WO2006101462A2 - Pharmaceutical preparation comprising perindopril erbumine and method of preparation and stabilisation thereof - Google Patents

Pharmaceutical preparation comprising perindopril erbumine and method of preparation and stabilisation thereof Download PDF

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Publication number
WO2006101462A2
WO2006101462A2 PCT/SK2006/000008 SK2006000008W WO2006101462A2 WO 2006101462 A2 WO2006101462 A2 WO 2006101462A2 SK 2006000008 W SK2006000008 W SK 2006000008W WO 2006101462 A2 WO2006101462 A2 WO 2006101462A2
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Prior art keywords
weight
perindopril erbumine
pharmaceutical preparation
preparation
mixture
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PCT/SK2006/000008
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French (fr)
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WO2006101462A3 (en
Inventor
Lubos Mgr. Dorsic
Vendelin Smahovsky
Viera Barigova
Jana Psenkova
Ladislav Jezek
Valdemar Stalmach
Ivan Varga
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Vulm, A.S.
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Publication of WO2006101462A2 publication Critical patent/WO2006101462A2/en
Publication of WO2006101462A3 publication Critical patent/WO2006101462A3/en

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    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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

Definitions

  • composition comprising perindopril erbumine and method of preparation and stabilisation thereof
  • the invention in the field of pharmacy relates to a pharmaceutical preparation containing perindopril erbumine, the preparation of a pharmaceutical composition containing perindopril erbumine and the way of stabilisation of the product prepared thereof.
  • the composition can be used for preparation of tablet cores, tablets, micro-tablets, for preparation of pellets, powders, granules and as the fill in capsules.
  • the drug product is used for treatment of hypertension, it acts as an ACE inhibitor.
  • Patent EP 1 354 873 (patent application WO03087050) describes the preparation of tablets containing various salts of perindopril, and describes exposition of individual pharmaceutical preparations containing various salts of perindopril to heat stress. Based on the stress tests, the arginine salt of perindopril was selected and used in the stability tests at the aforesaid conditions. The stability results show that the arginine salt of perindopril is more suitable for preparation of a stable pharmaceutical preparation than perindopril erbumine (perindopril tert-butylamine).
  • patent EP 1 354 873 does not address stabilisation of a pharmaceutical product containing perindopril erbumine. Based on the aforesaid facts from the point of view of stability, the preparation of a stable pharmaceutical product containing perindopril might be possible, or more eligible, if the arginine salt of perindopril is used.
  • the patent GB 2 394 660 A deals with stabilisation of the pharmaceutical composition containing an ACE inhibitor, thus also perindopril, by elimination of an acidic excipient having a big specific surface area, where colloidal silicon dioxide is presented as an example. According to the patent GB 2 394 660 A, the stabilisation of the product is ensured by elimination of colloidal silicon dioxide from a composition or tablets.
  • impurities B and F in accordance with PhEur. 4.
  • the impurity B is (2S,3aS,7aS)-l-[(S)-N-[(S)-l-carboxybutyl]alanyl]octahydro-lH- indol-2-carboxylic acid.
  • the impurity F is ethyl (2S)-2-[(3S,5aS,9aS,10aS)-3-methyl-l,4- dioxoperhydropyrazino [1 ,2-a]indol-2-yl]pentanoate.
  • the subject matter of the invention is a pharmaceutical preparation comprising perindopril erbumine in a stable form within the rage 1 to 40 % by weight and at least one excipient and/or a mixture of excipients within the range 1 % - 99 % by weight, whereas at least one excipient is a substance of basic character maintaining pH 7.1 to 14.
  • Substances of basic character are pharmaceutical excipients maintaining pH between 7.1 and 14, preferably those maintaining pH between 7.1 and 12.
  • Substances of basic character are substances of the group of oxides, hydroxides, hydrogen carbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, citronates of alkali or alkaline earth metal salts and hydrates thereof.
  • a further embodiment of the present invention provides a pharmaceutical preparation comprising perindopril erbumine in the form of a tablet and/or coated tablet and/or fill of capsules in which the active ingredient - perindopril erbumine - is contained in an amount 1 - 50 mg, i.e.
  • a principal excipient in a composition is a substance of basic character maintaining pH, in an amount 0.1 - 40% by weight
  • other excipients are polyols, and/or mixtures thereof, and/or mixtures of polyols and other fillers, and/or mixtures of polyols and disintegrants, and/or mixtures of polyols and glidants, and/or mixtures of polyols and glidants and disintegrants, and/or mixtures of polyols, glidants, disintegrants and other fillers.
  • a further embodiment of the present invention provides a pharmaceutical preparation comprising a substance of basic character in an amount 0.1 - 40 % by weight, preferably 0.1 - 15 % by weight.
  • a further embodiment of the present invention provides a pharmaceutical preparation comprising in an amount 1 to 99 % by weight, preferably 10 to 95 % by weight, polyols and/or mixtures thereof, preferably mannitol and/or mixtures thereof.
  • a further embodiment of the present invention provides a pharmaceutical preparation comprising other fillers in an amount 1 to 99 % by weight, preferably 10 to 95 % by weight, preferably microcrystalline cellulose with reduced content of water.
  • a further embodiment of the present invention provides a pharmaceutical preparation comprising in an amount 1 to 25 % by weight, preferably 1,5 to 10 % by weight, a disintegrant or disintegrants, preferably sodium crosscarmellose.
  • a further embodiment of the present invention provides a pharmaceutical preparation comprising 0.1 to 10 % by weight, preferably 0.5 to 4 % by weight, a glidant or glidants, preferably magnesium stearate.
  • the subject matter of the invention is also a method of preparing a pharmaceutical preparation consisting in preparation of a composition of the active ingredient with at least one excipient of basic character by mixing of powder components, and/or briqueting, and/or compacting, modification of particle size in the range 100 to 2000 ⁇ m, preferably, 800 ⁇ m, whereas the prepared composition is used for compression of tablet cores, and/or tablets, and/or micro-tablets, and/or preparation of pellets, and/or micro-pellets, and/or powders and/or granules, and/or fill in capsules.
  • the subject matter of the invention is also the packing of the pharmaceutical form of the pharmaceutical preparation in pharmaceutical containers protecting he preparation from air humidity, preferably comprising Al (aluminium) / OPA (orientated polyamide) / PVC (polyvinyl chloride) / Al (aluminium).
  • the subject matter of the invention is also the way of stabilising a composition, or pharmaceutical form, containing perindopril erbumine as active ingredient, used in the treatment of hypertension.
  • the principle of stabilization of a composition or pharmaceutical product consists in preparation of a composition by mixing of powder components, and/or briqueting, and/or compacting (absence of water in the process of preparation -> stabilisation of impurity B of perindopril erbumine), containing a substance buffering pH in the range 7.1 - 14 (stabilisation of impurity F of perindopril erbumine), and/or modification of particle size of a composition.
  • composition prepared in this way may be used for compression of tablet cores, and/or tablets, and/or micro-tablets, and/or preparation of pellets, and/or micro-pellets, and/or powders and/or granules, and/or fill in capsules.
  • the presented ways of preparation do not include stress procedures as adding a wetting substance in a composition comprising an active ingredient and excipients.
  • the presented ways of preparation and the choice of excipients as described in this invention also ensure good stability of the preparation and required physical characteristics of the pharmaceutical form.
  • a composition, or pharmaceutical form, as described in the invention may comprise besides the active ingredient perindopril erbumine of the formula:
  • a substance basifying a composition or pharmaceutical form also other excipients as: microcrystalline cellulose and polyols - fillers, substances modifying flowing properties of a composition, glidants - substances making compression of tablets easier, disintegrants - substances speeding up disintegration of tablets.
  • sodium hydrogen carbonate powdered sodium hydroxide, powdered potassium hydroxide, sodium citrate and hydrates thereof, potassium phosphate, sodium phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, magnesium oxide and other basifying substances.
  • Microcrystalline cellulose was used as an excipient, a substance used in the pharmaceutical industry. Properties of this excipient ensure acceptable flowing properties of a composition and easy compression of pressed pieces (tablet cores, tablets, micro-tablets, pellets, micro-pellets).
  • Polyols used are excipients which are ideally suitable for formulation of solid pharmaceutical forms using a dry procedure.
  • the physico-chemical parameters of these excipients ensure a very good stability of the preparation and complying physico-chemical parameters of tablets.
  • the aforementioned properties described in this invention were repeatedly achieved by use of physically modified polyols, for example mannitol.
  • the modified mannitol used is a white, crystalline powder (or granulate).
  • the properties of this excipient ensure very good flowing characteristics of a composition and a very good ability of direct compression. Other characteristics include a low hygroscopicity and a chemical stability. These characteristics ensure an excellent stability of a preparation comprising perindopril erbumine prepared as described in this invention.
  • disintegrants As disintegrants following substances were used: starches, modified starch, derivatives of cellulose, cross-linked polyvinylpyrrolidones, and others.
  • glidants used in the pharmaceutical industry salts of higher aliphatic acids were used, for example: stearates, oleates, laurylsulphates, and others.
  • a principle of the technological procedure is mixing of the active ingredient perindopril erbumine and/or at least one excipient with:
  • a substance of basic reaction stabilisation of impurity F of perindopril erbumine by maintaining pH in the range 7.1 - 14, preferably pH in the range 7.1 - 12, in an amount 0.1 to 40 % by weight, preferably 0.1 to 15 % by weight; or
  • microcrystalline cellulose preferably microcrystalline cellulose with reduced content of water (stabilisation of impurity B of perindopril erbumine), and/or a substance of basic reaction (stabilisation of impurity F of perindopril erbumine) maintaining pH in the range 7.1 - 17 % by weight, preferably 7.1 - 12 % by weight, in an amount 0.1 to 40 % by weight, preferably 0.1 to 15 % by weight; or a mixture comprising 1 to 99 % by weight, preferably 50 to 90 % by weight, of a substance of a group of polyols of a particle size 10 - 1000 ⁇ m, and/or mannitol of a particle size 100 to 520 ⁇ m, preferably 180 to 360 ⁇ m, and/or microcrystalline cellulose, preferably microcrystalline cellulose with reduced content of water (helps to stabilise impurity B of perindopril erbumine), and/or a substance of basic reaction (stabilisation of impur
  • compositions or tablets may be prepared from the aforesaid compositions by dry procedure using a few manufacturing methods, or a combination of these, namely:
  • the solid dosage forms prepared according to this invention ensure that a manufacturing process is reproducible.
  • Example 1 a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows: Composition Amount in g % by weight Perindopril erbumine 0.00400 g 2.50 % Microcrystalline cellulose 0.03200 g 20.00 % Mannitol 0.1120O g 70.00 % Magnesium oxide 0.00080 g 0.50 % Sodium crosscarmellose 0.00800 g 5.00 % Magnesium stearate 0.00320 g 2.00 % Total sum: 0.1600O g 100.00 % b) method of preparing:
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and magnesium oxide are added to Premix I and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added.
  • the mixture is homogenised for 15 minutes.
  • magnesium stearate is added.
  • the mixture is homogenised for 15 minutes. Tablets of the prescribed C C C tQQfQrqff mass and appearance are compressed from the composition prepared in this way.
  • Example 2 a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows:
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and sodium hydrogen carbonate are added to Premix I and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added.
  • the mixture is homogenised for 15 minutes.
  • magnesium stearate is added.
  • the mixture is homogenised for 15 minutes. Tablets of the prescribed mass and appearance are compressed from the composition prepared in this way.
  • Example 3 Example 3:
  • composition Amount in g % by weight Perindopril erbumine 0.00800 g 2.50 % Microcrystalline cellulose 0.12800 g 40.00 % Mannitol 0.1136O g 35.50 % Sodium citrate 0.04800 g 15.00 % Sodium crosscarmellose 0.01600 g 5.00 % Magnesium stearate 0.00640 g 2.00 % Total sum: 0.32000 g 100.00 % b) method of preparing:
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and sodium citrate are added to Premix I and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added.
  • the mixture is homogenised for 15 minutes.
  • magnesium stearate is added.
  • the mixture is homogenised for 15 minutes. Tablets of the prescribed mass and appearance are compressed from the composition prepared in this way.
  • Example 4 a) a pharmaceutical preparation in the dosage form of coated tablets of the composition as follows:
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and sodium hydroxide are added to Premix I and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and one half of the charge of mannitol is added.
  • the mixture is homogenised for 15 minutes.
  • One half of the charge of magnesium stearate is added.
  • the mixture is homogenised for 15 minutes.
  • Briquets of resistance to crushing 40 - 70 N are compressed from a composition prepared in this way which are then milled through a sieve of a mesh size 0.8 mm. Rest of the charge of mannitol is added to the mixture prepared in this way. The mixture is homogenised for 15 minutes. The rest of the charge of magnesium stearate is added to the mixture in the homogenisation apparatus. The mixture is mixed for 15 minutes. Tablet cores are compressed from the prepared composition on a tabletting press. Tablet cores are coated with a suspension prepared from film-formation substances.
  • Example 5 a pharmaceutical preparation in the dosage form of powder in a sachet of the composition as follows:
  • composition Amount in g % by weight Perindopril erbumine 0.00400 g 2.50 % Microcrystalline cellulose 0.1176O g 73.50 % Mannitol 0.01600 g 10.00 %
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and sodium citrate dihydrate are added to Premix l and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and a half of the charge of mannitol and a half of the charge of sodium crosscarmellose are added.
  • the mixture is homogenised for 15 minutes.
  • One half of the charge of magnesium stearate is added to the homogenised raw materials.
  • the mixture is homogenised for 15 minutes.
  • the mixture prepared in this way is compacted, the compactate is then milled through a sieve of a mesh size 0.8 mm. 50 % of the charge of mannitol and the rest half of the charge of sodium crosscarmellose are added to the mixture prepared in this way.
  • the mixture is homogenised for 15 minutes.
  • the rest of the charge of magnesium stearate is added to the mixture in the homogenisation apparatus.
  • the mixture is mixed for 15 minutes.
  • the prepared composition is filled in OPA/Alu/PVC sachets.
  • Example 6 a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows:
  • composition Amount in g % by weight Perindopril erbumine 0.0040 g 40.00%
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and sodium hydrogen phosphate are added to Premix I and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added.
  • the mixture is homogenised for 15 minutes.
  • magnesium stearate is added.
  • the mixture is homogenised for 15 minutes.
  • Micro-tablets of the prescribed mass and appearance are compressed from the composition prepared in this way.
  • Example 7 a) a pharmaceutical preparation in the dosage form of powder filled in capsules of the composition as follows:
  • Composition Amount in g % by weight Perindopril erbumine 0.00400 g 2.50 % Microcrystalline cellulose 0.03200 g 20.00 % Mannitol 0.1112O g 69.50 %
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and potassium phosphate are added to Premix l and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and mannitol and sodium, crosscarmellose are added.
  • the mixture is homogenised for 15 minutes.
  • magnesium stearate is added.
  • the mixture is homogenised for 15 minutes.
  • the prepared composition is filled in gelatine capsules.
  • Example 8 a pharmaceutical preparation in the dosage form of powder filled in capsules of the composition as follows:
  • composition Amount in g % by weight Perindopril erbumine 0.00200 g 1.00 %
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and potassium hydroxide are added to Premix l and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and a half of the charge of mannitol and a half of the charge of sodium crosscarmellose are added.
  • the mixture is homogenised for 15 minutes.
  • One half of the charge of magnesium stearate is added to the homogenised raw materials.
  • the mixture is homogenised for 15 minutes.
  • the mixture prepared in this way is compacted, the compactate is then milled through a sieve of a mesh size 0.8 mm. 50 % of the charge of mannitol and the rest half of the charge of sodium crosscarmellose are added to the mixture prepared in this way.
  • the mixture is homogenised for 15 minutes.
  • the rest of the charge of magnesium stearate is added to the mixture in the homogenisation apparatus.
  • the mixture is mixed for 15 minutes.
  • the prepared composition is filled in gelatine capsules.
  • Example 9 a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows:
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and magnesium oxide are added to Premix I and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added.
  • the mixture is homogenised for 15 minutes.
  • magnesium stearate is added.
  • the tablets are packed in blisters made of PVC/PVDC/A1 foil.
  • Example 10 a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows: Composition Amount in g % by weight Perindopril erbumine 0.00400 g 2.50 % Microcrystalline cellulose 0.03200 g 20.00 % Mannitol 0.1120O g 70.00 % Magnesium oxide 0.00080 g 0.50 % Sodium crosscarmellose 0.00800 g 5.00 % Magnesium stearate 0.00320 g 2.00 % Total sum: 0.16000 g 100.00 %
  • the active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus.
  • the mixture is homogenised for 10 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I).
  • Rest of microcrystalline cellulose and magnesium oxide are added to Premix I and the mixture is homogenised for 15 minutes.
  • the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II).
  • Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added.
  • the mixture is homogenised for 15 minutes.
  • magnesium stearate is added.
  • the tablets are packed in blisters made of OPA/Alu/PVC/Al foil.
  • Dissolution apparatus complying with Ph.Eur., paddle type, rotation speed 50 rpm
  • the invention may be utilised in the production of stable pharmaceutical forms - powder compositions, tablet cores, tablets, coated tablets, micro-tablets, for preparation of pellets, micro-These dosage forms comprising perindopril erbumine may be used in the treatment of hypertension.

Abstract

The subject matter of the invention is a pharmaceutical preparation comprising perindopril erbumine in a stable form within the rage 1 to 40 % by weight and at least one excipient and/or a mixture of excipients within the range 1 % - 99 % by weight, whereas at least one excipient is a substance of basic character maintaining pH 7.1 to 14. The subject matters of the invention are also a method of preparing, stabilising and packing of an oral pharmaceutical preparation in the dosage form of tablets, and/or coated tablets, and/or capsules which is used as an oral therapeutic of hypertension. The principle of manufacturing method consists in preparation of a compound comprising an alkalising excipient by dry mixing of powder components, and/or briqueting, and/or compacting, and modification of particle size of a compound. The compound prepared in this way may be used for compression of tablet cores, and/or tablets, and/or micro-tablets, and/or preparation of pellets, and/or micro-pellets, and/or powders and/or granules, and/or fill in capsules.

Description

Pharmaceutical preparation comprising perindopril erbumine and method of preparation and stabilisation thereof
Technical Field
The invention in the field of pharmacy relates to a pharmaceutical preparation containing perindopril erbumine, the preparation of a pharmaceutical composition containing perindopril erbumine and the way of stabilisation of the product prepared thereof. The composition can be used for preparation of tablet cores, tablets, micro-tablets, for preparation of pellets, powders, granules and as the fill in capsules. The drug product is used for treatment of hypertension, it acts as an ACE inhibitor.
Beckground Art
At present the dose of active pharmaceutical ingredient perindopril erbumine administered in pharmaceutical forms of oral medicinal products manufactured worldwide and showing a quick commencement of effect is within the range 2 mg to 8 mg. Low stability of a product prepared from the active pharmaceutical ingredient perindopril erbumine (API), as described in the patent EP 1 354 873 (patent application WO03087050), at the conditions 4O0C ± 2°C, RH 75% ± 5% or 300C ± 20C, RH 60% ± 5% is a disadvantage of the active pharmaceutical ingredient. Stabilisation of the pharmaceutical preparation by use of a new salt of perindopril (arginine salt of perindopril) is described in the aforesaid patent application. The medicinal preparation prepared from the arginine salt of perindopril shows significantly better stability at the defined conditions:
250C ± 2°C, RH 60% ± 5% 300C ± 2°C, RH 60% ± 5% 4O0C ± 20C, RH 75% ± 5%, than the pharmaceutical preparation prepared from perindopril erbumine (perindopril tert- butylamine).
Patent EP 1 354 873 (patent application WO03087050) describes the preparation of tablets containing various salts of perindopril, and describes exposition of individual pharmaceutical preparations containing various salts of perindopril to heat stress. Based on the stress tests, the arginine salt of perindopril was selected and used in the stability tests at the aforesaid conditions. The stability results show that the arginine salt of perindopril is more suitable for preparation of a stable pharmaceutical preparation than perindopril erbumine (perindopril tert-butylamine).
The patent EP 1 354 873 (patent application WO03087050) does not address stabilisation of a pharmaceutical product containing perindopril erbumine. Based on the aforesaid facts from the point of view of stability, the preparation of a stable pharmaceutical product containing perindopril might be possible, or more eligible, if the arginine salt of perindopril is used.
In spite thereof perindopril erbumine is used worldwide for preparation of tablets used in human medicine as an oral therapeutic of hypertension.
The patent GB 2 394 660 A deals with stabilisation of the pharmaceutical composition containing an ACE inhibitor, thus also perindopril, by elimination of an acidic excipient having a big specific surface area, where colloidal silicon dioxide is presented as an example. According to the patent GB 2 394 660 A, the stabilisation of the product is ensured by elimination of colloidal silicon dioxide from a composition or tablets.
In the aforementioned patents, in the stability tests or compatibility tests two principal impurities are controlled, named as impurities B and F in accordance with PhEur. 4.
The impurity B is (2S,3aS,7aS)-l-[(S)-N-[(S)-l-carboxybutyl]alanyl]octahydro-lH- indol-2-carboxylic acid.
Figure imgf000003_0001
The impurity F is ethyl (2S)-2-[(3S,5aS,9aS,10aS)-3-methyl-l,4- dioxoperhydropyrazino [1 ,2-a]indol-2-yl]pentanoate.
Figure imgf000004_0001
Disclosure of the Invention
The subject matter of the invention is a pharmaceutical preparation comprising perindopril erbumine in a stable form within the rage 1 to 40 % by weight and at least one excipient and/or a mixture of excipients within the range 1 % - 99 % by weight, whereas at least one excipient is a substance of basic character maintaining pH 7.1 to 14.
Substances of basic character are pharmaceutical excipients maintaining pH between 7.1 and 14, preferably those maintaining pH between 7.1 and 12.
Substances of basic character are substances of the group of oxides, hydroxides, hydrogen carbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, citronates of alkali or alkaline earth metal salts and hydrates thereof.
A further embodiment of the present invention provides a pharmaceutical preparation comprising perindopril erbumine in the form of a tablet and/or coated tablet and/or fill of capsules in which the active ingredient - perindopril erbumine - is contained in an amount 1 - 50 mg, i.e. 1 - 40% by weight, and a principal excipient in a composition is a substance of basic character maintaining pH, in an amount 0.1 - 40% by weight, and other excipients are polyols, and/or mixtures thereof, and/or mixtures of polyols and other fillers, and/or mixtures of polyols and disintegrants, and/or mixtures of polyols and glidants, and/or mixtures of polyols and glidants and disintegrants, and/or mixtures of polyols, glidants, disintegrants and other fillers.
A further embodiment of the present invention provides a pharmaceutical preparation comprising a substance of basic character in an amount 0.1 - 40 % by weight, preferably 0.1 - 15 % by weight.
A further embodiment of the present invention provides a pharmaceutical preparation comprising in an amount 1 to 99 % by weight, preferably 10 to 95 % by weight, polyols and/or mixtures thereof, preferably mannitol and/or mixtures thereof. A further embodiment of the present invention provides a pharmaceutical preparation comprising other fillers in an amount 1 to 99 % by weight, preferably 10 to 95 % by weight, preferably microcrystalline cellulose with reduced content of water.
A further embodiment of the present invention provides a pharmaceutical preparation comprising in an amount 1 to 25 % by weight, preferably 1,5 to 10 % by weight, a disintegrant or disintegrants, preferably sodium crosscarmellose.
A further embodiment of the present invention provides a pharmaceutical preparation comprising 0.1 to 10 % by weight, preferably 0.5 to 4 % by weight, a glidant or glidants, preferably magnesium stearate.
The subject matter of the invention is also a method of preparing a pharmaceutical preparation consisting in preparation of a composition of the active ingredient with at least one excipient of basic character by mixing of powder components, and/or briqueting, and/or compacting, modification of particle size in the range 100 to 2000 μm, preferably, 800 μm, whereas the prepared composition is used for compression of tablet cores, and/or tablets, and/or micro-tablets, and/or preparation of pellets, and/or micro-pellets, and/or powders and/or granules, and/or fill in capsules.
The subject matter of the invention is also the packing of the pharmaceutical form of the pharmaceutical preparation in pharmaceutical containers protecting he preparation from air humidity, preferably comprising Al (aluminium) / OPA (orientated polyamide) / PVC (polyvinyl chloride) / Al (aluminium).
The subject matter of the invention is also the way of stabilising a composition, or pharmaceutical form, containing perindopril erbumine as active ingredient, used in the treatment of hypertension.
Selection of factors causing instability of a preparation containing perindopril erbumine is based on results of a series of tests of compatibility of compositions containing perindopril erbumine and excipients and a series of stress tests of finished product. Air humidity was identified as one of the principal factors incurring increase of impurity B. That is why elimination of water or humidity in excipients, in the process of preparation and during storage is essential. The principal factor stabilizing the impurity F was maintaining pH in the range 7.1 - 14. The principle of stabilization of a composition or pharmaceutical product consists in preparation of a composition by mixing of powder components, and/or briqueting, and/or compacting (absence of water in the process of preparation -> stabilisation of impurity B of perindopril erbumine), containing a substance buffering pH in the range 7.1 - 14 (stabilisation of impurity F of perindopril erbumine), and/or modification of particle size of a composition.
The composition prepared in this way may be used for compression of tablet cores, and/or tablets, and/or micro-tablets, and/or preparation of pellets, and/or micro-pellets, and/or powders and/or granules, and/or fill in capsules.
The aforementioned pharmaceutical forms prepared in this way are packed in aluminium containers or containers comprising aluminium - aluminium combined with various types of polymers used in the pharmaceutical industry as packing material(s) - stabilisation of impurity B (protection from air humidity)
The presented ways of preparation do not include stress procedures as adding a wetting substance in a composition comprising an active ingredient and excipients. The presented ways of preparation and the choice of excipients as described in this invention also ensure good stability of the preparation and required physical characteristics of the pharmaceutical form.
A composition, or pharmaceutical form, as described in the invention, may comprise besides the active ingredient perindopril erbumine of the formula:
Figure imgf000006_0001
and a substance basifying a composition or pharmaceutical form, also other excipients as: microcrystalline cellulose and polyols - fillers, substances modifying flowing properties of a composition, glidants - substances making compression of tablets easier, disintegrants - substances speeding up disintegration of tablets.
As substances maintaining pH in the range 7.1 - 14, common excipients were used, for example: sodium hydrogen carbonate, powdered sodium hydroxide, powdered potassium hydroxide, sodium citrate and hydrates thereof, potassium phosphate, sodium phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, magnesium oxide and other basifying substances.
Microcrystalline cellulose was used as an excipient, a substance used in the pharmaceutical industry. Properties of this excipient ensure acceptable flowing properties of a composition and easy compression of pressed pieces (tablet cores, tablets, micro-tablets, pellets, micro-pellets).
Polyols used are excipients which are ideally suitable for formulation of solid pharmaceutical forms using a dry procedure. The physico-chemical parameters of these excipients ensure a very good stability of the preparation and complying physico-chemical parameters of tablets. The aforementioned properties described in this invention were repeatedly achieved by use of physically modified polyols, for example mannitol.
The modified mannitol used (Pearlitol) is a white, crystalline powder (or granulate). The properties of this excipient ensure very good flowing characteristics of a composition and a very good ability of direct compression. Other characteristics include a low hygroscopicity and a chemical stability. These characteristics ensure an excellent stability of a preparation comprising perindopril erbumine prepared as described in this invention.
As disintegrants following substances were used: starches, modified starch, derivatives of cellulose, cross-linked polyvinylpyrrolidones, and others.
As glidants used in the pharmaceutical industry salts of higher aliphatic acids were used, for example: stearates, oleates, laurylsulphates, and others.
A principle of the technological procedure is mixing of the active ingredient perindopril erbumine and/or at least one excipient with:
- a substance of basic reaction (stabilisation of impurity F of perindopril erbumine) by maintaining pH in the range 7.1 - 14, preferably pH in the range 7.1 - 12, in an amount 0.1 to 40 % by weight, preferably 0.1 to 15 % by weight; or
- a mixture of microcrystalline cellulose, preferably microcrystalline cellulose with reduced content of water (stabilisation of impurity B of perindopril erbumine), and/or a substance of basic reaction (stabilisation of impurity F of perindopril erbumine) maintaining pH in the range 7.1 - 17 % by weight, preferably 7.1 - 12 % by weight, in an amount 0.1 to 40 % by weight, preferably 0.1 to 15 % by weight; or a mixture comprising 1 to 99 % by weight, preferably 50 to 90 % by weight, of a substance of a group of polyols of a particle size 10 - 1000 μm, and/or mannitol of a particle size 100 to 520 μm, preferably 180 to 360 μm, and/or microcrystalline cellulose, preferably microcrystalline cellulose with reduced content of water (helps to stabilise impurity B of perindopril erbumine), and/or a substance of basic reaction (stabilisation of impurity F of perindopril erbumine) maintaining pH in the range 7.1 - 14, preferably pH 7.1 - 11, in an amount 0.1 to 40 % by weight, preferably 0.1 to 15 % by weight; or a mixture comprising 1 to 99 % by weight, preferably 50 to 90 % by weight, substances of a group of polyols of a particle size 10 - 1000 μm, and/or mannitol of a particle size 100 to 520 μm, preferably 180 to 360 μm, and/or microcrystalline cellulose, preferably microcrystalline cellulose with reduced content of water (helps to stabilise impurity B of perindopril erbumine), and/or a substance of basic reaction (stabilisation of impurity F of perindopril erbumine) maintaining pH in the range 7.1 - 14, preferably pH 7.1 - 12, in an amount 0.1 to 40 % by weight, preferably 0.1 to 15 % by weight, and/or 1 to 25 % by weight, preferably 1.5 to 10 % by weight of disintegrant, preferably sodium crosscarmellose; or a mixture comprising 1 to 99 % by weight, preferably 50 to 90 % by weight, substances of a group of polyols of a particle size 10 - 1000 μm, and/or mannitol of a particle size 100 to 520 μm, preferably 180 to 360 μm, and/or microcrystalline cellulose, preferably microcrystalline cellulose with reduced content of water (helps to stabilise impurity B of perindopril erbumine), and/or a substance of basic reaction (stabilisation of impurity F of perindopril erbumine) maintaining pH in the range 7.1 - 14, preferably pH 7.1 - 12, in an amount 0.1 to 40 % by weight, preferably 0.1 to 15 % by weight, and/or 0.1 to 10 % by weight, preferably 0.5 to 4 % by weight of glidant, preferably magnesium stearate.
A composition or tablets may be prepared from the aforesaid compositions by dry procedure using a few manufacturing methods, or a combination of these, namely:
1. direct compression (preparation of a composition → solid dosage form)
2. compacting (preparation of a composition → compacting → modification of particle size→ solid dosage form) 3. briqueting (preparation of a composition → briqueting → modification of particle size → solid dosage form).
The solid dosage forms prepared according to this invention ensure that a manufacturing process is reproducible.
These processes are neither much energy nor long time demanding, what is of advantage, especially in the first procedure of the aforementioned procedures of preparation of a composition and solid dosage forms comprising perindopril erbumine.
The aforementioned processes of preparation of a composition comprising the active ingredient and excipients, and solid dosage forms comprising perindopril erbumine by direct compression (without adding of water or increasing moisture content as one of the principle factors incurring increase of impurity B of perindopril erbumine), or use of excipients maintaining pH in the range 7.1 - 14 in accordance with this invention enable to prepare a stable composition of the active ingredient and excipients or stable dosage forms with complying physical and chemical parameters.
Maintaining pH in the alkaline range significantly improves stability of impurity F which was within the specified acceptance limits in the stress tests, consequently the active ingredient perindopril erbumine was more stable in a dosage form described in this invention, where a basic component was used, than in a dosage form prepared without a basic component - stabilisation of impurity F.
The elimination of transfer of air humidity is the last but not least in the process of stabilisation of a preparation prepared according to this invention, where a pharmaceutical container suitable for this purpose is used (example: containers comprising aluminium - aluminium combined with various types of polymers used in the pharmaceutical industry as packing material(s), whereas these containers may be provided with a drier) - stabilisation of impurity B.
Best Mode for Carrying Out the invention
It is understood that the present invention is described by way of examples. The examples are not intended to limit the scope of the invention.
Example 1: a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows: Composition Amount in g % by weight Perindopril erbumine 0.00400 g 2.50 % Microcrystalline cellulose 0.03200 g 20.00 % Mannitol 0.1120O g 70.00 % Magnesium oxide 0.00080 g 0.50 % Sodium crosscarmellose 0.00800 g 5.00 % Magnesium stearate 0.00320 g 2.00 % Total sum: 0.1600O g 100.00 % b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and magnesium oxide are added to Premix I and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added. The mixture is homogenised for 15 minutes. Then magnesium stearate is added. The mixture is homogenised for 15 minutes. Tablets of the prescribed C C C tQQfQrqff mass and appearance are compressed from the composition prepared in this way.
Example 2: a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows:
Perindopril erbumine 0.00200 2.50 %
Microcrystalline cellulose 0.00800 10.00 %
Mannitol 0.06600 g 82.50 %
Sodium hydrogen carbonate 0.00240 3.00 %
Sodium crosscarmellose 0.00120 S 1.50 %
Magnesium stearate 0.00040 g 0.50 %
Total sum: 0.08000 100.00 %
b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and sodium hydrogen carbonate are added to Premix I and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added. The mixture is homogenised for 15 minutes. Then magnesium stearate is added. The mixture is homogenised for 15 minutes. Tablets of the prescribed mass and appearance are compressed from the composition prepared in this way. Example 3:
a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows:
Composition Amount in g % by weight Perindopril erbumine 0.00800 g 2.50 % Microcrystalline cellulose 0.12800 g 40.00 % Mannitol 0.1136O g 35.50 % Sodium citrate 0.04800 g 15.00 % Sodium crosscarmellose 0.01600 g 5.00 % Magnesium stearate 0.00640 g 2.00 % Total sum: 0.32000 g 100.00 % b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and sodium citrate are added to Premix I and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added. The mixture is homogenised for 15 minutes. Then magnesium stearate is added. The mixture is homogenised for 15 minutes. Tablets of the prescribed mass and appearance are compressed from the composition prepared in this way.
Example 4: a) a pharmaceutical preparation in the dosage form of coated tablets of the composition as follows:
Perindopril erbumine 0.00400 g 2.50 % Mannitol 0.15200 g 95.00 %
Sodium hydroxide 0.00080 g 0.50 % Magnesium stearate 0.00320 g 2.00 % Total sum: 0.1600O g 100.00 %
5% of
Mixture of film-formation substances 0.00800 g tablet core mass Water purified / Ethanol 0.04500 g b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and sodium hydroxide are added to Premix I and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and one half of the charge of mannitol is added. The mixture is homogenised for 15 minutes. One half of the charge of magnesium stearate is added. The mixture is homogenised for 15 minutes. Briquets of resistance to crushing 40 - 70 N are compressed from a composition prepared in this way which are then milled through a sieve of a mesh size 0.8 mm. Rest of the charge of mannitol is added to the mixture prepared in this way. The mixture is homogenised for 15 minutes. The rest of the charge of magnesium stearate is added to the mixture in the homogenisation apparatus. The mixture is mixed for 15 minutes. Tablet cores are compressed from the prepared composition on a tabletting press. Tablet cores are coated with a suspension prepared from film-formation substances.
Example 5: a pharmaceutical preparation in the dosage form of powder in a sachet of the composition as follows:
Composition Amount in g % by weight Perindopril erbumine 0.00400 g 2.50 % Microcrystalline cellulose 0.1176O g 73.50 % Mannitol 0.01600 g 10.00 %
Sodium citrate dihydrate 0.00800 g 5.00 % Sodium crosscarmellose 0.00800 g 5.00 % Magnesium stearate 0.00640 g 4.00 % Total sum: 0.1600O g 100.00 %
b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and sodium citrate dihydrate are added to Premix l and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and a half of the charge of mannitol and a half of the charge of sodium crosscarmellose are added. The mixture is homogenised for 15 minutes. One half of the charge of magnesium stearate is added to the homogenised raw materials. The mixture is homogenised for 15 minutes. The mixture prepared in this way is compacted, the compactate is then milled through a sieve of a mesh size 0.8 mm. 50 % of the charge of mannitol and the rest half of the charge of sodium crosscarmellose are added to the mixture prepared in this way. The mixture is homogenised for 15 minutes. The rest of the charge of magnesium stearate is added to the mixture in the homogenisation apparatus. The mixture is mixed for 15 minutes. The prepared composition is filled in OPA/Alu/PVC sachets.
Example 6: a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows:
Composition Amount in g % by weight Perindopril erbumine 0.0040 g 40.00% Microcrystalline cellulose 0.0008 g 8.00% Mannitol 0.0035 g 35.00%
Sodium hydrogen phosphate 0.0005 g 5.00% Sodium crosscarmellose 0.0010 g 10.00% Magnesium stearate 0.0002 g 2.00% Total sum: 0.0100 g 100.00% b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and sodium hydrogen phosphate are added to Premix I and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added. The mixture is homogenised for 15 minutes. Then magnesium stearate is added. The mixture is homogenised for 15 minutes. Micro-tablets of the prescribed mass and appearance are compressed from the composition prepared in this way.
Example 7: a) a pharmaceutical preparation in the dosage form of powder filled in capsules of the composition as follows:
Composition Amount in g % by weight Perindopril erbumine 0.00400 g 2.50 % Microcrystalline cellulose 0.03200 g 20.00 % Mannitol 0.1112O g 69.50 %
Potassium phosphate 0.0016O g 1.00 % Sodium crosscarmellose 0.00800 g 5.00 % Magnesium stearate 0.00320 g 2.00 % Total sum: 0.16000 g 100.00 % b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and potassium phosphate are added to Premix l and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and mannitol and sodium, crosscarmellose are added. The mixture is homogenised for 15 minutes. Then magnesium stearate is added. The mixture is homogenised for 15 minutes. The prepared composition is filled in gelatine capsules.
Example 8: a pharmaceutical preparation in the dosage form of powder filled in capsules of the composition as follows:
Composition Amount in g % by weight Perindopril erbumine 0.00200 g 1.00 % Microcrystalline cellulose 0.04000 g 20.00 % Mannitol 0.1438O g 71.90 %
Potassium hydroxide 0.00020 g 0.10 % Sodium crosscarmellose 0.01000 g 5.00 % Magnesium stearate 0.00400 g 2.00 % Total sum: 0.20000 g 100.00 %
b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and potassium hydroxide are added to Premix l and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and a half of the charge of mannitol and a half of the charge of sodium crosscarmellose are added. The mixture is homogenised for 15 minutes. One half of the charge of magnesium stearate is added to the homogenised raw materials. The mixture is homogenised for 15 minutes. The mixture prepared in this way is compacted, the compactate is then milled through a sieve of a mesh size 0.8 mm. 50 % of the charge of mannitol and the rest half of the charge of sodium crosscarmellose are added to the mixture prepared in this way. The mixture is homogenised for 15 minutes. The rest of the charge of magnesium stearate is added to the mixture in the homogenisation apparatus. The mixture is mixed for 15 minutes. The prepared composition is filled in gelatine capsules.
Example 9: a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows:
Composition Amount in g % by weight
Perindopril erbumine 0.00400 g 2.50 %
Microcrystalline cellulose 0.03200 g 20.00 %
Mannitol 0.1120O g 70.00 %
Magnesium oxide 0.00080 g 0.50 %
Sodium crosscarmellose 0.00800 g 5.00 %
Magnesium stearate 0.00320 g 2.00 %
Total sum: 0.1600O g 100.00 % b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and magnesium oxide are added to Premix I and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added. The mixture is homogenised for 15 minutes. Then magnesium stearate is added. The mixture is homogenised for 15 minutes. Tablets of the prescribed mass and appearance are compressed from the composition prepared in this way. The tablets are packed in blisters made of PVC/PVDC/A1 foil.
Example 10: a) a pharmaceutical preparation in the dosage form of tablets of the composition as follows: Composition Amount in g % by weight Perindopril erbumine 0.00400 g 2.50 % Microcrystalline cellulose 0.03200 g 20.00 % Mannitol 0.1120O g 70.00 % Magnesium oxide 0.00080 g 0.50 % Sodium crosscarmellose 0.00800 g 5.00 % Magnesium stearate 0.00320 g 2.00 % Total sum: 0.16000 g 100.00 %
b) method of preparing:
The active ingredient is placed together with part of microcrystalline cellulose into a homogenisation apparatus. The mixture is homogenised for 10 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix I). Rest of microcrystalline cellulose and magnesium oxide are added to Premix I and the mixture is homogenised for 15 minutes. Then the mixture is sieved through a sieve of a mesh size 0.40 mm (Premix II). Premix II is transferred into a homogenisation apparatus and mannitol and sodium crosscarmellose are added. The mixture is homogenised for 15 minutes. Then magnesium stearate is added. The mixture is homogenised for 15 minutes. Tablets of the prescribed mass and appearance are compressed from the composition prepared in this way. The tablets are packed in blisters made of OPA/Alu/PVC/Al foil.
Results of dissolution of active ingredient
Dissolution of active pharmaceutical ingredient perindopril erbumine in vitro was tested under the conditions as follows:
Apparatus used: Dissolution apparatus complying with Ph.Eur., paddle type, rotation speed 50 rpm
Medium: 0.1 moll"1 HCl, volume 500 ml
Temperature: 37 °C ± 0.5 °C
Method of determination of dissoluted active ingredient HPLC
The dissolution of active pharmaceutical ingredient from the dosage form is illustrated on examples of embodiment No. 1, 9 and 10, and the results of dissolution test are presented in the following table.
Table:
Dissolution of active harmaceutical in redient
Figure imgf000016_0001
The results of dissolution of active pharmaceutical ingredient show that within 5 minutes all amount of active pharmaceutical ingredient is dissoluted from a dosage form. Results of stability of preparation
The content of related substances (purity) is illustrated on examples of embodiment No. 1, 9 and 10, and the results of stability are presented in the following table.
Stabilisation of impurity B - comparison of tablets comprising a basifying component packed in the PVC/PVDC/A1 blister with those packed in the AIu- AIu blister.
Figure imgf000017_0001
Tablets comprising perindopril were controlled in accordance with Ph.Eur. 4.
Stabilisation of impurity F - comparison of tablets comprising basifying component with those without basifying component, both packed in container AIu- AIu
Figure imgf000017_0002
Tablets comprising perindopril were controlled in accordance with Ph.Eur. 4. Industrial Applicability
The invention may be utilised in the production of stable pharmaceutical forms - powder compositions, tablet cores, tablets, coated tablets, micro-tablets, for preparation of pellets, micro-These dosage forms comprising perindopril erbumine may be used in the treatment of hypertension.

Claims

C L A I M S
1. A pharmaceutical preparation comprising perindopril erbumine in a stable form within the rage 1 to 40 % by weight and at least one excipient and/or a mixture of excipients within the range 1 % to 99 % by weight, characterised in that at least one excipient is a substance of basic character maintaining pH in the range 7.1 to 14.
2. A pharmaceutical preparation comprising perindopril erbumine of claim 1 characterised in that the substances of basic character are excipients maintaining pH in the range 7.1 to 14, preferably maintaining pH in the range 7.1 to 12.
3. A pharmaceutical preparation comprising perindopril erbumine of claims 1 and 2, characterised in that the substances of basic character are substances of the group of oxides, hydroxides, hydrogen carbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, citronates of alkali or alkaline earth metal salts and hydrates thereof.
4. A pharmaceutical preparation comprising perindopril erbumine of claims 1 to 3 characterised in that it is in the form of a tablet and/or coated tablet and/or fill of capsules in which the active ingredient - perindopril erbumine - is contained in an amount 1 - 50 mg, i.e. 1 - 40% by weight, and a principle excipient in a composition is a substance of basic character maintaining pH as presented in claims 1 to 3, in an amount 0.1 - 40% by weight, and other excipients are polyols, and/or mixtures thereof, and/or mixtures of polyols and other fillers, and/or mixtures of polyols and disintegrants, and/or mixtures of polyols and glidants, and/or mixtures of polyols and glidants and disintegrants, and/or mixtures of polyols, glidants, disintegrants and other fillers.
5. A pharmaceutical preparation comprising perindopril erbumine of claims 1 to 4 characterised in that it contains a substance of basic character in an amount 0.1 to 40 % by weight, preferably 0.1 to 15 % by weight.
6. A pharmaceutical preparation comprising perindopril erbumine of claims 1 to 5 characterised in that it contains in an amount of 1 to 99 % by weight, preferably 10 to 95 % by weight, polyols and/or mixtures thereof, preferably mannitol and/or mixtures thereof.
7. A pharmaceutical preparation comprising perindopril erbumine of claims 1 to 6 characterised in that it contains in an amount of 1 to 99 % by weight, preferably 10 to 40 % by weight, other fillers, preferably microcrystalline cellulose with reduced content of water.
8. A pharmaceutical preparation comprising perindopril erbumine of claims 1 to 7 characterised in that it contains in an amount 1 to 25 % by weight, preferably 1.5 to 10 % by weight, a disintegrant or disintegrants, preferably sodium crosscarmellose.
9. A pharmaceutical preparation comprising perindopril erbumine of claims 1 to 8 characterised in that it contains in an amount 0.1 to 10 % by weight, preferably 0.5 to 4 % by weight, a glidant or glidants, preferably magnesium stearate.
10. A method of preparing a pharmaceutical preparation of claims 1 to 9 characterised in that a composition of the active ingredient with at least one excipient of basic character is prepared by dry mixing of powder components, and/or briqueting, and/or compacting, modification of particle size in the range 100 to 2000 μm, preferably, 800 μm, whereas the prepared composition is used for compression of tablet cores, and/or tablets, and/or micro- tablets, and/or preparation of pellets, and/or micro-pellets, and/or powders and/or granulates, and/or fill in capsules.
11. A method of stabilising a pharmaceutical preparation comprising perindopril erbumine of claims 1 to 10 characterised in that the pharmaceutical form of the pharmaceutical preparation is packed in pharmaceutical containers preventing transfer of air humidity to the preparation, preferably comprising Al (aluminium) / OPA (orientated polyamide) / PVC (polyvinyl chloride) / Al (aluminium).
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WO2007120930A2 (en) * 2006-04-19 2007-10-25 Teva Pharmaceutical Industries Ltd. Stable pharmaceutical compositions of 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivatives
WO2007120930A3 (en) * 2006-04-19 2008-02-07 Teva Pharma Stable pharmaceutical compositions of 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivatives
US8470869B2 (en) 2007-06-27 2013-06-25 Krka, Tovarna Zdravil D.D. Novo Mesto Salts of perindopril
WO2016178591A2 (en) 2015-05-05 2016-11-10 Gene Predit, Sa Genetic markers and treatment of male obesity

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