WO2007142628A1 - Formulation stable contenant un ou des médicaments sensibles à l'humidité et son procédé de fabrication - Google Patents

Formulation stable contenant un ou des médicaments sensibles à l'humidité et son procédé de fabrication Download PDF

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Publication number
WO2007142628A1
WO2007142628A1 PCT/US2006/021586 US2006021586W WO2007142628A1 WO 2007142628 A1 WO2007142628 A1 WO 2007142628A1 US 2006021586 W US2006021586 W US 2006021586W WO 2007142628 A1 WO2007142628 A1 WO 2007142628A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
cilazapril
moisture sensitive
binder
tablet
Prior art date
Application number
PCT/US2006/021586
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English (en)
Inventor
Michael Fox
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, 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 Teva Pharmaceutical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Priority to PCT/US2006/021586 priority Critical patent/WO2007142628A1/fr
Priority to CNA2006800548240A priority patent/CN101460191A/zh
Priority to JP2009513120A priority patent/JP2009538905A/ja
Priority to BRPI0621739-7A priority patent/BRPI0621739A2/pt
Priority to MX2008015343A priority patent/MX2008015343A/es
Priority to CA002652620A priority patent/CA2652620A1/fr
Publication of WO2007142628A1 publication Critical patent/WO2007142628A1/fr
Priority to IL195060A priority patent/IL195060A0/en
Priority to NO20085423A priority patent/NO20085423L/no

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to stable pharmaceutical compositions comprising moisture sensitive drugs, in particular an angiotensin converting enzyme (ACE) inhibitor, such as Cilazapril, as the active ingredient and methods for preparing such stable pharmaceutical compositions.
  • moisture sensitive drugs in particular an angiotensin converting enzyme (ACE) inhibitor, such as Cilazapril
  • ACE angiotensin converting enzyme
  • Cilazapril is apparently an angiotensin converting enzyme ("ACE") inhibitor, which enzyme inhibits the formation of angiotensin II from angiotensin I by inhibiting the angiotensin converting enzyme.
  • ACE angiotensin converting enzyme
  • Cilazapril is reported to be (lS,9S)-9-[(S)-l- Ethoxycarbonyl-3 -phenylpropylamino] - 10-oxoperhydro ⁇ yridazino [ 1 ,2-a] [ 1 ,2] diazepine- 1 - carboxylic acid and is understood to be disclosed in U.S. Patent No. 4,512,924.
  • Cilazapril has been prescribed in treating patients suffering from hypertension.
  • a stable pharmaceutical composition does not exhibit substantial decomposition of the active pharmaceutical ingredient during the time between the manufacture of the composition and its use by a patient.
  • Cilazapril and a number of other drugs suffer from instability problems because the active pharmaceutical ingredient rapidly degrades in the presence of water/moisture.
  • Such active pharmaceutical ingredients can therefore be characterized as moisture-sensitive drugs.
  • tablet blends may be dry mixed, dry-granulated or wet-granulated before tableting.
  • the choice of the processing procedure, dry mixing, dry granulation, wet granulation, or some other granulation process, depends on the properties of the drug and the chosen excipients. Generally, a dry manufacturing process is thought to be preferable for moisture-sensitive drugs.
  • water scavenger compounds may be incorporated into a tablet matrix.
  • a water scavenger compound is the binder Copovidone (Plasdone S-630 ® ), which binder is specifically recommended for moisture sensitive drugs.
  • Plasdone S-630 ® binder Copovidone
  • Cilazapril tablets using this material in a dry granulation process. In such Cilazapril tablets degradation of the active pharmaceutical ingredient was apparent.
  • compositions or formulation comprising the moisture sensitive drug and a binder such as Copovidone, wherein the formulation/composition is prepared using a wet granulation process, comprising wetting and then drying the composition at an elevated temperature.
  • the invention provides stable Cilazapril compositions and methods of their preparation.
  • the present invention provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising; a) a moisture sensitive active pharmaceutical ingredient; and b) at least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient.
  • at least one excipient is a binder.
  • the present invention provides a method of preparing a granular composition comprising a wet granulated moisture sensitive active pharmaceutical ingredient comprising the following steps of a) providing a moisture sensitive active pharmaceutical ingredient; b) mixing the moisture sensitive active pharmaceutical ingredient with at least one pharmaceutically acceptable excipient other than a binder, forming a mixture; and c) wet granulating the mixture with a solution of a binder excipient dissolved in one or more processing solvents thus forming a granulate.
  • the present invention also provides a method of treating a patient suffering from a disease comprising administering to a patient in need thereof a therapeutically effective amount of a stable pharmaceutical composition comprising a moisture sensitive active pharmaceutical ingredient, preferably Cilazapril, and at least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of the at least one pharmaceutical excipient.
  • Figure 1 Shows a comparison of the degradation at 55 °C during stability test of various
  • Cilazapril tablets packed in aluminum cold-form blister, according to the invention with a dry granulated tablet and a commercially available tablet.
  • Alcohol based tablet coating (Opadry II (85 Series) and a Hydroxypropyl
  • Methylcellulose based tablet coating
  • moisture sensitive active pharmaceutical ingredient refers to an active pharmaceutical ingredient which rapidly degrades in the presence of water/ moisture.
  • the present invention provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a moisture sensitive active pharmaceutical ingredient, exemplified by Cilazapril, and at least one pharmaceutically acceptable excipient, wherein at least one pharmaceutically acceptable excipient is a binder.
  • the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients.
  • a stable pharmaceutical composition comprising; a) a moisture sensitive active pharmaceutical ingredient; and b) at least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient.
  • the moisture sensitive active pharmaceutical ingredient is Cilazapril and at least one pharmaceutical excipient is a binder.
  • the amount of the moisture sensitive active pharmaceutical ingredient in the composition is about 0.1% to about 25%, more preferably of about 0.5% to about 15%, of the total weight of the composition.
  • a most preferred amount of the active pharmaceutical ingredient in the composition is about 0.6% to about 2.7% of the total weight of the composition.
  • the present invention provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a moisture sensitive active pharmaceutical ingredient and at least one pharmaceutically acceptable excipient, wherein the formulation contains not more than 3% (w/w of the initial amount of the active pharmaceutical ingredient) of a degradation product after storage in a package with moisture sensitive barrier properties which are at least as efficient as aluminum-aluminum cold form blisters.
  • the concentration of the degradation product in the stable pharmaceutical composition of the present invention after storage as described above is not more than 2%. More preferably, the concentration of the degradation product in the stable pharmaceutical composition of the present invention after storage as described above is not more than 1%.
  • Storage may comprise storage at a temperature of 55°C for 14 days and storage at a temperature of 40°C and 75% relative humidity for three months.
  • the degradation product may be detected by HPLC analysis.
  • the moisture sensitive active pharmaceutical ingredient is Cilazapril and the degradation product is its major degradation product Cilazaprilat.
  • a stable pharmaceutical composition of the present invention therefore provides a pharmaceutical composition of a moisture sensitive active pharmaceutical ingredient, preferably Cilazapril, characterized by comprising not more than 3%, preferably not more than 2%, most preferably not more than 1% , by weight per weight of said pharmaceutical ingredient, of its major degradation Cilazaprilat product upon storage.
  • a moisture sensitive active pharmaceutical ingredient preferably Cilazapril
  • the stable pharmaceutical composition of the present invention comprises at least about 4% of a binder by total weight of the composition.
  • the pharmaceutical composition comprises from about 4% to about 20%, more preferably from about 5% to about 10% of a binder by total weight of the composition.
  • the binder comprises for example, one or more of, a cellulose derivative, a polyvinyl pyrrolidone (PVP) and its derivatives, a polyvinylacetate (PVA) or a polyvinyl alcohol.
  • suitable cellulose derivatives as a binder in the present invention are Hydroxypropylmethyl cellulose (HPMC) or Hydroxypropyl cellulose (HPC).
  • the binder is the Copovidone, exemplified by Plasdone ® S-630 (Copovidone), which is a synthetic, 60:40, linear, random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and which has a reduced hydrophilicity and a reduced polymer glass transition temperature (Tg) in comparison to a polyvinyl pyrrolidone (PVP) homopolymer.
  • Copovidone exemplified by Plasdone ® S-630 (Copovidone)
  • Plasdone ® S-630
  • Tg polymer glass transition temperature
  • PVP polyvinyl pyrrolidone
  • the stable pharmaceutical compositions comprising a moisture sensitive active pharmaceutical ingredient of the present invention may further contain excipients such as tablet and capsule fillers and diluents (such as microcrystaUme cellulose, lactose, starch and tri-basic calcium phosphate), disintegrants (such as starch, croscarmellose sodium, crospovidone and sodium starch glycolate), and glidants (such as colloidal silicon dioxide and talc), lubricants (such as magnesium stearate, sodium lauryl sulfate, stearic acid and sodium stearyl fumarate).
  • excipients such as tablet and capsule fillers and diluents (such as microcrystaUme cellulose, lactose, starch and tri-basic calcium phosphate), disintegrants (such as starch, croscarmellose sodium, crospovidone and sodium starch glycolate), and glidants (such as colloidal silicon dioxide and talc), lubricants (such as
  • suitable diluents and fillers for use in the pharmaceutical composition of the present invention include microcrystalline cellulose (e.g. Avicel ® ), lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, sodium chloride, sorbitol and talc.
  • microcrystalline cellulose e.g. Avicel ®
  • lactose lactose
  • starch pregelatinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • dextrin dextrin
  • dextrose dibasic calcium phosphate dihydrate
  • tribasic calcium phosphate magnesium carbonate
  • maltodextrin mannitol
  • powdered cellulose sodium chloride
  • Solid pharmaceutical compositions of the present invention that are compacted into a dosage form, such as a tablet, may include the addition of a disintegrant to the composition.
  • Disintegrants include croscarmellose sodium (e.g. Ac Di Sol ® , Primellose ® ), crospovidone (e.g. Kollidon ® , Polyplasdone ® ), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate (e.g. Explotab ® , Primoljel ® ) and starch.
  • Glidants can be added to improve the flowability of a solid composition before compaction and to improve the accuracy of dosing especially during compaction and capsule filling.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, and talc.
  • a lubricant can be added to the composition to reduce adhesion and/or ease the release of the product from e.g. the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fUmarate, stearic acid, talc and zinc stearate.
  • excipients that may be incorporated into the formulation include preservatives, surfactants, antioxidants, or any other excipient commonly used in the pharmaceutical industry.
  • the stable formulation comprises in addition to Cilazapril, copovidone, lactose monohydrate, sodium starch glycolate, talc extra fine and sodium stearyl fumarate.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, and rectal administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts.
  • the pharmaceutical composition of the present invention may be prepared in any dosage form such as a compressed granulate in the form of a tablet for example. Also, uncompressed granulates and powder mixes that are obtained by the method of the present invention in the pre-compression steps can be simply provided in a dosage form of a capsule or sachet. Therefore, dosage forms of the pharmaceutical composition of the present invention include solid dosage forms like tablets, powders, capsules, sachets, etc.
  • the dosage form of the present invention may also be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • a moisture sensitive active pharmaceutical ingredient preferably Cilazapril, solid composition
  • it is preferably formulated into pharmaceutical formulations such as conventional dosage forms, including tablets and capsules. Tablets are a preferred dosage form.
  • the tablets may be coated with an optional cosmetic tablet coating. More preferably this cosmetic coat has "moisture barrier" properties. This moisture barrier property provides protection against environmental moisture for sensitive cores, enhances product stability, and improves shelf life.
  • the cosmetic coating is a tablet coating based on polyvinyl alcohol. More preferably, the cosmetic coating comprises polyvinyl alcohol, talc and polyethylene glycol (PEG). Most preferably, the cosmetic coating further comprises an opacifier and/or a colorant, e.g. titanium dioxide and/or iron oxide.
  • the stability of a tablet coated with Opadry®II 85F (a coating with moisture barrier properties) and a tablet coated with a HPMC based coat.
  • this Opadry series of products comprise Talc, PEG 3350, Titanium Dioxide and pigments.
  • the tablets of the present invention comprise a cosmetic coat of about 2% to about 6% of the tablet weight, more preferably of about 2.5% to about 4.5% of the tablet weight, most preferably of about 3% to about 3.5% of the tablet weight.
  • Li another embodiment the present invention provides a method of preparing a granular composition comprising a wet granulated moisture sensitive active pharmaceutical ingredient, preferably Cilazapril, comprising the following steps of a) providing a moisture sensitive active pharmaceutical ingredient; b) mixing the moisture sensitive active pharmaceutical ingredient with at least one pharmaceutically acceptable excipient, preferably other than a binder, forming a mixture; and c) wet granulating the mixture with a solution of a binder in a processing solvent, forming a granulate.
  • a typical granulation process involves mixing the active ingredient and possibly excipients in a mixer.
  • the binder is dissolved in the solvent used for granulating although a further portion of binder or another binder may be one of the excipients added in the dry mix state.
  • the granulating solvent, solution or suspension is added to the dry powders in the mixer and mixed until the desired characteristics are achieved. This usually produces a granule that will be of suitable characteristics for producing tablets with adequate hardness, dissolution, content uniformity, and other physical characteristics.
  • the product is most often dried and then milled after drying, to obtain a major percentage of the product within a desired size range.
  • the product after wet granulation is dried until the loss on drying (LOD) is not more than about 1.5%, more preferably not more than about 1.1%.
  • the product is milled or sized through an 1 mm screen, more preferably through a 0.8 mm screen.
  • the stable pharmaceutical composition of the present invention is prepared by wet granulation with a suitable solvent/processing solvent.
  • a suitable solvent/processing solvent is able to dissolve the selected binder.
  • the solvent/processing solvent is capable of dissolving the binder to reach a concentration of at least about 10% W/W. More preferably, the solvent/processing solvent is selected from the group consisting of ethanol, isopropyl alcohol, water, and combinations thereof.
  • the stable formulation prepared by wet granulation comprises at least 4%, preferably about 4% to about 20%, more preferably about 5% to about 10%, of a binder by weight of the formulation.
  • the binder comprises at least Copovidone and more preferably, the binder is applied as a solution in ethanol or water.
  • a preferred solution of the binder in ethanol or water comprises about 25% to about 55% (w/w) binder, preferably Copovidone, more preferably about 30% to about 50% (w/w) binder, preferably Copovidone.
  • This effect maybe characterized as related to the concentration of the moisture sensitive active pharmaceutical ingredient in the dried granulate. Therefore, dried granulates comprising about 0.6% of the active pharmaceutical ingredient are preferentially prepared by wet granulation with an alcoholic granulation processing solvent, whereas dried granulates comprising about 2.7% of the active pharmaceutical ingredient are preferentially prepared by wet granulation with an aqueous granulation processing solvent. Granulates with intermediate concentrations of the active pharmaceutical ingredient display an intermediate effect.
  • final pharmaceutical compositions of the present invention comprising not more than about 1.7 % of the moisture sensitive active ingredient in the dried granulate are preferably prepared by wet granulation with an alcoholic granulation process solvent.
  • wet granulation with an alcoholic processing solvent is used for such compositions comprising not more than about 0.6% of the moisture sensitive active ingredient in the dried granulate.
  • Pharmaceutical compositions comprising more than about 1.7% of the moisture sensitive active ingredient in the dried granulate are preferably prepared by wet granulation with water (an aqueous granulation) as the granulation processing solvent.
  • wet granulation with an aqueous processing solvent is used for such compositions comprising not less than about 2.7% of the moisture sensitive active ingredient in the dried granulate.
  • the preferred moisture sensitive active pharmaceutical ingredient being Cilazapril.
  • the method of the present invention may further comprise steps in preparing a tablet of the pharmaceutical composition of the present invention.
  • the method further comprises the steps of d) mixing the granulate with one or more excipients forming a final blend; e) pressing the final blend into a tablet; and f) optionally coating the tablet with a cosmetic coat.
  • the cosmetic coat has moisture barrier properties.
  • Examples of such cosmetic coatings are tablet coatings based on polyvinyl alcohol.
  • the optional cosmetic coating of the tablet preferably comprises preparing a suspension comprising about 10% to about 25%, preferably about 12% to about 15%, more preferably about 12% to about 13%, of a powder mixture for cosmetic coating, and applying the suspension on the tablet.
  • the cosmetic coating suspension is preferably prepared such that the tablet comprises about 2% to about 6%, preferably 2.5% to about 4.5%, of a tablet cosmetic coat.
  • the tablet cosmetic coat in the present invention preferably has "moisture barrier" properties.
  • the commercially available series of powder mixes for coating suspension sold as the Opadry ® II 85F series, available from Colorcon, which are based on Polyvinyl alcohol, are examples of such cosmetic coat.
  • Capsules comprising either a hard or soft shell and containing the composition of the present invention may be prepared.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • a capsule filling of the present invention may comprise the granulates that were described with reference to tableting, a final blend of a granulate composition of the present invention mixed woth one or more excipients, however they are not subjected to a final tableting step. Further, such capsules may be prepared by any of the methods well known in the pharmaceutical arts.
  • the present invention provides a method for preparing a stable pharmaceutical composition
  • a method for preparing a stable pharmaceutical composition comprising: a) mixing cilazapril, lactose, talc and sodium starch glycolate; b) adding a solution of copovidone to the mixture obtained from step a) to form a granulate; c) drying and then milling the granulate; d) combining the milled granulate with further sodium starch glycolate and mixing; and e) adding sodium stearyl glycolate to the blend obtained from step iv) and mixing to obtain a final blend.
  • the pharmaceutical composition is a 1 mg tablet and step b) is performed using a granulation solution comprising ethanol.
  • the pharmaceutical composition is a 5 mg tablet and step b) is performed using an aqueous granulation solution.
  • the present invention also provides a method of treating a patient suffering from a disease comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a moisture sensitive active pharmaceutical ingredient, preferably Cilazapril, and at least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of the at least one pharmaceutical excipient.
  • the disease is hypertension.
  • the blend was pressed into slugs on a rotary tablet press and the slugs were milled to a granulate in an oscillating granulator through 0.8 mm screen.
  • the obtained granulate was combined with 64g screened Sodium Starch Glycolate (type A) and mixed in a Y-cone blender for 10 minutes.
  • 8g screened Sodium Stearyl Fumarate was added and all materials were mixed in a Y-cone blender for 5 minutes.
  • Tablets were pressed in a rotary tablet press. Subsequently, a part of the tablets cores were coated with: a)Opadry ® II 85F22055 (Yellow) , which comprises polyvinyl alcohol, talc, PEG
  • Packaged tablets were either stored at 55°C or at 40°C and 75% relative humidity (PvH).
  • the presence of the main degradation product, Cilazaprilat was determined using the HPLC method.
  • figure 1 the presence of this main degradation product of Cilazapril after such storage is shown.
  • figure 3 compares the degradation of Cilazapril tablets, as a function of the presence of this main degradation product after storage, of tablets coated with a cosmetic coating of Opadry® II 85 F22055 with tablets having a cosmetic coat of Opadry® 02G222555 (HPMC based).
  • the milled granulate was combined with 8g Sodium Starch Glycolate -type A (disintegrant) and mixed in a Y-cone blender for 10 minutes. 4g screened Sodium Stearyl Fumarate (lubricant) was added to the blend and mixed for 5 minutes to obtain a final blend.
  • Tablets were pressed from the final blend in a rotary tablet press.
  • the tablets were coated with a commercially available tablet coating powder blend Opadry®II 85F22055 (Yellow) as a 12% aqueous suspension, using a Glatt film coater, to obtain approximately a 3% w/w coating.
  • the tablets were packaged in aluminum blister covered with aluminum foil. Packaged tablets were stored at 55°C. The presence of the main degradation product, Cilazaprilat, was determined using HPLC method. Example 3.
  • the milled granulate was combined with 16Og screened Sodium Starch Glycolate (type A) and mixed in a Y-cone blender for 10 minutes. 4Og screened Sodium Stearyl Fumarate was added to the blend and mixed in a Y-cone blender for 5 minutes to obtain a final blend.
  • Tablets were pressed from the final blend in a rotary tablet press.
  • the tablets were coated with Opadry® II 85F22055 Yellow as a 13% aqueous suspension, using an O'HARA film coater, to obtain approximately a 3.5% w/w coating.
  • the tablets were packaged in aluminum blister covered with aluminum foil. Packaged tablets were stored either at 55°C or at 40°C and 75% RH. The presence of the main degradation product, Cilazaprilat, was determined using the HPLC method.
  • the milled granulate was combined with 16g Sodium Starch Glycolate (type A) and mixed in a Y-cone blender for 10 minutes. 4g screened Sodium Stearyl Fumarate was added to the blend and mixed in a Y-cone blender for 5 minutes to obtain a final blend.
  • Tablets were pressed on a rotary tablet press.
  • the tablets were coated with Opadry ® II 85F22055 Yellow as a 12% aqueous suspension, using a Glatt film coater, to obtain approximately a 3% w/w coating.
  • the tablets were packaged in aluminum blister covered with aluminum foil. Packaged tablets were stored at 55°C. The presence of the main degradation product, Cilazaprilat, was determined using an HPLC method.
  • the following components were mixed for 1 minute in a high shear mixer; 10.4 g Cilazapril Monohydrate, 318g Lactose Monohydrate, 16g Talc Extra Fine and 16 g Sodium Starch Glycolate (type A). 50 g of a 40% (w/w) aqueous solution of Copovidone was added and mixed in the high shear mixer for 5 minutes. The granulate achieved was dried using a fluid bed dryer until the Loss On Dry (LOD) of the dried granulate was not more than (MMT) 1.1 % as tested at 80 o C. the dried granulate was milled in an oscillating granulator through 0.8 mm screen.
  • LOD Loss On Dry
  • the milled granulate was combined with 16g of screened Sodium Starch Glycolate (type A) and mixed in a Y-cone blender for 10 minutes.
  • screened Sodium Starch Glycolate type A
  • 4g of screened Sodium Stearyl Fumarate was added and mixed in a Y-cone blender for 5 minutes to achieve a final blend.
  • the tablets were pressed in a rotary tablet press.
  • the tablets were packaged in aluminum blisters covered with aluminum foil.
  • Packaged tablets were stored at either 55°C or at 40°C and 75% RH.
  • the presence of the main degradation product, Cilazaprilat, was determined using an HPLC method.
  • the stability of pharmaceutical compositions according to the present invention were compared with the stability of a dry granulated comparative example of a Cilazapril tablet and with a commercialized product.
  • the samples of the commercialized product were Vascace ® 1 mg tablets, produced by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
  • Table 1 shows the formulations of these pharmaceutical compositions with the exception of the commercialized product which was obtained as a finished product.
  • Table 1 Comparison of formulations and manufacturing methods.
  • Stability was measured by determining the presence of the major Cilazapril degradation product Cilazaprilat in the pharmaceutical composition after storage.
  • An HPLC test method was applied to determine the quantity of the degradation products of Cilazapril.
  • the mobile phase was a mixture of triethylamine buffer, tetrahydrofuran and acetonitrile.
  • the detector was a UV spectrophotometer set at 214 nm.
  • Figure 1 shows stability test results comparing degradation after storage at 55°C for 14 days of various Cilazapril tablets, prepared according to the invention by wet granulation process, with the (control) tablets prepared by dry granulatio and commercially available tablets. All tested tablets were packed in aluminum blisters. The commercially available product is also packed in aluminium blister. The presence of increasing levels of Cilazaprilat over time was determined. Further, test results for degradation of some of these formulations under standard stress conditions are shown in Table 2. Table 2. Degradation under standard "stress" conditions (40°C and 75% RH), of Cilazapril displayed as function of different formulations and manufacturing methods.
  • the milled granulate was combined with 16Og screened Sodium Starch Glycolate (type A) and mixed in a Y-cone blender for 15 minutes. 40g screened Sodium Stearyl Fumarate was added to the blend and the materials mixed in a Y-cone blender for 5 minutes to obtain a final blend.
  • Tablets were pressed in a rotary tablet press.
  • the tablets were coated with Opadry ® II 85F22055 Yellow as a 13% aqueous suspension, using an O'HARA film coater, to obtain approximately a 3.5% w/w coating.
  • the tablets were packaged in aluminum blisters covered with aluminum foil. Packaged tablets were stored at 40°C and 75% RH. The presence of the main degradation product, Cilazaprilat, was determined using the HPLC method described above.
  • the milled granulate was combined with 160.00 g screened Sodium Starch Glycolate (type A) and mixed in a Y-cone blender for 15 minutes. To the mix 40.00 g screened Sodium Stearyl Fumarate was added and the materials mixed in a Y-cone blender for 5 minutes.
  • the tablets were pressed in a rotary tablet press.
  • the tablets were coated with Opadry ® II 85F24033 Pink as a 13% aqueous suspension, using O'HARA film coater, to obtain approximately a 3.5% w/w coating.
  • the tablets were packaged in aluminum blisters covered with aluminum foil. Packaged tablets were stored at 40°C and 75% RH. The presence of the main degradation product, Cilazaprilat, was determined using the HPLC method as described.
  • the following components were mixed for 2 minutes in a high shear mixer; 522 g Cilazapril Monohydrate, 30678 g Lactose Monohydrate, 160Og Talc Extra Fine and 160Og Sodium Starch Glycolate (type A). 660Og of a 54.55% (w/w) solution of Copovidone in Alcohol (95%) was added and mixed in the high shear mixer for 3.5 minutes.
  • the granulate obtained was dried using a fluidized bed dryer until the LOD of the dried granulate was not more than (NMT) 1.1% as tested by a Mettler HR73 at 80°C, level 5.
  • the dried granulate was milled in a hammer mill through a 0.84 mm screen.
  • the milled granulate was combined with 1600 g screened Sodium Starch Glycolate (type A) and mixed in a Y-cone blender for 15 minutes. 400 g screened Sodium Stearyl Fumarate was added to the blend and the materials mixed in a Y-cone blender for 5 minutes to obtain a final blend.
  • the tablets were pressed from the final blend in a rotary tablet press.
  • the tablets were coated with Opadry ® II 85F25401 Red as a 13% aqueous suspension, using an O ⁇ ARA film coater, to obtain approximately a 3.5% w/w coating.
  • the tablets were packaged in aluminum blister covered with aluminum foil. Packaged tablets were stored at 40°C and 75% RH. The presence of the main degradation product, Cilazaprilat, was determined using the HPLC method as described.
  • the obtained granulate was dried using a fluid bed dryer (LOD of the dried granulate was not more than (NMT) 1.1% as tested by a Mettler HR73 at 80°C, level 5) and milled in an oscillating granulator through 0.8 mm screen.
  • the milled granulate (359.34 g) was combined with 15.13 g screened Sodium Starch Glycolate (type A) and mixed in a Y-cone blender for 15 minutes.
  • 3.78 g screened Sodium Stearyl Fumarate was added and the materials were mixed in a Y-cone blender for 5 minutes.
  • the tablets were pressed in a single punch tablet press.
  • the tablets were packaged in aluminum blister covered with aluminum foil.
  • Packaged tablets were stored either at 55°C or at 40°C and 75% RH.
  • the presence of the main degradation product, Cilazaprilat, was determined using the HPLC method.
  • Table 4 Compositions of Cilazapril tablets, formulated by wet granulation process. Water was used as a process solvent.
  • Example 11 Stability comparisons of various Cilazapril pharmaceutical compositions.
  • the stability of pharmaceutical compositions according to the present invention prepared with either ethanol (95%) or water as the processing solvent were compared.
  • the stability of commercially available products was determined under the same testing conditions.
  • the samples of the commercially available product were Vascace ® tablets, produced by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
  • comparable formulations of Cilazapril processed predominantly using ethanol which only differ with respect to the content of Cilazapril in mg/tablet have very different degradation profiles, such that the lmg tablets are the most stable and the 5mg the least stable.
  • Table 5 Monitoring results of Cilazapril tablets, placed under standard stress conditions (40°C & 75% RH), in comparison to a commercially available roduct. Packa in - aluminum blister.
  • table 6 shows that comparable formulations of Cilazapril processed predominantly using water as processing solvent which only differ with respect to the content of Cilazapril in mg/tablet have the opposite degradation characteristics, such that the 5mg tablets are the most stable and the lmg the least stable.

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Abstract

La présente invention concerne des compositions pharmaceutiques stables contenant des médicaments sensibles à l'humidité, en particulier un inhibiteur de l'enzyme de conversion de l'angiotensine (ACE) tel que le Cilazapril, en tant que principe actif, et au moins un excipient pharmaceutique, l'ingrédient pharmaceutique actif étant préparé par granulation humide avec une solution d'au moins un excipient pharmaceutique. L'invention concerne également des procédés de préparation de telles compositions pharmaceutiques stables.
PCT/US2006/021586 2006-06-02 2006-06-02 Formulation stable contenant un ou des médicaments sensibles à l'humidité et son procédé de fabrication WO2007142628A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
PCT/US2006/021586 WO2007142628A1 (fr) 2006-06-02 2006-06-02 Formulation stable contenant un ou des médicaments sensibles à l'humidité et son procédé de fabrication
CNA2006800548240A CN101460191A (zh) 2006-06-02 2006-06-02 包含湿敏性药物的稳定制剂及其制备方法
JP2009513120A JP2009538905A (ja) 2006-06-02 2006-06-02 感湿性薬物を含んで成る安定性製剤及びその製造方法
BRPI0621739-7A BRPI0621739A2 (pt) 2006-06-02 2006-06-02 formulação estável que consiste em drogas sensìveis à umectação e seu procedimento de fabricação
MX2008015343A MX2008015343A (es) 2006-06-02 2006-06-02 Formulacion estable que comprende farmacos sensibles a la humedad y procedimiento de fabricacion de ella.
CA002652620A CA2652620A1 (fr) 2006-06-02 2006-06-02 Formulation stable contenant un ou des medicaments sensibles a l'humidite et son procede de fabrication
IL195060A IL195060A0 (en) 2006-06-02 2008-11-02 Stable formulation comprising moisture sensitive drug/s and manufacturing procedure thereof
NO20085423A NO20085423L (no) 2006-06-02 2008-12-30 stabil formulering omfattende fuktighetsfolsomt legemiddel og fremgangsmate for fremstilling derav

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008020701A1 (de) 2008-04-24 2009-10-29 Bayer Technology Services Gmbh Formulierung mit reduzierter Hygroskopizität
US11020350B2 (en) 2012-06-01 2021-06-01 Ceva Santé Animale Palatable oral veterinary compositions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107441495A (zh) * 2012-02-17 2017-12-08 埃吉斯药物私人有限公司 稳定性提高的药物制剂

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US5442008A (en) * 1987-11-24 1995-08-15 Hoechst Aktiengesellschaft Stabilized polymer film coated compounds and stabilized formulations in compressed from using same
WO2003075842A2 (fr) * 2002-03-08 2003-09-18 Teva Pharmeceuticals Usa, Inc. Formulations stables d'inhibiteurs de l'enzyme de conversion de l'angiotensine (ace)
US20050009806A1 (en) * 2003-07-11 2005-01-13 Patel Ashish Anilbhai Stable pharmaceutical compositions containing an ace inhibitor

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DE19952030A1 (de) * 1999-10-28 2001-05-03 Basf Ag Verfahren zur Herstellung von hochreaktiven Polyisobutenen
TW201240679A (en) * 2004-03-12 2012-10-16 Capsugel Belgium Nv Pharmaceutical formulations

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Publication number Priority date Publication date Assignee Title
US5442008A (en) * 1987-11-24 1995-08-15 Hoechst Aktiengesellschaft Stabilized polymer film coated compounds and stabilized formulations in compressed from using same
WO2003075842A2 (fr) * 2002-03-08 2003-09-18 Teva Pharmeceuticals Usa, Inc. Formulations stables d'inhibiteurs de l'enzyme de conversion de l'angiotensine (ace)
US20050009806A1 (en) * 2003-07-11 2005-01-13 Patel Ashish Anilbhai Stable pharmaceutical compositions containing an ace inhibitor

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GU L ET AL: "DRUG-EXCIPIENT INCOMPATIBILITY STUDIES OF THE DIPEPTIDE ANGIOTENSIN-CONVERTING ENZYME INHIBITOR, MOEXIPRIL HYDROCHLORIDE: DRY POWDER VS WET GRANULATION", PHARMACEUTICAL RESEARCH, NEW YORK, NY, US, vol. 7, no. 4, 1990, pages 379 - 383, XP009009003, ISSN: 0724-8741 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008020701A1 (de) 2008-04-24 2009-10-29 Bayer Technology Services Gmbh Formulierung mit reduzierter Hygroskopizität
US11020350B2 (en) 2012-06-01 2021-06-01 Ceva Santé Animale Palatable oral veterinary compositions
US11090270B2 (en) 2012-06-01 2021-08-17 Ceva Santé Animale Palatable oral veterinary compositions

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NO20085423L (no) 2009-02-25
CA2652620A1 (fr) 2007-12-13
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IL195060A0 (en) 2011-08-01
MX2008015343A (es) 2008-12-16
JP2009538905A (ja) 2009-11-12

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