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WO2016114726A1 - Time-controlled prednisone delayed release tablet - Google Patents

Time-controlled prednisone delayed release tablet Download PDF

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Publication number
WO2016114726A1
WO2016114726A1 PCT/TR2015/000007 TR2015000007W WO2016114726A1 WO 2016114726 A1 WO2016114726 A1 WO 2016114726A1 TR 2015000007 W TR2015000007 W TR 2015000007W WO 2016114726 A1 WO2016114726 A1 WO 2016114726A1
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WO
WIPO (PCT)
Prior art keywords
coating
core
tablet
axis
prednisone
Prior art date
Application number
PCT/TR2015/000007
Other languages
French (fr)
Inventor
Hatice Öncel
Yilmaz Çapan
Onur PINARBAŞLI
Sibel AKANSEL
Original Assignee
Ilko Ilaç Sanayi Ve Ticaret Anonim Şirketi
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Application filed by Ilko Ilaç Sanayi Ve Ticaret Anonim Şirketi filed Critical Ilko Ilaç Sanayi Ve Ticaret Anonim Şirketi
Priority to PCT/TR2015/000007 priority Critical patent/WO2016114726A1/en
Publication of WO2016114726A1 publication Critical patent/WO2016114726A1/en

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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

  • the present invention is related to time-controlled delayed release tablet comprising prednisone whose release active ingredient from core after a lag time wherein said, time-controlled delayed release tablets are press-coated tablets comprising a core and a coating covering said core.
  • Prednisone is an active substance used as anti-inflammatory or immunosupresant and prodrug of prednisolone.
  • the chemical name for prednisone is 1 ,4-Pregnadiene- 17alpha,21-diol-3,11,20-trione. It is white, odourless and very slightly soluble in water and is available.
  • the structural formula is represented below:
  • Prednisone is generally recommended in the treatment of immunoinflamatory disorders like, ulcerative colitis, osteoarthritis, psoriasis, rheumatoid arthritis, Crohn's disease, ankylosing spondylit, fibromyalgia and autoimmune diseases such as asthma, type I diabetes, multiple sclerosis, systemic lupus erythematosus, scleroderma, atopic dermatitis and acquired hemolytic anemia.
  • immunoinflamatory disorders like, ulcerative colitis, osteoarthritis, psoriasis, rheumatoid arthritis, Crohn's disease, ankylosing spondylit, fibromyalgia and autoimmune diseases such as asthma, type I diabetes, multiple sclerosis, systemic lupus erythematosus, scleroderma, atopic dermatitis and acquired hemolytic anemia.
  • Time-controlled release formulations are known in the art that are able to deliver drug substances with a defined release rate after a lag time during which no drug substance is released.
  • the coating acts as a barrier to the ingress of aqueous media into an active- agent-containing core and thereby creating a lag time during which no drug substance is released.
  • the coating acts as a medium through which drug is released in a delayed or modified manner.
  • Time-controlled delayed release tablets allow treatment of diseases according to circadian rhythm. Especially if symptoms a disease become apparent at night, or in the early hours at morning, the time when a patient must take its medication in order to affect the best clinical outcome requires detailed consideration. For example, stiffnes and pain associated with rheumatoid arthritis and osteoarthritis occur in the early waking hours, which is believed to be as a result of the secretion of lnterleukin-6 (IL-6) in the early hours of the morning, e.g.
  • IL-6 lnterleukin-6
  • Time controlled delayed release formulations are known in the art that are able to deliver drug substances with a defined release after a lag time during which no drug substance is released.
  • Press-coated tablet is a type of these formulations.
  • Press-coated tablet consist of a core (fast disintegration or modified release) which is coated by compression with a solid barrier.
  • the barrier could contain polymeric material, diluents (as a release modifier).
  • Press- coated tablets could be modulated to provide different release patterns depending on the drug distribution and also with different type of controlling polymer used in core and coat. Based on this concept, the possibly obtainable modified drug releases are extended release and delayed release (time, pH and microbially control) for specific region of gastrointestinal tract.
  • a delayed release tablet consist of a drug core which is press-coated with different polymeric (pH independent) barriers. This delayed drug release is programmed for the treatment of disease that depends on circadian rhythms.
  • the lag time of drug release is controlled by the compression coating, which prevents drug release from the core until the polymer coat is completely eroded, swollen or ruptured. Drug release pattern depends on the compression-coat properties.
  • the press-coating could be performed with water soluble polymers (hydroxypropylcellulose, hydroxypropylmethylcellulose, pectin, polyethylene oxide), water insoluble polymer (ethylcellulose) and wax (Behenic acid).
  • Such a dosage form is disclosed in WO 02/072033.
  • This dosage form is characterized by a coating containing a natural or synthetic gum that gels in the presence of aqueousmedia.
  • the gellable coating act as a medium through which drug is released in a delayed or modified manner.
  • US 6,365,185 relates to tablets which are time-controlled to release active agent at different rates in different regions of the digestive tract in order to maintain a substantially constant concentration in the blood.
  • a modified release drug delivery system for once a day peroral use, consist of a solid core comprising an active agent together with hydrogel, with the solid core being coated with a semi-permeable, self destructing membrane which is optionally drilled to provide a release orifice, and then optionally further coated with the same or different active agent material.
  • the device delivers the active agent in a substantially constant effective dose for the duration of the transit through the stomach and small intestine, followed by accelerated release when reaching the large intestine.
  • EP1631251 B1 discloses the delayed release tablet core with a defined geometry.
  • the characteristic of the formulation is that, the coatingruptures upon immersion in an aqueous medium after a period of between about 2 to 6 hours to release the drug and the core being disposedwithin said coating such that the coating thickness about an axis (X- Y) is thicker than the coating about an axis (AB)orthogonal to (X-Y), and wherein the thickness of the coating about the axis (X-Y), wherein the axis (A-B) is the axis of the direction of movement of the punch used in the press-coating of the tablet.
  • the inventors also assert that the thickness of the coating around or about the axis (A-B) is not critical for controlling the lag time.
  • EP1615626 (Jagotec AG) is related to Prednisone delayed release tablet formulation with colored core. This patents relates to the use' of a colouring agent or excipient in such tablets to determine whether the core is centrally located within the core, to check the integrity of the core, and to ensure that there is no contaminating core material on or near the surface of the coating. Description of the Invention:
  • EP1631251 B1 discloses the coating ruptures upon immersion in an aqueous medium after a period of between about 2 to 6 hours to release the drug and the core being disposed within said coating such that the coating thickness about an axis (X- Y) is thicker than the coating about an axis (A-B) orthogonal to (X-Y), and wherein the thickness of the coating about the axis (X-Y), wherein the axis (A-B) is the axis of the direction of movement of the punch used in the press-coating of the tablet.
  • the inventors also assert that the thickness of the coating around or about the axis (A-B) is not critical for controlling the lag time.
  • the core tablet size and also the coating material amount related to release of drug substance are critical controlling the lag time likewise the coating about the axis (X-Y). Because, the lag time depends on the ratio of the coating's and core tablet's surface areas. In addition, the coating's and core tablet's surface areas are related with coating and core tablet weight, respectively. In this aspect, the applicant developed formulations that the coating thickness about an axis (A-B) is thicker than or equal the coating about an axis (X-Y).
  • the thickness of the coating about the axis (A-B) is about 1.85 to about 2.125 mm.
  • the coating thickness either side of the core on the axis (A-B) may or may not be equal.
  • the coating on a first side of the core (A-core) may have a thickness of about 1.80 to 2.00 mm, more preferably 1.95 to 2.05 mm, whereason the other side of the core (B-core) the thickness may be about 1.8 to 1.90 mm, more preferably 1.85 to 1.90 mm.
  • the coating thickness about an axis (A-B) is 1.85mm- 2.125mm and the coating an axis (X-Y) is 1.6-1.9 mm, about 1.75 mm.
  • core tablet shape is round and flat
  • press-coated tablet shape is round and biconvex.
  • the diameter and thickness of core tablet is about 5.5 mm and about 2mm, respectively.
  • the diameter and thickness of press-coated tablet is about 9mm and about 5.85 mm, preferably 5.75-6.25mm respectively.
  • the core tablet size alters the coating material amount needed to targeted lag time.
  • the core tablet size should belarge enough to press and placed precisely in the center of the die. And it should be small enough to require less coating material needed to targeted lag time and also swallow offinal tablet.
  • the present invention also provides for a press-coated tablet having an in vitro dissolution profile which is a median lag time of about 4 hours (3.5 - 4.5 hours) and at least about % 90 of prednisone is released after 5 hours.
  • the present invention provides press-coated tablet comprising a core comprising prednisone and a coating around said core, wherein said core is released drug substance 2-6 hours, preferably 4 hours, after oral administration.
  • the present invention provides press-coated tablet comprising a core comprising prednisone and a coating around said core, wherein said prednisone from 4 to 17 % by weight oftotal core tablet.
  • the weight of the core tablet is 50-80mg, preferably about 60mg.
  • the present invention also provides for a press-coated tablet comprising a core comprising prednisone and a coating around said core, wherein said the amount of coating from 3 to 10 fold, preferably 5-7 fold, more preferably about 6 fold by weight of core tablet.
  • the amount of coating is 300-380mg, preferably 320-360mg, more preferably about 340mg.
  • the core tablet comprising prednisone and a one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, fillers, disintegrants, lubricants, glidants, colorants, or combination thereof.
  • the coating is water ' insoluble or substantially water insoluble, hydrophobic and may contain one or more of the excipients selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and derivatives thereof; fatty acids or their esters or salts; long chain fatty alcohols; polyoxyethylene alkyl ethers; polyoxyethylene stearates and like.
  • cellulose derivatives such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and derivatives thereof
  • fatty acids or their esters or salts long chain fatty alcohols
  • polyoxyethylene alkyl ethers polyoxyethylene stearates and like.
  • hydrophobic excipients for coatings may be selected from any waxy substance known for use as tablet excipients. Preferably they have a HLB value of less than 5, and more preferably about 2.
  • Suitable hydrophobic agents include waxy substances such as carnauba wax, parafin, microcrystalline wax, beeswax, cetyl ester wax and the like; or non-fatty hydrophobic substances such as calcium phosphate salts, e.g. dibasic calcium phosphate.
  • the coating contains a calcium phosphate salt, glyceryl behenate, and polyvinyl pyrollidone, or mixtures thereof, and one or more adjuvants, diluents, lubricants or fillers.
  • Cores are preferably formed according to wet granulation techniques generally known in the art. Prednisone and pharmaceutically acceptable excipients are sieved and blended. Water is then added to the blend and the mixture and the mixture is homogenized to form a granulate, which is then dried to obtain a granulate with requisite residual moisture. Preferably residual moisture content is from 0.8- to 3.0 %by weight. The granulate is then sized by passing it through screens of desired aperture. The obtained granules are lubricated and pressed into tablets.
  • Coating are preferably formed according to wet granulation techniques generally known in the art. Hydrophobic polymer and suitable excipients are mixed and granulated with water. Then granules are dried and sieved. The obtained granules are lubricated and with core tablets pressed into press-coated tablets.
  • the hardness of a press-coated tablet at least 60 Newtons, and more particularly 65 to 75 Newtons.
  • the delayed release prednisone tablets comprise 1 mg to 5mgprednisone.
  • Prednisone Delayed Release Tablet is prepared according to the unit formula below:
  • Prednisone, lactose, polyvinyl pyrrolidone and crospovidone is sieved through a 0.8 mm sieve and prepared for wet granulation by adding water.After the sieving and drying of wet granulates, they are mixed with magnesium stearate and compressed as tablets.
  • glyceryl behenate, polyvinyl pyrrolidone and dibasic calcium hydrogen phosphate is sieved through a 0.8 mm sieve and prepared for wet granulation by adding water. After the sieving and drying of wet granulates, they are mixed with magnesium stearate.
  • Dissolution Medium ' and Method: Water, App. II (Paddle) with sinker, 500 ml_, 100 rpm

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Abstract

The present invention is related to time-controlled delayed release tablet comprising prednisone whose release active ingredient from core after a lag time, and this lag time depends on core tablet size, coating material amount and thereof the ratio of coating material and core tablet surface area. Wherein said, time-controlled delayed release tablets are press-coated tablets comprising a core and a coating covering said core.

Description

TIME-CONTROLLED PREDNISONE DELAYED RELEASE TABLET
DESCRIPTION
Technical field:
The present invention is related to time-controlled delayed release tablet comprising prednisone whose release active ingredient from core after a lag time wherein said, time- controlled delayed release tablets are press-coated tablets comprising a core and a coating covering said core.
Prior Art:
Prednisone is an active substance used as anti-inflammatory or immunosupresant and prodrug of prednisolone. The chemical name for prednisone is 1 ,4-Pregnadiene- 17alpha,21-diol-3,11,20-trione. It is white, odourless and very slightly soluble in water and is available. The structural formula is represented below:
Figure imgf000002_0001
Prednisone is generally recommended in the treatment of immunoinflamatory disorders like, ulcerative colitis, osteoarthritis, psoriasis, rheumatoid arthritis, Crohn's disease, ankylosing spondylit, fibromyalgia and autoimmune diseases such as asthma, type I diabetes, multiple sclerosis, systemic lupus erythematosus, scleroderma, atopic dermatitis and acquired hemolytic anemia.
It is described in US 2897216. The pharmaceutical products comprising prednisone are present Deltacone, Lodotra, Prednicot, Sterapred, Rayos etc. in the market with the trade names. Through them Rayos and Lodotra are the time-controlled prednisone delayed release tablet which is developed by Horizon Pharma, which are marketed with trade names in United States of America and Europe, respectively.
Time-controlled release formulations are known in the art that are able to deliver drug substances with a defined release rate after a lag time during which no drug substance is released. The coating acts as a barrier to the ingress of aqueous media into an active- agent-containing core and thereby creating a lag time during which no drug substance is released.The coating acts as a medium through which drug is released in a delayed or modified manner. These formulations are completely independent of pH. In other words, release the active ingredient after a lag time regardless of the physiological pHenvironment in the gastrointestinal tract or by excipients that might alter the pH microclimate.
Time-controlled delayed release tablets allow treatment of diseases according to circadian rhythm. Especially if symptoms a disease become apparent at night, or in the early hours at morning, the time when a patient must take its medication in order to affect the best clinical outcome requires detailed consideration. For example, stiffnes and pain associated with rheumatoid arthritis and osteoarthritis occur in the early waking hours, which is believed to be as a result of the secretion of lnterleukin-6 (IL-6) in the early hours of the morning, e.g. around 2 am to 4 am.- Accordingly, there remains a need to provide dosage forms that can be taken at a convenient hour before bedtime that will release an effective dose of a drug substance only after a pre-determined lag time in order to synchronise peak plasma concentrations of drug with a particular circadian rhythm. Therefore these formulationsenhance patient's life quality and compliance of treatment.
Otherwise, if drug substance which have a narrow absorption window, or in the case of treat to local condition in the colon such as Crohn's disease, Ulcerative Colitis, IBS and IBD there is also a need to provide a dosage form that rapidly releases the drug substances after reaching the end of lag time, likewise time-controlled delayed release tablets.
Time controlled delayed release formulations are known in the art that are able to deliver drug substances with a defined release after a lag time during which no drug substance is released. Press-coated tablet is a type of these formulations. Press-coated tablet consist of a core (fast disintegration or modified release) which is coated by compression with a solid barrier. The barrier could contain polymeric material, diluents (as a release modifier). Press- coated tablets could be modulated to provide different release patterns depending on the drug distribution and also with different type of controlling polymer used in core and coat. Based on this concept, the possibly obtainable modified drug releases are extended release and delayed release (time, pH and microbially control) for specific region of gastrointestinal tract.
A delayed release tablet consist of a drug core which is press-coated with different polymeric (pH independent) barriers. This delayed drug release is programmed for the treatment of disease that depends on circadian rhythms. The lag time of drug release is controlled by the compression coating, which prevents drug release from the core until the polymer coat is completely eroded, swollen or ruptured. Drug release pattern depends on the compression-coat properties. The press-coating could be performed with water soluble polymers (hydroxypropylcellulose, hydroxypropylmethylcellulose, pectin, polyethylene oxide), water insoluble polymer (ethylcellulose) and wax (Behenic acid).
Such a dosage form is disclosed in WO 02/072033. This dosage form is characterized by a coating containing a natural or synthetic gum that gels in the presence of aqueousmedia. The gellable coating act as a medium through which drug is released in a delayed or modified manner.
US 6,365,185 relates to tablets which are time-controlled to release active agent at different rates in different regions of the digestive tract in order to maintain a substantially constant concentration in the blood. In one embodiment, a modified release drug delivery system, for once a day peroral use, consist of a solid core comprising an active agent together with hydrogel, with the solid core being coated with a semi-permeable, self destructing membrane which is optionally drilled to provide a release orifice, and then optionally further coated with the same or different active agent material. The device delivers the active agent in a substantially constant effective dose for the duration of the transit through the stomach and small intestine, followed by accelerated release when reaching the large intestine.
EP1631251 B1 (Jagotec AG) discloses the delayed release tablet core with a defined geometry. The characteristic of the formulation is that, the coatingruptures upon immersion in an aqueous medium after a period of between about 2 to 6 hours to release the drug and the core being disposedwithin said coating such that the coating thickness about an axis (X- Y) is thicker than the coating about an axis (AB)orthogonal to (X-Y), and wherein the thickness of the coating about the axis (X-Y), wherein the axis (A-B) is the axis of the direction of movement of the punch used in the press-coating of the tablet.The inventors also assert that the thickness of the coating around or about the axis (A-B) is not critical for controlling the lag time.
EP1615626 (Jagotec AG) is related to Prednisone delayed release tablet formulation with colored core. This patents relates to the use' of a colouring agent or excipient in such tablets to determine whether the core is centrally located within the core, to check the integrity of the core, and to ensure that there is no contaminating core material on or near the surface of the coating. Description of the Invention:
EP1631251 B1 (Jagotec AG) discloses the coating ruptures upon immersion in an aqueous medium after a period of between about 2 to 6 hours to release the drug and the core being disposed within said coating such that the coating thickness about an axis (X- Y) is thicker than the coating about an axis (A-B) orthogonal to (X-Y), and wherein the thickness of the coating about the axis (X-Y), wherein the axis (A-B) is the axis of the direction of movement of the punch used in the press-coating of the tablet. The inventors also assert that the thickness of the coating around or about the axis (A-B) is not critical for controlling the lag time. However wehave surprisingly found that the core tablet size and also the coating material amount related to release of drug substance. Also the coating around or about the axis (A-B) is critical controlling the lag time likewise the coating about the axis (X-Y). Because, the lag time depends on the ratio of the coating's and core tablet's surface areas. In addition, the coating's and core tablet's surface areas are related with coating and core tablet weight, respectively. In this aspect, the applicant developed formulations that the coating thickness about an axis (A-B) is thicker than or equal the coating about an axis (X-Y).
Preferably, the thickness of the coating about the axis (A-B) is about 1.85 to about 2.125 mm. The coating thickness either side of the core on the axis (A-B) may or may not be equal. For example, on a first side of the core (A-core) the coating may have a thickness of about 1.80 to 2.00 mm, more preferably 1.95 to 2.05 mm, whereason the other side of the core (B-core) the thickness may be about 1.8 to 1.90 mm, more preferably 1.85 to 1.90 mm.
According to present invention the coating thickness about an axis (A-B) is 1.85mm- 2.125mm and the coating an axis (X-Y) is 1.6-1.9 mm, about 1.75 mm.
According to present invention core tablet shape is round and flat, press-coated tablet shape is round and biconvex. The diameter and thickness of core tablet is about 5.5 mm and about 2mm, respectively. The diameter and thickness of press-coated tablet is about 9mm and about 5.85 mm, preferably 5.75-6.25mm respectively.
According to present invention, the core tablet size alters the coating material amount needed to targeted lag time. The core tablet size should belarge enough to press and placed precisely in the center of the die. And it should be small enough to require less coating material needed to targeted lag time and also swallow offinal tablet.
The present invention also provides for a press-coated tablet having an in vitro dissolution profile which is a median lag time of about 4 hours (3.5 - 4.5 hours) and at least about % 90 of prednisone is released after 5 hours.
The present invention provides press-coated tablet comprising a core comprising prednisone and a coating around said core, wherein said core is released drug substance 2-6 hours, preferably 4 hours, after oral administration.
The present invention provides press-coated tablet comprising a core comprising prednisone and a coating around said core, wherein said prednisone from 4 to 17 % by weight oftotal core tablet. The weight of the core tablet is 50-80mg, preferably about 60mg.
The present invention also provides for a press-coated tablet comprising a core comprising prednisone and a coating around said core, wherein said the amount of coating from 3 to 10 fold, preferably 5-7 fold, more preferably about 6 fold by weight of core tablet. The amount of coating is 300-380mg, preferably 320-360mg, more preferably about 340mg.
The core tablet comprising prednisone and a one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, fillers, disintegrants, lubricants, glidants, colorants, or combination thereof.
The coating is water' insoluble or substantially water insoluble, hydrophobic and may contain one or more of the excipients selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and derivatives thereof; fatty acids or their esters or salts; long chain fatty alcohols; polyoxyethylene alkyl ethers; polyoxyethylene stearates and like.
Other hydrophobic excipients for coatings may be selected from any waxy substance known for use as tablet excipients. Preferably they have a HLB value of less than 5, and more preferably about 2. Suitable hydrophobic agents include waxy substances such as carnauba wax, parafin, microcrystalline wax, beeswax, cetyl ester wax and the like; or non-fatty hydrophobic substances such as calcium phosphate salts, e.g. dibasic calcium phosphate.
Preferably the coating contains a calcium phosphate salt, glyceryl behenate, and polyvinyl pyrollidone, or mixtures thereof, and one or more adjuvants, diluents, lubricants or fillers.
Cores are preferably formed according to wet granulation techniques generally known in the art. Prednisone and pharmaceutically acceptable excipients are sieved and blended. Water is then added to the blend and the mixture and the mixture is homogenized to form a granulate, which is then dried to obtain a granulate with requisite residual moisture. Preferably residual moisture content is from 0.8- to 3.0 %by weight. The granulate is then sized by passing it through screens of desired aperture. The obtained granules are lubricated and pressed into tablets.
Coating are preferably formed according to wet granulation techniques generally known in the art. Hydrophobic polymer and suitable excipients are mixed and granulated with water. Then granules are dried and sieved. The obtained granules are lubricated and with core tablets pressed into press-coated tablets.
The hardness of a press-coated tablet at least 60 Newtons, and more particularly 65 to 75 Newtons.
The delayed release prednisone tablets comprise 1 mg to 5mgprednisone. Example 1
Prednisone Delayed Release Tablet is prepared according to the unit formula below:
Table 1. Unit formula of Prednisone Delayed Release Tablet
Ingredients (%)
Core tablet
Prednisone 4-17
Lactose 20-90
Polyvinylpyrrolidone 1-10
Crosscarmellose sodium 1-10
Magnesium stearate 1-3
Total 100
Coating
Glyceryl behenate 15-80
Dibasic calcium hydrogen phosphate 15-80
Polyvinyl pyrrolidone 1-10
Yellow iron oxide 0.01-1
Magnesium stearate 1-3
Total 100 Prednisone, lactose, polyvinyl pyrrolidone and crospovidone is sieved through a 0.8 mm sieve and prepared for wet granulation by adding water.After the sieving and drying of wet granulates, they are mixed with magnesium stearate and compressed as tablets.
For preparation of coating; glyceryl behenate, polyvinyl pyrrolidone and dibasic calcium hydrogen phosphate is sieved through a 0.8 mm sieve and prepared for wet granulation by adding water. After the sieving and drying of wet granulates, they are mixed with magnesium stearate.
Process for preparing a press-coated tablet of prednisone comprising the steps of: a) forming a core comprising prednisone and one or more pharmaceutically acceptable excipients; b) forming a mixture containing a coating material and; c) press-coating the mixture containing the coating material around the core. Table 2.Comparative Dissolution data of Prednisone 5 mg Delayed Release Tablets and Lodotra ® 5 mg Tablet (n=6)
Dissolution Medium' and Method: Water, App. II (Paddle) with sinker, 500 ml_, 100 rpm
20
Figure imgf000008_0001

Claims

1. A press-coated tablet comprising a core containing prednisone and a coating around said core, wherein said the amount coating from 3 to 10 fold by weight of total core tablet and the coating thickness about the axis (A-B) is equal to or thicker than the coating thickness about the axis (X-Y), wherein the axis (A-B) is the axis of the direction of movement of the punch used in the press coating of the tablet and upon administration to a patient the lag time before drug release is 2 to 6 hours.
2. A tablet according to claim 1 , the amount coating is 5 to 7 fold by weight of total core tablet.
3. A tablet according to claim 1-2, wherein it hasan in vitro dissolution profile which is a median lag time of about 4 hours and at least about % 90 of drug substance is released after 5 hours.
4. A tablet according to claim 1, wherein the coating thickness about an axis (A-B) is 1.85mm-2.125mm and the coating an axis (X-Y) is 1.6-1.9mm.
5. A tablet according to claim 1, wherein the coating is a water insoluble or poorly soluble hydrophobic material.
6. A tablet according .to any preceeding claims, prednisone and optionally along with one or more pharmaceutically acceptable excipients is granulated by wet granulation technique.
7. A tablet according to any preceeding claims, coating surrounding the said core comprising inorganic salts of calcium ion and glyceryl behenate which are granulated by wet granulation technique.
8. A tablet according to any preceeding claims, the hardness of a press-coated tablet at least 60 Newtons, and more particularly 65 to 75 Newtons.
PCT/TR2015/000007 2015-01-12 2015-01-12 Time-controlled prednisone delayed release tablet WO2016114726A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004093843A1 (en) * 2003-04-24 2004-11-04 Jagotec Ag Delayed release tablet with defined core geometry
WO2013030726A1 (en) * 2011-08-26 2013-03-07 Wockhardt Limited Programmed drug delivery
US20130243861A1 (en) * 2012-03-16 2013-09-19 Cadila Healthcare Limited Press-coated tablets of prednisone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004093843A1 (en) * 2003-04-24 2004-11-04 Jagotec Ag Delayed release tablet with defined core geometry
WO2013030726A1 (en) * 2011-08-26 2013-03-07 Wockhardt Limited Programmed drug delivery
US20130243861A1 (en) * 2012-03-16 2013-09-19 Cadila Healthcare Limited Press-coated tablets of prednisone

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