DD236453A5 - PROCESS FOR THE PREPARATION OF NIFEDINPRAEPARATES - Google Patents

Abstract

The invention relates to a process for the preparation of Nifedipinpraeparaten with improved bioavailability for use as medicaments, in particular as Coronar and blood pressure. 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 adding 1 part by weight of nifedipine and 1.0 to 20 parts by weight of a slightly water-soluble filler, such. As lactose and / or mannitol granulated together with auxiliary and Traegerstoffen and optionally further processed this granules to usual application forms.

Description

(II)

H ₃ COOC

with the enamine compound of formula III

H ₃ CC = CH-COOCH ₃ (HI)

NH ₂

in the presence of lower alcohols (1-4 C-atoms), preferably isopropanol, as a solvent at temperatures between 0 and 40 ° C and converts the resulting nifedipine according to the 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 preparations in solid form with improved bioavailability, containing nifedipine and readily soluble fillers. The preparations prepared according to the invention are used as medicaments, 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, there are a number of difficulties encountered in the pharmaceutical preparation of proprietary medicinal products, as evidenced by numerous patents and patent applications for specific formulations of this drug. So z. B. the UP-PS 3784684 special nifedipine-containing Gelatinbeißkapseln, through 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. Also in EP-OS 1 247 the absorbability of dihydropyridines 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 drug. So z. For example, comminution of active ingredient particles, alteration of the crystal structure, production of salt forms, addition of wetting agents, complex formation with other substances, use of biological carriers, preparation of solid dispersions (coprecipitates) or the production of surface absorbants have been proposed (cf., SHYalkowskay, Drugs and the pharmaceutical science, 12, 135-180 (1981) 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

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while ensuring good bioavailability, 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 also leads in preparations with a weight over 400 mg and not always satisfactory results. The more frequent intake of smaller preparations is not a satisfactory solution.

Object of the invention

The aim of the invention is the provision of novel nifedipine preparations which have improved bioavailability.

Explanation of the essence of the invention

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

According to the invention, new solid nifedipine preparations with improved bioavailability are prepared, containing 1 part by weight of nifedipine and 1.0 to 20, preferably 2.0 to 15, parts by weight of a readily water-soluble filler and optionally further customary auxiliaries and carriers.

Of particular interest are nifedipine preparations according to the invention which, as well water-soluble fillers, contain sugar and / or sugar-carbon, such as, for example, As lactose, sucrose, fructose, glucose, mannitol, sorbitol and / or salts such as magnesium, calcium, potassium, sodium, ammonium salts, wherein the anion ζ. As chloride, carbonate, citrate, tartrate, lactate, acetate, bicarbonate may contain.

Suitable water-soluble fillers are all physiologically acceptable substances whose solubility is at least 15 g per 100 ml of water, in particular at least 20 g per 100 ml of water at 25 ⁰ C.

In particular, mannitol, lactose, sodium chloride and potassium citrate may be mentioned.

The preparation of the preparations according to the invention is carried out by granulating nifedipine and the slightly water-soluble filler together and optionally compressed into tablets.

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

(ID

with an enamine compound of general formula III

Hr-C = CH-C00CH (III)

J ι J

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

A preferred process variant is to remove 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 mito-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 6O ⁰ C. The enamine compound of formula III is prepared by reacting a Ketocarbonsäureesters with ammonia in a lower alcohol (1-4 C-atoms), preferably in isopropanol, at temperatures between 0 and 40 ⁰ C. The reactant ammonia can also be used in aqueous solution.

With knowledge of the prior art, it is extremely surprising that the joint granulation of nifedipine with one of the readily soluble fillers mentioned a significant increase in the release and thus a significant improvement in the bioavailability of nifedipine can be achieved. This effect is not dependent on the presence of additional adjuvants which, to the knowledge of the prior art, increase the rate of release, e.g. As complexing agents or surfactants.

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

Paddle speed 100U / min.

were after 1 hour release rates of nifedipine of 100% achieved for inventive preparations (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 containing the same excipients, shows after 1 hour only a release rate of 43%. The course of the release is shown in Table 1.

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Table 1

In Vitro Release of Nifedipine-Containing Tablets (USP Paddle Method)

cumulative release of nifedipine as a percentage of the dose used release time tablet tablet

/ h / Example 1 Comparative Example

0.25 95% 18%

0.5 100% 30%

1 100% 43% '.

Comparative example

100 g of nifedipine, 2080 g of corn starch, 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.

embodiments

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

example 1

100 g of nifedipine, 1 590 g of corn starch, 1400 g of lactose and 300 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 O sieve insert) and dried in a fluidized bed dryer to a final water content of about 4.5%. The dried granules are leveled 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, 3160 g of corn starch, 1800 g of lactose and 700 g of cellulose powder are heated in a fluidized bed granulator (Glatt WSG5) and first sprayed with an aqueous sodium lauryl sulfate solution (Ge'halt 10g). The powder is then granulated with an aqueous hydroxypropylmethylcellulose solution (content 400 g) and dried to a final moisture content of about 4.5%, sieved (0.8 mm thick) and mixed in a cube mixer with 20 g of magnesium stearate. The ready-to-press granules can be made into 314.5 mg tablets and coated in an accela coater with an opaque shell.

Example 3

1,000 g of mannitol, 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 m is obtained. The granules are passed through a rasp (sieve insert 2.0 mm 0) and dried in a fluid bed dryer (eg Glatt WST5) to a final moisture content of about 4.0% water. The dried granules are mixed with 100 g of magnesium stearate in a mixer for 10 minutes and then pressed into tablets having an average diameter of 9 mm and a weight of about 237 mg. The resulting tablets may additionally be coated with an opaque paint shell containing, for example, red iron oxide as a sunscreen.

Example 4

500 g lactose, 200 g nifedipine, 450 g cellulose powder, 400 g corn starch, 650 g calcium carbonate, 25 g Tween 80 and 50 g magnesium stearate are mixed in a cube mixer and then dry compacted (Alexander roll WP50; compaction pressure 35 bar). The slugs are pre-shredded, leveled 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 to 250mg tablets with 9mm 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.

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Example 5

750g mannitol, 300g nifedipine, 855g cornstarch, 975g magnesium carbonate, 150g pregelatinised cornstarch and 600g cellulose powder are mixed for 8 minutes in a planetary mixer (Collette MP20) and for 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 with 75 g of magnesium stearate and pressed into tablets weighing 247 mg.

The resulting tablets may additionally be coated with a daylight-impermeable envelope. The granules can alternatively be filled into hard gelatin capsules.

Claims (5)

-1- 765 58 Invention claim: 1. A process for the preparation of solid nifedipine preparations with improved bioavailability, characterized in that granulated 1 part by weight of nifedipine and 1.0 to 20 parts by weight of a slightly water-soluble filler 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 nifedipine preparation is prepared which contains 2 to 15 parts by weight of a slightly water-soluble filler. 3. The method according to item!, Characterized in that a nifedipine preparation is prepared which contains lactose and / or mannitol as a water-soluble filler. 4. The method according to item!, Characterized in that 1 part by weight of nifedipine together with 2 to 15 parts by weight of a readily soluble filler with starch, cellulose and optionally other conventional excipients in a granulator aqueous granulated and the resulting granules also converted into a conventional administration form. 5. A process for the preparation of preparations according to item 1, characterized in that the ylidene compound of the formula II