WO2002096347A2 - Dosage et conditionnement de medicaments a liberation controlee - Google Patents

Dosage et conditionnement de medicaments a liberation controlee Download PDF

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Publication number
WO2002096347A2
WO2002096347A2 PCT/US2002/016185 US0216185W WO02096347A2 WO 2002096347 A2 WO2002096347 A2 WO 2002096347A2 US 0216185 W US0216185 W US 0216185W WO 02096347 A2 WO02096347 A2 WO 02096347A2
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WO
WIPO (PCT)
Prior art keywords
combination
delivery package
pharmaceutical delivery
plus
pharmaceutical
Prior art date
Application number
PCT/US2002/016185
Other languages
English (en)
Other versions
WO2002096347A3 (fr
Inventor
Andrew L. Abrams
Anand V. Gumaste
Original Assignee
Microdose Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Microdose Technologies, Inc. filed Critical Microdose Technologies, Inc.
Priority to US10/479,438 priority Critical patent/US20040156903A1/en
Priority to EP02731902A priority patent/EP1408907A4/fr
Priority to JP2002592860A priority patent/JP2005514966A/ja
Priority to CA002448997A priority patent/CA2448997A1/fr
Priority to AU2002303840A priority patent/AU2002303840A1/en
Priority to NZ529696A priority patent/NZ529696A/en
Priority to BRPI0209720A priority patent/BRPI0209720A2/pt
Publication of WO2002096347A2 publication Critical patent/WO2002096347A2/fr
Publication of WO2002096347A3 publication Critical patent/WO2002096347A3/fr
Priority to US11/549,492 priority patent/US20070087048A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • the present invention relates to the metering and packaging of precise quantities of pharmaceuticals and drugs for medical uses.
  • the invention has particular utility in the metering and packaging of combinations of two or more pharmaceuticals and drugs for the same or co-morbid therapy, and will be described in connection with such utility / although other utilities are contemplated.
  • a pharmaceutical delivery package comprising fixed unit dose quantities of fixed quantities of two or more different active pharmaceutical ingredients (a) combined in a single delivery package,-and (b) segregated from one another within the package.
  • Previously direct placement of medication onto a substrate generally was Hmited to medical placement of large doses or required technology where the active pharmaceutical was mixed with the substrate or matrix to provide differential delivery, or coated with a material with desired release characteristics.
  • oiled-release is used to describe a system, i.e. method and materials for making an active ingredient available to the patient in accordance with a preselected condition, i.e. time, site, etc..
  • Controlled- release includes the use of instantaneous release, delayed release and sustained release.
  • Instantaneous release refers to immediate release to the patient.
  • Dellayed release means the active ingredient is not made available until some time delay after administration. Typically, dosages are administered by oral ingestion, although other forms of administration are contemplated in accordance with the present invention.
  • sustained release refers to release of active ingredient whereby the level of active ingredient available to the patient is maintained at some level over a period of time. The method of effecting each type of release can be varied. For example, the active-ingredient can be placed on a semi-permeable membrane having predetermined diffusion, dissolution, erosion or breakdown characteristics.
  • the active ingredient can be masked by a coating, a laminate, etc.
  • the present invention contemplates delivery of a controlled-release system which utilizes one or more of the "release” methods and materials.
  • the present invention advantageously can be employed in the development of multiple different release system(s).
  • SR sustained release
  • polymeric capsules For common methods of obtaining SR systems, see "Sustained and Controlled Release Drug Delivery Systems," Robinson, Joseph R., Ed., PP 138-171, 1978, Marcel Dekker, Inc. New York, NY.
  • SR sustained release
  • Heterogeneous matrices for example, compressed tablets, control the release of their therapeutic agents either by diffusion, erosion of the matrix or a combination of both.
  • Other SR systems focus on the fabrication of laminates of polymeric material and therapeutic agent which are then formed into a sandwich, relying on different diffusion or erosion rates to control release of the therapeutic agent.
  • Liquid-liquid encapsulation in a viscous syrup-like solution of polymer also has been known to be useful in controlling release of the therapeutic agent. Additionally, it is generally known that heterogeneous dispersions or solutions of therapeutic agents in water-swellable hydrogen matrices are useful in controlling the release of the agent by slow surface-to-center swelling of the matrix and subsequent diffusion of the agent from the water- swollen part of the matrix.
  • the dosage form During dissolution of a controlled-release matrix tablet, the dosage form generally remains as a non-disintegrating, slowly eroding entity from which the therapeutic agent leaches out, through a diffusion controlled process.
  • Conventional SR formulations are generally designed to release their active ingredients over an extended period of time, usually 8-24 hours.
  • Conventional SR formulations use waxes or hydrophilic gums as the primary drug carriers to prolong the release of the active ingredients.
  • Starch USP (potato or corn) is commonly used as a component in conventional tablet or hard shell capsule formulations.
  • the existing sustained release technologies generally involve relatively complicated formulations and manufacturing processes which often are difficult and expensive to precisely control.
  • OROS SR delivery system
  • OROS SR delivery system
  • the dosage unit should be able to deliver the system without interfering with its release .pattern.
  • controlled-release systems have been provided in the form of beads or particles which are packaged in a gelatin capsule for oral dosage. This method of delivery of the controlled-release system prevents damage to the coating on the beads.
  • Electrostatic charge has been employed to attract a given quantity of powder to a surface.
  • An example of this is the laser printer or the electrostatic copy device where a drum is charged and toner particles are attracted and held in position by the charge. The charge on the drum is neutralized by the attracted toner powder, thus limiting the amount of toner in accordance with the charge image on the drum. The charged powder on the printer drum is then transferred to a sheet of paper or other carrier to give a final image.
  • Patent 5,699,649 electrostatic charge technology is employed for transferring a predetermined amount of a finely powdered pharmaceutical or drug to a ' carrier or an intermediate such as a drum, carrying a charge of predetermined intensity and area, rotating the charged drum surface, carrying the predetermined amount of powdered pharmaceutical or drug on its surface, to a transfer station where the charge is overcome and the dry powder is transferred to a package which is then sealed.
  • a transfer station where the charge is overcome and the dry powder is transferred to a package which is then sealed.
  • a belt, or other movable surface is charged to a given potential in a localized area.
  • a predetermined amount of powdered pharmaceutical or drug may be deposited directly in a package using electrostatic charge technology.
  • the charge and area of charge can be determined experimentally for each dose of pharmaceutical or drug and each particle size distribution. This can be done by controlling either the charged area for a given charge density or the total electrostatic charge on any individual charged area. These conditions can be adjusted to provide essentially the exact desired amount of the particular pharmaceutical or drug to be transferred at the transfer station.
  • controlled quantities of powdered medication are formed in controlled release packages using electrostatic metering technology.
  • the present invention also provides, in another aspect, combination medication delivery systems in which the active ingredients are segregated from one another
  • Fig. 1 is a schematic flow diagram showing the various steps involved in practicing the present invention
  • Fig. 2 is an enlarged cross-sectional view of one embodiment of a controlled release tablet made in accordance with the present invention
  • Fig. 3 is a view, similar to Fig. 1, and showing alternative steps involved in practicing the present invention
  • Fig. 4 is a view, similar to Fig. 2, and showing an alternative form of a controlled release tablet made in accordance with the present invention
  • Fig.5 is a view similar to Fig.2, and showing yet another alternative embodiment of the present invention.
  • Fig. 6 is a view, similar to Fig. 2, and showing yet another embodiment of the invention.
  • Figs. 7 - 9 are views similar to Fig. 2, and showing yet other embodiments of the present invention.
  • Fig. 1 there is a schematic flow diagram of the various pieces of equipment needed to perform in the total process from powder supply to packaged pharmaceutical or drug, i.e. in controlled release tablet form, containing a specified amount of pharmaceutical or drug powder in the tablet or package.
  • the pharmaceutical or drug powder supply which is fed into a device 18 for creating an aerosol of the powder.
  • the powder particles are ionized at 20.
  • a carrier surface capable of maintaining a space charge on its surface. This can be a plastic belt, for example, or a selenium drum of the type used in Xerox TM photocopiers.
  • This carrier surface 24 is passed through a charging station 25 where a predetermined electrostatic charge 25 A (an electrostatic "image") is created on a predetermined area of the transfer surface.
  • This charged surface 25A then passes through a step 26 wherein powder is deposited on the carrier surface in a sufficient amount 26A to neutralize the charge carried by the carrier surface.
  • the carrier surface, carrying the predetermined amount 26A of powder on its surface is passed to a powder discharging device 30 which discharges the powder 26A from the surface 24 onto a membrane 29.
  • the powder may be placed directly onto the membrane 29.
  • the membrane 29 containing its charge of powder 26A then passes through a sealing step 32 wherein a second membrane 34 which may be porous, permeable or semi-permeable covers and seals the discharged powder 26A on the membrane 29. There is thus produced an aliquot of powdered medicine 26A sandwiched between semi-permeable or permeable membranes 29 and 34.
  • This sandwiched material is then passed to a cutting station 38 wherein the sandwich is cut into individual tablets or wafers 36.
  • the carrier surface with the electrostatic charge carries a known amount of charge on its surface and the polarity of this charge is opposite to that of the powder particles suspended in the chamber.
  • the charged particles migrate to the charged surface because of the attraction by the opposite nature of the charges. This migration of the particles continues until the charge on the carrier surface is neutralized.
  • the actual amount of powder mass transferred to the carrier surface is a function of the mass-to-charge ratio of the charged particles. Although it is difficult to achieve a linear relationship between the mass and the actual charge, it is possible to establish a fixed relationship between the surface area of the powder particles and the charge the powder particle is carrying at charge saturation. However, the surface area of a mixed group of powder particles of different sizes and shapes can be extremely difficult to calculate mathematically, particularly when the shapes are irregular, (e.g.
  • the simplest method of deterrnining the amount and area of charge to attract a given weight of particles is to estimate the correct area and charge and then apply the - estimated charge to the estimated area on the carrier surface 24 and expose this selectively charged area to a mass of powder which has been ionized in the ionizing step.
  • the amount of powder deposited can then be readily measured at the discharge step. Thereafter, either the size of the charged area or the amount of charge applied to the area at the charging station 25 can be adjusted upwardly or downwardly to provide the correct amount of charge, both in area and charge intensity, for picking up a desired weight of oppositely charged powder.
  • larger quantities of medication may be deposited.
  • a feature and advantage of the present invention is to produce carefully controlled doses of controlled release medication. Electrostatic metering and packaging as above described permits exact dosing. And, by employing selected porous, permeable or semi-permeable membranes for encapsulating the powdered medicine aliquots, drug release rate and also site of drug release can be determined by adjusting membrane material and/ or membrane thickness.
  • the membranes should be formed of ingestible materials having a selected permeability porosity to fluids at a selected site or sites within the alimentary canal, so as to permit controlled release of the medication.
  • one or both membranes 29., 34 may comprise acid-dissolvable materials when it is desired to release the medication into the stomach or the membranes 29, 34 may be alkaline-dissolvable materials at differing pH's to release into chosen locations within the intestine. Porosity, membrane thickness, etc., may be selected to provide desired rate of dissolution at the site of interest.
  • a two-component controlled release tablet 48 may be formed (see Fig.4) incorporating two different powdered medicines 50, 52, encapsulated between membranes 29 and 34 for simultaneous controlled release.
  • two different drugs 60, 62 may be layered on one another, separated by a membrane 64 so the two medications may be delivered sequentially either in the same location, or in different locations within the aUmentary canal.
  • Another feature and advantage of the multi-drug tablet of Fig. 4 and Fig. 5, as will be discussed in detail herein below, is that two normally incompatible drugs may be to be safely packaged in a single tablet.
  • the invention is susceptible to modification.
  • individual doses may be formed by electrostatic deposition in accordance with U.S. Patent No.5,714,007.
  • the tablet 70 may incorporate an adhesive layer 72 such as a mucosal adhesive, which in turn is covered by an acid or alkaline dissolvable protective membrane 74, which dissolves at a selected site allowing the adhesive to adhere, for example, to the intestinal wall, thereby increasing residence time of the medication in a chosen location.
  • an acid or alkaline activatable adhesive may be applied to the outer surface of the tablet.
  • the membrane may be a material which expands on contact with the acid or alkaline in the alimentary canal and becomes more porous whereby to slowly release medication in a chosen location within the alimentary canal.
  • a particular feature and advantage of the present invention is that it permits packaging, within a single tablet of two or more different drugs normally considered to be incompatible. Certain drugs are known to cause undesirable side effects which need to be countered by a second drug.
  • Omeprazole 1 which finds substantial utility as an oral antiulcer agent, also is known to block the release of B12 from its protein binding site in food. This can lead to pernicious anemia.
  • the present invention permits packaging of time-release Omeprazole with Vitamin B12 in an appropriate dosage of, e.g. 25 ⁇ gm - 1 mg. After taking the medication, one membrane will dissolve allowing absorption of the B12, while the remaining membrane package carrying the Omeprazole will pass into the small intestine where the drug is released and absorbed.
  • the invention is susceptible to modification.
  • the membranes have been described as being preformed, permeable, semiperrneable or porous material, one or both membranes could be formed in place from a gel or liquid.
  • the ability to accurately place the dose of medication onto a plurality of substrates and seal the dose with other membranes in accordance with the present invention allows for the fabrication of many different dosage forms; by altering the substrates and encapsulating material a single unit dose form can be fabricated with a plurality of different drugs in different coverings, membranes and barriers.
  • This will provide a single dosage form with multiple active ingredients each being delivered to the appropriate site for absorption.
  • two or more active medicaments may be combined in a single delivery container, i.e. pill, capsule or caplet without actually mixing the two or more ingredients.
  • the active ingredients are segregated from one another in a compartmentalized capsule 100.
  • two or more tablets 102, 104 each containing only one active ingredient could be placed in a larger absorbable capsule or encased in a larger tablet 106.
  • two or more active ingredients could each be formulated as encapsulated particles 108A, 108B, and the encapsulated mixed particles placed in a capsule 110 where the only contact is between the particle inert coatings, etc.
  • the combination of drugs of the present invention can be grouped into polypharmacy for a therapeutic area, and into polypharmacy for treatment of co-morbid diseases.
  • the invention will now be described with reference to the following non-lirniting examples.
  • Valacyclovir 2 and analogs and is used to treat Herpes Zoster. It is well known that two drugs Cimetidine 3 and Probenecid 4 both increase the AUC (area under curve) and Cmax. A combination drug can be constructed with a combination of either one or more of these components to provide more efficacy.
  • Enalapril 5 and analogs and isomers is an ACE inhibitor used for the treatment of hypertension.
  • This drug has been used with the following and analogs and isomers beta adrenegic-blocking agents, methyldopa, nitrate, calcium blocking agents, Hydralazine 6 , Prazosin 7 and Digoxin 8 without clinically significant side effects.
  • beta adrenegic-blocking agents beta adrenegic-blocking agents
  • methyldopa methyldopa
  • nitrate calcium blocking agents
  • Hydralazine 6 methyldopa
  • Prazosin 7 and Digoxin 8 without clinically significant side effects.
  • One or more of these agents may be combined with Enalapril to improve the compliance of patient with hypertension and hypertension and other cardiac diseases.
  • Ketoconazole 9 and analogs and isomers is used to treat fungal infections.
  • One of the side effects is the reduction of Testosterone. This side effect could be mitigated by the combination of Testosterone or one of its isomers or analogs to overcome the side effect.
  • Omeprazole 1 and analogs and isomers is also used in combination with Clarithoromycin 10 for ulcer treatment. These two drugs may be combined as a single dose for patient compliance.
  • Tamoxifen 11 and analogs and isomers used in treatment of breast cancer has a +/- 30% incident of water retention with weight gain > 5%. This can be a disturbing consequence for patients with an even more disturbing disease.
  • the addition of a diuretic or combination diuretic provides a single dosage form for reduction in side effect and compliance.
  • Isotretinoin 12 and analogs and isomers used for the treatment of postular acne has a severe danger if taken by a woman who is pregnant.
  • the incorporation of oral contraceptive medication eliminates the potential for pregnancy while medicated.
  • Metformin HO 13 and analogs and isomers are hypoglycemic agents which have been used in combination with Sulfonylurea 14 and analogs and isomers to treat Type 2 Diabetes. These two agents act in different ways on reducing glucose levels. A combination is helpful for those patients requiring more aggressive oral therapy for their diabetes.
  • Combinations for treating hypertension include: Combination # 1 Diuretic + Angiotensin converting enzyme inhibitor (ACE inhibitor)
  • An example includes the following classes of diuretics:
  • Carbonic anhydrase inhibitors - e.g. Dichlorophenamide 15 .
  • Loop diuretics e.g. Furosemide 16 .
  • a diuretic which is already formulated as a combination diuretic, e.g. Aldactazide, a combination of Spironolactone 20 (potassium sparing diuretic + hydrochlorothiazide).
  • This combination makes use of the different methods of action of two different diuretics separated by a barrier from an ACE inhibitor such as Enalapril maleate 21 , Fosinopril sodium 22 , or Lisinopril 23 .
  • Combination diuretics such as Zestoretic AstraZeneca a combination of Lisinopril 27 10 or 20 mg and Hydrochlorthiazide 17 12.5 or 25 mg, exist in tablet form comprising mixed active ingredients in the pill or tablet form.
  • the present invention segregates the Lisinopril and Hydrochlorthiazide.
  • Pills can be in the form of tablets, pills, capsules or other solid oral dosage forms.
  • Diuretics as described in combination drug # 1 plus an angiotensin II receptor antagonist such as Losartan potassium 24 and/ or Valsartan 25 .
  • a beta adrenergic blocking agent such as Bioprolol fumarate 26 or Metoprolol succinate 27 .
  • Combination # 5 Diuretic + Periferal Adrenergic Blocking Agent Diuretic as described in #11, plus a periferal adrenergic blocking agent such as: Prazosin hydrochloride 7 .
  • the drug barrier system of the present invention allows further drug combinations such as a Calcium chanel block combined with: beta blockers, ACE inhibitors, long acting nitrates, Digoxin 8 , oral hypoglycemic drugs as well as multiple combinations, and combinations with a diuretic and combination drugs # 2, 3 , 4 or more of the above-mentioned compounds.
  • the drug barrier system of the present invention also allows drug combinations such as ACE Inhibitors combined with Beta blockers, methyldopa nitrates, calcium channel blockers, Hydralazine 6 , Prazosin 7 , Digoxin 8 as well as multiple combinations, and combinations with a diuretic and combination drugs # 2, 3, 4 or more of the above-mentioned compounds.
  • drug combinations such as ACE Inhibitors combined with Beta blockers, methyldopa nitrates, calcium channel blockers, Hydralazine 6 , Prazosin 7 , Digoxin 8 as well as multiple combinations, and combinations with a diuretic and combination drugs # 2, 3, 4 or more of the above-mentioned compounds.
  • Biguanide such as Metaformin 13 with a sulfonylurea such as Glipizide 32 .
  • Biguanide such as Metaformin 13 with a thiazolidinedione such as Rosiglitazone maleate 33 .
  • HMG-CoA reductase inhibitor such as Simvastatin 35 , Atorvastatin 36 , or Pravastatin 37 with a bile acid sequestrant such as Colestipol hydrochloride 38 .
  • a HMG-CoA reductase inhibitor with a niacin compound A HMG-CoA reductase inhibitor with a niacin compound.
  • AntiMstamine plus Leukotriene modifier such as Loratadine 40 plus Montelukast 41 .
  • This example provides a drug combination for treating migraine.
  • This example provides a drug combination for treating postoperative/post-chemotherapy nausea.
  • Anti-nausea such as Doperidol 44 plus steroid such as Dexamethasone 45 .
  • This example provides various drug combinations for treating gastric/ duodenial ulcer.
  • SSRI Selective serotonin reuptake inhibitor
  • Protease inhibitor - ⁇ ndinayir (Crixivan 49 ) plus nuclear reverse transcriptase inhibitor - Efavirenz (Sustiva 50 ) " plus third drug, i.e.2 nd NRTT- Ziduvudine 51 or Azidothymidine 52 .
  • This example provides various drug combinations for treating anti-rejection cocktail after organ transplant.
  • Combination drug # 25 plus PPI/H2 for ulcer prevention - Omeprazole 1 Combination drug # 25 plus PPI/H2 for ulcer prevention - Omeprazole 1 .
  • This example provides a drug combination for treating infections with combination therapy such as tuberculosis.
  • combination drugs # 7-12 which are the combinations for control of the diabetes with any of combination drugs #1-7 or the single component medicaments used in the anti-hypertensive combinations.
  • a Calcium channel block such as Nifedipine 29 plus a vasodilator such as nitroglycerin.
  • This example provides a polypharmacy for treatment of seizure disorders.
  • a Gamma Aminobutyric analog such as Gabapentin 58 or a Gamma Aminobutyric stimulator such as Divalproex Sodium 59 plus a Benzodiazepine such as Alprazolam 60 .
  • An opioid and a non-opioid analgesic such as codeine and acetominophine.
  • Combination #34 An opioid and a bowel softener or evacuant.
  • This example provides polypharmacy for elimmating or minimizing gastric irritation caused by a primary drug.
  • a cyclooxygenase-2 inhibitor such as Celecoxib 61 plus Omeprazole 1 .
  • An anti-inflammatory such as Naproxen 62 plus Omeprazole 1 .
  • Prednisone 54 plus estrogen or progesterone to prevent bone mass loss. It is also possible to package two or more doses of the same active ingredient in slow and fast release forms.
  • This example provides polypharmacy for treating anxiety or panic disorder.
  • a selective serotonin reuptake inhibitor such as Paroxetine 63 plus a Benzodiazepine such as Lorazepam 64 .
  • An arninoketone such as Bupropion 65 plus Lorazepam 64 .
  • combination drugs including some of the above-listed combination drugs, also may be blended and packaged in a single tablet or capsule, when chemical interaction is not a problem.
  • the present invention also allows for the rapid production of different dosage medications using the same active ingredient, and allows for the development of medications with longer resident time.
  • Omeprazole 5-rnethoxy-2[[(4-methoxy-3,5-dimethyl-2-pyrindinly) methyl] sulfinyl]-lH-benzimidazole.
  • Valacyclovir L-valine, 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester, monohydrochlori.de.
  • Cimetidine N"-cyano-N-methyl-N , -[2-[[(5-methyl-l-H-imidazol-4-yl) methyl]thio]-ethyl]-quanidine.
  • Hydralazine 1-HydrazinophthaIazine monohydrochloride.
  • Prazosin HC1 hydrochoride salt of l-(4-amino-6,7-dimethoxy-2- quinazolinyl)-4- (2-f uroyl) piperazine .
  • Ketocanozole CIS - 1 - acetyl - 4[4 -[[2,4-dicheorophenyl -2-(lH- imidazol-1-ylmethyle) -l,3-dioxolan-4-yl] methocy] phenyl] piperazive.
  • Tamoxifen (Z)2-[4-(l,2-diphenyl-l-butenyl)phenoxy]-N, N- dimethylethanamine 2 hydroxy-l,2,3-propanetricarboxylate.
  • Isotretinoin 13-cis-retinoic acid.
  • Metformin N,N-dimemyHmidodcarbonimidic diamide hydrochloride.
  • Dichlorophenamide 4,5-dichloro-l,3- benzenedisulfonamide.
  • Furosemide 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid.
  • Aldactone 17-hydroxy-7 ⁇ /]9/t -mercapto-3-oxo-17fl, 7 ⁇ g-pregn-4-ene-21- carboxylic acid gg g-lactone acetate.
  • Hydrochlorthiazide 6-chloro-3, 4-dihydro-2H-l, 2, 4-benzothiadiazine- 7-sulfonamide 1, 1-dioxide.
  • Chlorthalidone 2-Chloro-5-(2,3-dihydro-l-hydroxy-3-oxo-lH-isoindol- l-yl)benzenesulfonamide.
  • Spirolactone 1 -hy droxy-7flZp/za-mercapto-3-oxo-l 7al-ph -pregn-4-er ⁇ e- 21-carboxylic acid gamma -lactone acetate.
  • Fosinopril sodium L-proline, 4-cyclohexyl-l-[[[2-methyl-l-(l- oxopropoxy) propoxyl](4-phenylbutyl) phosphinyl]acetyl]-,sodium salt, trans-.
  • Lisinopril (S)-l-[N 2 -(l-Carboxy-3- phenylpropyl)-L-lysyl]-L-proline dihydrate.
  • Losartan potassium 2-butyl-4-chloro-l[p-(o-lH-tetrazol-5- ylphenyl)benzyl]imida ' zole-5-methanol monopotassium salt.
  • Valsartan as N- ⁇ - ⁇ xopenty ⁇ -N-tp'- ⁇ H-tetrazol-S-y ⁇ tlA'-biphenyl] ⁇ - yl]methyl]-L-valine.
  • Bioprolol fumarate ( ⁇ )-l-(4-((2-(l- Methylethoxy)emoxy)methyl) ⁇ henoxy)-3-((l-methyleti ⁇ yl)arnino)-2- propanol (E)-2-butenedioate (2:1) (salt).
  • Metoprolol succinate ( ⁇ ) l-(isopropylamino)-3-[p-(2-methoxyefhyl) phenoxy]-2-propanol succinate (2:1) (salt).
  • Amlodipine (R.S.) 3-ethyl-5-methyl-2-(2-arninoethoxymethyl)-4-(2- chloro ⁇ henyl)-l,4-dihyro-6-methyl-3,5-pyridinedicarboxylate benzenessulphonate.
  • Nifedipine 3,5-pyridinedicarboxylic acid, l,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl)-,dimethyl ester.
  • Methyldopa levo-3-(3,4- dihydroxyphenyl)-2-methylalanine sesquihydrate.
  • Clonidine HCL (2,6-dic orophenylamino)-2- imidazoline hydrochloride.
  • Glucotrol l-cyclohexyl-3-[[p-(2-(5- methylpyrazinecarboxamido) ethyl]phenyl] sulf onyl]urea.
  • Rosiglitazone maleate (+)-5-[[4-[2-(methyl-2- pyridmylammo)ethoxy] ⁇ henyl]methyl]- 2,4-thiazolidinedione,(Z)-2- butenedioate.
  • Atorvastatin [R-(R*,R*)]-2-(4-fluorophenyl)-b,s-dihydroxy-5-(l- methylethyl)-3-phenyl-4 [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid, calcium salt (2:1) trihydrate.
  • Pravastatin l-Naphthalene-heptanoic acid, l,2,6,7,8,8a-hexahydro-b, d,6-trihydroxy-2-methyl -8-(2-methyl -1- oxobutoxy)-, monosodium salt,[lS-[la(bS*, d S*),2a,6a,8b(R*),8aa]]-.
  • Colestipol hydrochloride diethylenetriamine and 1 chloro-2,3- epoxypropane.
  • Loratadine ethyl4-(8-chloro-5,6-dihydro-llH-benzo[5,6]cyclohepta[l,2- &]pyridin-ll-yHdene)-l-piperidinecarboxylate.
  • Dexamethasone 9-fluoro-ll ⁇ ,17,21-trihydroxy- 16 ⁇ -methylpregna-l,4- diene-3,20-dione.
  • Famotidine l -(aminosulfonyl)-3-[[[2- [( ⁇ am omethylene)amino]-4- miazolyl]methyl]tMo]propanimidamide.
  • Buptopion ( ⁇ )-l-(3-chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l- propanone hydrochloride.
  • Crixivan is [l(lS,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2- hydroxy- lH-mden-l-yl)-5-[2-[[(l,l-dimethylethyl)amino]carbonyl]-4-(3- ⁇ yridmy]n ethyl)- l-piperazinyl]-2-(phenylmethyl)-D-erythro- pentonamide sulfate (1:1) salt.
  • Azidothymidine 3'-azido-3'-deoxythymidine.
  • Cyclosporine [R-[RR*(E) ⁇ ] cyclic(L-alanyl-D-alanyl-N-methyl-L-leucyl- N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2- amino-6-octenoyl-L- ⁇ -ammo-butyryl-N-methylglycyl-N-methyl-L- leucyl-L-valyl-N-methyl-L-leucyl).
  • Prednisone pregna-l,4-diene-3,ll,20-trione, 17,21-dihydroxy.
  • Isoniazid isonicotinic acid hydrazide.
  • Rifampin 3-(4-methyl-l-piperazinyl-iminom.ethyl)-rifamycin.
  • Gahapentin l-(aminomethyl)cyclohexanacetic acid.
  • Divalproex Sodium sodium hydrogen bis (2-pro ⁇ ylpentanoate).
  • Alprazolam 8-Chloro-l-methyl-6-phenyl-4H-s-triazolo [4,3-a][l,4] benzodiazepine.
  • Celecoxib 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-lH-pyrazoH-yl] benzenesulfonamide.
  • Naproxen 2-naphthaleneacetic acid, 5 methoxy- a-methyl-,(+).
  • Bupropion ( ⁇ )-l-(3-chlorophenyl)-2-[(l,l-dirnethylethyl)amino]-l- propanone hydrochloride.

Abstract

L'invention concerne le conditionnement de quantités contrôlées de médicaments en poudre, sous conditionnement pour libération contrôlée, ces quantités étant déterminées par mesure électrostatique. L'invention concerne également des formes de conditionnement se prêtant à une thérapie par délivrance combinée de médicaments, lesdits conditionnements comprenant au moins deux principes pharmaceutiques actifs séparés l'un de l'autre mais conditionnés ensemble.
PCT/US2002/016185 2001-05-31 2002-05-22 Dosage et conditionnement de medicaments a liberation controlee WO2002096347A2 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US10/479,438 US20040156903A1 (en) 2002-05-22 2002-05-22 Metering and packaging of controlled release medication
EP02731902A EP1408907A4 (fr) 2001-05-31 2002-05-22 Dosage et conditionnement de medicaments a liberation controlee
JP2002592860A JP2005514966A (ja) 2001-05-31 2002-05-22 放出制御型薬剤の計量およびパッケージング
CA002448997A CA2448997A1 (fr) 2001-05-31 2002-05-22 Dosage et conditionnement de medicaments a liberation controlee
AU2002303840A AU2002303840A1 (en) 2001-05-31 2002-05-22 Metering and packaging of controlled release medication
NZ529696A NZ529696A (en) 2001-05-31 2002-05-22 Metering and packaging of controlled release medication
BRPI0209720A BRPI0209720A2 (pt) 2001-05-31 2002-05-22 dosagem e embalagem de medicação com liberação controlada
US11/549,492 US20070087048A1 (en) 2001-05-31 2006-10-13 Oral dosage combination pharmaceutical packaging

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US29478601P 2001-05-31 2001-05-31
US60/294,786 2001-05-31

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/549,492 Continuation-In-Part US20070087048A1 (en) 2001-05-31 2006-10-13 Oral dosage combination pharmaceutical packaging

Publications (2)

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WO2002096347A2 true WO2002096347A2 (fr) 2002-12-05
WO2002096347A3 WO2002096347A3 (fr) 2003-03-27

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Country Status (8)

Country Link
EP (1) EP1408907A4 (fr)
JP (1) JP2005514966A (fr)
AU (1) AU2002303840A1 (fr)
BR (1) BRPI0209720A2 (fr)
CA (3) CA2614902A1 (fr)
NZ (1) NZ529696A (fr)
WO (1) WO2002096347A2 (fr)
ZA (1) ZA200402466B (fr)

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WO2004010978A1 (fr) 2002-07-25 2004-02-05 Glaxo Group Limited Forme posologique pharmaceutique a multicomposants
WO2007047371A2 (fr) * 2005-10-14 2007-04-26 Microdose Technologies, Inc. Conditionnement pharmaceutique d'une combinaison posologique orale
US7404968B2 (en) 1999-08-18 2008-07-29 Microdose Technologies, Inc. Metering and packaging of controlled release medication
US7670612B2 (en) 2002-04-10 2010-03-02 Innercap Technologies, Inc. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
US20100260669A1 (en) * 2004-05-13 2010-10-14 Anthony Joonkyoo Yun Treatment of Seasonal Conditions Through Modulation of the Autonomic Nervous System
US9974909B2 (en) 2010-01-05 2018-05-22 Microdose Therapeutx, Inc. Inhalation device and method
US11229378B2 (en) 2011-07-11 2022-01-25 Otsuka Pharmaceutical Co., Ltd. Communication system with enhanced partial power source and method of manufacturing same
US11529071B2 (en) 2016-10-26 2022-12-20 Otsuka Pharmaceutical Co., Ltd. Methods for manufacturing capsules with ingestible event markers

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US8912908B2 (en) 2005-04-28 2014-12-16 Proteus Digital Health, Inc. Communication system with remote activation
EP3827747A1 (fr) 2005-04-28 2021-06-02 Otsuka Pharmaceutical Co., Ltd. Système pharma-informatique
US9270025B2 (en) 2007-03-09 2016-02-23 Proteus Digital Health, Inc. In-body device having deployable antenna
US8439033B2 (en) 2007-10-09 2013-05-14 Microdose Therapeutx, Inc. Inhalation device
AU2009281876B2 (en) 2008-08-13 2014-05-22 Proteus Digital Health, Inc. Ingestible circuitry
CN102458236B (zh) 2009-04-28 2016-01-27 普罗秋斯数字健康公司 高可靠性的可摄入事件标记器及其使用方法
BR112012025650A2 (pt) 2010-04-07 2020-08-18 Proteus Digital Health, Inc. dispositivo ingerível miniatura
JP2014504902A (ja) * 2010-11-22 2014-02-27 プロテウス デジタル ヘルス， インコーポレイテッド 医薬品を有する摂取可能なデバイス
US9756874B2 (en) 2011-07-11 2017-09-12 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
WO2015112603A1 (fr) 2014-01-21 2015-07-30 Proteus Digital Health, Inc. Produit ingérable pouvant être mâché et système de communication associé
US9271897B2 (en) 2012-07-23 2016-03-01 Proteus Digital Health, Inc. Techniques for manufacturing ingestible event markers comprising an ingestible component
SG11201503027SA (en) 2012-10-18 2015-05-28 Proteus Digital Health Inc Apparatus, system, and method to adaptively optimize power dissipation and broadcast power in a power source for a communication device
JP2016508529A (ja) 2013-01-29 2016-03-22 プロテウス デジタル ヘルス， インコーポレイテッド 高度に膨張可能なポリマーフィルムおよびこれを含む組成物
JP5941240B2 (ja) 2013-03-15 2016-06-29 プロテウス デジタル ヘルス， インコーポレイテッド 金属検出器装置、システム、および方法
US9796576B2 (en) 2013-08-30 2017-10-24 Proteus Digital Health, Inc. Container with electronically controlled interlock
US10084880B2 (en) 2013-11-04 2018-09-25 Proteus Digital Health, Inc. Social media networking based on physiologic information
US11051543B2 (en) 2015-07-21 2021-07-06 Otsuka Pharmaceutical Co. Ltd. Alginate on adhesive bilayer laminate film
KR102051875B1 (ko) 2016-07-22 2019-12-04 프로테우스 디지털 헬스, 인코포레이티드 섭취 가능한 이벤트 마커의 전자기 감지 및 검출

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7404968B2 (en) 1999-08-18 2008-07-29 Microdose Technologies, Inc. Metering and packaging of controlled release medication
US7670612B2 (en) 2002-04-10 2010-03-02 Innercap Technologies, Inc. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
WO2004010978A1 (fr) 2002-07-25 2004-02-05 Glaxo Group Limited Forme posologique pharmaceutique a multicomposants
EP1528916B1 (fr) * 2002-07-25 2012-12-26 Capsugel Belgium NV Forme posologique pharmaceutique a multicomposants
US20100260669A1 (en) * 2004-05-13 2010-10-14 Anthony Joonkyoo Yun Treatment of Seasonal Conditions Through Modulation of the Autonomic Nervous System
WO2007047371A2 (fr) * 2005-10-14 2007-04-26 Microdose Technologies, Inc. Conditionnement pharmaceutique d'une combinaison posologique orale
WO2007047371A3 (fr) * 2005-10-14 2007-12-06 Microdose Technologies Inc Conditionnement pharmaceutique d'une combinaison posologique orale
US9974909B2 (en) 2010-01-05 2018-05-22 Microdose Therapeutx, Inc. Inhalation device and method
US10434267B2 (en) 2010-01-05 2019-10-08 Microdose Therapeutx, Inc. Inhalation device and method
US11229378B2 (en) 2011-07-11 2022-01-25 Otsuka Pharmaceutical Co., Ltd. Communication system with enhanced partial power source and method of manufacturing same
US11529071B2 (en) 2016-10-26 2022-12-20 Otsuka Pharmaceutical Co., Ltd. Methods for manufacturing capsules with ingestible event markers
US11793419B2 (en) 2016-10-26 2023-10-24 Otsuka Pharmaceutical Co., Ltd. Methods for manufacturing capsules with ingestible event markers

Also Published As

Publication number Publication date
AU2002303840A1 (en) 2002-12-09
NZ529696A (en) 2008-07-31
EP1408907A2 (fr) 2004-04-21
CA2614902A1 (fr) 2002-12-05
CA2448997A1 (fr) 2002-12-05
EP1408907A4 (fr) 2010-02-24
CA2614899A1 (fr) 2002-12-05
WO2002096347A3 (fr) 2003-03-27
ZA200402466B (en) 2006-07-26
JP2005514966A (ja) 2005-05-26
BRPI0209720A2 (pt) 2017-06-13

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