WO1997033569A1 - Medicament preparation for angiotensin converting enzyme (ace)-inhibitors - Google Patents

Abstract

The invention concerns a process for preparing oral depot forms containing captopril as active substance.

Description

 Pharmaceutical preparation for ACE inhibitors

Angiotensin converting enzyme (ACE) inhibitors have been used for many years to treat hypertension and heart failure. The medicinal preparations with ACE inhibitors, and here in particular captopril, are usually tablets which release the active ingredient quickly without a particular delay. So these are not slow release preparations. This is surprising in that the ACE inhibitors, and here in particular the captril in particular, can lead to side effects if the plasma level floods rapidly, as is the case after normally releasing medicinal preparations, e.g. a sharp drop in blood pressure, which is undesirable to this extent. For this reason, one has already started to divide the daily dose into 2-3 individual doses. In this way, one avoided a larger plasma level peak and converted it into 2 or 3 smaller peaks. However, it would be even cheaper if it were possible to continuously release the active ingredient from a sustained-release preparation in such a way that firstly there were no pronounced plasma peaks, which would improve the tolerability, and secondly a 1 x daily administration would suffice, which would be sufficient Patient compliance.

This invention describes the preparation of an oral sustained release formulation. The ACE inhibitor, in particular the captopril, can be mixed with an acidic substance that is physiologically harmless in a ratio of about 1: 1, and after the addition of other auxiliaries, small spheres, so-called pellets, can be formed that have a diameter about 0.6 - 1.8 mm. The production is preferably carried out by the so-called Marumerizer process, with an extrudate being produced first, which is then produced a rotating plate is converted to pellets. However, it is also possible to start from small neutral particles, such as nonpareills, to which the mixture of active ingredient, such as captopril, and the acidic substance is applied. This order is carried out in a coated tablet or in a fluidized bed apparatus.

The active ingredient-containing pellets can be divided into 4 different fractions. Fraction 1 can be left untreated or coated with a thin film protecting against moisture during manufacture and storage. Fraction 2 can, if necessary after coating the same film as in 1, be coated with another film which can dissolve at a pH of about 5.0 - 5.5. Fraction 3, if necessary after application of the same film as in 1., can be coated with a coating which can dissolve at a pH of 5.5-6 and fraction 4, if necessary after application of the same film as in 1st, with a coating that dissolves at pH 6.6 - 7. Acrylates can be used as coatings, e.g. the commercially available Eudragit® types from RÖHM, Darmstadt, or ethyl cellulose or hydroxypropylmethyl cellulose as phthalate or in the form of the acetate / succinate, e.g. the AQOATΘ types from SHINETSU, Japan, sold in Germany by SYNTAPHARM. Eudragit 30D from Röhm can also be used as a coating. The pellets are coated in drag pots or in fluidized-bed apparatuses, for example as are commercially available from the companies GLATT or HÜTTLIN.

The, for example, 4 fractions of the pellets coated in the manner described are mixed homogeneously and filled into hard gelatin capsules. The filling takes place in an amount so that, for example, 25, 50, 75 or 100 mg of captopril is contained in one capsule. The following examples illustrate this invention:

example 1

Production of approx. 13,000 capsules of 50 mg captopril in the form of coated pellets

Captopril USP XXII, finely powdered 0.735 kg

Glutamic acid DAB 10, finely powdered 0.735 kg

Lactose, finely powdered 2.346 kg

Cellulose, microcrystalline 0.587 kg

These components are mixed homogeneously in a mixer (= pul mixing). Then 0.044 kg of EDTA sodium (ethylenediaminetetraacetic acid, sodium salt) are dissolved in 1 liter of distilled water and the powder mixture is moistened with this solution in a kneader. Sufficient water is added until the resulting kneaded mass has the required consistency for processing in the extruder used and an extrudate is then produced. The extrudate is portioned into a Marumerizer, i.e. a machine with rotating profiled metal plate, given and pellets formed from it. The diameter of the pellets can be determined by selecting the perforated discs for the extruder. In this example, a diameter of 0.8-1.2 mm is created. The pellets are dried at 40 ° C. over a period of 24 hours. The remaining residual moisture is determined, provided that this is above 0.2%, drying is continued at 40 ° C. The pellets are then passed through a sieve with a mesh size of 1.2 mm, excess portions are removed, and smaller components are sieved through a sieve with a mesh size of 0.6 mm.

Yield: 4.0 kg, content of captopril in the pellets: 16.1% 4.0 kg of the pellets are coated in an Hüttlin fluidized bed apparatus with an 8% strength aqueous solution of 40 g of hydroxypropylmethyl cellulose (Pharmacoat® 603 from SYNTAPHARM). The pellets are then removed from the apparatus and divided into 4 equal parts by weight. Each of these 4 fractions weighs 1.01 kg. The first faction is set aside. The second fraction is coated in the fluidized bed system with the following solution:

Eudragit® L30D55 120 g

Triethyl citrate 15 g

Talc 80 g

Water q.s.

After covering, this fraction is also set aside. Then the third fraction of 1.01 kg pellets is coated with the following solution:

Eudragit® L100 320 g

Triethyl citrate 95 g

Talc 70 g

Water q.s.

After covering, this fraction is also set aside. The fourth fraction of 1.01 kg of pellets is then coated with the following solution:

Eudragit® S100 190 g

Triethyl citrate 95 g

Talc 70 g

Water q.s.

All fractions are dried in a drying cabinet at 40 ° C. for 24 hours and then mixed in a cube mixer. The mixture is in hard gelatin capsules filled so that each capsule contains so much pellets that this corresponds to 50 mg captopril. In this example it was 365 mg / capsule.

Example 2

Captopril USP XXII, finely powdered 0.735 kg

Glutamic acid DAB 10, finely powdered 0.735 kg

Lactose, finely powdered 2.346 kg

Cellulose, microcrystalline 0.587 kg

These components are mixed homogeneously in a mixer (= pul mixing). Then 0.044 kg of EDTA sodium (ethylenediaminetetraacetic acid, sodium salt) are dissolved in 1 liter of distilled water and the powder mixture is moistened with this solution in a kneader. Sufficient water is added until the resulting kneaded mass has the required consistency for processing in the extruder used and an extrudate is then produced. The extrudate is placed in portions in a Marumerizer and pellets are formed from it (diameter of 0.8-1.2 mm). The pellets are dried at 40 ° C. over a period of 24 hours. The remaining residual moisture is determined, provided that this is above 0.2%, drying is continued at 40 ° C. The pellets are then passed through a sieve with a mesh size of 1.2 mm, excess portions are removed, and smaller components are sieved through a sieve with a mesh size of 0.6 mm.

Yield: 4.0 kg, content of captopril in the pellets: 16.1% 33569

- 6 -

4.0 kg of the pellets are coated in an Hüttlin fluidized bed apparatus with an 8% strength aqueous solution of 40 g of hydroxypropylmethyl cellulose (Pharmacoat® 606 from SYNTAPHARM). The pellets are then removed from the

The apparatus was removed and divided into 4 equal parts by weight. The first faction is set aside. The second fraction is coated in the fluidized bed system with the following solution:

AQOAT HPMC AS-LF 140 g,

Triethyl citrate 30 g,

Talc 45 g,

Na lauryl sulfate 4 g,

Water ad 2.00 kg

After covering, this fraction is also set aside. Then the third fraction of 1.01 kg pellets is coated with the following solution:

AQOAT HPMC AS-MF 140 g triethyl citrate 40 g,

Talc 40 g,

Na lauryl sulfate 4 g,

Water ad 2.00 kg

After covering, this fraction is also set aside. The fourth fraction of 1.01 kg of pellets is then coated with the following solution:

AQOAT HPMC AS-HF 140 g triethyl citrate 50 g,

Talc 35 g,

Na lauryl sulfate 4 g,

Water ad 2.00 kg

All fractions are dried in a drying cabinet at 40 ° C. for 24 hours and then mixed in a cube mixer. The mixture is made in Hartge

filled latine capsules so that each capsule contains enough pellets to correspond to 50 mg captopril. In this example it was 362 mg / capsule.

Example 3

Captopril USP XXII, finely powdered 0.735 kg

Ascorbic acid DAB, finely powdered 0.735 kg

Lactose, finely powdered 2.346 kg

Cellulose, microcrystalline 0.587 kg

These components are mixed homogeneously in a mixer (= powder mixture). Then 0.05 kg of EDTA sodium (ethylenediaminetetraacetic acid, sodium salt) are dissolved in 1 liter of distilled water and the powder mixture is moistened with this solution in a kneader. Sufficient water is added until the resulting kneaded mass has the required consistency for processing in the extruder used and an extrudate is then produced. The Extrudate is placed in portions in a Marumerizer and pellets are formed therefrom with a diameter of 0.8-1.2 mm. The pellets are dried at 40 ° for 36 h. The pellets are then passed through a sieve with a mesh size of 1.2 mm, excess portions are removed, and smaller components are sieved through a sieve with a mesh size of 0.6 mm.

Yield: 4.2 kg, content of captopril in the pellets: 16.2%

4.0 kg of the pellets are coated in a Hüttlin fluidized bed apparatus with a 10% strength aqueous solution of 40 g of hydroxypropylmethyl cellulose (Pharmacoat® 606 from SYNTAPHARM). The pellets are then removed from the apparatus and divided into 4 equal parts by weight. The first

Faction is set aside. The second fraction is coated in the fluidized bed system with the following solution:

AQOAT HPMC AS-LF 120 g,

Triethyl citrate 25 g,

Talc 40 g,

Na lauryl sulfate 3.5 g,

Water ad 1.80 kg

After covering, this fraction is also set aside. Then the third fraction of 1.01 kg pellets is coated with the following solution:

AQOAT HPMC AS-MF 120 g

Triethyl citrate 35 g,

Talc 38 g,

Na lauryl sulfate 3.5 g,

Water ad 1.80 kg

After covering, this fraction is also set aside. The fourth fraction of 1.01 kg of pellets is then coated with the following solution:

AQOAT HPMC AS-HF 120 g

Triethyl citrate 45 g,

Talc 30 g,

Na lauryl sulfate 3.5 g,

Water ad 1.80 kg

All fractions are dried in a drying cabinet at 40 ° C. for 24 hours and then mixed in a cube mixer. The mixture is made in Hartge

filled latine capsules so that each capsule contains enough pellets to correspond to 50 mg captopril.

Example 4

Captopril USP XXII, finely powdered 0.735 kg

Ascorbic acid DAB, finely powdered 0.735 kg

Lactose, finely powdered 2.346 kg

Cellulose, microcrystalline 0.587 kg These components are mixed homogeneously in a mixer (= powder mixture). Then 0.05 kg of EDTA sodium (ethylenediaminetetraacetic acid, sodium salt) are dissolved in 1 liter of distilled water and the powder mixture is moistened with this solution in a kneader. Sufficient water is added until the resulting kneaded mass has the required consistency for processing in the extruder used and an extrudate is then produced. The extrudate is placed in portions in a Marumerizer and pellets are formed therefrom with a diameter of 0.8-1.2 mm. The pellets are dried at 40 ° for 36 h. The pellets are then passed through a sieve with a mesh size of 1.2 mm, excess portions are removed, and smaller components are sieved through a sieve with a mesh size of 0.6 mm.

Yield: 4.2 kg, content of captopril in the pellets: 16.2%

4.0 kg of the pellets are coated in a fluidized bed apparatus from Glatt with an 8% strength aqueous solution of 40 g of hydroxypropylmethyl cellulose (Pharmacoat® 603 from SYNTAPHARM). The pellets are then removed from the apparatus and divided into 4 equal parts by weight. The first faction is set aside. The second fraction is coated in the fluidized bed system with the following solution:

Eudiagit® L30D55 130 g,

Triethyl citrate 20 g,

Talc 70 g,

Water qs - 11 -

After covering, this fraction is also set aside. Then the third fraction of 1.01 kg pellets is coated with the following solution:

Eudragit® L100 130 g

Triethyl citrate 60 g

Talc 130 g

Water q.s.

After covering, this fraction is also set aside. The fourth fraction of 1.01 kg of pellets is then coated with the following solution:

Eudragit® S100 120 g

Triethyl citrate 60 g

Talc 120 g

Water q.s.

All factions become 2nd Hours in a drying cabinet at 40 ° C and then mixed in a cube mixer. The mixture is filled into hard gelatin capsules so that each capsule contains so much pellets that this corresponds to 50 mg captopril.

The content is determined analogously to the known pharmacopoeia method of USP XXIII “Captopril Capsules”.

The advantage of the preparation of captopril prepared in this way according to the invention over normal, commercially available tablets or dragées results from the release of the active substance over time. This is determined using the following method: Release principle of analysis

The content of an HG capsule is measured using the USP XXIII method (App. 1 = rotating basket) in various media from 0.1 N HCl via buffer pH 5.5 and pH 6.0 to pH 7.0 for a total of 5 hours. leave and measure the solution photometrically at 212 nm against a standard solution that was treated according to the samples.

Safety notice

Chemicals used

Captopril standard substance

Pure hydrochloric acid 37% z. B. Merck item no. 314 C: Corrosive!

Sodium hydroxide p.A. e.g. Merck Art.No. 6498 C: Corrosive!

Disodium hydrogen phosphate x 2 H20 p.A. e.g.

Merck Art.No. 1.06580

Pure hydrochloric acid 37% z. B. Merck Art.No. 314 C: Corrosive!

Water for HPLC z. B. MilliQ

Release conditions

Method USP XXIII App. 1 (basket)

Medium A) 0 - 1 h 600 ml 0.1 N HCl (corresponding to 8.28 ml HCl 37% per 1)

B) 1 - 2 h A + 300 ml 0.2 N Na ₂ HP0 ₃ x 2 H ₂ 0 (corresponding

35.6 g per 1) + approx.2.7 ml 0.1 N NaOH (adjust pH 5.5)

C) 2 - 3 h B + approx.6.3 ml 1 N NaOH (adjust pH 6.0)

D) 4 - 5 h C + approx. 30 ml 1 N NaOH (adjust pH 7.0) temperature 37 ° C ± 0.5 ° C stirring speed 50 s " ¹

Volume withdrawal: 10.0 ml (with prefilter Hanson sample filters

10 μm part no. 27/101/074) Withdrawal times: 1, 2, 3, 4, 5 hours

The contents of one capsule are used. default

The stock solution (pH 1) can be kept for a maximum of 1 day. The corresponding

Standard solutions with a higher pH value coincide with the pH changes in the

To produce release apparatus to the degradation of the beginning from pH 5.5

Produce active ingredient in parallel in the standard. after 1 hour establish standard pH 5.5, adjust pH 6.0 and 7.0 to 5.5 after 2 hours complete standard pH 6.0, adjust pH 7.0 to 6.0 after 4 hours standard pH Make 7.0

Stock solution

Approximately 27 mg of captopril, weighed exactly, are weighed into a 50 ml volumetric flask, mixed with 1 ml of methanol and briefly sonicated. Then add approx. 40 ml 0.1 N HCl (corresponding to 8.28 ml HCl 37% per 1) and place in the ultrasonic bath for 10 min. After cooling, make up to the mark with 0.1 N HCl (c = 540 μg / ml).

Standard solution pH 1.0 (approx. 25% release)

0.375 ml of the stock solution are pipetted into a 20 ml volumetric flask and made up to the mark with 0.1 N HCl (c = 10 μg / ml).

Standard solution pH 5.5 (approx. 50% release)

0.5 ml of the stock solution are pipetted into a 25 ml volumetric flask and 11.70 ml 0.1 N HCl and 6.30 ml 0.2 N Na ₂ HP0 ₄ x 2 H _z O are added and approx. 140 μl 1 N NaOH the pH was adjusted (V = 18.64 ml; c = 14.5 μg / ml).

Standard solution pH 6.0 (approx. 75% release)

0.5 ml of the stock solution are pipetted into a 25 ml volumetric flask and 7.70 ml 0.1 N HCl and 3.85 ml 0.2 N Na ₂ HP0 ₄ x 2 H ₂ 0 are added and approx. 120 μl 1 N NaOH the pH was adjusted (V = 12.17 ml; c = 22.2 μg / ml). Standard solution pH 7.0 (approx. 100% release)

0.5 ml of the stock solution is pipetted into a 25 ml4 volumetric flask and 5.50 ml 0.1 N HCl and 2.80 ml 0.2 N Na ₂ HP0 ₄ x 2 H ₂ 0 are added and approx. 340 μl 1 N NaOH the pH was adjusted (V = 9.14 ml; c = 28.0 μg / ml).

sample

10.0 ml with prefilter are drawn from the release medium at the respective times, diluted 1: 1 with the respective buffer and immediately measured photometrically together with the respective standard (c _u% = 27.8 μg / ml)

Photometric conditions

Wavelength: 212 nm

Cell 1 cm

Blank values 0.1 N HCl buffer pH 5.5 - pH 6.0 - pH 7.0

The result of the investigation showed a captopril release from one capsule

after 1 h 0.1 N HCl: 12.5 mg = 25% after 1 h 0.1 N HCl + 1 h pH 5.5: 32.5 mg = 65% after 1 h 0.1 N HCl + 1 h pH 5.5 + 2 h pH 6.0: 43.0 mg = 86% after 1 h 0.1 N HCl + 1 h pH 5.5 + 2 h pH 6.0 + 1 h pH 7.0: 50 , 0 mg = 100%

The result shows that a protracted release of captopril takes place over a period of several hours, which is not the case with normal tablets.

Claims

claims 1. prolonged-release pharmaceutical form in the form of pellets, filled into capsules, the pellets containing the ACE inhibitor captopril or captril and at least one diuretic as a further active substance. 2. sustained release dosage form according to claim 1, characterized in that the pellets contain a physiologically acceptable acid in an amount of 50 to 500 wt .-% and preferably 50 - 150 wt .-%, based on the amount of captopril. 3. sustained-release dosage form according to claim 1 or 2, characterized in that the acid is glutamic acid and / or ascorbic acid and / or tartaric acid. 4. sustained-release dosage form according to any one of the preceding claims, characterized in that each capsule contains different types of pellets, of which at least 50% differ from one another in that they dissolve in different pH ranges or at different pH values. 5. sustained release dosage form according to claim 4, characterized in that the pellets, which dissolve in different pH ranges, dissolve from pH 4 to pH 8 in total. 6. sustained-release dosage form according to claim 4 or 5, characterized in that each capsule contains pellets of their own, of which at least 50% differ from one another in that they differ in two to three different pH ranges or in two to three dissolve different pH values. 7. prolonged-release pharmaceutical form according to claim 6, characterized in that each capsule contains different types of pellets, of which at least 50% differ from one another in that they dissolve in the following pH ranges: 5.0 to 5.5; > 5.0 to 6.0; and > 6.0 and in particular 6.6 to 7.0. 8. prolonged-release pharmaceutical form according to claim 6, characterized in that each capsule contains pellets of different types, of which at least 50% differ from one another in that they dissolve in the following pH ranges: 5.3 to 5.7 and especially around 5.5; 5.8 to 6.2 and especially around 6.0; and 6.8 to 7.2, and especially about 7.0. 9. sustained release dosage form according to any one of the preceding claims, characterized in that the pellets have coatings based on acrylate, ethyl cellulose or hydroxypropyl methyl cellulose, optionally in the form of the phthalate or acetate / succinate. 10. sustained release dosage form according to claim 9, characterized in that the coatings contain or consist of Eudragit, in particular Eudragit ⁸ L30D, Eudragit "L30D55, Eudragit" L100 and / or Eudragit "S100. 11. sustained release dosage form according to claim 9, characterized in that the coatings contain or consist of AQOAT HPMC, in particular AQOAT HPMC AS-LF, AQOAT HPMC AS-MF and / or AQOAT HPMC AS-HF. 12. A method for producing a sustained-release dosage form in the form of pellets, characterized in that Provides pellets containing the ACE inhibitor captopril or captril with at least one diuretic as a further active ingredient and containing a physiologically acceptable acid, Divides the pellets formed into at least three and in particular three to four fractions, Leaves a first fraction untreated or coated with a film protecting against moisture before application and storage, • In the remaining fractions, the pellets are coated with such coatings that these fractions differ from one another in that they dissolve in different pH ranges or at different pH values and • Pellets of all fractions are mixed together and filled into capsules. 13. The method according to claim 11, characterized in that the first fraction make up less than 50% of the total weight and the remaining fractions at least 50% of the total weight, the remaining fractions can have approximately the same weight.