WO2008150245A2 - Stable formulation of amorphous perindopril salts, a process for the preparation thereof on industrial scale and use thereof in the treatment of hypertension - Google Patents

Stable formulation of amorphous perindopril salts, a process for the preparation thereof on industrial scale and use thereof in the treatment of hypertension Download PDF

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Publication number
WO2008150245A2
WO2008150245A2 PCT/SI2008/000031 SI2008000031W WO2008150245A2 WO 2008150245 A2 WO2008150245 A2 WO 2008150245A2 SI 2008000031 W SI2008000031 W SI 2008000031W WO 2008150245 A2 WO2008150245 A2 WO 2008150245A2
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Prior art keywords
perindopril
process according
preparation
alkali
alkaline earth
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PCT/SI2008/000031
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French (fr)
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WO2008150245A3 (en
Inventor
Rudolf Rucman
Pavel Zupet
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Silverstone Pharma
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.)
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Publication date
Application filed by Silverstone Pharma filed Critical Silverstone Pharma
Priority to EP08754036A priority Critical patent/EP2164469A2/en
Priority to CN2008800187504A priority patent/CN101742986B/en
Publication of WO2008150245A2 publication Critical patent/WO2008150245A2/en
Publication of WO2008150245A3 publication Critical patent/WO2008150245A3/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
    • A61K9/14—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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • B + represents an alkali or alkaline earth metal cation, a process for the preparation thereof on an industrial scale and the use thereof in treating hypertension.
  • formulations comprise the active component perindopril erbumine in different polymorphic forms of formula II:
  • Patent application US 6,696,481 discloses the salt of perindopril with arginine, which is more stable than erbumine. At the same time the disadvantages of erbumine are stated and it is also mentioned that sodium salt of perindopril in its pure form is unstable for the formulation, because it turns to oil and decomposes when exposed to air.
  • Our previous patent application WO 2007/058634 Al discloses the preparation of a stable formulation of perindopril in the form of an amorphous sodium salt on an inert carrier, starting from perindopril erbumine or perindopril erbumine hydrate.
  • the stable formulations of amorphous perindopril salts are prepared directly from perindopril (acid) without the intermediate step of erbumine salt.
  • Perindopril in the form of a free acid is (2S,3aS,7aS)-l-[(2S)-2-[[(l 1 S)-l- ethoxycarbonyl)butyl] amino- 1 -oxopropyl] octahydro- lH-indole-2-carboxylic acid of formula III:
  • Free acid of formula III can be used in the form of an oil, resinous substance, crystals, aqueous solution, or a solution in a water-solvent mixture.
  • perindopril salts with alkali and earth alkaline bases can be formed directly when perindopril is dissolved in alcohol and to which a solution of a suitable base in water in a molar ratio 1 : 1 is added during intense stirring. This solution is then sprayed onto a calculated amount of inert ingredients for tabletting (lactose, starch, cellulose) and dried in a stream of warm air at 30-50 0 C or in vacuum.
  • dry substance (first granulate) other additives are admixed, optionally also other active substances (diuretics), by trituration in order to obtain a final mixture - second granulate, which is then tabletted.
  • common disintegrating agents such as croscarmellose, crospovidone, aerosil etc.
  • This process can also be used to prepare said composition by triturating the first granulate, obtained after the granulation phase, in an air stream with other necessary ingredients, wherein simultaneously micronized indapamide is added.
  • the ratio of perindopril and indapamide is 4 : 1.25.
  • Perindopril (free acid) (7.9 g, 21.4 mmole) was dissolved separately in ethanol (96 %; 35 mL). The solution of sodium hydrogen carbonate (2.0 g, 23.8 mmole) in water (35 mL) was prepared separately. Both solutions were combined and stirred for 10 min, pH must be in the range from 7.0 to 7.5.
  • This mixture was then sprayed in a stream of warm air having a temperature of 30-50 0 C onto the previously prepared mixture consisting of lactose (142 g), corn starch (6 g) and microcrystalline cellulose (42.6 g). It was dried with warm air to reach the water content 0.5-1.5 % (K. Fischer method). About 200 g of the first granulate, containing 4.17 % of sodium salt of perindopril was obtained.
  • Perindopril (7.9 g, 21.4 mmole) was dissolved in ethanol (96 %; 35 mL).
  • Perindopril (7.9 g, 21.4 mmole) was dissolved in ethanol (96 %; 35 mL) and the obtained solution was slowly added to the suspension of calcium hydroxide (0.95 g, 12.8 mmole) during intense stirring, and stirred for 30 min.
  • the pH-value must be in the range from 7.0 to 7.5.
  • the obtained slightly turbid solution was filtered to clarify.
  • Example 1 The solution was further processed to granulate and tablets as described in Example 1.
  • Perindopril (7.9 g, 21.4 mmole) was dissolved in ethanol (96 %; 35 mL).
  • This mixture was then sprayed in a stream of warm air having a temperature of 30-50 0 C to the previously prepared mixture consisting of lactose (140.0 g), corn starch (5.9 g) and microcrystalline cellulose (41.75 g). It was dried in a stream of warm air to reach the water content of 0.5-1.5 %.
  • composition for 22000 tablets of perindopril sodium salt contains 3.53 mg of perindopril sodium (which corresponds to 4 mg of perindopril erbumine).
  • Perindopril (acid) (0.079 kg) was dissolved in ethanol (96 %; 400 mL). Separately a solution of sodium hydrogen carbonate (0.018 kg) in water (200 mL) was prepared. Both solutions were mixed whilst stirring.
  • WSG type Glatt GPCG-I a dry blend of the following ingredients was prepared:
  • the final granulate was used for tabletting. It was tabletted on the tabletting machine KILIAN RLA with the rate of 30000 tablets/hour.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention discloses a preparation of a stable formulation of alkali and alkaline earth salts of perindopril in an amorphous form, wherein perindopril in the form of a free acid, dissolved in alcohol, is neutralized with an aqueous solution of alkali or alkaline earth base, this solution is thereafter sprayed onto inert substances for the preparation of a granulate and dried in a stream of warm air at 30-50 °C or in vacuum. Substances to facilitate tabletting or additional active substances, such as diuretics, preferably indapamide, are added to this granulate to be tabletted.

Description

Stable formulation of amorphous perindopril salts, a process for the preparation thereof on industrial scale and use thereof in the treatment of hypertension
Technical Field
The present invention belongs to the field of pharmaceutical chemistry and relates to a stable formulation of amorphous perindopril salts of formula I:
Figure imgf000002_0001
wherein B+ represents an alkali or alkaline earth metal cation, a process for the preparation thereof on an industrial scale and the use thereof in treating hypertension.
Technical Problem
Best known as well as most used perindopril salt is erbumine, i.e. a salt with a tertiary butyl amine, which is a very effective vasodilatator and antihypertensive agent. The low boiling point of tert-butyl amine makes this salt very thermo-sensitive and prone to decompose at elevated temperatures. Therefore, the term of durability of a medicine is considerably short, especially in the countries having average high day temperatures. Thus, there was a need for a process for the preparation of a more stable formulation of pharmaceutical preparations. Prior Art
Known formulations comprise the active component perindopril erbumine in different polymorphic forms of formula II:
Figure imgf000003_0001
These polymorphic forms are protected by appropriate patent applications: α-form by the application WO 01/87835 Al, β-form by the application WO 01/87836 Al, and γ- form by the application WO 01/83439 Al.
To enhance the stability of the preparations with perindopril erbumine, the use of addition of weak basic components is also known, mostly sodium hydrogen carbonate in a solid form, as stated in patent applications WO 2005/094793 A and DE 102004019845 Al, wherein perindoprile remains in the form of erbumine and does not react with alkaline additives.
Patent application US 6,696,481 discloses the salt of perindopril with arginine, which is more stable than erbumine. At the same time the disadvantages of erbumine are stated and it is also mentioned that sodium salt of perindopril in its pure form is unstable for the formulation, because it turns to oil and decomposes when exposed to air. Our previous patent application WO 2007/058634 Al discloses the preparation of a stable formulation of perindopril in the form of an amorphous sodium salt on an inert carrier, starting from perindopril erbumine or perindopril erbumine hydrate.
Inventive Solution
According to the present invention the stable formulations of amorphous perindopril salts are prepared directly from perindopril (acid) without the intermediate step of erbumine salt. Perindopril in the form of a free acid is (2S,3aS,7aS)-l-[(2S)-2-[[(l1S)-l- ethoxycarbonyl)butyl] amino- 1 -oxopropyl] octahydro- lH-indole-2-carboxylic acid of formula III:
Figure imgf000004_0001
It is formed in a synthesis as a thick oily substance which is not prone to crystallisation, but can be converted into a solid form by drying in a high vacuum.
Free acid of formula III can be used in the form of an oil, resinous substance, crystals, aqueous solution, or a solution in a water-solvent mixture.
It has been found that the perindopril salts with alkali and earth alkaline bases can be formed directly when perindopril is dissolved in alcohol and to which a solution of a suitable base in water in a molar ratio 1 : 1 is added during intense stirring. This solution is then sprayed onto a calculated amount of inert ingredients for tabletting (lactose, starch, cellulose) and dried in a stream of warm air at 30-50 0C or in vacuum. To thus obtained dry substance (first granulate) other additives are admixed, optionally also other active substances (diuretics), by trituration in order to obtain a final mixture - second granulate, which is then tabletted. In this step also common disintegrating agents (such as croscarmellose, crospovidone, aerosil etc.), which improve disintegrating of tablets, can be added to the first granulate.
This process is better and more advanced than our previous process (WO 2007/058634 Al), since it enables higher yields of a valuable substance and is thus less expensive. The advantage of the new process is higher purity of granulate and tablets of perindopril sodium, because no traces of f-butyl amine, known for perindopril erbumine salt, are contained.
A combination of perindopril with diuretics, such as indapamide, has been known to be very favourable in the effective treatment of hypertension.
This process can also be used to prepare said composition by triturating the first granulate, obtained after the granulation phase, in an air stream with other necessary ingredients, wherein simultaneously micronized indapamide is added. Normally, the ratio of perindopril and indapamide is 4 : 1.25.
The invention is illustrated by the following Examples, by which it is not limited.
Example 1
Perindopril (free acid) (7.9 g, 21.4 mmole) was dissolved separately in ethanol (96 %; 35 mL). The solution of sodium hydrogen carbonate (2.0 g, 23.8 mmole) in water (35 mL) was prepared separately. Both solutions were combined and stirred for 10 min, pH must be in the range from 7.0 to 7.5.
This mixture was then sprayed in a stream of warm air having a temperature of 30-50 0C onto the previously prepared mixture consisting of lactose (142 g), corn starch (6 g) and microcrystalline cellulose (42.6 g). It was dried with warm air to reach the water content 0.5-1.5 % (K. Fischer method). About 200 g of the first granulate, containing 4.17 % of sodium salt of perindopril was obtained.
By trituration corn starch (5.8 g), talc (4.7 g) and magnesium stearate (2.4 g) were added to this solution, which was then thoroughly homogenized. The obtained (second) granulate was used for tabletting and tablets having the weight of 90 mg were prepared, said tablets containing 3.53 mg of sodium salt of perindopril, which corresponds to the common therapeutical dose of 4.0 mg of perindopril erbumine.
Example 2
Perindopril (7.9 g, 21.4 mmole) was dissolved in ethanol (96 %; 35 mL). A solution of sodium hydroxide (0.86 g, 21.4 mmole) in water (30 mL) was prepared separately. Both solutions were combined, thoroughly stirred and pH was adjusted to 7.0-7.5. Thereafter the solution was further processed to the granulate and tablets as described in Example 1, together with the other ingredients.
Example 3
Perindopril (7.9 g, 21.4 mmole) was dissolved in ethanol (96 %; 35 mL) and the obtained solution was slowly added to the suspension of calcium hydroxide (0.95 g, 12.8 mmole) during intense stirring, and stirred for 30 min. The pH-value must be in the range from 7.0 to 7.5.
The obtained slightly turbid solution was filtered to clarify.
The solution was further processed to granulate and tablets as described in Example 1.
Example 4
Perindopril (7.9 g, 21.4 mmole) was dissolved in ethanol (96 %; 35 mL). A solution of sodim hydrogen carbonate (2.0 g, 23.8 mmole) in water (35 mL) was prepared separately. Both solutions were combined and stirred for 10 min, pH was in the range from 7.0 to 7.5. This mixture was then sprayed in a stream of warm air having a temperature of 30-50 0C to the previously prepared mixture consisting of lactose (140.0 g), corn starch (5.9 g) and microcrystalline cellulose (41.75 g). It was dried in a stream of warm air to reach the water content of 0.5-1.5 %. 196 g of granulate was obtained, which was then homogeneously mixed with: indapamide (2.95 g), corn starch (5.9 g), talc (4.7 g) and magnesium stearate (2.4 g). This final granulate was used for the preparation of tablets having a weight of 90 mg, containing 3.53 mg of sodium salt of perindopril (corresponds to 4.0 mg of perindopril erbumine) and 1.25 mg of indapamide.
Example 5
Composition for 22000 tablets of perindopril sodium salt. Each tablet contains 3.53 mg of perindopril sodium (which corresponds to 4 mg of perindopril erbumine).
Perindopril (acid) 0.079 kg
Lactose monohydrate 1.420 kg
Microcrystalline cellulose 0.426 kg
Corn starch 0.118 kg Magnesium stearate 0.024 kg
Talc 0.047 kg
Sodium hydrogen carbonate 0.018 kg
Total 2.132 kg
Granulation:
Perindopril (acid) (0.079 kg) was dissolved in ethanol (96 %; 400 mL). Separately a solution of sodium hydrogen carbonate (0.018 kg) in water (200 mL) was prepared. Both solutions were mixed whilst stirring. In the granulation apparatus WSG type Glatt GPCG-I a dry blend of the following ingredients was prepared:
Lactose monohydrate 1.420 kg
Corn starch 0.059 kg
Microcrystalline cellulose 0.426 kg
To the dry blend of ingredients a solution of perindopril sodium (ethanol/water) was sprayed at a temperature 35—42 0C for two hours. The final humidity of the first granulate is 1-1.5 % of water.
In the next step a first granulte of perindopril sodium was blended in a homogeniser with the following ingredients:
Corn starch 0.059 kg
Talc 0.047 kg
Magnesium stearate 0.024 kg
The final granulate was used for tabletting. It was tabletted on the tabletting machine KILIAN RLA with the rate of 30000 tablets/hour.

Claims

Claims
1. Process for the preparation of a stable formulation of amorphous perindopril salts of formula I:
Figure imgf000009_0001
wherein B+ represents an alkali or alkaline earth metal cation, characterized in that perindopril in the form of a free acid of formula III:
Figure imgf000009_0002
is dissolved in alcohol and neutralized with an aqueous solution of alkali or alkaline earth base and the obtained neutral solution of salt is sprayed onto the homogenous mixture of inert ingredients for the preparation of a granulate, dried in a vacuum or in a stream of warm air, the substances to facilitate tabletting or other active substances, preferably diuretics are added, then homogenized and tabletted.
2. Process according to claim 1, characterized in that a free acid of formula III in the form of an oil, resinous substance, crystals, aqueous solution, or a solution in a water-solvent mixture is used.
3. Process according to claims 1 and 2, characterized in that an alkaline earth metal is calcium or magnesium and alkali metal is sodium or potassium, preferably sodium.
4. Process according to claims 1-3, characterized in that hydroxide, oxide, carbonate or hydrogen carbonate of alkali or alkaline earth metal is used as a base.
5. Process according to claims 1-4, characterized in that drying is carried out at a temperature from 30 0C to 50 0C.
6. Process according to claims 1-5, characterized in that a substance having a diuretic activity, preferably indapamide is used as another active substance in the final phase of granulate blending.
7. Use of the formulation prepared by the process according to claims 1-6 as a medicine having an antihypertensive and a vasodilatatory activity.
PCT/SI2008/000031 2007-06-04 2008-05-30 Stable formulation of amorphous perindopril salts, a process for the preparation thereof on industrial scale and use thereof in the treatment of hypertension WO2008150245A2 (en)

Priority Applications (2)

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EP08754036A EP2164469A2 (en) 2007-06-04 2008-05-30 Stable formulation of amorphous perindopril salts, a process for the preparation thereof on industrial scale and use thereof in the treatment of hypertension
CN2008800187504A CN101742986B (en) 2007-06-04 2008-05-30 Stable formulation of amorphous perindopril salts, a process for the preparation thereof on industrial scale and use thereof in the treatment of hypertension

Applications Claiming Priority (2)

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SI200700131A SI22542A (en) 2007-06-04 2007-06-04 Stable formulation of amorphous salts of perindopril, procedure for its preparation in industrial scale and its application for treatmentof hypertensia
SIP-200700131 2007-06-04

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WO2008150245A2 true WO2008150245A2 (en) 2008-12-11
WO2008150245A3 WO2008150245A3 (en) 2009-02-05

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009000909A2 (en) * 2007-06-27 2008-12-31 Krka, Tovarna Zdravil D.D. Novo Mesto Salts of perindopril
WO2011034509A2 (en) 2009-09-21 2011-03-24 Silverstone Pharma New benzathine salts of ace inhibitors, process for their preparation and their use for the treatment of cardiovascular diseases
AU2013201812B2 (en) * 2007-06-27 2015-04-02 Les Laboratoires Servier Salts of perindopril

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005068425A1 (en) * 2004-01-14 2005-07-28 Lek Pharmaceuticals D.D. New crystalline form of perindopril
WO2005068490A1 (en) * 2004-01-14 2005-07-28 Lek Pharmaceuticals D.D. Inclusion complexes of perindopril
WO2007058634A1 (en) * 2005-11-17 2007-05-24 Diagen Smartno Pri Ljubljani, D.O.O. Stable formulation of amorphous perindopril salts, a process for their preparation, especially industrial preparation, and their use in the therapy of hypertension

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2838648B1 (en) * 2002-04-18 2004-05-21 Servier Lab NEW PERINDOPRIL SALT AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING IT

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005068425A1 (en) * 2004-01-14 2005-07-28 Lek Pharmaceuticals D.D. New crystalline form of perindopril
WO2005068490A1 (en) * 2004-01-14 2005-07-28 Lek Pharmaceuticals D.D. Inclusion complexes of perindopril
WO2007058634A1 (en) * 2005-11-17 2007-05-24 Diagen Smartno Pri Ljubljani, D.O.O. Stable formulation of amorphous perindopril salts, a process for their preparation, especially industrial preparation, and their use in the therapy of hypertension

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009000909A2 (en) * 2007-06-27 2008-12-31 Krka, Tovarna Zdravil D.D. Novo Mesto Salts of perindopril
WO2009000909A3 (en) * 2007-06-27 2010-03-18 Krka, Tovarna Zdravil D.D. Novo Mesto Salts of perindopril
US20100298400A1 (en) * 2007-06-27 2010-11-25 Krka, Tovarna Zdravil D.D. Novo Mesto Salts of perindopril
EA017835B1 (en) * 2007-06-27 2013-03-29 Крка, Товарна Здравил, Д.Д., Ново Место Calcium salt of perindopril, a pharmaceutical composition comprising said salt and a process for preparation thereof
US8470869B2 (en) 2007-06-27 2013-06-25 Krka, Tovarna Zdravil D.D. Novo Mesto Salts of perindopril
AU2013201812B2 (en) * 2007-06-27 2015-04-02 Les Laboratoires Servier Salts of perindopril
WO2011034509A2 (en) 2009-09-21 2011-03-24 Silverstone Pharma New benzathine salts of ace inhibitors, process for their preparation and their use for the treatment of cardiovascular diseases

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WO2008150245A3 (en) 2009-02-05
CN101742986A (en) 2010-06-16
RU2009149675A (en) 2011-07-20
CN101742986B (en) 2013-07-17
RU2464022C2 (en) 2012-10-20
SI22542A (en) 2008-12-31

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