vehicles are manufactured by powder/solution layering on non pareils or inert pharmaceutical spheres.
- A complete or partial coating may be applied on one or more of the vehicle populations by spraying, molding and/or dipping. Finally, the various population of vehicles in the form of granules, beads, pellets and tablets are assembled in no particular order within a housing such as a chamber chamber/reservoir.
- In accordance with the present invention the housing that forms the chamber or reservoir for encapsulating the various vehicles comprising the different pharmaceutical formulations therein may additionally contain a non-toxic metal or metal alloy such as for example titanium, platinum and gold The housing may also contain non-toxic plastic, hard gelatin or hydroxypropyl methyl cellulose.
- The device of the invention is suitable for oral ingestion as well as via sublingual, intraocular, intramuscular, subcutaneous, anal and vaginal use as well as for implantation to a desired location within the body. The device of the present invention can be used for a variety of different applications including for human and veterinary use and agricultural use.
- The controlled release drug delivery system as taught in the preset invention provides a novel device in which a housing has incorporated therein a variety of different compositions in the form of pellets, granules, beads and tablets that each may provide a different dose, rate of input of a dose, chronological separation of doses, maxima, minima or plateau used for the unexpected and unobvious but precise delivery of similar, dissimilar or incompatible substances in a pulsatile manner in the environment of use.
- Oil components may also be used in the current invention. These include oils and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, metal salts of higher fatty acids, and the like. Specific examples of oils and fats include plant oils, e.g. cacao butter, palm oil, Japan wax (wood wax), coconut oil, etc.; animal oils, e.g. beef tallow, lard, horse fat, mutton tallow, etc.; hydrogenated oils of animal origin, e.g. hydrogenated fish oil, hydrogenated whale oil, hydrogenated beef tallow, etc.; hydrogenated oils of plant origin, e.g. hydrogenated rape seed oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated soybean oil, etc.; and the like. Of these hydrogenated oils are preferred as an oil component of the present invention. Specific examples of waxes include plant waxes, e.g. carnauba wax, candelilla wax, bayberry wax, auricurry wax, espalt wax, etc.; animal waxes, e.g. bees wax, breached bees wax, insect wax, spermaceti, shellac, lanolin, etc.; and the like. Of these preferred are carnauba wax, white beeswax and yellow beeswax. Paraffin, petrolatum, microcrystalline wax, and the like, are given as specific examples of hydrocarbons, with preferable hydrocarbons being paraffin and microcrystalline wax. Given as examples of higher fatty acids are caprilic acid, undecanoic acid, lauric acid, tridecanic acid, myristic acid, pentadecanoic acid, palmitic acid, malgaric acid, stearic acid, nonadecanic acid, arachic acid, heneicosanic acid, behenic acid, tricosanic acid, lignoceric acid, pentacosanic acid, cerotic acid, heptacosanic acid, montanic acid, nonacosanic acid, melissic acid, hentriacontanic acid, dotriacontanic acid, and the like. Of these, preferable are myristic acid, palmitic acid, stearic acid, and behenic acid. Specific examples of higher alcohols are lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachyl alcohol, behenyl alcohol, camaubic alcohol, corianyl alcohol, ceryl alcohol, and myricyl alcohol. Particularly preferable alcohols are cetyl alcohol, stearyl alcohol, and the like. Specific examples of esters are fatty acid esters, e.g. myristyl palmitate, stearyl stearate, myristyl myristate, behenyl behenate, ceryl lignocerate, lacceryl cerotate, lacceryl laccerate, etc.; glycerine fatty acid esters, e.g. lauric monoglyceride, myristic monoglyceride, stearic monoglyceride, behenic monoglyceride, oleic monoglyceride, oleic stearic diglyceride, lauric diglyceride, myristic diglyceride, stearic diglyceride, lauric triglyceride, myristic triglyceride, stearic triglyceride, acetylstearic glyceride, hydoxystearic triglyceride, etc.; and the like. Glycerine fatty acid esters are more preferable. Specific examples of metal salts of higher fatty acid are calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, zinc palmitate, zinc myristate, magnesium myristate, and the like, with preferable higher fatty acid salts being calcium stearate and magnesium stearate. Polyethoxylated castor oil (cremaphor) is also useful.
- These oil components and polymers can be used either singly or in combination of two or more. These are used in the following amounts, from about 1% to about 90% but preferably from about 1% to about 70%.
- The drug loaded cores used in this invention can be made using extrusion spheronization techniques or by layering of drugs on sugar spheres, microcrystalline cellulose spheres, non pareil seeds or any pharmaceutically acceptable microspheres which are less than 3 mm in diameter.
- Non drug loaded cores may be used in this invention to help provide homogeneity to ensure even distribution of the cores in the housing. Non drug loaded cores can be made using extrusion spheronization techniques. They can also be sugar spheres, microcrystalline cellulose spheres, non pareil seeds or any pharmaceutically acceptable microspheres which are less than 3 mm in diameter.
- The drug loaded or non-drug loaded cores that can be used range in size from about 1 micron to about 3000 microns in diameter and preferably from about 50 microns to about 1500 microns in diameter. From about 1% to about 100% and preferably from about 5% to about 100% of the drug loaded cores may be used in the housing. While from about 0% to about 90% and preferably from about 0% to about 70% of the non-drug loaded cores may be used in the housing.
- Pharmaceutical excipients such as diluents e.g., sugars, compression aids e.g., microcrystalline cellulose, surfactants e.g., sodium lauryl sulphate, surfactant micelles e.g., polyethoxylated castor oil (cremaphor), polymeric micelles e.g., amphiphilic block polymers (poloxamers), binders e.g., polyvinyl pyrolidone, glidants e.g., silicone dioxide, lubricants e.g., magnesium stearate etc. may be used in this invention. One skilled in the art will know what excipients to choose.
- In one embodiment of the invention, the composite is prepared by embedding the drug loaded depots and optionally the non-drug loaded depots in the release retarding polymer material and compressing to shape. This is accomplished by wet granulation to form wet granules and subsequent compression of the granules after they have been dried and lubricated.
- In another embodiment, the dosage form can also be prepared by direct compression of a lubricated homogeneous blend of the drug loaded cores and optionally non drug loaded cores. In yet another embodiment excipients may be added to aid in granulation or compression etc. Another method of manufacture is by melt granulation.
- In a further embodiment the dosage form is a layered tablet made by compression in a layer press. One layer is the release retarding layer and the other is an immediate release layer.
- In yet another embodiment the release retarding layer is sandwiched between non release retarding layers.
- The following examples are merely illustrative of the present invention and should not be considered limiting of the scope of the invention in any way. These examples and equivalents thereof will become more apparent to those skilled in the art in light of the present disclosure and the accompanying claims.
- Dexmethylphenidate Pulsed Release System.
- Composition, manufacture and assembly of cores:
-
Tablet I (%) Tablet II (%) Tablet III (%) d-threo-methylphenidate 32 32 16 hydrochloride Hydroxypropyl methyl — 12 — cellulose sodium starch glycolate 1 — 1 Lactose 45 40 61 Silicone dioxide 1 1 1 Microcrystalline cellulose 20 14 20 Magnesium stearate 1 1 1 - Each tablet population is manufactured by wet granulation or dry granulation of a homogeneous blend of d-threo-methylphenidate hydrochloride+pharmaceutical necessities with exception of magnesium stearate. The wet granules are dried and passed through a comill. The resulting milled granules are lubricated with magnesium stearate and compressed into a preselected shape to form one population. A delayed release coat of the type that is pH reactive specifically EUDAGRIT® L (anionic copolymer) is applied onto Tablet population designated Tablet II to give a coverage of 4 mg per cm2. A delayed release coat of the type that is pH reactive specifically EUDAGRIT® S (anionic copolymer) is applied onto Tablet population designated Tablet Ill to give a coverage of 6 mg per cm2. Coating application is done in a perforated side vented coating pan. Finally, one tablet each from the three populations of tablets are assembled in no particular order in the holding chamber/reservoir made of hard gelatin or hydroxypropyl methyl cellulose.
- Duloxetine Delayed Pulsed Release System.
- Composition, manufacture and assembly of cores:
-
Beads I (mg) Beads II (mg) Duloxetine hydrochloride 200 200 OPADRY ® II (pigmented PVA- 50 50 based film coating formulation) Sodium lauryl sulphate 50 50 Non pareil beads 1200 120 - Each duloxetine loaded bead population is manufactured by powder suspension layering of duloxetine hydrochloride unto non pareil beads in a fluid bed using top spray or bottom spray techniques. Duloxetine is suspended in OPADRY® II (pigmented PVA-based film coating formulation) aqueous suspension. A fluid set up for bottom spray is charged with non pareil beads. The duloxetine-OPADRY® II (pigmented PVA-based film coating formulation) suspension is sprayed unto the beads. A delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) is applied onto the duloxetine loaded beads I to give a coverage of 4 mg per cm2. An extended release coat, specifically a 50:50 ethylcellulose:hydroxypropyl methyl cellulose coat is applied to duloxetine loaded beads II to obtain a 4% weight gain. The extended release coated duloxetine loaded beads II is further coated with a delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) to give a coverage of 4 mg per cm2. These coats are applied in a fluid bed. Finally, the two populations of beads are assembled in a ratio of 1:3 (duloxetine coated beads I: duloxetine coated beads II) in the holding chamber/reservoir made of hard gelatin or hydroxypropyl methyl cellulose.
-
Rivastigmine 12 mg Delayed Extended Pulsed Release System. - Composition, manufacture and assembly of cores:
-
Spheroids I (mg) Spheroids II (mg) Rivastigmine 12 12 Microcrystalline cellulose 388 388 PH 101 Water qs qs - Each rivastigmine loaded bead population is manufactured by extrusion spheronization techniques. Rivastigmine is dissolved in water. Rivastigmine water solution is used to granulate microcrystalline cellulose in Hobart mixer. The wet granules are extruded in a Caleva extruder. The extrudate is charged into a Caleva spheroniser and spheronized to obtain rivastigmine loaded spheroids. The spheroids are dried to a loss of drying of less than 2%. A fluid set up for bottom spray is charged with spheroids!. A delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) is applied onto the rivastigmine loaded spheroids I to give a coverage of 4 mg per cm2. An extended release coat, specifically a 60:40 ethylcellulose:hydroxypropyl methyl cellulose coat is applied to rivastigmine loaded spheroids II to obtain a 4% weight gain. The extended release coated rivastigmine loaded beads II is further coated with a delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) to give a coverage of 4 mg per cm2. These coats are applied in a fluid bed. Finally, the two populations of beads are assembled in a ratio of 1:3 (rivastigmine coated spheroids I: rivastigmine coated spheroids II) in the holding chamber/reservoir made of hard gelatin or hydroxypropyl methyl cellulose.
- Respiridone 6mg Pulsed Extended Release System.
- Composition, manufacture and assembly of cores:
-
Tablet I (mg) Tablet II (mg) Risperidone 3 2 Hydroxypropyl methyl cellulose 12 — cross-linked N-vinyl-2-pyrrolidone — 2 Lactose 58 69 Sodium lauryl sulphate 5 5 Silicone dioxide 1 1 Microcrystalline cellulose 20 20 Magnesium stearate 1 1 - Each tablet population is manufactured by wet granulation or dry granulation of a homogeneous blend of risperidone+pharmaceutical necessities with exception of magnesium stearate. The wet granules are dried and passed through a comill. The resulting milled granules are lubricated with magnesium stearate and compressed into a preselected shape to form one population. A delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) is applied onto Tablet population designated Tablet II to give a coverage of 4 mg per cm2. 1 mg of risperidone is blended into OPADRY® II (pigmented PVA-based film coating formulation) 15% (wt/wt) suspension in water. This suspension is used to coat the tablet population designated Tablet I. The risperidone OPADRY® II (pigmented PVA-based film coating formulation) suspension is prepared sufficient to apply a weight gain of 3% to the tablet. Coating application is done in a perforated side vented coating pan. Finally, one tablet each from the two populations of tablets are assembled in no particular order in the holding chamber/reservoir made of hard gelatin or hydroxypropyl methyl cellulose.
- Duloxetine 60 mg Pulsed Extended Release System.
- Composition, manufacture and assembly of cores:
-
Tablet I (mg) Tablet II (mg) Duloxetine 40 20 Hydroxypropyl methyl cellulose 30 — cross-linked N-vinyl-2-pyrrolidone — 4 Lactose 76 96.4 Sodium lauryl sulphate 10 10 Silicone dioxide 2 2 Citric acid — 4 Tartaric acid — 8 Sodium bicarbonate — 13.6 Microcrystalline cellulose 40 40 Magnesium stearate 2 2 - Each tablet population is manufactured by direct compression of a homogeneous blend of duloxetine+pharmaceutical necessities which has been lubricated with magnesium stearate. A delayed release coat of the type that is pH reactive specifically EUDRAGIT® L (anionic copolymer) is applied onto Tablet population designated Tablet I to give a coverage of 4 mg per cm2. Tablet population designated Tablet II is not coated. Coating application is done in a perforated side vented coating pan. Finally, one tablet each from the two populations of tablets are assembled in no particular order in the holding chamber/reservoir made of hard gelatin or hydroxypropyl methyl cellulose.
- Those skilled in the art will appreciate that diverse modifications, alteration, reconstruction and omissions in the system portrayed and described can be made without departing from the essence of the invention.
Claims (24)
1. A drug delivery device for oral administration of an active pharmaceutical ingredient (API), the device comprising:
a) a first population of unit dosage forms comprising a core, wherein the core comprises a pharmaceutically acceptable bead and an API loaded coating, wherein the API loaded coating comprises an API and hydroxypropyl methyl cellulose and wherein the first population of unit dosage forms further comprises a pH-reactive coat; and
b) a second population of unit dosage forms comprising a core, wherein the core comprises a pharmaceutically acceptable bead and an API loaded coating, wherein the API loaded coating comprises the API and hydroxypropyl methyl cellulose and wherein the second population of unit dosage forms comprises an extended release coat on the core and further comprises a pH-reactive coat on the extended release coat.
2. The drug delivery device of claim 1 , wherein the API is duloxetine.
3. The drug delivery device of claim 2 , wherein the API is present in the API loaded coating in both the first population and second population in an amount of 67%.
4. The drug delivery device of claim 1 , wherein the pharmaceutically acceptable bead comprises a non pareil bead.
5. The drug delivery device of claim 4 , wherein the non pareil bead is less than 3 mm in diameter.
6. The drug delivery device of claim 1 , wherein the hydroxypropyl methyl cellulose is present in the API loaded coating of the first and second population of unit dosage forms in an amount of 17%.
7. The drug delivery device of claim 1 , wherein the API loaded coating of the first and second population of unit dosage forms further comprises an excipient in an amount of 17%.
8. The drug delivery device of claim 7 , wherein the excipient is sodium lauryl sulphate.
9. The drug delivery device of claim 1 , wherein the first and second population of unit dosage forms is each coated with the pH reactive coat to a coverage of 4 mg per cm2.
10. The drug delivery device of claim 1 , wherein the extended release coat of the second population of unit dosage forms comprises a mixture of ethylcellulose and hydroxypropyl methyl cellulose.
11. The drug delivery device of claim 10 , wherein the ratio of ethylcellulose and hydroxypropyl methyl cellulose is 50:50.
12. The drug delivery device of claim 1 , wherein the extended release coat of the second population of unit dosage forms is applied to a weight gain of 4%.
13. The drug delivery device of claim 1 , wherein the first and second population of unit dosage forms are present in the drug delivery device in a ratio of 1:3.
14. A drug delivery device for oral administration of an active pharmaceutical ingredient (API), the device comprising:
a) a first population of unit dosage forms comprising a core, wherein the core comprises an API and microcrystalline cellulose and wherein the first population of unit dosage forms further comprises a pH-reactive coat; and
b) a second population of unit dosage forms comprising a core, wherein the core comprises an API and microcrystalline cellulose and wherein the second population of unit dosage forms comprises an extended release coat on the core and further comprises a pH-reactive coat on the extended release coat.
15. The drug delivery device of claim 14 , wherein the API is rivastigmine.
16. The drug delivery device of claim 15 , wherein the API is present in both the first population and second population in an amount of 3%.
17. The drug delivery device of claim 14 , wherein the microcrystalline cellulose is present in the core of the first and second population of unit dosage forms in an amount of 97%.
18. The drug delivery device of claim 14 , wherein the core for the first and second population of unit dosage forms is made by dissolving the API in water, granulating the API solution with the microcrystalline cellulose, extruding the granulated API-microcrystalline cellulose mixture to produce an extrudate, and forming core particles from the extrudate.
19. The drug delivery device of claim 14 , wherein the core particles are spheroids.
20. The drug delivery device of claim 14 , wherein the first and second population of unit dosage forms is each coated with the pH reactive coat to a coverage of 4 mg per cm2.
21. The drug delivery device of claim 14 , wherein the extended release coat of the second population of unit dosage forms comprises a mixture of ethylcellulose and hydroxypropyl methyl cellulose.
22. The drug delivery device of claim 21 , wherein the ratio of ethylcellulose and hydroxypropyl methyl cellulose is 60:40.
23. The drug delivery device of claim 14 , wherein the extended release coat of the second population of unit dosage forms is applied to a weight gain of 4%
24. The drug delivery device of claim 14 , wherein the first and second population of unit dosage forms are present in the drug delivery device in a ratio of 1:3.
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US11/315,868 US10064828B1 (en) | 2005-12-23 | 2005-12-23 | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
US16/050,664 US20180333362A1 (en) | 2005-12-23 | 2018-07-31 | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
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US16/050,664 Abandoned US20180333362A1 (en) | 2005-12-23 | 2018-07-31 | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
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-
2005
- 2005-12-23 US US11/315,868 patent/US10064828B1/en active Active
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2018
- 2018-07-31 US US16/050,664 patent/US20180333362A1/en not_active Abandoned
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