CN1179099A - Transparent rapid-release preparations of non-steoid analgesics - Google Patents

Abstract

A transparent quick-release active substance preparation, which can be obtained by extruding a melt containing non-steroidal analgesics, homopolymer of N-vinylpyrrolidone, sugars or sugar alcohols, and sodium or potassium salts.

Description

Clear rapid release formulation of nonsteroidal analgesics

The present invention relates to transparent rapid-release formulations of non-steroidal analgesics, having antipyretic and anti-inflammatory effects, obtainable by extrusion and subsequent shaping of a melt containing, in addition to one or more active substances also contains

a) 50-100% by weight homopolymer of N-vinylpyrrolidone having a K value of 30 according to Fikentscher,

b) 0-30% by weight of water-soluble sugars or sugar alcohols or mixtures thereof,

c) 0-20% by weight of one or more physiologically acceptable sodium or potassium salts, wherein the amounts are based on the sum of a), b) and c).

Furthermore the invention relates to a process for the preparation of such formulations.

The rapid release of the active substance for a rapidly acting analgesic effect is of decisive importance especially for analgesics.

When the active substance, eg an analgesic acting organic acid, is poorly water soluble, it is often difficult to achieve rapid release of sufficient doses.

It is recommended in EP-A 607 467 that the rapid release of ibuprofen can be facilitated by the addition of basic salts which are added in aqueous solution to the active substance mixed with an adjuvant during tableting. The pellets are then compressed into tablets in the conventional manner. But this process is relatively expensive, so it is not very beneficial from an economic point of view.

It is also known that medicaments can be produced very economically by extrusion of active substance-containing polymer melts followed by continuous shaping.

EP-B 240 904 describes such a process for the preparation of solid pharmaceutical preparations by extrusion of active substance-containing polymer melts, wherein homopolymers or copolymers of N-vinylpyrrolidone are used as polymers.

In such a method, however, there is a fundamental problem that the polymers constituting the matrix are, on the one hand, sufficiently thermoplastically treatable at the processing temperature or become processable by adding plasticizing substances, and on the other hand, at the usual It should be made into a stable pharmaceutical form without "cold flow" at the storage temperature.

This problem is even more difficult to solve if a rapid release dosage form is to be prepared. For this purpose generally lower molecular weight polymers are particularly suitable, which dissolve rapidly in digestive fluids. But it happens that they have a strong "cold flow" phenomenon after they are made into medicaments. Higher molecular weight polymers generally do not release rapidly and can hardly be extruded without plasticizers because the glass transition temperature (DIN 52324) is rather high.

There is an additional problem if it is desired to prepare transparent doses by melt extrusion. Only in transparent dosage forms is the distribution of the active substance completely uniform without the occurrence of separate cavities. This is necessary for quick release. In addition, the use of clear dosage forms can simplify quality monitoring and patient compliance.

The object of the present invention was to find transparent, rapid-release formulations of nonsteroidal analgesics which can be produced in a simple manner by extrusion of the melt followed by shaping and which have good storage stability.

We have found that this object can be achieved by the formulations defined at the outset.

According to the invention, non-steroidal analgesics with antipyretic and anti-inflammatory action are suitable as active substances, which can also be used in symptomatic antirheumatic therapy.

Accordingly, suitable active substances are salicylic acid derivatives, such as acetylsalicylic acid and derivatives of other organic acids and pyrazole derivatives. Aromatic acids such as diclofenac, tolmetin or zomeac, as well as arylpropionic acid derivatives such as ibuprofen, naproxen, fenoprofen, flurbiprofen or ketoprofen, are considered active substances , or indole acetic acid derivatives and indene acetic acid derivatives such as indomethacin or sulindac. Suitable pyrazole derivatives are, for example, phenazone, amphenazone, Metamizol, proantipyrine, phenylbutazone or oxybuzone.

Preferred active substances are ibuprofen, acetylsalicylic acid and ketoprofen, sulindac, indomethacin, flurbiprofen.

It is also possible to use mixtures of active substances.

As component a) the preparations according to the invention contain a homopolymer of N-vinylpyrrolidone with a K value according to Fikentscher of 30 (see "H. Fikentscher, Cellulose-Chemie" for the definition of the K value , 13 (1932), pp. 58-64 and 71-74). The homopolymer has good water solubility, and "water solubility" here means that at least 0.5g, preferably at least 2g, of the polymer dissolves in 100g of water at 20°C, and may also be a colloidal solution. Methods for the preparation of such homopolymers are generally known.

Water-soluble sugars or sugar alcohols or mixtures thereof come into consideration as component b). Suitable sugars are especially mono- or disaccharides such as galactose, fructose, glucose, mannose, maltose, isomaltose (Palatinose), lactose or sucrose.

Suitable sugar alcohols are, for example, mannitol, xylitol, sorbitol, adonitol, dulcitol, generally pentitol and hexitol.

As component c) physiologically tolerated sodium and/or potassium salts such as sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium chloride or potassium chloride, Among them, sodium acetate is preferred.

According to the invention, the proportions of components a), b) and c) are selected so that the formulation contains a) 50-100% by weight, preferably 60-90% by weight of component a), b) 0-30% by weight, preferably 5-20% by weight of component b), c) 0-20% by weight, preferably 5-20% by weight of component c), where the amounts are based on the sum of a), b) and c).

Preferred formulations contain 80-95% by weight of component a) and 5-20% by weight of component c), based here on the sum of a) and c).

The total active substance content varies within wide ranges depending on the desired dose and release rate. The content of active substance can be 0.1-90, preferably 0.5-60% by weight of the total formulation.

The formulations according to the invention may additionally contain customary pharmaceutical adjuvants in customary amounts.

The active substance can be mixed with the polymeric binder and, if necessary, pharmaceutical adjuvants, before or after melting of the polymeric binder, according to methods customary in the art. The mixing is preferably carried out in an extruder, preferably a twin-screw extruder or a single-screw extruder with a mixing chamber.

The melt contains no solvent. That is to say: without adding water and organic solvents.

The preparation of the formulation is carried out by extrusion at 50-180° C., preferably 60-150° C., followed by shaping the still plastic extrudate, e.g. into tablets, e.g. according to EP-A 240 906 by Introduced between two relatively moving rollers, there are relative grooves in the outer jacket of the rollers, and its design determines the shape of the tablet. Also consider cold cuts.

Preference is given to so-called hot mincing. In this case, the extrudate is comminuted directly after exiting the nozzle of the extruder by, for example, a rotating knife or other suitable means, preferably into small pieces whose length is approximately equal to the diameter of the extrudate. These chopped pieces of melt are cooled in a stream of air or air, so that their surfaces are free of sticking before they come into contact with other pieces or container walls, but on the other hand the pieces are still malleable enough to allow, by collision, e.g. Collision with the wall of the subsequent cyclone can obtain a spherical shape. Approximately spherical or lentil-shaped segments having a diameter of 0.5 to 4 mm, preferably 0.8 to 2 mm, can be obtained in this simple manner. The preferred smaller segments are primarily suitable for filling capsules.

Solid dosage forms can also be given conventional coatings to improve their appearance and/or taste (sugar-coated tablets).

The non-steroid analgesic preparation of the present invention has antipyretic and anti-inflammatory effects, and is a transparent, storage-stable and quick-release dosage form. "Fast release" means that the release of the active substance is at least 70% after 30 minutes as determined by the Paddle method of USP XXII.

Surprisingly, despite the use of higher molecular weight polymers, even dosage forms with high weights of eg 1000 mg are able to release rapidly. Larger tablets also have the advantage that they can be used as lozenges without having to be swallowed, and that no taste problems arise due to the addition of sugar alcohols. Especially older patients or patients with dysphagia who often have difficulty swallowing larger tablets, such quick release buccal tablets would be of great advantage.

Example

The components described in each example were premixed and fed to the inlet of a twin-screw extruder (Werner & Pfeiderer). The melt extrusion was carried out with a product throughput of 3 to 4 kg/hour. The temperatures of the various zones of the extruder as well as the temperature of the heated die strip are specified separately in the test. Large tablets of 1000 mg weight are prepared from the extrudate according to the calendering method described in EP-B 240 906.

The release of the active substance is measured by the stirring wing method (Paddle method according to USP XXII). This in vitro test method is used to determine the dissolution rate of active substance-containing preparations such as tablets.

Here 900 ml of pH 6.8 phosphate buffer were added with 0.1% sodium lauryl sulfate and brought to a temperature of 37° C. in a 1 L container with a round bottom. Weigh the corresponding dose. In this "invariant test" according to US XXI, the active substance release of the bolus was determined with a UV spectrometer after 30 minutes at a stirring wing rotation number of 100 rpm. Example 1

The temperature of each zone (1-5 zone) of the extruder is 20, 80, 140, 130, 130°C, the temperature of the extruder head is 130°C, and the temperature of the nozzle row is 130°C. Vinylpyrrolidone

K value 30, 80% by weight released 82% after 30 minutes Example 2

The temperature of each zone (zone 1-5) of the extruder is 60, 120, 120, 110, 120°C, the temperature of the extruder head is 130°C, the temperature of the nozzle row is 120°C Active substance Ingredient a Ingredient b Ibuprofen 20 weight % Polyvinylpyrrolidone D-mannitol 10% by weight

K value 30, 70% by weight released 72% after 30 minutes Example 3

The temperature of each zone of the extruder (zone 1-5) is 60, 120, 120, 120, 130°C, the temperature of the extruder head is 130°C, and the temperature of the nozzle row is 160°C Active substance Ingredient a Ingredient b Ibuprofen 20 weight % Polyvinylpyrrolidone D-mannitol 20% by weight

K value 30, 60% by weight released 70% after 30 minutes Example 4

The temperature of each zone (zone 1-5) of the extruder is 70, 130, 130, 140, 130°C, the temperature of the extruder head is 130°C, and the temperature of the nozzle row is 160°C Active substance Ingredient a Ingredient c Ibuprofen 20 weight % Polyvinylpyrrolidone Sodium acetate 13.5% by weight

K value 30, 66.5% by weight released 95% after 30 minutes Example 5

The temperature of each zone (zone 1-5) of the extruder is 70, 130, 130, 140, 130°C, the temperature of the extruder head is 130°C, the temperature of the nozzle row is 160°C Active substance Component a Component c Ibuprofen 20 weight % Polyvinylpyrrolidone Sodium acetate 5% by weight

K value 30, 75% by weight released 95% after 30 minutes Example 6

The temperature of each zone of the extruder (zone 1-5) is 60, 120, 120, 120, 130°C, the temperature of the extruder head is 130°C, and the temperature of the nozzle row is 160°C Active substance Ingredient a Ingredient b Ingredient c Ibuprofen 20% by weight Polyvinylpyrrolidone D-Mannitol Sodium acetate

K value 30, 70% by weight 5% by weight 5% by weight releases 80% after 30 minutes.

Claims (5)

1. the transparent quick-release formulation of on-steroidal analgesic, it has analgesic and effect antiinflammatory, can obtain by a kind of like this fused mass of extruding and with postforming, and this fused mass also contains except that containing one or more active substances

A) homopolymer of 50-100 weight %N-vinyl pyrrolidone, its K value according to Fikentscher is 30,

B) 0-30 weight % water-soluble saccharides or sugar alcohol or its mixture,

C) can received sodium salt or potassium salt on one or more physiology of 0-20 weight %, wherein said amount is based on a), b) and summation c).

2. according to the preparation of claim 1, contain the composition c of 5 to 20 weight %).

3. according to the preparation of claim 1 or 2, contain ibuprofen as active substance.

4. according to the preparation of one of claim 1 to 3 item, contain sodium acetate) as composition c.

5. preparation is characterized by according to the method for each transparent quick-release formulation in the claim 1 to 4: 50-180 ℃ of extruding and with postforming, this fused mass also contains except that containing one or more active substances with a kind of like this fused mass

B) homopolymer of 50-100 weight %N-vinyl pyrrolidone, its K value according to Fikentscher is 30,

C) 0-30 weight % water-soluble saccharides or sugar alcohol or its mixture,

D) can received sodium salt or potassium salt on one or more physiology of 0-20 weight %,

Wherein said amount is based on a), b) and summation c).