DD237114A5 - NIFEDIPIN COMBINATION PREPARATES AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

The invention relates to a process for the preparation of Nifedipinkombinprapraparepaten with improved bioavailability for use as a medicament. The aim of the invention is to provide new preparations in which the active ingredient nifedipine has a better solubility. According to the invention, the novel nifedipine preparations are prepared by granulating 1 part by weight of nifedipine and 0.5 to 10 parts by weight of a b-blocker, preferably from the group acebutolol, atenolol, nadolol, propranolol, pindolol or timolol, together with excipients and carriers and, if appropriate, this granulate is further processed into customary forms of application.

Description

(II)

H ₃ COOG COCH ₃

with the enamine compound of formula III

H ₃ CC = CH-COOCH ₃ (HI)

NH ₂

in the presence of lower alcohols (1 -C atoms), preferably isopropanol, as a solvent at temperatures between 0 and 4O ⁰ C and converts the resulting nifedipine according to item 1 in a suitable administration form.

Field of application of the invention

The invention relates to a process for the preparation of novel nifedipine combination preparations in solid form with improved bioavailability, containing nifedipine and β-blocker. The preparations prepared according to the invention are used as medicines, in particular as coronary and blood pressure agents.

Characteristic of the known technical solutions

It has already become known that nifedipine has very strong effects on the circulation (compare GB-PS 1173862). Due to the severe solubility of nifedipine, the pharmaceutical formulation of proprietary medicinal products encounters a number of difficulties, as evidenced by numerous patents and patent applications for specific formulations of this drug. So z. For example, US Pat. No. 3,784,684 discloses special nifedipine-containing gelatin bite capsules by which the coronary action of nifedipine can be used to advantage. In GB-PS 1 456618 solid pharmaceutical preparations are further described and claimed, which should also ensure a good bioavailability of nifedipine. Also in DE-OS 2822882 solid dosage forms are described in which by the use of certain solubilizers and surface-active substances, the poor solubility of the drug to be compensated. In EP-OS 1 247, the absorbability of nifedipine is to be improved by the use of polyethylene glycol and certain porous carrier substances.

Various methods for improving bioavailability directly related to improved solubility are also described in the literature. In addition to the change in the chemical structure, for. B. by incorporation of solubility-improving substituent groups, numerous methods are described which relate to a change in the physical properties of the active ingredient. So z. For example, the comminution of active ingredient particles, modification of the crystal structure, the production of salt forms, addition of wetting agents, complex formation with other substances, use of biological carriers, preparation of solid dispersions (co-precipitates) or the production of Oberflächenadsorbaten proposed (see SHYalkowskay, Drugs and the pharmaceutical science, 12, 135-180 (1980) and J. Polderman, Formulation and preparation of dosage forms, Elsevier / North-Holland Biomedical Press, 1977, 215-219).

All previous attempts to compensate for the poor solubility of nifedipine by certain measures and at the same time to ensure good Bioverfüg availability, have a number of disadvantages. The use of surface-active substances, solubilizers and certain excipients which have a special surface, for. As are porous, often leads to forms of administration in which the preparations are undesirably large. To facilitate swallowing such tablets or capsules are often in specific forms such. As ellipsoids or longitudinal forms, but this also does not always lead to satisfactory results in preparations with a weight over 400 mg. The more frequent intake of smaller preparations is not a satisfactory solution.

For pharmaceutical preparations is that both the number and the amount of excipients and carriers should be kept as low as possible. When comparing two proprietary medicinal products, preference will always be given to that preparation which, in addition to the active ingredient, contains as few auxiliaries and additives as possible in order to largely avoid undesired biological side effects.

Object of the invention

The aim of the invention is to provide novel nifedipine combination preparations which have improved bioavailability.

Explanation of the essence of the invention

The invention has for its object to find ways to make sparingly soluble nifedipine more soluble.

According to the invention, new solid combination preparations having improved bioavailability are prepared, containing 1 part by weight of nifedipine and 0.5 to 10 parts by weight of a β-blocker and customary excipients and carriers.

Of particular interest are combination preparations according to the invention which contain a β-blocker from the group acebutolol, atenolol, nadolol, propranolol, pindolol or timolol.

In particular, acebutolol and atenolol may be mentioned.

Of particular interest are combination preparations according to the invention containing 1 part by weight of nifedipine, and 1 to 5 parts by weight of acebutolol or atenolol.

The combination preparations according to the invention are prepared by granulating nifedipine and the β-blocking agent together with known excipients and carriers together by means of a wet granulation method or a dry compacting method and optionally compressed with at least one tablet filler to give tablets.

The nifedipine used according to the invention is preferably prepared by reacting an ylidene compound of the formula II

(II)

with an enamine compound of general formula III

H ^ C-C = CH-COOCH (III)

in lower alcohols having 1 to 4 carbon atoms at temperatures between 40 and 100 ^° C.

A preferred process variant consists in removing the water of reaction by azeotropic distillation. The compounds II and III can be used either in molar amounts or with a slight excess of the enamine compound III.

The preparation of the ylidene compound II is carried out by reaction of molar amounts of a ketocarboxylic acid ester with o-nitrobenzaldehyde in the presence of lower alcohols having 1 to 4 carbon atoms as solvent and in the presence of catalytic amounts of piperidine acetate at temperatures between 20 and 60 ° C. The enamine compound of formula III is prepared by reacting a ketocarboxylic acid ester with ammonia in a lower alcohol (1-4 carbon atoms), preferably in isopropanol, at temperatures between 0 and 40 ⁰ C. The reaction partner ammonia can also be used in aqueous solution.

As adjuvants may be mentioned by way of example:

Disintegration promoters such as starch, modified starch, cellulose, cellulose derivatives, cross-linked polyvinylpyrrolidone (PVPP),

0.25 49 0.5 76 1 85

Sodium alginate and colloidal silica; Binders such as gelatin, tragacanth, glucose syrup, starch pastes, polyvinylpyrrolidone (PVP), cellulose derivatives, polyethylene glycol MG 1 000-5000 (PEG), un alginates; Lubricants such as magnesium stearate, calcium stearate, stearic acid, paraffin, talc, vegetable or animal fats, oils and water, polyethylene glycol MG 1 000-5000 and silicones.

Examples of fillers are:

Calcium sulfate, di- and tribasic calcium phosphates, magnesium carbonate, magnesium hydroxycarbonate, sodium chloride, sodium and potassium citrates, tartrates and succinates, starch, modified starch, cellulose, cellulose powder, sugars such as lactose, sucrose or dextrose, and sugar alcohols such as mannitol or sorbitol.

Of particular interest are fillers from the starch group, modified starch such as starch paste, cellulose, PVP, PVPP, colloidal silica, lactose, magnesium hydroxycarbonate, magnesium stearate and calcium stearate.

With knowledge of the state of the art, it is extremely surprising that the joint granulation of nifedipine with one of the mentioned β-blockers can achieve a significant increase in the release and thus a significant improvement in the bioavailability for nifedipine. This effect is not dependent on the presence of additional excipients which, to the knowledge of the prior art, increase the rate of release, e.g. As complexing agents, surfactants or water-soluble polymers.

In the release test according to the USP paddle method under the following conditions, 900 ml of 0.1 N hydrochloric acid

Paddle speed 110U / min.

were released after 1 hour release rates for nifedipine of 85% for combination preparations according to the invention (product according to Example 1). A corresponding preparation of a conventional nifedipine tablet, in which the nifedipine was used in the same crystalline composition and contains the same excipients, shows after 1 hour only a release rate of less than 40%. The course of the release is shown in Table 1.

Table 1

In vitro release of nifedipine containing tablets (USP paddle method) cumulative release of nifedipine in

Percent of dose used Release time / h / tablet tablet '

Example 1 Comparative Example

19 28 39

Comparative example

100 g of nifedipine, 2080 g of corn pieces, 1150 g of cellulose powder and 50 g of lactose are mixed in a planetary mixer for 5 minutes and granulated with an aqueous polyvinylpyrrolidone / Tween 80 solution (solids content 200 g / 5 g) for 15 minutes. The moist mass is passed through a rasp (2.0 mm 0 sieve insert) and dried in a fluidized bed dryer to a final water content of about 5%. The dried granules are equalized by sieving (1.0 mm sieve mesh size) and intensively mixed with 15 g magnesium stearate. Subsequently, the granules are compressed into tablets weighing 360 mg.

embodiment

The invention is explained in more detail below with reference to some examples.

example 1

100 g of nifedipine, 1 508 g of acebutolol HCl, 1 372 g of corn starch, 100 g of lactose and 400 g of cellulose powder are mixed in a planetary mixer for 5 minutes and granulated with an aqueous polyvinylpyrrolidone / Tween 80 solution (solids content 200 g / 5 g) for 15 minutes. The moist mass is passed through a rasp (2.0 mm 0 sieve insert) and dried in a fluidized bed dryer to a final water content of about 4.5%. The dried granules are equalized by sieving (1.0 mm sieve mesh size) and intensively mixed with 15 g magnesium stearate. Subsequently, the granules are compressed into tablets weighing 360 mg. The tablets can be coated with a protective varnish.

Example 2

200 g of nifedipine, 2216 g of acebutolol HCl, 2494 g of corn starch, 50 g of lactose and 900 g of cellulose powder are heated in a fluidized bed granulator (Glatt WSG 5) and first sprayed with an aqueous sodium lauryl sulfate solution (content 10 g). Thereafter, the powder is granulated with an aqueous hydroxypropylmethylcellulose solution (content 400 g) and dried to a final moisture content of about 4.5%, screened (mesh size 0.8 mm 0) and mixed in a cube mixer with 20 g of magnesium stearate. The ready-to-use granules can be processed to 314.5 mg heavy tablets and coated in an Accela Coater with an opaque shell.

Example 3

1000 g of atenolol, 400 g of nifedipine, 600 g of cellulose powder, 1 200 g of corn starch, 1 200 g of magnesium carbonate and 40 g of sodium lauryl sulfate are mixed in a mixing granulator (eg Lödige MGT30) for 1 minute and granulated for 5 minutes with starch paste (starch content 200 g) at a rotor speed of the granulator of 200 U / min. By chopper stage II an average particle size of about 200-300 μ is obtained. The granules are passed through a rasp (sieve insert 2.0 mm α) and dried in a fluid bed dryer (eg Glatt WST 5) to a final moisture content of about 4.0% water. The dried

Granules are mixed with 10Og magnesium stearate in a mixer for 10 minutes and then pressed into tablets with a mean diameter of 9mm and a weight of about 237mg.

The resulting tablets may additionally be coated with an opaque paint shell, the z. B. contains red iron oxide as a sunscreen.

Example 4

500 g of atenolol, 200 g of nifedipine, 450 g of cellulose powder, 400 g of corn starch, 650 g of calcium carbonate, 25 g of Tween 80 and 50 g of magnesium stearate are mixed in a cube mixer and then dry-compacted (Alexander roll WP50; compaction pressure 35 bar). The pens are chopped, equalized with a 1.25 mm sieve and mixed homogeneously with a mixture of 25 g magnesium stearate and 200 g corn starch. The finished granules are pressed into 250 mg tablets of 9 mm 0.

The tablets obtained can be used directly or, alternatively, a protective varnish, consisting of hydroxypropylmethylcellulose, polyethylene glycol and iron oxides or other physiologically acceptable color pigments or dye lakes obtained.

Example 5

750g of atenolol, 300g of nifedipine, 855g of corn starch, 975g of magnesium hydroxycarbonate, 150g of pregelatinized corn starch and 600g of cellulose powder are mixed for 8 minutes in a planetary mixer (Collette MP20) and 15 minutes after continuously adding 250ml of 2.0% aqueous sodium lauryl sulfate solution. Granulated at increased speed of the mixer. The moist mass is grated, dried in a fluidized bed dryer to approx. 3.8% final moisture and leveled by sieving (1.0 mm mesh size). The final mixture is obtained after mixing of 75 g of magnesium stearate and pressed into 247 mg heavy tablets.

The resulting tablets may additionally be coated with a daylight-impermeable envelope. The granules can alternatively be filled in Hargelatinekapseln.

Claims (6)

Invention claim: 1. A process for the preparation of solid combination preparations with improved bioavailability, characterized in that granulated 1 part by weight of nifedipine and 0.5 to 10 parts by weight of a ß-block together with excipients and carriers and optionally further processed this granules to conventional administration forms. 2. The method according to item 1, characterized in that a combination preparation is prepared which contains a ß-blocker from the group acetutolol, atenolol, nadolol, propranolol, pindolol and timolol. 3. The method according to item 1 and 2, characterized in that a combination preparation is prepared which contains acebutolol as ß-blocker. 4. The method according to item 1 and 2, characterized in that a combination preparation is prepared which contains atenolol as ß-blocker. , 5. The method according to item 1, characterized in that 1 part by weight of nifedipine and 1 to 5 parts by weight beta-blocker with starch, cellulose and optionally other conventional excipients in a granulator aqueous granulated and the resulting granules also converted into a conventional administration form. 6. A process for the preparation of combination preparations according to item 1, characterized in that the ylidene compound of the formula II