Method and device for producing a parenteral medicament

Details Method and device for producing a parenteral medicament Method and device for producing a parenteral medicament

1998-05-12

2001-12-18

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C264S004100, C264S004300, C264S004600, C428S402200

Reexamination Certificate

active

06331314

ABSTRACT:

This application is a 371 of PCT/EP96/04795 filed Nov. 04, 1996.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a procedure for the production of a formulation for parenterally administrable pharmaceutical preparations having a liposome dispersion as a carrier for the pharmaceutical active compound, an aqueous predispersion of amphiphilic substances beings fed to a high-pressure homogenizer for the preparation of the liposome dispersion.
2. Description of Related Art
A large number of procedures have been described for the preparation of liposomes (see, for example, Arndt, “Liposomes”, Akademie-Verlag Berlin, 1986). The subject of these studies are often experiments on the laboratory scale. A customary starting process here is the dissolution of phospholipids in organic solvents which are removed again before the homogenization in the course of the further preparation process (DE 35 15 335).
A process of the type described in the foregoing Field of the Invention is described in principle in DE 42 07 481.
In the direct dispersion procedure according to DE 42 07 481, the phospholipid and the crystalline active compound are dispersed directly in water. After swelling of the phospholipids in water coarsely divided liposomes first result, which must then be mechanically comminuted. The active compound deposits or accumulates here on the resulting lipid bilayers of the resulting liposomes. Since many liposome formulations are not heat-sterilizable (particle aggregation, phospholipid hydrolysis), comminution of the liposomes by high-pressure homogenization is necessary until the liposomal dispersion can be sterile-filtered (particle size <200 nm).
Comminution in this case takes place in two steps:
a) First the liposome dispersion is comminuted using a high-speed rotor/stator machine to particle sizes of 500 to 5000 &mgr;m.
b) Then a fine comminution takes place to particle sizes of 40 to 100 nm using high-pressure homogenizers known per se.
SUMMARY OF THE INVENTION
The invention is based on the object of developing a procedure for the preparation of liposomes with the finest possible particle size for parenteral administration in reproducible product quality. The liposome dispersion should in this case on the one hand be sterile-filterable without filter residue and on the other hand so fine that the active compound can pass through the finest branchings of the blood vessels on parenteral administration.
This object is achieved according to the invention in that an aqueous predispersion of amphiphilic substances is pumped under a pressure of 500 to 900 bar, preferably 700 bar to 800 bar, through a cylindrical homogenizer nozzle having a diameter of 0.1 mm to 0.5 mm, preferably 0.1 mm to 0.2 mm. Under these conditions, extremely finely particulate dispersions having average particle sizes of 30 nm to 100 nm can be achieved.
Suitable amphiphilic substances are, in particular, phospholipids, cholesterol derivatives and synthetic amphiphiles.
For the preparation of the predispersion, a primary dispersion consisting of the aqueous dispersion containing amphiphilic substances and the pharmaceutical active compound is advantageously pumped through a relatively coarse cylindrical homogenizer nozzle having a diameter of 0.3 mm to 0.7 mm. By this type of prehomogenization, the particle contamination occurring in the rotor/stator machines frequently used until now for predispersion can be avoided.
According to a preferred embodiment, the predispersion is recirculated through the homogenizer nozzle by pumping until the average particle size of the liposome dispersion is in the range between 35 nm and 80 nm with a standard deviation of 3 nm to 7 nm. These particle properties are achieved, in particular, when the predispersion is allowed to flow through the homogenizer nozzle 10 to 30 times in circulation.
Particularly good results are achieved when the dispersion is heated to a temperature in the range from 50° C. to 70° C. in the homogenization circuit by a heat exchanger connected before the homogenizer nozzle.
The storage container is preferably kept at a relatively low temperature level and the dispersion is heated only immediately before the nozzle.
Since energy dissipation and thus warming takes place in the homogenizer nozzle, it is expedient to cool the dispersion again to temperatures in the range from 50° C. to 70° C. immediately after the homogenizer nozzle by means of a heat exchanger connected after it.
For recycling the liposome dispersion, a high-pressure diaphragm-type reciprocating pump is advantageously used which has the advantage that no abrasion and no lubricant can reach the pump chamber, and thus deposit as a contamination source.
The device for carrying out the procedure consists of at least one homogenizer nozzle having an inlet and an outlet channel and is characterized in that the homogenizer nozzle consists of a hard ceramic plate with a bore of 0.1 mm to 0.5 mm, preferably 0.1 mm to 0.2 mm, pressed into a steel body and that the inlet channel to the bore and the outlet channel from the bore are likewise incorporated into the steel body.
In order to achieve high nozzle service lives, hard ceramic plates made of zirconium oxide or silicon carbide are advantageously pressed into the steel body.
According to a further development of the invention, the steel body has several homogenizer nozzles facing one another in pairs, the inlet channels of the homogenizer nozzles being connected in parallel and the outlet channels in the steel body opening into a common collection channel. This embodiment has proved highly suitable, in particular at high throughputs. In this way, an accurate scale-up can be achieved.
The following advantages are achieved by the invention:
Preparation and provision of stable, liposomal formulations, in particular with active compounds which are poorly soluble in water
Achievement of a narrow particle size distribution with high reproducibility
Gentle treatment, in particular of temperature-sensitive active compounds
Problem-free and accurate scale-up due to modular construction of the nozzle homogenizer device
Reduction of contamination sources due to minimization of nozzle abrasion and use of a high-pressure diaphragm-type reciprocating pump
Good purification possibilities as a result of low gap and dead-space construction
Improved service lives of the unit.


REFERENCES:
patent: 4529561 (1985-07-01), Hunt et al.
patent: 4976964 (1990-12-01), Schlossmann et al.
patent: 4207481 (1993-09-01), None
patent: 4328331 (1995-02-01), None
patent: 185756 (1990-08-01), None
patent: 560138 (1993-09-01), None
patent: 83/00089 (1983-01-01), None
patent: 94/08626 (1994-04-01), None
Martin in Specialized Drug Delivery System Ed. Praveen Tyle Marcel Dekker Inc., 1990.*
Liposome Technology, vol. 1, Chapter 3, “Liposome Preparation Using High-Pressure Homogenizer”, Martin Brandl, et al., pp. 49-65.
English Abstract of WO 94/08626, Apr. 28, 1998.

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