WO2006027266A1 - Comprimes a liberation gastro-intestinale du principe actif regulee en fonction du temps et du site - Google Patents

Comprimes a liberation gastro-intestinale du principe actif regulee en fonction du temps et du site Download PDF

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Publication number
WO2006027266A1
WO2006027266A1 PCT/EP2005/009726 EP2005009726W WO2006027266A1 WO 2006027266 A1 WO2006027266 A1 WO 2006027266A1 EP 2005009726 W EP2005009726 W EP 2005009726W WO 2006027266 A1 WO2006027266 A1 WO 2006027266A1
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WO
WIPO (PCT)
Prior art keywords
tablet
active ingredient
release
coating
prednisone
Prior art date
Application number
PCT/EP2005/009726
Other languages
English (en)
Inventor
Achim Schäffler
Original Assignee
Nitec Pharma Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE102004043863A external-priority patent/DE102004043863A1/de
Priority to MX2007002898A priority Critical patent/MX2007002898A/es
Priority to CA2579732A priority patent/CA2579732C/fr
Priority to BRPI0515345-0A priority patent/BRPI0515345A/pt
Priority to JP2007530659A priority patent/JP5134955B2/ja
Priority to KR1020077007634A priority patent/KR101363563B1/ko
Application filed by Nitec Pharma Ag filed Critical Nitec Pharma Ag
Priority to RU2007113168/15A priority patent/RU2435568C2/ru
Priority to CN2005800342686A priority patent/CN101035517B/zh
Priority to AU2005281797A priority patent/AU2005281797B2/en
Priority to EP05778455A priority patent/EP1807058A1/fr
Publication of WO2006027266A1 publication Critical patent/WO2006027266A1/fr
Priority to IL181680A priority patent/IL181680A/en
Priority to NO20071806A priority patent/NO20071806L/no
Priority to HK08101360.2A priority patent/HK1110509A1/xx

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats

Definitions

  • the present invention describes a pharmaceutical dosage form with site- o and time-controlled gastrointestinal release of active ingredient.
  • o Coated tablets have been described frequently, especially with the aim of delayed release of active ingredient, in which case an initial phase without release of the active ingredient (lag phase) is followed by the active ingredient leaving the tablet.
  • lag phase an initial phase without release of the active ingredient
  • WO 02/072033 discloses that the amount of coating material applied determines the lag phase.
  • the coating consists of a swellable material through the pores of which the active ingredient is then released. In this case, the diffusion through the swellable matrix of the coating becomes the release-determining factor.
  • release through the pores often does not take place spontaneously after the desired lag phase; on the contrary, there is onset of more or less rapid release.
  • the influences of food on swelling and eroding coatings are very important.
  • US 5 464 633 describes a tablet for delayed release of an active substance.
  • the tablet consists of a core which comprises the active ingredient and a polymer, and of a polymer-containing coating.
  • EP 0 463 877 describes a pharmaceutical preparation for controlled release of an active ingredient, which comprises a core and a coating layer, where the coating layer comprises a water-repellent salt and a copolymer.
  • a pharmaceutical preparation consisting of a core and of a multilayer coating for release of the active ingredient in the lower part of the gastrointestinal tract (colon) is known for example from EP 0 366 621. Film coatings which are degraded only in the colon by bacteria present therein are, however, unsuitable for releasing the active ingredient in upper sections of the intestine.
  • WO 01/80824 (Eurand) describes a pharmaceutical form having a core which, besides the active ingredient, also comprises a hydrophilic, swelling polymer, and having a surrounding coating consisting of at least one water- insoluble polymer.
  • EP 0 939 623 B1 and US 6 183 780 describe an oral dosage form with delayed release consisting of a core and of a coating, where the coating consists of one or more polymers, of a water-soluble plasticizer and of a substance which increases the brittleness of the coating.
  • the disadvantages of this form are, in particular, that influences of food are possible.
  • EP 1 067 910 (Bar-Shalom) describes an oral dosage form having at least one erodable surface.
  • EP 1 275 381 (Yamanouchi) likewise describes a core tablet with coating, the latter consisting of a swellable hydrophilic polymer. The effects of food in these cases are also great.
  • dilitiazem in the form of biologically inert pellets with a plurality of layers is described in US 6 620439 (Elite Labs). In this case, the active ingredient is released some hours after intake to treat arterial occlusions in the morning.
  • US Patent 5 792476 describes a pharmaceutical composition for peroral administration for rheumatoid arthritis, which comprises a glucocorticoid as active ingredient and which leads to release in the small intestine.
  • the composition is a granulate which is laminated with an inner layer which is resistant to a pH of 6.8, and with an outer layer which is resistant to a pH of 1.0.
  • US Patent 6488 960 describes a pharmaceutical dosage form for controlled release of corticoids, reference being made to the formulations described in US Patent 5 792 476.
  • WO 01/08421 describes a tablet having a core which is coated by at least two layers, one of which completely encloses the other.
  • the coating layers can be produced by spray coating and/or pressing.
  • WO 01/68056 discloses a pharmaceutical preparation having a release profile with a time delay, comprising a core and at least one hydrophilic or lipophilic coating surrounding the core, where the coating is slowly swollen, dissolved, eroded or changed in its structure in another way through the water present in the release medium, so that the core or parts of the core become accessible to the release medium.
  • the coating may be formed for example as pressed coating.
  • WO 02/072034 discloses a pharmaceutical dosage form for delayed release, 5 having a core which comprises as active ingredient a glucocorticoid and a material which brings about delayed release and includes at least one natural or synthetic gum.
  • WO 2004/093843 discloses a tablet with a specific core geometry to release the active ingredient in a specific delayed release manner.
  • the problem underlying the present invention was to provide a pharmaceutical dosage form with site- and time-controlled release of active ingredient, which makes reproducible in vivo release possible in the particular desired sections of the intestine irrespective of the patient's food intake. It was further intended also for the active ingredient release process o itself to be controllable as optimally as possible depending on the relevant medical indication.
  • a pharmaceutical dosage form with site- and time- controlled gastrointestinal release of active ingredient comprising 5 (a) a core having at least one active ingredient and having at least one swellable adjuvant such that the active ingredient is rapidly released from the dosage form when the core is contacted with gastrointestinal fluids; and
  • the present invention is directed to a method for the treatment of a patient in need of therapy with an active ingredient in a site- and time-controlled dosage form, said method comprising administering to said patient the pharmaceutical dosage form described herein.
  • the present invention is directed to a kit comprising at least one unit dosage of a dosage form described herein with site- and time- controlled gastrointestinal release of active ingredient.
  • the kit optionally contains instructional material for use of the unit dosage form.
  • the present invention relates to a method of producing a tablet which releases a corticosteroid active ingredient at a predetermined variable location in the Gl tract, said method comprising: determining the location in the Gl tract at which it is desired to deliver the corticosteroid; s forming a coated tablet having a core comprising the corticosteroid and a swellable adjuvant, and an inert outer coating; and compressing the coating of said tablet at a pressure chosen to result in the release of the corticosteroid at said predetermined position.
  • the present invention relates to a coated tablet having a core of a corticosteroid active ingredient and a coating, capable of releasing the corticosteroid at a predetermined variable location the Gl tract, the coating being compressed to a degree which results in the release of the corticosteroid at said predetermined location. 5
  • the present invention relates to a method of producing a tablet which releases a corticosteroid active ingredient at a predetermined variable location in the Gl tract, said method comprising: determining the location in the Gl tract at which it is desired to o deliver the corticosteroid; forming a coated tablet having a core comprising the corticosteroid and a swellable adjuvant, and an inert outer coating; compressing the coating of said tablet at a pressure chosen to result in the release of the corticosteroid at said predetermined position; and testing the in vitro release characteristics in a dissolution apparatus in order to confirm release of the active ingredient at a specific lag 5 time.
  • the present invention relates to a method for the treatment of a local bowel disorder in the lower sections of the intestine, which comprises administering to a patient in need thereof a coated tablet o having a core of a corticosteroid active ingredient and a coating, the coating being compressed to a degree that results in the release of the corticosteroid in the lower sections of the intestine.
  • Figure 1 shows the in vitro release of the novel tablet containing 5 mg of prednisone ("Prednisone TR”) with a lag phase of about 4 h (500 ml of water, paddle, USP)
  • Prednisone TR prednisone
  • lag phase 500 ml of water, paddle, USP
  • FIG. 2 shows the in vivo plasma level of prednisone after administration of
  • Figure 3 shows the in vivo plasma level of prednisolone after administration of o
  • Figure 4 shows the in vitro release of a "Prednisone TR" tablet containing 5 mg of prednisone with a lag phase of 6 h (500 ml of water, paddle, USP)
  • Figure 5 shows an in vivo plasma level profile after administration of prednisone tablets.
  • a first preferred embodiment therefore provides a pharmaceutical dosage form with a release of active ingredient in the upper sections of the intestine within a period of 2-6 hours.
  • a second preferred embodiment provides a pharmaceutical dosage form with a site- and time-controlled release of active ingredient in the lower sections of the intestine within a period of 6-10 hours after intake.
  • TR timed-release
  • Prednisone TR model substance
  • other active ingredients e.g. corticosteroids
  • novel "TR" dosage form described herein differs from prior art preparations. It surprisingly shows with a specific geometry of the press coating with inert adjuvants and accurately adjusted production process parameters a reproducible lag phase and subsequent rapid release (drug release phase) of the active ingredient or the active ingredient combination.
  • the inert coating initially prevents release of the active ingredient or the active ingredient combination over an exactly defined period, so that no absorption can occur.
  • the water present in the gastrointestinal tract penetrates slowly in through the coating and, after a time which is previously fixed by the pressure for compression, reaches the core.
  • the coating ingredients show neither swelling nor erosion of parts of the coating.
  • the core is reached, the water penetrating in is very rapidly absorbed by the hydrophilic ingredients of the core, so that the volume of the core increases greatly and, as a consequence thereof, the coating completely bursts open, and the active ingredient and the active ingredient combination respectively 5 is released very rapidly.
  • a particularly advantageous embodiment of this press-coated "TR" tablet is achieved when a previously compressed core tablet is subsequently compressed with a multilayer tablet press to a press-coated tablet.
  • the tablet coating typically consists of the following materials in order to achieve a delayed release profile: polymer or copolymer of acrylic acid, methacrylic acid etc. (e.g. Eudragits or Carbopol), s - cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, ethylcellulose, cellulose acetate, - polyvinyl alcohol, polyethylene glycol, o - salts of higher fatty acids, esters of monohydric or polyhydric alcohols with short-, medium- or long-chain, saturated or unsaturated fatty acids.
  • stearic acid triglycerides e.g. Dynersan
  • glycerol behenate e.g. Compritol
  • further adjuvants should also be added to these materials so that the tablet coating can be compressed.
  • fillers such as lactose, various starches, celluloses and calcium hydrogen phosphate.
  • the glidant used is normally magnesium stearate, and in exceptional cases also talc and glycerol behenate.
  • a plasticizer is often also added to the coating o material, preferably from the group of polyethylene glycol, dibutyl phthalate, Diethyl citrate or triacetin.
  • the tablet core In order to achieve an optimal release profile, the tablet core must also fulfil certain tasks and exhibit certain properties. Thus, after the lag phase has elapsed, a rapid release profile is achieved if typical disintegrants are added to the inner core, which are derived for example from the group of the following substances: cellulose derivatives, starch derivatives, crosslinked
  • the tablet core typically consists additionally of matrix or filling ingredients (e.g. lactose, cellulose derivatives, calcium hydrogen phosphate or other substances known from the literature) and o lubricant or glidant (usually magnesium stearate, in exceptional cases also talc and glycerol behenate).
  • matrix or filling ingredients e.g. lactose, cellulose derivatives, calcium hydrogen phosphate or other substances known from the literature
  • o lubricant or glidant usually magnesium stearate, in exceptional cases also talc and glycerol behenate.
  • the size of the core tablet preferably should not exceed 6 mm (preferably 5 mm) in diameter, because otherwise the press-coated tablet becomes too s large for convenient ingestion.
  • the dosages of the active ingredients are in the range from 0.1 to 50 mg, very particularly between 1 and 20 mg.
  • the in vitro release profile of the "TR" dosage form according to the o invention is preferably such that less than 5% of the active ingredient is released during the lag phase. After the release phase has started, preferably ⁇ 80%, particularly preferably ⁇ 90%, of the active ingredient is released within one hour.
  • the in vitro release is preferably determined using the USP paddle dissolution model in water. 5
  • the employed active ingredients are preferably derived from the group of glucocorticoids and all show comparable physicochemical properties.
  • Such include cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fludrocortisone, o fluocortolone, cloprednole, deflazacort, triamcinolone, and the corresponding salts and esters thereof.
  • prednisone prednisolone
  • methylprednisolone methylprednisolone
  • budesonide dexamethasone
  • fluocortolone fluocortolone
  • cloprednole cloprednole
  • deflazacort deflazacort
  • the coating preferably comprises:
  • the tablet coating preferably also consists of binders, e.g. polyvinylpyrrolidone (PVP), typically in concentrations of about o 4-12%, specifically about 7-10%, and glidants such as magnesium stearate, in concentrations of about 0.1-2%, in the specific case of about 0.5-1.5%.
  • binders e.g. polyvinylpyrrolidone (PVP)
  • PVP polyvinylpyrrolidone
  • glidants such as magnesium stearate
  • Colloidal silicon dioxide can for example be used as flow regulator, normally in concentrations of about 0.25-1%.
  • a colorant can be added to 5 the tablet coating, preferably an iron oxide pigment in concentrations of about 0.001-1%.
  • the core tablet preferably comprises:
  • an active ingredient or an active ingredient combination from the o group of glucocorticoids preferably prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fludrocortisone, fluocortolone, cloprednole, deflazacort, and triamcinolone, and the corresponding salts and esters thereof.
  • the dosages of the active ingredients are in the region of about 0.1-50 mg, very especially between about 1 and 20 mg;
  • the core tablet preferably comprises a filler such as, for example, lactose, starch derivatives or cellulose derivatives. Lactose
  • the filler is typically present in concentrations of about 50-90%, specifically of about 60-80%.
  • a disintegrant is additionally present and is typically crosslinked PVP or sodium carboxymethylcellulose, typically in concentrations of about 10-20%.
  • a binder e.g. PVP
  • a lubricant such as magnesium stearate
  • Colloidal silicon dioxide is normally used as flow regulator, normally in concentrations of about 0.25-1%. It is s additionally possible, for visually distinguishing the core from the coating, to add a colorant, preferably an iron oxide pigment in concentrations of about 0.01-1%.
  • the pharmaceutical dosage form according to the invention is preferably o distinguished by the in vitro release and the in vivo release (on oral intake) of the active ingredient not differing by more than about one hour, particularly preferably not more than about 30 minutes. It is further preferred for the in vitro release to be substantially independent of the pH of the release medium or/and of additions in the release medium which simulate high-fat 5 and low-fat food, i.e. to vary by preferably not more than about ⁇ 20%. It is further preferred for the in vivo release to be substantially independent of food intake, with the time to reach the maximum plasma concentration (W) varying by not more than about ⁇ 20%.
  • the plasma level reached on in vivo release is preferably independent of the gastrointestinal pH and of food o intake.
  • a maximum plasma level (C max ) reached or/and an area reached under the plasma curve (AUC), as for a rapid- release dosage form are achieved. It is particularly preferred for a C max of at least about 70%, preferably of at least about 80%, of the C max of a rapid- release dosage form, and an AUC which does not vary by more than about 5 ⁇ 25%, to be achieved.
  • C max maximum plasma level
  • AUC area reached under the plasma curve
  • the latter embodiment of the invention is thus particularly suitable for the treatment of local inflammatory bowel disease such as Crohn's disease or ulcerative o colitis, where a systemic effect is not desired.
  • the first-mentioned embodiment, with which absorption takes place in the upper sections of the intestine, is by contrast suitable in particular for the treatment of inflammatory diseases of the joints, associated with pain, such as, for example, rheumatoid arthritis, allergies and nocturnal severe asthmatic s attacks, where a systemic effect is desired.
  • the process for producing the tablet takes place under usual conditions of the pharmaceutical industry.
  • standard technologies are used in the production of the core tablet, such as weighing, sieving, mixing, aqueous 0 granulation in a high-speed mixer, fluidized-bed drying of the granules, mixing and compression.
  • Comparable methods are employed to produce the coating, namely weighing, sieving, mixing, aqueous granulation in a high ⁇ speed mixer, fluidized-bed drying of the granules, mixing and compression to press-coated tablets. 5
  • the geometry of the press-coated tablet has, in addition to the composition, a very great importance. It can be achieved only using a tablet machine for producing press-coated tablets; spray coatings are unsuitable.
  • the ratio of the thickness of the press-coating on the sides of the tablets to the upper side or lower side is preferably about 2.2-2.6 mm (for the side edges):about 1.2-1.6 mm for the upper side of the tablet and about 1.0-1.4 mm (for the lower side of the tablet), particularly preferably about 2.35-2.45 mm:about 1.35-1.45 mm (upper side of the tablet) and about 1.15-1.25 mm (lower side). This geometry results in the tablet remaining sufficiently small to avoid problems with swallowing.
  • the timed-release ("TR") of active ingredient can be controlled by setting the compressive forces during the application of the coating to the tablet core.
  • the compressive forces used for release in the upper sections of the intestine are preferably up to about 600 kg, particularly preferably about 250-600 kg, whereas the compressive forces used for release of the active ingredient in the lower sections of the intestine are preferably above about 600 kg, particularly preferably about 600-800 kg.
  • the pharmaceutical dosage form is particularly preferably in the form of a tablet, but it is also possible to produce the dosage form as capsule.
  • Core tablet consisting of:
  • Coating consisting of:
  • Corticosteroid from the group of substances including cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fludrocortisone, fluocortolone, cloprednole, deflazacort, triamcinolone and the corresponding salts and esters thereof.
  • composition of the tablets ensures that the influences of food, pH and motility of the gastrointestinal tract have no influence, and the active ingredient escapes very rapidly from the tablet after completion of the lag phase.
  • Example 2 Production process and in vitro release
  • the lag phase of active ingredient release is determined exclusively by the variably adjustable compressive force.
  • Prednisone was used as active ingredient in this case.
  • the lag phase is determined by means of the USP paddle dissolution model with 100 rpm in water at a temperature of 37 0 C.
  • Figure 1 shows typical release behaviour (batch G360).
  • Table 2 Lag phases and drug release phases [h] of the novel "Prednisone TR" tablet with the active ingredient prednisone in different release media, in vitro dissolution release, 500 ml, paddle, USP
  • testing of the in-vitro characteristics of each batch in a dissolution apparatus is preferred to confirm release of the active at a specific lag-time. This can easily be monitored by a color change of the dissolution medium. The color is released from the colored core tablets.
  • the aim of the kinetics study was to achieve comparable plasma level profiles in relation to C max and AUC for the novel tablet "Prednisone TR" "semi-fasted” compared with “fed state” in relation to a standard “Prednisone IR” tablet (with rapid release of active ingredient).
  • the novel tablet described herein with the active ingredient prednisone showed that comparable plasma level profiles can be achieved.
  • the plasma samples were taken at intervals of 0.5 and later of 1 hour.
  • tmax and tag values are means (range).
  • the other values are geometric means (90% Cl) obtained from ANOVA.
  • prednisolone a comparability between U ma x and AUC of the novel "Prednisone TR" tablet "semi-fasted” with "fed state".
  • the plasma level profile of the metabolite prednisolone is therefore also independent of food intake.
  • the plasma samples for determining prednisolone were taken at intervals of 0.5 and later of 1 hour.
  • t ma x and ti a g values are means (range).
  • the other values are geometric means (90% Cl) obtained from ANOVA.
  • Typical achieved C max values for 5 mg prednisone tablets after ingestion will be in the range of from about 15 to about 25 ng/ml, and the AUC of prednisone is from about 75 to about 150 h*ng/mL
  • the achieved C ma ⁇ values for the prednisolone metabolite will be in the range of from about 100 to about 160 ng/ml, and the AUC of prednisolone is from about 500 to about 700 h*ng/ml_.
  • Table 5 Coefficients of variation for C max ⁇ tmax, AUC for prednisone plasma levels after administration of a standard tablet
  • Prednisone IR of the novel tablet "Prednisone TR” "semi-fasted” and in "fed state"
  • Typical achieved C ma ⁇ values for such 5 mg prednisone tablets after o ingestion will be in the range of less than 15 ng/ml, and the AUC of prednisone is less than 75 h*ng/ml_.
  • the achieved C ma ⁇ values for the prednisolone metabolite will be in the range of less than 100 ng/ml, and the AUC of prednisolone is less than 500 h*ng/mL
  • the composition of the tablet, its specific geometry and a compressive force which can be adjusted variably make it possible for the coating of the tablet to release the active ingredient very rapidly from the core tablet after an exactly fixed time. This is very o advantageous because the site of release can also be fixed accurately via this precise presetting.
  • TR timed-release
  • the coating of the novel timed- release (“TR") tablet exposes the active ingredient-containing core after less than 6 hours, and the active ingredient can then be very rapidly dissolved and absorbed.
  • TR timed- release
  • One application thereof is, for example, the administration of corticoids for the treatment of inflammatory disorders to the joints, where pro ⁇ inflammatory cytokines are released in the early hours of the morning and are thought to be responsible for the pain in the morning and the stiffness of fingers in the morning.
  • the tablets of the present invention may be ingested once daily at bed-time, for example between about 8 pm and about 12 am, and more preferably between about 9 pm and about 11 pm.
  • the present invention also provides a method for producing a tablet that releases a corticosteroid active ingredient at a predetermined variable location in the Gl tract, said method comprising: determining the location in the Gl tract at which it is desired to deliver the corticosteroid; forming a coated tablet having a core comprising the corticosteroid and a swellable adjuvant, and an inert outer coating; compressing the coating of said tablet at a pressure chosen to result in the release of the corticosteroid at said predetermined position; and testing the in vitro release characteristics in a dissolution apparatus in order to confirm release of the active ingredient at a specific lag time. The in vitro release characteristics can then be correlated to the suitable in vivo release lag time.
  • the tablet core comprises a coloring material
  • the in vitro release of the active ingredient is determined by a color change.
  • the dissolution apparatus may be any standard apparatus in the industry, and preferably is in accordance with USP XXVIII.

Abstract

L'invention concerne une forme posologique pharmaceutique à libération gastro-intestinale du principe actif régulée en fonction du temps et du site.
PCT/EP2005/009726 2004-09-10 2005-09-09 Comprimes a liberation gastro-intestinale du principe actif regulee en fonction du temps et du site WO2006027266A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
EP05778455A EP1807058A1 (fr) 2004-09-10 2005-09-09 Comprimes a liberation gastro-intestinale du principe actif regulee en fonction du temps et du site
CN2005800342686A CN101035517B (zh) 2004-09-10 2005-09-09 具有活性成分位点和时间-可控胃肠释放的片剂
BRPI0515345-0A BRPI0515345A (pt) 2004-09-10 2005-09-09 comprimidos de liberação gastrointestinal com local e hora controlados de ingrediente ativo
JP2007530659A JP5134955B2 (ja) 2004-09-10 2005-09-09 活性成分の部位時間制御胃腸放出作用を有する錠剤
KR1020077007634A KR101363563B1 (ko) 2004-09-10 2005-09-09 활성성분의 부위 및 시간 제어적 위장관 방출 정제
MX2007002898A MX2007002898A (es) 2004-09-10 2005-09-09 Tableta con liberacion gastrointestinal controlada en sitio y tiempo del ingrediente activo.
RU2007113168/15A RU2435568C2 (ru) 2004-09-10 2005-09-09 Таблетки с высвобождением активного ингредиента, происходящим в определенном месте и в определенное время
CA2579732A CA2579732C (fr) 2004-09-10 2005-09-09 Comprimes a liberation gastro-intestinale du principe actif regulee en fonction du temps et du site
AU2005281797A AU2005281797B2 (en) 2004-09-10 2005-09-09 Tablets with site and time-controlled gastrointestinal release of active ingredient
IL181680A IL181680A (en) 2004-09-10 2007-03-01 Tablets with gastrointestinal release of active and controlled substance
NO20071806A NO20071806L (no) 2004-09-10 2007-04-03 Tabletter med steds- og tidsregulert gastrointestinal frigivelse av aktiv bestanddel.
HK08101360.2A HK1110509A1 (en) 2004-09-10 2008-02-05 Tablets with site time-controlled gastrointestinal release of active ingredient

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE102004043863A DE102004043863A1 (de) 2004-09-10 2004-09-10 Tabletten mit orts- und zeitgesteuerter Wirkstofffreisetzung im Gastrointestinum
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US11/216,469 US20060057200A1 (en) 2004-09-10 2005-09-01 Tablets with site- and time-controlled gastrointestinal release of active ingredient
US11/216,469 2005-09-01

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WO2010084188A1 (fr) 2009-01-26 2010-07-29 Nitec Pharma Ag Traitement de l'asthme par glucocorticoïde à libération retardée
US8822438B2 (en) 2006-08-25 2014-09-02 Janssen Oncology, Inc. Methods and compositions for treating cancer
US10799489B2 (en) 2012-09-26 2020-10-13 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US11160796B2 (en) 2017-10-16 2021-11-02 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer

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JOP20200097A1 (ar) * 2013-01-15 2017-06-16 Aragon Pharmaceuticals Inc معدل مستقبل أندروجين واستخداماته
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US8920838B2 (en) 2006-08-03 2014-12-30 Horizon Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
WO2008015018A1 (fr) 2006-08-03 2008-02-07 Nitec Pharma Ag Traitement glucocorticoïdique à libération retardée de maladie rhumatoïde
US9504699B2 (en) 2006-08-03 2016-11-29 Hznp Limited Delayed-release glucocorticoid treatment of rheumatoid disease
EA015304B1 (ru) * 2006-08-03 2011-06-30 Нитек Фарма Аг Лечение ревматоидного заболевания глюкокортикоидами с отсроченным высвобождением
CN101466385B (zh) * 2006-08-03 2014-01-08 耐特克药物股份公司 类风湿病的延迟释放糖皮质激素治疗
JP2009545546A (ja) * 2006-08-03 2009-12-24 ニテック ファーマ アクチエンゲゼルシャフト リウマチ性疾患の遅延放出型グルココルチコイド治療
US8822438B2 (en) 2006-08-25 2014-09-02 Janssen Oncology, Inc. Methods and compositions for treating cancer
US10702540B2 (en) 2006-08-25 2020-07-07 Janssen Oncology, Inc. Methods and compositions for treating cancer
WO2010084188A1 (fr) 2009-01-26 2010-07-29 Nitec Pharma Ag Traitement de l'asthme par glucocorticoïde à libération retardée
US10849888B2 (en) 2012-09-26 2020-12-01 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US10799489B2 (en) 2012-09-26 2020-10-13 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
USRE49353E1 (en) 2012-09-26 2023-01-03 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US11160796B2 (en) 2017-10-16 2021-11-02 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer
US11491149B2 (en) 2017-10-16 2022-11-08 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer

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KR101363563B1 (ko) 2014-02-14
KR20070098989A (ko) 2007-10-08
CA2579732A1 (fr) 2006-03-16
JP5134955B2 (ja) 2013-01-30
CA2579732C (fr) 2014-08-12
JP2008512419A (ja) 2008-04-24
EP1807058A1 (fr) 2007-07-18
AU2005281797A1 (en) 2006-03-16
NO20071806L (no) 2007-06-08

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